Clear Cell Tumor With Melanocytic Differentiation and ACTIN-MITF Translocation

Abstract

Clear cell morphology is an uncommon finding in tumors. A subset of clear cell neoplasms also shows melanocytic differentiation, including clear cell sarcoma, PEComa, and some subtypes of renal cell carcinoma. A hallmark of these tumor types is the activation of a member of the MIT/TFE family of transcription factors, which includes MITF, TFE3, TFEB, and TFEC. Microphthalmia transcription factor (MITF is the master regulator of melanin synthesis, while TFEB plays a critical role in lysosome biogenesis. Cytogenetic translocations involving TFE3 and TFEB are now well described in multiple tumor types, but there has been little evidence to suggest similar regulation of MITF. Here we describe a series of 7 clear cell cutaneous neoplasms with melanocytic differentiation that are characterized by ACTIN-MITF gene fusions, either ACTB-MITF or ACTG1-MITF. The chromosomal breakpoints preserve MITF’s dimerization and transcriptional activation domains, suggesting that these fusion proteins likely result in hyperactive MITF function, analogously to the previously reported TFE3 and TFEB fusions. Our findings indicate that MITF gene rearrangements may be key drivers of tumor pathogenesis and expand the spectrum of neoplasia associated with the MIT/TFE family.

The WHO 2018 Classification of Cutaneous Melanocytic Neoplasms: Suggestions From Routine Practice

“…Based on these data, PEM and atypical Spitz tumor might represent melanocytic tumors of low-grade (mostly lymphotropic) malignancy different from "classical" melanoma: it seems thus reasonable to include atypical Spitz tumor into the "melanocytoma" rubric, as suggested since the beginning (49). Interestingly enough, the list of putative low-grade melanocytic malignancies with a peculiar genetic and morphologic profile has been growing for the last years and has thus been increasingly supporting the concept itself (50)(51)(52)(53). An example of CRTC1-TRIM11 (50) fused melanocytoma is provided in Figure 2; like several other melanocytomas, such a putatively low-grade malignant melanocytic tumor does not likely progress from a common nevus.…”

Recent advances in the diagnosis, classification and molecular pathogenesis of cutaneous mesenchymal neoplasms

“…Expression of the ACTIN::MITF fusion protein is probably driven by the highly expressed promoter of the ACTB or ACTG1 N‐terminal fusion partner, analogous to the mechanism of ACTB :: FOSB fusions in pseudomyogenic haemangioendothelioma and ACTB :: GLI1 fusions in pericytoma and other mesenchymal tumours with GLI1 fusions 113–115 . This fusion protein contains the dimerisation and transcriptional activation domains of MITF , accounting for the melanocytic differentiation of these tumours 104 . The ACTG1 :: MITF fusion has also been reported in a renal cell carcinoma; this fusion protein was shown to be more stable than wild‐type MITF in in‐vitro studies 116 .…”

“…There are emerging classes of dermal clear cell neoplasms with MITF gene fusions that, like clear cell sarcoma and cutaneous PEComa, show melanocytic differentiation and lack epidermal origin. Clear cell neoplasms with melanocytic differentiation and ACTB :: MITF and ACTG1 :: MITF fusions (collectively, ‘ ACTIN :: MITF fusions’) are the better‐characterised of this emerging group, with a recently published index series of seven tumours 104 . All seven reported clear cell neoplasms with ACTIN :: MITF fusions occurred in female patients, with six occurring in the extremities and one occurring in the breast.…”

“…S100 protein expression is variable but was strongly and diffusely positive in approximately half of cases in the initial series, arguing against classifying these tumours as a PEComa subtype. Clinical follow‐up data were available for two patients in this series, who did not develop recurrence or metastasis 7 and 17 years after resection of the primary tumours 104 …”

Cutaneous Melanocytic Tumor with CRTC1::TRIM11 Fusion: Review of the Literature of a Potentially Novel Entity

“…Clear cell tumor with melanocytic differentiation and MITF rearrangements: Recently, de la Fouchardiere et al [ 39 ] reported seven cases of an intradermal tumor with clear cell features and expression of melanocytic markers, harboring the ACTIN ( ACTG1 or ACTB ) ::MITF fusion. Similar to CMTCT, as well as to CSS, the neoplasm presented as a dermal nodule, occasionally involving the subcutis, in patients of all ages.…”