The Hawaii Pathology Conference: The Mighty Women of Pathology

Mixed Müllerian Tumors: Does Adenofibroma Exist? Do You Grade ? If So, How? Are All Equal?

Teri A Longacre, MD, Richard L Kempson Endowed Professor of Surgical Pathology, Department of Pathology, Stanford Medicine Notice of Faculty Disclosure

US Pathology Biomarker Advisory Board, Merck

Teri Ann Longacre, MD Introduction

• Polypoid adenomyoma - Atypical polypoid adenomyoma • Adenofibroma – Adenosarcoma • Benign Glands + Benign Stroma • Polypoid Adenomyoma (PA) • Atypical Polypoid Adenomyoma (APA) • Atypical Polypoid Adenomyoma of Low Malignant Potential (APA-LMP)

• Adenofibroma • Other (benign) polyps Case 1

• 32 year old with cervical

Is it?

• Adenofibroma • Adenosarcoma • Atypical polypoid adenomyoma • Other Polypoid Adenomyoma (PA) • Age range from 26 to 64 (median, 47 years) • Abnormal • Size 0.3 to 17 cm • Corpus, most submucosal (80%) • uncommon (10%) • Firm, cystic polypoid masses

Int J Gynecol Pathol 2000;19:195-205 Polypoid Adenomyoma (PA) • Circumscribed • Fibromuscular tissue – endometrial stroma often present around glands • Simple, rounded or tubular shaped glands & cysts – no atypia! • Focal tubal metaplasia • Squamous (morules) metaplasia rare, but may be present

Int J Gynecol Pathol 2000;19:195-205

Desmin

CD10 Polypoid Adenomyoma (PA)

• Uncommon • Probably related to • No clear association with • No risk of recurrence

Int J Gynecol Pathol 2000;19:195-205 Summary: Polypoid Adenomyoma

• Uncommon • No gland architectural abnormalities • Squamous metaplasia rare • No risk of recurrence • Important to distinguish from atypical polypoid adenomyoma Case 2

• 38 year old with cervical polyp APA APA Is it?

• Complex • Adenosarcoma • Low-grade endometrial adenocarcinoma • Polypoid adenomyoma • Other Atypical Polypoid Adenomyoma (APA) • Circumscribed • Fibromuscular tissue – endometrial stroma may be present • Crowded, architecturally complex glands with atypia • Squamous (morular) metaplasia (90%) • Stromal mitotic figures may be focally increased MICRO: Morules Atypical Polypoid Adenomyoma (APA)

• Reproductive age (mean, 38 years) • Vaginal bleeding or infertility work-up • Lower uterine segment polyp – can be removed by curettage Atypical Polypoid Adenomyoma (APA) • Mimics myoinvasive endometrial carcinoma in curettings • Look for dimorphic pattern: APA + normal proliferative or secretory • Immunostains for SMA, desmin not useful! • CD10 (so-called fringe pattern) expression in myoinvasive but not APA may be useful

Hum Pathol 2008;39:1446-53. Atypical Polypoid Adenomyoma (APA) • Atypical polypoid adenomyoma has risk of recurrence, but can be treated by polypectomy in reproductive-age women • Rarely atypical polypoid adenomyoma develop into low grade adenocarcinoma & very rarely spread beyond

Am J Surg Pathol 1996;20:1-20 Atypical Polypoid Adenomyoma of Low Malignant Potential

• Looks like low grade cancer, invades like low grade cancer… • So, probably is very low grade cancer • But to date, deep myometrial invasion very uncommon and very rare instances of extension beyond uterus, so clinical behavior is that of a low malignant potential tumor

Atypical Polypoid Adenomyoma of Low Malignant Potential

• More architecturally complex than APA Higher rate of recurrence than APA: 60% versus 33% • Higher rate of progression to carcinoma than APA: up to 20% may have superficial myoinvasion

Am J Surg Pathol 1996;20:1-20

Summary: Atypical Polypoid Adenomyoma

• Gland architectural abnormalities • Squamous metaplasia common • Risk of recurrence 33-60% • Can be managed conservatively • Important to distinguish from endometrioid adenocarcinoma Case 3

• 42 year old with vaginal bleeding

Is it?

• Complex endometrial hyperplasia • Adenosarcoma • Low-grade endometrial adenocarcinoma • Polypoid adenomyoma • Other

Well Differentiated Endometrioid Adenocarcinoma • Myoinvasive adenocarcinoma in endometrial sampling is very uncommon • When present, glands are haphazardly set in myofibromatous stroma with stromal reaction • Evidence of adenocarcinoma often present elsewhere in sampling: glands typically more complex with more cytologic atypia Case 4

• 44 year old with vaginal bleeding

Is it?

• Complex endometrial hyperplasia • Adenosarcoma • Low-grade endometrial adenocarcinoma • Polypoid adenomyoma • Other Focal Polypoid (Nodular) Hyperplasia

• Similar presentation as APA/APA-LMP • Dimorphic pattern • Can probably be managed as APA Case 5

• 44 year old with vaginal bleeding

Is it?

• Adenofibroma • Adenosarcoma • Benign • Polypoid adenomyoma • Other Benign Glands + Malignant Stroma

• Low-grade adenosarcoma Mesodermal Adenosarcoma

• Uncommon • Biphasic composed of benign glands and sarcomatous stroma • Corpus > > Cervix • Peritoneal and extra-genital sites • Rare in testis, seminal vesicle, prostate Mesodermal Adenosarcoma

• Assoc. w/ , esp extragenital sites • Unopposed , tamoxifen, radiation • Slow growing, recurrences at 5 or more years (sometimes >10 years) • Clinical behavior depends on: – site – stromal overgrowth – heterologous elements and/or high grade sarcomatous element Adenofibroma/Adenosarcoma Spectrum

AdenoFib AdenoSarc Uterine Adenosarcoma

• Postmenopausal, may occur in reproductive years • Polyp or polypoid lesion protruding through cervical os (1-17 cm; mean, 5 cm) • Vaginal bleeding • Often history of “recurrent polyps”

Cancer 1981;48:354-366; Hum Pathol 1990;21:363-368 Cervical Adenosarcoma

• Younger women, 13–67 years (mean, 38) • Vaginal bleeding • Initially interpreted as “benign cervical polyps” • Often smaller than their uterine counterparts (2–8 cm) • Arise in ecto- or endocervix, most low stage Ovarian Adenosarcoma

• Reproductive & postmenopausal (50% less than 50 years) • Unilateral • Solid & cystic, 5.5-50 cm (mean, 14 cm) • +/- assoc. w/ endometriosis • Poor prognosis compared to uterine/cervix adenosarcoma

Am J Surg Pathol 2002;26:1243-1258 Peritoneal Adenosarcoma • Mean age 41 years, but wide range • History of prior many years prior to presentation: from unrecognized uterine primary or true de novo? • Assoc w/ endometriosis • Bladder, colorectum, omentum, recto- vaginal septum, pouch of Douglas, retroperitoneum Adenosarcoma by Location

Recurrences Deaths

Corpus 15-25% 10-25% (45-70%**) (54%**) Cervix 18% 12%

Ovary 77% 64%

Peritoneum 60% 40%

** Stromal overgrowth Do You Grade Adenosarcoma?

• Actually…you do Adenosarcoma: 3 Groups

• Group 1: Usual (low-grade) adenosarcoma (Exclude benign tumor) • Group 2: Adenosarcoma with high grade (R/O other sarcoma) • Group 3: Adenosarcoma with stromal overgrowth (SO), defined as pure sarcoma comprising >25% of tumor volume – usually high-grade, often heterologous (rhabdomyosarcoma) Adenosarcoma: Usual • Uniform distribution of irregular, often cystic glands with polypoid intrusions (phyllodes-like) • Variably cellular stroma with accentuation or condensation around glands (cambium layer) • Stromal cytologic atypia (usually mild) • Stromal mitotic figures: threshold varies from 2* to 4** MF/ 10 HPF

* Clement & Scully, 1990; ** Zaloudek & Norris, 1981 MMMT Adenosarcoma Endometrioid Squamous

Ciliated (Eosinophilic) Mucinous Nondescript Decidualized

Sex cord elements Smooth muscle Adenosarcoma with High Grade Sarcomatous Stroma

• High-grade sarcoma present but no stromal overgrowth – usually with heterologous elements • Rhabdomyosarcoma • Chondrosarcoma • Osteosarcoma

Adenosarcoma with Stromal Overgrowth (SO)

• Defined as pure sarcoma comprising >25% of tumor volume • Usually high-grade sarcoma, often heterologous • Rarely, low-grade sarcoma (slightly improved prognosis?) Adenosarcoma: Treatment

• Surgical excision is mainstay • Radiation, chemotherapy or both for metastatic disease • Hormonal therapy for low stage disease – the stromal component frequently expresses hormone receptors Adenosarcoma: Differential Diagnosis

• Adenofibroma • Endometrial polyp • Polypoid endometriosis • Carcinosarcoma Summary: Adenosarcoma

• Biphasic benign epithelial and malignant stromal proliferation • Low-grade delayed, local recurrence vs high-grade sarcomatous overgrowth rapid recurrence with metastatic potential • Behavior depends also on site of origin Case 6

• 54 year old with vaginal bleeding

Is it?

• Adenofibroma • Adenosarcoma • Benign endometrial polyp • Polypoid adenomyoma • Other Benign Glands + Benign Stroma

• Adenofibroma Adenofibroma - Adenosarcoma

• Paucicellular, fibromatous • Uniform distribution of or fibrotic stroma irregular, often cystic • Stroma is mitotically glands with polypoid active intrusions • Multiple epithelial • Periglandular stromal differentiated types: condensation is minimal endometrioid, squamous, or absent mucinous, etc • Polypectomy is adequate • Variably cellular stroma treatment, provided that’s with accentuation or all there is condensation around • If in doubt, imaging, re- glands (cambium layer) sampling, close f/u • Hysterectomy is treatment of choice Does Adenofibroma Exist?

• Controversial • Spectrum problem • May not be single entity Adenofibroma Is Genetically Heterogeneous

• MDM2 amplification 26-28% • MYBL1 (sarcomatous overgrowth) 22% • PIK3CA/AKT/PTEN pathway 72% • ATRX (sarcomatous overgrowth) 17% • Chromosomal instability in aggressive tumors

J Pathol 2015;235:37-49; J Pathol 2016;238:381-8; Mod Pathol 2016; 29:1070-82 Case 7

• 54 year old with vaginal bleeding

Is it?

• Adenofibroma • Adenosarcoma • Low-grade stromal sarcoma vs stromal nodule • Polypoid adenomyoma • Other (Benign) Endometrial Polyp • Common – may be multiple and recurrent • May have increased mitotic figures – up to 5MF/10HPF • May have decidualized stroma simulating stromal proliferative process • May have atypical stromal cells similar to atyical stromal cells in vulva, and cervix Atypical Endometrial Polyps • Generally small (< 3cm) • May have phyllodes-like growth pattern • May have hypercellular or hypocellular stromal cuffs • May have stromal atypia • Mitotic index may also be increased

Am J Surg Pathol 2015;39:116-26 Atypical Endometrial Polyps

BUT • Each of these changes are typically focal and poorly developed

Am J Surg Pathol 2015;39:116-26

Polypoid Endometriosis • Exuberant endometriosis presenting as polypoid or mass lesions, simulating neoplastic process • Slightly older age than usual endometriosis with 60% in women > 50 years of age • Exhibits various types of epithelial metaplasia, but no increased stromal cellularity or atypia • Benign, but may transform over time – adenosarcoma or stromal sarcoma Am J Surg Pathol 2004;28:285-297

Summary: Atypical Endometrial Polyps

• Atypical endometrial polyps may exhibit features associated with malignant polyps (e.g., phyllodes-like growth pattern, hypercellular or hypocellular stromal cuffs, stromal atypia, increased mitotic index) • BUT these changes are focal in an otherwise usual type endometrial polyp Case 8

• 58 year old with large intrauterine necrotic polyp

Diagnosis?

• Leiomyosarcoma • Undifferentiated sarcoma • High grade endometrial stromal sarcoma • STUMP • Sarcomatous component of carcinosarcoma

Malignant Glands + Malignant Stroma

• Carcinosarcoma Carcinosarcoma

• <5% of all uterine tumors • Postmenopausal (median, 65 years) • Bleeding, abdominal pain, polyp • Associated with radiation • Some associated with BRCA1/2 Carcinosarcoma

• Sarcoma or less commonly, carcinoma may be focal • Sarcoma may not be detected in primary, but present in recurrence • Carcinosarcoma may metastasize/recur as carcinoma only, sarcoma only, or as both components Carcinosarcoma • Homologous vs heterologous • S-M-K data suggest low stage heterologous tumors may be more aggressive than homologous tumors • So, may be important to confirm heterologous differentiation if possible (i.e., rhabdomyosarcoma vs eosinophilic “rhabdoid” cells) Carcinosarcoma Cardinal Features

• Biphasic tumor • Distinct epithelial and mesenchymal elements • Both elements almost always high grade Monophasic Tumor: NOT Carcinosarcoma Tumor with Altered Stroma: NOT Carcinosarcoma Biphasic Tumor with Merged Elements: NOT Carcinosarcoma Sarcomatous Component of Carcinosarcoma

• Clinical cues: – Postmenopausal – Necrotic polypoid mass • Histologic cues: – Eosinophilic droplets & globules – Cartilage or chondroid matrix – Focal gland formation Mesenchymal Elements

• Homologous – Stromal sarcoma – Leiomyosarcoma • Heterologous – Rhabdomyosarcoma – Chondrosarcoma – Osteosarcoma

Epithelial Elements

Serous/undifferentiated: 2/3 Endometrioid: 1/3 * * FIGO G3: >3/4 Carcinosarcoma vs High-Grade Endometrial Adenocarcinoma 1.0 0.8 0.6 Proportion Disease-Free Proportion 0.4 0.2 Carcinosarcoma High Grade Endometrial Ca. 0.0

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months from Date of Diagnosis

Disease-free survival in women with stage I carcinosarcoma vs stage I high-grade endometrial carcinoma, P = 0.001 (Courtesy of Rob Soslow) Homologous vs Heterologous Carcinosarcoma 1.0 0.8 0.6 Proportion Surviving Proportion 0.4 0.2

Carcinosarcoma - Homologous Carcinosarcoma - Heterologous 0.0 High Grade Endometrial Ca.

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months from Date of Diagnosis

Overall-survival in women with stage I carcinosarcoma with heterologous versus homologous components versus stage I high-grade endometrial adenocarcinoma, P = 0.001 (Courtesy of Rob Soslow) Carcinosarcoma • Heterologous elements bear no relation to prognosis unless uterine low stage? • Carcinosarcomas likely represent metaplastic carcinomas • Serous carcinoma may precede carcinosarcoma (unrecognized vs progression) • Metastases & recurrences may be solely carcinoma or sarcoma Are all Carcinosarcomas Equal? Carcinosarcoma 5-year survival

FIGO I FIGO >II

OVARY USUAL HG SEROUS 83% 24-38%

OVARY CARCINO- SARC 73% 13-24%

ENDO CARCINO- SARC 50% 0-25% Unresolved Questions

• Does percent sarcoma (or carcinoma) matter? • Does type of carcinoma matter? • Does type of sarcoma (homologous vs heterologous) matter? Differential Diagnosis

• Adenosarcoma with stromal overgrowth • Corded and hyalinized endometrial carcinoma (CHEC) • High-grade carcinoma, NOS • Sarcoma (LMS, rhabdomyosarcoma, etc) • Undifferentiated sarcoma, NOS Uterine Tumor Resembling (“Low Grade”) Carcinosarcoma: What Is It? • Low grade endometrial carcinoma may have prominent spindled epithelial component, osteoid-like or cellular corded patterns simulating carcinosarcoma, but • Absence of marked cytologic atypia • Few or absent mitotic figures in spindled areas • Squamous differentiation in most (70%) • Younger age (50 versus 60 years) Am J Surg Pathol 2005;29:157-166 Uterine Tumor Resembling (“Low Grade”) Carcinosarcoma: What Is It?

• So-called corded and hyalinized endometrial carcinoma (CHEC)

Am J Surg Pathol 2005;29:157-166 Osteoid Chondroid

Cellular Corded

Undifferentiated Uterine Sarcoma • No histologic evidence of smooth muscle, endometrial stromal or epithelial differentiation • High grade • High mitotic index • Subset may express CD10, but this does not warrant classification as endometrial stromal sarcoma • Highly aggressive

Summary

• Confirm carcinosarcoma cardinal features • Always search for heterologous elements • Absence of sarcoma at presentation may occur (rarely presents as sarcoma) • Metastases may be carcinoma, both, or rarely, sarcoma Thank you Stanford University