LO & WEEK 4

1) BPH (Benign Prostatic Hyperplasia) and how to differentiate with Prostate Cancer

a. BPH

BPH is known as a enlargement of prostate that characterized by proliferation of the cellular elements of the
prostate. Cellular accumulation and gland enlargement may result from epithelial and stromal proliferation,
impaired preprogrammed cell death (apoptosis), or both.

BPH involves the stromal and epithelial elements of the prostate arising in the periurethral and transition
zones of the gland (see Pathophysiology). The hyperplasia presumably results in enlargement of the prostate
that may restrict the flow of urine from the bladder.

- Considered a normal part of the aging process in men and is hormonally dependent on testosterone
and dihydrotestosterone (DHT) production
- 50% of men demonstrate histopathologic BPH by age 60 years
- Will increases to 90% by age 85 years.

Patophysiology

Prostatic enlargement depends on the potent androgen dihydrotestosterone (DHT). In the prostate gland, type
II 5-alpha-reductase metabolizes circulating testosterone into DHT, which works locally, not systemically. DHT
binds to androgen receptors in the cell nuclei, potentially resulting in BPH.

However, the fact that serum testosterone levels decrease with age, yet the development of BPH increases,
suggests that other agents play an etiologic role. Possible factors include the metabolic syndrome,
hyperinsulinemia, norepinephrine, angiotensin II, and insulin-like growth factors.

Sign and Symtoms

 Urinary frequency
 Urinary urgency
 Nocturia- Needing to get up frequently at night to urinate
 Hesitancy - Difficulty initiating the urinary stream; interrupted,
weak stream
 Incomplete bladder emptying - The feeling of persistent
residual urine, regardless of the frequency of urination
 Straining - The need strain or push (Valsalva maneuver) to
initiate and maintain urination in order to more fully empty
the bladder
 Decreased force of stream - The subjective loss of force of the
urinary stream over time
 Dribbling - The loss of small amounts of urine due to a poor
urinary stream as well as weak urinary stream

Diagnosis

To diagnose BPH in men who present with LUTS. D-IMPACT found that a
diagnostic algorithm including only the objective variables of age,
International Prostate Symptom Score (IPSS) and prostate-specific
antigen level (PSA)
NOTE : Having BPH does not cause prostate cancer and unlike prostate cancer, it cannot spread to other areas
of the body.

Laboratory tests may include:

 Prostate specific antigen (PSA) – a blood test that measures the level of PSA, a protein produced by
prostate cells, in the blood; it may be elevated in men with prostate cancer but can also be elevated in
those with BPH, although levels are usually only slightly elevated. When evaluating the results, the
healthcare practitioner must consider both the concentration of PSA in the blood and the size of the
man's prostate.
 Urinalysis – a group of tests used to look for signs of a urinary tract infection (UTI) or blood in the urine
(hematuria)
 Urine culture – another test used to look for indication of a UTI
 Electrolytes, blood urea nitrogen (BUN) and creatinine – blood tests to evaluate kidney function

Non-laboratory tests may include:

 Digital rectal exam (DRE)--to determine the approximate size of the prostate
 Transrectal ultrasound – to help measure the size of the prostate and evaluate the volume of urine
retained in the bladder
 Cystoscopy – an evaluation of the urethra and/or bladder using a thin, flexible scope
 Urine flow and/or pressure studies – to evaluate how fast urine can travel through the urethra and how
much pressure is being put on the bladder by urine retention
 Postvoid residual urine (PVR) studies – to measure urine left in the bladder after urinating
 Prostate biopsy – collection of one or more small samples of prostate tissue and evaluation of its cellular
structure under the microscope for abnormal cells and any signs of prostate cancer. PSA levels may be
increased up to ten-fold for 8-10 weeks post biopsy.

b. Prostate Cancer

Prostate cancer is due to uncontrolled growth of prostate cancer cells. In the early stages, prostate cancer has
no symptoms. It is not until it has advanced that symptoms begin to appear, which can include many of the
same as BPH but may also include:

Sign and Symptoms

 Painful or burning urination

 Blood in the urine
 Erectile dysfunction
 Painful erection
 Less fluid during ejaculation
 Blood in semen

During the physical exam of the prostate, may notice it feels nodular or bumpy as well as firm and enlarged.
Blood tests will also show a higher PSA and alkaline phosphatase. Typically, prostate cancer usually grows very
slowly and is found more frequently in men older than 65.

STAGING OF PROSTATE CANCER

Prostate cancer is also given a grade called a Gleason score. This score is based on how much the cancer looks
like healthy tissue when viewed under a microscope, how the cancer cells are arranged in the prostate and
assigns a score on a scale of 3 to 5 from 2 different locations and in addition to stage to help plan treatment.
 Gleason X: The Gleason score cannot be
determined.
 Gleason 6 or lower: The cells are well
differentiated, meaning they look similar to
healthy cells.
 Gleason 7: The cells are moderately
differentiated, meaning they look somewhat
similar to healthy cells.
 Gleason 8, 9, or 10: The cells are poorly
differentiated or undifferentiated, meaning they
look very different from healthy cells.
Gleason scores are often grouped into simplified
Grade Groups:
 Grade Group 1 = Gleason 6
 Grade Group 2 = Gleason 3 + 4 = 7
 Grade Group 3 = Gleason 4 + 3 = 7
 Gleason Group 4 = Gleason 8
 Gleason Group 5 = Gleason 9 or 10

STAGES OF CANCER

Stage I: Cancer in this early stage is usually slow growing. The tumor cannot be felt and involves one-half of 1
side of the prostate or even less than that. PSA levels are low. The cancer cells are well differentiated, meaning
they look like healthy cells (cT1a–cT1c or cT2a or pT2, N0, M0, PSA level is less than 10, Grade Group 1).

Stage II: The tumor is found only in the prostate. PSA levels are medium or low. Stage II prostate cancer is
small but may have an increasing risk of growing and spreading.

 Stage IIA: The tumor cannot be felt and involves half of 1 side of the prostate or even less than that.
PSA levels are medium, and the cancer cells are well differentiated (cT1a–cT1c or cT2a, N0, M0, PSA
level is between 10 and 20, Grade Group 1). This stage also includes larger tumors confined to the
prostate as long as the cancer cells are still well differentiated (cT2b–cT2c, N0, M0, PSA level is less
than 20, Group 1).
 Stage IIB: The tumor is found only inside the prostate, and it may be large enough to be felt during
DRE. The PSA level is medium. The cancer cells are moderately differentiated (T1–T2, N0, M0, PSA
level less than 20, Grade Group 2).
 Stage IIC: The tumor is found only inside the prostate, and it may be large enough to be felt during
DRE. The PSA level is medium. The cancer cells may be moderately or poorly differentiated (T1–T2,
N0, M0, PSA level is less than 20, Grade Group 3–4).

Stage III: PSA levels are high, the tumor is growing, or the cancer is high grade. These all indicate a locally
advanced cancer that is likely to grow and spread.

 Stage IIIA: The cancer has spread beyond the outer layer of the prostate into nearby tissues. It may
also have spread to the seminal vesicles. The PSA level is high. (T1–T2, N0, M0, PSA level is 20 or
more, Grade Group 1–4).
 Stage IIIB: The tumor has grown outside of the prostate gland and may have invaded nearby
structures, such as the bladder or rectum (T3–T4, N0, M0, any PSA, Grade Group 1–4).
 Stage IIIC: The cancer cells across the tumor are poorly differentiated, meaning they look very
different from healthy cells (any T, N0, M0, any PSA, Grade Group 5).

Stage IV: The cancer has spread beyond the prostate.

 Stage IVA: The cancer has spread to the regional lymph nodes (any T, N1, M0, any PSA, any Grade
Group).
 Stage IVB: The cancer has spread to distant lymph nodes, other parts of the body, or to the bones
(any T, N0, M1, any PSA, any Grade Group).

DIFFERENCE OF BPH AND PROSTATE CANCER

 PRESENTATION BPH Prostate Cancer
Role of androgen Proliferative Proliferative
Role of estrogen ERα adverse : inflammation, proliferation,
induction
Aromatase increased which is stimulated by
inflammation
ERβ beneficial : pro-apoptopic,
antiproliferative
Prostatic zone Transitional Peripheral
Age predilection Increases with aging Increases with aging
Risk factor Genetics, aging Genetic, race, aging, diet
Symptoms Obstructive, irritative Obstructive, irritattive, bone pain, cord
compression
Signs (DRE) Nodular hyperplasia : Smooth, median Adenocarcinoma : Induration, hard
sulcus palpable, firm, elastic, enlarged consistency. Others : regional
lymphadenopathy, cord compression signs
Location Central/periurethra Posterior subcapsular
Diagnosis DRE Prostate biopsy, PSA screening
Weight loss No Yes
Obstructive
symptoms
PSA Elevated between 4-10 or can be normal Elevated PSA > 10 and ALP

2) Rule of biopsy
a. What to look for?

Indications

- aggressive bone or soft tissue lesions

- soft tissue lesions larger than 5cm, deep to fascia, or overlying bone/neurovascular structures
- unclear diagnosis in a symptomatic patient
- solitary bone lesions in a patient with history of carcinoma

When a biopsy is not indicated

- asymptomatic latent bone lesions or a symptomatic active bone lesions which appear entirely benign
on imaging don't necessarily need a biopsy
- soft tissue lesion which are completely benign on MRI don't necessarily need a biopsy (e.g. lipoma,
hemangioma)

TYPES OF BIOPSY

- Fine Needle Aspiration (FNA)

o provides cytologic (cellular) specimen
o frequently used for carcinoma
o not typically used for sarcoma
- Core biopsy (Tru-cut)
o allow for tumor structural examination
 can evaluate both the cytologic and stromal elements of the tumor
o frequently used for sarcoma
- Incisional biopsy
o small surgical incision carefully placed to access tumor without contamination of critical
structures
 - Excisional biopsy
o select indications: small, superficial soft tissue masses

b. Classification of tumor based on tissue cell of origin (histopathology)

Tissue Benign Tumors Malignant Tumors

CONNECTIVE TISSUE
Adult fibrous tissue Fibroma Fibrosarcome
Embryonic (myxomatous) fibrous Myxoma Myxosarcoma
tissue
Fat Lipoma Liposarcoma
Cartilage Chondroma Chondrosarcome
Bone Osteoma Osteosarcoma
Notochord - Chordoma
Connective tissue probably fibrous Fibrous histiocytoma Malignant fibrous histiocytima
ENDOTHELIUM AND MESOTHELIUM
Blood vessels Hemangioma, Hemangiosarcoma, angiosarcoma
hemangiopericytoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Mesothelium - Mesothelioma
Blood and lymphoid cells
Hematopoietic cells Preleukimias, MyeloproliferativeD Leukemia
Lymphoid tissue plasmacytosis Plasmacytoma, multiple myeloma
MUSCLE
Smooth muscle Leiomyoma Leiomyosarcoma
Striated muscle Rhabdomyoma Rhabdomyosarcoma
Epithelial tissues
Stratified squamous Papilloma, seborrheic keratosis Squamous cell carcinoma,
and skin adnexal tumors epidermoid ca, some malignancies
Glandular epithelium Adenoma Adenocarcinoma

- Liver Hepatic adenoma Hepatoma: hepatocellular

- Kidney Renal tubular adenoma carcinoma
- Bile duct Bile duct adenoma Renal cell carcinoma;
hypernephroma
Cholangiocarcinoma

Transitional epithelium Transitional cell papilloma Transitional cell carcinoma

Placenta Hydatidiform mole Choriocarcinoma
Testis - Seminoma, embryonal cell ca
NEURAL
Glial cells Glioma, grades I-III, anaplastic;
glioblastoma multiforme (grade IV)
Nerve cells — Neuroblastoma
— Medulloblastoma
Ganglioneuroma —
Meninges Meningioma Malignant meningioma
Nerve sheath Schwannoma, neurilemmoma Malignant meningioma
Neurofibroma Malignant schwannoma
Neurofibrosarcoma
AMINE PRECURSOR UPTAKE AND DECARBOXYLATION
Pituitary Basophilic adenoma
Eosinophilic adenoma
 Chromophobe adenoma
Parathyroid Parathyroid adenoma Parathyroid ca
Throid C cell hyperplasia Medullary carcinoma of thyroid
Bronchial lining - Bronchial carcinooid, oat cell ca
Adrenalmedulla Pheochromocytoma Malignan pheochromocytoma
pheochromocytoma
Pancreas Islet celladenoma, insulinoma, Islet cell carcinoma
gastrinoma
Stomach and intestines Carcinoid Malignant carcinoid
Carotid body and chemoreceptor Chemodectoma, paraganglioma Malignantcarcinoid
system Malignant paraganglioma
OTHER NEURAL CREST-DERIVED CELLS
Pigment-producing cells in skin, Nevus Melanoma
eyes, and occasional other sites
Schwann cells of peripheral Schwannoma, or neurilemmoma Malignant schwannoma
nervous system
Merkel cells in squamous Merkel cell neoplasm (similar to
epithelium (unknown function) oat cell)
TUMORS
Breast fibroadenoma Cystosarcome phylloides
Renal anlage - Wilms tumor

3) Tumor markers
a. The rules

The ideal marker would be a "blood test" for cancer in wich a positive result would occur only in patients with
malignancy, one that would correlate with stage and response to treatment and that was easily and
reproducibly measured. No tumor marker now available has met this ideal.

Tumor markers can be used for one of four purposes: (1) screening a healthy population or a high risk
population for the presence of cancer; (2) making a diagnosis of cancer or of a specific type of cancer; (3)
determining the prognosis in a patient; (4) monitoring the course in a patient in remission or while receiving
surgery, radiation, or chemotherapy.
 b. Describe types of tumor markers (cell surface markers, genetic markers, tumor markers in the
blood or other body fluid)

Carbohydrate Tumor Markers

CA-125 The most important clinical significance of CA125 is to reflect the ovarian cancer, with positive rate
of 61.4%, and CA125 is a good indicator of the treatment efficacy and recurrence of ovarian cancer.
If the treatment is effective, the CA125 will decline, and once recurrence occurs, CA125 will be
elevated before the symptoms. N: <35u/mL
CA15-3 Clinical significance in the diagnosis of breast cancer. In the early stage of breast cancer, the
sensitivity is low, 30%, but in the late stage, the sensitivity is up to 80%, which has important value in
the efficacy, prognosis, recurrence and metastasis diagnosis of breast cancer. Other malignant
tumors also have a certain positive rate, and in the liver, gastrointestinal tract, lung, breast, ovarian
and other non-malignant tumor disease, the positive rate of less than 10%.
CA19-9 Important indicator of digestive system tumors. In pancreatic cancer, gallbladder carcinoma and
cholangiocarcinoma, CA19-9 is significantly increased, especially in pancreatic cancer the positive
rate is 75%. N : <37u/mL
CA242 The clinical application of CA242 is relatively less, and it is significantly increased in adenocarcinoma,
while in non-squamous tissue the level of CA242 is higher than that of squamous cell carcinoma.
CEA, together with CA242 can improve the detection sensitivity of adenocarcinoma. CA242 is used as
a escalator of CA19-9, as its sensitivity is similar to that of CA199 in pancreatic cancer and
cholangiocarcinoma, but its specificity is better than that of CA199, which was less affected by
benign diseases such as pancreatitis, hepatitis and cirrhosis. In colorectal cancer, its sensitivity is up
to 60% to 72%.
CA50 CA50 is also a very broad tumor marker, and in liver, lung, stomach, knot / rectum, pancreas,
gallbladder, kidney, uterus, ovary, breast, bladder, prostate cancer, lymphoma, melanoma
pneumonia, nephritis, pancreatitis, colitis and other infectious diseases, it will also increase. In
addition, some ulcerative disease, autoimmune diseases also make CA50 rise.
CA72-4 The positive rate of CA72-4 can reach 65% to 70% in gastric cancer, higher in patients with
transference. In the colorectal cancer, pancreatic cancer, liver cancer, lung cancer, breast cancer,
 ovarian cancer, CA72-4 with a certain positive rate can be used as an important indicator in cancer
treatment follow-up, recurrence and prognosis.

Cell keratin fragment antigen 21-1 (CYFRA21-1) → The best indicator to detect lung cancer. If the lungs have
no clear ring shadow, while serum CYFRA21-1 concentration> 30ng / ml, there is a high possibility of lung
cancer. Early diagnosis of lung cancer once found CYFRA21-1 increased, it can be used as an important
indicator of the prognosis of lung cancer.

Tissue peptide antigen (TPA) → TPA consists of cell keratin proteins 8, 18 and 19, and can directly reflect the
degree of cell proliferation, differentiation and tumor infiltration. Patients with lung cancer will have increased
TPA, whose sensitivity is close to CYFRA21-1, with quite positive rate of about 61%. In bladder cancer, prostate
cancer, breast cancer, ovarian cancer and gastrointestinal malignancies, TPA will be increased; acute hepatitis,
pancreatitis, pneumonia and gastrointestinal diseases and 3 months after pregnancy can also see TPA
increased.

Squamous cell carcinoma antigen (SCCA) → Specific marker for Squamous cell carcinoma. It is used for the
diagnosis of squamous cell carcinoma, cervical cancer, lung cancer, head and neck cancer, as its concentration
increased with the condition increased. Its increase can also be seen in hepatitis, cirrhosis, pneumonia,
tuberculosis and other benign diseases.

Human epididymal secretory protein 4 (HE4) → HE4 is a very good tumor marker for the diagnosis of ovarian
cancer with a sensitivity of 72.9% (above CA 125) and a specificity of 95%. CA125 + HE4 is the best combination
for the diagnosis of ovarian cancer.

c. Oncofetal proteins (α fetoproteins and carcinoembryonic antigen/CEA)

1. α fetoproteins (AFP)
 AFP is an ancient but excellent tumor marker, whose specificity in primary liver cancer is very high,
with the positive rate of 70%. If a patient has a history of hepatitis B, and has liver mass, with AFP>
400ng / ml and for 1 month, he can be diagnosed as liver cancer. In addition to liver cancer, AFP will
also be elevated in endodermal sinus cancer, teratoma, testicular cancer, ovarian cancer, gastric
cancer with liver metastases. The vast majority of viral hepatitis/cirrhosis patients will also see AFP
increase, normal range <40mg/l. Women AFP begin to rise after pregnancy for 3 months and reach
the peak during 7 to 8 months, and 3 weeks after delivery it’ll return to normal level. Protein yang
diproduksi dari liver dan yolk sac AFP akan menurun setelah lahir. Fungsi : screening untuk bayi pada
saat hamil, utk diagnosis penyakit liver, screen atau monitor cancer.

2. Carcinoembryonic antigen (CEA)

Found in 1965, CEA can be described as the most broad spectrum of indicators, as its rise can be seen in the
colorectal cancer, stomach cancer, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, uterus and
cervical cancer, urinary tract tumors, and other malignant tumors with different degrees of positive rate. In
short, CEA is most likely to rise in adenocarcinoma, followed by squamous cell carcinoma and poorly
differentiated carcinoma. When there is a late tumor stage, loaded tumor, or tumor metastasis, there will be
increased CEA. Normal <2,5mg/l dan protein yg ada ketika bayi masih dalam kandungan

d. Enzyme related to neoplasm (β HCG, thyrocalcitonin, PSA, LDH)

1. Free β HCG
It is the most sensitive indicator for Germ cell cancer, especially for choriocarcinoma, with sensitivity up to
100%. If people have block on the liver along with the AFP increase, then there is a high degree of primary liver
cancer; if Free-β-HCG is increased, then it is suspected as germ cell cancer. Gemelli, choriocarcinoma,
hydatidiform mola, testicular ca. Free-β-HCG increase also suggests a high degree of malignancy, poor
prognosis.

2. Thyrocalcitonin

A low level of calcitonin means that it is unlikely that symptoms are due to C-cell hyperplasia or medullary
thyroid cancer. An elevated concentration of calcitonin means that excessive amounts are being produced.
Significantly elevated levels of calcitonin are a good indicator of C-cell hyperplasia or medullary thyroid cancer;
however, the healthcare practitioner will use other procedures, such as a thyroid biopsy, scan, and ultrasound,
to establish the diagnosis.

3. PSA

The "normal" PSA serum concentration remains a debate, however, for most laboratory readings, it should be
less than 4.0 ng/mL.

- The prostate gland generally increases in size and produces more PSA with increasing age, so it is
normal to have lower levels in young men and higher levels in older men. Due to these normal
changes in PSA with age, the concept of age-adjusted PSA normals have been described and
recommended.
- What is considered to be a normal PSA level also depends on ethnicity and family history of prostate
cancer.
- Once an initial PSA has been obtained, the change in the PSA over time, the PSA velocity, plays a role
in clinical decision making. It is felt that the PSA velocity over a year should be less than 0.75 ng/mL.
For example, a man 50 to 59 years of age with a PSA level that is 0.5 ng/mL one year and increases to
2.5 ng/mL the following year, may be viewed as having a normal PSA level, but the rate of change in
his PSA (PSA velocity) would be worrisome for an underlying prostate cancer.

ACS recommends that screening start at the following ages:

 Age 50 years in men at average risk for prostate cancer who are expected to live at least 10 more years
 Age 45 years in men at high risk for prostate cancer (African Americans and men with a first-degree
relative diagnosed with prostate cancer before age 65)
 Age 40 years in men at very high risk (those with more than one first-degree relative who had prostate
cancer at an early age).
4. LDH
 N :105-333 IU/L
 Abn : meningkat pada ischemia, heart attack, hemolytic anemia, infectious mononucleosis, hepatitis,
muscular dystrophy, stroke, pancreatic and testicular cancer

e. Important miscellaneous markers (β2 microglobulin, serum ferritin, thyroglobulin, paraprotein)

1. β2 microglobulin
A protein called beta-2 microglobulin (B2M) in the blood, urine, or cerebrospinal fluid (CSF). People with
cancers of the bone marrow and blood often have high levels of B2M in their blood or urine. These cancers
include multiple myeloma, lymphoma, and leukemia.High levels of B2M in cerebrospinal fluid can mean that
cancer has spread to the brain and/or spinal cord.

 N = 0-0,3μg/mL (urine) 0-3 μg/mL (serum/ plasma)

 Meningkat pada serum : multiple myeloma, leukimia
 Meningkat pada urine : tubular disorder of kidney
 Meningkat pada CIF multiple sclerosis, AIDS dementia complex, meningeal spread of hematologic
tumor

2. Ferritin (Ft)

Ft is associated with a variety of tumors, but is not a direct evidence of the tumor. When there is blood
transfusion, iron therapy, aplastic anemia, hemolytic anemia, thalassemia, primary hemosiderosis, connective
tissue disease, a variety of liver disease and chronic renal failure, infectious diseases, the Ft level will increase,
while the patients with iron deficiency anemia will appear Ft decline. N Male 12-200 ng/mL, Female 12-150
ng/mL

3. Thyroglobulin

A thyroglobulin test is mostly used as a tumor marker test to help guide thyroid cancer treatment. If
thyroglobulin levels stay the same or increase after treatment, it may mean there are still thyroid cancer cells
in the body. If thyroglobulin levels decrease or disappear after treatment, it may mean there are no normal or
cancerous thyroid cells left in the body.

4. Paraprotein : Ig yang diproduksi oleh multiple myeloma

4) General staging of cancer

5) Population kinetics of cancer cells

 1) Tumor doubling time

The tumor volume doubling time (DT) is the time taken by a tumor to double in volume. This concept was first
introduced by Collins et al.,[7] who showed that the growth rate of malignant tumors was constant and
exponential and could be estimated in terms of the DT.

The cell cycle is crucial to understanding the basis of the various methods employed for computing “tumor
doubling time.” The cycle may be divided into four phases, the duration of each of which is subject to extreme
variation. Loss of neoplastic cells is a major factor in this variability, among the explanation of the loss being
death of cells, exfoliation, and metastasis. The actual “tumor doubling time,” which represents the net effect
of all parameters of cytokinetics, always is longer than the potential doubling time, which represents the time
that would elapse were every daughter cell from each generation to survive.

2) G0 phase regulations
3) Treatment of prostate cancer
4)