TY - JOUR
T1 - Genomic Profiling Aids Classification of Diagnostically Challenging Uterine Mesenchymal Tumors With Myomelanocytic Differentiation
AU - Selenica, P.
AU - Conlon, N.
AU - Gonzalez, C.
AU - Frosina, D.
AU - Jungbluth, A.A.
AU - Beets-Tan, R.G.H.
AU - Rao, M.K.
AU - Zhang, Y.M.
AU - Benayed, R.
AU - Ladanyi, M.
AU - Solit, D.B.
AU - Chiang, S.
AU - Hyman, D.M.
AU - Hensley, M.L.
AU - Soslow, R.A.
AU - Weigelt, B.
AU - Murali, R.
N1 - Funding Information:
Conflicts of Interest and Source of Funding: Supported in part through the NIH-NCI Cancer Center Support Grant P30 CA008748. B.W. is funded in part by Cycle for Survival, Stand Up To Cancer, and Breast Cancer Research Foundation grants. D.M.H. is currently a salaried employee of Loxo Oncology Inc. For the remaining authors none were declared.
Funding Information:
Conflicts of Interest and Source of Funding: Supported in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. B.W. is funded in part by Cycle for Survival, Stand Up To Cancer, and Breast Cancer Research Foundation grants. D.M.H. is currently a salaried employee of Loxo Oncology Inc. For the remaining authors none were declared.
Publisher Copyright:
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Although diagnosis of high-grade uterine mesenchymal tumors (UMTs) exhibiting classic morphologic features is straightforward, diagnosis is more challenging in tumors in which prototypical features are poorly developed, focal, and/or coexist with features seen in other neoplasms. Here, we sought to define the repertoire of somatic genetic alterations in diagnostically challenging UMTs with myomelanocytic differentiation, including some reported as perivascular epithelioid cell tumors (PEComas). In 17 samples from 15 women, the tumors were histologically heterogenous. Immunohistochemical expression of at least 1 melanocytic marker (HMB45, Melan-A, or MiTF) was identified in all tumors, and of myogenic markers (desmin or smooth muscle actin) in most tumors. Targeted massively parallel sequencing revealed several genetic alterations, most commonly in TP53 (41% mutation, 12% deletion), TSC2 (29% mutation, 6% deletion), RB1 (18% deletion), ATRX (24% mutation), MED12 (12% mutation), BRCA2 (12% deletion), CDKN2A (6% deletion) as well as FGFR3, NTRK1, and ERBB3 amplification (each 6%). Gene rearrangements (JAZF1-SUZ12; DNAJB6-PLAG1; and SFPQ-TFE3) were identified in 3 tumors. Integrating histopathologic, immunohistochemical, and genetic findings, tumors from 4 patients were consistent with malignant PEComa (1 TFE3-rearranged); 6 were classified as leiomyosarcomas; 3 showed overlapping features of PEComa and other sarcoma types (leiomyosarcoma or low-grade endometrial stromal sarcoma); and 2 were classified as sarcoma, not otherwise specified. Our findings suggest that diagnostically challenging UMTs with myomelanocytic differentiation represent a heterogenous group of neoplasms which harbor a diverse repertoire of somatic genetic alterations; these genetic alterations can aid classification.
AB - Although diagnosis of high-grade uterine mesenchymal tumors (UMTs) exhibiting classic morphologic features is straightforward, diagnosis is more challenging in tumors in which prototypical features are poorly developed, focal, and/or coexist with features seen in other neoplasms. Here, we sought to define the repertoire of somatic genetic alterations in diagnostically challenging UMTs with myomelanocytic differentiation, including some reported as perivascular epithelioid cell tumors (PEComas). In 17 samples from 15 women, the tumors were histologically heterogenous. Immunohistochemical expression of at least 1 melanocytic marker (HMB45, Melan-A, or MiTF) was identified in all tumors, and of myogenic markers (desmin or smooth muscle actin) in most tumors. Targeted massively parallel sequencing revealed several genetic alterations, most commonly in TP53 (41% mutation, 12% deletion), TSC2 (29% mutation, 6% deletion), RB1 (18% deletion), ATRX (24% mutation), MED12 (12% mutation), BRCA2 (12% deletion), CDKN2A (6% deletion) as well as FGFR3, NTRK1, and ERBB3 amplification (each 6%). Gene rearrangements (JAZF1-SUZ12; DNAJB6-PLAG1; and SFPQ-TFE3) were identified in 3 tumors. Integrating histopathologic, immunohistochemical, and genetic findings, tumors from 4 patients were consistent with malignant PEComa (1 TFE3-rearranged); 6 were classified as leiomyosarcomas; 3 showed overlapping features of PEComa and other sarcoma types (leiomyosarcoma or low-grade endometrial stromal sarcoma); and 2 were classified as sarcoma, not otherwise specified. Our findings suggest that diagnostically challenging UMTs with myomelanocytic differentiation represent a heterogenous group of neoplasms which harbor a diverse repertoire of somatic genetic alterations; these genetic alterations can aid classification.
KW - allelic loss
KW - cell neoplasm pecoma
KW - endometrial stromal sarcomas
KW - expression
KW - genetics
KW - leiomyoma
KW - leiomyosarcoma
KW - melanocytic differentiation
KW - mutations
KW - myomelanocytic differentiation
KW - pathology
KW - pecoma
KW - perivascular epithelioid cell tumor
KW - practical issues
KW - smooth-muscle tumors
KW - somatic mutations
KW - tsc2 gene
KW - uterus
KW - TSC2 GENE
KW - CELL NEOPLASM PECOMA
KW - LEIOMYOSARCOMA
KW - MUTATIONS
KW - PEComa
KW - ENDOMETRIAL STROMAL SARCOMAS
KW - LEIOMYOMA
KW - PRACTICAL ISSUES
KW - SMOOTH-MUSCLE TUMORS
KW - ALLELIC LOSS
KW - EXPRESSION
U2 - 10.1097/PAS.0000000000001572
DO - 10.1097/PAS.0000000000001572
M3 - Article
C2 - 32889887
SN - 0147-5185
VL - 45
SP - 77
EP - 92
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
IS - 1
ER -