Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms

Abstract

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:-an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.

Uterine mesenchymal tumours: recent advances

“…In our study, S100 highlighted <10% of cells in all tumours that were negative for CD34 and SOX10 and retained H3K27me3 expression . In another study, all tumours expressed CD34 and S100, the latter often diffusely . Most tumours express cyclin D1 in ≥80% of cells (Figure ), but BCOR staining is absent or present in <5% of cells.…”

“…Fibrosarcoma‐like uterine sarcomas can harbour COL1A1–PDGFB fusions, the same alteration seen in virtually all dermatofibrosarcoma protuberans (Figure ) . Disease distribution is similar to NTRK fusion‐positive sarcomas, but tumours affect postmenopausal women .…”

“…NTRK fusion‐positive uterine sarcomas can express focal SMA, but are negative for desmin, ER and PR . Reported CD34 and S100 staining patterns are conflicting.…”

“…[16][17][18] PDGFB encodes a growth factor that binds and activates PDGF receptor tyrosine kinases important in regulating embryonic development, cell proliferation, cell migration, survival and chemotaxis. 19 NTRK rearrangements are oncogenic events in a wide variety of human cancers, 17,[20][21][22][23][24] including common and rare tumour types such as infantile fibrosarcomas, 20 lipofibromatosis-like neural tumours 20 and fibrosarcoma-like uterine sarcomas. 22,24 TPM3-NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA-NTRK1, TPR-NTRK1, RBPMS-NTRK3 and EML4-NTRK3 fusions are rare 22,24 (Figure 3).…”

“…19 NTRK rearrangements are oncogenic events in a wide variety of human cancers, 17,[20][21][22][23][24] including common and rare tumour types such as infantile fibrosarcomas, 20 lipofibromatosis-like neural tumours 20 and fibrosarcoma-like uterine sarcomas. 22,24 TPM3-NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA-NTRK1, TPR-NTRK1, RBPMS-NTRK3 and EML4-NTRK3 fusions are rare 22,24 (Figure 3). NTRK break-points vary, but the full-length coding sequence of the tyrosine kinase domain remains unaltered, with fusion leading to increased expression of the kinase domain.…”