Cutaneous Hemangioma With Epithelioid Features Harboring TPM3/4::ALK Fusions : A Distinct Entity or a Molecular Variant of Epithelioid Hemangioma?

Abstract

Vascular neoplasms with epithelioid cytomorphology encompass a wide spectrum of benign and malignant lesions, including epithelioid hemangioma (EH), cutaneous epithelioid angiomatous nodule (CEAN), epithelioid hemangioendothelioma (EHE), and epithelioid angiosarcoma (EAS). Recently, the first case of a cutaneous hemangioma with epithelioid features harboring a TPM3::ALK fusion was reported. Herein, we report 4 additional cases, including 1 case with an alternate TPM4::ALK fusion, and expand on the clinicopathologic and molecular genetic features of these unusual vascular lesions. Including the previously reported case, 5 tumors occurred in 4 male and 1 female patients with a median age of 14 years (range: 2 to 38 y) and involved the shoulder region (2), the lower extremity (1), trunk (1), and head and neck (1). Clinical follow-up (3 patients; 60%) showed no evidence of disease at the last follow-up (median: 5 mo; range: 1 to 16 mo). Histologically, all tumors showed highly similar morphologic features, including an epidermal collarette, well-formed vascular channels composed of epithelioid endothelial cells with intracytoplasmic vacuoles, and admixed inflammatory cells. Immunohistochemically, all tumors were positive for vascular markers such as ERG and CD31, along with strong and diffuse cytoplasmic expression of ALK. RNA sequencing revealed recurrent TPM3 exon 8 :: ALK exon 20 (4) and TPM4 exon 7 :: ALK exon 20 fusions (1). We conclude that cutaneous hemangiomas with epithelioid features harboring TPM3/4::ALK fusions show consistent morphologic, immunophenotypic, and molecular genetic features. It remains to be determined whether this neoplasm represents a distinct entity or a molecular variant of epithelioid hemangioma.

Keywords: ALK; TPM3; TPM4; cutaneous hemangioma; epithelioid hemangioma.

Figure 1:. Histopathologic findings of case 2

(A) Low power examination reveals a dermal cellular proliferation surrounded by an epidermal collarette. (B) Intermediate power shows abundant vascular channels lined by epithelioid endothelial cells within a background of inflammatory cells. (C) Peripherally, ectatic vessels are noted. The endothelial cells expressed CD31 (D), ERG (E) and ALK (F).

Figure 2:. Histopathologic findings of case 3

(A) On low power examination, there is a well-circumscribed lesion composed of a densely cellular proliferation of cells surrounded by an epidermal collarette. (B) This proliferation shows a vaguely storiform proliferation of epithelioid endothelial cells forming vascular channels with (C) admixed lymphocyte-predominant inflammation at the periphery in addition to ectatic vessels similar to those seen in the prior example. (D) ERG and (ALK) are strongly positive.

Figure 3:. Histopathologic findings of case 4

(A) This case presents as an exophytic, multinodular lesion. (B-C) Similar to prior cases, the proliferation shows vascular channels lined by epithelioid endothelial cells and admixed clusters of lymphocytes. (D) Rare mitotic figures are noticeable. (E) This case also showed scattered eosinophils. (F) The ALK stain shows strong, cytoplasmic staining.

Figure 4:. Histopathologic findings of case 5

(A) This case shows an irritated lesion comprised of a cellular and infiltrative proliferation of epithelioid cells with less conspicuous vascular lumina. (B) Abundant red cell extravasation, scattered mixed inflammatory cells and focal hemosiderin deposition are noted as well as occasional intracytoplasmic vacuoles (C). (D) There is strong and diffuse cytoplasmic ALK expression.

Figure 5:. Molecular findings of cases 2 and 5

A, Detection of TPM3::ALK fusion. Representative image of targeted RNA sequencing using custom 168 gene panel showing the in-frame fusion event between TPM3 (Exon 8) at the 5’ end with ALK (Exon 20) at the 3’ end. The fusion event passed the quality control filters (212 unique RNA reads supporting the fusion (cutoff >10) and 56 unique RNA start site reads (cutoff >5). Red dots represent breakpoints; red arrow delineates the position of the primer generating the fusion read. B) Integrated genome viewer showing the different reads and their corresponding directions (red and blue) spanning the breakpoints of the fusion event along with the BED contigs annotations showing a very robust mapping to TPM3 at the 5’ and ALK at the 3’ end. (C) Representative image of targeted RNA sequencing shows an in-frame fusion event between TPM4 (Exon 7) at the 5’ end with ALK (Exon 20) at the 3’ end.