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KRISTIN HENRY LECTURE, BELFAST 2017:

TYPING OF OVARIAN AND ENDOMETRIAL CARCINOMAS: A STORY OF SUCCESS AND

FAILURE

W Glenn McCluggageBelfast, United Kingdom

British Division of the InternationalAcademy of Pathology (BDIAP)

The BDIAP Kristin Henry Lecture1982-90 Treasurer of BDIAP1995-96 President of BDIAP1997-98 Cunningham Medal2009-10 President’s Medal2005-08 Chair Finance Committee2008-11 Chair Education Committee

Presidents of the IAP from the UK

Kristin Henry2010-2012

Roger Cotton1982-1983

TYPING OF OVARIAN AND ENDOMETRIAL CARCINOMAS: A STORY OF SUCCESS AND

FAILURE• Ovarian carcinoma- typing• Recent developments regarding “ovarian”

serous carcinomas• Endometrial carcinoma- typing• Small cell carcinoma of the ovary of

hypercalcaemic type (SCCOHT)

OVARIAN CARCINOMA TYPING

•SUCCESS

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REPRODUCIBILITY OF OVARIAN CARCINOMA TYPING

• Brugghe et al (IJGC, 1995) - 61%• Bertelsen et al (IJGC, 1993) - 72% (serous and

endometrioid); 86% (mucinous); 100% (clear cell)• Baak et al (AQCH, 1986) - significant variation• Cramer et al (APLM, 1987) – suboptimal• Lund et al (APMIS, 1991) – 68%• Sakamoto et al (Gynecol Oncol, 1994) -53%• ICON 5- POOR ++

OVARIAN EPITHELIAL CARCINOMA (WHO 2014)- 5 major histotypes

• low grade serous • high grade serous• mucinous • endometrioid• clear cell• Brenner• seromucinous• undifferentiated

RECENT POPULATION BASED (WASHINGTON / BRITISH COLUMBIA)

• 68-71% serous (17-18:1 ratio HGSC to LGSC)• 3% mucinous• 9-11% endometrioid• 12-13% clear cell88% OF ADVANCED STAGE OVARIAN

CARCINOMAS ARE SEROUS

DIFFERENCES FROM PREVIOUS STUDIES

• increase in serous• decrease in endometrioid• marked decrease in mucinous (exclusion of

secondaries)• reversal of endometrioid and clear cell ratio

REASONS FOR INCREASE IN SEROUS AND DECREASE IN ENDOMETRIOID

• Recognised that many neoplasms that were previously diagnosed as high grade endometrioid are actually high grade serous carcinoma (HGSC)

• Importance of WT1- Al-Hussaini et al. Histopathology 2004; 44; 109-115.

IMPORTANCE OF TYPING OF OVARIAN CARCINOMA

• at present typing of some (but increasing) therapeutic significance; treatment traditionally more dependent on stage and grade

• NOW DIFFERENT THERAPY FOR DIFFERENT OVARIAN CANCER TYPES (surgery, traditional chemotherapy, targetted therapies, hormone therapy)

• carcinoma grading (differs between different types)• screening, personal and family history risk (BRCA,

Lynch)

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OVARIAN CARCINOMA GRADING-INTERNATIONAL COLLABORATION ON CANCER

REPORTING (ICCR)• serous- low grade and high grade (2 different

types)• endometrioid- like uterine corpus• clear cell- automatically high grade• mucinous- as for endometrioid

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INTERNATIONAL COLLABORATION ON CANCER REPORTING-ICCR

• Alliance between RCPath UK, RCPath Aus, CAP, ESP, Canadian Partnership Against Cancer

• Purpose of developing standardised evidence based cancer datasets for each site

• Ovarian/ fallopian tube/ primary peritoneal dataset- Modern Pathology 2015;28;101-122

• http://www.iccr-cancer.org/datasets

RECENT STUDY ON REPRODUCIBILITY OF OVARIAN CARCINOMA TYPING

• Koebel et al, Am J Surg Pathol 2010;34;984-93.• excellent agreement• participants had training in modern criteria• important for subtype specific ovarian cancer

treatments• CONTRAST WITH UTERINE CARCINOMA• good marker- WT1

HISTORIC AREAS OF DIAGNOSTIC DIFFICULTY

• Serous (high grade) versus endometrioid• Serous (high grade) versus clear cell• Serous (high grade) versus transitional• Serous (high grade) versus undifferentiated

HIGH GRADE SEROUS CARCINOMA-MORPHOLOGIC DIVERSITY

• Papillary/ micropapillary• Slit-like • Glandular• Microglandular/ microcystic• Cystic• Solid • Multinucleate cells• Signet ring cells• Oncocytic/ clear cell• OFTEN ADMIXTURE OF PATTERNS

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PSEUDOENDOMETRIOID MORPHOLOGY IN HGSC CLEAR CELL CHANGE IN HGSC (SOMETIMES POSTCHEMOTHERAPY)

TRANSITIONAL-LIKE MORPHOLOGY IN HGSC

OVARIAN HIGH GRADE SEROUS CARCINOMA

WT1 in PSEUDOENDOMETRIOID AREAS IN HGSC WT1 in CLEAR CELL AREAS IN HGSC

p53 WT1

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WT1 IN TRANSITIONAL-LIKE AREAS IN HGSC

UNDIFFERENTIATED OVARIAN CARCINOMA

WT1

MIXED OVARIAN CARCINOMAS

• historically quite common (up to 10-20%)• most commonly historically reported were mixed

serous/ endometrioid; mixed serous/clear cell; mixed serous/ transitional; mixed serous/undifferentiated (mostly variants of high grade serous carcinoma- doubtful if these combinations exist)

• occasionally get mixed endometrioid/ clear cell (association with endometriosis)

• occasionally others• CATEGORY DROPPED FROM WHO 2014

Mixed Ovarian Carcinomas• Improved recognition of types has virtually abolished

mixed tumours– 15 of 871 cases reviewed (1.7%) by H/E using modern

diagnostic criteria• 22 cases thought to be mixed were investigated further by

immunohistochemistry and molecular testing • Only 13 true mixed carcinomas when

immunohistochemistry and molecular data incorporated• Mixed carcinomas account for less than 1% of ovarian

carcinomasMacKenzie et al. Am J Surg Pathol 2015; 39: 1548-1557

TRANSITIONAL CARCINOMA

• dropped from WHO 2014• most are variants of high grade serous

(“transitional-like”) (more typical areas if sample well; omental metastases may look like high grade serous; WT1 positive; aberrant p53)

• some are variants of endometrioid carcinoma (transitional-like morphology)

• still categories of benign, borderline and malignant Brenner

MORPHOLOGY OF BRCA ASSOCIATED HIGH GRADE SEROUS CARCINOMAS

• SET pattern (Solid, pseudoEndometrioid, Transitional)

• Higher mitoses; more geographical necrosis• ? Increased tumour intraepithelial T lymphocytes• Different patterns of metastatic disease

(“pushing” rather than “infiltrative”)• Similarities to breast carcinomas in BRCA• PROBABLY ALL PATIENTS WITH HGSC SHOULD

UNDERGO BRCA TESTING- FUNDING QUESTIONS

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HGSC WITH CLEAR CELL CHANGE VERSUS CLEAR CELL CARCINOMA

• Look for areas of typical HGSC or clear cell carcinoma

• Look for endometriosis• Status of tubes

HGSC WITH CLEAR CELL CHANGE

HGSC WITH CLEAR CELL CHANGE VERSUS CLEAR CELL CARCINOMA

• IMMUNOHISTOCHEMISTRY USEFUL• HGSC: mutation-type p53 (95%), block-type

p16 (70%), ER (70%- often diffuse), Napsin A negative

• Clear cell carcinoma: wild-type p53, patchy p16, ER negative (sometimes focally positive), Napsin A usually positive

• HNF1-beta less useful

IMMUNOHISTOCHEMISTRY- HGSC WITH CLEAR CELL CHANGE

p53 WT1

IMMUNOHISTOCHEMISTRY- CLEAR CELL CARCINOMA

HNF1 beta Napsin A

HGSC VERSUS ENDOMETRIOID ADENOCARCINOMA

• Many previously diagnosed as high grade endometrioid adenocarcinoma are HGSC

• Squamous elements, endometriosis, obvious low grade endometrioid areas, normal tube are suggestive of endometrioid carcinoma

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IMMUNO- HGSC VERSUS HIGH GRADE ENDOMETRIOID ADENOCARCINOMA

• WT1- HGSC• p53- wild-type suggestive of endometrioid;

some high grade endometrioid carcinomas have mutation-type (may be clonal pattern suggestive acquisition of TP53 mutation during progression)

PITFALL

• WT1 (only about 95% of tubo-ovarian HGSCs positive)

• High grade ovarian endometroidadenocarcinomas rarely WT1 positive

• Low grade ovarian endometroidadenocarcinomas may be WT1 positive

p53• p53 immunohistochemistry- lot of confusion• only consider positive/significant if diffuse strong nuclear

immunoreactivity (75-80% cells suggested- associated with missence mutation)

• p53 null consistent with serous carcinoma (different type of mutation (nonsense) or deletion resulting in truncated protein which is not detected by immunohistochemistry)

• third pattern of mutation-type staining- cytoplasmic (rare pattern)• most normal tissues and tumours exhibit focal, weak, heterogenous

staining (“wild-type” staining) (usually <50%) (about 5% of HGSCs with TP53 mutation exhibit wild-type staining)

• DON’T REPORT AS POSITIVE OR NEGATIVE- REPORT AS “WILD-TYPE” or “MUTATION-TYPE/ ABERRANT”

StopgainIndelSplicing

Interpretation of p53 immunohistochemistryNo TP53 mutation

Nonsynonymous=missense

p53 overexpression p53 complete absence p53 cytoplasmic

Wild type pattern

Abnormal; mutation-type

Normal

StopgainIndelSplicing

J Pathol Clin Res 2016;2:247

2016: www.thebagp/resources

“OVARIAN” SEROUS CARCINOMA (OSC) –RECENT DEVELOPMENTS

• two distinct tumour types (called low grade and high grade OSC) (recognised in WHO 2014)

• not two grades of same neoplasm• different neoplasms with different underlying

pathogenesis, molecular events, behaviour, prognosis

• high grade much more common than low grade (approximately 17-18:1)

• use instead of traditional grading schemes

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PATHOGENESIS (LOW GRADE SEROUS)

• low grade arise from pre-existing benign and borderline tumour (probably not all cases)

• micropapillary variant of serous borderline may be intermediate stage in development of low grade serous carcinoma

• well-defined adenoma-carcinoma sequence

MOLECULAR (LOW GRADE SEROUS)

• Mutations in genes associated with MAPK pathway (KRAS or BRAF mutations in approximately half (sometimes early in evolution – mutations found in benign and borderline tumours; identical mutations in borderline and malignant areas in same tumour)

• KRAS and BRAF mutations are usually mutually exclusive; equivalent effect on tumorigenesis

• no TP53 mutations/abnormalities

PATHOGENESIS (HIGH GRADE SEROUS)

• traditionally thought to arise directly from ovarian surface epithelium or epithelium of cortical inclusion cysts; now clear that most cases arise from epithelium of distal fallopian tube

• precursor lesion is serous tubal intraepithelial carcinoma (STIC)

• doesn’t arise from borderline tumour

MOLECULAR (HIGH GRADE SEROUS)

• TP53 mutations (early in evolution-seen in early microscopic

tumours eg BRCA1/2) (p53 mutation found in almost 100% high

grade serous using stringent methods) (IJGP; PMID 26166714)

• BRCA1/2 abnormalities (germline or somatic mutations or

hypermethylation)

• no BRAF and only occasional KRAS mutations

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CLINICAL BEHAVIOUR- LGSC and HGSC

• LGSC (mean 52) younger than HGSC (mean 62)• HGSC poor prognosis (usually presents at advanced

stage, responds well initially to chemo but usually recurs; occasional long term survivors)

• LGSC more indolent (good prognosis for early stage; advanced stage- patients usually die of tumour) (IJGP 2013; 32; 529-535- stage 2-4, <30% survival at 10 years; not significantly different to HGSC); (AJSP 2016;40;627-635; 5 year survival 62.3% LGSC, 43.9% HGSC but no survival difference at 10 years)

DISTINCTION BETWEEN LOW GRADE AND HIGH GRADE SEROUS CARCINOMA

• Important distinction for management purposes

• Usually straightforward• Occasionally difficult (especially in small

biopsies)• Only reliable marker is p53

HIGH GRADE SEROUS MIMICKING LOW GRADE

p53

MICROPAPILLARY ARCHITECTURE IN HGSC

LGSC WITH “BIGGER” NUCLEI LGSC

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p53 in LGSC

TRANSFORMATION LOW GRADE INTO HIGH GRADE

• rare (AJSP 2012; 36; 368-375) (serous borderline or low grade serous carcinoma)

• can be misdiagnosed (bigger nuclei in low grade serous)

• can transform to HGSC, anaplastic carcinoma, carcinosarcoma

• p53 NOT reliable in such cases (often not p53 mutated)

TRADITIONAL VIEW OF PATHOGENESIS OF HIGH GRADE

SEROUS CARCINOMA

• traditionally thought to arise directly from ovarian surface epithelium (OSE) or epithelium of cortical inclusion cysts

• thought that some cases might arise from secondary Mullerian system (peritoneum)

• doesn’t arise from borderline tumour

IS TUBAL FIMBRIA THE ORIGIN OF EXTRAUTERINE HIGH GRADE SEROUS CARCINOMA?

• proposal that tubal fimbria (distal tube) (secretory cells) is site of origin of many/most extrauterine (ovary, peritoneum and fallopian tube) high grade serous carcinomas

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INITIAL EVIDENCE

• came from prophylactic risk reducing salpingo-oophorectomy specimens (RRSO) (BRCA1/2)

• once tubes were examined in their entirety, tubal lesions (distal) were occasionally seen with little/ nothing in ovary

• tubal lesions may be STIC (serous tubal intraepithelial carcinoma) or small HGSCs

• now well established in BRCA patients that tube is origin of HGSCs

• ? does same hold true for sporadic HGSCs

p53 in STIC

MIB1 IN STIC p53 SIGNATURES IN TUBE• small foci of intense p53 immunoreactivity in absence of

morphological changes• equally common in BRCA1/2 tubes and in control tubes

(occur in all age groups)• most common in fimbria• involves secretory cells• may contain TP53 mutations (? Mutations occurring all

the time but most spontaneously regress)• don’t diagnose STIC in isolation in absence of

morphological features and confirmatory p53 and MIB1• overinterpretation of normal fallopian tube morphology;

“dangerous” to do p53 on “normal” tubes

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p53

WHAT ABOUT SPORADIC HGSCs

• Usually present at advanced stage• Tube (s) often obliterated and embedded in

tubo-ovarian mass• Difficult to study precursor lesions• STIC/ mucosal HGSC found in carefully

sectioned tubes (when both visible) in significant percentage of cases (up to two-thirds) of sporadic HGSC

Implications for specimen handling

• SEE-FIM protocol ESSENTIAL for identifying STIC/tubal involvement- now routinely done in tubo-ovarian HGSC

? FIELD-EFFECT IN HGSC

• same TP53 mutations in HGSC at multiple sites• evidence that clonally related and not part of

“field-effect”• no/ minimal evidence of field-effect in HGSC• one site is primary with metastasis to the

others

BUT IS TUBAL LESION PRIMARY OR METASTATIC?

• Intramucosal metastasis from a variety of sites may occur in tubes and mimic an in-situ lesion

• Gynaecological or non-gynaecological tumours when spread to tube exhibit mucosal involvement and even mimic STIC (AJSP 2015;39;35-51)

• Some molecular evidence that tube is initial site but difficult to prove by molecular techniques

• RECENT OBSERVATIONAL STUDIES PROVIDE FIRM EVIDENCE THAT TUBE IS PRIMARY

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USC INVOLVING FALLOPIAN TUBE GASTRIC TYPE CERVICAL ADENOCA INVOLVING TUBE

INCIDENTAL SPORADIC HIGH GRADE SEROUS CARCINOMA

• established that incidental tumours in patients with BRCA1/2 mutation are of tubal origin

• 4 papers recently published- unsuspected STIC/ HGSC incidentally detected (AJSP 2015; 39; 357- 364)

• PROVES that sporadic HGSC of tubal origin (FINAL PIECE OF EVIDENCE)

Am J Surg Pathol, 2014

Study Total

cases

Cases

with

STIC

Invasive

HGSC

in tube

Invasive

HGSC in

ovary

Organ-

confined

Disease

(tube OR

ovary)

Organ-

confined:

tube

Organ-

confined:

ovary

Rabban,

2014

4 4 3 1 3 3 0

Morrison,

2014

22 22 6 1 21 21 0

Gilks, 2014 21 20 12 2 18 18 0

Total 47 47 22 4 43 43 0

Summary of findings of incidental HGSC in a non-prophylactic setting

Ovarian?Peritoneal?Tubal?Undesignated?

…. CHAOS!

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EXTRAUTERINE HIGH GRADE SEROUS CARCINOMA- SITE OF ORIGIN

• FIGO 2014- same staging system (ovary, tube, peritoneum, undesignated)

• FIGO 2014 and WHO 2014- no recommendations regarding designating site of origin

• WHO- the decision as to primary site should be pragmatic, based on experience and professional judgement

• DOMINANT MASS THEORY TRADITIONALLY USED (ovary designated as primary site in most cases)

• possibilities- pelvic high grade serous; extrauterine; Mullerian; tubo-ovarian; undesignated

• implications:- epidemiology, tumour incidence/mortality, cancer registries, entry into clinical trials

• different viewpoints- STIC/ in situ criteria; dominant mass criteria

SURVEY: INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY – PMID 27801755

• 173 respondents• Widespread acceptance of tubal origin (86%

pathologists, 92% clinicians)• Clinicians thought it more important to

correctly assign a primary site than pathologists (71% versus 49%)

PROPOSAL FOR DESIGNATING SITE OF ORIGIN OF HGSC

• extensive examination of tube (SEE-FIM)• any STIC or mucosal serous ca in tube- tubal origin• if fallopian tube or fimbria not identified (obliterated by mass)- tubal

origin• ovarian primary if tumour in ovary and nothing in mucosa of tube (STIC or

invasive) (both tubes need to be clearly visible and examined by SEE-FIM protocol)

• primary peritoneal- nothing in tube or ovary (vanishingly rare- will likely disappear) (WHO 2014)

• post-chemo (if no residual) or on small biopsy- designate as tubo-ovarian• USING THESE CRITERIA- approximately 80% tubal primaries• undesignated- very small proportion• (Histopathology 2014; 65; 149-154; Gynecological Oncology 2016;141;195-

198; International Journal of Gynecological Pathology 2016;35;230-237)• CRITERIA ADOPTED BY ICCR

Criteria Primary site Comment

STIC present Fallopian tube Regardless of presence and

size of ovarian and peritoneal

disease

Invasive mucosal carcinoma

in tube, with or without STIC

Fallopian tube Regardless of presence and

size of ovarian and peritoneal

disease

Distal end or entire tube

incorporated into ovarian

mass

Fallopian tube Regardless of presence and

size of ovarian and peritoneal

disease

No STIC or invasive mucosal

carcinoma in either tube in

presence of ovarian mass

Ovary Regardless of presence and

size of peritoneal disease

Both tubes and both ovaries

grossly and microscopically

normal or involved by

benign process in presence

of peritoneal HGSC

Primary peritoneal HGSC As recommended in WHO

blue book 201457

Summary of site assignment guidelines proposals

RETROSPECTIVE (n=151) PROSPECTIVE (n=111)

Primary

site

T O P U T O P U

Chemo

naive

63

(79%)

16

(20%)

0

(0%)

1

(1%)

44

(83%)

9

(17%)

0

(0%)

0

(0%)

Post-

NACT

48

(68%)

16

(22%)

7

(10%)

0

(0%)

44

(76%)

7

(12%)

4

(7%)

3

(5%)

Singh et al, 2015

Basis for tubal assignment in 44 chemonaivecases

Criterion Number (%)STIC only 5 (11%)Invasive mucosal +/- STIC 26 (59%)Entire tube or part of tube incorporated in mass

13 (30%)

Total 44

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Unilateral versus bilateral tubal and ovarian involvement in HGSC

Unilateral Bilateral TotalOvary 18 (38%) 29 (62%) 47Fallopiantube

37 (84%) 7 (16%) 44

• Bilaterality = strong indicator of secondary spread• In 53 chemo-naïve cases, ovarian involvement in HGSC was

significantly more frequently bilateral• Tubal involvement unilateral in 84% supporting primary

rather than metastatic involvement

Singh et al, 2015

General implications

• Consistency and uniformity in reporting and in message to patients

• Tumour registry data• Sharing data and good practice

ENDOMETRIAL CARCINOMA TYPING

•FAILURE

ENDOMETRIAL CARCINOMA TYPING

•FAILURE (BUT PROMISE OF BETTER TO COME)

DUALISTIC PATHWAY OF ENDOMETRIAL CARCINOGENESIS

• Bokhmann 1983• type 1 and 2• useful as broad concept but much overlap

(clinical, morphology) and controversy as to which tumours fall into which group- move away from this broad concept

Type I Endometrial Cancer• prototype is endometrioid carcinoma • perimenopausal and early postmenopausal years• associated with oestrogen excess (unopposed oestrogens,

PCOS), obesity, hypertension, diabetes• arises on background of atypical hyperplasia• often low grade and early stage• hormone receptor positive• good prognosis• associated with beta catenin, PTEN, KRAS, PIK3CA , ARID1A

mutations and microsatellite instability

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ENDOMETRIOID ADENOCARCINOMA Type II Endometrial Cancer• prototype is uterine serous carcinoma• elderly postmenopausal• not associated with oestrogen excess• no association with endometrial hyperplasia• precursor lesion not well defined- serous endometrial

intraepithelial carcinoma (serous EIC)• by definition high grade• often advanced stage• hormone receptor negative• poor prognosis• associated with p53, PIK3CA and PPP2R1A mutations (serous)

p53

HIGH GRADE ENDOMETRIAL CARCINOMAS

• grade 3 endometrioid, serous, clear cell, carcinosarcoma, undifferentiated, mixed

• significant interobserver variability in classification (classification of endometrial carcinomas much more problematic than classification of ovarian carcinomas)

INTEROBSERVER VARIABILITY

• AJSP 2013;37;874-881- Gilks, Oliva, Soslow• 56 cases diagnosed as “high grade” endometrial carcinoma• 62% - agreement between all 3• 36% - major diasgreement (subtype or even whether high

grade carcinoma was present)• no consistent pattern between observers• major problems- serous v clear cell; serous v grade 3

endometrioid; serous versus undifferentiated• need for molecular tools and development of biomarkers

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WHY IS IT SO DIFFICULT TO TYPE ENDOMETRIAL CARCINOMAS?

• mixed tumours (possibly more common than in ovary but probably being over-diagnosed)

• morphologically ambiguous tumours • no good marker (WT1 in ovary)

TCGA Molecular Classification of Endometrial Cancers

• COPY NUMBER LOW (INTERMEDIATE PROGNOSIS) (39%)

• MICROSATELLITE INSTABILITY HYPERMUTATED(INTERMEDIATE PROGNOSIS) (28%)

• COPY NUMBER HIGH (TP53 mutations) (mostly, but not all, serous) (WORST PROGNOSIS) (26%)

• POLE ULTRAMUTATED (BEST PROGNOSIS) (7%)

Mutation Spectra Across Endometrial Carcinomas

Getz et al Nature 2013; 497: 67-73

TYPING OF ENDOMETRIAL CANCERS

• TCGA classification of endometrial cancers is of prognostic significance

• Tumour histotyping is not (because of poor interobserver reproducibility)

• Morphology is not reliable in separating into TCGA categories

STATEGIES FOR TYPING (TCGA)

• POLE mutation analysis- identifies POLE ULTRAMUTATED

• MMR staining (MSH2 and MSH6)- identifies MICROSATELLITE INSTABILITY HYPERMUTATED

• p53 staining- mutation-type staining identifies COPY NUMBER HIGH

• Left with COPY NUMBER LOW• Important for prognosis, management/ targeted

therapies

ProMisE (Proactive Molecular ClasssificationTool for Endometrial Cancers)

‒ Stratified (N=143) endometrial carcinomas into 4 TGCA molecular groups ‒ POLE exonuclease domain mutations‒ Mismatch repair protein IHC‒ p53 IHC

n=143

POLE (n=12)

MSI (n=41)

CN-L (n=63)CN-H (n=25)

n=102

n=88

Talhouk A, et al. Br J Cancer. 2015 Jul 14;113(2):299-310

“Simplified TCGA classifier”

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UK HISTOPATHOLOGY LABORATORIES

• Need to be developing POLE testing• ? Individual laboratories, ? Centralised testing• ? Can we develop surrogate markers of POLE

mutation

UNDIFFERENTIATED ENDOMETRIAL CARCINOMA

• may be associated with low grade endometrioid

adenocarcinoma (dedifferentiated endometrioid

adenocarcinoma or mixed endometrioid and

undifferentiated carcinoma)

• similar tumours in ovary

• VERY POOR PROGNOSIS

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DEDIFFERENTIATED CARCINOMA IMMUNOHISTOCHEMISTRY• usually positive for keratins and EMA but staining may

be very focal, although strong; EMA staining more consistent than cytokeratins

• minor neuroendocrine marker positivity not uncommon (10%)

• often abnormalities in MMR protein expression• loss of ER, PR and PAX8 in undifferentiated/

dedifferentiated areas• usually wild-type p53• loss of E-cadherin in undifferentiated/ dedifferentiated

areas

EMA

MOLECULAR PATHOLOGY OF UNDIFFERENTIATED/ DEDIFFERENTIATED CARCINOMA

• Not studied in TCGA (also clear cell carcinomas and carcinosarcomas)

• Probably don’t fit into ProMisE algorithm• Up to 50% (? True (pure) undifferentiated/

dedifferentiated carcinomas) associated with mutations in SWI/ SNF pathway with resultant loss of immunohistochemical staining (SMARCA4, SMARCA2, SMARCB1, ARID)

• Also high incidence of MMR abnormalities

LOSS OF SMARCA4 (BRG1) SMALL CELL CARCINOMA OF OVARY OF HYPERCALCAEMIC TYPE- SCCOHT

• usually young females (peak in 2nd and 3rd

decades)• may occur in older females (large series of 150

cases; AJSP 1994;18;1102-1116; age 9-43; average 24 years)

• hypercalcaemia in two-thirds • usually unilateral ovarian tumour• rare familial cases (may be bilateral)• extremely aggressive with poor prognosis

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Small Cell Carcinoma of Hypercalcaemic Type- MISNOMER

• Small- cells not always small• Carcinoma- no proof that epithelial neoplasm• Hypercalcaemic- serum calcium only elevated

in 2/3 cases

HISTOGENESIS- SCCOHT

• unknown (WHO 2014- categorise among miscellaneous ovarian neoplasms)

• epithelial, germ cell, sex cord and neuroendocrine origin suggested

• never (until recently) described in association with another neoplasm

RECENT DEVELOPMENTS• 3 papers in Nature Genetics 2014• SMARCA4/BRG1 mutated in about 98% of SCCOHT (somatic or

germline mutations) (up to 40-50% have germline) (others mostly have SMARCB1 mutations)

• SMARCA4/BRG1 (2%) and SMARCB1/INI1 (98%) mutated in virtually all malignant rhabdoid tumours and atypical teratoid/ rhabdoid tumours of CNS

• SMARCA4 and SMARCB1 are core members of SWI/ SNF complex

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IS SCCOHT A FORM OF MALIGNANT RHABDOID TUMOUR?

• Clinical similarities (young, aggressive neoplasms)• Morphological similarities (rhabdoid and non-

rhabdoid cells)• Molecular similarities (SMARCA4, SMARCB1)• SCCOHT is a form of malignant rhabdoid tumour

(could be renamed malignant rhabdoid tumour of the ovary) (but SCCOHT terminology is well established)

SMARCA4 (BRG1) IMMUNOHISTOCHEMISTRY

• Loss of nuclear staining in SCCOHT secondary to mutation

• Very useful marker of SCCOHT (no useful marker previously)

• Retention of nuclear staining in almost all mimics

SMARCA4/ BRG1 IMMUNOHISTOCHEMISTRY

DIAGNOSTIC/GENETIC TESTING ALGORITHM FOR SCCOHT

• Have the tumour reviewed by a gynaecological pathologist and the diagnosis confirmed (this may necessitate SMARCA4/ BRG1 immunohistochemical staining)

• Once the diagnosis is confirmed, counsel the patient for germline SMARCA4 sequencing

• In the case of a germline mutation, consider removal of the unaffected ovary in unilateral SCCOHT if only one ovary has been removed

• In the case of a germline mutation, test family members for mutation ( ? Role of prophylactic oophorectomy)

• In the case of no germline mutation, if appropriate according to age and clinical context, retain unaffected ovary in unilateral SCCOHT

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HISTOPATHOLOGY 2017; 70; 1147-1154- PMID 28130795

• 2 cases of SCCOHT in association with teratomas

• Several similar cases reported in literature• SUGGESTS THAT SCCOHT MAY BE A PRIMITIVE

GERM CELL TUMOUR ARISING FROM A TERATOMA

CASE ASSOCIATED WITH TERATOMA

GROWING NUMBER OF TUMOURS WITH SMARCA4 LOSS

• SCCOHT• Undifferentiated/ dedifferentiated carcinomas

endometrium and ovary• Similar lung, urothelial tract, sinonasal and GI

tumours• ? ARE THESE RHABDOID TUMOURS (dyscohesive,

sometimes rhabdoid, limited expression of epithelial markers) (? Are dedifferentiated endometrial carcinomas really funny carcinosarcomas)

The BDIAP Kristin Henry Lecture 2017