Gynecologic Evening Specialty Conference. Karuna Garg, MD University of California San Francisco

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1 Gynecologic Evening Specialty Conference Karuna Garg, MD University of California San Francisco

2 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.

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

4 Ovary

5 Ovary

6 Ovary

7 Ovary

8 CD117

9 Case Gastrointestinal stromal tumor?

10 DOG 1

11 CD10

12 MIB 1

13 Cyclin D1

14 Endometrial biopsy

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

16 Case Patient underwent hysterectomy

17 Hysterectomy

18

19

20 CD10

21 Cyclin D1

22 Case High grade endometrial stromal sarcoma

23 Outline Changes in classification of endometrial stromal neoplasms Rationale High grade endometrial stromal sarcoma Diagnosis and differential diagnosis

24 Evolution in classification of endometrial stromal tumors Endometrial stromal tumors Endometrial stromal nodule Low grade ESS High grade ESS

25 Evolution in classification of endometrial stromal tumors Endometrial stromal tumors Endometrial stromal nodule Low grade ESS 2003 WHO classification High grade ESS Endometrial stromal nodule Low grade ESS Undifferentiated endometrial sarcoma

26 Evolution in classification of endometrial stromal tumors Endometrial stromal tumors Endometrial stromal nodule Low grade ESS High grade ESS 2003 WHO classification Endometrial stromal nodule Low grade ESS 2014 WHO classification Undifferentiated endometrial sarcoma Endometrial stromal nodule Low grade ESS High grade ESS Undifferentiated uterine sarcoma

27 Endometrial stromal tumors: 2014 WHO classification 1. Endometrial stromal nodule 2. Low grade endometrial stromal sarcoma 3. High grade endometrial stromal sarcoma 4. Undifferentiated uterine sarcoma

28 Evolution in classification of endometrial stromal tumors: Rationale Stromal neoplasms ( composed of cells identical to or closely resembling endometrial stroma ) Endometrial stromal nodule Low grade ESS <10 mitoses per 10 hpf High grade ESS 10 mitoses per 10 hpf 10 year survival 100% 5 year survival 55% Other features evaluated but not found to be prognostic: Cellular atypia: More in high grade but overlap Necrosis Norris and Taylor, Cancer 1966

29 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

30 Evolution in classification of endometrial stromal tumors: Rationale Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma are distinct Mitotic activity in a typical ESS has no prognostic significance Evans, HL. Cancer 1982

31 Evolution in classification of endometrial stromal tumors: Rationale 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 cytologic atypia not predictive of clinical outcome in stage 1 patients Chang KL, et al. Am J Surg Pathol 1990

32 Evolution in classification of endometrial stromal tumors: Rationale 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 undifferentiated sarcoma group. Chang KL, et al. Am J Surg Pathol 1990

33 Stage I Stage III/IV Increasing cytologic atypia associated with increase in relapse rate High grade ESS Chang KL, et al. Am J Surg Pathol 1990

34 Evolution in classification of endometrial stromal tumors Endometrial stromal tumors Endometrial stromal nodule Low grade ESS High grade ESS Endometrial stromal nodule 2003 WHO classification Low grade ESS Undifferentiated endometrial sarcoma

35 Evolution in classification of endometrial stromal tumors: Rationale 2003 WHO classification: 1. Endometrial stromal nodule 2. Low grade endometrial stromal sarcoma 3. Undifferentiated endometrial sarcoma

36 Evolution in classification of endometrial stromal tumors: Rationale 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

37 Evolution in classification of endometrial stromal tumors: Rationale 1. Low grade ESS 2. Undifferentiated endometrial sarcoma with uniform nuclei (UES U) 3. Undifferentiated endometrial sarcoma with pleomorphic nuclei (UES P) LG ESS UES U UES P Aberrant p % 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

38 Evolution in classification of endometrial stromal tumors: Rationale

39 The Clinicopathologic Features of YWHAE FAM22 Endometrial Stromal Sarcomas: A Histologically Highgrade 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): , May DOI: /PAS.0b013e31824a7b1a FIGURE 7. Proposed classification for pure uterine sarcomas Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

40 Increasing cytologic atypia associated with increase in relapse rate High grade ESS Stage III/IV Chang KL, et al. Am J Surg Pathol 1990

41 Evolution in classification of endometrial stromal tumors Endometrial stromal tumors Endometrial stromal nodule Low grade ESS High grade ESS Endometrial stromal nodule 2003 WHO classification Low grade ESS Undifferentiated endometrial sarcoma 2014 WHO classification Endometrial stromal nodule Low grade ESS High grade ESS Undifferentiated uterine sarcoma

42 Evolution in classification of endometrial stromal tumors: Rationale 2014 WHO classification: 1. Endometrial stromal nodule 2. Low grade endometrial stromal sarcoma 3. High grade endometrial stromal sarcoma 4. Undifferentiated uterine sarcoma

43 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)

44 YWHAE FAM22 rearranged ESS YWHAE NUTM2 t(10;17)(q22;p13) years (mean 50 yrs) Abnormal vaginal bleeding Pelvic mass Extra uterine disease at presentation Lee CH, et al. Am J Surg Pathol 2012

45 YWHAE FAM22 rearranged ESS Gross features: Exophytic polypoid or intramural mass Tan yellow cut surface Hemorrhage and necrosis Often deep myometrial invasion Extra uterine disease

46 YWHAE FAM22 rearranged ESS Tongue like myometrial invasion Rich capillary network Vascular invasion No pleomorphism Unlike low grade ESS: Higher grade nuclei, mitoses and necrosis

47 YWHAE FAM22 rearranged ESS Round 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 areas Spindle 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)

48 Round cell component Spindle cell component

49 Spindle cell component Round cell component

50 Spindle cell component Round cell component

51 Lee CH, et al. Am J Surg Pathol 2012

52 YWHAE FAM22 rearranged ESS 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

53 CD10 in spindle cell component CD10 in round cell component

54 Cyclin D1 in spindle cell component Cyclin D1 in round cell component Strong nuclear staining in >70% of tumor cells

55 YWHAE FAM22 rearranged ESS: Cyclin D1 Sensitive Not specific for the presence of YWHAE rearrangement YWHAE ESS = Cyclin D1 +/ CD10 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): , October DOI: /PAS.0b013e31825fa Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

56 CD117: Cytoplasmic and membranous staining in round cell component

57 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

58 YWHAE FAM22 rearranged ESS 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

59 YWHAE FAM22 rearranged ESS 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) Lee CH, et al. Am J Surg Pathol 2012

60 YWHAE FAM22 rearranged ESS Therapeutic implications: Limited data suggests that adjuvant chemotherapy and radiation may provide survival benefit No response to hormonal therapy

61 Differential diagnosis 1. Low grade endometrial stromal sarcoma 2. Undifferentiated endometrial sarcoma 3. Smooth muscle tumors 4. Gastrointestinal stromal tumor (GIST) 5. Ewing sarcoma

62 Low grade versus high grade ESS Morphology: Low grade ESS High grade ESS 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

63 Low grade versus high grade ESS Prognostic and therapeutic implications Can be problematic

64 Low grade ESS

65 Low grade versus high grade ESS?

66 Low grade versus high grade ESS?

67 ER Mib 1 CD10 Cyclin D1

68 Undifferentiated uterine sarcoma No resemblance to endometrial stroma Lacks specific differentiation Nuclear pleomorphism and anaplasia Immunophenotypic overlap Tp53 mutations (Aberrant p53 staining may favor undifferentiated sarcoma) Complex chromosomal changes Very poor prognosis

69

70 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

71

72

73

74 EMA

75 Gastrointestinal stromal tumor (GIST) Problematic differential in extra uterine sites such as ovary Morphologic overlap Immunophenotypic overlap

76 Gastrointestinal stromal tumor (GIST)

77 Gastrointestinal stromal tumor (GIST)

78 DOG 1

79 High grade ESS versus GIST CD117 Cyclin D1 DOG 1 High grade +/ +/ ESS GIST + +/ + Panel should include c kit, cyclin D1 and DOG 1

80 Back to our case.. High grade ESS

81 Case Tumor sent to Mayo Clinic for FISH No rearrangement of the JAZF1, PHF1 or YWHAE genes identified Diagnosis? High grade ESS (permeative myometrial invasion, resemblance to endometrial stroma and nuclear uniformity) What other tumor types belong to high grade ESS?

82 1. YWHAE rearranged ESS 2. De differentiated ESS 3. Other uniform high grade sarcomas that lack YWHAE rearrangements

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

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

85 High grade ESS Other uniform high grade sarcomas that lack YWHAE rearrangements? Further studies Better delineation

86 High grade ESS Round cells and/or spindle cells Low grade ESS and high grade sarcoma Uniform cells nonspecific morphology ER/PR /focal+ CD10 Cyclin D1 + ER/PR /focal+ CD10 Cyclin D1 ER/PR /focal+ CD10 /+ Cyclin D1 /+ YWHAE rearranged ESS De differentiated ESS High grade ESS, NOS

87 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 highgrade 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?

88 Thank you

89 References 1. 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): 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): 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): Lee CH, Ou WB, Marino Enriquez A, et al fusion oncogenes in high grade endometrial stromal sarcoma. Proceedings of the National Academy of Sciences of the United States of America. Jan ;109(3): 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): Lee CH, Marino Enriquez A, Ou W, 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): 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):

90 Important Information Regarding CME/SAMs The Online CME/Evaluations/SAM claim process will only be available on the USCAP website until October 2, No claims can be processed after that date! After October 2, 2015 you will NOT be able to obtain any CME or SAMs credits for attending this meeting.

91 Thank You! Please go to the USCAP website to complete your Evaluation of the course and claim CME and/or SAMs Credits.

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