Rapidly enlarging <i>ACTIN::MITF</i> rearranged clear cell tumour with melanocytic differentiation

Sir: MITF pathway-driven cutaneous mesenchymal neoplasms with melanocytic differentiation encompass three newly characterised tumour entities, distinguished by ACTIN::MITF, CRTC1::TRIM11 and MITF::CREM gene fusions. To date, eight cases of ACTIN::MITF rearranged clear cell tumours with melanocytic differentiation have been documented, seven of which were reported in a 2021 case series by Fouchardiere et al.1, 2 Clinically, these tumours have shown a strong female predominance (eight of eight cases) with a median age of 40 years (range = 15–75), primarily affecting extremities (seven of eight cases), presenting as relatively small lesions (mean size = 1.8 cm, ranging from 1.2 to 3.3 cm), without significant skin ulceration. They exhibit mild nuclear atypia, low mitotic activity (0–1/10 high-power fields (HPFs) and no recurrence in three cases with available follow-up (7–17 years) (1-2). Herein, we report a case of ACTIN::MITF rearranged clear cell tumour with melanocytic differentiation that demonstrates unique clinicopathological features. A 53-year-old male with a complex medical history initially presented with a 4-cm polypoid mass on the medial aspect of the left lower extremity, characterised by irregular borders and no skin disruption. After 13 months, he returned with a rapidly enlarging mass (> 10 cm) exhibiting marked ulceration and sanguineous discharge. Computerised tomography (CT) imaging revealed a 12.9 × 8.8 × 4.6-cm heterogenous exophytic subcutaneous mass with a feeding artery, early draining veins, mixed internal attenuation and no involvement of the deep peripheral fascia (Figure 1C–E). Additionally, CT of the chest demonstrated no evidence of metastatic disease. A core biopsy and subsequent resected specimen revealed an infiltrative tumour involving dermis and focally subcutis and composed of loose nests, sheets and fascicles of spindled to ovoid cells with vesicular nuclei, prominent nucleoli and abundant palely eosinophilic to focally clear cytoplasm with numerous small-sized interspersed blood vessels. A subset of tumour cells with significant cytological atypia and increased mitotic activity with up to three mitoses per 10 high-power fields (HPF) were noted (Figure 2A–D). Skin ulceration with prominent granulation tissue, acute and chronic inflammation, abscess formation and haemosiderin deposition were noted. Immunohistochemistry showed that the tumour cells were diffusely positive for MITF, focally positive for HMB45 and desmin, and negative for S100, SOX10, SMA, CD34, cytokeratin AE1/AE3, Melan-A, cathepsin K, CAM5.2, caldesmon, EMA, and PRAME (Figure 2E–H). Comprehensive oncomine NGS testing did not reveal any mutations or copy number alterations. Whole transcriptomic sequencing (RNAseq) identified an ACTG1::MITF gene fusion between exon 3 of ACTG1 (chr17:79478928, NM_001199954.1) and exon 3 of MITF (chr3:69986972, NM_000248.3), resulting in an in-frame fusion product that preserves the dimerisation and transcriptional activation domains of MITF (Figure 3). The immediate postoperative period was uneventful, and the patient received adjuvant brachytherapy due to the tumour's aggressive clinical features. Unfortunately, no long-term follow-up data are available, given the short interval since resection. Our case shares several clinical, morphological and immunophenotypical characteristics with previously described cases, including extremity predilection, dermal-based lesion, spindle-to-epithelioid morphology and expression of melanocytic markers. However, novel findings include large tumour size with rapid growth, marked surface ulceration, cytological atypia and increased mitotic activity. Additionally, while prior cases involved only female patients, our present case is a male, with ACTG1::MITF fusion showing chromosomal breakpoints similar to two of seven previously reported cases. The striking morphological and immunophenotypic resemblance to PEComa raises the question of whether these entities represent distinct diagnoses or if ACTIN::MITF rearranged clear cell tumours may, in fact, constitute a variant of PEComa. Fouchardiere et al.2 noted S100 expression as characteristic of this new entity; however, our case lacked S100, similar to most PEComas. Additionally, John Hanna et al.3 reported MITF expression in a PEComa series, with one case showing ACTG1::MITF fusion. However, cathepsin K expression, typically seen in PEComas, was absent in our case.4 If classified according to the proposed criteria for PEComas, this tumour would be categorised as malignant.5 Further studies are essential to clarify its relationship with PEComa or lack thereof. Current data, although limited, suggest an indolent course for ACTIN::MITF rearranged clear cell tumour, with reported cases being small and lacking surface ulceration. However, the unusual features in our case, including large tumour size, surface ulceration, significant cytological atypia and increased mitotic activity, introduce uncertainty regarding its biological behaviour. Additional studies are needed to more clearly understand the prognostic significance of various clinicopathological features, which may ultimately impact disease progression and patient outcomes. No funding was received for this study by any author. No competing interest for any author. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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