THE EMERGING SPECTRUM OF NON-HPV

RELATED CERVICAL ADENOCARCINOMAS AND

THEIR PRECURSORS

W Glenn McCluggage
Belfast
United Kingdom
 TO DISCUSS
• non-HPV related cervical
adenocarcinomas and their possible
precursors
• vaginal adenocarcinomas and
possible precursors
 Cervical Epithelial Lesions (WHO 2014)
Squamous cell tumours and precursors
• Squamous intraepithelial lesions
– Low-grade squamous intraepithelial lesion (HPV only, CIN 1)
– High grade squamous intraepithelial lesion (CIN 2, CIN 3)
• Squamous cell carcinoma (keratinising, non-keratinising etc)

Glandular tumours and precursors

• Adenocarcinoma in situ (High grade CGIN)
• Adenocarcinoma
– Endocervical adenocarcinoma, usual type
– Mucinous carcinoma, NOS
• Gastric type (including adenoma malignum / minimal deviation adenocarcinoma)
• Intestinal type
• Signet-ring cell type
– Villoglandular adenocarcinoma
– Endometrioid adenocarcinoma

– Clear cell adenocarcinoma

– Serous adenocarcinoma
– Mesonephric adenocarcinoma
– Adenocarcinoma admixed with neuroendocrine carcinoma
 NON-HPV RELATED CERVICAL
ADENOCARCINOMAS
• emerging category of primary cervical
adenocarcinomas (about 10-15%)
• tend to be older than HPV related adenocarcinomas
• gastric type (including adenoma malignum)
• clear cell carcinoma (most)
• mesonephric adenocarcinoma
• possibly intestinal type (some)
• HPV screening programmes will not detect
• precursor lesions not well defined
 ADENOMA MALIGNUM
• mucinous variant of minimal deviation
adenocarcinoma (MDA)
• uncommon variant of cervical adenocarcinoma (1-3%
of cervical adenocarcinomas)
• non-HPV related
• association with Peutz-Jeghers syndrome
• highly differentiated
• thought to exhibit gastric/pyloric differentiation (HIK
1083/MUC6)
 ADENOMA MALIGNUM
• risk of underdiagnosis as normal/hyperplastic
endocervical glands
• risk of overdiagnosis- endocervical glandular
hyperplasias, tunnel clusters, endocervicosis,
mesonephric hyperplasia etc
• “flat” negative with hormone receptors (ER,
PR)
HIK1083
 GASTRIC TYPE CERVICAL
ADENOCARCINOMA
• HPV negative variant of cervical adenocarcinoma
• included in WHO 2014 (subtype of mucinous adenocarcinoma)
• cells with abundant clear or eosinophilic cytoplasm; sometimes
prominent cell membranes; often lot of inflammatory cells
• often low mitotic and apoptotic activity
• positive with gastric markers (but don’t need to diagnose)
• EMERGING AS SECOND COMMONEST FORM OF CERVICAL
ADENOCARCINOMA
• PART OF SPECTRUM WITH ADENOMA MALIGNUM AND OFTEN GET
ADMIXTURES (just call GASTRIC TYPE ADENOCARCINOMA)
 PROGNOSIS
• poor prognosis with tendency to abdominal/adnexal
dissemination and metastasis to other unusual sites (5
year survival 30 versus 77% for usual type) (AJSP
2007;31;664-672)
• AJSP (2015;39;1449-1457): 59% stage II-IV at
presentation; 50% lymph node metastasis; 35% ovarian
involvement; 20% abdominal involvement; disease
specific survival at 5 years 42% versus 91% for usual
type adenocarcinoma; no survival differences between
well differentiated (adenoma malignum) and more
poorly differentiated (non-adenoma malignum) (calls
into question value of grading- consider all as one
tumour type)
USUAL HPV RELATED CERVICAL
ADENOCARCINOMA

p16
pancreaticobiliary-like
NEUROENDOCRINE CELLS

synaptophysin
OMENTAL METASTASIS
OMENTAL METASTASIS
OVARIAN METASTASIS
OVARIAN METASTASIS- p53
UPWARD SPREAD- ENDOMETRIUM
GASTRIC TYPE CERVICAL ADENOCA INVOLVING
TUBE
 IMMUNOHISTOCHEMICAL RESULTS-
AJSP (26685087)
• CK7 - 47/47 (usually diffuse) (100%)
• CK20- 23/47 (usually focal) (49%)
• CEA- 25/31 (focal or diffuse) (81%)
• CA125- 36/45 (usually focal) (80%)
• CA19.9 (11/11)(usually diffuse) (100%)
• PAX8- 32/47 (usually diffuse) (68%)
• CDX2- 24/47 (usually focal) (51%)
• MUC6- 17/21 (focal or diffuse) (81%)
• HNF1 beta- 12/13 (usually diffuse) (93%)
 RESULTS continued
• CA IX- 20/24 (focal or diffuse) (83%)
• ER- 2/31 (occasional cells) (6%)
• PR- 1/11 (occasional cells) (9%)
• PAX2- 1/19 (5%)
• HER2- 1/25 (4%)
• p53- 27/46 (wild-type) (59%); 19/46 (mutation-type)
(41%) (11 diffuse; 8 null)
• p16- 29/47 negative (62%); 14/47 focal (30%); 4/47
diffuse (9%)
• Loss of MSH6 in 1/20 cases (patient with Lynch
syndrome) (all MMR proteins retained in others)
 SIGNIFICANT RESULTS
• Lot of immunophenotypic overlap with pancreas/
biliary adenocarcinomas (CK7, CK20, CEA, CDX2,
CA125)
• PAX8 may be useful (usually, but not always, diffusely
positive; uncommon in other mucinous
adenocarcinomas)
• HNF1 beta- usually positive (differential with clear cell
ca)
• p53- about half “mutation-type” staining
• p16 occasionally diffusely positive (HPV studies done
on 2 cases exhibiting block-type immunoreactivity and
these were negative)
HPV related adenoca mimicking gastric type
p16
 POSSIBLE ASSOCIATION BETWEEN NON-HPV
RELATED CERVICAL ADENOCARCINOMAS AND
LYNCH SYNDROME
• anecdotal cases
• gastric type/ clear cell carcinoma
• LUS endometrial carcinomas associated with
Lynch syndrome
• non-HPV related cervical adenocarcinomas
may arise high in endocervical canal
• no association between Lynch syndrome and
HPV related cervical adenocarcinomas
GASTRIC-TYPE ADENOCARCINOMA IN
LYNCH SYNDROME

MSH2

MSH6
 GASTRIC TYPE CERVICAL LESIONS- Advances in
Anatomic Pathology 2013;20;227-237
BENIGN
lobular endocervical glandular hyperplasia (complex pyloric/gastric
metaplasia)
simple gastric/pyloric metaplasia
type A tunnel cluster
PREMALIGNANT
atypical lobular endocervical glandular hyperplasia
adenocarcinoma in situ of gastric type
MALIGNANT
gastric type adenocarcinoma
minimal deviation adenocarcinoma
SPECIFIC CONDITIONS
synchronous mucinous metaplasia and neoplasia of the female genital tract
Peutz-Jeghers syndrome
LOBULAR ENDOCERVICAL GLANDULAR
HYPERPLASIA (LEGH)
• very rare
• sometimes associated with Peutz-Jeghers
• complex gastric (pyloric) metaplasia
• often high in endocervical canal
• positive with gastric markers
• may be difficult to distinguish from adenoma malignum
• “atypical” forms described (atypical LEGH) (cytologic and architectural
abnormalities)
• atypical LEGH probably spectrum from mild reactive changes to precursor
of adenoma malignum/ gastric type adenocarcinoma
• MOST/ ALL GASTRIC LESIONS ARE FLAT ER NEGATIVE (useful in distinction
of LEGH from other benign glandular lesions)
intestinal metaplasia
NEUROENDOCRINE CELLS

chromogranin
MUC6
chromogranin
atypical LEGH
atypical LEGH
atypical LEGH
atypical LEGH
 SIMPLE GASTRIC/PYLORIC
METAPLASIA
• very rare and subtle
• positive with gastric markers (HIK1083,
MUC6); ER negative
• one study- 0.7% of cervices
• pale eosinophilic rather than basophilic
cytoplasm
MUC6
 AIS OF GASTRIC TYPE
• very rare and not well described
• subtle lesion
 CLEAR CELL CARCINOMA
• uncommon
• assocation with in-utero exposure to DES (usually not
nowadays)
• bimodal age peaks (20s and 60/70s)
• similar to uterine corpus/ovarian counterparts
• in older women especially, exclude spread from uterine
corpus/ovary
• usually not HPV related (recent study- approx one quarter
HPV associated)
• MGH/Arias-Stella affect may come into differential
CLEAR CELL CARCINOMA
 INTESTINAL TYPE ADENOCARCINOMA
• primary cervical adenocarcinoma resembling large intestinal
adenocarcinoma- goblet cells, dirty necrosis etc
• probably not associated with HPV
• usually CK7 positive, CK20 negative, focal or diffuse, CDX2
positive, hormone receptor negative
• immunohistochemistry useful in distinction from metastasis
or direct spread from colorectal carcinoma (but some rectal
adenocarcinomas CK7 negative)
• different than adenocarcinomas which arise from intestinal
AIS
INTESTINAL TYPE ADENOCARCINOMA
CERVIX
INTESTINAL TYPE ADENOCARCINOMA

CK7 CDX2
 CERVICAL MESONEPHRIC
ADENOCARCINOMA
• rare
• admixture of morphological patterns is
characteristic
• may get spindle cell component
(carcinosarcoma)
• no association with HPV
• may be associated with and arise from
hyperplastic mesonephric remnants
• immunohistochemistry of limited value (lots of
markers suggested to be of value)
 PATTERNS
• tubular
• ductal
• retiform
• solid
• sex cord-like
• spindle cell
 IMMUNOHISTOCHEMISTRY OF MESONEPHRIC
ADENOCARCINOMA
• diagnosis largely based on morphology (no
pathognomonic markers)
• CD10, inhibin, calretinin, vimentin may be
positive (but variable and not reliable)
• GATA 3 may be positive
• EMA positive, CEA negative
• ER, PR characteristically totally negative
CD10
 CD10 vimentin

calretinin CA125

inhibin ER
PAX8 HMGA2

TTF1 p16
GATA3
 BEHAVIOUR
• probably similar to other cervical
adenocarcinomas stage for stage
• may be more indolent than Mullerian
counterparts
• ? propensity for late metastasis
 DIFFERENTIATION FROM HYPERPLASTIC
MESONEPHRIC REMNANTS

• diagnose mesonephric carcinoma only after exclusion of

mesonephric hyperplasia
• mass lesion versus incidental microscopic finding
• lobular pattern suggests hyperplasia
• more crowding and destructive stromal invasion in carcinoma
• stromal reaction
• nuclear atypia and mitotic activity
• vascular and perineural infiltration
• extension beyond cervix
• OCCASIONALLY IMPOSSIBLE
CD10
DUCTAL MESONEPHRIC REMNANTS
 DUCTAL MESONEPHRIC REMNANTS

GATA3 vimentin
 DUCTAL MESONEPHRIC REMNANTS

ER PR
 MOLECULAR EVENTS IN CERVICAL
MESONEPHRIC ADENOCARCINOMAS
• Modern Pathology 2015; 28; 1504-1514
• 13 of 16 (81%) had KRAS or NRAS mutation
• 62% had mutations in chromatin remodelling
genes (ARID1A, ARID1B, SMARCA4)
• Different molecular events than in other
cervical adenocarcinomas and endometrial
adenocarcinomas
 CONCLUSIONS
• Non-HPV related adenocarcinomas account for 2-4% of
cervical carcinomas
• HPV vaccination will have no effect
• Won’t be prevented by primary HPV screening
programmes
• Gastric type adenocarcinoma (including adenoma
malignum) is most common
• Also mesonephric adenocarcinomas and most clear cell
carcinomas
• Precursor lesions not well established
• ? Need for different chemotherapeutic agents
 MESONEPHRIC-LIKE MULLERIAN
ADENOCARCINOMAS
• May also rarely occur in uterus or ovary
• Look like mesonephric adenocarcinomas
• Flat negative with ER/ PR; often diffusely
positive with TTF1
• Histopathology (26484981) (Mesonephric-like
adenocarcinomas)
• Similar molecular events to mesonephric
adenocarcinomas (almost all KRAS mutations;
some PIK3CA mutations)
 MESONEPHRIC-LIKE
ADENOCARCINOMA OF UTERUS
 MESONEPHRIC-LIKE
ADENOCARCINOMA OF UTERUS

ER TTF1
 MESONEPHRIC-LIKE
ADENOCARCINOMA OF UTERUS
POINTS IN FAVOUR OF POINTS IN FAVOUR OF TRUE
UNUSUAL ENDOMETRIOID MESONEPHRIC
ADENOCARCINOMA ADENOCARCINOMA
- Sometimes associated - Morphology
with endometriosis in - Immunophenotype
ovary - Molecular
- Location in uterus
(appear to arise in
endometrium)
- No mesonephric
remnants
 CERVICAL SQUAMOUS CARCINOMA
• virtually 100% thought to be HPV related
• occasional examples may be non-HPV related
 NON HPV-RELATED CERVICAL SCC
• 54 year old
• borderline nuclear abnormalities on smear- HPV negative
• locally advanced cervical scc- well differentiated; p16 negative
• HPV negative- linear array HPV genotyping and SPF-10 system
(highly sensitive)
• ? similar to non HPV-related vulval SCC (morphology and
pathogenesis- don’t arise from CIN)
• few similar cases in literature
NON HPV-RELATED CERVICAL SCC
 WHO 2014- VAGINAL
ADENOCARCINOMAS
• endometrioid
• clear cell
• mucinous (endocervical or intestinal type)
• mesonephric
 TYPES OF PRIMARY VAGINAL
ADENOCARCINOMA
• clear cell
• endometrioid
• serous
• endocervical-like
• intestinal
• gastric-type
• mesonephric
• Skene’s gland
 PRIMARY VAGINAL
ADENOCARCINOMA
• endometrioid, serous, clear cell, gastric,
endocervical-like, mesonephric- always
exclude primary elsewhere in female genital
tract
• intestinal- always exclude large intestinal
primary (even if confined to surface and
seems to arise from pre-existing adenoma)
RECURRENT UTERINE ENDOMETRIOID
ADENOCARCINOMA
 ENDOMETRIOID ADENOCARCINOMA
OF VAGINA
• AJSP 2007;31;1490-1501
• 18 cases
• association with unopposed oestrogens
• no DES history
• many cases had endometriosis
• good prognosis
 CLEAR CELL
• DES- associated
• non- DES- associated
• often associated adenosis
• identical (morphology and
immunohistochemistry) to other sites in
female genital tract (need to exclude spread)
• About 25% HPV related
 ENDOCERVICAL-LIKE
ADENOCARCINOMA
• HPV related
• identical to usual (HPV-related) cervical
adenocarcinoma
• need to exclude cervical primary
• p16 diffuse
 IMMUNOHISTOCHEMISTRY

p16 ER
 GASTRIC TYPE VAGINAL
ADENOCARCINOMA
• 2 cases published as such (1 with uterus
didelphys) (others likely described as
“mucinous” adenocarcinomas)
• both arose in adenosis (non-DES associated)
• identical to cervical adenocarcinomas of
gastric type
• HIK1083 and MUC6 positive
• mutation-type p53
 GASTRIC TYPE

HIK1083 MUC6
 GASTRIC TYPE

p53
p53
 VAGINAL INTESTINAL TYPE
GLANDULAR LESIONS
• AJSP 2014;38;593-603
• 14 cases- identical features to corresponding
large intestinal neoplasms
• non-neoplastic polyps
• adenomas
• adenocarcinomas (often associated with
adenoma)
• often positive with CK7, CK20, CDX2, CEA
CDX2
 SKENE’S GLAND ADENOCARCINOMA
• extremely rare
• derived from periurethral Skene’s glands
• female counterpart of prostatic glands
• positive with prostatic markers
• PART OF SPECTRUM OF SKENE’S GLAND
LESIONS IN LOWER FEMALE GENITAL TRACT