ENODMETRIAL CARCINOMA: SPECIAL & NOT SO SPECIAL VARIANTS

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1 ENODMETRIAL CARCINOMA: SPECIAL & NOT SO SPECIAL VARIANTS Pacific Northwest Society of Pathologists Vancouver, B.C. September 26, 2015 Teri A. Longacre, M.D. Stanford University, Stanford, CA

2 Disclosure of Relevant Financial Relationships ASCP requires that anyone in a position to influence or control the content of all CME activities disclose any relevant relationship(s) which they or their spouse/partner have, or have had within the past 12 months with a commercial interest(s) [or the products or services of a commercial interest] that relate to the content of this educational activity and create a conflict of interest. Complete disclosure information is maintained in the ASCP office and has been reviewed by the CME Advisory Committee. Teri Longacre declares no conflict(s) of interest to disclose.

3 Special Variants: When Does It Matter? Serous carcinoma Clear cell carcinoma Locational issues (endocervix vs endometrium): mucinous Unusual transformation (trophoblast, yolk sac) Squamous cell carcinoma Neuroendocrine carcinoma

4 Serous Cancer

5 Uterine Serous Carcinoma Type II cancer High grade! Mean age decade older than usual adenocarcinoma No background hyperplasia - traditionally Uterus may not be enlarged; scanty sampling May be minimally invasive with widespread disease

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16 Serous Endometrial Intraepithelial Carcinoma (SEIC): Non-invasive Serous Carcinoma Typically elderly woman Normal endometrial (often atrophic) glandular structure is preserved Lining cells exhibit marked nuclear atypia, enlargement, and hyperchromasia Strong nuclear p53 overexpression Assoc w/ high grade serous-type disease elsewhere often peritoneal Am J Surg Pathol 2000;24:

17 MICRO: EIN

18 Serous Cancer P53-positive (every single cell or null pattern) P16-positive WT1-negative (mostly) ER-positive/negative PR-positive/negative HER2-positive (subset)

19 High Single Copy Number Abnormalities TP53 MYC ERBB2 CCNE1 FGFR3 SOX17

20 p53

21 Uterine serous carcinoma

22 p16

23 Serous Carcinoma Mimics: The Good, The Bad and The Ugly Papillary metaplasia Syncytial papillary metaplasia Villoglandular endometrioid Glandular serous vs endometrioid with grade 3 nuclei Serous carcinoma from elsewhere in the genital tract

24 Simple Papillary Proliferations Atrophic, weakly proliferative, or proliferative cells without atypia lining coarse connective tissue papillary cores Spectrum of metaplastic changes Frequently focal, in endometrial polyps in atrophic endometria Benign papillary hyperplasia/proliferation Am J Surg Pathol 2013;37:167-77

25 Simple Papillary Proliferation

26 Complex Papillary Proliferations May be associated with concurrent or subsequent endometrial hyperplasia and carcinoma Analogous to atypical hyperplasia (even in the absence of significant cytological atypia) Complex papillary hyperplasia/proliferation" Am J Surg Pathol 2013;37:167-77

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30 p53

31 MICRO: Papillary syncytial metaplasia Papillary Syncytial Change

32 Papillary Syncytial Change BE WARY OF THE p53 STAIN!!! p53

33 Papillary Syncytial Change (Metaplasia) Decreased expression of ER Increased expression of p53 (although still wild-type staining) and p16, the latter marker typically being diffusely positive Low MIB1 proliferation index In problematic cases, IHC may result in a misdiagnosis Int J Gynecol Pathol 2012;31:206-10

34 Papillary Problems: Strategy Mixed epithelium argues benignancy Some degree of cytologic atypia is permitted in metaplastic papillary lesions (even expected) but marked nucleomegaly & pleomorphism is not Serous carcinoma is a cytologic diagnosis p53 & p16 should be used with caution

35 Papillary Problems: Serous vs Endometrioid Serous Endometrioid Basic Structure Papillary Villoglandular Papillae Short, stubby Long, slender Cores Broad, bulbous Thin, elongate Epithelium Polygonal Columnar Nuclei Grade 3 Grade 1-2 Assoc. Findings Atrophy or EIC Hyperplasia

36 Papillary Problems: Serous vs Endometrioid Serous Endometrioid Basic Structure Papillary Villoglandular Papillae Short, stubby Long, slender Cores Broad, bulbous Thin, elongate Epithelium Polygonal Columnar Nuclei Grade 3 Grade 1-2 Assoc. Findings Atrophy or EIC Hyperplasia

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41 Glandular Serous cancer Endometrioid ca with grade 3 nuclei

42 Serous Carcinoma Staging What to do with intraepithelial serous carcinoma in endometrium, cervix, fallopian tube, peritoneum? Describe distribution of disease We don t use the term EIC or minimal volume serous carcinoma Stage according to distribution, but admit outcome data sparse

43 Don t Forget Carcinosarcoma Often misdiagnosed as serous carcinoma Stromal component may be focal look for the cartilage (or bone) Stromal component may be overlooked as reactive stroma look for pink hyalin droplets May recur as serous cancer, carcinosarcoma or rarely, sarcoma

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45 Clear Cell Carcinoma

46 Clear Cell Carcinoma RARE in uterus, esp. pure variety Histologically similar to clear cell cancer in ovary: papillary, tubulocystic, diffuse (solid) Clear or eosinophilic cytoplasm Hobnail cells Almost a diagnosis of exclusion in the uterus High grade!!!

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55 Napsin

56 Clear Cell Carcinoma ER-negative PR-negative P16-negative P53-negative HNF1-beta-positive Napsin-positive but can see variable patterns

57 Clear Cell Carcinoma Mimics Arias-Stella reaction & pill effect Endometrioid carcinoma with clear cytoplasm Serous carcinoma with clear cells tough differential diagnosis - original Stanford series of uterine serous carcinoma featured tumors with areas of clear cell: does it matter? Mucinous carcinoma (less likely)

58 MICRO: Arias-Stella reaction

59 Endometrioid Carcinomas with Clear Cytoplasm Secretory carcinoma - subnuclear and supranuclear vacuoles, low grade (nuclear grade 1-2) cytology Endometrioid carcinoma with clear cytoplasm, due to glycogen, lipid, other Squamous glycogenization has other areas of classic squamous differentiation Lipid, other causes of artifactually clear cytoplasm have low grade nuclear features, merge with classic endometroid carcinoma Am J Surg Pathol 2007;31:1203-8

60 Endometrioid vs Clear Cell Carcinoma

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62 Mucinous Carcinoma

63 Mucinous Adenocarcinoma, Endometrial Origin Less than 10% of all endometrial cancer Definitions vary WHO uses >90% mucin component Most mixed with endometrioid Type 1 cancer (estrogen) Most low grade (FIGO 1 or 2) Most low stage

64 Low Single Copy Number Abnormalities CTNNB1 KRAS SOX17 Mutually exclusive, so different mechanisms activating WNT signaling

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70 Mucinous Adenocarcinoma, Endometrial Origin Often deceptively bland cytology Complex architecture may not always be present Copious mucin May mimic microglandular hyperplasia or minimal deviation adenocarcinoma If in doubt: complex mucinous endometrial proliferaiton, cannot exclude carcinoma

71 Endometrial vs Endocervical: All About (Predicting) Location Endocervical or endometrial? Lower uterine segment? Metastasis? Benign or malignant?

72 Mucinous Endocervical Ca Endometrial Ca

73 Microglandular: Benign vs Malignant MGH MGH-like Ca

74 Strategies Physical exam Differential or fractional curettage Imaging studies Histologic features Immunohistochemical features

75 Localization of Adenocarcinoma in Uterine Curettage Specimens Endocervical 1. ER (or ER/PR) - negative 2. Vimentin-negative 3. p16 INK4 -positive/hpv in situ-positive Endometrial 1. ER (or ER/PR) - positive 2. Vimentin-positive 3. p16 INK4 -negative/hpv in situ-negative

76 Endocervical ER Endometrial Vimentin p16

77 p16 Endometrioid Adenocarcinoma

78 p16 Uterine serous carcinoma p16 Endometrial squamous morules

79 Squamous Carcinoma

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87 Uterine Squamous Cell Carcinoma Rare (less than 0.5%) Postmenopausal Most well to moderately differentiated Must have no glandular component High-risk HPV detected in rare cases

88 Undifferentiated Carcinoma

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90 MSI Hypermutated ARID5B KRAS Frameshift deletions in RPL22 Most with MLH1 promoter hypermethylation 10-fold increased mutation frequency

91 Dedifferentiated Endometrioid Carcinoma Low grade component with well-formed glands Undifferentiated component Typically abrupt transition Poor prognosis Subset assoc. with mismatch repair protein defects & Lynch syndrome

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95 Carcinoma with Yolk Sac Differentiation

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100 Carcinoma with Yolk Sac Differentiation High-grade endometrioid or serous May have elevated serum AFP May present in recurrent tumor, suggesting transformation Few cases, so best treatment not clear

101 Mesonephric Carcinoma

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104 Mesonephric Adenocarcinoma Rare often no surface component Wide age range Not linked to HPV Can have ductal, retiform, tubular, solid, spindle patterns May arise in corpus

105 Mesonephric Adenocarcinoma Cytokeratin positive CK7 negative or weak positive Calretinin positive CD10 positive

106 Neuroendocrine Carcinoma

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110 GYN: Low-Grade Neuroendocrine Well differentiated, grade 1 ( carcinoid ) have a low Ki-67 index ( 2%) and low mitotic count (< 2 per 10 high power fields) Well differentiated, grade 2 tumors ( atypical carcinoid ) have increased Ki-67 index (3-20%) and increased mitotic count (2-20 per 10 high power fields). Necrosis may be present in the atypical carcinoid tumors.

111 GYN: High-grade Neuroendocrine Neuroendocrine carcinoma (small cell or large cell type). Neuroendocrine carcinoma is considered grade 3; High Ki-67 index (>20%) and high mitotic counts (>20 per 10 high power fields). Multifocal necrosis is common.

112 Molecular Classification (TCGA Data) POLE ultramutated Microsatellite instability hypermutated Copy number low Copy number high

113 POLE Ultramutated Mutations in exonuclease domain of POLE Increased C to A transversion PTEN PIK3R1 PIK3CA KRAS Improved progression-free survival

114 MSI Hypermutated ARID5B KRAS Frameshift deletions in RPL22 Most with MLH1 promoter hypermethylation 10-fold increased mutation frequency

115 Low Single Copy Number Abnormalities CTNNB1 KRAS SOX17 Mutually exclusive, so different mechanisms activating WNT signaling

116 High Single Copy Number Abnormalities Serous (94%) Mixed histology (62%) Endometrioid (12%) 24% Gr 3 & 5% Gr 1-2

117 High Single Copy Number Abnormalities TP53 MYC ERBB2 CCNE1 FGFR3 SOX17

118 Thank you Stanford University