Pacific Northwest Society of Pathologists Vancouver, B.C.

September 26, 2015

Teri A. Longacre, M.D. longacre@stanford.edu

Stanford University, Stanford, CA

ENODMETRIAL CARCINOMA: SPECIAL & NOT SO SPECIAL

VARIANTS

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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.

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

Serous Cancer

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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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;24:726-732

MICRO: EIN

Serous Cancer

• P53-positive (every single cell or null pattern)

• P16-positive • WT1-negative (mostly) • ER-positive/negative • PR-positive/negative • HER2-positive (subset)

High Single Copy Number Abnormalities

• TP53

• MYC

• ERBB2

• CCNE1

• FGFR3

• SOX17

p53

Uterine serous carcinoma

p16

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

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

Simple Papillary Proliferation

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

p53

MICRO: Papillary syncytial metaplasia

Papillary Syncytial Change

Papillary Syncytial Change

p53

BE WARY OF THE p53 STAIN!!!

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

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

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

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

Glandular Serous cancer

Endometrioid ca with grade 3 nuclei

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

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

Clear Cell Carcinoma

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!!!

Napsin

Clear Cell Carcinoma • ER-negative • PR-negative • P16-negative • P53-negative • HNF1-beta-positive • Napsin-positive

…but can see variable patterns

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)

MICRO: Arias-Stella reaction

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

Endometrioid vs Clear Cell Carcinoma

Mucinous Carcinoma

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

Low Single Copy Number Abnormalities

• CTNNB1

• KRAS

• SOX17

Mutually exclusive, so different mechanisms activating WNT signaling

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”

Endometrial vs Endocervical: All About (Predicting) Location

• Endocervical or endometrial? • Lower uterine segment? • Metastasis? • Benign or malignant?

Endocervical Ca Endometrial Ca

Mucinous

MGH MGH-like Ca

Microglandular: Benign vs Malignant

Strategies

• Physical exam • Differential or fractional curettage • Imaging studies • Histologic features • Immunohistochemical features

Localization of Adenocarcinoma in Uterine Curettage Specimens

Endocervical 1. ER (or ER/PR) -

negative 2. Vimentin-negative 3. p16INK4-positive/HPV

in situ-positive

Endometrial 1. ER (or ER/PR) -

positive 2. Vimentin-positive 3. p16INK4-negative/HPV

in situ-negative

Vimentin

ER

p16

Endocervical Endometrial

Endometrioid Adenocarcinoma

p16

p16

p16

Uterine serous carcinoma

Endometrial squamous morules

Squamous Carcinoma

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

Undifferentiated Carcinoma

MSI Hypermutated

• ARID5B

• KRAS

• Frameshift deletions in RPL22

• Most with MLH1 promoter hypermethylation

• 10-fold increased mutation frequency

“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

Carcinoma with Yolk Sac Differentiation

SALL-4

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

Mesonephric Carcinoma

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

Mesonephric Adenocarcinoma

• Cytokeratin positive • CK7 negative or weak positive • Calretinin positive • CD10 positive

Neuroendocrine Carcinoma

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.

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.

Molecular Classification (TCGA Data)

• POLE ultramutated • Microsatellite instability hypermutated • Copy number low • Copy number high

POLE Ultramutated

• Mutations in exonuclease domain of POLE

• Increased C to A transversion • PTEN

• PIK3R1

• PIK3CA

• KRAS

• Improved progression-free survival

MSI Hypermutated

• ARID5B

• KRAS

• Frameshift deletions in RPL22

• Most with MLH1 promoter hypermethylation

• 10-fold increased mutation frequency

Low Single Copy Number Abnormalities

• CTNNB1

• KRAS

• SOX17

Mutually exclusive, so different mechanisms activating WNT signaling

High Single Copy Number Abnormalities

• Serous (94%) • Mixed histology (62%) • Endometrioid (12%)

– 24% Gr 3 & 5% Gr 1-2

High Single Copy Number Abnormalities • TP53

• MYC

• ERBB2

• CCNE1

• FGFR3

• SOX17

Stanford University

Thank you