PATHOLOGY CONSULTANTS UNIVERSITY MEDICAL CENTER

Patient:                             Pathology No:
Med. Rec. No.:
Sex:                   Age:                       Date of Birth:
Account No.:
Date of Procedure:              Date Received:

Physician(s):

 
SPECIMEN SUBMITTED: 16 SLIDES (30 UNSTAINED SLIDES ADDED) 

DIAGNOSIS: UTERUS, CERVIX AND BILATERAL FALLOPIAN TUBES, HYSTERECTOMY

• CERVIX: No significant abnormality.


• ENDOMETRIUM: Inactive endometrium with exogenous progestin effect.


• MYOMETRIUM: Low-grade epitheliod neoplasm with myomelanocytic differentiation, of uncertain malignant potential (8.1 cm) (see comment) FISH negative for TFE3 gene rearrangement


• SEROSA: No significant abnormality.


• FALLOPIAN TUBES, BILATERAL: No significant abnormality.

COMMENT: 

Thank you for sending this challenging case for consultation to our Gynecologic Pathology Consult Service. Microscopic examination of the myometrial mass demonstrates well-demarcated variably cellular lesion composed ofepithelioid cells with granular to clear cytoplasm, imparting a foamy appearance, set in a variably sclerotic background. The lesional cells have mild to moderate cytologic atypia with irregular nuclear contours and small distinct nucleoli.  There are no mitotic figures seen in 50 high-power fields. tumor cells necrosis is absent; however, lymphovascular invasion is identified. 

Immunohistochemical stains performed at our institution on unstained slides provided from block AS demonstrate the tumor cells expressing HMB-45 (strong; patchy), cathepsin-k (strong; diffuse), MiTF (strong; diffuse), desmin (moderate; patchy) and caldesmon (moderate; patchy), with no expression of Melan-A, CDIO, inhibin or SF-I, PTEN expression is retained (normal). 

We note the lack of gene mutations identified by MSK-IMPACT Solid Sequencing analysis (M21-43426), particularly involving TSCJ/TSC2 or other mTOR pathway genes, and lack of fusions via targeted RNA Archer analysis (M21-46452), most notably TFE3, which have been implicated in the two major genetic alterations driving the pathogenesis of PEComas  (see references). Fluorescence in situ hybridization for TFE3 gene rearrangement performed at UMC is negative, lending no support for an underlying TFE3 gene fusion.  

This is a challenging case. Overall, this is a morphologically low-grade epithelioid neoplasm with abundant clear to granular cytoplasm demonstrating evidence of both smooth muscle (desmin, caldesmon) and melanocytic (HMB-45, MITF, CathepsinK) differentiation via immunohistochemistty. Diagnostic consideration was given to epithelioid leiomyoma given the histomorphologic features and smooth muscle marker expression; however, the presence of lymphovascular invasion precludes this diagnosis, and the observed melanocytic immunopositivity is more consistent with the diagnosis of PEComa The lack of either mitotic activity or significant atypia argues against the diagnosis of leiomyosarcoma. Despite the lack of overt molecular evidence for mTOR pathway alterations, we favor this tumor to represent a perivascular epithelioid cell tumor (PEComa) given the combined morphologic and immunophenotypic features. Within the PEComa category, the WHO and various groups have proposed that having greater than two of the following features may portend an aggressive clinical course: size >5 cm, infiltrative growth pattern, high-grade nuclear atypia, high cellularity, mitoses> 1 per 50 HPF, necrosis or lymphovascular invasion (see references). Of these features, the current tumor meets only two criteria (size> 5 cm and lymphovascular invasion), and in our opinion, is consistent with a PEComa of uncertain malignant potential and does not meet criteria for “malignant PEComa”. We acknowledge the lack of supportive molecular alterations in this particular case, however, not all PEComas harbor these specific gene mutations, alterations, or fusions (see references) and their absence does not preclude this diagnosis. Clinical correlation and close follow-up is recommended. 

REFERENCES:

Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW. Perivascular epithelioid cell neoplasms ofsoft tissue and gynecologic origin: a clinicopathologic study of26 cases and review of the literature. Arn J Surg Pathol. 2005 Dec;29(12):1558-75. 

Schoolrneester JK, Howitt BE, Hirsch MS, Dal Cin P, Quade BJ, Nucci MR. Perivascular epithelioid cell neoplasm (PEComa) ofthe gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases. Arn J Surg Pathol. 2014 Feb;38(2):176-88. 

Bennett JA, Oliva E. Perivascular epithelioid cell tumors (PEComa) of the gynecologic tract. Genes Chromosomes Cancer. 2021 Mar;60(3):168-179. 

Bennett JA, Braga AC, Pinto A, Van de Vijver K, Cornejo K, Pesci A, Zhang L, Morales-Oyarvide V, Kiyokawa T, Zam1oni OF, Carlson J, Slavik T, Tornos C, Antonescu CR, Oliva E. Uterine PEComas: A M01phologic, Immunohistochemical, and Molecular Analysis of 32 Tumors. Arn J Surg Pathol. 2018 Oct;42(10): 1370-1383. 

Selenica P, Conlon N, Gonzalez C, Frosina D, Jungbluth AA, Beets-Tan ROH, Rao MK, Zhang Y, Benayed R, Ladanyi M, Solit DB, Chiang S, Hyman DM, Hensley ML, Soslow RA, Weigelt B, Murali R. Genomic Profiling Aids Classification ofDiagnostically Challenging Uterine Mesenchymal Tumors with Myomelanocytic Differentiation. Am J Surg Pathol. 2021 Jan;45(1):77-92. 

FISH DESCRIPTION:

Interphase fluorescence in situ hybridization (FISH*) was performed with the TFE3 separation probe (Empire Genornics) which identifies rearrangement of the TFE3 gene on the X sex chromosome. Analysis of200 nuclei was negative for clonal separation of 5' and 3' TFE3 signals. This result is interpreted as negative for TFE3 gene rearrangement within the referred tissue section. TFE3 gene rearrangement with the ASPSCRI gene is observed in alveolar soft part sarcoma and a subset of renal cell carcinoma. TFE3 gene rearrangement is also observed in rare angiomyolipomas and a subset of renal cell carcinoma. TFE3 gene rearrangement is also observed in rare angiomyolipomas.  

*Note: This test was developed and its performance characteristics determined by the University Hospital and Clinics Cytogenetics Laboratory. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessaty, this test is used for clinical diagnostic purposes. It should not be regarded as investigational or for research. This laboratory is certified under the Clinical Laboratmy Improvement Amendments of 1988 (CLIA-88) as qualified to perform high complexity clinical laboratory testing. 

CLINICAL HISTORY:

XX-year-old female with presented with enlarged fibroid uterus, status post elective surgical management with hysterectomy and bilateral salpingectomy.  

MATERIALS:

Sixteen stained slides and thirty unstained slides were received for consultation courtesy of Dr. XX of and Dr. XX of. 

I have reviewed the specimen and agree with the interpretation above

M.D. Electronically signed 

DATE: