Gynecologic Evening Specialty Conference - USCAP Conference (EC)/EC08-15... · Lee, Cheng‐Han; MD, PhD; Marino‐Enriquez, Adrian; Ou, Wenbin ... • Tan‐yellow cut surface •

Gynecologic Evening Specialty Conference

Karuna Garg, MDUniversity of California San Francisco

Disclosure of Relevant Financial Relationships

The USCAP 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 USCAP office and has been reviewed by the CME Advisory Committee.

Dr. Karuna Garg declares he/she has no conflict(s) of interest to disclose.

Case

• 54 year old female• Abdominal pain• Cholecystectomy• Surgeon noted ascites and ovarian masses

Ovary

Ovary

Ovary

OvaryOvary

CD117

Case

• Gastrointestinal stromal tumor?

DOG‐1

CD10

MIB‐1

Cyclin‐D1

Endometrial biopsy

Case

• Additional stains:Negative for ER/PR, smooth muscle markers, epithelial markers, FOXL‐2, WT1

Case

• Patient underwent hysterectomy

Hysterectomy

CD10

Cyclin‐D1

Case

• High grade endometrial stromal sarcoma

Outline

• Changes in classification of endometrial stromal neoplasms

• Rationale• High grade endometrial stromal sarcoma• Diagnosis and differential diagnosis

Endometrial stromal tumors

Endometrial stromal nodule

Low grade ESS High grade ESS

Evolution in classification of endometrial stromal tumors




2003 WHO classification


Low grade ESSUndifferentiated endometrial sarcoma






Low grade ESS

Undifferentiated endometrial sarcoma


Low grade ESS High grade ESS Undifferentiated uterine sarcoma




Endometrial stromal tumors: 2014 WHO classification

1. Endometrial stromal nodule2. Low grade endometrial stromal sarcoma3. High grade endometrial stromal sarcoma4. Undifferentiated uterine sarcoma

Low‐grade ESS<10 mitoses per 10 hpf

High‐grade ESS≥10 mitoses per 10 hpf

5 year survival 55%10 year survival 100%

Other features evaluated but not found to be prognostic:‐ Cellular atypia: More in high grade but overlap‐ Necrosis

Norris and Taylor, Cancer 1966

Stromal neoplasms (“composed of cells identical to or closely resembling endometrial stroma”)


Evolution in classification of endometrial stromal tumors: Rationale

Problems with high‐grade ESS:• Definition of high grade ESS not followed (no

resemblance with endometrial stroma)• Range of tumors including leiomyosarcoma, MMMT,

undifferentiated sarcoma• Mitotic count alone not significant



‐ Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma are distinct

‐ Mitotic activity in a typical ESS has no prognostic significance

Evans, HL. Cancer 1982


• 117 cases• Included cases “composed exclusively of uniform cells with scant cytoplasm that resembled the cells of proliferative‐phase endometrial stroma” (although cells could have grade 1‐3 atypia)

• Stage most important prognostic factor• On univariate analysis: Mitotic index and cytologicatypia not predictive of clinical outcome in stage 1 patients

Chang KL, et al. Am J Surg Pathol 1990


FIG. 2. Endometrial sarcoma with cellular atypism. The cytologic features illustrated here represent the most severe degree of atypia (Grade 3) we accept within the endometrial stromal sarcoma category. The nuclei are slightly enlarged, and the nuclear membranes are somewhat irregular; but the cells are mostly uniform, and the chromatin is still delicate. Sarcomas composed of cells with greater pleomorphism and nuclear anaplasia are placed in the undif‐ferentiated sarcoma group.


Stage I

Stage III/IV

High grade ESS


“Increasing cytologic atypiaassociated with increase in relapse rate”






Low grade ESS




2003 WHO classification:1. Endometrial stromal nodule2. Low‐grade endometrial stromal sarcoma3. Undifferentiated endometrial sarcoma


Problems with 2003 WHO classification:• Undifferentiated endometrial sarcoma heterogeneous category

• Tumors with intermediate features or high grade ESS like features (grade 2‐3 atypia)

• Tumors with components of high grade and low grade ESS


LG‐ESS UES‐U UES‐P

Aberrant p53 0 0 50%

ER + ‐/+ ‐

JAZF1 fusion 6/12 (50%) 1/3 (33%) 0/3 (0%)

Dead of disease 0/13 (0%) 4/7 (57%) 3/5 (60%)

Kurihara S, et al. Am J Surg Pathol 2008

1. Low grade ESS2. Undifferentiated endometrial sarcoma with uniform nuclei (UES‐U)3. Undifferentiated endometrial sarcoma with pleomorphic nuclei (UES‐P)


© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

The Clinicopathologic Features of YWHAE‐FAM22 Endometrial Stromal Sarcomas: A Histologically High‐grade and Clinically Aggressive Tumor.Lee, Cheng‐Han; MD, PhD; Marino‐Enriquez, Adrian; Ou, Wenbin; Zhu, Meijun; Ali, Rola; Chiang, Sarah; Amant, Frederic; Gilks, C; van de Rijn, Matt; MD, PhD; Oliva, Esther; Debiec‐Rychter, Maria; Dal Cin, Paola; Fletcher, Jonathan; Nucci, Marisa

American Journal of Surgical Pathology. 36(5):641‐653, May 2012.DOI: 10.1097/PAS.0b013e31824a7b1a

FIGURE 7 . Proposed classification for pure uterine sarcomas.

Stage III/IV

High grade ESS


“Increasing cytologic atypiaassociated with increase in relapse rate”






Low grade ESS




Low grade ESS High grade ESS Undifferentiated uterine sarcoma



• 2014 WHO classification:1. Endometrial stromal nodule2. Low grade endometrial stromal sarcoma3. High grade endometrial stromal sarcoma4. Undifferentiated uterine sarcoma

High grade endometrial stromal sarcoma

WHO definition:“A malignant tumor of endometrial stromal derivation with high‐grade, round‐cell morphology sometimes associated with a low‐grade spindle cell component that is mostly fibromyxoid.” (ESS with YWHAE rearrangement)

“Rarely a high grade sarcoma is seen with areas that have the appearance of a conventional low‐grade ESS and can also be diagnosed as high‐grade ESS.” (but also included in undifferentiated uterine sarcoma)

YWHAE‐FAM22 rearranged ESS

• YWHAE‐NUTM2• t(10;17)(q22;p13)• 28‐67 years (mean 50 yrs)• Abnormal vaginal bleeding• Pelvic mass• Extra‐uterine disease at presentation

Lee CH, et al. Am J Surg Pathol 2012


Gross features:• Exophytic polypoid or intramural mass• Tan‐yellow cut surface• Hemorrhage and necrosis• Often deep myometrial invasion• Extra‐uterine disease


‐ Tongue‐like myometrial invasion‐ Rich capillary network‐ Vascular invasion‐ No pleomorphism

Unlike low‐grade ESS: Higher grade nuclei, mitoses and necrosis

YWHAE‐FAM22 rearranged ESSRound‐cell component: ‐ Cellular‐ Nested with a rich capillary network‐ Round epithelioid cells with scant to moderate clear to pink cytoplasm‐ Large nuclei with irregular contours and inconspicuous nucleoli‐ Brisk mitoses‐ Necrosis‐ Can have pseudoglandular, pseudopapillary or sex‐cord like areasSpindle‐cell component: ‐ Resembles fibromyxoid low‐grade ESS‐ Low cellularity‐ Bland spindle cells in a fibromyxoid matrix‐ Low mitotic activity‐ No necrosis

• May be composed of one or both components (abruptly juxtaposed)

Round‐cell component Spindle‐cell component

Round‐cell component

Spindle‐cell component

Spindle‐cell component Round‐cell component



Round cell component:‐ CD10 negative ‐ ER/PR negative/focal‐ Cyclin‐D1: Positive‐ C‐kit: Positive‐ MIB‐1: 20‐30%

Spindle cell component:‐ CD10 positive‐ ER/PR positive‐ Cyclin‐D1: weak/patchy‐ C‐kit: weak/patchy‐ MIB‐1: Low

CD10 in spindle cell component CD10 in round cell component

Cyclin‐D1 in spindle cell component Cyclin‐D1 in round cell component

Strong nuclear staining in >70% of tumor cells

© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Cyclin D1 as a Diagnostic Immunomarker for Endometrial Stromal Sarcoma With YWHAE‐FAM22 Rearrangement.Lee, Cheng‐Han; MD, PhD; Ali, Rola; Rouzbahman, Marjan; Marino‐Enriquez, Adrian; Zhu, Meijun; Guo, Xiangqian; Brunner, Alayne; Chiang, Sarah; Leung, Samuel; Nelnyk, Nataliya; Huntsman, David; Blake Gilks, C; Nielsen, Torsten; MD, PhD; Cin, Paola; van de Rijn, Matt; MD, PhD; Oliva, Esther; Fletcher, Jonathan; Nucci, Marisa

American Journal of Surgical Pathology. 36(10):1562‐1570, October 2012.DOI: 10.1097/PAS.0b013e31825fa931

YWHAE‐FAM22 rearranged ESS: Cyclin‐D1

YWHAE ESS = Cyclin‐D1 +/ CD10‐

‐Sensitive‐Not specific for the presence of YWHAE rearrangement

CD117: Cytoplasmic and membranous staining in round cell component

YWHAE‐FAM22 rearranged ESS: c‐kit

• Moderate to strong cytoplasmic and membranous staining for c‐kit in round‐cell component

• Fibromyxoid/spindle component negative or patchy cytoplasmic staining

• No c‐kit mutations detected• DOG‐1 negative

Lee CH, et al. Mod Pathol 2014


Molecular analysis:• FISH• RT‐PCR

• Specific rearrangement• Not seen in multiple adult tumors including smooth muscle tumors, adenosarcoma, carcinosarcoma and undifferentiated uterine sarcoma

• Also seen in clear cell sarcoma of the kidney• YWHAE and JAZF1 rearrangements mutually exclusive


Clinical outcome• Patients frequently present at high stages• Clinically aggressive‐ 2/10 dead of disease (2 years)‐ 7/10 alive with disease (1‐10 years)‐ 1/10 No evidence of disease (3.75 years)



Therapeutic implications:‐Limited data suggests that adjuvant chemotherapy and radiation may provide survival benefit‐No response to hormonal therapy

Differential diagnosis

1. Low‐grade endometrial stromal sarcoma2. Undifferentiated endometrial sarcoma3. Smooth muscle tumors4. Gastrointestinal stromal tumor (GIST)5. Ewing sarcoma


Morphology:

Nuclei Small, smooth contours Large, irregular contours

Mitotic activity Usually <5 mitoses per 10 hpf High

Tumor necrosis Absent Frequently present

Immunophenotype:

CD10, ER, PR Positive Negative/focal

Mib‐1 Low High

CD117 Focal/patchy Can be positive

Cyclin‐D1 Focal/patchy Can be positive

Molecular genetics:

JAZF1/SUZ12/PHF1/EPC1 rearrangements

YWHAE‐FAM22 rearrangement

Low‐grade versus high‐grade ESS

Low‐grade versus high‐grade ESS

• Prognostic and therapeutic implications• Can be problematic

Low‐grade ESS

Low‐grade versus high‐grade ESS?

Low‐grade versus high‐grade ESS?

ER Mib‐1

CD10 Cyclin‐D1

Undifferentiated uterine sarcoma

• No resemblance to endometrial stroma• Lacks specific differentiation• Nuclear pleomorphism and anaplasia• Immunophenotypic overlap• Tp53mutations (Aberrant p53 staining may favor undifferentiated sarcoma)

• Complex chromosomal changes• Very poor prognosis

Undifferentiated carcinoma

• Morphologic overlap• Presence of hyperplasia or low grade endometrioid adenocarcinoma

• Presence of lymph node metastasis?• Immunohistochemistry of limited use‐ Focal but strong staining for epithelial markers‐ Cyclin‐D1 probably not helpful‐ MMR proteins

EMA

Gastrointestinal stromal tumor (GIST)

‐ Problematic differential in extra‐uterine sites such as ovary

‐ Morphologic overlap‐ Immunophenotypic overlap



DOG‐1

CD117 Cyclin‐D1 DOG‐1

High grade ESS

+/‐ +/‐ ‐

GIST + +/‐ +

Panel should include c‐kit, cyclin‐D1 and DOG‐1

High‐grade ESS versus GIST

High‐grade ESS

Back to our case…..

Case

• Tumor sent to Mayo Clinic for FISH‐ No rearrangement of the JAZF1, PHF1 or YWHAE genes identified

‐ Diagnosis?‐ High grade ESS (permeative myometrialinvasion, resemblance to endometrial stroma and nuclear uniformity)

What other tumor types belong to high‐grade ESS?

1. YWHAE rearranged ESS2. De‐differentiated ESS3. Other uniform high grade sarcomas that lack YWHAE rearrangements

High grade ESS

De‐differentiated ESS: ‐ Low grade ESS and high grade sarcoma ‐ Heterologous differentiation ‐ Cyclin‐D1 negative‐ At presentation or in recurrence

De‐differentiated ESS

‐ Classification?‐WHO 2014: Included in both high grade ESS and undifferentiated uterine sarcoma‐ Clinical outcome? More aggressive?

High grade ESS

• Other uniform high grade sarcomas that lack YWHAE rearrangements?

‐ Further studies‐ Better delineation

High grade ESS

Round cells and/or spindle cells

ER/PR ‐/focal+CD10 ‐Cyclin‐D1 +

YWHAE rearranged ESS

Low grade ESS and high grade sarcoma

ER/PR ‐/focal+CD10 ‐Cyclin‐D1 ‐

De‐differentiated ESS

Uniform cells non‐specific morphology

ER/PR ‐/focal+CD10 ‐/+Cyclin‐D1 ‐/+

High grade ESS, NOS

Conclusions• High grade ESS re‐introduced in 2014 WHO classification of

endometrial stromal tumors• Some (but not all) have YWHAE rearrangements

• Further work:‐ Refinement of tumor types belonging to category of high‐

grade ESS (expansion of WHO definition?)‐ Clinical and therapeutic implications of a diagnosis of high

grade ESS? ‐ Do different subtypes have significant clinical differences?‐ Low grade ESS with increased mitoses and/or tumor

necrosis?

Thank you

References1. Norris HJ, Taylor HB. Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors. Cancer. Jun 1966;19(6):755‐766.2. Chang KL, Crabtree GS, Lim‐Tan SK, Kempson RL, Hendrickson MR. Primary uterine endometrial stromal neoplasms. A clinicopathologic study of 117 cases. The American journal of surgical pathology. May 1990;14(5):415‐438.3. Kurihara S, Oda Y, Ohishi Y, et al. Endometrial stromal sarcomas and related high‐grade sarcomas: immunohistochemical and molecular genetic study of 31 cases. The American journal of surgical pathology. Aug 2008;32(8):1228‐1238.4. Lee CH, OuWB, Marino‐Enriquez A, et al. 14‐3‐3 fusion oncogenes in high‐grade endometrial stromal sarcoma. Proceedings of the National Academy of Sciences of the United States of America. Jan 17 2012;109(3):929‐934.5. Sciallis AP, Bedroske PP, Schoolmeester JK, et al. High‐grade endometrial stromal sarcomas: a clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features. The American journal of surgical pathology. Sep 2014;38(9):1161‐1172.6. Lee CH, Marino‐Enriquez A, OuW, et al. The clinicopathologic features of YWHAE‐FAM22 endometrial stromal sarcomas: a histologically high‐grade and clinically aggressive tumor. The American journal of surgical pathology. May 2012;36(5):641‐653.7. Lee CH, Ali RH, Rouzbahman M, et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE‐FAM22 rearrangement. The American journal of surgical pathology. Oct 2012;36(10):1562‐1570.

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Documents

Gynecologic Evening Specialty Conference - USCAP Conference (EC)/EC08-15... · Lee, Cheng‐Han; MD, PhD; Marino‐Enriquez, Adrian; Ou, Wenbin ... • Tan‐yellow cut surface •