TAX1BP1::BRAF Fusion in BRAF-Mutated Atypical Spitz Tumor/Spitz Melanocytoma: A Novel Molecular Finding With Histopathological Insights

To the Editor: We are writing to report a novel molecular driver identified in 1 case of atypical Spitz tumor (AST)/Spitz melanocytoma, consisting of TAX1BP1::BRAF gene fusion. To the best of our knowledge, this is the first time such molecular alteration is identified within the spectrum of Spitz neoplasms. A 13-year-old male patient presented to our attention for a pigmented papule of 0.8 cm located on the left outer ear. The lesion had appeared 2 years ago and clinically resembled a dermal naevus. Incisional biopsy was performed. Histopathology revealed a compound, symmetric, well-circumscribed, highly cellular melanocytic proliferation made up of both epithelioid and spindle-shaped cells, without clear evidence of maturation with depth. Both architectural (large junctional nests with “raining-down” appearance, clefting) and cytological features (large cells with monotonous cytology, abundant clear or powdery cytoplasm, round nuclei with centrally placed nucleolus) were characteristic of the Spitz lineage. Moreover, the dermal component exhibited a vaguely plexiform pattern, with melanocytes embedded in a hypocellular sclerotic stroma. Kamino bodies, ulceration, necrosis, and pagetoid spreading were absent. Furthermore, a mitotic count of 2 mitosis/mmq was recorded. Figures 1A–D illustrates histopathological features of this case.FIGURE 1.: A, Histological photomicrograph showing a compound, highly cellular melanocytic proliferation organized into nested and sheet-like arrangement (H&E, ×4). B, Higher magnification showing the junctional nested component with epithelioid morphology and spindle-shaped cells (H&E, ×10). C, Higher magnification showing the sheet-like component with epithelioid spitzoid morphology. D, Histopathological details with no clear evidence of maturation in deep portion of the lesion, with scattered nuclear/nucleolar atypia. H&E, haematoxylin-eosin.Immunohistochemistry showed diffuse positivity for Melan-A and checkerboard expression of p16. BRAFV600E was negative, and HMB-45 was diffusely expressed, while anaplastic lymphoma kinase, ROS1, pan-tropomyosin receptor kinase, and preferentially expressed antigen in melanoma were negative (Figs. 2A–D). In addition, no BAP1 loss was identified, ruling out the possibility of a BAP1-inactivated tumor/melanocytoma.FIGURE 2.: Immunohistochemistry for Melan-A (A), HMB-45 (B), p16 (C), and PRAME (D). PRAME, preferentially expressed antigen in melanoma.The subsequent molecular evaluation detected the presence of TAX1BP1(exon 5)::BRAF(exon 9) fusion transcript, through ribonucleic acid-based next-generation sequencing (SureSelect XT-HS2 ribonucleic acid, Agilent); no molecular promoter hot-spot mutations in telomerase reverse transcriptase were found. Given the size (0.8 cm), the presence of high cellularity, the deep dermal extension without clear maturation, and the presence of mitotic activity, a final diagnosis of AST/Spitz melanocytoma TAX1BP1::BRAF-rearranged was rendered.1,2 The exceptionality of this case relies in the fact the TAX1BP1::BRAF fusion has never been described in AST/Spitz melanocytomas. In particular, Tax1-binding protein 1 (TAX1BP1) encodes for a ubiquitin-binding adapter that participates in inflammatory, antiviral, and innate immune processes, including downregulation of NF-kappa-B and interferon regulatory factor 3 signaling as well as selective autophagy promotion.3,4 Instead, BRAF encodes a serine/threonine kinase belonging to the mitogen-activated protein kinase/extracellular signal-regulated kinases (ERK) signaling cascade. Mutations or, more rarely, gene fusions involving BRAF are well-known drivers of melanocytic lesions. In particular, a recent paper by Roy et al reported 58 cases of melanocytic lesions with activating BRAF fusion, the majority of which was represented by Spitz neoplasms; 16 different fusion patterns were described, never involving our own.5 Furthermore, our AST/Spitz melanocytoma shows close similarities to some cases described by Sharma N et al that reported 39 BRAF-fused Spitz neoplasms, of which 37 of 38 were negative for mutation in telomerase reverse transcriptase promoter and 16 of 21 were entirely positive for p16 immunohistochemical staining.6 In particular, fusions involving BRAF typically result in the loss of its regulatory domains, thus leading to impaired kinase control and increased phosphorylation of downstream MEK1, MEK2, ERK1, and ERK2, ultimately promoting cell proliferation.7–9 To date, TAX1BP1::BRAF fusion has very rarely been reported in melanocytic lesions, being limited to 3 cases of malignant melanoma,10–12 but never in benign melanocytic proliferation and within the spectrum of Spitz neoplasms.