Clinical Oncology For Students

Clinical Oncology
for students
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Contents
Articles
Epidemiology and social impact of cancer 1
Screening and prevention 5
Cancer biology: Molecular and genetic basis 8
Cancer biology: Familial cancers and genetic testing 23
Cancer diagnosis: Histopathology, cytology and tumour markers 28
Cancer diagnosis: staging and imaging 34
Principles of cancer management 37
Principles of cancer surgery 42
Principles of radiotherapy 45
Principles of medical therapy 48
Principles of palliative care 51
Cancer survivorship 54
Doctor patient communication and psychosocial care 56
Ethics and professional development 58
Breast cancer 61
Colorectal cancer 65
Oesophageal cancer 69
Pancreatic cancer 73
Lung cancer 77
Urogenital cancers 82
Haematopoietic and lymphoid malignancies 84
Gynaecological cancers 88
Soft tissue sarcomas 94
Bone tumours 99
Melanoma and skin 111
Central nervous system tumours 115
Head and neck cancer 117
Cancer of unknown primary 121
Oncological emergencies 125
Epidemiology and social impact of cancer

<heading level="2">Information on authorship and revision</heading> Last modified:
22 October 2014 01:05:39
Author(s):
• Associate Professor Sabe Sabesan MBBS FRACP — Author
• Dr Sid Selva-Nayagam MBBS FRACP — Author
• Professor Martin Stockler — Co-author
• Cancer Council Australia Oncology Education Committee — Co-author
<ccabutton class="cca-expand-button cca-button-simple " link="# " icon="Cite icon revised.png ">Cite this
page</ccabutton>
Sabesan, S, Selva-nayagam, S, Professor Martin Stockler, Cancer Council Australia Oncology Education Committee. Epidemiology and social
impact of cancer [Version URL:http:/ / wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited
2016 Oct 8]. Available from http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Epidemiology_and_social_impact_of_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available from:
http://wiki.cancer.org.au/oncologyformedicalstudents/Clinical_Oncology_for_Medical_Students.
Cancer in Australia
Details of this chapter were collated from Cancer in Australia: key facts, published by the Australian Institute of
Health and Welfare.[1][2]
Incidence
The estimated total number of new cancers diagnosed in 2012 was 120,710. Of these new cancers diagnosed, 67,260
were diagnosed in males, and 53,460 in females.
The estimated five most commonly diagnosed cancers in 2012 were prostate (18,560), bowel (15,840), breast
(14,680), melanoma of the skin (12,510) and lung (11,280) as in Figure 1.
Figure 1: Commonest cancers in Australia in 2012
Please note that this material is only current to the date and time stamped on this document
as content is updated continuously.
In 2009, the risk for Australian males of being diagnosed with cancer before their 85th birthday was 1 in 2. The most
common diagnoses were prostate (1 in 5 males), bowel (1 in 10), lung (1 in 13), and skin (1 in 14) as in Figure 2.
Figure 2: Cancers in men in 2012

In 2009, the risk for Australian females of being diagnosed with cancer before their 85th birthday was 1 in 3. The
most common diagnoses were breast (1 in 8 females), bowel (1 in 15), lung (1 in 22), and skin (1 in 23) as in Figure
3.
Figure 3: Cancers in women

in 2012
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Deaths
In 2010, cancer accounted for about 3 of every 10 deaths (30%) registered in Australia.
The 5 most common causes of death from cancer in 2010 were lung (8,099), bowel (3,982), prostate (3,235), breast
(2,864) and pancreas (2,434).
Figure 4:
Commonest causes of cancer death
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Survival rates
In 2006-10, for people newly diagnosed with cancer, their chance of surviving 5 years was 65% for males and 67%
for females. The improvement in survival and cure rates over time has been attributed to screening programs and
advances in cancer therapies.
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Prevalence
At the end of 2007, there were 774,674 people (381,164 males and 393,510 females) diagnosed with cancer in the
previous 26 years who were still alive.
Disparity in cancer outcomes in regional and rural Australia and among Indigenous
Australians
There are inequalities in cancer survival among people in rural, regional and remote areas of Australia.[3] Studies
from NSW showed that people living in the most remote parts of NSW were 35% more likely to die as a result of
their cancer within five years of diagnosis in 1992-96, than people living in areas with the greatest access to
services.[4] This is illustrated in Figure 5, using Hazard ratios.
Figure 5: Disparity in cancer survival based on remoteness.

Compared with other Australians, survival rates are worse for colorectal, breast, lung, cervix and non Hodgkin
lymphoma in Indigenous Australians.[5] Reasons could be disparities in cancer treatment; greater levels of
socioeconomic disadvantage; higher proportion of Indigenous Australians in rural areas; limited access to primary
care, specialist and preventive services; and more advanced stage at presentation.
For example, in a lung cancer study in North Queensland,[6] time from onset of symptoms to first presentation to GP
was longer for Indigenous patients compared with non-Indigenous patients (92 days vs 57 days; p=0.05). Time from
GP to review by specialists was longer for rural and remote patients (rural and remote 31.5 days, urban 15 days,
p=0.017).
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References
[1] Australian Institute of Health and Welfare. Cancer. [homepage on the internet] Australia: AIHW; 2013 [cited 2014 May 29; updated 2013].
Available from: http:/ / www. aihw. gov. au/ cancer/ .
[2] Australian Institute of Health and Welfare. Cancer in Australia: key facts. [homepage on the internet] Canberra: AIHW; 2013 [cited 2014
May 22; updated 2013]. Available from: http:/ / www. aihw. gov. au/ cancer/ cancer-in-australia/ . Cites::Citation:Australian Institute of
Health and Welfare 2013 2
[3] Heathcote K, Armstrong B. Disparities in cancer outcomes in regional and rural Australia. Cancer Forum 2007 Jul [cited 2014 Jun 5];31(2)
[Abstract available at http:/ / cancerforum. org. au/ Issues/ 2007/ July/ Forum/ Disparities_cancer_outcomes_regional_rural_Australia. htm].
[4] Jong KE, Smith DP, Yu XQ, O'Connell DL, Goldstein D, Armstrong BK. Remoteness of residence and survival from cancer in New South
Wales. Med J Aust 2004 Jun 21;180(12):618-22 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 15200358].
[5] Condon JR, Barnes T, Armstrong BK, Selva-Nayagam S, Elwood JM. Stage at diagnosis and cancer survival for Indigenous Australians in
the Northern Territory. MJA 2005 [cited 2014 Jun 5];182(6):277-280 [Abstract available at https:/ / www. mja. com. au/ journal/ 2005/ 182/
6/ stage-diagnosis-and-cancer-survival-indigenous-australians-northern-territory].
[6] Joshi A, Sabesan S, Beuttner P, Varma S, Otty Z. Times to presentation and treatment: a prospective comparison of rural and urban lung
cancer patients in North Queensland. In: Journal of Thoracic Oncology. 15th World Conference on Lung Cancer. 2013 Oct 28; Sydney,
Australia. Sydney: International Association for the Study of Lung Cancer; 2013 [cited 2014 Jun 5]. p. S723. Available from: http:/ / www.
2013worldlungcancer. org/ documents/ WCLC2013-AbstractBook. pdf.
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Screening and prevention

19 March 2015 10:43:32
Author(s):
• Professor Ian Olver AM MBBS MD PhD CMin FRACP FAChPM MRACMA — Author
page</ccabutton>
Olver, I, Cancer Council Australia Oncology Education Committee. Screening and prevention [Version URL: http:/ / wiki. cancer. org. au/
oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Screening_and_prevention. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia.
Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/ Clinical_Oncology_for_Medical_Students.
Introduction
One third of cancer deaths could be prevented by lifestyle changes alone. Population screening for cancer can detect
precancerous lesions or early cancer when it is curable surgically.[1]
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Tobacco
Tobacco causes 20.1% of Australia’s cancer burden and nearly 21% of cancer deaths.[2][3] It is responsible for 16
different cancers -- particularly lung, head and neck and bladder cancers. Just over 15% of Australians smoke daily,
as do 47% Indigenous Australians.[4] Price is the most effective tool for decreasing smoking when added to
eliminating advertising (including on packs), mass media campaigns, smoke free work and public places and
regulating supply. For those smokers who can’t quit “cold turkey”, nicotine replacement patches or gums are
available.
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Nutrition and physical activity

Appropriate nutrition and physical activity could prevent a quarter of cancers.[5] Physical inactivity accounted for
5.6% of the total cancer burden, high body mass for 3.9% and low fruit and vegetable consumption for 2%.
Being overweight (BMI 25-30) or obese (BMI 30+) increases the risk of cancers of the oesophagus, pancreas, bowel,
breast (post-menopausal), endometrium and kidney.[6] One in four Australian adults is obese.
Physical activity independent of weight control has been shown to protect against bowel cancer and probably against
post-menopausal breast cancer and endometrial cancer.[6] Prolonged sedentary periods, irrespective of physical
activity, increases the risk of bowel, endometrial, ovarian and prostate cancer. The World Cancer Research Fund
dietary advice includes eating mainly fruit and vegetables and unprocessed cereals and pulses, and limiting the
consumption of energy-dense food, sugary drinks, red meat (to 500 gm/wk), processed meats and salt. The usual
recommendation for physical activity is at least 150 minutes over 5 sessions in a week, the more intense the better.[7]
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Alcohol
Up to 5.8% of cases of cancer in Australia have been attributed to the chronic use of alcohol.[8] Starting at zero, the
more consumed the greater the risk, irrespective of the type of drink. The NHMRC advises that alcohol consumption
should not exceed 2 standard drinks each day.[9] The related cancers include breast, mouth, pharynx and larynx,
oesophagus, bowel and liver cancers.[6] In head and neck and upper gastrointestinal cancers, tobacco has a
synergistic effect.[10]
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UV radiation
Exposure to UV radiation is the major cause of skin cancer, with intermittent exposure linked more to melanoma and
cumulative exposure to non-melanoma skin cancer. There are over 1800 deaths from skin cancer with around 1300
from melanoma.[11] In Australia there are almost 12,000 cases of melanoma and estimations of over 400,000
non-melanoma squamous cell and basal cell skin cancers annually.[12] Sun protection, by avoiding the sun when it is
most intense in the middle of a summer day and covering up with hats, sunglasses and clothing supplemented by
sunscreen (SPF 50+, broad spectrum and water resistant), is recommended when the UV index is 3 or above.[13]
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Occupational exposures
In 2006, it was estimated that 6.5% of cancer cases in Australia in 2005 could be attributed to workplace exposures
(10.8% in men, 2.2% in women).[14] Mesothelioma related to asbestos exposure is the best known. Other well
established associations are between cadmium in electroplating and lung cancer, benzene and leukaemia and
aromatic amine dyes and bladder cancer. The building industry has the highest occupation exposure, not only to
silica and diesel exhaust but outdoor sun exposure.[15] Relating occupational exposure to pesticides to cancer in
particular occupations is difficult but studies show associations with lymphoma. Emerging concerns requiring
research are manufacturing processes that involve nanoparticles.[16]
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Vaccines
Human papillomavirus (HPV) is necessary for the development of cervical cancer and there is a vaccination program
for 12-13 year old boy and girls. Vaccinating against types 16 and 18 will reduce the incidence by 70%.[17]
To prevent liver cancer, hepatitis B vaccination could be given to neonates or adults at high risk; such as IV drug
users or those living in populations with a high incidence of hepatitis B infection.[18]
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Screening
There are 3 national screening programs for cancers of the cervix, breast and bowel. These are recommended
because of the associated mortality reduction when weighed against overdiagnosis and its adverse effects.
Papanicolaou tests (Pap tests) for cancer of the cervix commencing with sexual activity and repeated every 2 years
have halved the incidence of cancer of the cervix since their introduction in 1991.[19]
Free screening mammography is encouraged for women from 50-74 years old and available for high-risk women
from 40 years. There has been a 29% age-standardised decrease in breast cancer mortality compared to the decade
before 1991, and we estimate at least half of that is due to screening.[20]
The bowel cancer screening program was introduced in 2006 and aims to send faecal immunochemical testing kits to
everyone from 50-74 years every 2 years by 2020, with the positives followed up by colonoscopy. Comparing
screened with unscreened people there has been a halving in the presentation of stage 4 disease.[21]
PSA testing is not recommended as a population screening test because a small survival gain is currently matched by
widespread adverse effects stemming from overdiagnosis and overtreatment.[22]
People are encouraged to get to know their skin lesions and promptly report any change rather than relying on formal
annual skin checks. Likewise, promptly reporting symptoms and signs related to the testicles is recommended over
regular screening examinations.[23]
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References
[1] Cancer Council Australia. Risk factors. [homepage on the internet] Sydney: Cancer Council Australia; 2012 Sep 4 [cited 2014 May 7;
updated 2012 Sep 4]. Available from: http:/ / www. cancer. org. au/ policy-and-advocacy/ prevention-policy/ risk-factors/ .
Cites::Citation:Cancer Council Australia 2012
[2] Begg S, Vos T, Barker B, Stevenson C, Stanley L, Lopez AD et al. The burden of disease and injury in Australia 2003. Canberra: AIHW;
2007. Report No.: PHE 82. Available from: http:/ / www. aihw. gov. au/ publication-detail/ ?id=6442467990.
[3] AIHW. Cancer in Australia: an overview, 2008. AIHW; 2008 Dec 19 [cited 2014 May 8]. Report No.: Cat. no. CAN 42. Available from:
http:/ / www. aihw. gov. au/ publication-detail/ ?id=6442468196.
[4] Cancer Council Australia's Tobacco Issues Committee. Tobacco Control. [homepage on the internet] Cancer Council Australia; 2013 Apr 1
[cited 2014 May 8; updated 2013 Dec 8]. Available from: http:/ / wiki. cancer. org. au/ prevention/ Tobacco_control/ Overview.
[5] World Cancer Research Fund, American Institute for Cancer Research. Policy and action for cancer prevention. Food, nutrition, and physical
activity: a global perspective. Washington, DC: American Institute for Cancer Research; 2009 Jan 1 [cited 2014 May 8] Available from: http:/
/ www. dietandcancerreport. org/ cancer_resource_center/ downloads/ chapters/ pr/ Introductory%20pages. pdf.
[6] World Cancer Research Fund, American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a
global perspective. Washington DC: AICR; 2007 [cited 2014 May 20] Available from: http:/ / www. aicr. org/ assets/ docs/ pdf/ reports/
Second_Expert_Report. pdf.
[7] Vainio H, Bianchini F. IARC monographs on the evaluation of carcinogenic risks to humans, volume 6. Weight control and physical activity.
Lyon, France: International Agency for Research on Cancer; 2002 [cited 2014 May 20] Available from: http:/ / www. iarc. fr/ en/ publications/
pdfs-online/ prev/ handbook6/ Handbook6-0. pdf. Cites::Citation:Vainio H, Bianchini F 2002
[8] Cancer Council Australia Public Health Committee - Nutrition and Physical Activity Subcommittee. Alcohol and cancer: overview.
[homepage on the internet] Sydney: Cancer Council Australia; 2012 Apr 1 [cited 2014 May 20; updated 2013 Sep 3]. Available from: http:/ /
wiki. cancer. org. au/ prevention/ Alcohol/ Overview.
[9] National Health and Medical Research Council. Australian guidelines to reduce health risks from drinking alcohol. Commonwealth of
Australia: NHMRC; 2009 Feb [cited 2014 May 20] Available from: http:/ / www. nhmrc. gov. au/ guidelines/ publications/ ds10.
[10] Doll R, Forman D, La Vecchia C, Wouterson R. Alcoholic beverages and cancers of the digestive tract and larynx. In: Verschuren PM.
Health issues related to alcohol consumption. Washington: DC: ILSI Europe; 1193 [cited 2014 May 20]. p. 125-66.Cites::Citation:Doll R,
Forman D, La Vecchia C, Wouterson R 1193
[11] Australian Bureau of Statistics. Causes of death, Australia, 2008. Canberra: ABS; 2010 Mar 20 [cited 2014 May 20]. Report No.: 3303.0.
Available from: http:/ / www. ausstats. abs. gov. au/ ausstats/ subscriber. nsf/ 0/ E39670183DE1B0D9CA2579C6000F7A4E/ $File/
33030_2010. pdf.
[12] Australian Institute of Health and Welfare and Cancer Australia. General practice consultations, hospitalisation and mortality. Canberra:
AIHW; 2008 Jan 1 [cited 2014 May 20]. Report No.: 43. Cat. No. 39. Available from: http:/ / www. aihw. gov. au/ WorkArea/
DownloadAsset. aspx?id=6442454591.
[13] World Health Organization, World Meteorological Organization, United Nations Environment Programme, International Commission on
Non-Ionizing Radiation Protection. Global solar UV index: a practical guide. Geneva, Switzerland: WHO; 2002 [cited 2014 May 20]
Available from: http:/ / www. unep. org/ pdf/ Solar_Index_Guide. pdf. Cites::Citation:World Health Organization, World Meteorological
Organization, United Nations Environment Programme, International Commission on Non-Ionizing Radiation Protection 2002
[14] Fritschi L. Occupational cancer in Australia. Canberra: Australian Safety and Compensation Council, Commonwealth of Australia; 2005
[cited 2014 May 20] Available from: http:/ / www. safeworkaustralia. gov. au/ sites/ swa/ about/ Publications/ Documents/ 411/
Occupational_Cancer_Australia_April_2006. pdf.
[15] Cancer Council Australia Occupational and Environmental Cancer Committee. Occupational cancers: the link between occupation and
cancer. [homepage on the internet] Sydney: Cancer Council Australia; 2011 Feb 1 [cited 2014 May 20; updated 2014 Mar 19]. Available
from: http:/ / wiki. cancer. org. au/ prevention/ Occupational_cancers/ Link_between_occupation_and_cancer.
[16] Commonwealth Scientific and Industrial Research Organisation. Understanding nanosafety. [homepage on the internet] Sydney: CSIRO;
2011 Jun 9 [cited 2014 May 20; updated 2013 Dec 24]. Available from: http:/ / www. csiro. au/ Organisation-Structure/ Divisions/ CMSE/
Surfaces-and-Nanosciences/ Understanding-nanosafety. aspx. Cites::Citation:Commonwealth Scientific and Industrial Research Organisation
2011
[17] Stanley M, Lowy DR, Frazer I. Chapter 12: Prophylactic HPV vaccines: underlying mechanisms. Vaccine 2006 Aug 31;24 Suppl
3:S3/106-13 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 16949996].Cites::Citation:Stanley M, Lowy DR, Frazer I 2006
[18] Bialek SR, Bower WA, Novak R, Helgenberger L, Auerbach SB, Williams IT, et al. Persistence of protection against hepatitis B virus
infection among adolescents vaccinated with recombinant hepatitis B vaccine beginning at birth: a 15-year follow-up study. Pediatr Infect Dis
J 2008 Oct 1;27(10):881-5 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 18756185].Cites::Citation:Bialek SR, Bower WA,
Novak R, Helgenberger L, Auerbach SB, Williams IT, et al 2008
[19] Australian Institute of Health and Welfare. Cervical Screening in Australia 2010-2011. Canberra: AIHW; 2013 Jan 1 [cited 2014 May 20].
Report No.: Cancer series 76. Cat. no. CAN 72. Available from: http:/ / www. aihw. gov. au/ WorkArea/ DownloadAsset.
aspx?id=60129543399. Cites::Citation:Australian Institute of Health and Welfare 2013
[20] Roder DM, Olver IN. Do the benefits of screening mammography outweigh the harms of overdiagnosis and unnecessary treatment?--yes.
Med J Aust 2012 Jan 16;196(1):16 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 22256917].Cites::Citation:Roder DM,
Olver IN 2012
[21] Olver IN, Grogan PB. Early success for Australia's bowel screening program: let's move it along. Med J Aust 2013 Apr 1;198(6):300-1
[Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 23545018].Cites::Citation:Olver IN, Grogan PB 2013
[22] Cancer Council Australia Public Health Committee. Prostate cancer: overview. [homepage on the internet] Sydney: Cancer Council
Australia; 2012 Aug [cited 2014 May 20; updated 2013 May 27]. Available from: http:/ / wiki. cancer. org. au/ prevention/ Prostate_cancer/
Overview. Cites::Citation:Cancer Council Australia Public Health Committee 2012
[23] Cancer Council Australia. Testicular cancer. [homepage on the internet] Sydney: Cancer Council Australia; 2014 Mar 4 [cited 2014 May
20; updated 2014 Mar 4]. Available from: http:/ / www. cancer. org. au/ about-cancer/ types-of-cancer/ testicular-cancer. html.
Cites::Citation:Cancer Council Australia
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Cancer biology: Molecular and genetic basis

23 September 2014 23:46:33
Author(s):
• Associate Professor Ulrich–Axel Bommer PhD — Author
• Dr Kara L Perrow (nee Vine) PhD — Author
page</ccabutton>
Bommer, U, Dr Kara L Perrow (nee Vine) PhD, Cancer Council Australia Oncology Education Committee. Cancer biology: Molecular and
http:/ / wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016
genetic basis [Version URL:
Oct 8]. Available from http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Cancer_biology:_Molecular_and_genetic_basis. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available from:
Cellular basis of carcinogenesis

Cancer is a disease of uncontrolled growth and proliferation whereby cells have escaped the body’s normal growth
control mechanisms and have gained the ability to divide indefinitely. It is a multi-step process that requires the
accumulation of many genetic changes over time (Figure 1). These genetic alterations involve activation of
proto-oncogenes to oncogenes, deregulation of tumour suppressor genes and DNA repair genes and ‘immortalisation’
which will be discussed in this chapter.
Figure 1: Overview of the road to cancer. Cells may acquire mutations in genes that control proliferation, such as proto-oncogenes and/or
tumour suppressor genes. Each new mutation may provide a selective advantage for this cell, leading to ‘clonal expansion’. Cellular properties
changed in this process include cell cycle deregulation, apoptosis prevention and cell adhesion properties (CAMs – Cellular adhesion molecules).
[1]
Source: Alison MR. Cancer. Encyclopedia of Life Sciences, 2001 Reproduced with permission from John Wiley & Sons.
Cell cycle regulation and the importance of apoptosis

In normal cells, proliferation and progression through the cell cycle is strictly regulated by groups of proteins that
interact with each other in a specific sequence of events (Figure 2). Checkpoints ascertain that individual stages of
the cell cycle are completed correctly and ensure that incompletely replicated DNA is not passed onto daughter cells.
Core to this control system are cyclin-dependent kinases (CDKs). CDKs are ‘master protein kinases’ that drive
progression through the different phases of the cell cycle by phosphorylating and activating other downstream
kinases. CDK activity is dependent on the presence of activating subunits called cyclins which are synthesised and
degraded in a cell cycle-dependent manner. Cyclin-CDK complexes are further tightly regulated by CDK inhibitors.
Figure 2: Cyclins and cyclin-dependent kinases (CDKs) regulate the cell cycle. CDK’s and their regulatory subunits, cyclins (A, B, D & E)
tightly control transition through the cell cycle. The brackets indicate the periods in which the cyclin-CDK complexes are active and orchestrate
all events necessary in this period. The restriction point (R point) is a point in G1 at which the cell becomes ‘committed’ to the cell cycle and
after which extracellular proliferation signals are no longer required.
[2]
Source: Weinberg RA. The biology of cancer 1st ed. Garland Science, 2007 Reproduced with permission of Garland Science/Taylor & Francis
LLC.
The re-entry of cells into the cell cycle is decided at the restriction point (R point). This decision is influenced by
extracellular mitogenic signals which are transmitted via signalling pathways to key regulatory proteins, such as
transcription factors (e.g. E2F) in the nucleus (refer to Figure 3, Section 2). These regulatory proteins ultimately
activate the S-phase CDKs, which trigger the start of DNA synthesis.
In normal cells, activation of another transcription factor, p53, often referred to as the ‘guardian of the genome’, can
impose cell cycle arrest and induce apoptosis (programmed cell death) through its ability to:
• induce the expression of cell cycle inhibitors to prevent proliferation of a cell until any damage has been repaired
or
• initiate apoptosis, if the genomic damage is too great and cannot be repaired.
In >50% of all human tumours the p53 pathway is aberrant. Inactivation of the p53 protein renders it unable to signal
and activate the cell’s apoptotic machinery resulting in increased survival of cancer cells.
Cell immortalisation and tumourigenesis

Immortalisation is defined as the acquisition of an infinite lifespan. Normal mammalian somatic cells proliferate a
limited number of times before undergoing senescence. Senescent cells may remain metabolically active even
though they have permanently ceased proliferation. Immortalisation is an essential step in the malignant
transformation of normal cells and can be attributed, in part, to the presence of telomerase, the enzyme responsible
for maintaining telomeres at the ends of chromosomes. By extending telomeric DNA, telomerase is able to counter
the progressive telomere shortening that would otherwise lead to cell death. Unlike normal cells that lack detectable
levels of telomerase activity, approximately 90% of human tumours consist of cells that contain an active telomerase
enzyme.
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Cell signalling in carcinogenesis
Growth factors and their receptors

Growth factors (GFs) play an important physiological role in the normal process of growth control aimed at
maintaining tissue homeostasis. They transmit growth signals from one cell to another. These signals are sensed on
the cell surface by specific growth factor receptors (GFRs). GFRs transfer the growth signal via signalling pathways
to activate target molecules that promote proliferation (Figure 3).
Figure 3: The MAP kinase pathway as an example of a growth signalling pathway. The mitogen (or growth factor) binds to its receptor, a
receptor tyrosine kinase. Tyrosine phosphorylation of the receptor leads to activation of several docking proteins, and eventually to the activation
Ras, bound to the inside of the cell membrane. Active Ras in turn activates the MAP kinase signalling cascade, beginning with Raf (not shown
here). The final MAP kinase in this sequence activates several target proteins, for example a transcription factor that activates expression of the
Myc gene. Myc itself is a transcription factor that activates the expression of cell cycle regulatory genes. Source: Alberts B, Johnson A, Lewis J,
[3]
Raff M, Roberts K, Walter P. Molecular biology of the cell, 4th ed. Garland Science/Taylor & Francis LLC; 2002 Reproduced with permission
of Garland Science/Taylor & Francis LLC.
Steps that characterise normal cell proliferation include:

• the binding of a GF to its specific receptor on the cell membrane
• transient and limited activation of the GFR, which, activates several signal-transducing proteins (e.g. Ras) on the
inner leaflet of the plasma membrane
• transmission of the signal by signal transduction molecules, either to cytosolic targets or to the nucleus where they
activate transcription of specific genes
• entry of the cell into the cell cycle, ultimately resulting in cell division.
This pathway is often derailed in cancer and allows wayward cells to generate their own internal signals that
stimulate proliferation and become independent of their environments. Cancer cells are able to induce their own
growth stimulatory signals when mutations in the GFR gene occur, which facilitates activation in the absence of GFs
or when overproduction of GFs results in an autocrine signalling loop.
Other elements of cell signalling

An alternative strategy by which cancer cells can become GF independent involves constitutive activation of internal
signalling components. For example, the Ras protein in normal cells is switched off and does not signal unless a
GFR becomes activated, which through a series of intermediaries, is able to activate the Ras protein, converting it
from its quiescent state to an active, signal-emitting state. Thereafter, the Ras protein is able to release further
downstream signals that are capable of inducing proliferation. In cancer cells, this signalling pathway is deregulated
because structurally altered Ras proteins are able to continuously send growth stimulatory signals into the interior of
the cell in the absence of GFs.
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Genes frequently mutated in cancer

The genes that have been implicated in carcinogenesis are divided into two broad categories oncogenes (‘cell
accelerators’) and tumour suppressor genes (‘cell brakes’) but also include DNA repair genes (see The importance of
DNA repair systems for further detail).
Cellular oncogenes
Genes that promote autonomous cell growth in cancer cells are called oncogenes, and their normal cellular
counterparts are called proto-oncogenes. Proto-oncogenes are physiologic regulators of cell proliferation and
differentiation while oncogenes are characterised by the ability to promote cell growth in the absence of normal
mitogenic signals. Their products, oncoproteins, resemble the normal products of proto-oncogenes with the
exception that oncoproteins are devoid of important regulatory elements. Their production in the transformed cells
becomes constitutive, that is, not dependent on growth factors or other external signals. Proto-oncogenes can be
converted to oncogenes by several mechanisms including point mutation and gene amplification resulting in:
• Overproduction of growth factors
• Flooding of the cell with replication signals
• Uncontrolled stimulation in the intermediary pathways
• Cell growth by elevated levels of transcription factors
The RAS oncogene is the most frequently mutated oncogene in human cancer. It encodes a GTP-binding protein
Ras that functions as an on-off ‘switch’ for a number of key signalling pathways controlling cellular proliferation. In
a normal cell, Ras is transiently activated and recruits Raf, to activate the MAP-kinase pathway to transmit
growth-promoting signals to the nucleus. The mutant Ras protein is permanently activated leading to continuous
stimulation of cells without any external trigger. Other oncogenes frequently mutated in cancer are listed in Table 1.
Table 1. Selected oncogenes and associated cancers
Category / Protein Function Proto-oncogene Mode of Activation Associated Cancer
Growth Factors SIS Overexpression Astrocytoma, osteosarcoma

PDGF (β chain) HST-1 Overexpression Stomach cancer
Fibroblast growth factors INT-2 Amplification Bladder & breast cancer
Transforming growth factor α TGFα Overexpression Melanoma
Astrocytomas
Hepatocellular carcinomas
Growth Factors Receptors ERB-B1 Overexpression SCC of the lung, gliomas

EGF-receptor family ERB-B2 Amplification Breast and ovarian cancers
PDGF receptor PDGF-R Overexpression Gliomas
Receptor for stem cell (steel) factor KIT Point Mutation Gastrointestinal stromal tumours
Proteins Involved in Signal K-RAS Point mutation Colon, lung, pancreatic tumours
Transduction H-RAS Point mutation Bladder & kidney tumours
GTP-binding N-RAS Point mutation Melanoma, leukaemia, lymphoma
Non-receptor tyrosine kinase ABL Translocation CML, ALL
RAS signal transduction BRAF Point mutation Melanomas
WNT signal transduction β-catenin Point mutation/Overexpression Hepatoblastomas & HCC
Nuclear Regulatory Proteins C-MYC Translocation Burkitt lymphoma

Transcriptional activators N-MYC Amplification Neuroblastoma, small cell carcinoma of
L-MYC Amplification lung
SCC of the lung
Cell-Cycle Regulators CYCLIN D Translocation Mantle cell lymphoma

Cyclins CYCLIN E Amplification Breast & oesophageal cancers
Cyclin-dependent kinase CDK4 Overexpression Breast cancer
Amplification or Glioblastoma, melanoma, sarcoma
Point mutation
Adapted from Table 7-6, Kumar V, Abbas AK, Fausto N, Aster J. Robbins & Cotran pathologic basis of disease, 8th edition. Elsevier; 2010
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Tumour suppressor genes

Tumour suppressor genes (Table 2) encode proteins that are:
• receptors for secreted hormones that function to inhibit cell proliferation
• negative regulators of cell cycle entry or progression
• negative regulators of growth signalling pathways (e.g. APC or PTEN)
• checkpoint-control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal
• proteins that promote apoptosis DNA repair enzymes.
The transformation of a normal cell to a cancer cell is accompanied by the loss of function of one or more tumour
suppressor genes and both gene copies must be defective in order to promote tumour development (see Alteration of
genetic mechanisms in cancer).
Table 2. Examples of tumour suppressor genes
Gene Protein function Inherited Disease Spontaneous Tumours
APC Negative regulator of the signalling pathway Adenomatous polyposis coli Most colon cancers
(APC)
BRCA1, Components of DNA repair systems Familial breast and ovarian Spontaneous breast cancers
BRCA2 cancer
CDH1 E-cadherin, a cell adhesion molecule Hereditary diffuse gastric cancer Many epithelial cancers
CDKN2A INK4a, inhibitor of cyclin-dependent kinase Some familial melanomas Some esophageal and pancreatic cancers
Cdk4
MEN1 Transcription factor and protein kinase Multiple endocrine neoplasia Many metastatic cancers
NF1 Neurofibromin, Ras-GTPase activation Neurofibromatosis type 1 Some tumours of neural crest origin
PTEN Negative regulator of PI3K growth signalling Cowden disease 30%-50% of spontaneous cancers
pathway
RB Repression of transcription factor E2F Retinoblastoma, osteosarcoma Retinoblastoma, sarcomas, several

carcinomas
SMAD4 Signal transducer in TGF-signalling Juvenile polyposis Colon and pancreatic cancers
TP53 Transcription factor; guardian of the genome' Li-Fraumeni syndrome Most frequently mutated in human cancers
TSC1, TSC2 Inhibitor of mTOR Tuberous sclerosis Rare
VHL Ubiquitin ligase von Hippel-Lindau disease Many renal cell carcinomas
WT1 Transcription factor Wilms tumour Some leukaemias
[2]
Adapted from Table 7.1 Weinberg RA. Biology of cancer, 1st ed. Garland Science, 2007
The retinoblastoma (Rb) protein is a tumour suppressor gene that controls the cell cycle transition from G1 to S
Phase. Rb protein binds regulatory transcription factor E2F which is required for the synthesis of DNA replication
enzymes. When Rb is bound to E2F, transcription/replication is blocked. The presence of growth factors (via the Ras
pathway) activates cyclin-dependent kinase 4/6 (Figure 2) Active CDK4/6- phosphorylates and inhibits Rb, taking
the brakes off E2F, and transition to S phase occurs. Disruption/deletion of the Rb gene therefore leads to
uncontrolled cell proliferation.
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Causes of cancer
Mutations and cancer

Cancer development is based on the accumulation of somatic mutations over lifetime. Germ line mutations are
typically not involved, but in very rare cases of inherited cancer predisposition, they are contributing to disease
progression.
Typically the basal mutation rate is low in humans, but it may be enhanced through one of the three following groups
of environmental carcinogens: chemical mutagens, radiation and tumour viruses. Exposure to mutagens or
radiation greatly increases the mutation rate and thus the probability of developing cancer.
Chemical mutagens comprise a quite disparate group of chemicals that modify DNA through a range of
mechanisms, such as alkylation or deamination of DNA bases, or through intercalation between base pairs and
formation of DNA adducts (e.g. aromatic hydrocarbons). Oxidative damage may also affect DNA integrity.
X-rays and radioactive radiation tend to induce DNA double-strand breaks, whereas UV radiation results in the
formation of pyrimidine dimers, by cross-linking of adjacent pyrimidine bases.
Viral causes of cancer

Certain viruses, derived from quite different taxonomic groups (Table 3), are able to induce cancer development. We
distinguish the highly oncogenic viruses, which contain viral oncogenes in their genomes that are in most cases
derived from cellular proto-oncogenes, whereas slowly transforming viruses do not contain such genes. They tend
to use one of the following mechanisms to stimulate proliferation of their host cells:
• Insertion of a strong promoter in the vicinity of a host cell proto-oncogene
• Expression of proteins that neutralise host cell tumour suppressor proteins
• Expression of proteins that prevent or delay apoptosis
Characteristics of viral carcinogenesis include:
• Tumour viruses often establish persistent infections in the human host
• Host factors are important determinants of virus-induced carcinogenesis
• Viruses are rarely complete carcinogens; they require additional factors to fully activate carcinogenesis.
Table 3. Human tumour viruses
Virus (Group) Associated Human Cancer
DNA VIRUSES
Papilloma virus family Genital tumours, squamous cell carcinoma

Human papilloma virus (HPV)
(various subtypes)
Herpes virus family Kaposi sarcoma

Human herpes virus 8 (HHV8) Burkitt's lymphoma, Hodgkin's disease, Nasopharyngeal carcinoma
Epstein-Barr virus (EBV)
Hepadnavirus family Hepatocellular carcinoma

Hepatitis B virus
RNA VIRUSES
Retrovirus family Adult T-cell leukaemia

Human T-cell leukaemia virus AIDS-related malignancies
Human immunodeficiency virus
Flavivirus family Hepatocellular carcinoma

Hepatitis C virus
Adapted from Table 43-1, Brooks GF, Carroll KC, Butel JS, Morse SA. Jawetz, Melnick & Adelberg’s medical microbiology, 24th ed.
[4]
McGraw-Hill, 2007 )
The importance of DNA repair systems

Sophisticated DNA repair systems have evolved in order to maintain the human genome, by fixing damage that may
have occurred to the DNA. Principal DNA repair mechanisms include: mismatch repair, base and nucleotide
excision repair, repair of depurinated sites and repair of double-strand breaks.
The importance of these repair systems for protection against accelerated mutagenesis and the development of cancer
is impressively demonstrated through rare inherited cancer predisposition syndromes based on mutations in DNA
repair enzyme systems (Table 4).
Table 4. Inherited diseases caused by DNA repair defects
Disease Protein Affected Affected Function Manifestation
Bloom syndrome 13 different proteins Recombination repair? Immunodeficiency, cancer susceptibility,

chromosome breaks
Breast cancer susceptibility BRCA1, BRCA2; proteins of Homology-directed DNA repair Breast and ovarian cancer
DNA repair complexes
Cockayne syndrome Nucleotide excision repair Transcription-coupled nucleotide Poor growth, early senility, neurological
protein excision repair degeneration
Fanconi anemia 8 different proteins Repair of DNA cross-links? Anaemia, leukaemia, chromosome
breakage
Hereditary nonpolyposis colon Proteins of mismatch repair Post-replication mismatch repair Cancer susceptibility
cancer (HNPCC)
Nijmegen breakage syndrome Activator of nuclear protein Signalling for DNA double-strand Growth retardation, immunodeficiency,
kinases break repair cancers
Werner syndrome DNA helicase and exonuclease Unknown Premature aging, short telomeres
Xeroderma pigmentosum Nucleotide excision repair Genome-wide nucleotide excision Cutaneous photosensitivity
proteins repair
[5]
(Adapted from Table 9.1, Meisenberg G, Simmons WH. Principles of medical biochemistry, 3rd ed. Mosby/Elsevier, 2012 )
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Multistep carcinogenesis
Carcinogenesis can be considered as a complex micro-evolutionary process, which requires the accumulation of a
range of (somatic) genetic mutations (Figure 1). Under selection pressure and through these mutations, cells acquire
new characteristics, which provide them with an advantage in growth behaviour and other cellular properties, such as
enhanced survival and invasiveness. This process is in most cases drawn out over many years and requires a series of
individual steps.
The main stages of carcinogenesis – an overview

There are three major qualitative changes, which cells have to undergo in order to successfully proceed through the
complete process of carcinogenesis, malignant transformation, invasion of neighbouring tissues and metastasis.
Each one of these major stages comprises a series of genetic alteration of cells affecting specific genes that are
involved in regulating cell properties relevant for the individual stage, i.e. growth behaviour (for malignant
transformation), invasive properties and metastatic potential.
Early steps characterised in colon cancer

The best characterised example supporting the theory of multi-step carcinogenesis is colorectal cancer. This is
largely due to the relative accessibility of colon cancer samples and due to the availability of the distinct
histo-morphological description of early stages of cancer development. Genetic characterisation of a large number of
early, intermediate and late adenomas and frank carcinomas led to the establishment of a ‘preferred’ sequence of
genetic alterations during the adenoma-adenocarcinoma pathway of colorectal cancer (Figure 4). These include the
activation of the K-ras oncogene from its cellular proto-oncogene (pink letters) and the loss for three tumour
suppressor genes (blue letters), where loss of APC (adenomatous polyposis coli) is an early event, whereas loss of
p53 is normally a late event.
Figure 4: Genetic events in early colon carcinoma progression. Approximate correlation of early genetic events in the development of colon
carcinoma (the adenoma-adenocarcinoma pathway) with histopathological features. Note that clinical staging typically refers to the later
observations and cannot be correlated with the genetic events. Genetic events are indicated by vertical arrows and colour-coded as follows: Blue:
loss of tumour suppressor gene (TSG) function, red: activation of oncogenes, green: epigenetic events. The sequence of genetic events is not
necessarily obligatory, but loss of APC is typically the first event and loss of p53 typically the last one.
[2]
Source: Weinberg RA. The biology of cancer, 1st ed. Garland Science, 2007 Reproduced with permission of Garland Science/Taylor & Francis
LLC.
Cellular principles of invasion and metastasis

The spread of cancer cells to distant sites in the body via the blood stream/lymphatics is known as metastasis and is
the most lethal form of the disease (Figure 5). Metastatic cells are less adhesive than normal cells and are able to
degrade and penetrate tissue barriers such as the extracellular matrix (ECM) of surrounding connective tissue and the
basement membrane of blood vessels. After gaining access to the systemic circulation they can invade normal tissue
at various sites in the body forming secondary colonies. The invasion - metastasis cascade involves:
1. Acquisition of local invasiveness
2. Invasion of the cell into blood/ lymph vessels (intravasation)
3. Transport through the blood/lymph vessels to distant tissue sites
4. Escape of the cancer cells from circulation (extravasation)
5. Ability to adapt to the local tissue environment and to proliferate
Figure 5: Steps involved in the metastatic cascade. During metastatic progression, tumour cells exit their primary sites of growth (local
invasion, intravasation; 1 & 2), translocate systemically (survival in the circulation, arrest at a distant organ site, extravasation; 3 & 4), and adapt
to survive and thrive in foreign microenvironments (5).
[6]
Source: Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011
Epithelial-mesenchymal transition (EMT) is a key transition enabling cancer cells to become motile and invasive,
and ultimately form metastases in distant tissues.
Cell motility is regulated by small G proteins that are activated by cytoplasmic signalling pathways controlling the
assembly of new actin cytoskeleton.
Cell invasiveness is enhanced through overexpression of various matrix metalloproteinases (MMPs) that degrade
components of the ECM.
Angiogenesis, the growth of the new blood vessels, is necessary for solid tumours to continue growing beyond a
certain size. More than a dozen different proteins and several small molecules are released by tumours as signals for
angiogenesis. Two proteins most important for sustaining tumour growth are vascular endothelial growth factor
(VEGF) and basic fibroblast growth factor (bFGF).
Stromal microenvironment and carcinogenesis

Cross talk between stromal cells within the ECM and tumour cells is also vital for carcinogenesis. The following
factors are thought to contribute to malignant transformation:
• Cleavage of matrix components releases angiogenic factors (VEGF) promoting new vessel growth and proteolytic
fragments that favour cancer cell motility.
• The ECM stores GFs in inactive forms, which are released by active matrix proteases and stimulate the growth of
tumour cells in a paracrine manner.
• Stromal cells within the ECM may directly transmit oncogenic signals to tumour cells.
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Other genetic aspects of cancers

Apart from the three major types of genes frequently altered in cancer, i.e. tumour suppressor genes,
proto-oncogenes and DNA repair genes, there are several other genetic alterations observed in tumours, which will
be briefly described here.
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Genetic instability of tumour cells

Genetic analysis of solid tumours revealed the presence of a high degree of genetic abnormalities, such as
aneuploidy, chromosome translocations etc. This is likely due to the lack of active p53 protein, and the ability of
cancer cells to avoid cell death through apoptosis. Other mechanisms may also play a part here, e.g. mitotic defects
that result in chromosome miss-segregation. Chromosomal instability (CIN) is widespread in cancer cells from
epithelial origin, but much rarer in haematopoietic tumours.
Alteration of genetic mechanisms in cancer

Three different alterations of genetic mechanisms often observed in cancer will be briefly explained below.
Loss of heterozygosity (LOH): This describes a genetic phenomenon often seen with tumour suppressor genes in
cancer. Since the human karyotype is diploid, mutation of one allele of a tumour suppressor gene is not sufficient to
cause cancer. In heterozygous individuals, the wildtype allele will provide for a functional phenotype. However,
when a ‘second hit’ occurs, e.g. through missegregation of chromosomes, this individual (or cell) may lose its
‘heterozygosity’, leading to a full cancerous phenotype. Genetic analyses of LOH helped to identify the chromosomal
location of many tumour suppressor genes.
Microsatellite instability (MIN): This is a phenomenon often seen in colorectal cancer cells with defective DNA
mismatch repair system, e.g. in hereditary nonpolyposis colorectal cancer (HNPCC). Microsatellites are regions of
repetitive DNA sequences in the genome that are prone to shortening or extension if the mismatch repair enzymes
are defective. Genetic analysis of these regions can be used to identify such defects.
DNA hyper- or hypomethylation: DNA methylation of gene promoter regions on CpG
(cytosine-phosphate-guanine) sequences is an important epigenetic control mechanism to silence specific genes. In
cancer, DNA hypermethylation is often involved in the silencing of tumour suppressor genes. Conversely, DNA
hypomethylation may contribute to the activation of oncogenes, although the former occurs much more commonly.
Inherited predisposition to cancer

Whilst cancer as such is not inherited, there are a wide range of rare familial syndromes that predispose affected
family members to cancer development. We mentioned above cancer predisposition syndromes that are based on
mutations in DNA repair enzyme systems (Table 4, in The importance of DNA repair systems). A by far larger
number of familial cancer syndromes is based on mutations of tumour suppressor genes, of which a selection is
shown in Table 2. It is interesting to note that germ line mutations of activated oncogenes are normally not inherited.
They may arise during gametogenesis, but the mutant alleles are typically dominant at the cellular level, which
results in disturbance of normal embryonic development, and reduced viability of these embryos. Fortunately, the
inherited cancer predisposition syndromes listed in Tables 2 and 4 are extremely rare diseases, but they represent
powerful illustrations for the importance of DNA repair and tumour suppressor genes for maintaining body
homeostasis.
Principal applications of genetic testing in cancer

As an increasing number of cancer-related genes or gene mutations is characterised, the potential of DNA and RNA
expression testing for cancer-related applications is being explored. Principal applications include:
Gene mutation screening in families with inherited cancer predisposition syndromes, which identifies at- risk
individuals in such families and allows for decisions to be made about early disease monitoring, aggressive treatment
regimens and prophylactic surgery (e.g. mastectomy in familial breast cancer).
Gene expression microarray analysis can be used for classification of cancer subtypes, e.g. in breast cancer or for
the distinction between acute lymphoblastic and acute myeloid leukaemia. Other applications include the diagnosis
of benign vs. malignant tumours or the monitoring of response to therapies.
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Modern treatment modalities arising from cancer cell biology
Tumour immunology and immunotherapy

The immune system is able to launch attacks not only against foreign invaders, but also against body cells that may
display ‘foreign’ antigens, such as cancer cells. The ‘immune surveillance theory’ is supported by the observation that
the incidence of certain cancers is drastically increased in immune-compromised patients. Tumour cells may be
recognised by the immune system through the expression of tumour-associated antigens, but the antigenicity varies
considerably between different types of antigens.
In order to avoid an attack by the immune system, tumour cells use a range of strategies, such as suppression of
expression of tumour-associated antigens or of MHC class 1 molecules, or even counterattack against immune cells.
Research into immunotherapy of cancers aims to devise novel strategies to support the anti-cancer immune
response; principal approaches include:
• Antigen-independent cytokine therapy (e.g. interleukins or interferons)
• Stimulating cell-mediated immune responses (adoptive T-cell transfer, vaccines)
• Passive immunotherapy using monoclonal antibodies (e.g. Herceptin, Rituxan).
Novel approaches arising from cancer cell biology

The progress in our knowledge about gene mutations frequently occurring in cancers, combined with the
development of modern molecular biology methods has led to both new diagnostic tools (see Principal applications
of genetic testing in cancer) and new treatment modalities that have shown some success in the management of
selected types of cancers. The knowledge about cancer–associated genes and their role in cellular growth signalling
pathways has led to the development of a considerable number of anti-cancer drugs targeting such signalling
pathways: 1) monoclonal antibodies that target the extracellular domains of growth factor receptors and 2)
small-molecule inhibitors, targeting either receptor tyrosine kinases or other components of growth signalling
pathways, such as Ras, b-Raf or mTOR (Figure. 6). Two examples of such successful anti-cancer agents are the
monoclonal antibody Herceptin for the treatment of a specific subtype of breast cancer, and the small-molecule
inhibitor Gleevec targeting the fusion protein Bcr-abl, a mutant tyrosine kinase, involved in the development of
chronic myeloic leukaemia (CML). A third group of potential drug targets are some anti-apoptotic proteins that are
frequently overexpressed in cancer cells.
Figure 6. Targets of novel anti-cancer drugs in cellular growth signalling pathways. The cell membrane is indicated in light grey, red
diamonds represent growth factors, green shows the growth factor receptor with the intracellular tyrosine kinase domain (Tk) indicated by the red
circle. Coloured rectangles symbolise signalling components belonging to specific pathways (Blue: PI3K/Akt pathway; ochre: Ras/MAP kinase
pathway). Dotted (black) arrows point to cell biological outcomes of these pathways. Groups of novel anticancer drugs and their targets are shown
in red.
[2]
Source: Weinberg RA. The biology of cancer. Garland Science, 2007
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Summary: The hallmarks of cancer

To summarise the core points, we are listing the ‘hallmarks of cancer’, which describe the biological capabilities
acquired by cells during the multistep development of human tumours (Figure 7):
Figure 7: A summary of the 6 hallmarks of cancer. Additional capabilities crucial to cancer phenotypes that are not shown here include defects
in DNA repair mechanisms and signalling interactions of the tumour microenvironment.
[7]
Source: Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011
Self-sufficiency in growth signals: Tumours have the capacity to proliferate without external stimuli, usually as a
consequence of oncogene activation.
Insensitivity to growth-inhibitory signals: Tumour cells may not respond to molecules that are inhibitory to the
proliferation of normal cells.
Evasion of apoptosis: Tumours may be resistant to programmed cell death, as a consequence of inactivation of p53
or overexpression of anti-apoptotic proteins.
Defects in DNA repair: Tumours may fail to repair DNA damage caused by carcinogens or unregulated cellular
proliferation.
Limitless replicative potential: Tumour cells have unrestricted proliferative capacity, associated with maintenance
of telomere length and function.
Sustained angiogenesis: Tumours are not able to grow without formation of a vascular supply, which is induced by
various factors, the most important being vascular endothelial growth factor (VEGF).
Ability to invade and metastasise: Tumour metastases are the cause of the vast majority of cancer deaths and
depend on processes that are intrinsic to the cell or are initiated by signals from the tissue microenvironment.
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Further reading
• Chapter 20. Cancer. In: Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular biology of the
cell, 5th edition. New York: Garland Science; 2007 [cited 2014 Jun 5] Available from: http://www.
garlandscience.com/product/isbn/9780815341055.
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation Cell 2011 Mar 4;144(5):646-74 [Abstract
available at http://www.ncbi.nlm.nih.gov/pubmed/21376230].
• Karp G. Chapter 16. Cancer. In: Karp G. Cell and molecular biology: concepts and experiments, 6th edition.
Australia: Wiley; 2010 [cited 2014 Jun 5] Available from: http://au.wiley.com/WileyCDA/WileyTitle/
productCd-EHEP000329.html.
• Stricker TP, Kumar V. Chapter 7. Neoplasia. In: Kumar V, Abbas AK, Fausto N, Aster JC, Perkins JA. Robbins
and Cotran pathologic basis of disease, 8th ed. USA: Saunders; 2010 [cited 2014 Jun 5] Available from: http://
www.us.elsevierhealth.com/pathology/robbins-cotran-pathologic-basis-of-disease-hardcover/9781416031215/
.
• Weinberg RA. The biology of cancer, 2nd ed. USA: Garland Science; 2013 [cited 2014 Jun 5] Available from:
http://www.garlandscience.com/product/isbn/9780815342205.
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References
[1] Alison MR. Cancer. eLS: Encyclopedia of Life Sciences; 2001 Apr 19 [cited 2014 Jun 5] Available from: http:/ / onlinelibrary. wiley. com/
doi/ 10. 1038/ npg. els. 0001471/ abstract?systemMessage=Wiley+ Online+ Library+ will+ be+ disrupted+ Saturday%2C+ 7+ June+ from+
10%3A00-15%3A00+ BST+ %2805%3A00-10%3A00+ EDT%29+ for+ essential+ maintenance. Cites::Citation:Alison MR 2001
[2] Weinberg RA. The biology of cancer. USA: Garland Science; 2007 [cited 2014 Jun 5] Available from: http:/ / www. garlandscience. com/
product/ isbn/ 9780815340782. Cites::Citation:Weinburg RA 2007
[3] Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular biology of the cell, 4th ed. New York: Garland Science/Taylor &
Francis LLC; 2002 [cited 2014 Jul 22] Available from: http:/ / onlinelibrary. wiley. com/ doi/ 10. 1002/ bmb. 2003. 494031049999/ full.
Cites::Citation:Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P 2002
[4] Brooks GF, Carroll KC, Butel JS, Morse SA. Jawetz, Melnick & Adelberg’s medical microbiology, 24th ed. Sultan Qaboos University:
McGraw-Hill; 2007 [cited 2014 Jun 5] Available from: http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC3074881/ .
Cites::Citation:Brooks GF, Carroll KC, Butel JS, Morse SA 2007
[5] Meisenberg G, Simmons WH. Principles of medical biochemistry. USA: Saunders; 2011 [cited 2014 Jun 5] Available from: https:/ / www.
elsevier. com/ books/ principles-of-medical-biochemistry/ meisenberg/ 978-0-323-07155-0. Cites::Citation:Meisenberg G, Simmons WH 2011
[6] Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011 Oct 14;147(2):275-92 [Abstract
available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 22000009].Cites::Citation:Valastyan S, Weinberg RA 2011
[7] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011 Mar 4;144(5):646-74 [Abstract available at http:/ / www.
ncbi. nlm. nih. gov/ pubmed/ 21376230].Cites::Citation:Hanahan D, Weinberg RA 2011
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Cancer biology: Familial cancers and genetic

testing
12 September 2014 05:37:09
Author(s):
• Dr Hilda High BSc MBBS (Hons) MCH FRACP — Author
• Associate Professor Desmond Yip MBBS FRACP — Author
page</ccabutton>
High, H, Yip, D, Cancer Council Australia Oncology Education Committee. Cancer biology: Familial cancers and genetic testing [Version URL:
http://wiki.cancer.org.au/oncologyformedicalstudents_mw/index.php?oldid=, cited 2016 Oct 8]. Available from http://
wiki. cancer. org. au/ oncologyformedicalstudents/ Cancer_biology:_Familial_cancers_and_genetic_testing. In:
Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available from: http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/Clinical_Oncology_for_Medical_Students.
Cancer biology: Familial cancers and genetic testing
Epidemiology
Inherited cancer syndromes are rare, explaining less than 5-10% of cancers. However, they are associated with high
penetrance, resulting in significantly increased risks of specific cancers or groups of cancers. Most syndromes are
autosomal dominant, caused by a single germline mutation in a tumour suppressor gene, particularly a DNA repair
gene, or an oncogene. The sex-specific distribution of certain cancers can give the impression of a X-linked inherited
pattern (e.g. the preponderance of females of affected with breast and/or ovarian cancer compared to males with
breast or prostate cancer, in BRCA1 or BRCA2 mutation carriers.)
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Risk factors
Family history is the single biggest risk factor. However, for some highly penetrant syndromes associated with
childhood cancers, up to 50% of mutation occur de novo (e.g. familial adenomatous polyposis (FAP), Li Fraumeni
and Multiple Endocrine Neoplasia (MEN) 2B). Ethnicity is important in some syndromes (e.g. Ashkenazi Jewish
heritage and specific BRCA1 and BRCA2 mutations) due to founder effects.
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Cancer biology
Cancers in inherited cancer syndromes may be more aggressive, disseminate early and be associated with poor
prognosis (e.g. medullary thyroid cancer in MEN2B). They also may contain targetable mutations or be more
sensitive to standard therapy providing better prognosis (e.g. ovarian cancer in BRCA1 or BRCA2 mutation carriers)
or indistinguishable from non-heritable cancers.
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Clinical presentation
While some inherited cancer syndromes are associated with a specific phenotype (e.g. macrocephaly in Cowden
syndrome or mucosal freckling in Peutz Jegher syndrome), many are not. Presentations suggestive of a germline
mutation include the 3:2:1 rule (3 relatives, in 2 generations where 1 is was diagnosed under 50), cancer diagnosed at
a young age; and multiple cancers in a patient or family. Tumour characteristics include bilateral or multifocal
tumours, rare tumours or uncommon types of common cancers (e.g. triple negative breast cancer).
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Diagnosis
Diagnosing an inherited cancer syndrome usually relies on family history. Risk calculators that examine family and
personal history (e.g. Manchester score or BOADICEA in breast cancer) are often used to determine the pre-test
likelihood of a germline mutation.
Tumour testing is also used to determine the likelihood of a germline cause. For example, universal testing of bowel
cancers, looking for loss of IHC staining of the proteins associated with the mismatch repair genes that cause Lynch
syndrome, is a cost effective screening test and guides which gene to test first. Genetic testing of tumours to
demonstrate biallelic loss of a particular gene is also used, for example in Von Hippel Lindau (VHL) as well as
retinoblastoma.
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Principles of management
For example: Surgery, medical, radiation, palliative care, allied health
The key to good management is to maintain a high degree of suspicion of inherited cancer syndromes and refer
patients for assessment and/or testing in a timely manner. Alternate treatments may be offered if a specific mutation
is identified (e.g. choosing mastectomy over lumpectomy to avoid unnecessary radiation in Li Fraumeni syndrome,
which is associated with a germline TP53 mutation).
Genetic testing should only occur after effective counselling and informed consent. This includes discussing the
limitations of genetic testing, the impact on relatives, risk reducing strategies and the psychosocial issues that may go
beyond those encountered in general oncology practice.
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Follow-up and survivorship

After the initial diagnosis, follow-up may occur via screening clinics or at specific times, such as when a family is
planned, a child reaches an appropriate age for testing, risk reducing surgery is contemplated, or the family history
changes.
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Oncology patients with germline mutations may be at risk of other malignancies. Screening usually starts earlier and
incorporates more sensitive modalities (e.g. breast MRI from age 30 in BRCA1, BRCA2 or TP53 mutation carriers
or colonoscopy in Lynch syndrome). Where screening is ineffective, surgery, if feasible, is recommended (e.g.
risk-reducing salpingo-oophorectomy in BRCA1 at age 40, colectomy around age 21 in APC mutation carriers).
Screening may be performed in high-risk or multidisciplinary specialist clinics (e.g. VHL).
Prevention applies to relatives and offspring as well. After the initial mutation is identified, cascade testing involves
informing at-risk relatives and offering counselling and genetic testing. Testing is not performed in minors, unless
there is a clinical need to do so (e.g. genetic testing in infancy in MEN2 to offer to offer lifesaving thyroidectomy).
IVF and pre-implantation genetic diagnosis can be used to prevent the family mutation being inherited by future
generations, although expense and toxicity limit its application within adult-onset cancer conditions.
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Case studies
Case study 1. (Young onset breast cancer)
Rachel, age 37, has just had a wide local excision and sentinel node biopsy for a right sided, invasive duct
carcinoma. The pathology report states that it is 15mm, grade 3, ER-/PR-/HER2-, no nodes are involved.
She denies any cancers on her mother’s side. What else do you need to know?
• Paternal history
• Any Ashkenazi Jewish heritage
• Size of family and age at which relatives died
• Any phenotypic characteristics that would suggest other inherited cancer syndromes associated with an increased
risk of breast cancer (see eviQ referral guidelines)
Her paternal grandmother had some sort of gynaecological cancer at 71 and her paternal uncle had prostate cancer at
48. Does she meet criteria for genetic testing? If so, for what gene(s)?
• Yes: BRCA1 and BRCA2 mutation search
• Genetic testing for BRCA mutations offered to all triple negative breast cancer <40yrs, even if no family
history
• Manchester score >16 (>10% pre test likelihood) if gynaecological cancer was a high-grade, epithelial
non-mucinous ovarian cancer. Pathology and/or death certificate required.
• Other inherited cancer syndromes unlikely: no phenotypic features of Cowden or Peutz Jegher syndrome and no
strong history of Li Fraumeni related cancers
She undergoes a BRCA mutation search after informed consent is obtained and a mutation in BRCA1 is identified.
Describe alternate treatment plans (if any), other management options and implications for the family?
• Contralateral breast cancer risk high – offer bilateral mastectomy as alternate to WLE + RTx
• Standard chemotherapy regimen
• Risk reducing salpingo-oophorectomy (RRSO) should be strongly recommend at age 40
• Cascade testing, starting with parents and adult siblings (at 50% risk due autosomal dominant inheritance and
very low rate of de novo mutations)
Case study 2. (Young onset bowel cancer)
James, age 29, presented with PR bleeding. Colonoscopy demonstrated obstructing lesion in sigmoid colon. Biopsy
demonstrated an adenocarcinoma. What other workup is required at/after surgery?
• Staging of tumour and tumour testing (IHC for MMR proteins +/- MSI)
• Family history
• Completion colonoscopy and types of polyp(s) (if any found)
• Phenotypic characteristics that would suggest other inherited cancer syndromes associated with an increased risk
of bowel cancer (see eviQ referral guidelines)
Tumour invades through muscularis, 3/25 nodes involved. Normal staining for MMR proteins and MSI-low. Family
history reveals no history of bowel, uterine, ovarian, other GI or other cancers in his family. Completion
colonoscopy demonstrated 9 polyps (mainly adenomas but no hamartomatous or juvenile polyps). What germline
conditions should be considered? Does the lack of family history change your thinking?
• Not Lynch syndrome – very unlikely in presence of normal IHC staining
• Incomplete penetrance means family history may be absent even though de novo mutation rate is very low
• May be Attenuated Familial Adenomatous Polyposis (AFAP) associated with mutations in the APC gene
(oncogene) or MUTYH Associated Polyposis (MAP) associated with mutations in the MUTYH gene (a base
excision repair tumour suppressor gene).
• FAP associated with a high de novo mutation rate, so family history may be absent
• Attenuated FAP more likely than FAP as polyp load in FAP usually much higher at this age
• MAP inherited in autosomal recessive manner with no significant increase in risk for heterozygotes, so parents
usually unaffected
What information would help to determine which gene, APC or MUTYH to test first?
• APC gene mutations causes FAP and AFAP which are associated with a phenotype that includes
• Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in >70% and is usually present at birth
• Supernumary teeth
• Osteoma of the jaw
• Epidermal cysts
• MUTYH gene mutation associated with MAP which is an autosomal recessive condition so increased likelihood
if consanguinity, parents close relations or specific ethnic group
No evidence of CHRPE or other FAP phenotypic features. Parents are from England and are distantly related.
Decide to perform MUTYH first. Homozygous mutations are identified in MUTYH. Describe alternate treatment
plans (if any), other management options and implications for family.
• Repeat colonoscopy and polpectomy or proceed to colectomy if polyp load too great
• Standard chemotherapy regimen
• Upper endoscopy (see eviQ MUTYH management guidelines)
• Cascade testing, starting adult siblings (at 25% risk due autosomal recessive inheritance). No significant increased
risk for heterozygotes
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Further reading and links

• Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) [1]
• Cancer Genetics section of eviQ for information on risk management, referral guidelines, germline genetic testing
and family cancer clinics: www.eviQ.org.au [2]
• Manchester score [3] (requires login)
• Evans DGR, Lalloo F, Cramer A, Jones EA, Knox F, Amir E, et al. Addition of pathology and biomarker
information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2
testing. J Med Genet 2009 May 12 [cited 2014 Jun 5];46:811-817 [Abstract available at http://jmg.bmj.com/
content/46/12/811.abstract].
• Hodgson SV, Foulkes WD, Eng C, Maher ER. A practical guide to human cancer genetics, 4th edition. London:
Springer; 2007 [cited 2014 Jun 5] Available from: http://link.springer.com/book/10.1007/
978-1-4471-2375-0.
• Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C, et al. GeneReviews®. [homepage on the
internet] Seattle: Seattle (WA): University of Washington; 32202 Jan 1 [cited 2014 Jun 5; updated 2014 Jan 1].
Available from: http://www.ncbi.nlm.nih.gov/books/NBK1116/.
• BRCA1 and BRCA2 [4]
• FAP [5]
• Li-Fraumeni Syndrome [6]
• Multiple Endocrine Neoplasia (MEN) Type 2 [7]
• Cowden Syndrome [8]
• Peutz-Jegher Syndrome [9]
• Von Hippel-Lindau Disease [10]
• Retinoblastoma [11]
• MUTYH-Associated Polyposis (MAP) [12]
• Tobias ES, Connor M, Ferguson-Smith M. Essential medical genetics, 6th edition. Australia: Wiley-Blackwell;
2011 [cited 2014 Jun 5] Available from: http://au.wiley.com/WileyCDA/WileyTitle/
productCd-EHEP002300.html.
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References
[1] http:/ / ccge. medschl. cam. ac. uk/ boadicea/
[2] http:/ / www. eviQ. org. au
[3] https:/ / www. eviq. org. au/ Protocol/ tabid/ 66/ id/ 1143/ Default. aspx?popup=1
[4] http:/ / www. ncbi. nlm. nih. gov/ books/ NBK1247/
Cancer diagnosis: Histopathology, cytology and

tumour markers
22 October 2014 04:12:48
Author(s):
• Dr Eugene Moylan MBBS FRACP — Author
page</ccabutton>
Moylan, E, Cancer Council Australia Oncology Education Committee. Cancer diagnosis: Histopathology, cytology and tumour markers [Version
URL: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from
http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Cancer_diagnosis:_Histopathology,_cytology_and_tumour_markers. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council
Australia. Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Clinical_Oncology_for_Medical_Students.
Introduction
Establishing a diagnosis of cancer begins with a thorough history and physical examination. There should always be
a strong correlation between the clinical diagnosis of cancer and the results of diagnostic tests. If there is any concern
regarding diagnostic “fit”, the case should be discussed with the reporting pathologist. This is as relevant in the
diagnosis of recurrent or metastatic disease as it is in the primary setting.
There should be a high level of communication between the clinician and the pathologist to avoid error arising in the
diagnostic phase. Accurate labelling of specimens (correct patient name, tumour side, site and specimen orientation)
is extremely important, particularly when dealing with high specimen volumes (skin lesions, endoscopy specimens,
multiple breast biopsies) where incorrect assignment of the result could have dire consequences for the patient.
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Is tissue always necessary?

There are very few circumstances where the diagnosis of malignancy is made in the absence of pathological
confirmation, particularly as diagnostic procedures have become less invasive over the past few decades. A clinical
diagnosis alone is most often made in the context of advanced malignancy in a poor performance status patient
where anti-cancer therapy would neither improve quality of life nor survival. Thus, the majority of patients have the
diagnosis of cancer confirmed on tissue pathology. The diagnosis of recurrent and/or metastatic disease may be made
on the basis of the pattern of relapse combined with knowledge of the initial tumour stage and underlying tumour
biology. However, caution should be taken to consider “benign” pathology that may mimic metastatic malignancy
(e.g. pulmonary sarcoidosis, hepatic haemangioma, osteoporotic vertebral fracture, Paget’s disease of bone,
ischaemic cerebrovascular accident). Additionally, tumour heterogeneity may result in differential tumour behaviour
between the primary and metastatic sites (such as hormone responsiveness or HER2 expression in breast cancer),
giving rise to different treatment options for the metastatic disease compared with what might have been anticipated
based on the pathology of the primary tumour.
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Obtaining tissue
An important principle is to obtain diagnostic material via the least invasive approach. An example is the cytological
evaluation of a palpable supraclavicular lymph node by fine needle aspiration biopsy (FNAB) in a patient with a
lung mass or known intra-abdominal malignancy. The diagnosis of cancer by the least invasive procedure (FNAB or
core biopsy) facilitates appropriate staging investigations, planning of the definitive treatment and discussion of
these treatment recommendations with the patient and their support person(s). Specific consideration needs to be
given to the amount of tissue required to direct treatment. For example, cytology on a neck node that confirms
metastatic squamous cell carcinoma from an oropharyngeal primary would be sufficient to direct ongoing
management, whereas in lymphoma, a larger biopsy or the entire node may be required to evaluate nodal architecture
in order to decide optimal first-line management.
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Histopathology/cytopathology
Historically, histopathology and cytopathology have been the main tools utilised in the diagnosis of cancer. These
techniques have evolved from an era of diagnosis based on haematoxylin and eosin (H&E) stained slides (Figure 1)
to the current regular evaluation of tumours by immunocytochemistry (IHC) to confirm tumour histogenesis and
subtype. In breast cancer, this means the routine IHC evaluation of hormone receptors (oestrogen (Figure 2) and
progesterone receptors) as well as evaluation of HER2 expression (Figure 3) and Ki67 (a marker of tumour
proliferation). These factors strongly influence prognosis and the selection of anti-cancer treatments. Molecular
histopathology using in-situ hybridization (ISH) techniques also provides additional information influencing
prognosis and treatment in breast cancer (Figure 4) and other cancers. More recently, gene profiling technology
(Figure 5) has been used to define subgroups of breast cancer patients. For example, it has identified the Luminal-A
breast cancer subtype for whom adjuvant chemotherapy is unlikely to be of benefit. These gene profiling techniques
are likely to be used in the management of other tumours over coming years.
Figure 1: High grade breast cancer H&E section Source: Dr Ala Enno Consultant Histopathologist at Liverpool Hospital
Figure 2: Breast cancer IHC ER positive Source: Dr Ala Enno Consultant Histopathologist at Liverpool Hospital
Figure 3: Breast cancer IHC HER2 positive Source: Dr Ala Enno Consultant Histopathologist at Liverpool Hospital. Permission to
use.
Figure 4: Breast cancer SISH HER2 gene amplification Source: Dr Ala Enno Consultant Histopathologist at Liverpool Hospital.
Permission to use.
Figure 5: Classes of breast cancer based on gene expression profiles Source: Sørlie T et al : Gene expression patterns of
breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001, 98:10869-10874. Permission to use.
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Molecular genetics/cytogenetics
Molecular and cytogenetic studies have demonstrated that the development and progression of human malignancies
involves multiple genetic changes, and techniques identifying these changes have become major diagnostic tools in
oncology. Studies have shown a specific gene translocation to characterise chronic myeloid leukaemia t(9;22)
(Figure 6). Amplification and/or activation of tumour oncogenes such as c-myc, and deletion and/or inactivation of
tumour suppressor genes such as p53 and Rb1, are identified with specific solid tumours. Cytogenetic results are
increasingly important in confirming the diagnosis of malignancy and directing the optimum therapeutic strategy.
Figure 6: 9:22 Translocation Source: Medindia health [1]. Permission to use.

The 9:22 translocation brings together the breakpoint cluster region gene (BCR) on chromosome 22 and the Ableson
leukaemia virus gene (ABL) on chromosome 9. The resulting BCR-ABL hybrid gene codes for a protein, endowed
with tyrosine kinase activity, which has the ability to activate signal transduction pathways.
Mutations in genes involved in cellular signalling are common and these can be used to define patients that are more
likely to benefit form a particular ‘targeted’ cancer therapy -- e.g. an epidermal growth factor receptor (EGFR)
mutation in metastatic adenocarcinoma of the lung identifies a subgroup of patients that can be treated preferentially
with first-line EGFR-targeted tyrosine kinase inhibitor therapy rather than chemotherapy. Similarly, patients with
metastatic colorectal cancer exhibiting wild-type KRAS may benefit from EGFR-antibody therapy, whereas those
with mutant-KRAS are resistant to such treatment.
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Tumour markers/biomarkers
Tumour markers are substances released by cancer cells into the blood. They are used as an adjunct to other
investigations in primary diagnosis and should not be used as blind screening tools in the absence of evidence to
support their use in this setting. Tumour markers are most useful in the evaluation of how well a patient has
responded to treatment and to check for tumour recurrence.
Biomarkers are physiological markers or substances expressed by the body that can indicate the presence of a tumour
that is not necessarily expressed by tumour cells. Another distinction between tumour marker and biomarker is that
biomarkers can also apply to non-solid tumour cancers.
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Useful markers of internal malignancy

Prostate-specific antigen (PSA): An elevated PSA level in the blood may indicate prostate cancer, but other
conditions such as benign prostatic hyperplasia (BPH) and prostatitis can also raise PSA levels. PSA levels are used
to evaluate how a patient has responded to treatment and to check for tumour recurrence. The use of PSA as a
screening tool for prostate cancer remains controversial.
Alpha-fetoprotein (AFP): This is normally elevated in pregnant women since it is produced by the foetus. In men,
and in women who are not pregnant, an elevated level of AFP may indicate liver cancer or cancer of the testis or
ovary. Noncancerous conditions such as chronic active hepatitis may also cause elevated AFP levels.
Human chorionic gonadotropin (HCG): This is another substance that appears normally in pregnancy and is
produced by the placenta. If pregnancy is ruled out, HCG may indicate cancer in the testis, ovary, liver, stomach,
pancreas and lung. Marijuana use can also “falsely” raise HCG levels.
Carcinoembryonic antigen (CEA): Colorectal cancer is the most common cancer where this tumour marker is
used, but many other epithelial cancers can also raise levels.
CA 125: Ovarian cancer is the most common cause of elevated CA 125, but cancers of the uterus, cervix, pancreas,
liver, colon, breast, lung and digestive tract can also raise CA 125 levels through peritoneal involvement. Several
noncancerous conditions can also elevate CA 125 (e.g. non-malignant ascites). CA 125 is mainly used to monitor the
treatment of ovarian cancer.
CA 19-9: This is associated with cancers in the colon, stomach, and bile duct. Elevated levels of CA 19-9 may
indicate advanced cancer in the pancreas, but it is also associated with noncancerous conditions, including
gallstones, pancreatitis, cirrhosis of the liver and cholecystitis.
CA 15-3: This is most useful in evaluating the effect of treatment for women with advanced breast cancer. Elevated
levels of CA 15-3 are also associated with cancers of the ovary, lung, and prostate, as well as noncancerous
conditions such as benign breast or ovarian disease, endometriosis, pelvic inflammatory disease and hepatitis.
Pregnancy and lactation also can raise CA 15-3 levels.
There are many other markers used in monitoring specific cancers, e.g. calcitonin in medullary carcinoma of the
thyroid, chromogranin-A (CgA) in neuroendocrine carcinoma, thyroglobulin in thyroid cancer, neuron specific
enolase (NSE) in small cell carcinoma of the lung, immunoglobulins/light chains in multiple myeloma and
beta-2-microglobulin in multiple myeloma and non-Hodgkin’s lymphoma. Lactate dehydrogenase (LDH) is a
non-specific marker that is of prognostic significance in metastatic melanoma, small cell lung cancer, germ cell
tumours of the testis/ovary, non-Hodgkin’s lymphoma and neuroblastoma.
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References
[1] http:/ / www. medindia. net/ patients/ patientinfo/ chronic_myeloid_leukemia_causes. htm
Cancer diagnosis: staging and imaging

29 October 2014 04:04:25
Author(s):
• Dr Alex Tan MBBS FRANZCR — Author
page</ccabutton>
http:/ / wiki.
Tan, A, Cancer Council Australia Oncology Education Committee. Cancer diagnosis: staging and imaging [Version URL:
cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Cancer_diagnosis:_staging_and_imaging. In: Sabesan S, Olver I, editors. .
Sydney: Cancer Council Australia. Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Introduction
After diagnosis, the extent of tumour spread (tumour stage) must be determined as accurately as possible; it has
implications on optimal management and allows for prognostication. A standardised system aids in communication,
standardisation of treatment and allows for consistency in reporting of disease outcomes.
There are several staging systems used in oncology. The most frequently used one is the TNM (Tumour, Node,
Metastasis) system maintained by the Union for International Cancer Control (UICC).
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The TNM staging system

This divides the elements of tumour spread into three categories: extent of tumour invasion (T), involvement of
regional lymph nodes (N), and distant haematogenous metastases (M).
The definition of T, N and M differs for each disease site. The principles are below:
x cannot be assessed
0 occult (no primary tumour evident)
T
is in situ (i.e. non invasive)
1-4 increasing T stage implies increasing size and/or degree of invasion into the organ or surrounding tissues.
x cannot be assessed
N 0 node negative
1-3 N stage increases with increasing number of nodes, presence of large or matted nodes, or nodes more distant from the primary tumour.
0 no metastases
M
1 metastatic disease present (usually implying haematogenous spread)
Other modifiers
Prefixes are used to provide more detail of the TNM staging. Common ones are:
c: clinical stage, meaning the stage has been determined by clinical examination and imaging
p: pathologic stage, meaning the stage has been confirmed via histology or cytology.
y: indicates the TNM stage has been determined after completion of neoadjuvant therapy.
For example, ypT3N1M0 rectal cancer is one that has been resected after neoadjuvant therapy, with histology
showing invasion through the full thickness of the rectal wall and involvement of 1-3 regional lymph nodes.
Each tumour type has a stage grouping, which is the categorisation of malignancies into stages from I to IV. A single
stage grouping may have multiple TNM stages assigned within it, generally those with a similar prognosis. In lung
cancer for example, T4N0M0, T3-4N1M0 and T1-3N2M0 all lie within Stage IIIA. Stage IV disease is almost
universally when there has been haematogenous spread and in most cases indicates the disease is incurable.
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Other staging systems

While the TNM system is most common, there are some malignancies (e.g. cervix, lymphoma) where it is not used
at all and other systems are well established.
Female reproductive system cancers (cervix, uterus, ovary, vagina)
The FIGO (International Federation of Gynaecology and Obstetrics) system is used. The stage is determined by
features such as degree of invasion, ureteric obstruction, lymphadenopathy and peritoneal seeding. It ranges from
Stage I to IV.
Lymphoma
The Ann Arbor classification is used to describe how many lymph node regions are involved and whether the nodes
are on one or both sides of the diaphragm. The presence or absence of “B symptoms” (night sweats, fevers, weight
loss of >10%) is an important prognostic factor and this has been incorporated into the staging system as a suffix
after the stage descriptor.
For example, Stage IIIB Hodgkin’s lymphoma indicates the presence of B symptoms and involvement of nodal
stations on both sides of the diaphragm.
Colon cancer
This has a TNM system, however the Dukes Classification system is still widely used. In this, the stage is classified
from A to D based on depth of invasion, nodal involvement and distant metastases.
Small cell lung cancer
This does utilise TNM staging, however more commonly it is simply divided into limited and extensive stage, based
on whether the disease is intrathoracic and can be encompassed within a radiation portal. Extensive stage disease is
generally considered incurable.
Other (non staging) parameters
It would be remiss to discuss staging and prognostication without mentioning other disease parameters which play a
very important role in determining treatment and prognosis. The important variables differ depending on the tumour
site but include:
• tumour grade
• hormone receptor status
• specific serum markers (eg PSA, LDH, hCG)
• chromosomal abnormalities (eg 1p19q co-deletion in oligodendroglioma)
• Clark level (melanoma).
Performance status and weight loss are independent prognostic factors, and a patient with apparent early stage
disease but a poor performance status or significant, unexplained weight loss is unlikely to tolerate, or be cured by,
aggressive treatment.
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Imaging modalities
Imaging is one of the most important ways to determine the disease stage. These can be divided into structural and
functional imaging.
Structural imaging
This includes plain X-ray, CT or MRI. These will demonstrate gross tumour due to the size and shape of the tumour,
enlarged lymph nodes or destructive lesions. The sensitivity of such imaging may be improved by the use of
contrast, including intravenous or intraluminal contrast. Tumours generally display contrast enhancement due to the
leakiness of abnormal blood vessels within the tumour (neovascularisation). Intraluminal contrast can be used to
demonstrate filling defects -- for example, a barium swallow may demonstrate a tumour in the oesophagus.
Functional imaging
These fall within the realm of nuclear medicine. A radioactive isotope is administered which localises to specific
areas. The areas of tracer accumulation are collected by a special detector (e.g. gamma camera) and reconstructed to
form a picture. These can quickly highlight abnormal areas which may be difficult to see on structural scans.
A bone scan (using technetium-99m) is used to identify bone metastases. It is taken up in areas of high bone
turnover, so is not specific for metastases; “hot spots” may correlate to areas of bone healing (e.g. fracture) or
infection (e.g. osteomyelitis). Similarly, predominantly lytic metastases may not be detected on bone scan.
Positron Emission Tomography (PET) scanning is the gold standard of staging for many cancers. A variety of
different tracers may be used but by far the most common is 18-fluorodeoxyglucose (18-FDG). FDG is a glucose
analog and concentrates in areas of high metabolic activity. There is physiological uptake in the brain, heart and
urinary tract (it is excreted renally) and false positives may result from infection, inflammation or granulomatous
diseases. Particularly when fused with a low dose CT, PET helps differentiate benign from malignant lymph nodes
and identifies small metastatic deposits in bone and soft tissue that may be occult on conventional imaging. It is not
useful in all cancers however, particularly those with low metabolic rate, e.g. prostate cancer.
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Reference list
• Sobin LH, Gospodarowicz MK, Wittekind C. The TNM classification of malignant tumours 7th edition.
Wiley-Blackwell; 2009 [cited 2014 Jul 22] Available from: http://au.wiley.com/WileyCDA/WileyTitle/
productCd-1444332414.html#see-less-toc.
• Benedet JL, Bender H, Jones III H, Ngan HYS, Pecorelli S. Staging classifications and clinical practice guidelines
of gynaecologic cancers. Elsevier; 2000 [cited 2014 Jul 22] Available from: http://www.igcs.org/files/
TreatmentResources/FIGO_IGCS_staging.pdf.
• Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s disease staging classification.
Cancer Res 1971 Jan 1 [cited 2014 Jul 22];31:1860–1861 [Abstract available at http://cancerres.aacrjournals.
org/content/31/11/1860.full.pdf+html].
• Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al. Report of a committee convened
to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting J Clin Oncol 1989
Nov;7(11):1630-6 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2809679].
• Dukes CE. The classification of cancer of the rectum. J Pathol Bacteriol 1932 [cited 2014 Jul 22];35(3): 323-32
[Abstract available at http://onlinelibrary.wiley.com/doi/10.1002/path.1700350303/abstract].
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Principles of cancer management

22 October 2014 04:31:32
Author(s):
• Associate Professor Sabe Sabesan MBBS FRACP — Author
• Dr Joanna Dewar MBBS, FRACP — Author
• Dr David Wyld — Author
page</ccabutton>
Sabesan, S, Dewar J, Dr David Wyld, Cancer Council Australia Oncology Education Committee. Principles of cancer management [Version
URL: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from
http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/ Principles_of_cancer_management. In: Sabesan S, Olver I,
editors. . Sydney: Cancer Council Australia. Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Introduction
Cancer is a chronic disease, and like any other chronic medical condition, cancer patients have families, jobs,
businesses and other commitments. Therefore, our aim is to cure the cancer if possible, and if not curable, then
control the symptoms to improve quality of life and prolong the person's life by a few months (for example 2, 3, 6,
18 months or, if lucky, longer).
Table1: Examples of curable and incurable cancers
Malignancy Curable Incurable
Lung-non small cell Up to locally advances Metastatic
Lung-small cell Limited stage Extensive stage
Breast Up to node positive Metastatic
Colon Up to node positive Metastatic

Except solitary liver or lung mets
Cervical Early and locally advanced Metastatic
Head and neck Early and locally advanced Metastatic
Germ cells/choriocarcinoma Mostly
Lymphomas Mostly
Sarcomas Even metastatic

Ewings, osteosarcome
Leukaemia Mostly
Increasingly, cancer is managed in a multidisciplinary team setting to improve outcome and decrease morbidity of
treatment. Some centres make decisions at multidisciplinary tumour boards, while some centres have dedicated
multidisciplinary clinics.
Members of multidisciplinary team include surgeons, radiation and medical oncologists/hematologists, palliative
care physicians, radiologists, pathologists, general practitioners, nurses and allied health professionals. Cancer care
coordinators also play an important role in the provision of coordinated care.
In Australia, training programs to become cancer specialists are determined by respective colleges.
Table 2: Examples of roles of various multidisciplinary team members
Specialties Examples of roles
Medical oncologist Chemotherapy, biological therapy, hormonal therapy
Radiation oncologist External beam radiotherapy, brachytherapy, systemic

radiation
Palliative care Symptom control, hospice care
Oncological surgeons Definitive and palliative surgery
Allied health: Relevant to each speciality

Dietician, physiotherapy, occupational therapy, social work, pharmacy and
psychology
Cancer nurses Care coordination, clinical trials, chemotherapy

administration
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Medical therapies including chemotherapy, biological therapy and hormones

Medical therapies are offered to patients with the following aims:
Curative
E.g. Leukaemia, lymphoma, germ cell tumours, choriocarcinoma, Ewing sarcoma/osteosarcoma
Adjuvant (to eliminate micro metastatic disease after surgery or radiotherapy)
E.g. Breast, colon, ovarian, sarcoma
Concurrent with radiation therapy (as radio sensitisers)
E.g. Head and neck, cervical, lung
Palliative (to improve quality of life and prolong survival)
E.g. Metastatic cancers
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Radiation therapy
Curative
E.g. Head and neck, cervical, lung, prostate, sarcoma
Adjuvant (to eradicate micro metastatic disease after surgery)
E.g. head and neck, breast, brain
Palliative (to improve symptoms)
E.g. Advanced local disease and metastatic cancers
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Palliative care
Aim of palliative care is to improve quality of life by controlling symptoms
If a tumour can be shrunk by chemotherapy or radiotherapy, this would be an efficient option for controlling
symptoms. In most cases, concurrent use of palliative care services and active anti-cancer therapy are necessary to
maintain quality of life.
In all these situations, it is important to identify and treat the cause of the symptoms rather than adopting a 'one size
fits all' arbitrary management plan.
Examples of symptoms and management are outlined below:
Pain: simple analgesics, narcotics, parenteral narcotics
Nausea: metoclopramide, 5HT3 antagonist, steroids
Loss of appetite: steroids
Cough/SOB: codeine, narcotics, nebulisers.
Depression: control symptoms, correct causes, counselling, antidepressants
family support, aids, home visits, physiotherapy, nutrition, occupational therapy, social work
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Surgery
Surgery is performed for cure by removing the primary cancer and lymph nodes and for palliation by removing the
mass causing symptoms in selected cases. In some cases, removing solitary or limited metastasis could achieve cure.
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Overall approach to cancer management

Three main questions to consider are:
1. What is the type of cancer?
In most cases, this requires a tissue diagnosis. In modern oncology, it is unusual or inappropriate to start treatment
based on clinical diagnosis alone without tissue diagnosis. Tissue diagnosis is also important to perform molecular
studies to select appropriate targeted therapies.
2. What is the extent of the spread of the cancer?
This is answered by staging scans including CT scans, bone scans and PET scans.
3. Is it curable or not curable?
This depends on the type of cancer and the presence or absence of and the extent of metastasis.
For curable cancers, rate of cure is determined by prognostic factors (for example: tumour size and nodal status in
breast cancer).
For incurable cancers, duration of survival is expressed in median survival rather than in absolute time frame.
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Incurable metastatic cancers

Aim is to prolong survival and improve quality of life.
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Why is quality of life important?

• Good for the patient and families
• Cost effective to the patient and health system by continuing to function normally, having less hospital
admissions, causing less burden on community support systems
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How does treating with chemotherapy or radiotherapy improve quality of life?

• By shrinking the cancer mass
• By decreasing the need for the sedative effect of analgesics
• By living longer
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Concept of median survival

Survival figures are obtained from large data bases. Therefore, we can only quote median figures rather than absolute
numbers for expected duration of survival. The meaning of median survival needs to be clearly explained to patients
and families to illustrate uncertainty.
Table 3: Examples of median survival for selected cancers
Malignancy Without treatment With treatment
Non-small cell lung 6-9 months 9-12 months
Small cell lung 6-8 weeks 12 months
Colon 6-9 months 20 months
Breast 1-2 years 3-4 years
(Note: With current treatment options, survival figures continue to increase)
Case study
A 70-year-old lady presented with abdominal pain, vomiting and bloating. She commenced on morphine which was
complicated by confusion and loss of mobility. CAT scan show extensive peritoneal deposits and cancer was
protruding through umbilicus as well.
Figure 1: CAT scan of abdomen and pelvis of the patient
Biopsy of the umbilical mass reveals that the patient has metastatic ovarian cancer. She was deemed fit for palliative
chemotherapy and underwent 6 cycles of Carboplatin and Paclitaxel with complete resolution of masses and
symptoms. She did not require narcotics anymore. Chemotherapy was well tolerated. She lived for 4 years with good
quality of life.
Figure 2: CAT scan of the abdomen and pelvis after chemotherapy.
Models of care
In larger cities, cancer care is delivered at dedicated cancer centres. In regional or rural centres, it is through shared
care models where local doctors and visiting specialists work in partnership. At smaller centres where outreach visits
are not viable or feasible, telemedicine models (teleoncology) are increasingly adopted.
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Teleoncology
Teleoncology models are used for seeing new cases, reviewing urgent cases and for conducting multidisciplinary
meetings at rural centres to provide specialist services closer to home. At some centres, various chemotherapy agents
are supervised remotely by medical oncologists. These models are acceptable to Indigenous and non-Indigenous
patients, welcomed by health professionals and provide savings to the health systems. However, further studies are
needed to see if these models improve outcomes above and beyond improving access to disadvantaged populations.
An example of a video case study is found here:
http://www.youtube.com/watch?v=N5l7UexKcTU
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Principles of cancer surgery

22 October 2014 04:39:19
Author(s):
• Dr. Anita Skandarajah MBBS MD FRACS — Author
page</ccabutton>
Skandarajah, A, Cancer Council Australia Oncology Education Committee. Principles of cancer surgery [Version URL: http:/ / wiki. cancer.
org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki. cancer. org.
au/ oncologyformedicalstudents/ Principles_of_cancer_surgery. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council
Introduction
Cancer surgery has evolved over the decades from a radical ‘one size fits all’ approach to a patient-specific,
cancer-specific direction, which means that surgeons rely on their multidisciplinary partners in the assessment of
patients. As surgeons are frequently the first specialists involved with most solid tumours, familiarity with
pre-operative imaging, pathological biopsy and patient-selection, careful surgical technique and staging are
fundamental to the surgeon’s armamentarium.
Pre-operative imaging and TNM staging

Most solid tumours require adequate and site-specific imaging. This facilitates diagnosis and staging of the primary
tumour and staging for distal metastases. Not all modalities are appropriate for all sites. For example mammography
using the BIRADS system and ultrasound are used in breast cancers to assess a primary breast cancer. Meanwhile,
an oesophageal cancer requires a CT and a low rectal cancer will be best assessed with MRI or endorectal
ultrasound, whilst a thyroid cancer is best evaluated with neck ultrasound.
The goals of imaging the primary tumour are to assess tumour size, invasion into surrounding structures and
operability. Imaging to stage a tumour aims at assessing nodal involvement and distal metastases.
The TNM staging system (American Joint Commission on Cancer AJCC) is devised for cancers to allow an
assessment of T- tumour, N- nodal metastases and M- distal metastases. The goal of having a site-specific staging
system is to estimate prognosis, facilitate treatment planning including the sequence of treatments and allow
comparisons of treatment for different stages. Generally, a combination of different ‘T’, ‘N’, and ‘M’ allows the
cancer to be grouped into stages. Stages I-IV usually depict a tumour in the following state: Stage 1- early and
superficial cancer, Stage 2- locally advanced, Stage 3- regionally advanced with lymph node metastases and Stage 4-
distant metastatic disease.
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Pathological biopsy
Despite suggestive imaging, a cancer is not diagnosed until histopathological biopsy. Biopsies where tissue (as
opposed to cells) are provided to the pathologist increase the accuracy of the pre-operative diagnosis but may not
always be feasible. Biopsies may be undertaken percutaneously -- for example, a core biopsy of the breast, fine
needle aspiration of thyroid or endoscopically such as in gastric cancer or colon cancer.
A biopsy should confirm the tumour type, grade, may show lymphovascular invasion and in some cases, special
immunohistochemical stains may be performed to assess hormone receptor status such as in breast cancer or flow
cytometry may be performed to assess subtypes such as in lymphoma. Staging may also require a biopsy of draining
lymph nodes.
The goals of a biopsy should be to provide a diagnosis without excessive morbidity to the patient. Areas that are not
suitable for percutaneous biopsy include adrenal tumours or paraaortic masses.
Needle biopsy is not always adequate to aid treatment and occasionally incisional or excisional biopsies may be
required. Lymphoma is a common tumour that may require a larger tissue sample to make the diagnosis.
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Patient-selection and timing of surgery

One of the biggest challenges for the surgeon is to choose the correct surgery for the correct patient and with the
tumour type and biology in mind. Although surgery removes a tumour and provides further pathological information
to estimate prognosis and influence adjuvant therapies, the surgery cannot cause more morbidity than the cancer and
must achieve surgical goals without compromising tumour biology.
When tumours are locally advanced, a neoadjuvant approach with chemotherapy, radiotherapy or targeted therapies
may be important to ‘control’ the growth of a tumour, down-stage a tumour to render it operable, or because the
impact of systemic disease risk may outweigh those of local control. Similarly, patients with metastatic disease may
still require surgery to prevent complications of the primary tumour, such as bowel obstruction from a colon cancer.
The pre-operative multidisciplinary team including anaesthetists, cardiologists, dieticians, psychologists and social
workers, and tumour-specific specialist nurses often assesses fitness for cancer surgery and the psychosocial impact
of surgery.
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Surgery of the primary tumour

The aims of any cancer surgery are to remove the cancer with an adequate margin of normal tissue with minimal
morbidity. Clear margins have an impact on local control. Margin requirements differ according to the origin of the
tumour and the functional impact must be considered.
Two examples of margins versus function/cosmesis include rectal cancer and breast cancer. A low rectal cancer
requires an adequate margin above the anal sphincters to enable a primary anastomosis (anterior resection) that is not
under tension and therefore at risk of anastomotic leak. As a cancer encroaches on the level of the sphincter muscles,
the sphincters must be sacrificed in order achieve an adequate margin (abdominoperineal resection). In breast cancer,
a wide local excision may be adequate for many breast cancers but if the result is poor cosmesis/ shape, a
mastectomy may be a better operation to achieve a clear margin.
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Surgery of the lymph node basin

Many solid tumours require removal of the draining lymph nodes for the purpose of staging and/or to achieve local
control. Levels of prophylactic lymph nodes dissection vary according to tumour type and may increase surgical
morbidity. Surgery in some tumours has become more conservative with the advent of sentinel node biopsy when
lymph node metastases are not evident pre-operatively. Sentinel node biopsy is frequently used in breast cancer and
melanoma. The aim of the sentinel node biopsy is to provide an assessment as a staging tool to predict prognosis and
influence use of adjuvant therapies.
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Surgery in metastatic disease and emergencies

Local control may become an issue in some patients with metastatic disease. Surgery may be undertaken in an
elective or emergency setting in colorectal cancer to prevent or manage a bowel obstruction, to bypass a segment of
small bowel involved with peritoneal disease or to place an endoscopic stent, for example in a metastatic
cholangiocarcinoma or oesophageal cancer. In addition, in some tumour types, such as breast cancer, colorectal
cancer or liver metastases, removal of the primary in a patient who has stable metastatic disease may improve
prognosis and survival.
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Surgery for prophylaxis

Cancer surgery includes managing patients at high risk of cancer in their lifetimes, usually due to an inherited
mutation such as BRCA 1 or 2 or Lynch Syndrome. Although some medications, such as tamoxifen, may reduce risk
of cancer, surgery in some organs reduces the risk of cancer in that site by about 95-97%. Organs removed in
surgical prophylaxis include the breast/s, colon, stomach and thyroid.
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Principles of radiotherapy
22 October 2014 04:51:53
Author(s):
• Professor Michael Barton OAM MBBS MD FRANZCR — Author
page</ccabutton>
http:/ / wiki. cancer. org.
Barton, M, Cancer Council Australia Oncology Education Committee. Principles of radiotherapy [Version URL:
au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Principles_of_radiotherapy. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia.
Radiotherapy and multidisciplinary cancer care

Radiotherapy can prolong survival, contribute to the preservation of organs affected by malignancy, provide
palliation and improve patients’ quality of life. Recent research shows that about 50% of patients with
newly-diagnosed cancers (other than non-melanotic skin cancers) would benefit from radiotherapy[1]. One-quarter of
these patients may need further treatment after relapse.
The provision of a safe and effective radiation oncology service is complex. It requires a substantial capital
investment in radiotherapy equipment and specially-designed buildings, an ongoing investment in maintenance and
replacement of the equipment, expert teams of doctors, therapists and physicists, and good access to engineering
support.
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How radiotherapy works

• Radiotherapy ionises chemicals within cells. The crucial lesion is DNA strand breakage which may be repaired or
fixed and lead to apoptotic or mitotic cell death.
• Different types of normal and malignant cells vary in their susceptibility to ionising radiation. Clinical
radiotherapy schedules are designed to exploit the differences between normal tissues and tumours, so that as
many malignant cells as possible are killed, while damage to normal tissue is minimised. In radical curative
treatments, total radiation doses are close to the tolerance of normal tissues. In palliative treatments, usually low
doses are used.
• Some tumours, such as seminoma of the testis and lymphoma, are very sensitive to radiotherapy and can be
treated with relatively low doses, with an expectation of cure. Other tumours, such as melanoma of the skin and
glioblastoma multiforme in the brain, are notoriously resistant, even to large doses.
• A course of radiotherapy may be spread over days or weeks. This is known as fractionating, and the radiation
delivered to a patient in a single treatment session is called a fraction. Fractionating allows normal tissues to
repair much of the radiation damage, while tumour cells, which are less efficient at repair, do not recover. A beam
of radiation is called a field. A fraction consists of one or more fields delivered sequentially.
• In general, most modern radiotherapy is delivered with very high-energy, highly-focused beams, which can reach
deeper tumour tissues while depositing relatively small doses in the normal tissues through which they pass.
External-beam radiotherapy can be delivered by cobalt machines or linear accelerators, collectively known as
megavoltage machines.
• However, both acute (early) and late (chronic) side effects do occur. The side effects depend on several factors,
including the body site being treated, the volume of normal tissue irradiated (the larger the volume, the higher the
risk and severity of side effects), the total dose, and the rate of dose accumulation (the amount per week).
• Early side effects result from damage to proliferating tissues, such as the mucosa (lining) of the gastro-intestinal
tract or the skin. For example, radiotherapy to an abdominal tumour may damage the mucosa of the small bowel,
causing malabsorption and diarrhoea. Most patients recover completely.
• Late reactions occur at least three months after a treatment course has ended, and are usually permanent or
progressive. They usually result from damage to non-proliferating differentiated tissues, which cannot
compensate for cell death by dividing to replace lost cells. Once late effects occur, it is very difficult to reverse
them, but they are very uncommon.
• Late effects, such as second cancers, may occur many years after treatment. Even relatively low doses of radiation
may increase the risk of developing a malignancy. There is a long latent period after exposure. Leukaemia may
appear up to 7 years after exposure and solid tumours may develop 10 or 20 years later.
• Side effects of radiation can be minimised by meticulous planning and delivery of a course of radiotherapy.
Late-reacting tissues are particularly sensitive to the size of each radiation dose, so they can be protected to a
large extent by giving small fractions of radiation, provided the total dose is not too high.
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Role of radiotherapy in cancer management

Radiotherapy acts only on the irradiated tissues and can treat large areas of the body that may contain cancer. One
dose of radiotherapy kills about half the cancer cells in the treated region. This powerful effect means that
radiotherapy is also useful for palliation since low doses can result in significantly shrinking tumours with few side
effects.
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Curative radiotherapy
At least half of all patients for whom radiotherapy is prescribed, either alone or combined with surgery and/or
chemotherapy, are treated with the goal of achieving a cure.
Radiotherapy is used by itself when it is the best treatment available because of the known cure rate or because it is
likely to have fewer side effects. Examples include treatment for advanced cervix cancer, pituitary tumours,
deep-seated gliomas and arterio-venous malformations, nasopharyngeal cancer and early stage low-grade
lymphomas.
Because normal tissues recover from radiation damage better than tumours, it is possible to treat a cancer without
destroying the host organ. Even if surgically removing the organ would lead to a more definite initial cure, provided
radiotherapy is effective it is usually preferable so that the organ can be salvaged. Examples include larynx cancer
and prostate cancer.
In the case of large tumours, radiotherapy is often combined with surgery to enable the whole tumour site to be
treated without unduly affecting the patient’s ability to function normally.
In general, radiotherapy is combined with surgery when:
• organ preservation is desirable -- for example, breast conservation treatment consisting of lumpectomy and
radiotherapy
• the tumour is advanced with a high risk of local recurrence after surgery, for example, after a positive neck
dissection or before surgery for rectal cancer
• an inoperable cancer can be rendered operable -- for example, fixed rectal cancers
• close surgical margins need treating to prevent local recurrence.
Chemotherapy may improve the results of radiotherapy through several mechanisms outlined in Table 1.
Table 1: Beneficial interactions between radiotherapy and chemotherapy.
Mechanism Benefits Examples of

cancer
Spatial cooperation Radiotherapy cures the high volume local cancer and chemotherapy cures micro-metastases. Hodgkin’s
lymphoma
Rectal cancer
Independent toxicity Because radiotherapy and chemotherapy have different dose limiting toxicities, it is possible to deliver a Cervix cancer
higher anti-tumour dose with fewer side-effects than with radiotherapy alone. Oesophageal
cancer
Enhanced tumour Even if the effects of radiotherapy and chemotherapy are only additive, the steep dose response of Anal cancer
response tumours means that there can be greater rates of cure than with radiotherapy alone.
Protection of normal Some dose-limiting normal tissues can be protected by chemical modifiers such as amifostine, allowing Head and neck
tissues increases in the dose tolerated. cancers
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Palliative radiotherapy
Incurable cancer causes many problems from local effects and the effects of spread to distant organs. Radiotherapy is
the most effective treatment for people with incurable lung cancer. It can alleviate shortness of breath, cough and
haemoptysis. It is also useful for patients with advanced and incurable cancers that are causing symptoms in the sites
that they have arisen in. For breast cancer radiotherapy can control fungating masses, and for prostate cancer it can
be used to relieve urinary obstruction.
Short course radiotherapy is an excellent treatment for the palliation of bone pain, brain metastases and compression
of vital structures such as the spinal cord. In 80% of patients, a single dose of radiotherapy will relieve the pain
caused by metastatic cancer in the bone[2]. Radiotherapy is also very effective at relieving pain from compression of
nerves[3]. Radiotherapy can reverse the effects of spinal cord compression and prevent paraplegia.
Radiotherapy may be used to prolong the life of patients with incurable cancers such as high-grade gliomas. Longer
courses are required so that a sufficiently high dose may be given. Radiotherapy is more effective in these cases than
chemotherapy alone[4].
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References
[1] Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of
evidence-based clinical guidelines. Cancer 2005 Sep 15;104(6):1129-37 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
16080176].
[2] Steenland E, Leer JW, van Houwelingen H, Post WJ, van den Hout WB, Kievit J, et al. The effect of a single fraction compared to multiple
fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999 Aug;52(2):101-9 [Abstract
available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 10577695].
[3] Roos DE, Turner SL, O'Brien PC, Smith JG, Spry NA, Burmeister BH, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of
radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 2005
Apr;75(1):54-63 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 15878101].
[4] Laperriere NJ, Bernstein M.. Radiotherapy for brain tumors. CA Cancer J Clin 1994 [cited 2014 May 8] [Abstract available at http:/ /
onlinelibrary. wiley. com/ doi/ 10. 3322/ canjclin. 44. 2. 96/ abstract].
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Principles of medical therapy

22 October 2014 05:21:37
Author(s):
• Associate Professor Mathew George DM FRACP — Author
• Professor Max Schwarz MBBS (Hons) FRACP FACP FAChPM — Author
• Professor Ross McKinnon BPharm BSc (Hons) PhD — Author
page</ccabutton>
Associate Professor Mathew George DM FRACP, Professor Max Schwarz MBBS (Hons) FRACP FACP FAChPM, Professor Ross McKinnon
http:/ /
BPharm BSc (Hons) PhD, Cancer Council Australia Oncology Education Committee. Principles of medical therapy [Version URL:
wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Principles_of_medical_therapy. In: Sabesan S, Olver I, editors. . Sydney: Cancer
Council Australia. Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Introduction
Medications in cancer care are utilised to achieve the following goals:
1. to exert anti-cancer effects by killing or controlling cancer cells
2. to treat complications arising from anti-cancer therapies
3. to minimise the effects of cancer on body parts
4. to control symptoms from cancer and complications of cancer treatments.
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Medications to achieve cancer cell death or cancer control

Chemotherapy, small molecules, monoclonal antibodies and hormonal agents are used for this purpose.
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Chemotherapy
These agents achieve cancer control by several mechanisms. Some examples include:
1. damage to the DNA by various mechanisms during different phases of the cell cycle
2. inhibition of mitosis by interfering with microtubules.
Chemotherapy is used for the following purposes:
1. cure (e.g. leukaemia, lymphoma, germ cell tumours)
2. adjuvant, to eradicate micro metastasis following surgery or radiotherapy (e.g. breast, colon, ovarian cancers)
3. in combination with radiotherapy to sensitize radiotherapy (e.g. head and neck, rectum, lung ,cervical cancers)
4. palliation of symptoms and prolong survival (e.g. most metastatic cancers).
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Small molecules
Many new medications inhibit various kinases along the signal transduction pathways that are associated with cell
proliferation, survival, metastasis and angiogenesis.[1] Most of these agents inhibit the activity of these kinases by
competing for ATP binding.
Medication Target Kinases Current Use
Imatinib Bcr-abl Chronic myeloid leukaemia, gastrointestinal stromal tumour
Erlotinib,gefitinib EGFR Non-small cell lung cancer
lapatinib Her1 and 2 receptor Breast cancer
Sunitinib PDGFR, VEGFR, Kit Renal, GIST
Afinitor mTOR Breast, renal
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Monoclonal antibodies
Humanised monoclonal antibodies cause cancer cell death by the following mechanisms:[2]
1. direct action of antibody (receptor blockade or agonist activity, delivery of a drug or cytotoxic agent)
E.g. Trastuzumab in HER2 positive breast cancer
2. Complement dependant cytotoxicity
3. Antibody-dependent cellular cytotoxicity (ADCC)
E.g. Rituximab binds to CD 20 on lymphoma cells and stimulate ADCC
4. Regulation of T cell function
E.g. Ipilimumab
In cancers like melanoma, antigen presenting cells (APC) present tumour antigen to the T cell via MHC
complex. When tumour antigen binds with T cell receptors (B7 on APC with B28 on T cells), this leads to T
cell activation and release of inflammatory proteins. When intracellular CTLA4 molecule is expressed on the
surface of the T cell, binding of CTLA4 to B7 turns off the T cell activation. Ipilimumab binds to the CTLA4
and inhibit the binding of CTLA4 and B7. This means the T cell remains activated. Ongoing release of
inflammatory proteins is expected to exert tumour control.
5. Specific effect on tumour vasculature and stroma
E.g. Bevacizumab binds to VEGFR on stromal tissues and inhibit angiogenesis within cancer deposits.
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Hormonal agents
These agents inhibit the actions of various hormones on hormone responsive cancer cells. Side effects are usually
related to hormone depletion.
Medication How it works Used in
Tamoxifen Oestrogen receptor blockade Breast cancer
Aromatase inhibitors Inhibition of conversion of androgens to oestrogen Breast cancer
Gonadotrophin releasing Decrease the ovarian production of oestrogen and testicular production of Breast cancer and prostate
hormone(GnRH) testosterone cancer
Anti androgens Androgen receptor blockade Prostate cancer
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Managing chemotherapy side effects

Most side effects are due to non-specific damage to normal cells. They do not always occur and not all the patients
experience the same side effects.[3]
Examples:
1. Nausea, vomiting -- Some drugs are more emetogenic than others; prophylactic antiemetic medications use can
decrease the incidence. Details are found in the “Medical oncology hand book for junior medical staff”[3] accessed
via the following link: http://www.health.qld.gov.au/townsville/Documents/clinicians/
med-onc-jnr-handbook.pdf
2. Alopecia -- Not all the medications cause alopecia. Most breast cancer medications cause complete alopecia;
most colorectal regimens do not cause complete alopecia.
3. Myelosuppression and neutropenic sepsis -- Neutropenic sepsis is treated with broad spectrum antibiotics. Risk of
neutropenia can be reduced by the use of granulocyte colony stimulating factors. Anaemia and thrombocytopenia
can be treated with transfusions of packed red cells and platelets respectively.
4. Fatigue
5. Infertility -- Not all the drugs cause this side effect. It is important that pregnancy is avoided during and at least
12 months after completing chemotherapy. In ER negative cancers, ovarian suppression during chemotherapy can
reduce the risk of infertility.
6. Effects on other organs -- E.g. cisplatin and neuropathy, anthracyclines and cardio toxicity, bleomycin and
interstitial pneumonitis.
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Medications to minimise the impact of cancer on organs

Examples:
Bisphosphonates (e.g. zelodronic acid, pamidronate) or RANKL inhibitor denosumab can decrease the incidence of
skeletal related events in patients with bone metastasis from various cancers, including breast, prostate and multiple
myeloma. Skeletal-related events include fracture, pain and hypercalcemia. These agents can also decrease the rate
of osteoporosis/osteopenia caused by anti-hormonal agents like aromatase inhibitors.
Note: RANK is a surface receptor on pre-osteoclasts. RANK is activated by RANKL (RANK ligand) found on the
surface of osteoblasts. Binding of RANK to RANKL leads to maturation of pre-osteoclasts to mature osteoclasts and
subsequent destruction of the bones.[4]
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Managing symptoms caused by cancer or complications of treatments

When we attempt to treat cancers, it is important to make sure the quality of life of the patients is improved or
maintained by controlling the cancer-related symptoms and treatment-related complications. Patients with metastatic
disease can gain important benefits when their care is shared between various health professionals, including
palliative care professionals.
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References
[1] Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009 Jan;9(1):28-39 [Abstract
[2] Scott A, Wolchok J, Old L. Antibody therapy of cancer. Nature Reviews Cancer 2012 Apr [cited 2014 Jul 22];12:278-287 [Abstract available
at http:/ / www. nature. com/ nrc/ journal/ v12/ n4/ abs/ nrc3236. html].Cites::Citation:Scott A, Wolchok J, Old L 2012
[3] Joshi A, Otty Z, Sabesan S, Varma S. Medical oncology hand book for junior medical officers. Townsville: Department of Medical Oncology
Townsville Cancer Centre; 2013 [cited 2014 Jul 22] Available from: http:/ / www. health. qld. gov. au/ townsville/ Documents/ clinicians/
med-onc-jnr-handbook. pdf. Cites::Citation:Joshi A, Otty Z, Sabesan S, Varma S 2013
[4] McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low
bone mineral density. N Engl J Med 2006 Feb 23;354(8):821-31 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
16495394].Cites::Citation:McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al 2006
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Principles of palliative care

18 September 2014 00:56:39
Author(s):
• Dr. David Thorne MBBS FAChPM — Author
• Professor Carole Steketee BA(Ed) BEd(Hons) PhD — Contributor
page</ccabutton>
Thorne, D, Steketee, C, Cancer Council Australia Oncology Education Committee. Principles of palliative care [Version URL: http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Principles_of_palliative_care. In: Sabesan S, Olver I, editors. . Sydney: Cancer
Introduction
Palliative care arose from the early Hospice Movement founded by Dame Cicely Saunders (1918-2005) in the UK.
Dame Cicely was a nurse who re-trained as a medical social worker and eventually as a physician. She researched
and championed effective pain management and promoted a more compassionate and holistic approach to patient
care. Canadian urological surgical oncologist Dr Balfour Mount readily took up her reforms but because the word
“hospice” did not translate well into the French-speaking province of Quebec, the term “palliative care” was adopted.
The World Health Organization has defined palliative care as “an approach that improves the quality of life of
patients and their families facing the problem(s) associated with life-limiting illness, through the prevention and
relief of suffering by means of early identification and impeccable assessment and treatment of pain and other
problems—physical, psychosocial and spiritual.”[1] Currently, more than half of the world’s countries have some
form of palliative care services.

The principles of contemporary palliative care challenge a concept of cancer management that involves sometimes
debilitating therapies and interventions, proceeding doggedly until the decision is made to “withdraw active
treatment” and opt instead for comfort care and quality of life. Clinicians now opt for a more collaborative and
cooperative management plan whereby symptom management, supportive care and amelioration of psychosocial,
existential and spiritual concerns are acknowledged and managed conjointly between the primary care practitioners,
oncologists and an interdisciplinary palliative care team. A patient may both appreciate and benefit from palliative
care input early in the course of their cancer journey, and may prefer to negotiate a more gradual transition from
active cancer treatments to management with primarily palliative care intent.
A reason for not discussing or offering palliative care in a more timely fashion is the concern that it will cause
patients to lose hope. However, empathic and skillful communicators argue that it is possible to be honest without
destroying all prospect of hope, and that the intent of treatment ought to be clearly presented to patients and their
families.
The general public, and some health care practitioners, often misunderstand the contemporary definition of palliative
care. There remains the mistaken belief that palliative care is only about the last few days or weeks of life. This
belief is reinforced by the late referral of patients when they are seen to be “actively dying”. To some extent, the
limited number of palliative care services in Australia and New Zealand, and the limited resources and staff available
to meet palliative care needs, exacerbates this situation.
When is it appropriate to request the involvement of palliative care?

Palliative care is a recognised specialty that is uniquely needs-based. Palliative care is not defined by a diagnosis,
organ or system (as in cardiology or urology), but rather by the fact that any patient with a potentially life-limiting
illness may experience suffering. That suffering may arise from the pathophysiological effects of a cancer (or
non-cancer) diagnosis, the realisation of their own mortality, or the adverse effects of a range of surgical, physical or
pharmacological therapies. If a patient is suffering persistent or difficult-to-control symptoms or emotional distress,
then consultation with a palliative care practitioner should be considered.
Palliative care practitioners have considerable expertise in managing pain, nausea and vomiting, dyspnoea, delirium
and the spectrum of symptoms experienced by cancer patients. They work collaboratively in an interdisciplinary
team comprising a range of providers from medical, nursing, allied health, spiritual and supportive disciplines. The
focus of this care is to anticipate problems that might arise and to minimise the impact of the progressing illness so
that patients can experience the maximum function and comfort that is possible within the limits of their illness.
It is important to guard against the use of “palliative” as a label that defines a patient or that describes the extent of,
or limitations to intended treatment. The spectrum of investigations and interventions consistent with a palliative
approach is guided by goals and expectations of individual patients and family, and by accepted standards of health
care rather than being bound by preconceptions of what is or is not "palliative".
Palliative care is very often for people with cancer, but is also applicable to, and provided for, patients with a range
of non-malignant life-limiting conditions. Increasingly, palliative care is provided to cancer patients in parallel to
active treatments such as surgery, chemotherapy or radiation therapy and there is emerging evidence that the
“parallel model of palliative care” improves patient and family comfort.
Despite recent advances in the prevention, detection and treatment of malignant disease, cancer remains one of the
most dreaded diseases of our age. The role of the healthcare professional is not only to treat, but also to support,
guide and empower the patient along their cancer journey. The national code of conduct for all doctors registered to
practice medicine in Australia imposes a professional obligation to provide or arrange appropriate palliative care for
all patients who need it or request it.
Case study
A 40-year-old married woman with a 5-year-old daughter presented to the emergency department of a peripheral
regional hospital with a 2 week history of increasing pelvic and left flank pain, and urinary symptoms. Clinical
examination was limited and vaginal speculum examination not possible because of severe pain. CT revealed a mass
anterior to the vagina, and she was transferred to the gynaecologic oncology hospital in the capital city. Due to
severe pain, the palliative care consultant was asked to advise on and supervise pain management. An examination
under anaesthesia confirmed infiltrating tumour in the vagina anteriorly and posteriorly with palpable tumour
between the rectum and vagina. Cystoscopy and sigmoidoscopy were normal. Satisfactory analgesia was attained,
management of opioid side effects of constipation and sedation were adequately controlled, and the patient was
discharged. The formal diagnosis was Stage 3B Grade 3 squamous cell carcinoma of the vagina.
The patient was treated as an outpatient with radiation therapy and concurrent chemotherapy.
She was referred to the local community palliative care team and was visited at home by the visiting palliative care
physician who diagnosed a pulmonary embolism.
Further palliative care physician reviews were required 9 months later when a vesico-vaginal fistula was identified
and PET scans also revealed new disease activity in the left pelvic side-wall.
Some 1 year and 4 months after her initial diagnosis, the patient was requiring regular analgesic reviews by the
community palliative care nurses, and the palliative care physicians negotiated an inpatient admission at a
metropolitan specialist hospice for review and possible transition to methadone for control of her complex pain
syndrome.
The physicians and nurses at the hospice successfully changed her to methadone and also negotiated with the
orthopaedic surgeons at a major hospital to accept her for a left THR because of malignant erosion of the
acetabulum.
Monitoring of symptoms, adjustments to analgesia, financial and practical community supports necessitated frequent
home visits by palliative care doctors, nurses and a social worker. Although the patient was planning an overseas
flight to undergo complementary and alternative medicine (CAM), she was by this time emaciated in the upper body,
but grossly lymphoedematous in the lower limbs. The palliative care physician again visited her in her home, and
expressed concern about the risks of a prolonged international flight. The palliative care physician and community
palliative care nurses negotiated a re-admission into an inpatient hospice bed, and counselors at the hospice were
requested to address concerns for the patient and her parents, husband and daughter. She died peacefully in the
hospice 2 years and 10 months after her initial diagnosis and referral to palliative care. The inpatient hospice and
community palliative care team have jointly provided bereavement counseling and ongoing support to the family
after her death.
This case illustrates early palliative medicine involvement, collaboration between a spectrum of disciplines within
palliative care, and cooperation with oncologists and orthopaedic surgeons to achieve optimal outcomes. As in this
case, a network of palliative care providers from specialist consulting rooms, hospital wards, domiciliary visiting
services and inpatient hospice may contribute significantly to a patient and loved ones comfort and support
throughout the course of a difficult cancer journey.
References
[1] World Health Organization. WHO Definition of Palliative Care. [homepage on the internet] World Health Organization; 2016 Oct 8 [cited
2014 May 8]. Available from: http:/ / www. who. int/ cancer/ palliative/ definition/ en/ .
Cancer survivorship
12 September 2014 05:43:12
Author(s):
• Pamela Bell PhD — Author
• Professor Bogda Koczwara BM BS FRACP MBioethics — Author
page</ccabutton>
http:/ / wiki. cancer.
Bell, P, Koczwara, B, Cancer Council Australia Oncology Education Committee. Cancer survivorship [Version URL:
au/ oncologyformedicalstudents/ Cancer_survivorship. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia.
Care of cancer survivors

Approximately 65% of people diagnosed with cancer in Australia will survive more than five years after diagnosis
and active treatment.
Objectives of follow-up care are to achieve the following:
1. Detection of earlier recurrence
Examples: Local recurrence of breast cancer in an irradiated breast may be curable by surgery, whereas
metastasis to bone is not curable. Therefore, regular mammography is recommended for patients who had
previous breast cancers to detect local recurrence as well as contralateral breast cancer; whereas bone scans or
CT scans are not recommended.
2. Management of side effects and late effects of cancer treatment
Examples: Patients on aromatase inhibitors are prone to develop osteopenia or osteoporosis. Regular bone
densitometry can detect deterioration in bone health that can be treated with bisphosphonates.
3. Health promotion for primary and secondary prevention
Examples: Reduction in the rate of smoking can decrease the risk of further smoking related cancers in
patients who survive smoking related cancers, such as head and neck and lung cancers. Follow-up visits also
offer opportunities to discuss other lifestyle factors, such as diet and exercise.
4. To address other concerns
Fear of recurrence and uncertainty about the future are common issues that survivors identify as needing help
with. A recent (2009) study found that 5 years following diagnosis, most survivors had adjusted well and
reported levels of anxiety and depression similar to Australian population norms. A recent meta-analysis
suggests that anxiety is more likely to be a long-term problem than depression in both patients with cancer and
their spouses compared with healthy controls.
Duration of follow-up varies from cancer to cancer. In addition to history and examination, tumour markers and
imaging studies can be useful. In some cancers like breast cancer, extensive imaging studies haven’t been shown to
improve survival.
Case study
Julie, 62 years, is an early breast cancer survivor currently on aromatase inhibitor therapy following lumpectomy and
radiotherapy. Follow-up is to monitor for side effects and late effects of treatment and to detect recurrent disease.
In her case, follow-up should involve:
1. history of side effects including arthralgia and hot flushes
2. physical examination of breast, axillary and supraclavicular areas to detect early recurrence
3. annual breast imaging tests (mammogram and/or ultrasound)
4. bone densitometry at required intervals to detect deterioration in bone health due to aromatase inhibitor.
She needs to be reassured that unless she has symptoms suggestive of metastasis, bone scans and CT scans have not
been found to improve survival outcome. Survivors’ reactions are individual -- some patients may be reassured by
regular follow-up tests, while others may become very anxious. It is important to be aware that annual check-ups can
be a cause of stress for cancer survivors and irrespective of their reaction, survivors benefit from the emotional
support of a clinician who is willing to listen to their fears and provide an opportunity to talk about how they are
feeling.
References
1. Jefford M. Improving outcomes for cancer survivors in Australia. Australia: Cancer Forum; 2009 Nov [cited
2014 Jun 5] Available from: http://www.cancerforum.org.au/Issues/2009/November/Forum/
Overview_Improving_outcomes_for_cancer_survivors_in_Australia.htm.
2. Cancer Australia. Follow-up after breast cancer. [homepage on the internet] Australia: Cancer Australia; 2012
Sep 17 [cited 2014 Jun 5; updated 2012 Sep 17]. Available from: http://canceraustralia.gov.au/affected-cancer/
cancer-types/breast-cancer/life-after-breast-cancer/follow-after-breast-cancer.
3. Breast Cancer Network Australia. Living with breast cancer. [homepage on the internet] Australia: BCNA; 2010
[cited 2014 Jun 5; updated 2010]. Available from: http://www.bcna.org.au/living-breast-cancer.
4. American Cancer Society. How is breast cancer staged? [homepage on the internet] America: American Cancer
Society, Inc; 2014 Dec 1 [cited 2014 Jun 5; updated 2014 Dec 1]. Available from: http://www.cancer.org/
cancer/breastcancer/detailedguide/breast-cancer-staging.
5. Sklar HL. Who gets breast cancer and who survives? [homepage on the internet] WebMD; 2014 Jan 1 [cited 2014
Jun 5; updated 2014 Jan 1]. Available from: http://www.webmd.com/breast-cancer/features/
who-gets-breast-cancer-who-survives.
6. National Rural Health Alliance, Clinical Oncology Society of Australia. Cancer in rural Australia. Canberra:
National Rural Health Alliance; 2012 Jan [cited 2014 Jun 5] Available from: http://ruralhealth.org.au/sites/
default/files/publications/fact-sheet-08-cancer-rural-australia.pdf.
7. Mitchell AJ. Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a
systematic review and meta-analysis. Lancet Oncol 2013 Jun 5 [cited 2014 Jun 5];14(8):721-732 [Abstract
available at http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70244-4/abstract].
8. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, et al. Chronic health
conditions in adult survivors of childhood cancer N Engl J Med 2006 Oct 12;355(15):1572-82 [Abstract available
at http://www.ncbi.nlm.nih.gov/pubmed/17035650].
Doctor patient communication and psychosocial

care
18 September 2014 00:55:57
Author(s):
• Professor Martin Henry Norman Tattersall AO MA MD MSc FRCP FRACP MBBChir — Author
page</ccabutton>
Tattersall, M, Cancer Council Australia Oncology Education Committee. Doctor patient communication and psychosocial care [Version URL:
http://wiki.cancer.org.au/oncologyformedicalstudents_mw/index.php?oldid=, cited 2016 Oct 8]. Available from http://
wiki. cancer. org. au/ oncologyformedicalstudents/ Doctor_patient_communication_and_psychosocial_care. In:
Cancer is the most feared disease in most communities, and all age groups are at risk. Cancer is life threatening, but
potentially curable. Cancer treatments are feared because of their distressing side effects. For many types of cancer,
patients can participate in choosing between treatments which have different side effects and similar outcomes. Fear
of recurrence after cancer treatment is a concern for many patients. Some cancers are preventable, and for many
patients, early diagnosis is important for the best outcomes. These features of cancer and its treatment generate
particular information needs for patients and their families which are compounded by the multitude of health
practitioners who participate in cancer care and control.
Pamphlets prepared for cancer patients describing aspects of cancer care according to cancer type, disease extent and
treatment goals are widely available, and these can improve patient understanding of their situation. Pamphlets
describing different cancer treatments and their side effects may reduce patient misunderstanding and fear, and
prompt question-asking. Doctors caring for cancer patients should be aware of the information contained in these
widely available pamphlets.
Communication in the cancer care setting must inform and support patients receiving a diagnosis of a
life-threatening illness. Patients frequently misunderstand or forget important information they need to participate in
decisions about their care. Patient misunderstanding may be compounded by inconsistent information given by
different members of the cancer care team. Patient denial is a coping strategy which enables living with uncertainty,
and may underpin hope. These considerations should guide communication with cancer patients and their families.
Tables 1-2 summarise clinician behaviours and the value of communication aids in cancer care consultations. Table
3 outlines the range of topics which are important in different phases of a cancer journey.
The substance of information given to cancer patients should be documented in patient records and this information
should be communicated to the general practitioner and members of the hospital-based treatment team.
Patients with advanced cancer want information about its effects on their life expectancy. Most oncologists find it
difficult to estimate and explain survival time, and frequently they are reluctant to discuss prognosis. Recent research
has found that most people with advanced cancer judge presentation of best case, worst case and typical survival
scenarios preferable and more helpful and reassuring than presentation of just the median survival time.
Cancer patients commonly receive chemotherapy and/or invasive investigations in the last days of their life, and
sometimes are inappropriately intubated/admitted to intensive care. Discussing end of life (EOL) care preferences
with incurable cancer patients is frequently not undertaken until the last days of life or at all. Patients who report
talking with their oncologist of their EOL care preferences have a better quality of death. Facilitating the preparation
of an Advance Care Plan to document patient’s EOL care preferences is a valuable means of promoting patient
discussion with their close family about their EOL preferences.
Table 1: Some patient-centred clinician behaviours which enhance the quality of a cancer patient consultation
Non-verbal behaviours Verbal behaviours
Maintaining eye contact Reviewing purpose of the consultation
Forward leaning to indicate attentiveness Asking patient understanding of their situation
Nodding to indicate understanding Encouraging patient participation and suggesting questions
Use of diagrams to inform understanding Acknowledging uncertainty and options for care
Reviewing images and results with the patient Checking patient understanding
Table 2: Communication aids developed and studied in cancer patient care
Communication aids in cancer patient care
Communication skills training courses change doctor and nurse consultation behaviours at least in the short term, but improved patient outcomes are
not convincingly documented.
Providing question prompt lists increases patient participation in oncology consultations, and increases question asking about the outcomes of care.
Patients do not recall most information provided during oncology consultations. Consultation audio-recordings enable patients to review
information provided. Studies report that most consultation recordings are listened to by patients and their families, and recordings are valued
particularly by patients from a non-English speaking background.
Decision aids have been developed for and evaluated in patients considering chemotherapy for advanced and incurable cancer, and for those
considering adjuvant chemotherapy.
Providing patients with copies of letters from cancer specialists to the referring doctors is valued by patients and enhances their recollection of
consultations.
Table 3: Context of doctor patient communication during the cancer experience
Fear of cancer * Relevance of family history

* Guilt related to smoking, ignoring early signs of cancer
Diagnosis of cancer * Fear of treatment

* Why me?
Staging * Fear of incurability

* Fear of treatment
Treatment * What is the goal?

* When do I know if I am cured?
* How do I know if treatment is working?
* Choosing between treatment options
Recurrence * Can the cancer be cured/controlled?

* Is treatment worthwhile?
* Do I need treatment now when I am well?
End of life * How long have I got?

* How will I die?
* Will I be in pain?
* What should I tell the family?
Ethics and professional development

22 October 2014 05:29:57
Author(s):
• Darren Starmer BN MEdStds (Hons) — Author
page</ccabutton>
Starmer, D, Cancer Council Australia Oncology Education Committee. Ethics and professional development [Version URL:http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Ethics_and_professional_development. In: Sabesan S, Olver I, editors. .
Sydney: Cancer Council Australia. Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
“It is not only what we do, but also what we do not do, for which we are accountable.” (Molière).
Medical ethics principles

Medical ethics is founded upon 4 moral obligations (principles):
• Autonomy: Competent adults have the right to decide what happens to them, regardless of the consequences their
decisions may have upon their health and wellbeing. For example, a patient may decide to refuse treatment, even
if doing so will end their life.
• Beneficence: A doctor must endeavour to achieve the best outcome for every patient and to improve the patient’s
health. Attention must be given to the idiosyncrasies of the individual patient, the disease process and potential
outcomes.
• Nonmaleficence: A doctor must avoid harming patients at all costs. Careful consideration should be given as to
whether the risk associated with a particular course of action outweighs the benefit to the patient.
• Justice: A doctor’s decisions must be fair, transparent and defensible.
Beneficence and nonmaleficence can be viewed as opposing ends of a continuum upon which the risks and benefits
of a particular course of action can be plotted. For example, considering the risk of death from general anaesthesia
against the benefit of surgery to treat colon cancer, or whether commencing a patient on a third line
chemotherapeutic agent known to have severe side effects outweigh the potential benefit to the patient if the
expected outcome is to extend their life by three months? When considering any risk-benefit ratio, the aim should be
one of an overall benefit to the patient. This is often referred to as beneficence without maleficence and whilst
desirable, it may not always be achievable. Unfortunately, ethics (like much of medicine) is not always black and
white, and careful consideration is necessary to navigate the grey areas.
The aforementioned principles have formed the basis of several expanded codes of ethics, which explicitly detail
obligations and behavioural guidelines for doctors. These commonly cover such areas as (but are not limited to),
patient care, clinical research, self-regulation and professional conduct. Examples of these can be seen in the
resources listed at the end of this chapter. It is important to be aware of all guidelines produced by the licensing
bodies with which you are registered, as well as those of your employer.
Ethical dilemmas commonly occur in cancer and palliative care in areas such as informed consent, treatment options
(e.g. cost/benefit ratio, early phase clinical trials), disclosure of information regarding disease (e.g. communication
of prognosis, whether the patient understands the information provided, or family member requests not to disclose
information to the patient), the introduction of end of life care and patient “do not resuscitate” preferences. Advances
in medical knowledge and discovery also give rise to discussion regarding their ethical merit (e.g. stem cell
research). Issues such as cost and availability of resources place additional pressures on fair and equitable delivery of
cancer care, as was recently highlighted by the limited supplies of chemotherapy agents. How does one decide who
receives limited optimal treatment and who receives a (lesser) alternative? Debate surrounding the cost benefit ratio
of expensive chemotherapeutic agents has been an ongoing issue of dispute for several years.
Clinical trials are commonplace in the treatment of cancer patients and the ethical conduct of human research is
paramount to ensuring that the health and wellbeing of patients are maintained and protected. Whilst Albert Moll
argued against the unethical clinical research on patients in the late 19th century[1], the basis of modern ethics in
research stemmed from the results of the Nuremburg trials, which were conducted after the atrocities of World War
II. In 1964 the World Medical Association published the Declaration of Helsinki, with the aim of ensuring that
patients taking part in clinical research have their rights, wellbeing and safety placed ahead of the consideration of
research (i.e. the patient comes first).[2][3] The Declaration of Helsinki formed the basis for the development of good
clinical practice (GCP) guidelines, which govern the conduct of clinical trials in Australia.[3]
Cancer patients are often vulnerable and therefore may be emotionally dependent upon their doctor, which may
influence their decision regarding treatment options, including participation in clinical trials.[4] Ensuring that the
patient fully understands the aim of the trial as well as the risks and benefits is critical to their participation. A phase
I trial to evaluate the safety of an experimental drug is a far cry from a phase II trial in which its efficacy is being
evaluated and patients may participate believing that the aim of the trial is to treat their cancer. Hellman and Hellman
question whether the dichotomous nature of the doctor as a physician and a scientist contradict one another in the
setting of the randomized control trial.[4] The authors argue that on one side the physician has a duty of care to the
patient, whilst the scientist has an obligation to the veracity of the trial. Accuracy and transparency are essential to
providing good informed consent, as is evaluating whether the patient has understood the information provided to
them.
Clinical trials may also raise issues in relation to frequency of imaging, which may exceed practice guidelines or
hospital policy, and expose the patient to high levels of radiation. The use of non-diagnostic tissue
sampling/bio-banking is another aspect of clinical trials that is often viewed as pushing ethical boundaries.
As with cancer, ethics is not restricted to one domain or area of medicine. Regardless of your future career path,
ethical conduct and professionalism will underpin and influence your clinical practice, research and education, and
will help define you as a doctor. Your core values, the way you interact with your patients, peers and the community
all draw upon these (often unconscious) moral values, beliefs and behaviours.
Of note, the majority of disciplinary action taken against medical practitioners is for breaches of professional
conduct and/or unethical behaviour. When looking at mandatory notifications in 2013, the Medical Board of
Australia reported 299 notifications for all states and territories. The grounds for those reported in all states (with the
exception of NSW) are shown in Table 1.
Table 1: Mandatory Notifications to the Medical Board of Australia about Medical Practitioners in 2013[5]
Number of Grounds for Notification

Notifications
138 The practitioner was placing the public at risk of harm due to practice that constituted a significant departure from
accepted professional standards
36 The practitioner had an impairment that was placing the public at risk
18 The practitioner had practised under the influence of alcohol or drugs
19 Sexual misconduct in connection with practice
1 Not specified
The implications of unprofessional or unethical behaviour are severe and can lead to fines, reprimands, suspended or
cancelled registration with licensing bodies, and even criminal proceedings.
A comprehensive overview of medical ethics is beyond the scope of this chapter and the following resources are
recommended for further information:
1. Australian Medical Association. AMA code of ethics - 2004. Editorially revised 2006. [homepage on the internet]
ACT: Australian Medical Association Limited; 2004 [cited 2014 May 29; updated 2006 Nov 20]. Available from:
https://ama.com.au/codeofethics
2. AHPRA. Australian health practitioner regulation agency. [homepage on the internet] Australia: AHPRA; 2014
[cited 2014 May 29; updated 2014 Feb 4]. Available from: http://www.ahpra.gov.au/
3. National Health and Medical Research Council. Australian clinical trials: Good clinical practice (GCP) in
Australia. [homepage on the internet] Australia: National Health and Medical Research Council; 2014 Jan 1 [cited
2014 May 29; updated 2014 Jan 1]. Available from: http://www.australianclinicaltrials.gov.au/node/36
4. World Medical Association. WMA international code of medical ethics. [homepage on the internet] France:
World Medical Association, Inc.; 2014 May 29 [cited 2014 May 29; updated 2014]. Available from: http://www.
wma.net/en/30publications/10policies/c8/index.html
5. Australian Medical Students' Association. Australian medical students' association: Code of ethics. Australia:
Australian Medical Students' Society; 2003 [cited 2014 May 29] Available from: http://media.amsa.org.au/
internal/official_documents/internal_policies/code_of_ethics_2003.pdf
References
[1] Maehle AH. 'God's ethicist': Albert Moll and his medical ethics in theory and practice. Med Hist 2012 Apr 1 [cited 2014 May
20];56(2):217-36 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 23002294].
[2] World Medical Association. World medical association declaration of Helsinki: ethical principles for medical research involving human
subjects. JAMA 2013 [cited 2014 May 20];Vol. 310, No. 20 [Abstract available at http:/ / jama. jamanetwork. com/ article.
aspx?articleid=1760318].
[3] Department of Health and Ageing Therapeutic Goods Administration. The Australian clinical trial handbook: a simple, practical guide to the
conduct of clinical trials to international standards of good clinical practice (GCP) in the Australian context. Canberra: Commonwealth of
Australia; 2006 Mar 1 [cited 2014 May 20] Available from: http:/ / www. australianclinicaltrials. gov. au/ node/ 36.
[4] Hellman S, Hellman DS. Of mice but not men. Problems of the randomized clinical trial. N Engl J Med 1991 May 30 [cited 2014 May
20];324(22):1585-9 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 2027362].
[5] The Australian Health Practitioner Regulation Agency. Regulating health practitioners in the public interest: annual report 2012/13.
Brisbane: AHPRA; 2013 Jan 1 [cited 2014 May 20] Available from: http:/ / www. ahpra. gov. au/ Publications/ Corporate-publications. aspx.
Cites::Citation:The Australian Health Practitioner Regulation Agency 2013
Breast cancer 61
Breast cancer
12 September 2014 06:02:37
Author(s):
• Dr. Anita Skandarajah MBBS MD FRACS — Author
page</ccabutton>
Skandarajah, A, Cancer Council Australia Oncology Education Committee. Breast cancer [Version URL: http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Breast_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available from:
Epidemiology
Breast cancer is the most commonly diagnosed cancer in women in Australia. By 85, one in 8 women will be
diagnosed with breast cancer. It is 100 times more common in women than men with 1 in 784 men diagnosed by age
85. In 2012, more than 14600 people had a breast cancer diagnosis, and >2860 people died of breast cancer in 2010.
In each state, the incidence has increased by approximately 2% each year. The mammographic screening program
BreastScreen, introduced in the 1980s, has been attributed with this increase. The greatest increase in incidence is in
the women aged 50-69 years targeted by BreastScreen.
Although women from Indigenous communities, Southern Europe and Asia have lower rates of breast cancer,
environmental and lifestyle factors play a role. When studying migrant communities in the higher risk areas, women
acquire the risk of the host community.
Risk factors
For most sporadic breast cancer, age and female sex are the two key risk factors with most women diagnosed after
menopause (median age 59). Family history especially in first or second-degree relatives is also important.
Oestrogen exposure has a role in the genesis of breast cancer, with early menarche, late menopause, and nulliparity
being risk factors, and parity, history of breast feeding being protective. Although the risk of breast cancer whilst on
the oral contraceptive pill is higher, the overall risk during one’s lifetime is small due to the young age at which
women are on the pill. Hormone replacement therapy can increase the risk of breast cancer.
Other lifestyle related risk factors increase high caloric intake during childhood and adolescence, obesity and
alcohol.
Some breast pathologies increase the risk of breast cancer such as ductal carcinoma in situ (DCIS), lobular
carcinoma in situ and atypical ductal hyperplasia.

Breast cancer can be inherited and although up to 30% of women may have a family history, only 1-2% of the breast
cancer is attributable to the BRCA1 and BRCA2 genes. Risk factors for carrying a mutation include 3 or more first
or second degree relatives with breast cancer, or two relatives with significant risk factors such as male breast cancer,
ovarian cancer under age 50, breast cancer under age 40, bilateral breast cancer, Ashkenazy Jewish heritage, or
breast and ovarian cancer in the same patient. Other gene mutations predisposing to breast cancer include P53,
PTEN, CDH1 and Peutz-Jeghers.
Breast cancer 62
Approximately 55% of women present with screen-detected cancers. Other presentations include a palpable mass,
skin tethering and nipple discharge. Only rarely does breast cancer present pain and erythema consistent with rare
inflammatory breast cancer.
Diagnosis and staging

Although masses may be clinically suspicious, radiological diagnosis is obtained with mammogram and ultrasound
and a core biopsy provides the definitive diagnosis. Although a fine needle aspiration may show a cancer,
histopathology is preferred to differentiate between DCIS and invasive cancer and thus plan appropriate surgical
management. Ultrasonography of the axillary lymph nodes is also standard and abnormal lymph nodes are assessed
pre-operatively with a fine needle aspiration.
Pre-operative staging with CT chest, abdomen and pelvis and a bone scan are not indicated unless a neo-adjuvant
approach is considered or there is a suspicion of metastatic disease.
Tumour markers such as Ca 15.3 are not sensitive for breast cancer.
Prognosis and mortality

Tumour size, higher grade, lymph node metastases, and oestrogen-receptor (ER) and progesterone-receptor (PR)
negativity are poor prognostic factors in breast cancer.
However, mortality rates have decreased by about 1% each year. From 2006-2010, the 5-year breast specific survival
was 89% compared to 72% from 1982-1986.
Breast cancer is truly multidisciplinary, involving the surgeon, medical oncologist, radiation oncologist, breast
cancer nurses, psychologists, plastic surgeons, palliative care physicians, and others. Patient care is generally
discussed in preoperative and postoperative multidisciplinary meetings.
Early breast cancer

Surgery for early breast cancer usually involves a wide local excision (WLE) and sentinel node biopsy (SNB). The
aim is to remove the mass with a margin of normal tissue and minimise morbidity to the axilla by removing the
sentinel nodes and not all the nodes. Pathologically confirmed lymphadenopathy (either preoperative or after SNB)
requires an axillary dissection.
Provided adjuvant radiotherapy is given, there is no difference in overall survival between women who undergo
breast conservation (WLE and adjuvant radiotherapy) versus mastectomy. Contraindications to breast conservation
are previous radiotherapy, large tumour size and small breast resulting in poor cosmesis and contraindication to
radiotherapy such as active SLE.
Adjuvant radiotherapy to the breast is offered to most women after breast conservation to prevent local recurrence.
Women with small tumours <1 cm who are over 70 do not require adjuvant radiotherapy.
Most cancers (80%) are ER positive and therefore an anti-oestrogen agent is used for 5-10 years to decrease local
recurrence, prevent systemic spread and prevent new primaries in the ipsilateral and contralateral breast. Examples
include selective oestrogen receptor modulators, such as tamoxifen, and aromatase inhibitors, such as anastrozole.
Chemotherapy may be indicated in early breast cancer if a patient has poorer prognostic features such as young age,
higher grade and receptor negative disease. HER-2 is a molecular marker that confers a risk towards local recurrence
and systemic recurrence. As such, a HER-2 positive patient with an early breast cancer will be offered trastuzamab, a
monoclonal antibody targeting the HER-2.
Breast cancer 63
Locally advanced breast cancer

Some women present with locally advanced cancers that are fixed to the pectoralis muscle or involved skin, and are
considered non-operable. Staging is performed in these women, and if clear, a neoadjuvant approach with
pre-operative chemotherapy is undertaken in order to make the tumour ‘operable’ and control micrometastatic
disease.
Metastatic disease
Breast cancer spreads initially through the lymphatics to draining lymph nodes and haematogenous spread is most
commonly to bone, liver and lungs. Bone-only metastatic disease can behave less aggressively than visceral
metastases. Symptomatic relief is the priority for management and may include an anti-oestrogen tablet such as
tamoxifen if hormone receptor positive, radiotherapy for bony pain or to prevent fractures, and sometimes even
surgery for local control.

Most breast cancer patients are followed-up indefinitely by the multidisciplinary team. Annual mammography is
advised and a 3-6 months interval for follow-up is advised for the first 2 years.
Many survivorship and supportive care plans are organised by breast care nurses to ensure good preventative
measures are taken and to address the impact of breast cancer on quality of life issues such as mood, body image and
sexuality.

BreastScreen Australia is a funded program for asymptomatic women aged 50-69 to undergo two yearly
mammograms. Approximately 60% of the eligible female population attend. Early detection is the aim, with a
two-fold increase in the number of small tumours <1 cm detected during the first and second decade of
mammographic screening. Approximately 20% of the tumours diagnosed are DCIS.
Since 2009, women under 50 who are considered at high risk of breast cancer (>30% lifetime risk due to family) are
able to have screening with MRI in addition to mammography. Smaller tumours are more difficult to detect in dense
breasts. These women are also offered tamoxifen as a preventative medication, which decreases the chance of breast
cancer at 10 years, by 40%. Prophylactic surgery by way of mastectomy confers a 95-97% risk reduction in gene
mutation carriers.
Case study 1
Laura is a 62 year old who presented to BreastScreen for a routine mammogram. She has a new mass seen and has
an ultrasound guided core biopsy which confirms a 1.8 cm invasive ductal breast cancer. No abnormal lymph nodes
are detected on US.
She is referred to a surgeon who offers her a wide local excision and sentinel node biopsy as a day case. Her
pathology reveals a 21 mm invasive ductal carcinoma which is ER+ve, PR+ve and HER-2 negative. Two sentinel
nodes are removed and do no have metastatic disease.
She is then referred to the radiation oncologist who recommends 5 weeks of radiotherapy (50 Gray) and sees the
medical oncologist who recommends tamoxifen.
At three years post diagnosis, she continues with tamoxifen and tolerates the hot flushes which result from her tablet.
She has been having annual mammography and she continues to work and play tennis regularly.
Breast cancer 64
Case study 2
Belinda is a 35 year old whose grandmother had ovarian cancer and mother died of breast cancer at age 34. Her two
other aunts were diagnosed with breast cancer in their early 40s. One aunt is found to be a BRCA1 carrier. Belinda
undergoes genetic testing and is also found to be a BRCA1 carrier.
She undergoes her first surveillance with mammogram and MRI which are normal. She presents 8 months later prior
to her next surveillance with a 1.2 cm mass in the right medial breast. This is confirmed to be a triple negative (ER-,
PR-, HER2 -) cancer. She chooses to have a bilateral mastectomy, implant reconstruction and sentinel node biopsy
on the right side.
She is node negative and the tumour size is 12 mm. As she is a BRCA1 carrier, she has chemotherapy. During the
last cycle of chemotherapy she complains of back pain. Staging is performed and she has widespread bony
metastases. She receives some radiotherapy to her right hip to prevent fractures and is commenced on oral morphine.
She decreases her work to three days a week, but she is found drowsy in bed three months later. She is admitted to
hospital and a CT reveals widespread brain metastases and pulmonary and liver metastases. She receives whole brain
irradiation and is admitted to the palliative care unit. She dies three weeks later, 14 months after her diagnosis.
Key points
Breast cancer has an excellent survival in early disease in older women. Young age and mutations such as BRCA1
can result in a more aggressive course.
References
1. Australian Institute of Health and Welfare. Cancer. [homepage on the internet] Australia: AIHW; 2013 [cited
2014 May 29; updated 2013]. Available from: http://www.aihw.gov.au/cancer/
2. National Breast Cancer Centre. Clinical practice guidelines management of early breast cancer: Second edition.
Canberra: National Health and Medical Research Clinic; 2001 Aug [cited 2014 May 29] Available from: http://
www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp74_management_early_breast_cancer_131223.
pdf
3. Cancer Council Australia. Cancer Council Australia. [homepage on the internet] Australia: Cancer Council
Australia; 2014 Jan 1 [cited 2014 May 29; updated 2014 Jan 1]. Available from: http://www.cancer.org.au/
4. Cancer Epidemiology Centre. CanStat digests. [homepage on the internet] Victoria: Cancer Council Victoria;
2014 [cited 2014 May 29; updated 2014]. Available from: http://www.cancervic.org.au/research/
registry-statistics/canstats
Colorectal cancer
12 September 2014 05:44:13
Author(s):
• Dr. Andrew Lee MB BS FRANZCR — Author
• Associate Professor Hany Elsaleh MB BS PhD FRANZCR — Author
page</ccabutton>
Lee, A, Elsaleh, H, Yip, D, Cancer Council Australia Oncology Education Committee. Colorectal cancer [Version URL: http:/ / wiki. cancer.
au/ oncologyformedicalstudents/ Colorectal_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available
from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/ Clinical_Oncology_for_Medical_Students.
Epidemiology
Colorectal cancer accounts for just under 13% of all cancer diagnoses in Australia. It is the second most common
cancer in both men and women.[1][2]
Risk factors
Colorectal cancers occur with highest frequency in Western societies. A diet high in red meat, tobacco and alcohol
use, and a sedentary lifestyle have all been implicated as risk factors. Inflammatory bowel disease is associated with
significantly increased risk. Familial syndromes such as Familial Adenomatous Polyposis (FAP) and Lynch
Syndrome often lead to development of malignancy at a young age.[3]
Cancer biology
Adenocarcinoma makes up over 90% of malignancies arising in the large bowel. Rare tumours, such as carcinoid,
lymphoma, melanoma and gastrointestinal stromal tumours, may also occur.[3]
Adenocarcinoma of the colon was the first malignancy in which the multistep nature of carcinogenesis was
described. Many cases progress from normal bowel epithelium, dysplasia, polyp formation, and finally invasion into
the submucosa. Each stage is associated with progressive mutations in both tumour suppressor genes and
oncogenes.[4]
One of the first genes lost in this pathway is APC. This occurs as a somatic mutation in sporadic cancers. In FAP, a
germline APC mutation results in 100's or 1000's of polyps, requiring colectomy around age 20. Routine IHC
staining for the mismatch repair proteins should be performed, regardless of family history. Lack of staining is
suggestive of Lynch syndrome. Loss of MLH1 in older patients is common. In these cases, demonstrating somatic
mutations in BRAF excludes Lynch syndrome.[3] (See Genetics of Cancer chapter).
The presentation of colorectal cancer is variable. Non-obstructing tumours in the colon may cause anaemia, rectal
bleeding and irregular bowel habits. Rectal tumours may give the sensation of tenesmus. Large bowel obstruction
requires emergency surgery.[5]
Less commonly, patients may present with symptoms of metastatic disease such as ascites, jaundice or bone pain.

In patients with a suspicion of colorectal cancer, the first step to perform colonoscopy to obtain histological
diagnosis. Locoregional staging of the rectum is best performed using magnetic resonance imaging or endoscopic
ultrasound. CT scan of the abdomen allows detection of nodal and liver metastases. FDG-PET scanning is
occasionally used to detect otherwise occult sites of spread in patient who are being considered for curative resection
of oligometastases.
Modern staging is performed using the TNM system[6]:
• Stage I: Confined to bowel wall
• Stage II: Invading through bowel wall without nodal metastases
• Stage III: Lymph node metastases
• Stage IV: Distant metastases
The historical Dukes Staging system denoted stage A, B and C which correspond to TNM stages I, II and III
respectively.
Prognosis
Patients with stage I disease have an excellent prognosis with 5 year survival above 90%. For stage II-III disease,
modern treatment has improved five year survival to near 90% and 70% respectively.[6]
Patients with resectable oligometastatic disease have 5 year survivals of 40-50% in case series. Those with extensive
metastatic disease have a median survival of 5-6 months with supportive care; this increases to 24 months with
modern systemic regimens.[7]
Management
Early stage disease (Stage I)
Stage I disease has a low risk of recurrence if treated with surgery alone, regardless of the location.[5]
Locally advanced (Stage II-III)
The colon and rectum are treated differently.
• Colon cancer is typically treated with surgical excision followed by adjuvant systemic therapy utilising a
fluoropyrimidine chemotherapy based combination for those with nodal involvement.[8][9] There is a lesser degree
of benefit of adjuvant chemotherapy in node negative stage II cancer.
• Rectal cancer is treated with neoadjuvant chemoradiotherapy given concurrently[10], followed by total mesorectal
excision.[5]
Metastatic disease (Stage IV)

Patients with metastatic disease are usually considered incurable. Systemic chemotherapy with combination
regimens that include drugs such as the fluoropyrimidines, oxaliplatin and irinotecan have demonstrated
improvement in median survival in the first and second line setting.[11] Targeted therapies such as bevacizumab[12]
and aflibercept[13] have demonstrated further improvement in response rates and survival when combined with
chemotherapy. The anti-EGFR monoclonal antibodies and cetuximab[14] and panitumumab[15] are also effective in
treating KRAS wild type metastatic colorectal cancers[16]. Regorafenib, an oral multikinase small molecule inhibitor,
has also demonstrated a survival benefit over best supportive care in patients with metastatic colorectal cancer
refractory to existing therapies.[17]
A small group of patients with solitary metastases in the liver or lung may be cured with surgical resection of their
metastasis.[18] Radiotherapy may be also used palliatively to treat symptomatic lesions.
Follow-up
Regular follow-up with imaging of the abdomen, tumour markers and clinical examination is essential and has been
shown to improve survival if isolated metastases are detected.[19] Colonoscopic surveillance for new bowel primaries
or adenomas that may be premalignant is recommended every 3-5 years.

Colorectal cancer is an ideal malignancy for population-based screening, being highly curable in clinically occult
early stages. Current evidence supports biennial faecal occult blood tests[20][21] or alternatively colonoscopy every
five years from the age of 50.[22] Australia is implementing immunohistochemical stool sampling at ages 50, 55 and
60 with a plan to move to biennial screening in 2018.[23]
Case examples
Case 1
Mr B, a 45 year old man, presents with rectal bleeding of 4 months duration. Examination demonstrates a mass 7 cm
above the anal verge, and biopsy confirms adenocarcinoma.
• What important staging information is required before an appropriate treatment plan can be developed?
A: The extent of the disease needs to be established by means of imaging. In this situation a CT scan of the chest
abdomen would be appropriate as well as a pelvic MRI or endorectal ultrasound.
• Assuming Mr B has a localised tumour, what would your recommended treatment be?
A: If staging shows that the tumour is confined to the bowel wall (Stage I) then resection should be carried out. Stage
II and III should be considered for preoperative chemoradiotherapy prior to surgical resection.
• Describe how you would follow up Mr B in the event of a complete response to therapy.
A: Surveillance with CEA levels and CT imaging as well as colonoscopies are required.
Case 2
Mrs C, a 68 year old previously fit woman presents to hospital with faeculent vomiting on a background of weight
loss, symptomatic anaemia and low back pain.
• What urgent measures are required for this woman?
A: IV fluids, nasogastric tube, correct anaemia with blood transfusion, abdominal X-ray or CT scan of the abdomen.
She is stabilised and CT imaging of the abdomen is obtained. The scan shows a large obstructing mass in the caecum
with dilated small bowel. Multiple liver metastases are seen affecting most lobes as well as some lytic lesions in the
lumbar spine.
• What treatment options are available?

A. i) Resection of caecal primary lesion ii) Palliative radiotherapy to the vertebral metastasis iii) Systemic
chemotherapy with biological therapy
• What is her expected outcome? How would you convey this news to the patient?
A: The cancer is not curable and her prognosis is a median survival of 24 months with systemic treatment.
B: Ensure the patient has support people present and discuss their diagnosis in a private area. Flag that you have
serious news, and ensure that you tell the patient the relevant facts. Make sure there is time for the patient to ask any
questions.
References
[1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Cancer incidence and mortality worldwide: GLOBOCAN 2008 v2.0. Lyon,
France: International Agency for Research; 2010 Jan 1. Report No.: IARC CancerBase No. 10. Available from: http:/ / globocan. iarc. fr.
[2] Australian Institute of Health and Welfare. Bowel cancer for Australia. Canberra: Australian Institute of Health and Welfare;
2012.Cites::Citation:Australian Institute of Health and Welfare 2012 3
[3] Hamilton SR, Aaltonen LA. Pathology and genetics of tumours of the digestive system. Lyon, France: International Agency for Research on
Cancer; 2000 [cited 2014 May 20] Available from: http:/ / w2. iarc. fr/ en/ publications/ pdfs-online/ pat-gen/ bb2/ BB2. pdf.
Cites::Citation:Hamilton SR, Aaltonen LA 2000
[4] Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993 Apr 1 [cited 2014 May 20];9(4):138-41 [Abstract available at
http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 8516849].Cites::Citation:Vogelstein B, Kinzler KW 1993
[5] Australian Cancer Network Colorectal Cancer Guidelines Revision Committee. Clinical practice guidelines for the prevention, early
detection and management of colorectal cancer. Sydney: The Cancer Council Australia/Australian Cancer Network; 2005 Dec 8 [cited 2014
May 20] Available from: http:/ / www. nhmrc. gov. au/ _files_nhmrc/ publications/ attachments/ cp106_0. pdf. Cites::Citation:Australian
Cancer Network Colorectal Cancer Guidelines Revision Committee 2005
[6] Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging handbook. New York: Springer; 2010 [cited 2014 May
20].
[7] Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer
Collaborative Group. BMJ 2000 Sep 2;321(7260):531-5 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
10968812].Cites::Citation:Simmonds PC 2000
[8] André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and
leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009 Jul 1;27(19):3109-16 [Abstract
[9] Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and
leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007 Jun
1;25(16):2198-204 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 17470851].
[10] Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for
rectal cancer. N Engl J Med 2004 Oct 21 [cited 2014 May 20];351:1731-1740 [Abstract available at http:/ / www. nejm. org/ doi/ full/ 10.
1056/ NEJMoa040694].
[11] de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as
first-line treatment in advanced colorectal cancer. J Clin Oncol 2000 Aug;18(16):2938-47 [Abstract available at http:/ / www. ncbi. nlm. nih.
gov/ pubmed/ 10944126].
[12] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and
leucovorin for metastatic colorectal cancer. N Engl J Med 2004 Jun 3;350(23):2335-42 [Abstract available at http:/ / www. ncbi. nlm. nih.
gov/ pubmed/ 15175435].
[13] Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and
irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an
oxaliplatin-based regimen. J Clin Oncol 2012 Oct 1;30(28):3499-506 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
22949147].
[14] Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med
2007 Nov 15;357(20):2040-8 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 18003960].
[15] Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional
fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated
metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010 Nov 1;28(31):4697-705 [Abstract available at http:/ / www. ncbi. nlm. nih.
gov/ pubmed/ 20921465].
[16] Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in
advanced colorectal cancer. N Engl J Med 2008 Oct 23;359(17):1757-65 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
18946061].
[17] Van Cutsem E, Sobrero AF, Siena S, Falcone A, Ychou M, Humblet Y, et al. Phase III CORRECT trial of regorafenib in metastatic
colorectal cancer (mCRC). J Clin Oncol 2012 Jan 1 [cited 2014 May 20];30(15):3502 [Abstract available at http:/ / meeting. ascopubs. org/
cgi/ content/ abstract/ 30/ 15_suppl/ 3502].Cites::Citation:Van Cutsem E, Sobrero AF, Siena S, Falcone A, Ychou M, Humblet Y, et al 2012
[18] Morris EJA, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, et al. Surgical management and outcomes of colorectal cancer liver
metastases. BJS 2010 Jun 2 [cited 2014 May 20];97(7):1110-1118 [Abstract available at http:/ / www. bjs. co. uk/ details/ article/ 892375/
Surgical-management-and-outcomes-of-colorectal-cancer-liver-metastases-. html].
[19] Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst
Rev 2007 Jan 24;(1):CD002200 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 17253476].
[20] Mandel JS, Church TR, Ederer F, Bond JH. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl
Cancer Inst 1999 Mar 3;91(5):434-7 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 10070942].
[21] Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, et al. Randomised controlled trial of faecal-occult-blood
screening for colorectal cancer. Lancet 1996 Nov 30;348(9040):1472-7 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
8942775].
[22] Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Prevention of colorectal cancer by colonoscopic
polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993 Dec 30;329(27):1977-81 [Abstract available at http:/ / www. ncbi.
nlm. nih. gov/ pubmed/ 8247072].
[23] Australian Government Department of Health. National bowel cancer screening program. [homepage on the internet] Australia: Australian
Government Department of Health; 2014 May 13 [cited 2014 May 20; updated 2014 May 13]. Available from: http:/ / www. cancerscreening.
gov. au/ internet/ screening/ publishing. nsf/ Content/ bowel-about. Cites::Citation:Australian Government Department of Health 2014
Oesophageal cancer
12 September 2014 06:04:51
Author(s):
• Dr. Andrew Lee MB BS FRANZCR — Author
• Associate Professor Hany Elsaleh MB BS PhD FRANZCR — Author
page</ccabutton>
http:/ / wiki.
Lee, A, Elsaleh, H, Yip, D, Cancer Council Australia Oncology Education Committee. Oesophageal cancer [Version URL:
cancer. org. au/ oncologyformedicalstudents/ Oesophageal_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council
Epidemiology
The predominant histologies of oesophageal carcinoma are squamous cell carcinoma (SCC) and adenocarcinoma. In
2008 the incidence of oesophageal cancer was ~3.4 per 100,000 people/year with a mortality rate of 3% of cancer
deaths.[1] Men account for 75% of cases. SCC incidence appears likely to fall in the future as smoking rates
decrease. The incidence of adenocarcinoma, previously rare, has increased in and in men it is now more common
than SCC.[2]
Risk factors
Squamous cell carcinoma is strongly associated with smoking and heavy alcohol intake and accounts for ~90% of all
cases in Australia. The consumption of very hot drinks in some countries is associated with SCC. Adenocarcinoma is
associated with conditions that cause Barrett’s oesophagus which include obesity and gastro-oesophageal reflux.
Smoking contributes to about 40% of cases.[3]
Cancer biology
SCC may arise de novo or within an area of squamous cell carcinoma in situ[3], often in the upper oesophagus.
Adenocarcinoma of the oesophagus often arises from Barrett’s oesophagus. This refers to metaplasia of the lower
oesophagus, with replacement of the stratified squamous epithelium with a glandular epithelium. Transformation to
intraepithelial neoplasia may occur within Barrett's oesophagus as a precursor to invasive malignancy[3]. Local
invasion through the oesophageal wall into neighboring thoracic structures is common, as is spread to regional
nodes. Haematogenous spread to the liver is common.[3]
Oesophageal cancer commonly causes progressive dysphagia, weight loss and subsequent malnutrition.
Tracheooesophageal fistula causing aspiration can also occur. Distant metastases can cause bone and/or abdominal
pain and jaundice from liver involvement.[3]

Histopathological diagnosis is obtained through gastroscopy. Endoscopic ultrasound (for locoregional staging) and
PET/CT scan (for regional and distant staging) are used.[4]
Oesophageal cancer is staged using the TNM system:[5]
• Stage I tumours are minimally invasive and/or low grade.
• Stage II tumours invade into or through the muscular coat of the oesophagus, or are minimally invasive with 1-2
lymph node metastases.
• Stage III tumours invade adjacent structures or have numerous regional nodal metastases.
• Stage IV tumours have metastasised to distant sites.
Prognosis
Five-year survival of patients with localised (or nodal) disease are 25% and distant metastases 4%.
Management
Stage I disease
Minimally invasive oesophageal cancers can be managed with surgical excision alone. Disease that more extensively
invades the submucosa or with lymph node metastases is managed as per Stage II disease.
Stage II-III disease
Patients with disease that invades the muscularis propria or beyond, or those with lymph node metastases, have
average survival rates at 5 years of less than 20% with single modality therapy.[6][7] Combination chemoradiotherapy
without surgery has demonstrated superiority to radiotherapy alone[8] and multiple trials have examined the
combination of chemoradiotherapy with surgery. Meta-analysis of trimodality studies has demonstrated
improvements in absolute survival advantage of 8.7% at two years[9] over surgery alone. Adenocarcinoma that arises
in the vicinity of the gastro-oesophageal junction may be treated similarly to gastric cancer with neoadjuvant and
adjuvant chemotherapy.[10]
Stage IV disease
Patients with distant metastases typically have a dismal prognosis. Palliative measures include endoscopic dilatation,
laser therapy, stenting the primary lesion or local external beam radiotherapy. Systemic therapy is typically with the
combination of a fluropyrimidine and platinum agent with improvements in quality of life and survival
improvements. About 20% of patients with gastroeosphageal adenocarcinoma are HER2 positive and in the
advanced disease setting the monoclonal antibody trastuzumab has shown to improve survival when added to
chemotherapy.
Supportive measures
In addition to local therapies aimed at maintaining swallowing, attention needs to be paid to nutrition including
enteral feeding and dietician review. The involvement of palliative care services is important.
Follow-up
Patients with oesophageal cancer should been seen regularly to monitor for complications of disease progression or
treatment.

Population screening has no proven benefit. Patients with Barrett's oesophagus may benefit from routine
surveillance, although only a limited number of patients progress to invasive cancer.[11]
Case examples
Case 1
Mrs J, a 55 year old woman otherwise in excellent health, presents with a 6-week history of progressive dysphagia to
solids.
• What initial investigation is warranted?
Gastroscopy confirms a SCC of the upper third of the oesophagus.
• What staging investigations would you perform?
Staging indicates invasion through the muscular wall of the oesophagus with no regional nodal metastases. What
treatment recommendations would you make?
Case 2
Mr B is a 75 year old man who has been diagnosed with dysphagia, distal oesophageal cancer and liver metastases.
• How would you manage the primary tumour site?
• How would you approach systemic treatment in this man?
References
[1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Cancer incidence and mortality worldwide: GLOBOCAN 2008 v2.0. Lyon,
France: International Agency for Research; 2010 Jan 1. Report No.: IARC CancerBase No. 10. Available from: http:/ / globocan. iarc. fr.
[2] Stavrou E, Baker D, McElroy H, Bishop JF. Oesophageal cancer in New South Wales. Sydney: Cancer Institute NSW; 2009 Feb [cited 2014
May 20] Available from: http:/ / www. cancerinstitute. org. au/ media/ 25194/ 2009-02_oesophageal_cancer_in_nsw. pdf.
Cites::Citation:Stavrou E, Baker D, McElroy H, Bishop JF 2009
[3] Hamilton SR, Aaltonen LA. Pathology and genetics of tumours of the digestive system. Lyon, France: International Agency for Research on
Cancer; 2000 [cited 2014 May 20] Available from: http:/ / w2. iarc. fr/ en/ publications/ pdfs-online/ pat-gen/ bb2/ BB2. pdf.
Cites::Citation:Hamilton SR, Aaltonen LA 2000
[4] van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD. Staging investigations for oesophageal cancer: a meta-analysis.
Br J Cancer 2008 Feb 12;98(3):547-57 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 18212745].Cites::Citation:Van Vliet
EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD 2008
[5] Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging handbook. New York: Springer; 2010 [cited 2014 May
20].Cites::Citation:Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A 2010
[6] Rice TW, Rusch VW, Apperson-Hansen C, Allen MS, Chen LQ, Hunter JG, et al. Worldwide esophageal cancer collaboration. Dis
Esophagus 2009;22(1):1-8 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 19196264].
[7] Earlam R, Cunha-Melo JR. Oesophogeal squamous cell carcinoms: II. A critical view of radiotherapy. Br J Surg 1980 Jul;67(7):457-61
[Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 6158354].
[8] Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with
radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992 Jun 11;326(24):1593-8 [Abstract available at http:/ / www.
ncbi. nlm. nih. gov/ pubmed/ 1584260].
[9] Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or
chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011 Jul;12(7):681-92 [Abstract
[10] Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery
alone for resectable gastroesophageal cancer. N Engl J Med 2006 Jul 6;355(1):11-20 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/
pubmed/ 16822992].Cites::Citation:Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al 2006
[11] Bhat S, Coleman HG, Yousef F, Johnston BT, McManus DT, Gavin AT, et al. Risk of malignant progression in Barrett's esophagus
patients: results from a large population-based study. J Natl Cancer Inst 2011 Jul 6;103(13):1049-57 [Abstract available at http:/ / www. ncbi.
nlm. nih. gov/ pubmed/ 21680910].Cites::Citation:Bhat S, Coleman HG, Yousef F, Johnston BT, McManus DT, Gavin AT, et al 2011
Pancreatic cancer
12 September 2014 06:05:26
Author(s):
• Dr. Ben Lawrence MBChB MSc FRACP — Author
• Professor Michael Findlay MBChB MD FRACP — Author
page</ccabutton>
Lawrence, B, Findlay, M, Cancer Council Australia Oncology Education Committee. Pancreatic cancer [Version URL: http:/ / wiki. cancer.
au/ oncologyformedicalstudents/ Pancreatic_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available
Epidemiology
Pancreas cancer accounts for 2.3% of new cancers in Australia.[1] The age standardised incidence is 6.6 per 100,000
persons, and mortality is similar at 5.6 per 100,000 as the majority of people will not survive.
The major histological subtype is adenocarcinoma arising from epithelial cells in the pancreatic duct. Cancers arising
from neuroendocrine cells in the pancreas (NETs) account for just less than 5% of pancreatic cancers.[2] Survival at 1
year is only 17% of Australians with pancreatic adenocarcinoma, compared with 78% with pancreatic NETs.[3]
Risk factors
Up to 20% of pancreatic adenocarcinoma may be attributed to inherited risk. Pancreatic adenocarcinoma can cluster
in families due to an unknown predisposition, but can also occur in people with recognised cancer syndromes such as
BRCA2, BRCA1, Peutz-Jegher syndrome, Familial Atypical Multiple Mole Melanoma, Ataxia-Teleangectasia,
Lynch syndrome, and Familial Adenomatous Polyposis. Risk of pancreatic cancer is also higher in people with
hereditary pancreatitis.
Rates of pancreatic adenocarcinoma are higher in people with diabetes, although in some cases this is a consequence
of the disease rather than the cause of it. Environmental factors associated with pancreas adenocarcinoma include
smoking and obesity.
A small proportion of pancreatic NETs are recognised in the inherited syndromes Multiple Endocrine Neoplasia 1,
von Hippel Lindau syndrome, Tuberous Sclerosis and Neurofibromatosis Type 1.
Cancer biology
Like all cancers, pancreatic cancer is caused by a series of changes in genes in a single cell that leads to malignant
transformation. In a few cases the gene changes are sequential in a manner similar to colon adenocarcinoma, an
observation supported by two recognised pre-cancerous states called intraductal pancreatic mucinous neoplasia
(IPMN)[4] and pancreatic intraepithelial neoplasia (PanIN).[5] However, in the majority of cases the pattern or
sequence of gene changes that lead to the cancer is not known.
Pancreas adenocarcinomas are genetically heterogenous, and multiple oncogenes and tumour suppressor genes have
been identified by whole genome mapping of large numbers of pancreatic adenocarcinomas.[6] The genes implicated
in pancreas cancer control fundamental cell characteristics such as growth, chromatin remodelling and DNA damage
repair.
The most common symptoms are jaundice, pain and weight loss. These usually occur late, and approximately 80%
have cancer that cannot be resected at diagnosis. Jaundice occurs because of obstruction of the biliary tree by the
primary mass or a metastasis. Pain is typically epigastric and radiates to the back or sides, and can be difficult to
manage if due to invasion of nerves in the coeliac plexus. Weight loss can be due to high tumour metabolism or
pancreatic insufficiency.

The diagnostic test is usually cross-sectional imaging with an abdominal CT scan. This might supplement ERCP in
cases of biliary obstruction. Biopsy is usually required, but is technically difficult and false negatives are common.
In some settings therefore the radiological appearances and an elevated tumour marker CA19-9 will be the basis of
the diagnosis.
Staging is conducted using the TNM system.
• Stage 1 – within the pancreas
• Stage 2 – extends beyond the pancreas by invasion or nodal metastases, but does not involve the coeliac axis or
superior mesenteric artery (i.e. technically resectable)
• Stage 3 – involves the coeliac axis or superior mesenteric artery (i.e. unresectable)
• Stage 4 – distant metastases
Prognosis
Survival from pancreatic adenocarcinoma is poor. At 5 years after surgery, less than 30% of patients with stage 1
disease will be alive, and only 10% with Stage 2 disease.[7] Median survival in Stage 3 and 4 disease is
approximately 6 months, but less without any treatment.
The outcome is often more favourable in pancreatic NETs, although not in all cases. Small low grade single NETs
can be considered cured after resection. However, by contrast, high grade metastatic pancreatic NETs have a
prognosis similar to adenocarcinoma.
Management
Patients with Stage 1 and 2 pancreatic adenocarcinoma who are fit enough for an operation will undergo surgical
resection aiming for cure. Resection typically requires pancreaticoduodenectomy (Whipple’s procedure), although
some localised cancers in the pancreatic tail might be suitable for partial pancreatectomy. After surgery, patients will
also be offered adjuvant chemotherapy, which aims to treat any microscopic metastatic disease. In pancreatic
adenocarcinoma this gives a small increase in survival. Sometimes adjuvant radiotherapy is used to reduce the rate of
local relapse.
Patients with Stage 3 and 4 pancreatic adenocarcinoma do not have resectable cancers by definition. The aim of
treatment is palliation to increase duration of survival and minimise symptoms. Options include chemotherapy, and
occasionally radiotherapy. Chemotherapy with single agent Gemcitabine is only mildly effective at best, providing a
small improvement in symptom control and survival up to a median of 6 months.[8] More recently the addition of
nab-paclitaxel or the use of multidrug regimens such as FOLFIRINOX has increased median survival up to 9-11
months in patients physically strong enough to tolerate them.[9][10] In general, the role for radiotherapy is more
limited in pancreatic cancer than most other cancers because of the systemic nature of the disease, and rapid progress
at sites outside the radiation field.
Patients with pancreatic NETs have a very variable outcome and management. Management options include
traditional surgery and chemotherapy, but also peptide receptor radionuclide therapy and somatostatin analogues in
some metastatic cases.
Supportive measures
Supportive care without additional treatment is a realistic treatment option that should be discussed with all patients
with unresectable or metastatic pancreatic adenocarcinoma. This would include analgesia, maintaining patency of the
biliary tree with biliary stenting, pancreatic enzyme replacement and nutritional supplementation.
Follow-up
Patients who have undergone resection of pancreas cancer are closely followed with history, clinical examination,
liver function test, plasma CA19-9 and CT scans. Detection of relapse provides an opportunity for palliative
chemotherapy, but not cure.
The follow-up of patients with pancreatic NETs varies widely depending on the size, grade and stage of the resected
tumour.

There is no proven role for population level screening. There is no known method of pancreas cancer prevention.
Case examples
Case 1
A slim 62 year old man with no other medical problems is referred to your surgical clinic with epigastric pain
radiating to his back. On examination you get the impression of an epigastric mass. You order a CT scan which
shows an irregular mass in the head of the pancreas which extends beyond the pancreas, but does not involve the
celiac axis or any blood vessels. There are no metastases. CA19-9 is only slightly elevated.
1. What is the next diagnostic test?
Endoscopic Ultrasound-guided biopsy
2. What Stage is this cancer?
Stage 2
3. How would you treat this patient?
Pancreaticoduodenectomy followed by adjuvant chemotherapy. Some centres would also offer radiotherapy.
4. What is the chance of survival at 5 years?
Approximately 10%
Case 2
An otherwise well 48-year-old woman is referred to your medical oncology clinic by a gastroenterologist. She had
presented to hospital with jaundice and CT scan showed a mass in the head of the pancreas, which was compressing
the distal common bile duct, causing biliary dilatation. The scan also showed enlarged lymph nodes around the
pancreas and multiple lesions in the liver consistent with metastases. A stent was successfully inserted into the bile
duct and jaundice resolved. Biopsy of one of the liver lesions was consistent with a pancreatic adenocarcinoma.
1. What stage is this cancer?
Stage 4
2. You have discussed best supportive care, but she wants active anti-cancer treatment. What would you advise?
Chemotherapy (with gemcitabine with nab-paclitaxel or FOLFIRINOX).
3. What is the median survival for people in her situation, if treated?
9 months using gemcitabine with nab-paclitaxel, or 11 months using FOLFIRINOX
Her family history shows a mother and a maternal aunt with breast cancer. What inherited cancer syndrome
should you consider first?
BRCA2 then BRCA1
References
[1] International Agency for Research on Cancer. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012.
[homepage on the internet] Lyon, France: IARC; 2012 [cited 2014 May 22]. Available from: http:/ / globocan. iarc. fr/ Pages/
fact_sheets_cancer. aspx.
[2] Luke C, Price T, Townsend A, Karapetis C, Kotasek D, Singhal N, et al. Epidemiology of neuroendocrine cancers in an Australian
population. Cancer Causes Control 2010 Jun;21(6):931-8 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 20419344].
[3] Luke C, Price T, Karapetis C, Singhal N, Roder D. Pancreatic cancer epidemiology and survival in an Australian population. APJCP 2009
[cited 2014 May 22];10(3):369-74 [Abstract available at http:/ / www. apocp. org/ cancer_download/ Volume10_No3/ 369cColin%20Luke.
pdf].Cites::Citation:Luke C, Price T, Karapetis C, Singhal N, Roder D 2009
[4] Kench JG, Eckstein RP, Smith RC. Intraductal papillary-mucinous neoplasm of the pancreas: a report of five cases with
immunohistochemical findings. Pathology 1997 Feb;29(1):7-11 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 9094170].
[5] Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE. Direct correlation between proliferative activity and dysplasia in pancreatic
intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod Pathol 2002 Apr;15(4):441-7
[6] Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in
axon guidance pathway genes. Nature 2012 Nov 15;491(7424):399-405 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/
23103869].
[7] Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993 Jan;165(1):68-72;
discussion 72-3 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 8380315].
[8] Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with
gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997 Jun;15(6):2403-13
[9] Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic
cancer. N Engl J Med 2011 May 12;364(19):1817-25 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 21561347].
[10] Von Hoff DD, Ervin T, Arena FP, Chiorean G, Infante J, Moore M. Increased survival in pancreatic cancer with nab-paclitaxel plus
gemcitabine. N Engl J Med 2013 Oct 31 [cited 2014 May 22];369:1691-1703 [Abstract available at http:/ / www. nejm. org/ doi/ full/ 10.
1056/ NEJMoa1304369].
Lung cancer 77
Lung cancer
18 September 2014 00:53:52
Author(s):
• Professor Ehtesham Abdi MBBS FRACP FACP MRACMA — Author
page</ccabutton>
Abdi, E, Cancer Council Australia Oncology Education Committee. Lung cancer [Version URL: http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Lung_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available from: http:/
/wiki.cancer.org.au/oncologyformedicalstudents/Clinical_Oncology_for_Medical_Students.
Introduction
The commonest malignant tumour found in the lungs is a metastasis from another primary cancer. In fact, metastatic
neoplasms to the lungs are more common than primary lung cancer. Based on clinicopathological data, the lungs are
involved by metastatic disease in one third to half of all malignant lesions. It is therefore critical to find out whether
the lesion in the lung is a primary lung cancer or metastasis. A biopsy is mandatory to make such distinction.
Routine histopathology with the assistance of appropriate immunohistochemistry is able to distinguish primary lung
cancer from a metastasis from a different primary tumour in a majority of cases. The common primary cancers
metastasising to the lungs are breast, kidney, uterus, melanoma, colorectal, testes and thyroid.
Primary lung cancer

About 95% of primary lung cancers are carcinoma of the bronchus, about 2% are alveolar tumours and 3% are
benign or less invasive malignant tumours.
Prognosis of primary lung cancer is very poor. The 5-year relative survival for lung cancer in Australia is about 15%.
There was an increase in 5-year relative survival for lung cancer from 8.7% for the period 1982-1987 to 14.1% for
2006-2010.
Epidemiology
Lung cancer has been the most common cancer in the world for several decades. An estimated 1.61 million people
across the world were diagnosed with lung cancer in 2008, accounting for 13% of the total. More than half (55%) of
the cases occurred in the developing world. Lung cancer is the fifth most commonly diagnosed cancer in Australia.
About 9% of all new cancers in Australia are lung cancers. In 2009, there were 10,193 new cases of lung cancer
diagnosed. In 2010, lung cancer was the commonest cause of cancer death, accounting for 19% of all cancer deaths.
The mortality rate from lung cancer in Australia is significantly lower than the rates for North America, Northern
Europe and East Asia. In 2010 in Australia, 3,165 people died of lung cancer and 2,864 peopel died of breast cancer.
Peak incidence of lung cancer is in 60-70 year age group and is often diagnosed in ex-smokers. Highest incidence is
in low socio-economic group due to high prevalence of smoking in this group.
Lung cancer 78
Aetiology
Smoking is responsible for over 90% of lung cancers. Tobacco smokes contains over 60 known carcinogens. Passive
smoking increases the risk of lung cancer by 1.5 fold and possibly accounts for about 5% of lung cancers. Other risk
factors include exposure to arsenic, radon, radiation, iron oxide, chromium, petroleum products and possibly coal
mining.
Types of lung cancer
There are 2 broad categories of lung cancer:
1. Small-cell lung cancer
SCLC accounts for about 20% of all lung cancers. It has a very aggressive behaviour and is considered a
“systemic” disease at diagnosis. It develops in 3-5 years and has a doubling time of 30 days. Up to 15 % of
patients with limited stage SCLC will have long-term survival. The commonest location of SCLC is around
the hilum and central areas of the lungs. SCLC is most frequently associated with several para-neoplastic
syndromes.
Small cell carcinomas arise from neuroendocrine cells and secrete many different polypeptides. Some of the
polypeptides have an auto feedback loop which induces further tumour growth. Often the initial presentation
of patients with SCLC is with a paraneoplastic syndrome, such as Cushing’s syndrome or Addison’s disease.
SCLC is extremely aggressive and spreads very early. Surgery does not play a part in most cases. Although
SCLC responds extremely well and quickly to chemotherapy and radiation therapy, even those patients who
respond usually relapse within 12 months.
2. Non-small cell lung cancer
Non-small cell lung cancer has 3 broad categories of histology. In non-small cell lung cancer histology is now
considered very important as treatment choices vary significantly between the various histologies. Genetic
changes include activation of oncogenes including EGFR, K-Ras, Myc and EML4-ALK, whereas a number of
tumour suppressor genes, e.g., 3p, 9p, p16, 13q, 17P and P53, may be switched off in certain lung cancers.
1. Adenocarcinoma: Now the most common non-small cell lung cancer and is the dominant lung cancer amongst
females. Non-smokers with lung cancer most often have adenocarcinoma. Approximately 40% of all lung
cancers would be adenocarcinoma.
Adenocarcinomas are typically slow growing and take over 15 years to develop with a tumour doubling time
in excess of 200 days. Adenocarcinomas are more often found peripherally and therefore often present late
with distant metastases present at time of diagnosis in most patients.
Adenocarcinomas arise from mucous cells in the bronchial epithelium. Adenocarcinoma involves mediastinal
lymph nodes and he pleura and spreads to bone and brain. Adenocarcinomas are sometimes confused with
mesothelioma and are most likely to cause pleural effusions.
2. Squamous cell: Incidence is declining and now accounts for approximately 25% of all lung cancers. There are
various subtypes, with some differences in presentation, behaviour and treatments. Squamous cell cancers are
somewhat more aggressive than adenocarcinoma and take 8 or more years to develop. With doubling time in
excess of 100 years, squamous cell carcinomas usually cause bronchial obstruction leading to infections. Up to
10% of squamous cell carcinomas may have cavitation. The cavitation occurs due to central necrosis of tumour
mass due to rapid growth of lung cancer. These cavitating lesions are often labelled as abscess or TB cavity
3. Large cell carcinoma: The least common variety accounts for about 10% of all lung cancer and is more
undifferentiated with clear cell and giant cell variants. These are considered variants of adenocarcinoma and
squamous cell carcinoma but because of poorly differentiated histology cannot be ascribed either. Large cell
carcinomas metastasise early and have poor prognosis.
4. A small number of lung cancers have mixed histology consisting either of adenocarcinoma and squamous cell
carcinoma admixed or less common a combination of small cell and non-small cell variant.
Lung cancer 79
Tumours arising in the main bronchi tend to present earlier than those arising peripherally and frequently are
associated with haemoptysis. About 80% of lung cancers are found in the lobar bronchi; the remainder are in larger
bronchi.
Tumour spread
Lung cancer can spread to the pleura either directly or via lymphatic drainage.
Local
Lung cancers can invade the chest wall, compressing the intercostal nerves or brachial plexus causing neuropathic
pain. Apical tumours in the superior sulcus can also affect the brachial plexus at C8, T1-2.
Apical tumours may also cause Pancoast syndrome that affect the first rib. Pancoast tumours affect the brachial
plexus and the sympathetic ganglion. The result is Horner’s syndrome which consists of ptosis meiosis and dilatation
lag. There may also be anhydrosis and enophthalmos on the affected side of the face.
Regional
The primary tumour spreads to the hilar, supraclavicular or mediastinal lymph nodes. Extensive nodal involvement
could compress the oesophagus, invasion of the great vessels including superior vena cava that causes superior vena
cava (SVC) syndrome. SVC syndrome causes early morning headaches, oedema of upper limbs, facial and
conjunctival congestion, distension of jugular vein and veins on the chest wall. The loco-regional nodal disease may
also cause phrenic or left recurrent nerve palsy causing a hoarse voice.
Distant
Through haematogenous route lung cancers often spread to the adrenal gland, brain, liver, bone and lungs. Brain
metastases can cause focal neurological symptoms including headaches, seizures and sometimes personality change.
Metastases to adrenal are almost never symptomatic and are found during routine staging procedures or at autopsy.
Bone metastases cause pain and if spinal involvement is present may lead to spinal cord compression.
Even a very small primary lung cancer can cause widespread distant metastases, especially small-cell lung cancer.
Non-metastatic manifestations
Endocrine complications: Syndrome of inappropriate ADH secretion presents itself with hyponatraemia. Treatment
of SIADH is fluid restriction rather than saline administration. Cushing’s syndrome is caused by ectopic ACTH
secretion. The clinical features are similar to Cushing’s syndrome caused by other causes but in lung cancer often
there is concomitant MSH production leading to skin pigmentation. Excessive secretion of parathormone related
protein leads to hypercalcaemia. Hypercalcaemia may also occur as a consequence of lytic bone metastases. Almost
all the endocrine and non-endocrine paraneoplastic syndromes are frequently seen in SCLC; hypercalcaemia or
PTHrP secretion is rare in SCLC.
Paraneoplastic syndromes
Paraneoplastic syndrome is a non-endocrine, non-metastatic complication of lung cancer. Paraneoplastic
syndrome can present themselves years before, at the time of, or subsequent to the diagnosis of lung cancer.
Neurological complications
Polyneuropathy: Caused by antibodies formed against the myelin sheath.
Lambert-Eaton myasthenic syndrome: Caused by an autoimmune reaction in which antibodies are
formed against presynaptic voltage gated calcium channels in the neuromuscular junction. The most
frequent consequence is muscle weakness of limbs.
Cerebellar degeneration: This is an autoimmune reaction targeted against Purkinje cells of cerebellum.
Neurological symptoms present insidiously and progress rapidly to a severely disabled state. Clinical
findings include cerebellar ataxia, dysarthria, vertigo, diplopia, nystagmus and emesis.
Hypertrophic pulmonary osteoarthropathy
Lung cancer 80
HPOA is the combination of finger clubbing and thickening of periosteum and synovium of the long
bones of upper and lower extremities. It is most often seen in non-small cell lung cancer and is rarely
seen in SCLC. There will be joint stiffness, severe pain in the wrists and ankles, and sometimes also
gynaecomastia. On X-ray there will be proliferative periostitis at the ends of the long bones, which have
an ‘onion skin’ appearance.
Presentation of lung cancer

1. Respiratory symptoms of persistent dry cough, haemoptysis, wheezing, “recurrent” pneumonia or dyspnoea.
a. Worsening of pre-existing COPD
b. Feeling of fullness in the chest or even severe pain
c. Change in character of smoker’s cough and pattern of dyspnoea
d. Occasionally stridor or wheeze
1. Systemic symptoms of weight loss, fevers, clubbing or fatigue
2. Symptoms from local compression: chest pain, bone pain, SVC obstruction, and dysphagia.
Examination
More often than not physical examination is normal. There may be unilateral pleural effusion or signs of
consolidation or collapse of a lobe of the lung. Other findings may include enlarged supraclavicular nodes, recurrent
laryngeal nerve paralysis, SVC syndrome and HPOA.
Investigations
1. CXR and if any abnormalities on chest x-ray then a CT scan of the chest. A normal CXR does not mean any
further investigation in the presence of persistent symptoms in a smoker over the age of 40. CXR will only
demonstrate approximately 60% of lung cancers, as the remainder are too central to be seen on lung fields.
2. CT Scans of chest and upper abdomen: The soft tissue windows will demonstrate any hilar, mediastinal or
subcarinal nodes. Also liver and adrenal metastases can be visualised. Lung windows may show other nodules,
which may be metastases. Bone windows may show any possible bony metastases. See PET scan below. MRI
scans play little or no part in the diagnosis of lung cancer.
3. Sputum cytology if available.
4. In all cases of haemoptysis and in most cases of “central” lung cancer a fibre-optic bronchoscopy with brushings,
washings and biopsies as appropriate. Use of endobronchial ultrasound guided biopsy of central lymph nodes in
experienced hands may be another method of obtaining cytological confirmation of lung cancer. Mediastinoscopy
may still have a role in staging lung cancer but is nowadays being increasingly supplanted by PET/CT scans.
5. CT guided percutaneous biopsy of peripheral lesions, not within reach of a bronchoscope.
6. Once a diagnosis of lung cancer is made a PET/CT scan may give information about distant spread of lung
cancer.
7. Standard haematology and biochemistry particularly looking at serum calcium and sodium levels as well as any
hepatic or renal dysfunction.
Lung cancer 81
Staging and treatment of lung cancer

Treatment depends on a number of factors including the precise histology, extent of disease and performance status
of the patient. Patients being considered for radical surgery must have adequate respiratory function.
Small-cell lung cancer
Limited stage, when the tumour is confined to one hemithorax, Extensive stage when there are distant
metastases or presence of pleural effusion.
Non-small cell lung cancer: Staged using TNM system as below:
• Tumour size:
• T1 < or = to 3cm
• T2 > 3cm
• T3 = local extension (parietal pleura, chest wall or within 2cm of carina)
• T4 = spread to great vessels, trachea, mediastinum, or oesophagus (un-resectable)
• Lymph Node
• N0 = no involvement
• N1 = hilar nodes
• N2 = mediastinal nodes
• N3 = contralateral nodes or ipsilateral supraclavicular (unresectable)
• Metastases
• M0 = none
• M1 = presence (unresectable)
• Stage IA - T1 N0 M0
• Stage IB - T2 N0 M0 (T > 3cm)
• Stage IIA - T1 N1 M0
• Stage IIB - T2 N1 M0; T3 N0 M0
• Stage IIIA - T3 N1 M0; T1-3 N2 M0
• Stage IIIB - Any T N3 M0; T4 Any N M0
• Stage IV - Any T Any N M1
Prognosis and treatment of lung cancer

Small-cell lung cancer
Small cell lung cancer is considered a systemic disease at the outset even if the staging shows limited stage
disease. Most of the patients are likely to have micrometastases.
Five-year survival is approximately 15% with treatment, however symptom control and short-term disease
response is seen in excess of 85% of patients.
Limited stage untreated life expectancy is 12-16 weeks and with treatment life span can be extended to beyond
12 months.
Extensive stage life expectancy is about 8-10 weeks and with treatment life can be extended to about 8
months.
Mainstay of treatment is chemotherapy with a platinum and etoposide doublet. In patients with limited stage
disease, radiation therapy to the site of primary tumour is also strongly recommended. Patients with limited
stage small-cell lung cancer who seem to achieve a complete response to chemoradiotherapy, may be offered
prophylactic cranial irradiation to prevent CNS recurrence due to the fact that chemotherapy does not penetrate
blood brain barrier and CNS recurrences are common.
Non-small cell lung cancer
Lung cancer 82
Surgery is the treatment of choice for tumours at the periphery with no metastatic spread. However, only
5-10% of cases are suitable for resection, and 70% of these will survive to 5 years. The types of surgical
procedures depend on the extent and the location of disease as well as other factors like age, pulmonary
reserve and other co-morbidities. Lobectomy and pneumonectomy are most frequent procedures but in some
cases a segmental resection can be done.
Stage I: Following surgery, 70% patients will survive 5 years.
Stage II: Following surgery only 40-50% patients will survive 5 years, as many patients have micrometastases
undetectable by routine staging including PET scans. Benefits from adjuvant chemotherapy are modest at
about 5%.
Stage IIIA: Often considered inoperable has a 5-year survival of <25% following surgery. Mainstay of
treatment these days is combined chemoradiotherapy given synchronously rather than sequentially.
Stage IIIB or IV: Untreated, only 5-10% will be alive at 12 months. With chemotherapy, over 20% will
survive beyond 12 months. Benefits from chemotherapy are only observed in patients with performance status
of WHO grade 0 or 1. Patients with performance status of grade 2 or more should not be offered
chemotherapy. There is no role for single agent chemotherapy. Many targeted therapies are being considered
depending on presence or absence of certain growth or promoting genes and histopathology plays a critical
role in determining appropriate and targeted therapy for NSCLC. Involvement of palliative care teams at an
early stage is very important in management of patients with Stages IIIb or IV.
Urogenital cancers
12 September 2014 05:45:13
Author(s):
• Professor Paul De Souza BScMed MB BS MPH PhD FRACP — Author
• Dr Damien Thomson MBBS FRACP — Author
page</ccabutton>
De Souza, P, Thomson, D, Cancer Council Australia Oncology Education Committee. Urogenital cancers [Version URL: http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Urogenital_cancers. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council
Cancers of the genitourinary system
Prostate cancer
Prostate cancer is the most common non-skin cancer diagnosed in men. Risk factors include increasing age and, less
commonly, a family history of the disease. By far the most common pathological subtype is adenocarcinoma;
grading is by the Gleason system; numbered from 1-5 (from well differentiated glandular structures to anaplastic)
and the scoring of the two most common histological growth patterns is added together, i.e. 4+3 = 7. Grading is a
strong predictor of prognosis. PSA is not recommended as a screening test for asymptomatic men as it results in
over-diagnosis of many cases where survival would not be altered.
When localised, prostate cancer can be cured by surgery or radiation, but “watchful waiting” (observation) is a
realistic management option, particularly when patients are elderly or have other co-morbidities, or the discovered
tumour is low grade.
In a proportion of men, prostate cancer recurs, sometimes years after definitive therapy. At that stage, androgen
deprivation, bilateral orchidectomy or LHRH (Leutinising Hormone Releasing Hormones) agonists are usually the
first treatment options entertained. This is not curative, however, and around 3 years later on average, men develop
rising PSA levels again, denoting castrate-resistant disease. Treatment options at that stage include chemotherapy
and newer hormonal drugs targeting androgen receptors and androgen scavenging pathways. Complications of
androgen deprivation therapy include osteoporosis, lack of libido, mood changes and metabolic syndrome, amongst
others. Complications of prostatic surgery and radiation include impotence, incontinence and proctitis.
Bladder cancer
More correctly called urothelial carcinoma because the epithelium lining the bladder, ureter and the renal pelvis is
the same, “bladder cancer” increases in incidence with age, smoking and exposure to dyes. The most common
presenting symptom is painless, frank haematuria. Patients presenting with haematuria require evaluation, including
a cystoscopy. The large majority of bladder cancer is superficial, and can be managed by local surgical techniques
(e.g. resection, fulguration), assisted with intravesical drug therapy such as instillation of chemotherapy or BCG to
control the disease. There is a small but real risk of disease progression to muscle invasive disease. In this instance,
cystectomy or radiotherapy can be considered. For muscle invasive disease requiring cystectomy, neo-adjuvant
chemotherapy improves survival by 5%. Chemotherapy for metastatic disease improves survival and can help
maintain quality of life.
Renal cancer
Most kidney cancers are now diagnosed incidentally, from imaging performed for other reasons. Clear cell
carcinoma is the most common subtype. The disease is often silent clinically until cancers reach a size large enough
to cause problems (e.g. haematuria, pain, inferior vena cava infiltration) or after it metastasises. For small cancers in
anatomically favourable locations (e.g. upper or lower pole of the kidney), resection is curative; however, loss of
nephrons leading to long term renal impairment has shifted thinking and careful observation with regular CT scans is
increasingly employed in these situations, since some renal cancers grow very slowly. The prognosis for patients
with metastatic disease is variable but has increased dramatically in recent years with the introduction of tyrosine
kinase inhibitors and other targeted therapies. Patients who have solitary metastases may be considered for resection.
Germ cell cancer

Typically presenting in young men as a lump in the testis, germ cell (reproductive cell) tumours include a wide
variety of histological subtypes (e.g. embryonal carcinoma, teratoma, yolk sac tumour and seminoma).
Management of germ cell tumours generally follows that of pure seminoma or non-seminoma; each is similar, but
not exactly the same. An inguinal orchidectomy is necessary for tissue diagnosis as well as management of the
primary site. If there is no evidence of metastatic disease on staging investigations (CT chest abdomen pelvis,
normalizing beta HCG, alpha fetoprotein and LDH), most patients are now placed on surveillance (clinical, markers
and CT scans) with systemic chemotherapy reserved for recurrence with cure rates approaching 100% In the past,
seminomas were managed by para-aortic radiation with the long term risk of second tumours.
In the setting of metastatic disease, combination chemotherapy can still cure over 90% of patients, suggesting
exquisite sensitivity of germ cell tumours to chemotherapy.
Important points
Given the risk of interstitial lung disease from bleomycin, monitoring of lung function is important. It is better to
avoid high-flow oxygen supplementation for some time; the duration of which is debatable.
Since the risk of infertility is high after chemotherapy, all men should be offered semen cryopreservation.
Haematopoietic and lymphoid malignancies

12 September 2014 01:17:48
Author(s):
• Dr. Rosemary Young MBBS MS FRACP — Author
page</ccabutton>
Young, R, Cancer Council Australia Oncology Education Committee. Haematopoietic and lymphoid malignancies [Version URL: http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Haematopoietic_and_lymphoid_malignancies. In: Sabesan S, Olver I, editors.
. Sydney: Cancer Council Australia. Available from: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/
Incidence
Non Hodgkin's lymphoma was the tenth most commonly diagnosed malignancy in Australia in 2010.[1] Hodgkin
lymphoma (HL) comprises approximately 10% of lymphomas and 0.6% cancers worldwide.
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Classification of haematopoietic and lymphoid malignancies

Various classifications have been used in older literature sources, however in current usage is the World Health
Organization (WHO) classification of 2001, updated in 2008. This incorporated the new knowledge of both
immunophenotypic and cytogenetic information.[2] The focus is on lineage derivation into myeloid, lymphoid or
dendritic/histiocytic entities, though there is sometimes biphenotypic differentiation or “lineage infidelity”,
suggesting derivation from multipotent progenitor cells.[3]
Myeloid: • acute myeloid leukaemias (of various subtypes, AML) with >20% blasts in marrow or peripheral blood, or specific genetic
abnormalities. Recurring genetic abnormalities, myelodysplastic features or extraosseous tissue deposits of “myeloid sarcoma”.
• myeloproliferative neoplasms (MPN) including chronic myeloid leukaemia, essential thrombocythaemia, polycythaemia vera,
chronic neutrophilic leukaemia, chronic eosinophilic leaukaemia, mastocytosis and primary myelofibrosis
• myelodysplastic syndromes (MDS) including <20% blasts and unilineage or multilineage dysplasia, specific recurring chromosomal
abnormalities and childhood MDS.
AML is inevitably aggressive in its course and needs immediate therapy. It may be a primary or secondary neoplastic
change, consequent on a prior immunological or haematological disturbance or therapy (eg prior chemotherapy or
radiation).
There may be an overlap between MPN and MDS and the course is very variable, but may evolve to AML.
Lymphoid: • Previous segregation of mass disease (lymphoma) vs bone marrow/blood involvement (leukaemia) has been relaxed, as there may
be an evolution either way.
• There may be a clinical segregation into 3 groups according to “indolent” (35-40% patients) vs “aggressive” vs “highly aggressive”
[4]
(5% patients) behaviour of B or T cell neoplasms, with Hodgkins lymphoma being classified separately.
• Highly aggressive histologies include precursor B or T lymphoblastic leukaemia/lymphomas and Burkitt lymphoma/leukaemia,
(which may have a relationship to EBV infection, endemic in African populations, but also be sporadic or related to
immunodeficiency in HIV and other groups).
• Intermediate and mature lymphoproliferative disorders (LPD) with histologies which are more variable in their clinical behaviour,
including B and T cell derivation, and with potential immune phenomena in B cell types affecting their clinical behaviour and the
need to treat rather than monitor. These include plasma cell neoplasms such as plasmablastic lymphoma (HIV associated) and
plasma cell plasmacytoma/myeloma, mature B cell neoplasms including follicular lymphoma, chronic lymphocytic
leukaemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma (“Waldenstrom’s macroglobulinaemia”), mantle cell
lymphoma, prolymphocytic lymphoma and diffuse large B cell lymphoma (comprising 25% of cases of NHL, the most common
entity).
• Hodgkin lymphoma (HL) is unique in that the malignant cells are the minority (Reed-Sternberg cells or variants derived from
germinal centre cells) in an inflammatory background. There are two main subtypes of nodular lymphocyte predominant HL and
“classical HL” including nodular sclerosis subtype, mixed cellularity (+/- EBV), lymphocyte depleted (EBV+/-) and lymphocyte
rich HL. Bimodal age distribution (20s and >70s).
• Mature T cell or natural killer (NK) cell lineage, including circulating disease, mass disease and cutaneous variants, with very
variable presentations and natural history.
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Histiocytic/dendritc • Uncommon primary presentations of antigen presenting cells (APC) and connective tissue macrophages
neoplasms: (histiocytes).
• Generally grouped into the “Langerhans cell histiocytoses”
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Background history
Connective tissue disorders as precursors for a secondary LPD. Also some increased risk in family members for HL.
Environmental exposures and past chemotherapy or radiotherapy as risk factors for a secondary leukaemia.
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Common presentations
Leukaemia
Cytopenia: • anaemia (marrow infiltration or haemolysis)
• neutropenia with bacterial and fungal infections
• thrombocytopenia and bleeding manifestations such as gum bleeding, petechial rash or ecchymoses, hollow organ or intracranial
bleeding.
• hyperviscosity symptoms (especially IgM paraprotein of Waldenstroms macroglobulinaemia and very high WCC in ALL)
• Mass organ involvement with hepatosplenomegaly, CNS involvement, obstructive complications (spinal cord, GIT, ureter,
bronchus)
• Coagulopathy incl. disseminated intravascular coagulation (esp. with acute promyelocytic leukaemia).
Lymphoma
Risk factors include HIV/EBV/ HCV infection, family history of lymphoprolferative disorder (LPD), background
autoimmune disorders for secondary lymphoproliferative disorder, inflammatory gastrointestinal disease (e.g.
Crohn’s disease, coeliac disease, Helicobacter pylori chronic gastritis), environmental exposures (see Table 2).[5]
Mass disease: • “lumps and bumps”, typically painless unlike inflammatory causes hepatosplenomegaly)
• obstruction of hollow organ, e.g. bronchus, ureter, CBD
• NS symptoms (CNS, brainstem, cord, nerve root)
• cutaneous rash, effusion (pleural/pericardial/peritoneal)
• cytopenia due to marrow infiltration
• Waldeyer’s ring, ocular apparatus
Constitutional • fatigue/drenching sweats/fevers >38º

disturbance:
• weight loss >10% body weight in 6mth
• known as “B symptoms” (originally described in HL).
Metabolic disturbance: • hypercalcaemia, hyperuricaemia, renal impairment, hyperviscosity associated with IgM paraproteinaemia
(Waldenstroms macroglobulinaemia.)
• elevated lactate dehydrogenase (in aggressive histologies and with high tumour burden)
Immune phenomena: • primary haemolysis/thrombocytopenia, less commonly neutropenia (potentially associated with splenomegaly)
• angioedema associated with acquired C1 esterase inhibitor deficiency
Paraneoplastic • neurological, metabolic, cutaneous presentations are rare.

phenomena:
Myeloma
Cytopenia: • anaemia, neutropenia, thrombocytopenia
• “reciprocal”hypogammaglobulinaemia and infection tendency
Mass disease: • bone pain/destructive (marrow bearing) lytic bone lesions
• vertebral destruction and cord compromise or radiculopathy
• soft tissue masses
Metabolic • hypercalcaemia
disturbance:
• hyperuricaemia
• hyperviscosity (especially multimers of IgA)
• renal impairment (due to above as well as light chain deposition and tubular casts, concurrent light chain amyloidosis)
• constitutional disturbance (weight loss, fevers, fatigue)
Coincidental • Elevated total serum protein

finding:
• Elevated total serum protein
• Urinalysis showing proteinuria
• Paraprotein estimation by electrophoresis of serum (IgG/A/D {rare}with kappa or lambda light chains, or free kappa or
lambda light chains only in up to 20%.) Approx. 5% truly nonsecretory of immunoglobulin or free light chains and with no
histochemical staining in plasma cells.
• Renal biopsy may show waxy, laminated casts and renal amyloidosis.
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Definitive diagnosis
Biopsy
Fine needle aspiration cytology may help define broad lymph node pathology, but architectural features and more
cellular material obtained by an excision biopsy allows full classification. Cytogenetics, flow cytometry and gene
rearrangements aid subclassification.
Bone marrow examination is routine and CSF may be sampled, especially in aggressive lymphoma histologies such
as Burkitt’s lymphoma and leukaemia/lymphoma, where it may be a “sanctuary site” for later relapse, as may be the
testes.
Bone marrow aspiration and trephine biopsy are essential to definitively diagnose myeloma and differentiate it from
monoclonal gammopathy of undetermined significance (MGUS).
Staging
Staging the extent of both NHL and HL is based on Ann Arbor classification Table 3, Ref. 4) as determined by
physical findings, CT, MRI and PET scan findings (see LN location Figure 1).[5] In addition, risk stratification is
assisted by use of the Revised International Prognostic Index (R-IPI) and follicular lymphoma prognostic index
(FLIPI) (see Table 3[6] and Table 4[7]).
Myeloma assessment is by skeletal survey to determine the volume of lytic disease in marrow bearing bones,
checking for end-organ damage in the form of hypercalcaemia/anaemia/renal failure, determining the burden of
disease related to paraprotein concentration (Durie and Salmon system 1975 and Table 5).[8] Serum and urine (Bence
Jones) electrophoresis and immunofixation
Management: • It is important to determine if a NHL is CD20+ where potential immune therapy with rituximab, a monoclonal antibody against
the “cluster determinant 20”, has importance in both indolent and diffuse large cell lymphomas. (Hence “R-IPI” rather than
earlier “IPI”, predating “the rituximab era”.)
• If indolent histology NHL, potentially “watch and wait” unless bulk of disease and compromise to organ function (eg ureteric
obstruction with retroperitoneal mass), immune phenomena or cytopenia due to marrow involvement dictate intervention.
• Otherwise usually systemic chemotherapy for “intermediate” and “aggressive” histologies of NHL and HL, with multi-agent
protocols, unless Stage 1 disease, able to be encompassed in a radiation field and potentially curable with localised therapy.
• In myeloma, host demographic factors, stage and cytogenetic/FISH profile help to determine the appropriate systemic therapy
protocol and/or autograft eligibility. Cytotoxics (especially alkylating agents), immunomodulatory drugs (thalidomide,
lenalidomide) and proteasome inhibitor (bortezomib) and importantly corticosteroid are options.
Prognosis: • Therapy for chronic and acute leukaemias is very complex and beyond the scope of the chapter, but includes cytotoxic
chemotherapy, immunomodulatory therapy, tyrosine kinase inhibitors, progenitor cell autograft and allograft (sibling donor and
matched unrelated donor).
• Intermediate and aggressive NHL and HLmay be {potentially} curable but control is the aim in indolent forms, unless Stage 1,
when systemic dissemination may not have yet occurred and local therapy may suffice.
• Myeloma is controlled, by systemic therapy with or without a progenitor cell autograft, but only cure may be achieved with an
allograft, sadly at high risk of fatal complications.
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References
[1] Australian Institute of Health and Welfare. Cancer in Australia: key facts. [homepage on the internet] Canberra: AIHW; 2013 [cited 2014
May 22; updated 2013]. Available from: http:/ / www. aihw. gov. au/ cancer/ cancer-in-australia/ .
[2] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H. WHO classification of tumours of haematopoietic and lymphoid tissues,
fourth edition. Lyon, France: IARC; 2008 [cited 2014 May 22] Available from: http:/ / apps. who. int/ bookorders/ anglais/ detart1.
jsp?sesslan=1& codlan=1& codcol=70& codcch=4002.
[3] Freedman AS, Friedberg JW, Aster JC. Classification of the hematopoietic neoplasms. [serial online]: UpToDate; 2013 Sep 9 [cited 2014
May 22] Available from: http:/ / www. uptodate. com/ contents/ classification-of-the-hematopoietic-neoplasms?source=search_result&
search=Classification+ of+ the+ hematopoietic+ neoplasms& selectedTitle=1~150. Cites::Citation:Freedman AS, Friedberg JW, Aster JC
2013
[4] Aster JC. Epidemiology, pathologic features, and diagnosis of classical Hodgkin lymphoma. [serial online]: UpToDate; 2014 Jan 14 [cited
2014 May 22] Available from: http:/ / www. uptodate. com/ contents/
epidemiology-pathologic-features-and-diagnosis-of-classical-hodgkin-lymphoma. Cites::Citation:Aster JC 2014
[5] Freedman AS, Friedberg JW, Aster JC. Clinical presentation and diagnosis of non-Hodgkin lymphoma. [serial online]: UpToDate; 2014 Feb
24 [cited 2014 May 22] Available from: http:/ / www. uptodate. com/ contents/
clinical-presentation-and-diagnosis-of-non-hodgkin-lymphoma?source=search_result& search=Clinical+ presentation+ and+ diagnosis+ of+
non-Hodgkin+ lymphoma& selectedTitle=1~150. Cites::Citation:Freedman AS, Friedberg JW, Aster JC 2014
[6] Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a better
predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007 Mar
1;109(5):1857-61 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 17105812].
[7] Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular lymphoma international prognostic index. Blood
2004 Sep 1;104(5):1258-65 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 15126323].
[8] Rajkumar SV. Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. [serial online]: UpToDate; 2014 Apr 4 [cited
2014 May 22] Available from: http:/ / www. uptodate. com/ contents/
clinical-features-laboratory-manifestations-and-diagnosis-of-multiple-myeloma?source=search_result& search=Rajkumar+ SV. + Clinical+
features%2C+ laboratory+ manifestations%2C+ and+ diagnosis+ of+ multiple+ myeloma& selectedTitle=2~150.
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Gynaecological cancers
31 October 2014 01:37:21
Author(s):
• Dr Peter Savas MBBS BMedSci FRACP — Author
• Associate Professor Kailash Narayan MBBS MD PhD FRANZCR — Author
• Associate Professor Linda Mileshkin MB BS FRACP — Author
page</ccabutton>
Savas, P, Narayan, K, Mileshkin, L, Cancer Council Australia Oncology Education Committee. Gynaecological cancers [Version URL: http:/ /
wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Gynaecological_cancers. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council
Ovarian cancer
Ovarian cancer is a common malignancy that usually presents with advanced intra-abdominal disease. It is the sixth
most common cancer in Australian women with a lifetime risk of 1 in 70 and a median age of diagnosis of 60 years.
It is most common in developed Western countries and less common in developing or Asian countries. A strong
family history of breast or ovarian cancer is the most relevant risk factor for ovarian cancer, with 10-15% of
diagnosed patients having a mutation in the BRCA gene that confers susceptibility. Other risk factors include
nulliparity, early menarche and late menopause. Protective factors include oral contraceptive use, pregnancy,
lactation, tubal ligation and prophylactic salpingo-oophorectomy in mutation carriers. The tumour marker CA125
and transvaginal ultrasound are not effective measures of screening for ovarian cancer and are not currently
recommended for use in asymptomatic women.
The symptoms of ovarian cancer are non-specific and include bloating, abdominal pain, early satiety and urinary
urgency or frequency. Such symptoms should then be investigated with further imaging and measurement of CA125.
Transvaginal US is the initial investigation of choice. Suspicious ovarian pathology should not be biopsied
percutaneously as this may cause tumour seeding. Referral to a gynaecologic oncologist for further evaluation is
recommended. In the event that ovarian carcinoma is discovered, extensive surgical staging should be performed
including a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal washings,
lymph node assessment and careful examination of all peritoneal surfaces. If advanced disease is evident, debulking
resection of all macroscopic disease to a residual of less than 1 cm, and surgery in a high volume specialised centre,
is associated with improved survival. The extent of disease determines the stage (see Table 1), which is the most
important determinant of long-term outcome.
Table 1: Stages of ovarian cancer
Stage Description Survival 5 years from

diagnosis
Stage 1 Tumour limited to one or both ovaries, +/- malignant ascites 80 – 90%
Stage II Tumour in one or both ovaries and extending into pelvic structures +/- malignant ascites 65 – 70%
Stage Tumour involving extra-pelvic peritoneum and/or retroperitoneal or inguinal lymph nodes +/- malignant 30 – 50%
III ascites
Stage Metastases beyond peritoneal surface into viscera or the pleural space 15%
IV
About 90% of ovarian cancer consists of epithelial ovarian cancer (EOC). Within EOC there are different histologic
sub-types, with the most common being high-grade serous carcinoma and less common types including endometroid,
clear cell and mucinous histology. It is now thought that high-grade serous EOC originates from the Fallopian tube
rather than the ovary itself. Less common histologies are malignant germ cell tumours of the ovary, carcinosarcomas
and sex cord-stromal tumours. Primary Fallopian tube carcinomas and primary peritoneal carcinomas behave and are
treated in a similar fashion to EOC. Australian guidelines recommend that all women diagnosed with a high-grade
serous, endometroid or clear cell EOC below the age of 70 are referred for BRCA1 and 2 mutation testing.
The majority of patients present with Stage III disease. Adjuvant chemotherapy following surgery is recommended
for some Stage I and all Stage II, III and IV disease in fit women, as this improves long-term survival. This usually
consists of 6 cycles of treatment with intravenous single-agent carboplatin or carboplatin plus paclitaxel. Evidence
also exists that women with Stage III disease who are debulked to minimal residual disease gain additional benefit
from some of the chemotherapy being given via an intra-peritoneal route. Patients with ovarian germ cell tumours
require different chemotherapy regimens and should be managed in specialised units.
Most patients with advanced disease will develop recurrence following this initial treatment. They may undergo
debulking surgery again but usually are treated with more chemotherapy with the aim of improving symptoms and
quality of life. The effectiveness of chemotherapy diminishes with each administration as the tumour becomes
progressively resistant, even if different drugs are used. Troublesome symptoms of advanced disease including
recurrent ascites, abdominal pain and small bowel obstruction require skilful palliation.
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Case study
Mrs KM is a 65 year old woman with no past medical history and a sister with breast cancer. She presents with loss
of appetite and increased abdominal girth. Clinical examination reveals a distended abdomen with shifting dullness.
Abdominal ultrasound reveals extensive ascites and the suggestion of bilateral adnexal masses, which are confirmed
on CT scan.
She is referred to a gynaecologic oncologist who performs an aspirate of the ascitic fluid. Cytological analysis
reveals the presence of malignant cells consistent with a serous carcinoma. Her serum CA125 is elevated. A
laparotomy is performed where ovarian masses are confirmed along with extensive peritoneal metastases and
omental involvement, indicating Stage III disease.
Resection of all macroscopic residual disease is performed including a partial large bowel resection. Two weeks after
surgery, Mrs KM commences adjuvant chemotherapy with carboplatin and paclitaxel for the next 5 months. During
primary treatment she is referred for genetic testing and found to carry a BRCA1 mutation.
Following treatment she remains well for 14 months until she develops left groin pain and bloating. Her CA125 has
also risen. CT abdomen shows recurrent disease in left sided pelvic lymph nodes as well as extensive peritoneal
disease and moderate ascites. She commences second line chemotherapy with carboplatin and liposomal doxorubicin
for 6 months. This improves her groin pain. Two months after finishing chemotherapy however her ascites returns
and her CA125 starts to rise again. After draining the ascites she receives further chemotherapy with weekly
paclitaxel infusions, but her ascites continues to reaccumulate rapidly. She also develops a partial small bowel
obstruction which is considered inoperable and fails to improve with bowel rest and corticosteroids. As she is too
unwell to have further chemotherapy, she is transferred to hospice. During her illness other family members are
tested with some also found to carry the BRCA mutation. Her sister and niece elect to undergo a prophylactic
bilateral salpingo-oophorectomy following completion of child-bearing and remain well long-term.
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Endometrial cancer
Endometrial cancer is the seventh most common malignancy, which will be diagnosed in 1 in 50 Australian women.
Oestrogen without progesterone use is a potent risk factor, as is obesity due to oestrone production by adipocytes. In
Western countries, it is the most common female genital tract malignancy with increasing incidence due to
increasing obesity. Inheriting a mutation in one of the Lynch syndrome genes is also a risk factor.
The presenting symptom in 90% of cases is post-menopausal bleeding, which permits diagnosis at an early stage.
This symptom should be investigated with endometrial sampling via bedside pipelle or dilation and curettage
performed under anaesthesia. The most common histological type of endometrial cancer (Type I) is endometrioid
adenocarcinoma, which originates from atypical endometrial proliferation and is oestrogen driven. Less common
Type II endometrial cancers are more aggressive and include serous, clear cell and carcinosarcoma.
Surgery is frequently curative treatment and provides additional staging information. The most relevant staging
criterion indicating disease at higher risk of relapse is the presence of lymph node involvement. High histologic
nuclear grade also indicates a worse prognosis. For early disease limited to the uterus, total abdominal hysterectomy
and bilateral salpingo-oophorectomy is sufficient, but more extensive surgical staging similar to EOC may be
recommended for more advanced disease. Lymph node sampling or dissection may be performed for disease with
deep uterine myometrial invasion or aggressive histology to give additional staging/prognostic information but has
not been shown to reduce mortality. Laparoscopic hysterectomy may be associated with reduced post-surgical
morbidity in appropriate cases.
Table 2: Stages of endometrial cancer

diagnosis
Stage 1 Tumour confined to uterus 75 - 80%
Stage II Tumour invades cervical stroma, but otherwise limited to uterus 70%
Stage Tumour invades serosa of uterus/adnexae/vagina/parametrium or involves pelvic or para-aortic lymph 45 -60%
III nodes
Stage Tumour invades bladder, bowel wall or has metastasised to distant organs 15%
IV
Those women diagnosed at a younger age or with a family history of other Lynch syndrome associated cancers such
as bowel cancer should be referred for consideration of genetic testing. Initial screening for this involves assessment
of the resected cancer for the presence of micro-satellite instability.
Optimum adjuvant treatment of endometrial cancer is still evolving. Most recurrences of endometrial cancer are
local, occurring in the surgical field. Radiotherapy delivered via external beam or by direct insertion of an applicator
containing radioactive source into the vagina (brachytherapy) reduces the chance of local recurrence but does not
impact on overall survival. For low risk early-stage disease (Type I, Stage I or II, low grade, without lymphovascular
invasion) the aim is to avoid over-treatment, and observation with or without vaginal brachytherapy is appropriate.
Such brachytherapy has less impact on quality of life than external beam treatment. For higher stage or high risk
disease, adjuvant chemotherapy may be used in addition to external beam pelvic radiotherapy, particular for those
with residual disease where the chance of developing metastatic disease is high. The role of chemotherapy in earlier
stage disease is being explored in clinical trials. For locally recurrent disease, salvage radiotherapy or surgery may
cure patients. For disseminated recurrence, treatment options include progestogens particularly for Type I
well-differentiated disease, or chemotherapy for Type II or aggressive Type I disease.
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Cervical cancer
Cervical cancer is the second most common cancer affecting women worldwide, particularly in developing
countries. It is caused by infection with the human papillomavirus (HPV), the most common sexually transmitted
infection in the world. Serotypes 16 and 18 of HPV are responsible for 70% of cervical cancer. Persistent HPV
infection leads to the development of cervical intraepithelial neoplasia, a precancerous lesion, at the transformation
zone of the cervix. Immunosuppression as seen in HIV or post organ transplant is a risk factor for persistent infection
and cancer development. Smoking is an additional risk factor. The precancerous lesions may be detected by cervical
smear and observed closely following it’s ablation via conisation, cauterisation or large loop excision of the
transformation zone (LLETZ). Because of the effectiveness of screening with Pap smears, cervical cancer is now
rare in Australia, with only around 800 cases diagnosed each year, mostly in those from disadvantaged backgrounds
who have not participated in screening. The recent development of HPV vaccines should eventually reduce the
incidence of cervical cancer by preventing the major risk factor.
Most cervical cancer is of squamous cell histology (80%), with adenocarcinoma being less common. It presents with
abnormal vaginal bleeding or vaginal discharge, and is also commonly discovered via screening cervical smear
which is recommended for all sexually active women. Staging is based on clinical examination, but may be aided by
the use of MRI and PET scans used to delineate invasion into surrounding structures or nodal spread and for
planning of appropriate treatment. The International Federation of Gynaecology and Obstetrics (FIGO) staging
system is shown in Table 3.
Table 3: Stages of cervical cancer

diagnosis
Stage 1 Tumour confined to the cervix 80-90%
Stage II Tumour invades beyond the uterus, but not to pelvic wall or lower third of vagina 60%
Stage III Tumour involves pelvic wall/lower third of vagina/causes hydronephrosis or involves regional lymph 35%
nodes
Stage Tumour invades mucosa of bladder or rectum or extends beyond true pelvis 15%
IV
For Stage I disease, surgery is an option, which may preserve ovarian function in younger patients. Outcomes are
equally good with external beam radiotherapy followed by brachytherapy, but this will induce menopause. For more
locally advanced disease, combination chemotherapy and radiotherapy is the treatment of choice and is able to cure
two thirds of women. Metastatic disease is managed with chemotherapy along with optimum palliative care.
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Case study
Mrs TD is a 45 year old unemployed smoker. She has had 6 months of bleeding post intercourse. Eventually she
attends for her first Pap smear, but the cervix is clearly abnormal on speculum. She is referred to a gynaecologic
oncologist. Cervical biopsy is performed, and confirms a squamous cell carcinoma of the cervix. She is clinically
staged to have FIGO stage IB disease. MRI suggests corpus uterine invasion and PET scan shows no lymph node
metastasis. She is treated with external beam radiotherapy for 5 weeks concurrent with weekly cisplatin
chemotherapy. Following this treatment she receives brachytherapy. She is advised to apply oestrogen cream to the
vagina with a vaginal cylinder to prevent post-radiotherapy vaginal stenosis. She is reviewed thereafter with
intermittent vaginal examination and management of survivorship issues including smoking cessation support. Her
disease does not recur.
Figure 1: Cervical cancer case study
Figure 2: MRI suggesting corpus uterine invasion
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References
• Wright JD, Barrena Medel NI, Sehouli J, Fujiwara K, Herzog TJ. Contemporary management of endometrial
cancer Lancet 2012 Apr 7;379(9823):1352-60 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/
22444602].
• Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer Lancet 2014 Apr 17 [Abstract available at
http://www.ncbi.nlm.nih.gov/pubmed/24767708].
• Monk BJ, Tewari KS, Koh WJ. Multimodality therapy for locally advanced cervical carcinoma: state of the art
and future directions J Clin Oncol 2007 Jul 10;25(20):2952-65 [Abstract available at http://www.ncbi.nlm.nih.
gov/pubmed/17617527].
• Tewari KS, Monk BJ. Invasive cervical cancer. In: DiSaia PJ, Creasman WT, eds. Clinical gynecologic oncology.
8th ed. Philadelphia: Mosby, 2012.
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Soft tissue sarcomas

12 September 2014 06:07:29
Author(s):
• David E Gyorki MBBS MD FRACS — Author
• Professor Michael A Henderson BS MD MB BMecSc — Author
page</ccabutton>
Gyorki, D, Henderson, M, Cancer Council Australia Oncology Education Committee. Soft tissue sarcomas [Version URL: http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Soft_tissue_sarcomas. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council
Epidemiology
Soft tissue sarcoma (STS) encompasses a broad group of cancers arising from mesenchymal cells and their
progenitors. There are over 50 subtypes of STS, classified according to their tissue of origin (see Table 1).
Approximately 1500 new cases of STS are diagnosed in Australia per year.
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Risk factors
Most sarcomas arise de novo. External beam radiotherapy, particularly at a young age can predispose to the
development of certain sarcomas, particularly angiosarcoma, malignant fibrous histiocytoma, leiomyosarcoma and
malignant peripheral nerve sheath tumours (MPNST). Chronic lymphoedema, particularly following surgery for
breast cancer, is a risk factor for a particularly aggressive form of angiosarcoma (Stewart-Treves syndrome). Certain
hereditary syndromes are associated with an increased risk of STS including Li Fraumeni (p53 mutation, multiple
sarcoma types) and neurofibromatosis type 1 (NF1 gene mutation associated with MPNST).
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Most STS can be divided into two main groups based on their mutational profile.[1] The majority of STS have a
complex unbalanced karyotype with genomic instability and heterogeneous mutations between tumours of the same
type. By contrast, about one third of STS have a specific translocation or characteristic point mutation (eg synovial
sarcoma, Ewing’s sarcoma, clear cell sarcoma).
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Clinical presentation depends on the location of the primary tumour. STS can simply be grouped into those found on
the extremity and those of the trunk (including retroperitoneum). The following clinical features should act as red
flags and raise suspicion for a diagnosis of sarcoma: - a mass with a diameter greater than 5 cm in size - a rapidly
growing mass - a mass which is atypical in clinical presentation These lesions should be imaged and referred to an
experienced sarcoma surgeon.
Diagnosis and staging (including histology, staging scans, tumour markers if applicable)
Any soft tissue lesion located deep to the deep fascia on imaging should raise the suspicion of a soft tissue sarcoma.
The AJCC staging system for soft tissue sarcoma involves tumour size, lymph node status, presence of metastatic
disease as well as grade (TNMG).[2] Other significant prognostic factors include anatomical location, tumour depth
relative to the deep fascia, mitotic rate and histological subtype.[2] Retroperitoneal sarcomas often grow to a very
large size prior to presentation as they characteristically push adjacent organs away and are located in an
inconspicuous location.
If a mass raises the suspicion of an STS, the optimal management is referral to a tertiary centre specialising in the
management of sarcoma prior to any intervention. The diagnosis is typically made on core biopsy. The biopsy
approach needs to be considered as part of the management as the biopsy tract is excised at the time of surgery. As
such the biopsy should be performed in consultation with the surgeon planning the resection. Given the rarity of the
disease, and the implication of the histological diagnosis, the pathology should be reviewed by an expert
histopathologist.
Staging of STS involves assessment of the primary and the identification of metastatic disease. For STS of the
extremity, the best primary staging modality is MRI. This provides excellent anatomical detail regarding the
relationship of the tumour to important adjacent structures. Functional imaging using thalium scan or PET can also
be useful to identify the focus of tumour with the highest metabolic activity to guide biopsy. A CT scan of the
abdomen and pelvis is the primary modality for imaging retroperitoneal sarcoma.
Lymph node metastases are rare in STS as metastasis is usually via the haematogenous route. The most common site
of metastatic disease is the lung and all patients with a new diagnosis of STS should be staged with a CT scan of the
chest.
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Prognosis (including prognostic factors, cure rates, median survival, stage dependence etc.)
Management of STS requires a multidisciplinary team. Surgery is the definitive therapy for most STS. The principles
of surgery include an en-bloc resection of the lesion with any adjacent involved tissues. For extremity sarcoma, limb
sparing surgery can be achieved in the majority of cases with only a small percentage requiring amputation.[3] For
retroperitoneal sarcoma, adjacent organs such as the kidney or colon may need to be resected to achieve a clear
margin.
Radiation therapy is often used as an adjunct to surgery to reduce the risk of local recurrence. Preoperative radiation
is preferred as a smaller area can be targeted, however there is an increased risk of wound complications following
neoadjuvant radiotherapy. Although radiotherapy reduces the risk of local recurrence, it has not been associated with
an improvement in overall survival. This is likely because the majority of patients who die from STS do so as a
result of metastatic disease.
Certain tumour types such as rhabdomyosarcoma are highly chemosensitive, others such as liposarcoma are
relatively chemoresistant.
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Soft tissue sarcomas, particularly of the retroperitoneum have a propensity to recur. The majority of recurrences
occur in the first 5 years, however recurrences are not uncommon beyond 10 years. Therefore patients with STS need
to be continually monitored for recurrence for an extended period of time. Surveillance involves an assessment of the
primary site as well as for evidence of pulmonary metastases.
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Case studies
Case 1
A 50-year-old man presented to his GP with 2 months of increasing abdominal distension and right lower abdominal
pain. He had been previously well with no significant past medical history. Examination revealed some mild
tenderness and fullness in the right iliac fossa.
A CT scan of the abdomen revealed a 10x16 cm solid mass in the retroperitoneum displacing the abdominal viscera
to the left. The mass was heterogenous, and given its deep location was suspicious for a soft tissue sarcoma.
The patient was staged with a CT scan of the chest and a PET scan. These demonstrated no evidence of metastatic
disease. The patient was referred to a specialist cancer centre with extensive experience in the management of soft
tissue sarcoma. A core biopsy was organised using the PET scan to identify the area of the tumour with the most
active FDG avidity and therefore the most informative area of the tumour to biopsy. The biopsy was consistent with
a high-grade dedifferentiated liposarcoma.
Given the absence of metastatic disease, a decision was made to continue with curative management. The patient
was planned for neoadjuvant radiotherapy in an attempt to maximise the chance of local control after definitive
surgical resection. After completion of radiotherapy, repeat imaging again did not demonstrate metastatic disease
and the patient underwent resection of the mass including the right kidney, an area of abdominal wall where the
tumour was adherent and an adherent loop of small bowel. Resection of adjacent viscera is often required for
retroperitoneal sarcoma in order to maximise the chance of a complete resection. Histopathology revealed a 17 cm
mass consistent with high grade dedifferentiated liposarcoma. There were some areas of necrosis in the tumour
consistent with the radiation effect but the response to radiotherapy was small. The tumour stage was Stage III (T2b,
N0, M0 G3).[2]
The patient made a good post-operative recovery and was followed up with a repeat CT scan of the chest, abdomen
and pelvis every 6 months looking for signs of recurrence or metastatic disease. The patient developed chronic
diarrhoea postoperatively consistent with radiation enteritis, a common side effect of abdominal radiation.
After 24 months, a CT scan demonstrated a new nodule on the posterior abdominal wall in the previous operative
field. This was highly suspicious for a local recurrence. Repeat staging investigations failed to identify any
metastatic disease and the patient was taken back to the operating room for resection of this mass.
The patient was again followed with repeat imaging every 6 months and after 15 months, presented with abdominal
pain. Repeat CT scan demonstrated five new masses consistent with multifocal recurrence. The patient was referred
for palliative chemotherapy due to the disease progression, which was now unresectable.
This case demonstrates a common disease course for patients with large high-grade retroperitoneal sarcoma which
due to their advanced initial presentation, have a high risk for local recurrence.
Case 2
A 45-year-old woman presented with a 4 week history of a lump in the inner right thigh. The lump was not painful
and was growing slowly. She presented to her GP who thought this may be an enlarged lymph node and arranged an
ultrasound. The ultrasound demonstrated a 5 cm mass within the adductor compartment of the thigh. Given the mass
was deep to the deep fascia, suspicion of a soft tissue sarcoma was raised.
The GP referred the patient to a unit specialising in the management of soft tissue tumours. An MRI of the thigh
showed a solid mass within the adductor compartment of the thigh. A PET scan demonstrated heterogenous uptake
but also showed two FDG avid lesions in the left lung. A core biopsy was performed of the most FDG avid area of
the mass in the thigh. This was consistent with high-grade malignant fibrous histiocytoma.
To better characterise the lung lesions, a CT scan of the chest was performed which demonstrated multiple bilateral
lung nodules, the largest of which was 15mm in diameter in the left upper lobe (figure 3). Given the large, high
grade primary lesion, these lung nodules were consistent with metastatic disease (Stage IV – T2b, N0, M1, G3).
As the primary lesion was asymptomatic, there was no role for local therapy (surgery or radiotherapy) and the patient
was referred to medical oncology and was commenced on palliative chemotherapy with doxorubicin and
iphosphomide. She achieved a partial response but progressed rapidly after 9 months. At this point, she was enrolled
in a clinical trial of a novel agent but progressed with widespread metastatic disease after 6 months.
This case demonstrates the propensity of high-grade sarcomas to metastasise to the lungs. This is associated with a
poor prognosis.
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Table 1: Soft tissue sarcomas are named according to their tissue of origin.
Tissue of Origin Sarcoma
fat liposarcoma
connective tissue fibrosarcoma
smooth muscle leiomyosarcoma
skeletal muscle rhabdomyosarcoma
endothelium angiosarcoma
nerve sheath malignant peripheral nerve sheath tumour
Undifferentiated mesenchymal origin malignant fibrous histiocytoma
Figure 1: CT scan of the abdomen demonstrating a large retroperitoneal mass.
Figure 2: CT chest demonstrating a lung metastasis in the left upper lobe.
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Further reading
1. Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults N Engl J Med 2005 Aug
18;353(7):701-11. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16107623
2. Taylor BS, Barretina J, Maki RG, Antonescu CR, Singer S, Ladanyi M. Advances in sarcoma genomics and new
therapeutic targets Nat Rev Cancer 2011 Jul 14;11(8):541-57. Abstract available at http://www.ncbi.nlm.nih.
gov/pubmed/21753790
3. National Cancer Institute. Stage information for adult soft tissue sarcoma. [homepage on the internet] America:
National Institute of Health; 2014 Feb 28 [cited 2014 May 29; updated 2014 Feb 28]. Available from: http://
www.cancer.gov/cancertopics/pdq/treatment/adult-soft-tissue-sarcoma/HealthProfessional/page3
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References
[1] Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med 2005 Aug 18;353(7):701-11 [Abstract available at
http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 16107623].
[2] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York, NY: Springer; 2010
[cited 2014 May 22] Available from: http:/ / www. springer. com/ medicine/ surgery/ book/ 978-0-387-88440-0.
[3] Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, et al. The treatment of soft-tissue sarcomas of the extremities:
prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant
chemotherapy. Ann Surg 1982 Sep;196(3):305-15 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 7114936].
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Bone tumours 99
Bone tumours
14 September 2014 23:56:43
Author(s):
• Professor Peter F.M. Choong MBBS MD FRACS FAOrthA — Author
• Grant Pang MBBS FRACS FAOrthA — Author
page</ccabutton>
Choong, P, Pang, G, Cancer Council Australia Oncology Education Committee. Bone tumours [Version URL: http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Bone_tumours. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available from:
Introduction
Embryologically, bone arises from the mesoderm. As such, primary tumours related to bone might comprise any
tissue of mesodermal origin. Bone tumours are common. The largest group are benign bone tumours, followed by
metastatic bone tumours, and, least commonly, primary bone malignancies.
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Benign bone tumours

Common benign bone tumours include:
• aneurysmal bone cyst
• simple bone cyst
• enchondroma
• giant cell tumour of bone.
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Bone tumours 100
Aneurysmal bone cyst

Aneurysmal bone cysts (ABC) may occur in any bone. The commonest sites include the appendicular skeleton
(20-25%), followed by the spine (15%) and pelvis (10%).
Figure 1(a). Antero-posterior and lateral radiograph of ankle. Aneursymal bone cysts are generally located
eccentrically in the metaphysis. They are radiolucent, expansile with thinning of the cortex and often have a
sharp sclerotic margin.
Figure 1(b). Coronal and sagittal magnetic resonance images of simple bone cyst of ankle.
Figure 1(c). Axial magnetic resonance images of aneurysmal bone cyst of ankle MRI scan shows a well defined
lesion, often lobulated with internal septations. Fluid-fluid levels are seen here as demonstrated (arrow).
Pathology
Bone tumours 101
There are 2 types of ABC. The typical ABC (95%) is a blood filled lytic expansion of bone which is often separated
into a multitude of compartments by thin septae of bone. A less common form, the solid ABC (5%), is characterised
by an expansion of bone which is filled with a mixture of fibrous, cellular and myxoid tissue in which blood filled
clefts are found.
Presentation
Because the wall of the cyst is thin, fracture may occur with minimal trauma (pathologic fracture). Prior to fracture,
normal stresses on the involved bone may also cause pain. Sometimes expansion of the bone may be significant and
patients may present with a lump associated with a bone or a general swelling/enlargement of one part of a bone.
Investigation
• plain radiographs
• nuclear bone scan
• computed tomography
• magnetic resonance imaging
• biopsy
Treatment
ABC can be treated with curettage of its contents, and filling of the defect with bone graft or synthetic material (bone
graft substitute or acrylic bone cement). Sometimes weakened bone also requires internal fixation.
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Simple bone cysts

Simple bone cysts occur in the young and are most commonly detected between the ages of 5-15 years. It is
characterized by an expansile cavity within bone. Most commonly there is only one compartment related to the cyst
(unicameral), but occasionally there may be a number of compartments (multicameral).
While simple bone cysts may occur in any bone the commonest bones are the proximal long bones (humerus,
femur).
Figure 2. Unicameral bone cysts are centrally located, well circumscribed within the metaphysis or diaphysis
of long bones. They have a radiolucent appearance, often expansile with thinning of the cortex. The
characteristic “fallen fragment” sign (arrow) can sometimes be seen. This represents a fracture fragment
which floats within the fluid-filled cyst.
Pathology
Bone tumours 102
Simple cysts are often only filled with a clear yellowish fluid. The lining of the cyst wall is by a bland pauci-cellular
membrane. There are two variants of simple bone cysts namely, active and latent. Active bone cysts are usually
located adjacent to the growth plate and increase in size as the child/teenager grows. Once skeletal growth slows or
ceases, cysts become inactive (latent). They are usually found further away from the growth plate at this stage.
Sometimes the proximity of the cyst to the growth plate interferes with normal growth and discrepancies in size or
length of the bone may be noted.
Presentation
Simple cysts become symptomatic when they break or are sufficiently stressed. The potential for ongoing growth of
the cyst during the period of childhood/adolescent activity may result in repeated fractures.
Investigation
• plain radiograph
• biopsy
Treatment
Simple bone cysts may heal spontaneously after fracture. Aspiration of the fluid from the cyst and injection with
corticosteroid may also lead to healing. Troublesome cysts with ongoing pain or repeated fractures may be treated
with evacuation and filling with bone graft. Occasionally internal fixation may be required.
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Enchondroma
An enchondroma is a benign cartilage tumour that arises within bone. Enchondromas may arise in any bone, may be
solitary or multiple, may be static or may grow. They are often noted incidentally on plain radiographs or bone scans
obtained for other reasons.
Figure 3. Enchondromas are commonly located in the metaphysis of long bones ie. proximal humerus, distal
femur and proximal tibia. They have a mixed sclerotic and lucent appearance with calcifications (arrow)
within the lesions.
Pathology
Enchondromas arise from embryological cartilage remnants that have failed to fully ossify. Under the influence of
the growing skeleton, enchondromas may also increase in size until skeletal maturity. Enchondromas when detected
in adulthood are often inactive, but in rare circumstances may continue to grow or even undergo malignant change.
The majority of tumours remain benign and indolent.
Enchondromas are lytic lesions filled with cartilage tissue. Erosion of the inner (endosteal) surface of bone may
occur from direct pressure of the cartilage tumour or by active bone destruction. If the latter occurs, then care should
be taken to exclude malignant change.
Bone tumours 103
Enchondromas may rarely be multiple (enchondromatosis) and is referred to as Ollier’s disease. The risk of
malignant transformation is higher with Ollier’s disease than with solitary enchondromas.
Presentation
Enchondromas are usually incidentally found when bones are investigated for other reasons. Sometimes,
enchondromas may undergo pathologic fracture with those located in the fingers and toes most vulnerable.
Investigation
• biopsy
Treatment
Enchondromas which are asymptomatic with no evidence of activity may be left untreated. Those which are
symptomatic may be treated with curettage, then filled with bone graft or synthetic graft material or acrylic bone
cement. If there is a suspicion that the enchondroma is undergoing malignant transformation, then the approach for
management is as for malignant bone tumours.
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Giant cell tumour of bone

Giant cell tumour (GCT) of bone is an expansile, destructive lesion that arises in the epiphysis of bone. It commonly
occurs in the age group 20-40 years and the knee (distal femur, proximal tibia) is the most frequent site affected.
Figure 4. Antero-posterior and lateral radiograph of wrist. Giant cell tumours are lytic lesions that are
located eccentrically in the metaphysis abutting the subchondral bone. They are generally well defined, often
expansile and may be associated with a soft tissue component.
Pathology
GCT is characterized by the proliferation of multinucleated giant cells which are scattered throughout the tumour
together with a population of mononuclear stromal cells. Sometimes, there are elements of ABC within the GCT.
Action by the giant cells results in lytic destruction of the bone. The long history of the tumour allows time for bone
remodeling which explains the expansile nature of the tumour. Although GCT is not malignant, it may sometimes
metastasise to lung. GCT of the radius is the site most commonly associated with lung metastases.
Presentation
Bone tumours 104
Pain is a feature of GCT and is characteristic of aggressive bone tumours. Typically, patients will complain of
constant deep seated bone pain which is unremitting and unresponsive to analgesia, and is worse at night. It is often
associated with enlargement of the epiphysis of the bone giving the impression that there is joint swelling. True
swelling is caused by extraosseus soft tissue extension of tumour. Acute pain usually represents pathologic fracture.
Investigations
• plain radiograph
• biopsy
Treatment
Currettage and filling of the cavity with bone graft or acrylic cement is the commonest treatment option for GCT.
When a joint cannot be adequately preserved then resection of the affected part of the bone and prosthetic
reconstruction is a recommended option.
GCT may recur locally in the area of the surgery or systemically as a pulmonary metastasis. Regular surveillance
with imaging of the affected bone and lungs is required for 5 years.
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Malignant bone tumours

The diagnosis of a malignant bone tumour is based on tumour behaviour, cell type and microscopic features of
malignancy.
Because bone has a mesodermal origin, tumours may arise from any component of the mesenchyme. Malignant
tumours of bone may also have components which arise from neuroectodermal tissue.
Tumour behaviour
The rapid multiplication of tumour cells leads to:
• extension of the tumour through the medullary canal of bone
• recruitment of osteoclasts by tumour cytokines resulting in osteolysis around the tumour
• migration of tumour cells through the cortex of bone results in stripping up of the periosteum of bone
• multiplication of tumour cells outside of bone (extraosseous extension) results in the formation of a mass.
Multiplication of cells within the confines of the bone together with osteolysis gives rise to the characteristic bone
pain. The rapid multiplication of cells outside of bone gives rise to the firm painful mass, which is restricted by the
periosteum. Stripping up of the periosteum by the invading tumour cells causes a reaction by the immature bone cells
within the periosteum to make bone. This is recognised by periosteal new bone formation on radiologic imaging of
the bone.
Cell type
The type of bone malignancy depends on the identification of the most differentiated cell within the abnormal
population. If the tumour cells are polygonal and make bone then they are referred to as osteosarcoma. If the tumour
cells are large and produce a chondroid matrix, they are referred to as a chondrosarcoma. If the cells are spindle
shaped, densely packed and associated with fibrous tissue formation, they are referred to as fibrosarcomas. A
particular bone tumour that arises from neuroectodermal tissue is the Ewing’s tumour. This is sometimes referred to
as a small round blue cell tumour because of the typical small round blue cells identified on histology.
The most common primary malignancies of bone include:
• osteosarcoma
• chondrosarcoma
Bone tumours 105
• Ewing’s sarcoma.
Histologic features of malignancy
Key histologic features that support a diagnosis of malignancy include:
• bizarre cell shapes (polymorphic)
• high cell counts
• mitoses
• spontaneous tumour necrosis
• microvascular invasion.
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Osteosarcoma
Osteosarcoma is the commonest primary malignancy of bone in the adolescent and young adult. It is a bone-forming
tumour where the production of a bone matrix is the “sine qua non” of osteosarcoma. It occurs most commonly
around the knee (distal femur, proximal tibia). Other areas include the proximal humerus, distal radius and pelvis. It
is a fatal disease that without appropriate systemic therapy results in widespread metastases. The lung is the
commonest site for spread.
Figure 5(a). Antero-posterio and lateral radiographs of distal femur and knee. Osteosarcomas are ill defined
bone lesions with a pattern of permeative bone destruction and irregular areas of sclerotic bone formation.
They are often associated with an aggressive appearing periosteal reaction (Codman’s triangle, lamellated or
sunburst (arrow)) and a soft tissue mass.
Figure 5(b). MRI scan of the lesion in distal femur showing a large soft tissue mass.
Bone tumours 106
Figure 5(c). MRI scans shows a medullary lesion with associated periosteal reaction and large soft tissue mass.
Pathology
Osteosarcoma usually occurs in the metaphysis of long bone. Commonly it is restricted by the growth plate, which
forms a barrier to tumour invasion. Extension of the tumour through metapyseal bone gives the classic diffuse
swelling associated with this tumour. Osteosarcoma may also arise from pre-existing abnormalities such as
osteochondromas, bone infarcts, Paget’s disease, and fibrous dysplasia. This is a rare event and accounts for a second
peak in middle-aged or elderly patients. There are a number of variants of osteosarcoma including chondrogenic
osteosarcoma, fibrogenic osteosarcoma, conventional osteosarcoma, small round cell osteosarcoma, telangiectatic
osteosarcoma, periosteal osteosarcoma, and 2 low grade variants referred to as parosteal osteosarcoma and low-grade
central osteosarcoma.
Osteosarcoma may be graded into low, intermediate and high grade, with the metastasis free survival decreasing as
the grade of tumour rises.
Presentation
Patients present with increasing limb pain, which is of an insidious onset but a progressive nature. The pain is often
described as a deep ache. Eventually the pain becomes unremitting and unresponsive to oral analgesics. The pain is
typically worse at night.
Limb swelling is often diffuse and periarticular giving the impression of joint swelling. Enlargement of the tumour
may cause restricted muscle function which may present with a loss of range of motion of an adjacent joint.
Significant osteolysis may also present with pathologic fracture of the affected bone.
Investigations
• functional imaging
• biopsy
Treatment
Modern multimodal treatment includes neoadjuvant chemotherapy followed by surgery then post-operative
chemotherapy. Osteosarcoma is sensitive to chemotherapy and the purpose of this is to control systemic spread of
disease. Chemotherapy also has an impact on the local tumour causing tumour necrosis, ossification, sometimes
reduction in size and the development of a fibrous rind around the tumour, which helps to protect against local
extension of disease.
Bone tumours 107
The mainstay of chemotherapy is doxorubicin (Adriamycin) but additional agents have also shown efficacy,
including methotrexate, ifosphamide and cisplatin.
Surgery is performed with wide margins to minmise local recurrence of disease. Reconstruction of the bone defect
after resection may include biologic or prosthetic reconstructions or combinations of the two. Amputation is reserved
for limb tumours that cannot be resected without ablation of the limb, or if removal of the tumour does not lead to a
functional limb afterwards.
Follow-up
The local recurrence rate after appropriate multimodal therapy is less than 10%. The 5-year survival rate is
approximately 75%. Regular surveillance is required to ensure that recurrent disease is detected early. This includes
periodic follow up (quarterly for the first 2 years, 6 monthly for the next 2 years and yearly for the next 4 years).
Chest CT and limb imaging are also performed at regular intervals.
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Chondrosarcoma
Chondrosarcoma is one of the more common sarcomas in adults. These occur in both the appendicular and the axial
skeleton including flat bones like the pelvis and scapula. This tumour is characterized by the production of a
chondroid matrix.
Figure 6(a). Anterio posterior radiograph of left shoulder. Chondrosarcomas are similarly located in the
metaphysis of long bones but unlike enchondromas, have more aggressive radiological features. These include
cortical thickening or remodeling, cortical scalloping or osteolysis and soft tissue extension.
Figure 6(b). Sagittal magnetic resonance image of chondrosarcoma of the proximal humerus showing
intramedullary and extraosseous extension.
Pathology
The type of matrix and cellular nature allow sub-classification of chondrosarcoma into various types including
conventional central chondrosarcoma, clear cell chondrosarcoma, mesenchymal chondrosarcoma and
dedifferentiated chondrosarcoma. Occasionally, chondrosarcoma may arise from benign conditions such as
Bone tumours 108
osteochondromas or enchondromas. Patients with multiple osteochondromas or enchondromas are more vulnerable
to malignant change than patients with solitary tumours.
Chondrosarcoma may be graded into low intermediate and high grade tumours with the metastasis free survival
decreasing with an increase in tumour grade.
Investigation
• biopsy
Treatment
Chondrosarcoma are rarely responsive to chemotherapy or radiotherapy. Surgery remains the mainstay of treatment.
Surgery usually involves resection with wide margins followed by reconstruction, which may be biologic, prosthetic
or a combination of the two.
Adequate surgical treatment usually results in good local control of disease (<10%) and low systemic recurrences.
Follow-up
The local recurrence rate after appropriate surgery is less than 10%. The 5-year survival rate is approximately 75%.
Regular surveillance is required to ensure that recurrent disease is detected early. High grade tumours are rarely
responsive to chemotherapy and in this group the rate of metastasis is very high. This includes periodic follow up
(quarterly for the first 2 years, 6 monthly for the next 2 years and yearly for the next 4 years). Chest CT and limb
imaging is also performed at regular intervals.
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Ewing’s Tumour
Ewing’s tumour is one of the family of peripheral neuroectodermal tumours. It metastasises early and is fatal without
treatment. It is sometimes referred to as a small round blue cell tumour because of its characteristic histologic
appearance. Ewing’s sarcoma like osteosarcoma is a disease of adolescents and young adults. Ewing’s affects both
flat and tubular bones with a preponderance for the midshaft of tubular bones.
Figure 7(a). Antero-posterior and lateral radiograph of Ewings sarcomas are often located in the diaphysis of
long bones and generally have a permeative pattern of bone destruction with an associated lamellated
periosteal reaction (onion-peel (arrow)) and a soft tissue mass.
Bone tumours 109
Figure 7(b). Coronal and axial magnetic resonance images demonstrate the presence of an extensive periosteal
reaction and soft tissue mass.
Pathology
A highly cellular tumour characterizes Ewing’s tumour where the tumour is packed with a large population of small
round blue cell tumours. The rate of proliferation is very high and usually gives rise to a very large soft tissue
extension of the tumour from bone. The tumour tends to permeate along the intramedullary canal of bone and
through the cortex.
The differential diagnosis of Ewing’s tumour includes other tumours that have high populations of small round blue
cell tumours including, lymphoma, neuroblastoma, small round cell osteosarcoma, rhabdomyosarcoma as well as
osteomyelitis.
This is one tumour where diagnostic accuracy is critical to planning effective treatment. Immunohistology is used to
detect MIC-2 staining. Chromosomal analyses are used to detect translocations of chromosome 11 and 22. Molecular
pathology is used to identify the fusion gene product (EWS-FLi) that results from chromosomal translocation
involving chromosome 11 and 22.
Investigation
• biopsy
Treatment
The key to effective Ewing’s treatment is neoadjuvant chemotherapy. Ewing’s tumour is highly sensitive to
chemotherapy, which often results in marked reduction in the soft tissue component of the tumour. The
responsiveness of the tumour to chemotherapy correlates with post-operative survival. Better survival is associated
with post-chemotherapy necrosis of >95%. Ewing’s tumour is also radiosensitive and this modality may be employed
with very large tumours; tumours that have not responded optimally to chemotherapy; tumours that may not be
amenable to resection; or following resection where margins have been narrow. Surgery usually involves resection
with wide margins followed by reconstruction, which may be biologic, prosthetic or a combination of the two.
Follow-up
Local tumour recurrence after appropriate surgical margins is <10%. Five-year survival following appropriate
treatment is between 50-60%. Because of the high risk of recurrent systemic disease, regular rigorous surveillance is
required. This includes periodic follow up (quarterly for the first 2 years, 6 monthly for the next 2 years and yearly
for the next 4 years). Chest CT and limb imaging is also performed at regular intervals.
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Bone tumours 110
Metastatic bone tumours

The commonest malignant tumours of bone are metastases from carcinoma. The commonest tumours that
metastasise to bone are the paired midline organs including:
• lung
• breast
• prostate
• kidney
• thyroid
Other carcinomas may also metastasise to bone but do so infrequently.
The rate of bone metastastasis is 60% but only 10% require surgical treatment. The commonest sites for bone
metastasis include the femur, proximal humerus, vertebral column and pelvis. Metastasis below the knee and elbow
is uncommon.
Pathology
Bone metastases may be lytic, sclerotic, or a combination of the two. While both lysis and sclerosis may weaken
bone, the former is more likely to lead to pathologic fracture.
The complications of bone metastases include:
• pain
• pathologic fracture
• immobility
• hypercalcaemia
• marrow suppression.
Presentation
Patients with bone metastases either present with bone pain of an insidious onset, or following pathologic fracture.
This may be the first presentation of malignant disease or the patient may already have a history of carcinoma.
Investigations
• biopsy
Treatment
Treatment of bone metastases depends on the presence of fracture or impending fracture. Depending on the bones
involved, radiotherapy alone may be utilized (e.g. in the spine, pelvis or skull). Surgery is used to strengthen affected
bone in order to protect a patient’s mobility (lower limb) and independence (upper limb). A stable and durable
construct is critical for ensuring adequate application. Different surgical techniques may be employed including
internal fixation with intramedullary rods or plates, and occasionally, joint replacement may also be required.
Amputation may sometime be employed if metastases have either destroyed bone, making it irreparable, or there is
fungation.
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Melanoma and skin

19 September 2014 04:37:17
Author(s):
• Associate Professor Brendon Coventry MBBS PhD FRACS — Author
page</ccabutton>
Conventry, B, Cancer Council Australia Oncology Education Committee. Melanoma and skin [Version URL: http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Melanoma_and_skin. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available
Epidemiology
Incidence
Australia and New Zealand skin cancer and melanoma rates are the highest in the world. Non-melanoma skin cancer
(NMSC) is the commonest type, with 1 in 2 Australians diagnosed with a BCC or SCC. Melanoma in Australia was
diagnosed in some 12,510 (7,440 males and 5,070 females) in 2012, based on state cancer registry data; with some
200,000 cases occurring worldwide. In Australia, the lifetime risk of cutaneous melanoma by the age of 85 was 1 in
14 for males and 1 in 23 for females.
Australia and New Zealand have the highest melanoma incidence rates in the world at about 62.7 per 100,000
population for males and 39.9 per 100,000 for females. The rates decrease in approximate proportion to skin colour,
with rates of about 3 per 100,000 for very dark skinned Indigenous people.
Mortality
In 2012, an estimated 1,560 people (1,070 males and 495 females) died from melanoma. In 2010, the lifetime risk of
death from melanoma by 85 years of age was 1 in 85 for males and 1 in 226 in females. Melanoma represents the
sixth most common cause of death in men and tenth most common in females. The rate of death from SCC was not
recorded accurately enough in most centres worldwide to determine figures. Mortality from BCC is very rare.
Prevalence and survival
In Australia, the prevalence of NMSC is not accurately known, but is extremely high. In 2007, there were 136,016
people alive following diagnosis of melanoma of the skin over the prior 26 years (70,654 males and 65,362 females).
For the 2006-2010 period, the probability of survival for 5 years was 89% for males and 94% for females. In
2010-2011, melanoma accounted for 1.2% of all cancer-related hospitalisations, or 10,457 hospitalisations.
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Risk factors
Personal history
The previous diagnosis of melanoma in a person increases the risk of subsequent primary melanoma in that
individual by about tenfold.
Family history
The history of a first-degree relative diagnosed with melanoma increases the risk of melanoma by in that individual
by about two-fold.
Skin type, eye colour, hair colour
The less the melanin pigmentation in the skin, eye iris and hair, the greater the risk of melanoma and other skin
cancers that individual has. Lighter vs darker for all features approximately doubles the risk.
Environmental exposure
The association between UV intensity and duration of exposure, especially associated with sunburn, has been well
documented. Higher exposure has relative risk of 1.5 times that of lower exposure.
Genetics
The precise role of genetics in determining melanoma risk is currently unclear and made complex by the many
factors that determine skin melanin levels, hereditary traits and cellular repair mechanisms.
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The molecular genetics of melanoma is gradually being elucidated, but apart from some pathways concerned with
B-raf, Mek and C-kit, relatively little is clearly understood.
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Typical skin cancer presentations are: BCC: Pink, nodular, raised lesion with 'pearly' edges; or flat pink lesion.
SCC: Whitish-pink, scaly, crusted, raised lesion; or pink flat lesion.
Melanoma: Has many clinical forms being termed the 'chamelion' of cancers. The primary melanoma may be flat or
raised, visible, itch or bleed, but occasionally the effects of metastatic spread may be the first apparent sign.
Primary melanoma is typically a pigmented, variegated skin lesion with recent change(s) in size, shape or colour.
Morphological types include: Superficial spreading, nodular, acral lentiginous, lentigo maligna. Amelanotic
melanoma is not uncommon and is often nodular, sometimes being confused with a basal cell carcinoma or
squamous cell carcinoma. Melanoma may involve the keratinised skin of the sun-exposed, as well as occasionally
the non-exposed regions of the body, including the mouth, nasal cavities, ear canal, vagina, and anal canal. Very
rarely, the oesophagus, stomach, small bowel or other organs can be involved with a primary melanoma, however,
most melanomas in these locations are metastases.
Secondary melanoma is metastatic usually from a cutaneous site, and can occur to any site, with skin/subcutaneous,
lung, liver, bone, brain, gut, adrenal gland and nerve being most common in approximately that order. Most
metastases are asymptomatic. Skin lumps are perhaps the commonest sign, than tiredness, fatigue, weight loss,
cough, jaundice, fracture, neurological disturbance, bowel obstruction or gastrointestinal bleeding.
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Diagnosis is usually by pathology using excision biopsy for primary lesions and fine /core needle biopsy for
secondaries. Occasionally, punch or shave biopsies may be required, but these may complicate pathological
diagnosis and/or treatment, and are less preferred, especially for melanoma. Lactate dehydrogenase (LDH) may be a
useful bio-marker in melanoma for metastatic disease, later recurrence, or risk of this. CT scanning (head/ chest/
abdomen; with neck/ pelvis depending on the melanoma site) may be useful to detect potentially operable/ treatable
metastases for patients with higher risk melanomas (Breslow > 2.5mm; ulcerated; high mitotic rate; elevated serum
LDH). The scanning results may alter surgery type. Head MRI scanning may be more useful to detect small brain
metastases, or to clarify metastases, especially in the neck. CT and MRI scanning may be useful for SCC, and rarely
for advanced BCC.
Staging (see TNM or AJCC for details): The Tumour; Node; Metastasis (TNM) classification, or American Joint
Committee on Cancer (AJCC) is usually used for staging of skin cancers into Stage I and II (localised); Stage III
(regional spread); and Stage IV (distant spread).
BCC: staging is usually not performed as most are confined to skin. Larger lesions are staged T1 <2cm diameter; T2
>2cm diameter; T3 invasion of bone or nerve; T4 skull invasion.
SCC: Tis - insitu SCC; T1 <2cm diameter; T2 >2cm diameter; T3 invasion of bone or nerve; T4 skull invasion. N0:
No lymph nodes spread; N1: Spread to 1 draining lymph node ≤ 3 centimeters (cm) diameter; N2: Spread to 1
ipsilateral draining lymph node [a = 1 LN 3-6cm size; b = >1 LN <6cm; c = contralateral lymph node(s)] N3: any
LN ≥ 6 cm across. M0: No spread; M1: Spread to distant organs.
Melanoma: Tis: Melanoma in situ; T1: < 1.0 mm thick; T2: 1.01 and 2.0 mm; T3: 2.01 and 4.0 mm; T4a: > 4.0 mm.
[a is added if absent; b if ulceration and/or the mitotic rate ≥ 1/mm2 is present.] N0: No lymph nodes spread; N1:
Spread to 1 draining lymph node; N2: Spread to 2-3 nodes, OR local intransit; N3: Spread to ≥ 4 nodes, OR spread
to lymph nodes that are clumped together, OR spread of melanoma to nearby skin or toward a lymph node area and
into the lymph node(s). [a is added if microscopic; b if visible; c for satellite/ intransit.] M0: No distant metastasis;
M1a: Skin/subcutaneous tissue, or non-draining lymph nodes; normal blood LDH level; M1b: Metastasis to the
lungs; normal blood LDH level; M1c: Metastasis to other organs, OR an elevated blood LDH level. Stage I
(localised); Stage II (deeper localised); Stage III (regional spread); Stage IV (distant spread).
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Prognosis
Prognosis for skin cancer is based on the characteristics of the primary tumour, and the AJCC and TNM Staging
system. BCC grows locally and usually has a good prognosis. Further new BCC/SCC are common. Recurrence rates
from BCC and SCC excised with adequate clear margins are low.
SCC: Approximate 10-year survival rates are Stage I & II 60-80%; Stage III 20%; Stage IV 10%.
Melanoma: Approximate 10-year survival rates: Stage I 90-95% Stage II 40-70%; Stage III 25-70%; Stage IV
<10%. Cure rates are high for Stage I, and decrease for Stage II, II and IV respectively (see AJCC JCO, 2009 for
further details).
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Surgery: Most skin cancer is effectively treated by surgery alone, especially for early stage primary lesions. This is
both diagnostic and curative. Even a considerable proportion surgery of metastatic spread: locally, intra-lymphatic
(intransit), and to regional lymph node basins, is effectively treated by surgery, and provides diagnosis, useful local
disease control, and can be curative. Adjuvant treatments remain incomplete, and the effectiveness of these remains
situational. Surgical treatment of metastases remains a challenge, however, good palliation and even long-term
survivals can be produced by selective surgery for metastases. It remains unpredictable exactly which patients will
gain the benefit after resection.
Medical: The mainstay of medical management has been dacarbazine and fotemustine chemotherapy with low rates
of response and very low cure rates. Recent evaluation of small molecule inhibitors against MEK and mutant BRAF,
and CTLA and PD1 inhibitory monoclonal antibodies have improved response rates and survival, but long term cure
rates remain to be proven. These are promising developments. It remains unpredictable exactly which patients will
gain the benefit after medical therapy.
Radiation: The role of adjuvant radiotherapy has been defined better for treatment of melanoma and SCC, with >3
positive nodes or extra-capsular spread being two key indicators for radiation. Radiation is useful for symptom
control, especially for bone metastases.
Palliative care: Good pain control, social/community supports, and planning are essential for managing patients and
their families at home and through often-difficult treatments, hospital visits and end of life matters/decisions.
GP, nursing and allied health: Often the role of the many important individuals including community nurses, GP,
rehabilitation staff, orthotist, physiotherapist, psychologist, pharmacist and occupational therapist, are vital for
adequate recovery, comfort and quality of life.
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Effective follow-up is an uncertain area with little guiding evidence. After skin cancer excision the principal risks are
development of another primary lesion and recurrence. No regimen template appears completely encompassing to
reduce these risks. Many recurrent or new lesions are detected by the patient between follow-up visits. After excision
of in-situ skin lesions, 6-12 monthly follow-up is probably adequate; after invasive lesions, 4-monthly for 2 years;
6-monthly for 2 years and then yearly thereafter is usually appropriate. For higher risk individuals more intensive
follow-up is recommended.
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Screening for skin cancer has been problematic as many people need to be screened to detect small numbers of
cancers, even despite the relatively high incidence. Although the rate of skin cancer is 1 in 2 Australians we have
difficulty with accurate prediction of exactly who will develop the cancer. The best 'yield' for detection of skin
cancers come from those groups of people who are at highest risk. These include those with a previous skin cancer, a
strong family history of skin cancer (especially melanoma), those with high sun exposure, numerous sunburns, fairer
skin and features, albinism, renal dialysis/transplant patients or those living in certain geographical locations. Even
in these groups, many people do not develop skin cancers, while some develop many.
Prevention is of two main types: primary and secondary.
Primary prevention is best applied early in life, to restrict the damaging effects of the sun and UV-light from causing
skin cancer. Avoidance of the sun at UV levels above 3, and protection using shade or clothing are the most effective
measures. Sunscreen reduces the burn-rate, but is of limited value.
Secondary prevention is for patients who have had a skin cancer removed previously, who are at greater risk of
another second primary cancer in the future, and may develop an occult skin cancer.
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References
1. Australian Institute of Health and Welfare. Cancer in Australia: An overview 2012. Canberra: AIHW; 2012 [cited
2014 May 29]. Report No.: Cancer series no. 74. Cat. no. CAN 70. Available from: http://www.aihw.gov.au/
WorkArea/DownloadAsset.aspx?id=60129542353
2. Australian Cancer Network Melanoma Guidelines Revision Working Party. Clinical practice guidelines for the
management and treatment of melanoma in Australia and New Zealand: Evidence based best practice guidelines.
Wellington: Cancer Council Australia, Australian Cancer Network and Ministry of Health, New Zealand; 2008
[cited 2014 May 29] Available from: http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/
cp111.pdf
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Central nervous system tumours

18 September 2014 00:50:44
Author(s):
• Dr Jeremy Ruben MD MBBCh(Hons) FCRadOnc FRANZCR, Mmed — Author
• Professor David Ashley, MBBS, FRACP, PhD — Author
• Mustafa Khasraw MBChB MD MRCP FRACP — Author
page</ccabutton>
Ruben, J, Professor David Ashley, MBBS, FRACP, PhD, Khasraw,M, Cancer Council Australia Oncology Education Committee. Central nervous
system tumours [Version URL: http:/ / wiki. cancer. org. au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016
http:/ / wiki. cancer. org. au/ oncologyformedicalstudents/ Central_nervous_system_tumours. In:
Oct 8]. Available from
Introduction
Tumours of the central nervous system (CNS) are an especially important group of tumours because of their
disproportionate impact on patients’ wellbeing and longevity. As with tumours elsewhere in the body, CNS tumours
may be classified as primary or secondary and as benign or malignant. In adults, the majority are secondaries from
systemic cancers, however in children most are primary brain tumours.
Brain metastases develop in about 15% (10-30%) of cancer patients, although incidence is significantly higher in
post-mortem series. In adults, the commonest tumours metastatic to the brain (in decreasing rate of incidence) are
lung, breast, melanoma and colorectal cancers. Prognosis in patients with brain metastases depends predominantly
on performance status, age, number of metastases and whether systemic disease is controlled or not. Treatment
depends on symptoms, prognosis, site and number of metastases. Treatment may comprise surgical resection with
control rates of 40-50%, radiosurgery (a highly focused and accurate form of radiotherapy) with control rates of
70-80% or whole brain radiotherapy. For very frail patients, supportive care alone may be the most appropriate
management. Dexamethasone is helpful for most patients to counteract brain oedema commonly associated with
metastases.
Primary CNS tumours represent just 2% of adult tumours but about 25% of childhood tumours and around 15% of
adolescent tumours. In adults, brain tumour incidence increases with age.
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Glioma
The commonest primary brain tumours of adults are gliomas which comprise about two-fifths of all primary brain
tumours. Gliomas span a spectrum from benign to malignant and are graded pathologically on a scale of one to four
according to the WHO classification. Gliomas of grades II-IV are conventionally considered ultimately incurable
although life may be significantly prolonged by treatment.
Glioblastoma Multiforme (GBM) account for 80% of gliomas. GBM is the most aggressive type and hence grade
four. Median survival in treated patients is about 17 months but better for younger, fitter patients. Treatment consists
of maximal safe surgery followed by radiotherapy, which is given concurrently with a chemotherapy tablet in fitter
patients. Chemotherapy is thereafter continued for an additional six cycles. Radiotherapy is the main component of
treatment, responsible for more than doubling survival times. As with all brain tumours, surgery may be limited or
contraindicated if tumour impinges on eloquent areas. In patients who are of limited performance status, supportive
care along with dexamethasone may be most appropriate.
Low grade glioma is grade II on the WHO scale. It is the second commonest primary malignant brain tumour.
Median survival is about 7-9 years with better prognosis associated with oligodendroglioma morphology compared
to mixed or pure astrocytoma. Surgery is the primary therapeutic modality although radiotherapy and chemotherapy
will be required at some point in almost all patients. WHO Grade III or anaplastic gliomas have median survivals of
3-5 years with oligodendrogliomas again tending to live longer than astrocytomas or mixed forms. Primary treatment
is surgery followed by radiotherapy. This is usually followed by chemotherapy especially if 1p19q deletions are
present. Again, almost all patients will require all three modalities over the course of their disease. Grade I gliomas
are benign and usually cured with surgery although radiosurgery may be used if lesions are irresectable or multiply
recurrent.
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Medulloblastoma
Medullobalstoma and primitive neuro epithelial tumours (PNET) are the next commonest primary CNS
malignancies. They are commoner in children than adults. The entire neuraxis is at risk and treatment typically
includes resection followed by craniospinal radiotherapy and chemotherapy.
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Other neoplasms
Just under half of primary adult brain tumours are benign. Unlike other tumour sites, even benign tumours in the
CNS may pose risk to life or functional impairment due to uncontrolled growth in the cranial cavity or spinal canal,
and most require definitive treatment at some point. This usually takes the form of surgery or radiosurgery. The
commonest benign brain tumours are meningiomas, pituitary adenomas and vestibular schwannomas.
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Meningioma
Meningiomas are usually benign (WHO grade 1). They comprise about a fifth of primary brain tumours. Surgery is
the conventional therapy, although radiotherapy is an alternative especially for skull base tumours since complete
resections are usually difficult to achieve without morbidity. Adjuvant radiotherapy is required after surgery for
grade II-III meningiomas.
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Head and neck cancer

18 September 2014 00:48:54
Author(s):
• Professor Peter Friedland MB BCh MMed FCS(SA) FRACS — Author
page</ccabutton>
http:/ / wiki. cancer. org.
Friedland, P, Cancer Council Australia Oncology Education Committee. Head and neck cancer [Version URL:
au/ oncologyformedicalstudents_mw/ index. php?oldid=, cited 2016 Oct 8]. Available from http:/ / wiki. cancer. org. au/
oncologyformedicalstudents/ Head_and_neck_cancer. In: Sabesan S, Olver I, editors. . Sydney: Cancer Council Australia. Available
Epidemiology and risk factors

Head and neck cancer (H&N cancer) is the sixth commonest cancer worldwide. There were 3031 new cases in
Australia in 2009. Risk factors for these cancers are the six S’s: Smoking, Spirits (alcohol), Sunlight
exposure/previous radiation to head and neck, chronic Sepsis, Sexually transmitted infections (HPV & HIV) and
male predominance and Spices (Betel quid chewing). Ninety-five percent of H&N cancers are associated with a
significant smoking history. They are heterogeneous and challenging to treat as they involve multiple structures,
including skin, muscle, cartilage, bone, nerves, blood vessels, lymphatics and both salivary and lymph glands.
Over the last two decades there has been a paradigm shift in the nature, age and cause of H&N cancers. Whereas in
the past, the average age of presentation was 60-70 years associated with a heavy smoking and or alcohol history, we
are now seeing a far younger cohort of patients in their thirties and forties who may never have smoked or consumed
excessive alcohol. Human papillomavirus (HPV) causes the cancers in this group and predominately occurs in the
oropharynx. These are the same high-risk subtypes of HPV that cause cancer of the cervix and are related to
orogenital contact. Although over the past three decades the incidence of smoking has decreased by 30%, there has
been no decline in H&N cancers. In fact, in Australia the prevalence of HPV related oropharyngeal tumours has
tripled in the last two decades. The incidence is 22 per 100 000 in males and 7.5 per 100 000 in females.
Cancer biology
The H&N cancers include six anatomic regions from the base of skull to the clavicles, and each anatomic region has
a different Tumour, Nodal status, and Metastasis (TNM) classification and tumor patterns. These six regions include
the Sino-nasal (nose and sinuses), Nasopharynx (the back of the nose and very top of the throat), Oral (from lips,
hard palate to anterior 2/3rds of the tongue), Oropharynx (posterior 1/3rd of the tongue, tonsils and soft palate),
Hypopharynx (the area of the throat behind the vocal cords and above the oesophageal opening) and the Larynx (area
of the voice box and airway inlet).
In many patients, the rich vascular supply and lymphatic drainage of their tumour area leads to spread into the lymph
nodes of the neck. There are multiple lymph nodes in the head and neck region. Most occur in Waldeyer’s ring
around the jaw including the submandibular, parotid capsule and tonsillar lymphatic tissue. There is a large chain of
lymph nodes that run with the internal jugular vein underneath the sternocleidomastoid muscle. This muscle runs
from behind the ear (mastoid bone) to the clavicle (cleido) and divides the neck into anterior and posterior triangles.
Lymph node spread is classified into levels by sites that are easily demonstrated on CT scanning and are constant
and standardized. Level I is submandibular and submental region, Level II to IV is from angle of jaw down to
clavicle, Level V includes the whole posterior triangle of the neck and level VI the paramedian tracheal and thyroid
area.
Staging and prognosis

H&N cancers are classified by the TNM system that represents Tumour/Nodal status in the neck and Metastases to
areas other than regional neck lymphnodes. In simplistic terms, the smaller the size of the tumour, the easier and
more successful the treatment. Nodal spread is highly significant and reduces the overall prognosis by 50%.
Treatment
Due to the complex structures that H&N cancer involves and the potentially devastating effects on basic daily
functions such as breathing and swallowing, eating, drinking, speech, sense of smell and taste, these patients are best
managed by a multidisciplinary team (MDT). This MDT meets weekly and includes ear nose and throat, plastic and
reconstructive, maxillofacial surgeons, dentists, radiation and medical oncologists and allied health members that
comprise speech pathology, dietetics, occupational and physiotherapists. A cancer care coordinator nurse, social
worker and palliative care expert are essential to the MDT. A statistician’s participation is necessary for staging,
treatment plans and outcomes for audit and review purposes.
Depending on the stage and site of the cancer, treatment may be curative or palliative and comprise one of three
different plans: 1) a single modality of surgery or radiotherapy treatment, 2) surgery combined with pre or
postoperative radiotherapy and 3) radiotherapy with concurrent or adjunctive chemotherapy and no surgery. The aim
of management is to effectively treat the cancer whilst preserving as much function as possible (organ preservation)
or reconstructing tissues to enable this. Where cancers are advanced and significant tissue in the mouth, neck or jaw
is removed, reconstruction is achieved with free micro vascular skin, muscle and bone flaps from distant sites.
Many H&N cancers present in advanced stages and here palliative care plays an extremely important role.
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Case examples
Case 1
Mr GB, 59 year old bus driver
• Initially presented with 3-4 month hx of hoarse voice
• Past Medical History
• Current smoker 40 pack yr history,
• Previous binge drinker
• HTN, cholesterol, T2DM, chronic back pain
• CT Head & Neck
• Subtle asymmetry of vocal cord
• Endoscopic laser excision (good view)
• Squamoproliferative lesion with features suggestive of early well differentiated squamous cell carcinoma, clear
of margins. Adjacent epithelium shows dysplasia.
Impression:
• T1N0 SCC-Highly curable
Plan:
• Endoscopic laser excision (good view) performed with histopathology above
Case 2
66 year old male smoker (30/d) with a 6 week history of hoarse voice, loss of weight of 6 kg and odynophagia
Past Medical History
• Mechanical fitter, lives with wife
• Tibial fracture
• Duodenal ulcer
• History of asbestos exposure in the navy.
Examination
• Laryngoscope-exophytic mass right aryepiglottic fold
• Vocal cords mobile
• Neck soft
• Microlaryngoscopy and biopsy of supraglottic (above vocal cords) mass
• Histopathology
• Invasive moderately differentiated Squamous carcinoma in anterior glottis (vocal cord) & right supraglottic
(above vocal cord) area
• CT neck and chest and PET

• Right supraglottic laryngeal neoplasia 26x17x23 mm.
• Level III involved lymph node
• No distant metastasis
Diagnosis
• T4aN1M0 right supraglottic SCC
MDT treatment plan -- curative intent
• Primary chemoradiation therapy for organ preservation
• Dietetics, speech pathology, social work and dentist referals
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Cancer of unknown primary

12 September 2014 05:48:36
Author(s):
• Professor David Christie MBChB FRANZCR — Author
page</ccabutton>
Christie, D, Yip, D, Cancer Council Australia Oncology Education Committee. Cancer of unknown primary [Version URL:http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Cancer_of_unknown_primary. In: Sabesan S, Olver I, editors. . Sydney: Cancer
Epidemiology
In Australia, cancer of unknown primary origin (CUP) is the eighth most commonly diagnosed cancer (about 3000
per year) and makes up about 5% of all cancers diagnosed. Of all cancer deaths, CUP causes about 5% and is the
fifth most common cause (AIWH). The median survival rate is about 6 months and the 5-year survival rate is about
16%. These figures are gradually changing. Each year, the incidence drops by about 2%, presumably reflecting better
diagnostic methods, particularly the PET/CT scan which can identify a primary site in about 40% of patients in
whom it would otherwise be unknown.[1] The risk of death also drops about 2% per year, probably due to better
treatment. The incidence and mortality in Indigenous populations are both almost double that of the remainder of the
population, possibly indicating delayed diagnosis and a lack of access to treatment. The incidence and mortality are
both about 1.4 times higher in remote areas than in the cities.
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Risk factors
As the diagnosis of CUP requires exclusion of other known primary cancers and indicates many potential types of
underlying primary cancer, risk factors have not been identified, except that the risk of CUP increases with age.
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By definition, CUP requires the presence of metastatic disease as indicated by a histologically confirmed type of
cancer occurring in an organ or part of the body which would not normally generate that type of primary tumour. For
example, if a cancer that usually arises in epithelial tissues, such as an adenocarcinoma, was found in a lymph node,
it is likely to have spread there from some other organ. Many cancer patients present with metastatic disease anyway,
but the term CUP is only for those in which a credible primary cancer cannot be found. There are favourable and
unfavourable patterns of presentation.[2] The favourable presentation occurs in about 20% of patients and shows a
pattern whereby a minimal amount of metastatic cancer in a particular location suggests a particular primary tumour
may be present, but the likely primary tumour cannot be found despite investigations relevant to that location.
Sometimes a primary site is identified at autopsy and of these, the most common primary sites are lung, oropharynx
and pancreas. However, most patients dying with metastatic cancer are not subjected to autopsy, as it would only be
of academic interest. Patients with an unfavourable pattern are those with more widespread disease at presentation
and are similar in presentation to those patients with metastatic disease of any of the known primary tumours. For
example, the patients may have widespread painful bony metastases or constitutional symptoms and signs such as
loss of appetite, generalised weakness and cachexia.
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As there are different types of CUP, a biopsy is required to determine the best treatment. Microscopy should be able
to determine whether cancer is present and which broad type it is (most are carcinomas, but a few are sarcomas,
melanomas, etc) and then identify which subtype (most are adenocarcinomas, but there are a few squamous cell
cancers, neuroendocrine cancers, etc). These can lead to avenues of further investigation, e.g. a serous papillary
carcinoma with a metastasis in the peritoneum in a female would suggest assessment of the ovaries could be
worthwhile. Immunohistochemical staining may indicate a primary origin, as well as indicating potentially useful
treatments, e.g. PSA or ER staining may indicate a role for hormone treatment, even if a primary tumour cannot be
identified. Gene expression profiling of biopsy tissue may identify patterns of gene expression more in keeping with
one type of primary cancer or another, e.g. colorectal cancer.
The extent of staging required is controversial and requires individual judgement. In patients showing a favourable
pattern of presentation, potential primary sites can sometimes be deduced, e.g. adenocarcinoma in an axillary node in
a female may be breast cancer and would lead to detailed breast imaging, including MRI scans where available. An
SCC in a level II neck node may be an indication of a primary tumour in the upper aerodigestive tract and would
lead to an endoscopic ENT assessment. PET/CT might identify more widespread disease in 10-20% of patients. If a
primary tumour is still not identified, it may be possible to apply a curative style of treatment to a presumptive
primary site in the absence of demonstrable tumour and obtain results similar to those with a primary cancer limited
to regional nodes.
Raised tumour markers can sometimes indicate suitable treatment -- for example a raised serum PSA level is likely
to respond to hormonal therapy suitable for metastatic prostate cancer. A raised CEA or CA19.9 serum tumour
marker level may point towards a gastrointestinal primary and upper and lower endoscopies may be warranted to
detect the primary. Elevated AFP and BHCG are suspicious of germ cell malignancy which may be potentially
curable despite being disseminated.
Patients with the unfavourable pattern of presentation tend to have more advanced disease at diagnosis. If the disease
is advanced, all of the information needed to select a suitable systemic treatment may be obtainable from the biopsy
of a metastatic lesion. The further pursuit of a primary site by imaging, endoscopy or other procedures may be of
little value as it may have no bearing on the chosen treatment and could delay effective palliative measures.
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Prognosis
Patients in the favourable subgroup have limited disease that fits into standard patterns and tend to have a better
prognosis.[3] Each of these specific patterns has its own outlook and prognostic factors. However, most patients with
CUP are in the unfavourable subgroup. The majority of these are poorly differentiated adenocarcinomas and have a
poor prognosis, with the median survival 8-12 months. Prognostic factors include age, performance status, number of
affected organs (particularly liver or adrenal glands) and elevated serum markers including ALP, albumin and
LDH.[4] Prognostic scoring systems have been proposed to help guide treatment decisions but none have proven
reliable enough to be clinically useful.
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Since CUP is a group of heterogeneous conditions, it would be inappropriate to consider one treatment suitable for
all of them. Patients with limited disease may be suitable for resection and regional radiotherapy, while those with
disseminated disease would be more suited to systemic treatment. Although institutional reports have indicated that
survival rates improved when platinum chemotherapy was introduced, a meta-analysis of chemotherapy treatment
has shown that there is no type of chemotherapy which is clearly better than any other, nor that any type is better
than supportive care alone.[5] Molecular profiling may identify subsets that respond better to systemic treatments (see
Table 1). Brief guidelines for treatment have been published.[6]
Table 1. Favorable Subsets Identified by Clinical and Pathologic Features (Reproduced with permission)[7]
Histology Clinical Subset Therapy Prognosis
Adenocarcinoma Women, axillary node involvement Treat as primary breast cancer Survival improved
Women, peritoneal carcinomatosis Treat as stage III ovarian cancer Survival improved
Men, blastic bone metastases or high serum Treat as metastatic prostate cancer Survival improved
PSA/tumor PSA staining Surgical resection and/or radiotherapy ± Survival improved
Single metastasis chemotherapy Survival improved
Colon cancer profile (IHC and/or molecular Treat as metastatic colon cancer
assay)
Squamous Carcinoma Cervical adenopathy Treat as locally advanced head/neck 25%–30% 5-yr survival
Inguinal adenopathy primary 15%–20% 5-yr survival
Inguinal node dissection, radiation
therapy, ± chemotherapy
Poorly Differentiated Extragonadal germ cell syndrome Treat as poor prognosis germ cell tumor 10%–20% cured
Carcinoma
Neuroendocrine Aggressive (small cell or large cell, poorly Treat as extensive-stage small cell lung High response
Carcinoma differentiated) cancer rate/survival improved
Low grade Treat as advanced carcinoid tumor Indolent biology/long
survival
Abbreviation: PSA, prostate-specific antigen.

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Survivorship issues for CUP are similar to those for incurable cancers generally, but also include dealing with issues
surrounding the uncertainty of the diagnosis. During the course of follow-up, there may be new opportunities to
further characterise the disease, for example if a more suitable lesion for biopsy becomes apparent then it may be
possible to identify either a primary site or more suitable forms of treatment. An Australian CUP action group exists
to provide support for patients.[8]
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There are no screening tests or prevention measures known for CUP.
Further reading
1. Australian Institute of Health and Welfare. Cancer in Australia: In brief 2012. Canberra: AIHW; 2012 [cited 2014
May 29]. Report No.: Cancer series no. 72. Cat. no. CAN 69. Available from: http://www.aihw.gov.au/
2. Australian Institute of Health and Welfare. Cancer in Australia: An overview 2012. Canberra: AIHW; 2012 [cited
2014 May 29]. Report No.: Cancer series no. 74. Cat. no. CAN 70. Available from: http://www.aihw.gov.au/
3. Riihimäki M, Thomsen H, Hemminki A, Sundquist K, Hemminki K. Comparison of survival of patients with
metastases from known versus unknown primaries: survival in metastatic cancer BMC Cancer 2013 Jan 28;13:36.
Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/23356713
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References
[1] Kwee TC, Basu S, Cheng G, Alavi A. FDG PET/CT in carcinoma of unknown primary. Eur J Nucl Med Mol Imaging 2009 Oct 31 [cited
2014 May 29];37(3):635–644 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC2822231/ ].
[2] Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012 Apr 14;379(9824):1428-35 [Abstract available at http:/ / www.
[3] Greco FA, Oien K, Erlander M, Osborne R, Varadhachary G, Bridgewater J, et al. Cancer of unknown primary: progress in the search for
improved and rapid diagnosis leading toward superior patient outcomes. Ann Oncol 2012 Feb;23(2):298-304 [Abstract available at http:/ /
www. ncbi. nlm. nih. gov/ pubmed/ 21709138].
[4] Ferté C, Penel N, Bonneterre J, Adenis A. Individual life expectancy estimation using validated prognostic scores for patients with cancer of
unknown primary. Oncology 2010;78(2):87-93 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 20357516].
[5] Golfinopoulos V, Pentheroudakis G, Salanti G, Nearchou AD, Ioannidis JP, Pavlidis N. Comparative survival with diverse chemotherapy
regimens for cancer of unknown primary site: multiple-treatments meta-analysis. Cancer Treat Rev 2009 Nov;35(7):570-3 [Abstract available
at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 19539430].
[6] Fizazi K, Greco FA, Pavlidis N, Pentheroudakis G, ESMO Guidelines Working Group. Cancers of unknown primary site: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011 Sep;22 Suppl 6:vi64-8 [Abstract available at http:/ / www. ncbi.
nlm. nih. gov/ pubmed/ 21908507].Cites::Citation:Fizazi K, Greco FA, Pavlidis N, Pentheroudakis G, ESMO Guidelines Working Group
2011
[7] Greco FA. Cancer of unknown primary site: improved patient management with molecular and immunohistochemical diagnosis. Am Soc
Clin Oncol Educ Book 2013;:175-81 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 23714493].Cites::Citation:Greco FA
2013
[8] CUP Action. Cancer of unknown primary action. [homepage on the internet] Australia: Cancer of Unknown Primary Inc; 2014 [cited 2014
May 29; updated 2014 May 29]. Available from: http:/ / www. actiononunknownprimary. org/ index. html. Cites::Citation:CUP Action 2014
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Oncological emergencies
22 October 2014 05:53:28
Author(s):
• Dr Abhishek Joshi MBBS MD DM FRACP — Author
• Dr Corinne Ryan BAppSci MBBS(Hons) FRACP — Author
• Professor Ian Olver AM MBBS MD PhD CMin FRACP FAChPM MRACMA — Author
page</ccabutton>
Joshi, A, Ryan, C, Olver, I, Cancer Council Australia Oncology Education Committee. Oncological emergencies [Version URL: http:/ / wiki.
cancer. org. au/ oncologyformedicalstudents/ Oncological_emergencies. In: Sabesan S, Olver I, editors. . Sydney: Cancer
This chapter covers important oncological emergencies, including hypercalcemia, superior venous caval obstruction,
spinal cord compression and neutropenic sepsis.
Oncological emergencies
Neutropenic sepsis
Neutropenic sepsis is defined as a single temperature of 38.30C orally or temperature of 380C or more orally lasting
an hour, in the presence of a neutrophil count of less than 500/microlitre (or 0.5x109/litre) or less than 1000/mcL and
a predicted decline to less than 500/mcL over the next 48 hours (http:/ / www. nccn. org/ professionals/
physician_gls/pdf/infections.pdf).
Without the administration of timely antibiotics, mortality may be higher. Principles of management are:
1. Assess haemodynamic status
2. Look for the source of infection including intravenous access sites. (In many case, a source may not be found.)
3. Investigations including FBC, electrolytes and liver function tests, blood cultures (from periphery and central
venous devices), Chest X-ray, urine analysis and cultures
4. Antibiotics need to be able to cover broad spectrum of organisms including gram positive, gram negative
organisms and anaerobes. Because of the risk of pseudomonal infection, agents covering this organism are
administered either as a single agent (anti pseudomonal penicillin or fourth generation cephalosporin) or in
combination depending on institutional protocols. When there is haemodynamic compromise or a risk of MRSA
infection, appropriate anti MRSA therapy is necessary.
Some low risk patients may be treated with oral antibiotics depending on institutional guidelines. Usually patients
require admission to isolation beds.
NB: Granulocyte colony stimulating factors usually do not improve the outcomes in neutropenic sepsis unless in
selected cases.
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Hypercalcaemia
Hypercalcaemia refers to elevated calcium level in blood (normal range 2.2-2.6 mmol/L) that occurs in 10-20%
patients with advanced cancers (most commonly in cancer of the breast, kidney, lung, prostate, head and neck and
multiple myeloma). The frequency and severity of hypercalcaemia in cancer patients has decreased in the past
decade due to early and wide spread use of bisphosphonates.
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Mechanism
Pathogenesis involves either focal bone destruction (osteolytic) or, more frequently, para neoplastic syndrome.
1. Osteolytic hypercalcaemia is the result of direct bone invasion by the tumour or metastasis (e.g. breast cancer)
releasing local cytokines resulting in activation of osteoclast activating factor which causes bone resorption and
loss of calcium from bone into blood. RANK ligand (RANKL) is a receptor on pre osteoclasts which plays and
important role in osteoclast maturation.
2. In para neoplastic hypercalcaemia, the tumour cells secrete parathyroid hormone related protein (PTHrP) which
can induce bone resportion without the cancer directly invading the bone (e.g lung cancer). PTHrP is elevated in
80% of patients with hypercalcaemia in cancer.
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Symptoms of hypercalcaemia include nausea, vomiting, constipation, polyuria and disorientation. A mnemonic for
these effects is “Stones, bones, groans, thrones and psychiatric overtones”.
Stones (renal or biliary)
Bones (bone pain)
Groans (abdominal pain, nausea and vomiting)
Thrones (polyuria)
Psychiatric overtones (depression 30-40%, anxiety, cognitive dysfunction, insomnia, coma)
Clinical evidence of volume contraction secondary to progressive dehydration may be apparent. Severe
hypercalcaemia (above 3.75-4.0 mmol/L) is a medical emergency and a poor prognostic sign. Investigations include
specific biochemistry like PTH, ECG to detect arrhythmias and imaging with Bone Scan or PET-CT scan to identify
metastatic bone disease.
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Causes of hypercalcaemia in cancer patients

Apart from the mechanisms described above, many other causes like calcium supplementation may need to be
considered in cancer patients.
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Management
Treat the hypercalcaemia first and the cause later:
1. Hydration & diuresis – 1-2 L of isotonic saline (NS) over 2 hours with 30-40 mg of frusemide expands
intravascular volume and enhances calcium excretion. In elderly and cardiac patients, rate of hydration needs to
be slower.
2. Bisphosphonates – via a complex mechanism inhibit osteoclast and in turn both normal and pathological bone
resorption. Commonly used bisphosphonates are:
1. Zolendronic acid – infused as 4 mg in 100 mls of NS over 15 mins. Normalisation of serum calcium occurs in
4-10 days and lasts 4-6 weeks. Therefore, if re-treatment is required, dose is repeated after 7 days
2. Ibandronate – 6 mg as 2 hour infusion or 50 mg PO daily
3. Pamidronate - 90 mg IV over 1-2 hours
3. RANKL inhibitor – Denosumab 120 mg subcutaneously every month
NB: Bisphosphonates and Denosumab cause increasing risk of osteonecrosis of jaw following extraction of teeth or
oral surgical procedures. Therefore, a dental review may be necessary to make sure the necessary dental procedures
are completed prior to commencing therapy.
Calcitonin – a thyroid hormone given 4-8 IU/kg IM or SC every 6-8 hours can bring about a rapid decline in calcium
levels, however tachyphylaxis limits its utility.
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Superior vena cava syndrome

Superior vena cava syndrome (SVCS) is the clinical expression for obstruction of blood flow through the SVC.
Malignancy (90%) is the most frequent cause of SVC obstruction. SVC obstruction in cancer patients can result
from:
• Extrinsic compression of SVC
1. lung Cancer (65%)
2. lymphomas (15%)
3. other cancers (10%)
• Intrinsic compression
1. thrombosis associated with central venous devices (10%)
SVC obstruction is a strong predictor of poor prognosis in patients with non-small cell lung cancer.
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Pathophysiology
As the flow of blood within the SVC becomes obstructed, venous collaterals form, establishing alternative pathways
for the return of venous blood to the right atrium. Collateral veins may arise from the azygos, internal mammary,
lateral thoracic, paraspinous, and oesophageal venous systems. However, even when well-developed collateral
drainage patterns are present, central venous pressures remain elevated, producing the characteristic signs and
symptoms of SVC syndrome.
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Common symptoms and physical findings of SVCS are:
1. dyspnoea
2. headache
3. oedema and change in colour in the areas drained by SVC(examples-face and upper limb)
4. venous distension of neck, upper chest and arms
5. cough
6. Pemberton’s sign (development of facial flushing, distended neck and head superficial veins, inspiratory stridor
and elevation of the jugular venous pressure (JVP) upon raising both of the patient's arms above his/her head
simultaneously, as high as possible (Pemberton's maneuver)).
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Diagnosis
1. Chest X ray (CXR) -- shows mediastinal widening and may show the presenting primary cause of SVCS.
2. CT scan Chest Abdomen and Pelvis with Contrast -- Easily and readily available in most centres (compared to
MRI). It is useful for establishing the diagnosis and staging of the malignancy.
3. Tissue diagnosis – It is important to characterize the malignancy so that it can be treated with the appropriate
modality.
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Treatment
Treatment of SVC syndrome is divided into supportive and definitive therapy.
• Supportive measures
1. Head elevation -- To decrease the hydrostatic pressure and thereby the edema. There are no data documenting the
effectiveness of this manoeuvre, but it is simple and without risk.
2. Glucocorticoid therapy (dexamethasone, 4 mg every 6 h) to relieve inflammation and oedema (to be avoided
before biopsy if lymphoma is suspected as steroid induced tissue necrosis might obscure the diagnosis)
3. Loop diuretics (Frusemide) are also commonly used, but it is unclear whether venous pressure distal to the
obstruction is affected by small changes in right atrial pressure.
• Definitive therapy
1. Radiation treatment to the malignant mass.
2. Chemotherapy – in chemo sensitive cancers like lymphoma, germ cell tumours or small cell lung cancer
3. SVC Stent – can be useful in cases of thrombosis and for patients not responding to cancer treatment
4. Removal of central venous device.
NB: It is advisable to avoid placement of intravenous lines in the arms so that fluid is not injected into the already
compressed SVC.
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Spinal cord compression and brain metastasis
Case study
Mr S, a 67 year old gentleman with a history of non-small cell lung cancer treated radically with chemotherapy and
radiotherapy 1 year prior, presents with a 3-week history of escalating back pain, headaches and a 1-day history of
bilateral lower limb weakness. On admission to hospital his lower limb power was grade 3-4 out of 5. Sensation was
impaired from the level of T10. Urgent MRI spine demonstrates a metastasis at T9 causing spinal cord compression,
as well vertebral metastases at C4 and L3. In the emergency department he has a witnessed tonic-clonic seizure
lasting two minutes that self resolves. Subsequent contrasted CT brain demonstrates a left frontal lobe metastasis,
measuring up to 3 cm with surrounding vasogenic oedema. Staging CT scan also demonstrates mediastinal nodal
metastases and 2 liver metastases. What is the appropriate management strategy for this patient?
Spinal cord compression threatens mobility, independence and longevity in patients with metastatic cancer and may
be the first presentation of curable malignancy in others. It most commonly occurs due to an enlarging vertebral
metastasis encroaching on the epidural space or due to pathologic fracture of a vertebra infiltrated by malignancy.
Immobilising the patient and obtaining urgent MRI whole spine (compression can occur at more than one level)
should be priorities. Corticosteroids should be initiated on suspicion of cord compression. Currently guidelines
suggest intravenous dexamethasone 10 mg immediately followed by 16 mg daily in divided doses. Higher dose
corticosteroids may increase adverse effects without evidence of increasing effectiveness.[1] Bladder catheterisation
is appropriate. Once spinal cord compression is confirmed, urgent neurosurgical opinion should be sought. There are
potential improvements in outcomes for patients treated with surgery upfront, though appropriateness for this will
depend upon spinal stability, patient and malignancy related factors.[2][3] For example, younger patients with low
burden of metastatic disease and reasonable life expectancy may be better served by upfront surgery whilst patients
with radiosensitive cancers best served by radiotherapy alone. In patients who are not candidates for upfront surgery,
the role of radiotherapy has been well established. Radiotherapy protocols can vary between institutions and may
depend upon patient and tumour factors. Radiotherapy may also be appropriate after surgery. Chemotherapy as a
sole treatment for spinal cord compression may rarely be appropriate in patients with highly chemotherapy
responsive tumours, such as lymphoma.
For patients with brain metastases, obtaining seizure control is a medical priority. In the case of our patient with
spinal cord compression, this could be particularly important. Corticosteroids may reduce peritumoural oedema with
typical doses of 10 mg intravenous dexamethasone followed by 16 mg daily in divided doses. Antiepileptic treatment
should be given to obtain seizure control, usually with intravenous phenytoin loading though choice may be
influenced by concurrent medications. Benzodiazepines are useful in terminating seizures but have potential sedating
effects. Surgical resection of brain metastases may improve outcomes including survival and should be considered,
particularly in patients with a single metastasis, those with limited systemic disease and those with good prognosis
otherwise.[4] Malignancy characteristics are also important in decision making in this regard. Patients who are not
candidates for surgery should be considered for whole brain radiotherapy or radiosurgery, and radiotherapy is
usually offered to patients after recovery from surgery.[5] With few exceptions, such as in lymphoma, chemotherapy
is usually not helpful in the sole management of patients with cerebral metastases. Newer agents, such as small
molecule epidermal growth factor receptor tyrosine kinase inhibitors in certain non-small cell lung cancer patients,
may provide greater hope for control of intracerebral metastases compared to traditional chemotherapeutics.[6]
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Tumour lysis syndrome

TLS occurs when there is rapid cell breakdown after chemotherapy most commonly for leukaemias and higher grade
lymphomas with large tumour burdens that respond quickly to chemotherapy.[7] The metabolic changes are
essentially caused by cell breakdown products. Potassium which is mainly intracellular spills into the blood which
can cause cardiac arrhythmias and muscle weakness. Likewise phosphate is released which can result in renal failure
due to the deposition of calcium phosphate crystals and the calcium levels decrease. Massive cell death and nuclear
products liberated nucleic acids and adenine and guanine are broken down to uric acid which precipitates as urate
crystals and causes urate renal failure. Lactic acidosis can occur.
To try to prevent tumour lysis syndrome, patients should be hydrated to achieve a high urine output and treated with
allopurinol or rasburicase to decrease uric acid. Once tumour lysis is established patients may require dialysis.
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References
[1] Heimdal K, Hirschberg H, Slettebø H, Watne K, Nome O. High incidence of serious side effects of high-dose dexamethasone treatment in
patients with epidural spinal cord compression. J Neurooncol 1992 Feb;12(2):141-4 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/
pubmed/ 1560260].
[2] Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, et al. Direct decompressive surgical resection in the treatment of spinal
cord compression caused by metastatic cancer: a randomised trial. Lancet 2005 Aug;366(9486):643-8 [Abstract available at http:/ / www.
[3] Young RF, Post EM, King GA. Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and
radiotherapy. J Neurosurg 1980 Dec;53(6):741-8 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 7441333].
[4] Barker FG 2nd. Craniotomy for the resection of metastatic brain tumors in the U.S., 1988-2000: decreasing mortality and the effect of
provider caseload. Cancer 2004 Mar 1;100(5):999-1007 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 14983496].
[5] Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single
metastases to the brain: a randomized trial. JAMA 1998 Nov 4;280(17):1485-9 [Abstract available at http:/ / www. ncbi. nlm. nih. gov/
pubmed/ 9809728].
[6] Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain
metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012 Sep;77(3):556-60 [Abstract
available at http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 22677429].Cites::Citation:Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al
2012
[7] Rampello E, Fricia T, Malaguarnera M. The management of tumor lysis syndrome. Nat Clin Pract Oncol 2006 Aug;3(8):438-47 [Abstract
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Clinical Oncology For Students

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Clinical Oncology For Students

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Clinical Oncology

Epidemiology and social impact of cancer

Figure 1: Commonest cancers in Australia in 2012

Figure 2: Cancers in men in 2012

Figure 3: Cancers in women

Figure 5: Disparity in cancer survival based on remoteness.

Screening and prevention

Nutrition and physical activity

Cancer biology: Molecular and genetic basis

Cellular basis of carcinogenesis

Cell cycle regulation and the importance of apoptosis

Cell immortalisation and tumourigenesis

Cell signalling in carcinogenesis

Growth factors and their receptors

Steps that characterise normal cell proliferation include:

Other elements of cell signalling

Genes frequently mutated in cancer

Category / Protein Function Proto-oncogene Mode of Activation Associated Cancer

Growth Factors SIS Overexpression Astrocytoma, osteosarcoma

Growth Factors Receptors ERB-B1 Overexpression SCC of the lung, gliomas

Nuclear Regulatory Proteins C-MYC Translocation Burkitt lymphoma

Cell-Cycle Regulators CYCLIN D Translocation Mantle cell lymphoma

Tumour suppressor genes

Gene Protein function Inherited Disease Spontaneous Tumours

RB Repression of transcription factor E2F Retinoblastoma, osteosarcoma Retinoblastoma, sarcomas, several

TSC1, TSC2 Inhibitor of mTOR Tuberous sclerosis Rare

WT1 Transcription factor Wilms tumour Some leukaemias

Mutations and cancer

Viral causes of cancer

Virus (Group) Associated Human Cancer

Papilloma virus family Genital tumours, squamous cell carcinoma

Herpes virus family Kaposi sarcoma

Hepadnavirus family Hepatocellular carcinoma

Retrovirus family Adult T-cell leukaemia

Flavivirus family Hepatocellular carcinoma

The importance of DNA repair systems

Disease Protein Affected Affected Function Manifestation

Bloom syndrome 13 different proteins Recombination repair? Immunodeficiency, cancer susceptibility,

The main stages of carcinogenesis – an overview

Early steps characterised in colon cancer

Cellular principles of invasion and metastasis

Stromal microenvironment and carcinogenesis

Other genetic aspects of cancers

Genetic instability of tumour cells

Alteration of genetic mechanisms in cancer

Inherited predisposition to cancer

Principal applications of genetic testing in cancer

Modern treatment modalities arising from cancer cell biology

Tumour immunology and immunotherapy

Novel approaches arising from cancer cell biology

Summary: The hallmarks of cancer

Cancer biology: Familial cancers and genetic

Cancer biology: Familial cancers and genetic testing

Follow-up and survivorship

Screening and prevention

Further reading and links

Cancer diagnosis: Histopathology, cytology and

Is tissue always necessary?

Figure 6: 9:22 Translocation Source: Medindia health [1]. Permission to use.

Useful markers of internal malignancy

Cancer diagnosis: staging and imaging

The TNM staging system

Other staging systems