Case 1

31 years old female

Painful vulval lump
 Case 1 - diagnosis

Benign vaginal stromal polyp in

pregnancy
 Summary of microscopic
features
• ill-defined margin
• covered by squamous epithelium
• cellular groups of spindle-shaped cells
• less cellular myxoid areas
• small blood vessels
• central cellular nodule - stellate and spindle cells
• scattered multinucleate cells
• mild to moderate nuclear pleomorphism
• 5 mitoses/10hpf
vimentin
CD34
 Negative
immunohistochemistry
• smooth muscle markers
• striated muscle markers
• neural markers
 Case history cont’d

• originally diagnosed as low grade

myxoid sarcoma
• 39 (+5) weeks pregnant
• relatively rapidly growing lesion
• wide local excision - no evidence of
residual tumour
 Features that may give rise to an
erroneous diagnosis of malignancy
• marked hypercellularity
• marked cytological pleomorphism
• mitotic counts > 10/10hpf
• atypical mitoses
Increased cellularity in centre
of lesion – recently described
Nucci MR, Young RH, Fletcher CDM
Am J Surg Pathol 2000; 24: 231-240
 Features that give clues to the
diagnosis
• lack of an identifiable lesional margin
• extension of abnormal stromal tissue up to
the mucosal-submucosal interface
• frequent presence of individually scattered
multinucleate stromal cells, most often
located close to the surface epithelium
Other sarcomas to be considered in
the differential diagnosis
• leiomyosarcoma
• rhabdomyosarcoma
• low grade endometrial stromal sarcoma
• malignant mixed mullerian tumour
• malignant peripheral nerve sheath
tumour
• dermatofibrosarcoma protuberans
Smooth muscle markers

variable – but none of the recently

reported cases showed positivity for
both desmin and smooth muscle actin
 Other neoplasms to be considered
in the differential diagnosis
• aggressive angiomyxoma
• angiomyofibroblastoma
• cellular angiofibroma
Vulvo-vaginal fibroepithelial stromal
polyp and pregnancy
• knowledge of pregnancy is crucial
• may spontaneously regress following
delivery
 References
• Al-Nafussi et al Histopathology 1993; 22:
145-150
• Mucitelli et al Int J Gynecol Pathol 1990; 9:
20-40
• Nucci et al Am J Surg Pathol 2000; 24:
231-240
• Nucci & Fletcher Histopathology 2000; 36:
97-108
 Case 2

25 years old female

Delayed miscarriage. 105g of tissue
received with vesicles up to 4mm in
diameter
Case 2 - diagnosis

Early complete
hydatidiform mole
 Hydatidiform mole
• complete
• partial
• invasive
 Hydatidiform mole
histological features
• hydropic change
• cistern formation
• excessive trophoblast
• abnormal distribution of trophoblast
• trophoblastic inclusions
 Complete mole
• all chorionic villi affected
• pleomorphism of trophoblast
• absence of fibrosis
 Partial mole
• fetal parts may be present
• focal hydropic change
• cistern formation
• irregular profile of villi
• round trophoblastic pseudoinclusions
• excess trophoblast may be subtle
• abnormal (angiomatoid) vasculature in second
trimester
Partial mole
Partial mole
 Hydatidiform mole
gestational age at evacuation

• 1960s – 17 weeks
• 2000 – 9.4 weeks
 Early complete mole
• abnormally shaped villi –branching or
polypoid
• stromal mucin
• stromal vessels may be present
• STROMAL NUCLEAR DEBRIS
Early complete mole
Stromal nuclear debris

Ki-67

cases of partial mole and hydropic

miscarriage exhibit no or inconspicuous
karryorrhetic debris
Diploid complete
mole
Triploid partial
mole
 p57kip2

• cyclin-dependent kinase
• paternally imprinted, maternally expressed
gene
• expressed in cytotrophoblast in normal
pregnancy
• expressed in partial mole
• not expressed in androgenetic complete
mole
 p57kip2

• Chilosi et al Lab Invest 1998; 78: 269-

276
• Genest DR et al J Reprod Med 2002; 47:
342-346
• Jun et al Histopathology 2003; 43: 17-
25
 P57kip2 in hydatidiform mole

Complete mole
Cytotrophoblast –ve
Syncytiotrophoblast -ve Partial mole
Cytotrophoblast +ve
Syncytiotrophoblast -ve

Non-villous
trophoblast is p57
+ve even in
complete mole
(courtesy of Neil
Sebire)
Atypical
non-villous
trophoblast in
complete mole

Courtesy of Neil Sebire

 Case 3

41 years old female

Bilateral tumours and ascites
 Case 3 - diagnosis

Borderline serous tumour of the

ovary with stromal
microinvasion
 EPITHELIAL TYPES

• serous
• mucinous each of these can
• endometrioid be benign,
• clear cell borderline or
• transitional cell malignant
SEROUS BORDERLINE TUMOURS

The survival of patients with serous

borderline tumours confined to the
ovaries exceeds 99%
Does microinvasion in borderline serous
tumours represent a risk lesion?
• conventional wisdom: no
• Stanford data: yes
• microinvasion is an adverse prognostic factor
independent of stage of disease & implant status
in non-pregnant patients
• 71% v 97% 5 year survival

Am J Surg Pathol 2005; 29: 707-723

Am J Surg Pathol 2006; 30: 1209-1221
 SEROUS BORDERLINE TUMOURS
types of peritoneal lesions
• endosalpingiosis
• borderline
• desmoplastic, non-invasive
• invasive
endosalpingiosis
non-invasive implant
invasive implant
severe nuclear atypia in an
invasive peritoneal implant
PERITONEAL IMPLANTS:
5-10 YEAR SURVIVAL

• Non-invasive 95%

• Invasive 66%
Micropapillary serous carcinoma

CONTROVERSIAL!
 MICROPAPILLARY SEROUS
CARCINOMA
• well differentiated
• exophytic papillary growth pattern
• non-invasive
• strong association with invasive implants
• frequently recur as invasive carcinomas
• 10 year survival - 60%
 MICROPAPILLARY SEROUS CARCINOMA

• Burks et al Am J Surg Pathol 1996; 20: 1319

• Singer et al Am J Pathol 2002; 160: 1223
• Shappell et al Am J Surg Pathol 2002; 26:
1529
• Staebler et al Hum Pathol 2002; 33: 47
• Singer et al Int J Gynecol Pathol 2003; 22: 37
• Singer et al J Natl Cancer Inst 2003; 95: 484
 BRAF & KRAS mutations
(BRAF is a downstream mediator of KRAS)

• serous borderline tumours – 61%

• invasive micropapillary serous
carcinoma – 68%
• high-grade serous carcinoma – 0%
 Proposed dualistic pathway of ovarian serous carcinoma
ovarian surface
epithelium

benign serous
cystadenoma

usual serous borderline

ovarian cortical neoplasm
intraepithelial inclusion
neoplasia cysts
micropapillary variant of serous
borderline neoplasm

high grade ovarian low grade ovarian

serous carcinoma serous carcinoma
 Longacre et al Am J Surg Pathol 2005; 29:
707-723

• 276 patients with at least 5 years follow-up

• micropapillary architecture per se did not affect outcome
• high stage ovarian serous borderline tumours with
micropapillary architecture are associated with invasive
implants more frequently than high stage tumours
without micropapillary architecture
 Distal fallopian tube as the origin of serous
carcinoma
• detection of early tubal carcinoma in over 70% of
malignancies detected in BRCA+ women
following risk-reducing salpingo-oophorectomy

• detection of early tubal carcinoma in one-half of

ovarian and primary peritoneal serous
carcinomas irrespective of family history

Jarboe et al Histopathology 2008; 53: 127-138

p53
P53 “signature”
 Case 4
60 years old female
Continuous vaginal bleeding for 13weeks.
Examination demonstrated a 4cm diameter
polyp distending the cervix and extending
into the vagina
Case 4 - diagnosis

Uterine Mullerian
adenosarcoma
 UTERINE MULLERIAN ADENSARCOMA

• usually postmenopausal women

• 30% < 50 years of age
• abnormal vaginal bleeding
• tumour may protrude through the external os
• almost always stage 1
• history of recurrent ‘benign endometrial
polyps’ should suggest adenosarcoma
• local recurrence – correlates with myometrial
invasion
UTERINE MULLERIAN ADENOSARCOMA

• variety of epithelial types

• stroma resembles low grade endometrial
stromal sarcoma – mild/moderate nuclear
atypia
• stromal mitotic figures (>2 to 4 mf/10hpf) –
no prognostic significance
• cambium layer
• sarcomatous overgrowth may occur - poor
prognosis
 UTERINE MULLERIAN ADENSARCOMA
DIFFERENTIAL DIAGNOSIS

• benign endometrial polyp

• polypoid adenomyoma
• atypical polypoid adenomyoma
• MMMT
• endometrial stromal sarcoma
• Uterine Wilm’s tumour – rare!
UTERINE MULLERIAN ADENOSARCOMA

• Ostor AG, Rollason TP Mixed tumours of the uterus.

In: Haines & Taylor Obstetrical and Gynaecological
Pathology, Editors H Fox & M Wells, Churchill
Livingstone, 2003: 549-584 (adenosarcoma: 552-559)
• Baker P, Oliva E Endometrial stromal tumours of the
uterus: a practical approach using conventional
morphology and ancillary techniques. J Clin Pathol
2007; 60: 235-243.
 Case 5

45 years old female

Large pelvic mass. Left ovary
adherent to sigmoid colon
Case 5 - diagnosis

Ovarian dysgerminoma
 OVARIAN DYSGERMINOMA

•mutated c-kit gene

•usually unilateral
•3% - syncytiotrophoblastic cells
•5% - anaplastic
•granulomas in > 20%
•markers - PLAP, LDH
 OVARIAN DYSGERMINOMA

• Nogales FF Germ cell tumours of the ovary.

In: Haines & Taylor Obstetrical &
Gynaecological Pathology, Editors H Fox &
M Wells, 2003: 771-820 (dysgerminoma – 773-
777)
 Case 6

42 years old female

Bilateral ovarian tumours 6.5 and 11
cms in maximum diameter
Case 6 - diagnosis

Gastric adenocarcinoma
metastatic to the ovary
OVARIAN TUMOUR PATHOLOGY

Is it a metastasis?
 CYTOKERATINS IN PRIMARY AND METASTATIC OVARIAN
ADENOCARCINOMA

Primary Metastatic

Cytokeratin 7 positive negative

Cytokeratin 20 negative positive

Gynaecological tumour
pathology

Is it malignant
melanoma?
• 30 years old female
• 2007 - emergency admission with pelvic pain
• 10 x 15cms cystic & solid ovarian tumour
• CD10 +ve; HMB45 –ve
• high grade stromal sarcoma
• subsequent history – malignant melanoma of
right calf excised in 2001
A B

Melan A

C D
METASTATIC TUMOURS OF THE OVARY

• Fox H Metastatic tumours of the ovary. In:

Haines and Taylor Obstetrical and
Gynaecological Pathology, Editors H Fox &
M Wells, Churchill Livingstone, 2003: 879-896
• McCluggage & Wilkinson N Metastatic
neoplasms involving the ovary: a review with
an emphasis on morphological and
immunohistochemical features.
Histopathology 2005; 47: 231-247
 Case 8

20 years old female - right labial

mass 65mm in maximum
dimension.
CD99
 Case 8 - Diagnosis
primitive neuroectodermal tumour
of the vulva
 PNET
• highly cellular malignant tumour
• undifferentiaited neuroepithelial cells
• member of the Ewing’s sarcoma family of
tumours
• t(11;22)(q24;q12) translocation in 85-90%
of cases
PRIMITIVE NEUROECTODERMAL TUMOUR OF
THE VULVA - FISH

EWSR1 probe
shows a
rearrangement
of EWS
PRIMITIVE NEUROECTODERMAL TUMOUR OF
THE VULVA - FISH

Confirmed as due
to fusion of
EWS/FLI1 on
chromosome 22
using EWS/FLI1
probe – the
commonest type
of molecular
arrangement seen
in this group of
tumours
 PNET of the female genital tract
• only two previous reports of primary PNET
of the vulva
• rare cases (approx.8) reported in the
cervix
• well described in the ovary – largest series
25 cases
 PNET – differential diagnosis
• poorly differentiated carcinoma
• small cell carcinoma
• desmoplastic small cell tumour
• malignant melanoma
• lymphoma
CAM 5.2
MIC 2
MNF 116
PGP 9.5
 The patient developed pulmonary
metastases and has subsequently died
of her disease
McCluggage WG, Sumathi VP, Nucci MR, Hirsch
M, Cin PD , Wells M, Flanagan AM, Fisher C.
Ewing family of tumours involving the vulva and
vagina: report of a series of four cases
Journal of Clinical Pathology 2007; 60: 674-680
 Case 9

41 years old female

Cone biopsy
 Case 9 - diagnosis

High grade cervical glandular

intraepithelial neoplasia with focal
early stromal invasion
(adenocarcinoma)
WHO classification v Cervical Glandular
Intraepithelial Neoplasia (CGIN)

glandular glandular adeno-

atypia dysplasia carcinoma
in-situ

CGIN CGIN
low grade high grade
 Glandular dysplasia

“The concept that glandular dysplasia forms a

biological spectrum of cervical glandular intraepithelial
neoplasia remains controversial”

Wells et al 2003 Epithelial tumours and related lesions of

the uterine cervix In: WHO (“blue book”) Tumours of the
breast and female genital organs p. 276
 Is endocervical glandular dysplasia
(EGD) a precursor of
adenocarcinoma-in-situ (AIS)?
• EGD is found next to AIS
• EGD is found at a younger age than AIS or
adenocarcinoma
• HPV found in both EGD and AIS
• Higher frequency of EGD than AIS
 High grade CGIN
(Adenocarcinoma-in-situ/ severe glandular dysplasia)

• endocervical, intestinal, endometrioid, mixed

adenosquamous types
• tubal type recently described - ? reproducible
• frequent coexistent CIN or squamous carcinoma
(approx 50%)
• topography – conflicting data; most cases seem
to involve surface epithelium and superficial
glands near the transformation zone
 Low grade CGIN
(glandular dysplasia other than severe)
• no well defined criteria – subjective
• natural history – not established
• nuclear and architectural abnormalities of a
lesser degree than AIS
• reactive changes – relatively easily recognised

• some cases are HPV 16/18 +ve.

• higher mitotic index than reactive lesions
• neoplastic glycoprotein expression profile
 Benign Mimics of CGIN and
Adenocarcinoma
• Tubo-endometrioid • Atypical oxyphil
metaplasia metaplasia
• Endometriosis • Adenomyoma
• Microglandular • Radiation effects
hyperplasia • Ectopic prostate
• Inflammatory atypia • Arias-Stella effect
• Mesonephric remnants • Florid cystic
• Endocervical hyperplasia endosalpingiosis
• Tunnel clusters • Cautery artefact
• Deep cervical glands • Mullerian papilloma
• Endocervicosis • Villous adenoma
tubal metaplasia
 Mimics of HCGIN – special
techniques
MIB1 bcl2 p16INK4a

TEM <10% + cytoplasm Focal +

Endometriosis <10% + cytoplasm Focal +

MEH <10% - -

HCGIN >30% - 100% +

McCluggage. J Clin Pathol 2003; 56: 164

 MIB1

tubal metaplasia
 P16
in cervical glandular intraepithelial neoplasia

• encoded by CDKN2A gene on chromosome 9p21

• strong relationship between p16 expression and HPV-
encoded E6/E7 transcription
• overexpression associated with presence of high-risk
HPV
• all cases of CGIN – p16 positive
• tubo-endometrioid metaplasia and endometriosis may
also show focal p16 immunoreactivity

Cameron et al Histopathology 2002; 41: 313-321

Negri et al Am J Surg Pathol 2003; 27; 187-193
Tringler et al Hum Pathol 2004; 35: 689-696
p16
tubal metaplasia –
p16
 Criteria for Microinvasive
Adenocarcinoma
• obvious invasion to 5mm or less
• usually complete obliteration of the
normal endocervical crypts
• extension beyond the normal
glandular field
• a stromal response typical of
invasive carcinoma
“…I do not know how to make the diagnosis
of microinvasive cancer of the endocervix. I
do not know where the basal lamina is and I
do not know where to measure from. I do not
know what depth constitutes microinvasion.
We do not have the same data for
endocervical invasion that we have for the
lesions in the squamous epithelium”.
Richart R.
 Microinvasive adenocarcinoma
clinical features

• 12% of microinvasive carcinomas

• average age – 39yrs (7 years younger than
frankly invasive adenocarcinoma)
• most present with abnormal smears (66%)
• approximately one-third – oral contraceptive use
• approximately one-third – cigarette smokers
 Microinvasive adenocarcinoma

• most cases arise in the transformation zone

• “skip lesions” are rare
• cold knife cone biopsy preferable to LLETZ
• approximately 50% of patients with +ve
margins will show residual disease at
hysterectomy
 436 microinvasive adenocarcinomas reported in the
literature (Ostor Int J Gynecol Pathol 2000; 19:29-38)

Maximum No with Recurrences Deaths

depth of lymph node from
invasion metastases tumour

5mm 5/219 15 6
 Residual disease at hysterectomy
correlated with positive margins or disease within 3mm of margins of
loop specimens

low grade CGIN 43%

high grade CGIN 50%

microinvasive 33%
adenocarcinoma

Kurian & Al-Nafussi J Clin Pathol 1999; 52: 112-117

“Glandular lesions of the Uterine Cervix”
symposium
• International Journal of Gynecological Pathology
2002; 21: 313-367
In 4 parts with articles by RJ Zaino, WR Hart, MR
Nucci, M Wells & LJR Brown
Other references:
• McCluggage WG Endocervical glandular lesions:
controversial aspects and ancillary techniques. J
Clin Pathol 2003; 56: 164-173
• Brown LJR, Wells M. Premalignant and malignant
glandular lesions of the cervix. Haines & Taylor,
Obstetrical and Gynaecological Pathology, Editors H
Fox & M Wells, Fifth Edition, Chirchill Livingstone,
2003: 339-367.
 Case 10

35 years old female

Uterine tumour
Case 10 - diagnosis

Placental site trophoblastic

tumour
 Histopathological Classification of Gestational
Trophoblastic Disease

• Hydatidiform mole
- complete
- partial
• Invasive hydatidiform mole
• Choriocarcinoma
• Placental site trophoblastic tumour
• Epithelioid trophoblastic tumour
Placental site trophoblastic tumour
• weeks to years after
pregnancy
• average interval 18-30
months
• invasive uterine mass
(mean - 5cms diameter)
• mildly raised hCG
• paternal allele present
• absence of Y
chromosome
Placental site trophoblastic tumour mirrors properties of
normal non-villous trophoblast (extravillous or intermediate
trophoblast)

• occasional binucleate
/multinucleate cells

• myometrial infiltration

• intravascular tumour

• fibrinoid necrosis in
vessel wall
Placental site trophoblastic tumour
• cords, islands,
sheets of
polygonal, round
or spindle cells
• scattered mitoses
• Ki67 > 5%
• hPL, PLAP,
inhibin +ve
• focal hCG +ve
• p63 - ve
 Placental site trophoblastic tumour
factors associated with poor prognosis

•deep invasion

•clear cells

•extensive necrosis

•mitoses+
 Placental site trophoblastic tumour

• Baergen et al Gynecol Oncol 2006;

100:511-520
• Schmid et al Lancet 2009; 374: 48-55
Epithelioid trophoblastic tumour

• cells resemble chorion laeve

• nodular islands of trophoblast

surrounded by extensive
necrosis

• hyaline-like matrix

• cells smaller & less

pleomorphic than PSTT

• p63 positive
CYTOKERATIN
INHIBIN
ß HCG
Placental site/epithelioid
trophoblastic tumour
differential diagnosis

exaggerated placental site reaction

placental site nodule
decidua
choriocarcinoma
epithelioid leiomyosarcoma
squamous carcinoma
Placental site nodule
• usually incidental

• months / years
post pregnancy

• small, well
circumscribed

• hyalinised
Placental site nodule

• single cells, clusters

or cords of bland,
uniform cells
• no infiltration
• no mitoses
• Ki67 < 5%
 Placental site nodule v atypical
placental site nodule v epithelioid
trophoblastic tumour
• significant areas of necrosis
• increased Ki-67
• foci of calcification
• increased Cyclin E expression
Placental site nodule v Epithelioid
trophoblastic tumour

Ki-67 p63
PLACENTAL SITE TROPHOBLASTIC TUMOUR

• Paradinas FJ & Elston CW Gestational

trophoblastic diseases. In: Haines & Taylor
Obstetrical & Gynaecological Pathology,
Editors H Fox & M Wells, Churchill
Livingstone, 2003: 1359-1430 (PSTT – 1405-
1409
• Wells M The pathology of gestational
trophoblastic disease: recent advances.
Pathology 2007; 39: 88-96
 Case 11

19 years old female

Right ovarian cyst
 Case 11 - diagnosis

High grade (grade 2) immature

teratoma of the ovary
 IMMATURE TERATOMA OF THE OVARY

• stage 1 in 70% of cases

• solid and cystic
• subjective grading
• preponderance of neuroectodermal tissues
• gliomatosis peritonei – commonest
complication
 Norris et al 1976

• Grade 0 – all tissues mature

• Grade 1 – some immaturity limited to rare
low power field
• Grade 2 – higher immaturity; no more than 3
low-power fields per slide
• Grade 3 – immaturity prominent; 4 or more
low power fields per slide
 Steeper & Mukai 1984

• Grade 1 – < 10% is neuroepithelium

• Grade 2 – third of tumour is neuroepithelium
• Grade 3 – 50% of tumour is neuroepithelium
 O’Connor DM & Norris HJ
Int J Gynecol Pathol 1994; 13: 283-289

• Low grade (grade 1)

• High grade (grades 2 & 3)
 IMMATURE TERATOMA OF THE OVARY

• Nogales FF Germ cell tumours of the ovary.

In Haines & Taylor Obstetrical &
Gynaecological Pathology, Editors H Fox &
M Wells, 2003: 771-820 (immature teratoma –
788-794)
 Case 12

59 years old female

Postmenopausal bleeding;
polypoid endometrium
 Case 12 - diagnosis

Complex atypical hyperplasia

(high grade endometrial
intraepithelial neoplasia) [EIN]
Papillary endometrioid adenocarcinoma
High grade papillary serous carcinoma
 Endometrial carcinoma - two or three entities?
Sivridis et al Int J Gynecol Cancer 1998; 8:183-188
status of tumour-free endometrium

As sociated with As sociated with

hyperplastic atroph ic
en dome trium en dome trium

En dome trio id 10 0% 76.7%

Serous /othe rs 0% 6.2% / 17.1%

Molecular profile of endometrial carcinoma
Endometrioid Serous

ER/PR + -
p53 mutation - +
microsatellite
instability ++ (20-30%) + (11%)
PTEN mutation + (34-83%) -
k-ras mutation + (10-30%) -
-catenin mutation + (28-35%) -
 HIGH GRADE SEROUS
CARCINOMA

precursor lesion – endometrial

intraepithelial carcinoma (flat or
micropapillary pattern)
P53 expression = p53 mutation in endometrial
intraepithelial carcinoma
“Minimal uterine serous carcinoma”

• serous carcinoma limited to

endometrium (superficial
serous carcinoma) and without
stromal invasion (endometrial
intraepithelial carcinoma)
• associated with extrauterine
EIC tumours in 45% of cases –
recent evidence suggest that
this is metastatic disease (Hui
et al Mod Pathol 2005; 18: 75-
82)
• ovarian serous carcinoma –
WT-1 diffuse strong nuclear
positivity
• uterine serous carcinoma - WT-
1 negative
ovarian metastasis
 ENDOMETRIAL HYPERPLASIA &
INTRAEPITHELIAL NEOPLASIA

simple complex atypical

hyperplasia hyperplasia hyperplasia

endometrial
intraepithelial
hyperplasia neoplasia (EIN)

low grade high grade

Simple hyperplasia
Complex hyperplasia
Atypical hyperplasia
Low grade cytological atypia
High grade cytological atypia
 “Beware diagnosing an endometrial
intraepithelial neoplasia lesion if the
cytology is identical between areas with
crowded compared to uncrowded glands”
Mutter, J Clin Pathol 2002; 55:326-331
Papillary syncytial
metaplasia
Papillary syncytial metaplasia superimposed on endometrial
intraepithelial neoplasia
 ENDOMETRIAL INTRAEPITHELIAL
NEOPLASIA
• volume percentage stroma < 55%
• cytological changes
• >1mm diameter
• exclude cancer, polyps, secretory
endometrium, artefact etc
 References
• Mutter GL, Baak JP, Crum CP, Richart RM, Ferenczy A, Faquin
WC. Endometrial precancer diagnosis by histopathology, clonal
analysis and computerized moprphometry. J Pathol 2000; 190: 462-
469
• Baak JP et al. The molecular genetics and morphometry-based
endometrial intraepithelial neoplasia classification system predicts
disease progression in endometrial hyperplasia more accurately
than the 1994 World Health Organization classification system.
Cancer 2005; 103: 2304-2312
• Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ. Benign
endometrial hyperplasia sequence and endometrial intraepithelial
neoplasia. Int J Gynecol Pathol 2007; 26: 103-114.
 Case 13

35 years old female

Fibroid uterus
Case 13 - diagnosis

Leiomyoma with bizarre

nuclei
(symplastic leiomyoma)
 SMOOTH MUSCLE TUMOURS OF THE UTERUS

MITOTICALLY BIZARRE SARCOMA

ACTIVE

well defined yes yes no

margin
haemorrhage no no yes
necrosis possibly possibly yes
cellularity yes possibly yes
increased yes no yes
mitoses
cellular no yes yes
pleomorphism
associated with yes yes no
hormonal
therapy
Infiltrative margin
Nuclear pleomorphism, mitoses
 Vulval smooth muscle tumours
SIZE MATTERS!
Well differentiated epithelioid leiomyosarcoma
4 recurrences 2002-2007
• > 5cms (9.5cms)
• recurrent tumour showed infiltrative margins
• cytological atypia – more prominent in later
specimens
• 2002 - low mitotic count (6 per 50hpfs) [6 per
10hpfs in 2007]
• no necrosis
Nielsen et al, Am J Surg Pathol 1996; 20: 779-793
 LEIOMYOMA WITH BIZARRE NUCLEI

• Rollason TP & Wilkinson N Non-neoplastic

conditions of the myometrium and pure
mesenchymal tumours of the uterus. In
Haines & Taylor Obstetrical &
Gynaecological Pathology, Editors H Fox &
M Wells, Churchill Livingstone, 2003: 497-548
(bizarre leiomyoma – 526-527)
 Case 14

74 years old female

Vaginal “polyp”
Case 14 - diagnosis

Malignant melanoma
of the vagina
HMB45
MALIGNANT MELANOMA OF THE VAGINA - 1

• rare – 5% of malignant vaginal neoplasms; <

1% of all malignant melanomas
• 22-83 years; mean 53 years
• vaginal discharge, bleeding, mass
• more often in distal third of vagina
• melanocytes may be seen in 3% of vaginas
MALIGNANT MELANOMA OF THE VAGINA - 2

• nodular or polypoid
• usually 2-4cms
• no distinctive microscopic features for this
site
• excludes metastasis – lateral junctional
component
• differential diagnosis – poorly differentiated
carcinoma, sarcoma
• poor prognosis
MALIGNANT MELANOMA OF THE VAGINA

Schmidt WA Pathology of the vagina. In

Haines & Taylor Obstetrical &
Gynaecological Pathology, Editors H Fox
& M Wells, Churchill Livingstone, 2003:
147-245 (malignant melanoma – 208-210)
 Case 15

58 years old female

Right ovarian tumour
 Case 15

Endometrioid adenocarcinoma
of the ovary associated with
atypical endometriosis
 Endometriosis and ovarian cancer
-shared risk factors
• early menarche
• more regular periods
• shorter cycle lengths
• lower parity
• tubal ligation-protective for clear cell and endometrioid but
not for serous or mucinous carcinoma
• relative risk of ovarian cancer 4.2 with a long history of
endometriosis
• Brinton LA, Girdley G, Persson et al. Cancer risk after a
hospital discharge of endometriosis. Am J Obstet Gynecol
1997;176:572-79.
 Endometriosis - theories

• implantation v metaplastic
• superficial v deep endometriosis - role of
peritoneal factors
• endometrium of women with endometriosis shows
increased proliferative and angiogenic properties
• role of locally elevated oestrogen levels- uterine
hyperperistalsis
 Endometriosis - molecular pathology

• monoclonal
• loss of heterozygosity in 75% of cases
associated with adenocarcinoma but in 28%
of cases without associated carcinoma
• most frequently affected chromosomes - 9p,
11q, 22q
 Endometriosis - clonality

• monoclonal - but this must be clarified

• the available evidence now suggests that the
peritoneal endometriotic lesions are multicellular
(polyclonal) in origin, although individual glands of
the lesion are derived from single precursor cells
(monoclonal).
Nabeshima et al Fertil Steril 2003; 80: 1144-1150
Wu et al Fertil Steril 2003; 79 Suppl 1: 710-717
 ATYPIA (DYSPLASIA, INTRAEPITHELIAL
NEOPLASIA) IN ENDOMETRIOSIS
• 1.7% of cases without a neoplasm
• 61% of endometriosis associated with
tumours
• frequent association with endometrioid and
clear cell carcinoma
• endometriosis and adjacent/contiguous
ovarian carcinoma show identical genetic
lesions
METAPLASTIC CHANGES IN ENDOMETRIOSIS

• potential source of
diagnostic confusion with
pre-malignant neoplastic
atypia (endometriotic
intraepithelial neoplasia)
• full range of metaplastic
change seen in the
eutopic endometrium
 OVARIAN AND EXTRA-OVARIAN NEOPLASIA
ASSOCIATED WITH ENDOMETRIOSIS
• endometrioid
adenocarcinoma
• clear cell carcinoma
• mucinous borderline low grade
tumour of Mullerian type endometrioid
• mixed Mullerian tumour stromal sarcoma
associated with
(uncommon)
endometriosis
• endometrioid stromal
sarcoma (uncommon)
• squamous cell carcinoma
(rare)
 Endometriosis -reference
• Wells M. Recent advances in endometriosis with
emphasis on pathogenesis, molecular
pathology, and neoplastic transformation.
International Journal of Gynecological
Pathology, 2004; 23: 316-320