21/07/2017 British Division of the International Academy of Pathology (BDIAP) KRISTIN HENRY LECTURE, BELFAST 2017: TYPING OF OVARIAN AND ENDOMETRIAL CARCINOMAS: A STORY OF SUCCESS AND FAILURE W Glenn McCluggage Belfast, United Kingdom The BDIAP Kristin Henry Lecture Presidents of the IAP from the UK 1982-90 Treasurer of BDIAP 1995-96 President of BDIAP 1997-98 Cunningham Medal 2009-10 President’s Medal 2005-08 Chair Finance Committee 2008-11 Chair Education Committee Roger Cotton Kristin Henry 1982-1983 2010-2012 TYPING OF OVARIAN AND ENDOMETRIAL CARCINOMAS: A STORY OF SUCCESS AND OVARIAN CARCINOMA TYPING FAILURE • Ovarian carcinoma- typing • Recent developments regarding “ovarian” •SUCCESS serous carcinomas • Endometrial carcinoma- typing • Small cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) 1 21/07/2017 REPRODUCIBILITY OF OVARIAN OVARIAN EPITHELIAL CARCINOMA CARCINOMA TYPING (WHO 2014)- 5 major histotypes • Brugghe et al (IJGC, 1995) - 61% • low grade serous • Bertelsen et al (IJGC, 1993) - 72% (serous and • high grade serous endometrioid); 86% (mucinous); 100% (clear cell) • mucinous • Baak et al (AQCH, 1986) - significant variation • endometrioid • Cramer et al (APLM, 1987) – suboptimal • Lund et al (APMIS, 1991) – 68% • clear cell • Sakamoto et al (Gynecol Oncol, 1994) -53% • Brenner • ICON 5- POOR ++ • seromucinous • undifferentiated DIFFERENCES FROM PREVIOUS STUDIES RECENT POPULATION BASED (WASHINGTON / BRITISH COLUMBIA) • increase in serous • • 68-71% serous (17-18:1 ratio HGSC to LGSC) decrease in endometrioid • • 3% mucinous marked decrease in mucinous (exclusion of secondaries) • 9-11% endometrioid • reversal of endometrioid and clear cell ratio • 12-13% clear cell 88% OF ADVANCED STAGE OVARIAN CARCINOMAS ARE SEROUS REASONS FOR INCREASE IN SEROUS IMPORTANCE OF TYPING OF OVARIAN AND DECREASE IN ENDOMETRIOID CARCINOMA • Recognised that many neoplasms that were • at present typing of some (but increasing) previously diagnosed as high grade therapeutic significance; treatment traditionally endometrioid are actually high grade serous more dependent on stage and grade carcinoma (HGSC) • NOW DIFFERENT THERAPY FOR DIFFERENT OVARIAN CANCER TYPES (surgery, traditional chemotherapy, • Importance of WT1- Al-Hussaini et al. targetted therapies, hormone therapy) Histopathology 2004; 44; 109-115. • carcinoma grading (differs between different types) • screening, personal and family history risk (BRCA, Lynch) 2 21/07/2017 OVARIAN CARCINOMA GRADING- INTERNATIONAL COLLABORATION ON INTERNATIONAL COLLABORATION ON CANCER REPORTING (ICCR) CANCER REPORTING-ICCR • serous- low grade and high grade (2 different • Alliance between RCPath UK, RCPath Aus, CAP, types) ESP, Canadian Partnership Against Cancer • endometrioid- like uterine corpus • Purpose of developing standardised evidence • clear cell- automatically high grade based cancer datasets for each site • mucinous- as for endometrioid • Ovarian/ fallopian tube/ primary peritoneal dataset- Modern Pathology 2015;28;101-122 • http://www.iccr-cancer.org/datasets 14 RECENT STUDY ON REPRODUCIBILITY OF HISTORIC AREAS OF DIAGNOSTIC OVARIAN CARCINOMA TYPING DIFFICULTY • Koebel et al, Am J Surg Pathol 2010;34;984-93. • Serous (high grade) versus endometrioid • excellent agreement • Serous (high grade) versus clear cell • participants had training in modern criteria • Serous (high grade) versus transitional • important for subtype specific ovarian cancer • Serous (high grade) versus undifferentiated treatments • CONTRAST WITH UTERINE CARCINOMA • good marker- WT1 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 3 21/07/2017 PSEUDOENDOMETRIOID MORPHOLOGY IN HGSC CLEAR CELL CHANGE IN HGSC (SOMETIMES POSTCHEMOTHERAPY) TRANSITIONAL-LIKE MORPHOLOGY IN OVARIAN HIGH GRADE SEROUS HGSC CARCINOMA WT1 in PSEUDOENDOMETRIOID AREAS IN HGSC WT1 in CLEAR CELL AREAS IN HGSC p53 WT1 4 21/07/2017 WT1 IN TRANSITIONAL-LIKE AREAS IN UNDIFFERENTIATED OVARIAN HGSC CARCINOMA WT1 MIXED OVARIAN CARCINOMAS Mixed Ovarian Carcinomas • historically quite common (up to 10-20%) • Improved recognition of types has virtually abolished • most commonly historically reported were mixed mixed tumours – 15 of 871 cases reviewed (1.7%) by H/E using modern serous/ endometrioid; mixed serous/clear cell; diagnostic criteria mixed serous/ transitional; mixed • 22 cases thought to be mixed were investigated further by serous/undifferentiated (mostly variants of high immunohistochemistry and molecular testing grade serous carcinoma- doubtful if these • Only 13 true mixed carcinomas when combinations exist) immunohistochemistry and molecular data incorporated • occasionally get mixed endometrioid/ clear cell • Mixed carcinomas account for less than 1% of ovarian (association with endometriosis) carcinomas MacKenzie et al. Am J Surg Pathol 2015; 39: 1548-1557 • occasionally others • CATEGORY DROPPED FROM WHO 2014 MORPHOLOGY OF BRCA ASSOCIATED TRANSITIONAL CARCINOMA HIGH GRADE SEROUS CARCINOMAS • dropped from WHO 2014 • SET pattern (Solid, pseudoEndometrioid, • most are variants of high grade serous Transitional) (“transitional-like”) (more typical areas if sample • Higher mitoses; more geographical necrosis well; omental metastases may look like high • ? Increased tumour intraepithelial T lymphocytes grade serous; WT1 positive; aberrant p53) • Different patterns of metastatic disease • some are variants of endometrioid carcinoma (“pushing” rather than “infiltrative”) (transitional-like morphology) • Similarities to breast carcinomas in BRCA • • still categories of benign, borderline and PROBABLY ALL PATIENTS WITH HGSC SHOULD UNDERGO BRCA TESTING- FUNDING QUESTIONS malignant Brenner 5 21/07/2017 HGSC WITH CLEAR CELL CHANGE 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 IMMUNOHISTOCHEMISTRY- HGSC VERSUS CLEAR CELL CARCINOMA WITH CLEAR CELL CHANGE • 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 p53 WT1 IMMUNOHISTOCHEMISTRY- CLEAR HGSC VERSUS ENDOMETRIOID CELL CARCINOMA 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 HNF1 beta Napsin A 6 21/07/2017 IMMUNO- HGSC VERSUS HIGH GRADE PITFALL ENDOMETRIOID ADENOCARCINOMA • WT1- HGSC • WT1 (only about 95% of tubo-ovarian HGSCs • p53- wild-type suggestive of endometrioid; positive) some high grade endometrioid carcinomas • High grade ovarian endometroid have mutation-type (may be clonal pattern adenocarcinomas rarely WT1 positive suggestive acquisition of TP53 mutation • Low grade ovarian endometroid during progression) adenocarcinomas may be WT1 positive Interpretation of p53 immunohistochemistry p53 No TP53 mutation • p53 immunohistochemistry- lot of confusion • only consider positive/significant if diffuse strong nuclear immunoreactivity (75-80% cells suggested- associated with Normal missence mutation) • p53 null consistent with serous carcinoma (different type of mutation (nonsense) or deletion resulting in truncated protein Wild type pattern which is not detected by immunohistochemistry) • third pattern of mutation-type staining- cytoplasmic (rare pattern) Nonsynonymous Stopgain Stopgain • most normal tissues and tumours exhibit focal, weak, heterogenous =missense Indel Indel staining (“wild-type” staining) (usually <50%) (about 5% of HGSCs Splicing Splicing with TP53 mutation exhibit wild-type staining) • DON’T REPORT AS POSITIVE OR NEGATIVE- REPORT AS “WILD- TYPE” or “MUTATION-TYPE/ ABERRANT” p53 overexpression p53 complete absence p53 cytoplasmic Abnormal; mutation-type J Pathol Clin Res 2016;2:247 “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 2016: www.thebagp/resources 7 21/07/2017 PATHOGENESIS (LOW GRADE SEROUS) MOLECULAR (LOW GRADE SEROUS) • low grade arise from pre-existing benign and • Mutations in genes associated with MAPK borderline tumour (probably not all cases) pathway (KRAS or BRAF mutations in approximately half (sometimes early in • micropapillary variant of serous borderline evolution – mutations found in benign and may be intermediate stage in development of borderline tumours; identical mutations in low grade serous carcinoma borderline and malignant areas in same • well-defined adenoma-carcinoma sequence tumour) • KRAS and BRAF mutations are usually mutually exclusive; equivalent effect on tumorigenesis • no TP53 mutations/abnormalities PATHOGENESIS (HIGH GRADE SEROUS) MOLECULAR (HIGH GRADE SEROUS) • traditionally thought to arise directly from ovarian surface epithelium or epithelium of cortical inclusion cysts; now clear that most • TP53 mutations (early in evolution-seen in early microscopic cases