S100 and CD34 Expressing Mesenchymal Neoplasm With Rare PLEKHH2::ALK Fusion and Response to ALK Inhibition

Abstract

The PLEKHH2::ALK fusion is a rarely reported gene fusion identified predominantly in lung adenocarcinomas. Tumors with this fusion have been reported to be of durable response to ALK inhibitors. We herein present the case of a 21-year-old woman with a histomorphologically heterogenous mesenchymal neoplasm of the pelvis, expressing both s100 and CD34, with subsequently identified PLEKHH2::ALK fusion. To our knowledge, only a single mesenchymal neoplasm with this gene fusion has been previously reported. We propose that this tumor represents one with a novel ALK fusion in the emerging family of s100 and CD34 expressing mesenchymal neoplasms with oncogenic kinase alterations akin to NTRK-rearranged mesenchymal neoplasms, rather than inflammatory myofibroblastic tumor. Importantly, this tumor demonstrated a significant response to the ALK inhibitor brigatinib.

Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion–positive soft tissue tumors

“…The tumor in case 2 showed moderate to high cellular proliferation and stromal and perivascular hyalinization, which are consistent with morphological features reported by Suurmeijer et al (15). Similar to other reported S100-and CD34-co-expressing mesenchymal tumors harboring ALK rearrangement (6,8,9,12,13), inflammatory infiltration was found in both our cases. However, case 1 even showed IMT-like morphology, suggesting IMT in the differential diagnosis, but then we discarded the hypothesis due to the absence of myogenic expression and S100 and CD34 co-expression.…”

“…Morphologically, case 1 was intermediate-grade sarcoma composed of uniform spindle cells and epithelioid cells arranged in myxedematous and hyalinized stroma, with brisk mitosis, focal necrosis, and inflammatory cell infiltration. Although most of the kinase fusion-positive STTs were defined as spindle cell tumors, epithelioid cells have been observed in some areas of S100-and CD34-co-expressing tumors harboring RAF1, BRAF, and ALK gene rearrangements (3,9,19). Myxedematous stroma has been found in some cases of ALK-rearranged STTs with S100 and CD34 co-expression (6)(7)(8)(9)(10)(11).…”

“…Although most of the kinase fusion-positive STTs were defined as spindle cell tumors, epithelioid cells have been observed in some areas of S100-and CD34-co-expressing tumors harboring RAF1, BRAF, and ALK gene rearrangements (3,9,19). Myxedematous stroma has been found in some cases of ALK-rearranged STTs with S100 and CD34 co-expression (6)(7)(8)(9)(10)(11). However, tumor cells with brisk mitosis and focal necrosis, which were the features of intermediate-to high-grade sarcoma, have rarely been reported in ALK-rearranged STTs.…”

“…According to the 2020 WHO classification of soft tissue tumors (STTs), NTRK-rearranged spindle cell tumors are an emerging entity, which spans a wide spectrum of morphologies and histologic grades, with frequent immunohistochemical coexpression of S100 and CD34. Notably, the family of this entity is expanding, as tumors with similar clinicopathological features and morphology but alternative kinase genes fusions are constantly identified; among them, STTs with ALK gene rearrangement have emerged as a recent hot spot (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…Oncogenic activation of ALK kinase following ALK rearrangement has been reported in a variety of tumors, including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), IMT, epithelioid fibrous histiocytoma (EFH) (21), ALK-positive histiocytosis (22), renal cell carcinoma (23), thyroid cancer (24), secretory carcinomas (25), and gastrointestinal stromal tumor (GIST) (26). Recently, ALK rearrangements have been reported in S100-and CD34-coexpressing soft tissue tumors (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). A provisionally termed entity, superficial ALK-rearranged myxoid spindle cell neoplasm, has been coined to emphasize the characteristic swirling pattern of spindle cells arranged in myxoid or myohyaline stroma (6).…”