Disclosure of Uterine Sarcomas Marisa R. Nucci, M.D. I have - PowerPoint PPT Presentation

Recent Developments in the Diagnosis Disclosure of Uterine Sarcomas Marisa R. Nucci, M.D. • I have nothing to disclose Associate Professor of Pathology Division of Women’s and Perinatal Pathology Department of Pathology Brigham and Women’s Hospital Boston, MA UCSF Current Issues in Anatomic Pathology 2014 Endometrial Stromal Tumors Entities to Discuss “Old” Terminology: Norris and Taylor • Endometrial Stromal Sarcoma •Endometrial Stromal Nodule – Low and High Grade Subtypes •Endometrial Stromal Sarcoma • Undifferentiated Uterine Sarcoma – Low grade (< 10 mits/10 hpf) • Perivascular Epithelioid Cell Tumor – High grade (>10 mits/10 hpf) •Undifferentiated Uterine Sarcoma 1

K.L.Chang et al. AJSP 1990; 14: 415-438 •Endometrial Stromal Nodule 93/109 (85%) patients had follow-up information •Endometrial Stromal Sarcoma (“low grade”) –73/85 stage I with followup •Undifferentiated Uterine Sarcoma –36% of stage I relapsed (23% DOD) –Mitotic rate does not predict recurrence in stage I patients Endometrial Stromal Sarcoma Endometrial Stromal Sarcoma Clinical Features Most patients < 50 years old Dysfunctional uterine bleeding/enlargement Variable size (polypoid, bulky) Indolent, protracted course 2

Finger-like myometrial permeation Lymphovascular invasion – “worm-like” Resembles proliferative phase stroma 3

Foam cells Hyaline bands Fibrous Variant Fibrous Variant 4

Myxoid Variant Smooth Muscle Smooth Muscle Sex-cord differentiation 5

Glandular Variant Epithelial Endometrial Stromal Sarcoma Desmin Staining in Endometrial Stromal Neoplasms CD 10 Desmin Dot-like and perinuclear staining pattern 6

CD 10 Pitfall! Desmin and h-Caldesmon Staining in Positive in Leiomyosarcoma Endometrial Stromal Tumors CD 10 Desmin h-Caldesmon Differential Diagnosis of Endometrial Stromal Sarcoma � Endometrial Stromal Nodule • Highly Cellular Leiomyoma • Intravascular Leiomyomatosis 7

Well defined border Differential Diagnosis of Endometrial Stromal Sarcoma Endometrial stromal nodules and endometrial stromal tumors with limited • Endometrial Stromal Nodule infiltration: A clinicopathologic analysis of 50 cases. � Highly Cellular Leiomyoma Am J Surg Pathol 2002;26:567-581 • Intravascular Leiomyomatosis • 3 cases, 4-6 irregularities extending up to 9 mm • No F/U in two including those with greatest infiltration 8

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Highly Cellular Leiomyoma h-Caldesmon CD 10 10

Differential Diagnosis of Highly Cellular Leiomyoma Endometrial Stromal Sarcoma Distinguish from Stromal Neoplasia by : • Endometrial Stromal Nodule Fascicular architecture Large thick-walled vessels • Highly Cellular Leiomyoma Cleft-like spaces � Intravascular Leiomyomatosis “Merging” of cells at periphery Biomarkers (h-caldesmon, desmin) Intravenous Leiomyomatosis Intravenous Leiomyomatosis 11

Intravenous Leiomyomatosis 12

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Intravenous Leiomyomatosis Distinguish from Stromal Neoplasia by : Fascicular architecture Large thick-walled vessels Cleft-like spaces Hydropic change Multilobulated contours Biomarkers (h-caldesmon, desmin) – t(7;17) (most common) • JAZF1-SUZ12 JAZF1 break-apart – 6p21 rearrangements • t(6;7 ) PHF1-JAZF1 How Molecular Genetics Helped • t(6;10 ) EPC1-PHF1 “Re-Define” High Grade ESS • t(1;6) MEAF6-PHF1 PHF1 – der22t(X;22) ZC3H7-BCOR break-apart – t(X;17)(p11.2;q21.33) MBTD1-CXorf67 – t(10:17)(q22;p13) YWHAE-FAM22A/B – Some cases lack demonstrable genetic rearrangements JAZF1-PHF1 fusion 14

Clinical Features • Age at presentation: 28 to 67 years (median 50) The clinicopathologic features of YWHAE-FAM22 endometrial stromal • Presenting symptom: Abnormal vaginal bleeding (menorrhagia or peri/post-menopausal bleeding) sarcomas – a histologically high- grade and clinically aggressive tumor Am J Surg Pathol 2012; 36:641-53 15

High grade Endometrial Stromal Sarcoma High grade Endometrial Stromal Sarcoma 16

LG-ESS (JAZF1-SUZ12) HG-ESS (YWHAE-FAM22) Spindle cell area (more fascicular fibrous) Spindle cell area (fibromyxoid) CD 10 h- CD 17

BWH07B CD10 Gene expression profiles of uterine sarcoma 3’ end sequencing gene expression profile analysis on FFPE tumor tissues Ut LMS JAZF1 YWHAE (PLoS One. 2010: ER PR 536 genes 19;5:e8768) YWHAE-rearranged ESS displays a global gene expression profile that is distinct from JAZF1-rearranged ESS and high grade uterine leiomyosarcoma (Ut LMS). Proposed classification of uterine sarcoma • YWHAE-FAM22 ESS is a more rapidly Pleomorphic Non-pleomorphic progressive disease compared to JAZF1- UES (≈LMS) HG ESS LG ESS rearranged ESS • YWHAE-FAM22 ESS displays higher grade YWHAE- JAZF1-SUZ12 (but non-pleomorphic) histologic features, Complex FAM22A/B JAZF1-PHF1 karyotype (other EPC1-PHF1 compared to JAZF1-rearranged ESS (Other aberrations ) aberrations) • YWHAE-FAM22 ESS can show a mixture of high grade epithelioid/round cell component ER/PR/CD10- ER/PR/CD10+ (ER/PR/CD10-) and low grade spindle cell ↑ Nuclear size/Irregularity in nuclear contour High mitotic activity ↑ Mito�c ac�vity component (ER/PR/CD10+) Tumor necrosis Tumor necrosis Poor prognosis Intermediate prognosis Good prognosis 18

Cyclin D1 positive (> 75%) Cyclin D1 as a diagnostic in histologically high grade component immunomarker for endometrial stromal sarcoma with YWHAE- FAM22 rearrangement Am J Surg Pathol, 2012; 36: 1562-70 Uterine mesenchymal tumor Monomorphic Pleomorphic tumor * tumor LG spindle cell Biphasic HG round cell (fibrous/ • UES-P fibromyxoid) Cyclin D1 • LMS Undifferentiated Uterine CD10 IHC • LM (bizarre nuclei) • others** Sarcoma (UUS) Diffuse cyclin Non-diffuse Molecular D1 & negative cyclin D1 and/or study CD10 in round diffuse CD10 in cell area round cell area Positive Negative • UES-U • JAZF1 -ESS YWHAE-FAM22 • non-rearranged classic ESS LGESS or fibrous variant • others † 19

Undifferentiated Endometrial Sarcoma Histologic Features of Undifferentiated Endometrial Sarcoma (UES) (UES) • Heterogeneous group of sarcomas lacking diagnostic criteria for: Uniform – ESS* type – LMS – Adenosarcoma with sarcomatous overgrowth – Carcinosarcoma/poorly differentiated carcinoma • Some consider UES as 2 groups (Kurihara et al): – UES-uniform Pleomorphic type – UES-pleomorphic 20

UUS is a diagnosis of exclusion! • More sections often more helpful than large immunoperoxidase panel • Sampling of intracavitary component/uninvolved endometrium may show features diagnostic of adenosarcoma, carcinosarcoma • EMA, Cam5.2, reticulin useful for identifying as carcinoma 21

The PEComa Family • Angiomyolipoma • Clear cell sugar tumor of lung Perivascular Epithelioid Cell • Lymphangioleiomyomatosis (LAM) • Clear cell myelomelanocytic tumor of the Tumor (PEComa) falciform ligament/ligamentum teres • Abdominopelvic sarcoma of perivascular epithelioid cells • Primary extrapulmonary sugar tumor Association with Perivascular Epithelioid Cell Neoplasm (PEComa) of the Tuberous Sclerosis Complex Gynecologic Tract: Clinicopathologic and Immunohistochemical Characterization of 16 Cases • Renal AML, hepatic AML and pulmonary Schoolmeester JK, Howitt BE, Hirsch MS, Dal Cin P, Quade BJ, LAM commonly associated with TSC Nucci MR Am J Surg Pathol. 2014 Feb;38(2):176-88. • Other types of PEComa (including uterine PEComa) are rarely associated with TSC 22

Finger-like Permeation Spindled Nested, epithelioid 23

Radial Arrangement Arborizing Vasculature Foamy Cytoplasm Granular cytoplasm 24

Large nucleoli Large nucleoli Wreath-like Giant Cells Intranuclear pseudo-inclusions 25

Hyalinized Stroma PEComa Immunohistochemistry • PEComa characterized by co-expression of melanocytic (HMB45, Melan A, micropthalmia transcription factor) and muscle markers (smooth muscle actin, calponin, desmin) • Can express S100 but usually focal May be positive for TFE3 and harbor TFE3 • gene fusions (AJSP 2010; 34:1395-1406) Questions to address PEComa Immunohistochemistry • HMB 45 16/16 (100%) How do you separate PEComa from LMS? • Melan A 14/16 (88%) • MiTF 11/12 (92%) Why is it difficult to make this distinction? • Desmin 15/15 (100%) • SMA 14/15 (93%) Why is distinction of PEComa from LMS important? • h-caldesmon 11/12 (92%) • TFE3 5/13 (38%) 26

PEComa • Combination of epithelioid and spindled areas (varying proportions) How do you separate PEComa • Distinctive cytoplasmic appearance from Leiomyosarcoma? – Granular and pale • Other characteristic morphologic findings – Lipidized cells, “spider-like” cells, melanoma-like wreath-like giant cells and macronucleoli, hyalinized stroma (“sclerosing PEComa-like”), arborizing vasculature • Co-expression of melanocytic and muscle markers PEComa LMS Why is it difficult to make this distinction? 27