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THE EMERGING SPECTRUM OF NON-HPV RELATED CERVICAL ADENOCARCINOMAS AND

THEIR PRECURSORS

W Glenn McCluggageBelfast

United Kingdom

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%) (2-4% of cervical cancers)

• tend to be older than HPV related adenocarcinomas• gastric type (including adenoma malignum)• clear cell carcinoma (most)• mesonephric adenocarcinoma• probably intestinal type (most)• primary HPV screening programmes will not detect• HPV vaccination will not prevent• 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 • known 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 and others

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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)

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USUAL HPV RELATED CERVICAL ADENOCARCINOMA

p16

pancreaticobiliary-like

Goblet cells

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Foamy cytoplasm

NEUROENDOCRINE CELLS

synaptophysin

Signet ring cells

OMENTAL METASTASIS

OMENTAL METASTASIS

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OVARIAN METASTASIS RESULTS- AJSP 2016;40; 636-644• 47 cases of gastric type cervical adenocarcinoma• Lot of immunophenotypic overlap with pancreas/ biliary

adenocarcinomas (usually CK7 diffuse; often also positive with CK20, CEA, CDX2, CA19.9, CA125)

• PAX8 may be useful (usually, but not always, diffusely positive; uncommon in other mucinous adenocarcinomas)

• ER/PR- usually “flat” negative• Gastric markers usually positive• p53- about half “mutation-type” staining• p16 generally negative or focally positive• Loss of MSH6 in 1/20 cases (patient with Lynch syndrome)

(all MMR proteins retained in others)

IMMUNOHISTOCHEMISTRY

PAX8 ER

IMMUNOHISTOCHEMISTRY

MUC6 CDX2

p53

p53

p16

p16

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MANAGEMENT OF CERVICAL GASTRIC TYPE ADENOCARCINOMAS

• Tumour type (variant of adenocarcinoma) not usually factored into treatment decisions

• ? More intense radiological assessment (adnexa and omentum) preoperatively

• ? Should remove ovaries routinely (tend to be older)

• ? Poor response to chemotherapy, ? Choice of chemotherapy

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

BENIGNlobular endocervical glandular hyperplasia (complex pyloric/gastric

metaplasia)simple gastric/pyloric metaplasiatype A tunnel clusterPREMALIGNANTatypical lobular endocervical glandular hyperplasiaadenocarcinoma in situ of gastric typeMALIGNANTgastric type adenocarcinomaminimal deviation adenocarcinomaSPECIFIC CONDITIONSsynchronous mucinous metaplasia and neoplasia of the female genital tractPeutz-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 GASTRIC LESIONS ARE FLAT ER NEGATIVE (useful in distinction of

LEGH from other benign glandular lesions)

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intestinal metaplasia

NEUROENDOCRINE CELLS

chromogranin

MUC6

atypical LEGH atypical LEGH

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atypical LEGH

AIS OF GASTRIC TYPE

• very rare (PMID 28394803)• subtle lesion• to discuss later

CLEAR CELL CARCINOMA

• uncommon• association 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- approximately one

quarter HPV associated) (PMID 26096203)• occasional cases in patients with Lynch syndrome

CLEAR CELL CARCINOMA

INTESTINAL TYPE ADENOCARCINOMA

• primary cervical adenocarcinoma resembling large intestinal adenocarcinoma- goblet cells, dirty necrosis

• probably not associated with HPV (few cases reported)• usually CK7 positive; CK20 negative, focal or diffuse; CDX2 positive;

hormone receptor negative• need to exclude direct spread or metastasis from colorectal primary• immunohistochemistry of limited value in distinction from

metastasis or direct spread from colorectal carcinoma (some rectal adenocarcinomas CK7 positive)

• different than adenocarcinomas which arise from intestinal CGIN/ AIS

• may be part of spectrum of gastric type adenocarcinomas (gastrointestinal)

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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)

• GATA3 may be positive• EMA positive, CEA negative• p16 negative or mosaic• ER, PR characteristically totally negative

CD10 vimentin

calretinin CA125

inhibin ER

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GATA3

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

MESONEPHRIC REMNANTS

GATA3 vimentin

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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

MESONEPHRIC-LIKE ADENOCARCINOMAS

• Adenocarcinomas which occur in uterus and ovary and look like cervical mesonephric adenocarcinomas

• Flat negative with ER/PR; often diffusely positive with TTF1

• Histopathology (26484981) (Mesonephric-like adenocarcinomas) (? True mesonephric adenocarcinomas, ? Unusual endometrioidadenocarcinomas)

• Similar molecular events to mesonephric adenocarcinomas (KRAS mutations) (paper in preparation)

MESONEPHRIC-LIKE ADENOCARCINOMA OF UTERUS

MESONEPHRIC-LIKE ADENOCARCINOMA OF UTERUS

ER TTF1

MESONEPHRIC-LIKE ADENOCARCINOMA OF UTERUS

POINTS IN FAVOUR OF UNUSUAL ENDOMETRIOID ADENOCARCINOMA- Sometimes associated

with endometriosis in ovary

- Location in uterus (appear to arise in endometrium)

- No mesonephric remnants

POINTS IN FAVOUR OF TRUE MESONEPHRIC ADENOCARCINOMA- Morphology- Immunophenotype- Molecular

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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