OVARIAN EPITHELIAL TUMOURS: MORPHOLOGIC TYPES, NEW DEVELOPMENTS AND PATHOGENESIS

W Glenn McCluggage Royal Group Of Hospitals Belfast OVARIAN CARCINOMA

• second commonest female genital tract malignancy in developed countries • most cases advanced (stage 3-4) at diagnosis • overall prognosis is poor (approximately 35% 5 year survival) OVARIAN CARCINOMA • heterogeneous group of neoplasms • clinically often considered as one disease • pathogenesis until recently largely unknown • different morphological types have different underlying pathogenesis, molecular events, natural behaviour and prognosis • many studies/clinical trials lump all types together • studies/clinical trials must include good pathological review TO DISCUSS

• morphological types of ovarian carcinoma • pathogenesis of different types • grading • problematic areas in typing • proposed new classification of ovarian carcinomas • theory of origin of high grade pelvic serous carcinoma from fallopian tube WHO CLASSIFICATION (2003) OF OVARIAN CARCINOMAS

• serous • mucinous • endometrioid • clear cell • transitional • squamous • undifferentiated • mixed (10% rule) TYPING OF OVARIAN CARCINOMA • at present of limited therapeutic significance • treatment more dependent on stage and grade • NEW ERA OF DIFFERENT THERAPY FOR DIFFERENT OVARIAN CANCER TYPES (surgery, traditional chemotherapy, targetted therapies) • ongoing trials regarding alternative therapeutic agents in clear cell, mucinous and low grade serous carcinoma (chemoresistant neoplasms) OTHER REASONS FOR TYPING

• carcinoma grading (differs between different types) • personal and family history risk • clear cell and mucinous histology (although rare) are independent predictors of poor outcome in advanced stage • ? need for lymphadenectomy in stage 1 ovarian carcinoma RECENT POPULATION BASED (WASHINGTON / BRITISH COLUMBIA)

• 68-71% serous • 3% MUCINOUS • 9-11% endometrioid • 12-13% clear cell • 1% transitional • 6% mixed DIFFERENCES FROM PREVIOUS STUDIES • increase in serous • marked decrease in mucinous • reversal of endometrioid and clear cell ratio LOW STAGE (I/II) VERSUS HIGH STAGE (III/IV) I/II III/IV serous 36% 88% clear cell 26% 5% endometrioid 27% 3% mucinous 8% 1% POST-CHEMOTHERAPY

• up-front chemotherapy sometimes administered (poor operative risk, miliary disease etc) • CHORUS study in UK • MAY BE DIFFICULT TO TYPE UNLESS MINIMAL OR NO RESPONSE • require pre-chemotherapy biopsy (not just ascitic fluid) for typing of carcinoma and to have tissue available for studies/targetted and personalised treatments (recent NICE guidelines in UK) POST CHEMO

WT1 p16 GRADING OF OVARIAN CARCINOMA • no universal grading system • several in use (FIGO, WHO, Shimizu/Silverberg) but inconsistently applied • some systems are universal; some apply different criteria for different types OVARIAN SEROUS CARCINOMA (OSC)

• most common ovarian carcinoma • often advanced stage at diagnosis • traditionally graded as grade 1, 2, 3 (well, moderately, poorly differentiated) • several grading systems in use OVARIAN SEROUS CARCINOMA (OSC) – RECENT DEVELOPMENTS

• two distinct tumour types (called low grade and high grade OSC) • not two grades of same neoplasm • different neoplasms with different underlying pathogenesis, molecular events, behaviour, prognosis • high grade much more common than low grade • use instead of traditional grading schemes PATHOGENESIS (LOW GRADE SEROUS)

• low grade arise from pre-existing benign and borderline tumour (? not all cases) • micropapillary variant of borderline may be intermediate stage in development of low grade serous carcinoma • sometimes called invasive micropapillary serous carcinoma (poor term) • well-defined adenoma-carcinoma sequence PATHOGENESIS (HIGH GRADE SEROUS)

• thought to arise directly from ovarian surface epithelium or epithelium of cortical inclusion cysts or epithelium of distal fallopian tube • no well-defined precursor lesion (postulated to be serous tubal intraepithelial carcinoma)-rapid development • doesn’t arise from borderline tumour DEVELOPMENT OF LOW-GRADE AND HIGH-GRADE OVARIAN SEROUS CARCINOMA

fimbria of fallopian tube ovarian surface epithelium

benign serous cystadenoma

serous tubal ovarian cortical usual serous borderline intraepithelial intraepithelial inclusion neoplasm carcinoma neoplasia cysts

micropapillary variant of serous borderline neoplasm

high grade low grade serous carcinoma serous carcinoma MORPHOLOGY

• classification as high grade or low grade serous is reproducible (MD Anderson system) • distinction based mainly on nuclear atypia (not on architecture) in worst area of tumour • low grade serous – uniform nuclei with mild atypia; < 12 mitoses per 10 HPFs; usually approximately 2/10 HPFs; no necrosis or multinucleation • high grade serous – moderate to marked atypia; >12 mitoses per 10 HPFs; often necrosis and multinucleate cells

LOW GRADE OSC WITH “BIGGER” NUCLEI high grade serous high grade serous CORRELATION BETWEEN GRADING SYSTEMS • almost all grade 2 and 3 in old systems are high grade • grade 1 in old systems may be low grade or high grade

MOLECULAR (LOW GRADE SEROUS)

• KRAS or BRAF mutations in approx 2/3 (early in evolution – mutations found in benign and borderline tumours; identical mutations in borderline and malignant areas in same tumour) • ERBB2 mutations • KRAS and BRAF mutations are mutually exclusive; equivalent effect on tumorigenesis • no Tp53 mutations/abnormalities • progressive increase in chromosomal instability from benign to borderline to malignant MOLECULAR (HIGH GRADE SEROUS)

• Tp53 mutations (early in evolution-seen in early microscopic tumours eg BRCA1/2) (p53 dysfunction found in almost 100% high grade serous using stringent methods) • BRCA1/2 abnormalities (germline or somatic mutations or hypermethylation) • no BRAF and only occasional KRAS mutations • high chromosome instability (even in small early tumours) IMMUNOHISTOCHEMISTRY high grade OSC exhibits significantly higher expression of p53, MIB1, bcl2, C-Kit, HER-neu, p16, HLA-G than low grade OSC WT1 expressed in both 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) • most normal tissues and tumours exhibit focal, weak, heterogenous staining (“wild-type” staining) (usually <50%) • also of relevance in other areas of pathology (eg Barrett’s oesophagus) p53

• most ovarian high grade serous carcinomas diffusely positive or totally (“flat”) negative- aberrant staining • most low grade serous, clear cell, mucinous and endometrioid exhibit “wild- type” staining p53 Wild-type p53 BEHAVIOUR AND PROGNOSIS (LOW GRADE SEROUS)

• usually advanced at diagnosis • indolent behaviour (median survival 4.2 years; 5 year survival approx 55%; many cases survive longer eg >20 years) • often eventually fatal • poor response to chemotherapy • ? role of hormone therapy (aromatase inhibitors etc) (ER/PR positive) • possible targetted therapies (MEK inhibitors in tumours with RAS mutations) • rarely coexist with or evolve into high grade serous/undifferentiated carcinoma/carcinosarcoma LOW GRADE SEROUS EVOLVING INTO HIGH GRADE

MIB1 MIB1 BEHAVIOUR AND PROGNOSIS (HIGH GRADE SEROUS)

• usually advanced at diagnosis • aggressive behaviour • median survival 1.7 years • 5 year survival approx 25-30% • responds well initially to chemotherapy but usually recurs • ? role of PARP inhibitors (especially if BRCA abnormalities) PRIMARY PERITONEAL SEROUS CARCINOMA (PPSC)

• usually high grade • now being diagnosed more frequently • post-chemotherapy cases (probably cannot diagnose) • use GOG criteria (adopted by WHO) but often have to diagnose clinically/radiologically GOG CRITERIA FOR PPSC

• ovaries normal in size or enlarged by a benign process • tumour must be serous in type • microscopy- no tumour in ovary ; tumour confined to surface; <5mm invasion into stroma of ovary (arbitrary figure) • review slides (if <5 years) and, or, report of previous oophorectomy to document absence of tumour

OVARIAN MUCINOUS TUMOURS

• general issues • classification • morphology and immunohistochemistry • behaviour PREVALENCE

• previously mucinous carcinoma was considered to be second commonest variant of ovarian carcinoma • in most older studies, comprise 6-25% of primary ovarian carcinomas (mean 12%) RECENT POPULATION BASED (WASHINGTON / BRITISH COLUMBIA)

• 68-71% serous • 3% MUCINOUS • 9-11% endometrioid • 12-13% clear cell • 1% transitional • 6% mixed REASONS FOR DECLINE IN MUCINOUS CARCINOMAS • exclusion of secondaries • pseudomyxoma peritonei (PMP) - usually appendiceal origin • redefinition of criteria for borderline mucinous (intraepithelial carcinoma) • VARIABILITY STILL EXISTS IN DIAGNOSIS BETWEEN BORDERLINE AT UPPER END OF SPECTRUM AND MUCINOUS CARCINOMA EXHIBITING EXPANSILE INVASION (accounts for variation in prevalence of mucinous carcinomas between different institutions) PROBLEMS WITH OVARIAN MUCINOUS TUMOURS • borderline at upper end of spectrum versus carcinoma with expansile invasion • primary versus secondary (borderline and malignant histology) INTESTINAL VERSUS MULLERIAN MUCINOUS

• applies to borderline and malignant • intestinal much more common (don’t need goblet cells) • based on morphology - architecture and cytology • markers may help • intestinal type more akin to pancreatic or gastric rather than large intestinal neoplasms Ovarian Mucinous Tumours (Intestinal Type) • cystadenoma (rarely adenofibroma) • cystadenoma with focal epithelial proliferation • borderline tumour (10%) • borderline with intraepithelial carcinoma • borderline with microinvasion • microinvasive carcinoma • carcinoma PATHOGENESIS

• continuum from benign - malignant (adenoma-carcinoma sequence) • K-RAS mutations common (occur early in pathway) • HER2 overexpressed/amplified in significant percentage of mucinous carcinomas • minority arise in teratomas (may exhibit overt large intestinal differentiation) • association with Brenner tumours (recent proposal that arise from Walthard’s rests) Her 2 INTESTINAL-TYPE MUCINOUS OVARIAN TUMOURS

• wide age range but may occur in young females • usually very large • usually unilateral multiloculated with or without solid areas • often mildly elevated CA125 due to associated mesothelial proliferation (tumour cells do not produce CA125) • serum CA19.9 and CEA may be elevated • CA19.9 levels of no value in predicting whether ovarian mucinous neoplasm is benign, borderline or maligant

INTRAEPITHELIAL CARCINOMA IN MUCINOUS BORDERLINE • only criterion is severe nuclear atypia (usually but not always associated with florid proliferation)

MICROINVASION IN MUCINOUS BORDERLINE • most common size criterion is 5mm (others 3mm or 10mm2 ) (may be multiple foci- do not add together) • 2 types- borderline with microinvasion and microinvasive carcinoma • useful to distinguish for future studies BORDERLINE WITH MICROINVASION • no intraepithelial carcinoma • cytology of small area of invasion is low grade and similar to adjacent borderline tumour • cytokeratins may reveal more invasive cells than appreciated morphologically

CK in microinvasion MICROINVASIVE CARCINOMA

• adjacent borderline tumour usually exhibits intraepithelial carcinoma • small invasive component is high grade and morphologically malignant • may be associated with adverse behaviour INVASION IN MUCINOUS TUMOURS • significant interobserver variability • expansile/ non-destructive/ confluent glandular (more common) (difficult to diagnose) (good prognosis) • destructive/ infiltrative (less common)(easy to diagnose) (implies guarded prognosis)

IMMUNOHISTOCHEMISTRY- INTESTINAL TYPE MUCINOUS • usually CK7 positive • often express enteric markers (CK20, CA19.9, CEA, CDX2)- focal or diffuse • ER, CA125, WT1 usually negative • Mullerian type express CK7, ER, CA125; enteric markers negative CA19.9 CA125 IN OVARIAN MUCINOUS NEOPLASMS OF INTESTINAL TYPE • almost always negative • may be positive in metastatic disease in some cases • ? may be positive in areas of destructive stromal invasion OMENTAL METASTASIS

CA125

CA125 GRADING OF MUCINOUS CARCINOMA • state whether expansile or destructive invasion • grade similar to endometrioid carcinoma (no real evidence)(RCPath document in UK) BEHAVIOUR OF OVARIAN MUCINOUS TUMOURS

• borderline (benign with caveats)-TUMOUR OF NO MALIGNANT POTENTIAL (largely only recur when spillage or incomplete excision) • borderline with intraepithelial carcinoma (extremely good prognosis with caveats) • borderline with microinvasion (extremely good prognosis with caveats) • microinvasive carcinoma (unknown but may be aggressive) BEHAVIOUR OF OVARIAN MUCINOUS TUMOURS Continued

• stage 1 carcinoma with expansile invasion (good prognosis- rarely aggressive) • stage 1 carcinoma with destructive invasion (guarded prognosis) • advanced stage mucinous carcinoma (poor prognosis; exclude secondary)

SAMPLING OF OVARIAN MUCINOUS NEOPLASMS • literature- if borderline, 1 block per cm (<10cm); 2 blocks per cm (>10cm) • apply common sense- need more blocks if marked proliferation or severe atypia (intraepithelial carcinoma) ARGUMENT FOR CONTINUING BORDERLINE TERMINOLOGY • serous-extraovarian disease • mucinous- heterogeneity and risk of missing small focus of invasion RECENT STUDY- INTESTINAL TYPE OVARIAN MUCINOUS NEOPLASMS • population based study (Northern Ireland) • 95 borderline mucinous neoplasms of intestinal type • 4 (4.2%) recurred as extraovarian mucinous carcinoma • may also recur in ovary if cystectomy performed • 3 of 27 (11.1%) mucinous carcinomas recurred MUCINOUS CARCINOMAS

• relatively uncommon • usually unilateral and stage 1 • differences in incidence between centres due to problems in distinguishing borderline from expansile invasion • always consider secondary (especially if advanced and destructive invasion) • NOW TENDENCY TO OVERPLAY LIKELIHOOD OF SECONDARY • ROUTINE PATHOLOGICAL EXAMINATION CAN DISTINGUISH BETWEEN PRIMARY AND SECONDARY IN VAST MAJORITY OF CASES MUCINOUS CARCINOMA- PRIMARY OR SECONDARY? • in most cases, can be accomplished by pathological examination (gross and microscopic) • distribution of disease important • immunohistochemistry may help but lot of overlap and often not paramount Features favouring metastasis with mucinous ovarian carcinoma

• bilateral • small tumours • nodular pattern of ovarian involvement • microscopic surface deposits of tumour • marked LVI (especially outside ovary and in hilum) • marked variation in growth pattern from one nodule to another • destructive stromal invasion • single cell infiltration and signet ring cells • cells “floating” in mucin • extraovarian spread • NONE PATHOGNOMONIC BUT OFTEN IN COMBINATION

ENDOMETRIOID ADENOCARCINOMA

• usually, but not always, low grade and stage • high grade and high stage relatively uncommon but do occur • generally good prognosis • high grade tumours occur but relatively uncommon and previous tendency to overdiagnose • often arise in endometriosis • triad of endometriosis, squamous elements, adenofibromatous pattern useful in diagnosis GRADING (RCPath-UK)

• identical to uterine endometrioid adenocarcinoma • predominantly architectural with modification depending on nuclear features

MOLECULAR EVENTS IN OVARIAN ENDOMETRIOID CARCINOMA • similar to uterine endometrioid • PTEN mutations • K-RAS mutations • microsatellite instability • β catenin mutation • ? p53 in some high grade (? secondary event) • ARID 1A mutations CLEAR CELL CARCINOMA

• often stage 1 but ? poor prognosis (unlike other types) • ? subtle omental involvement, ? skip abdomen) • relatively resistant to platinum-based chemotherapy (stage 3/4 have worse prognosis than stage 3/4 high grade serous) CLEAR CELL CARCINOMA

• classically admixture of patterns • hobnail cells • oxyphilic variant • get clear cells in serous and endometrioid carcinomas (tendency to misdiagnose as clear cell or mixed carcinoma) • majority arise in endometriosis (sample well) (endometriosis in ovary may be subtle) • may sometimes be associated benign or borderline adenofibroma CLEAR CELL CARCINOMA

GRADING OF CLEAR CELL CARCINOMA (RCPath) • automatically grade 3 • often mitotically inactive and relatively low architectural and cytological grade (risk of undergrading) (may be reason for poor chemoresponsiveness) MOLECULAR EVENTS

• absence of p53 mutations • PTEN mutations may occur • ARID1A mutations • some cases have microsatellite instability • similar genetic events to endometrioid carcinomas TRANSITIONAL CARCINOMA

• rare and poorly reproducible diagnosis • express Mullerian markers • do not express urothelial markers (unlike Brenner) • most are probably variants of high grade serous carcinoma (may contain areas of serous/metastasise or recur as serous/ WT1 positive) (transitional-like features in high grade serous) • others may be variant of endometrioid carcinoma (transitional-like features in some endometrioid carcinomas)

UNDIFFERENTIATED CARCINOMA

• solid with little or no glandular differentiation • most are probably extreme end of high grade serous (sample well) • most are WT1 positive • others represent dedifferentiation in endometrioid carcinoma UNDIFFERENTIATED OVARIAN CARCINOMA

WT1 MIXED TUMOURS (10% RULE)

• most commonly diagnosed is mixed serous and endometrioid or mixed serous and clear cell- BUT UNCOMMON • combination of endometrioid and clear cell occurs • in my opinion, true mixed tumours are uncommon and overdiagnosed PROBLEMATIC AREAS IN OVARIAN CARCINOMA TYPING

• significant interobserver variability, especially for poorly differentiated tumours (MUCH BETTER NOW) • main problem is high grade serous versus endometrioid • other problem is clear cells (true clear cell/clear cell change in serous or endometrioid) • WITH EMERGENCE OF TARGETTED THERAPIES,TYPING WILL BECOME MORE IMPORTANT- INCLUDING TYPING ON SMALL BIOPSIES REPRODUCIBILITY OF 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 HIGH GRADE SEROUS VERSUS ENDOMETRIOID

• look for better differentiated areas (especially omentum and peritoneum) • slit-like (serous) versus round, punched-out (endometrioid) spaces • psammoma bodies (serous) • scattered tumour giant cells (serous) • squamous elements, adenofibromatous elements, endometriosis (endometrioid) HIGH GRADE SEROUS VERSUS ENDOMETRIOID

serous endometrioid PSEUDOENDOMETRIOID HIGH GRADE SEROUS CARCINOMA TRUE CLEAR CELL VERSUS CLEAR CELL AREAS IN OTHER TUMOURS

• classic areas of serous (post-chemotherapy) or endometrioid • true clear cell- solid, papillary, tubulocystic patterns, hobnail cells, eosinophilic stromal hyalinisation • WT1, p16, p53 (serous +ve/ diffuse/aberrant; true clear cell -ve/ focal) • ER (clear cell almost always -ve; serous often +ve, endometrioid usually +ve) • hepatocyte nuclear factor 1 beta (useful marker of clear cell carcinoma) SEROUS WITH CLEAR CELLS POSTCHEMOTHERAPY CLEAR CELL CHANGE IN SEROUS CARCINOMA

USEFUL MARKERS

• WT1- most serous carcinomas positive • p53- most high grade serous positive or totally negative (“all or nothing”)- aberrant staining • p16- most high grade serous diffusely positive (aberrant staining) • hepatocyte nuclear factor 1 β- marker of clear cell carcinoma (not specific) • HMGA2- marker of serous (full specificity not ascertained) WT1

• good marker of ovarian, tubal, peritoneal serous carcinomas (>90%) (stood the test of time as quite specific marker of serous carcinoma in appropriate context) • endometrioid, clear cell, mucinous rarely diffusely positive • useful in distinction between serous and endometrioid or serous and clear cell • most ovarian undifferentiated and “transitional” carcinomas also positive WT1 AS EVIDENCE OF SITE OF ORIGIN • WT1 positive serous carcinomas arise from WT1 positive epithelia- OSE or tubal fimbria • WT1 negative endometrioid and clear cell carcinomas arise from WT1 negative epithelia- endometriosis • WT1 negative uterine serous carcinomas arising from WT1 negative endometrium WT1 p16

• most ovarian high grade serous carcinomas diffusely positive (aberrant staining) • most low grade serous, clear cell, mucinous and endometrioid focally positive or negative p16 SEROUS CARCINOMA- HMGA2 HEPATOCYTE NUCLEAR FACTOR 1 BETA • good marker of ovarian (and uterine) clear cell carcinoma (discovered from gene expression studies) • endometriosis (associated and not associated with clear cell carcinoma) may be +ve • some other neoplasms +ve • need more studies (and new monoclonal antibody) • ? positive in tumours with clear cells (? related to glycogen metabolism) • positive in secretory endometrium/Arias Stella effect HNF1 beta RECENT STUDY ON REPRODUCIBILITY OF TYPING • Kobel et al, Am J Surg Pathol 2010;34;984-93. • excellent agreeement • participants had training in modern criteria • important for subtype specific ovarian cancer treatments • CONTRAST WITH UTERINE CARCINOMA GENOTYPE CORRELATES WITH PHENOTYPE • similar genetic events in same tumour types within ovary and uterus OVARIAN TUMORIGENESIS: A PROPOSED MODEL BASED ON MORPHOLOGICAL AND MOLECULAR GENETIC ANALYSIS

• type I (usually low grade, slowly growing which arise in a stepwise manner from borderline neoplasms or some other precursor) (usually exhibit somatic mutations in genes encoding protein kinases and other signalling molecules) • type II (usually high grade neoplasms, rapidly growing for which precursor lesions not well identified) • terms not to replace morphologic subtypes but concerned with mechanisms of tumour development • parallels with type I and type II uterine cancer TYPE I OVARIAN CARCINOMAS

• low grade serous • mucinous carcinoma • endometrioid carcinoma • malignant Brenner tumour • ? clear cell carcinoma TYPE II OVARIAN CARCINOMAS

• high grade serous • carcinosarcoma • undifferentiated carcinoma ARGUMENTS AGAINST TYPE 1 AND 2 SCHEME • perpetuates error of lumping together unrelated tumour types • best not to use • similar arguments in uterus IS TUBAL FIMBRIA THE ORIGIN OF HIGH GRADE PELVIC SEROUS CANCER?

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

• tubal serous intraepithelial or invasive lesions (mostly fimbrial) in prophylactic BSO (BRCA1/2)(much more prevalent than ovarian lesions) • high incidence of tubal lesions (mostly fimbrial and intraepithelial) in carefully sectioned tubes in patients with sporadic ovarian high grade serous carcinoma (not seen with other morphological subtypes of ovarian carcinoma) SEROUS TUBAL INTRAEPITHELIAL CARCINOMA (SEROUS TIC) • high incidence in patients with ovarian high grade serous carcinoma but not other morphological subtypes (also small invasive lesions) • same Tp53 mutations as ovarian neoplasm (evidence that clonally related and not part of “field-effect”)

SEROUS TIC-p53 STIC

p53

High Grade Serous Carcinoma 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 p53 mutations (? occurring all the time, ? need second event) • don’t diagnose STIC in absence of morphological features and confirmatory p53 and MIB1 p53 BRCA Promotes p53 Signature to TIC

BRCA1 P53p53 NormalNormal P53p53P53 signaturesignaturesignature TICTICTIC

Hereditary: BRCA1 mutation constitutive

P53p53 BRCA1 NormalNormal p53P53P53 signaturesignaturesignature TICTIC

Sporadic: BRCA1 mutation new event WHY IS TUBAL FIMBRIA SO PRONE TO Tp53 MUTATIONS AND CANCER DEVELOPMENT

• transitional zone (tubal-peritoneal junction) • similar to squamocolumnar junction in cervix BRCA1/2 POSITIVE

• early onset of breast and ovarian cancers • ovarian cancers are invariably high grade serous • probably better prognosis (more chemoresponsive and PARP inhibitors) • higher risk of tubal lesions • examine tubes and ovaries in entirety in prophylactic specimens • tumours may be extremely small • risk of peritoneal disease, even after BSO

GYNAECOLOGICAL TUMOURS IN BRCA- PATHOLOGY • “ovarian” high grade serous carcinomas • younger age than sporadic cancers (53 versus 63 years) • controversial regarding uterine serous carcinoma- no definite evidence • other tumours- probably coincidental • about 10% of ovarian carcinomas have an inherited predisposition (BRCA, Lynch) HIGH GRADE SEROUS CARCINOMAS IN BRCA- ?are there specific morphological features • work in progress • limited data • often “undifferentiated” appearance, transitional-like, tumour giant cells, lot of intraepithelial lymphocytes (CD8+ T cells), prominent necrosis • SET(Solid, pseudoEndometrioid, Transitional-like) • ? can initiate BRCA testing on basis of morphology • ? can initiate BRCA testing on basis of immunohistochemistry IMPLICATIONS

• need to focus on tube to investigate early events in high grade serous carcinogenesis • ? not all cases arise from tube (recent study 60% HOSC have serous TIC) but ? still arise from tubal epithelium • high grade serous carcinomas disseminated from outset • implications for ovarian cancer screening- cannot downstage (? can pick up with lower burden of tumour) TERMINOLOGY

• ? no longer call high grade ovarian serous carcinoma • ? refer to as HIGH GRADE PELVIC SEROUS CARCINOMA LOW GRADE SEROUS CARCINOMA • often arise from serous borderline tumour • may see lesions in fallopian tube in association with ovarian serous borderline - presumed to be from ovary • possible precursor lesion is PTH (papillary tubal hyperplasia)- see not uncommonly in fallopian tubes in association with serous borderline tumour

SUMMARY

• different morphological types of ovarian carcinoma have different pathogenesis, behaviour and prognosis • studies/clinical trials must separate different types • typing will become more important in management- different chemotherapy, targetted/personalised therapies, surgical approaches • increasing realisation that most ovarian, tubal and peritoneal high grade serous carcinoma are same neoplasm and arise from fimbria of tube ? WHAT ARE TRUE PRIMARY OVARIAN NEOPLASMS • serous (high and low grade)- ? from fallopian tube • mucinous and transitional - ? from Walthard’s rests at tubo-peritoneal junction • endometrioid and clear cell- from uterus (endometriosis) • ? ONLY TRUE PRIMARY OVARIAN NEOPLASMS ARE GERM CELL AND SEX CORD-STROMAL TUMOURS (similar to testis)