Pediatric Acral Melanoma With a Novel ARL6IP1 – PRKCB Fusion

Melanocytic neoplasms harboring PRKC fusions are a recently described subset of melanocytic tumors that tend to arise in younger patients and often demonstrate a biphasic appearance with abundant associated pigmentation 1. Recent studies have characterized clinical, histologic, and molecular findings of these tumors, with the majority being classified as intermediate-grade lesions that occur most commonly on non-acral sites 2. We present the first reported case of a PRKC fusion-driven acral melanoma with a novel fusion partner in a pediatric patient. A 13-year-old male presented with a longstanding longitudinal dark streak of the right middle fingernail, first noted in 2021. By late 2023, the lesion had enlarged with increasing discomfort, nail deformity, and purulent drainage (Figure 1). Empiric antibiotic therapy was ineffective. On examination, an 8 × 8 mm soft tissue mass was noted along the dorsal fingertip, extending proximally beneath the nail plate. Histologic evaluation revealed an ulcerated, polypoid proliferation composed of markedly atypical melanocytes with brisk mitotic activity (8/mm2), extensive pagetoid spread, and deep dermal infiltration. The lesional cells contained enlarged, hyperchromatic nuclei with irregular nuclear contours and variably prominent nucleoli. They showed an epithelioid cytomorphology with many cells imparting a rhabdoid-like morphology (Figure 2). The lesion as a whole was poorly circumscribed and showed aggressive invasion essentially effacing the sampled dermis. A SOX10 immunostain was positive in the lesional melanocytes which were negative for PRAME but showed complete loss of p16. Next-generation DNA and RNA sequencing identified a novel gene fusion between exon 1 of ARL6IP1 and exon 6 of PRKCB (Figure 3), along with a high tumor mutational burden (8.09 variants/megabase). A high tumor mutational burden was defined as greater than 7.3 variants per megabase in the sequencing laboratory. The out-of-frame fusion retains a kinase domain within PRKCB, suggesting potential biological activity. No other pathogenic mutations were identified, including in TERT promoter or other important genes such as BAP1, SF3B1, and EIF1AX. The mechanism of p16 loss was not due to homozygous deletion, though further classification was beyond the abilities of the assay. Overall, we felt the constellation of clinical histologic and molecular findings was most in keeping with a diagnosis of invasive melanoma. A high-grade melanocytoma was also a diagnostic consideration, particularly due to the lack of other molecular alterations, but we felt the histologic appearance of the tumor (pleomorphism, abundant mitotic activity, size) was more indicative of melanoma. Melanocytic tumors harboring PRKC fusions comprise a rare and recently described subset of melanocytic lesions that typically arises in pediatric and young adult patients 1. These tumors often mimic blue nevi, pigmented epithelioid melanocytomas (PEMs), or Spitz nevi, though their morphologic range is broad and varied, including tumors that closely resemble conventional melanoma 1, 3. The majority of these tumors tend to be heavily pigmented with a biphasic appearance, though these features were not appreciated in this unique case. In the fifth edition of the WHO Classification of Skin Tumors, melanocytic neoplasms with PRKCA fusions are included within the blue nevus group, unless a co-occurring PRKAR1A mutation is present 4. This update reflects emerging molecular data indicating that, although these tumors were previously grouped with PRKAR1A-inactivated PEMs, they likely engage a different signaling pathway. PRKAR1A functions within the protein kinase A (PKA) pathway downstream of Gαs-coupled receptors, whereas PRKCA fusions are thought to activate protein kinase C (PKC), a downstream effector of the Gαq signaling cascade involving GNAQ, GNA11, two genes that encode the alpha subunits of the Gq and G11 heterotrimeric G proteins. The signaling profile of PRKCA-fusion tumors more closely resembles that of blue nevi and related neoplasms 1, supporting a classification model that accounts for convergence on shared pathways rather than solely the initiating genetic event. While PRKC fusions are rare in melanoma, some cases have shown aggressive behavior, including metastasis and death 1. Similar to blue nevus–like melanoma, PRKC fusion–positive melanomas may show BAP1 loss, which has been associated with worse outcomes 1. The co-occurrence of GNAQ or GNA11 mutations with BAP1 or SF3B1 alterations helps distinguish aggressive blue nevus–like melanomas from their benign counterparts 4. In our case, no BAP1 or SF3B1 mutation or deletion was detected. Due to the patient's age and aggressive appearance of the tumor, comprehensive molecular profiling proved to be very valuable in identifying this rare and unique fusion. While recent studies have characterized 14 different PRKC fusion partners, an ARL6IP1 fusion has not previously been reported. The involvement of certain signaling pathways in PRKC fusion-driven tumors further underscores the importance of precise molecular analysis in diagnostically challenging melanocytic lesions. The patient underwent partial digit amputation (final Breslow depth: 5.0 mm) and sentinel lymph node biopsy, which revealed metastatic melanoma in one lymph node (Figure 4). He was staged as pT4b N1a (Stage IIIC). Given the high-risk features—including deep invasion, nodal involvement, and elevated mutational burden—he was enrolled in an immunotherapy trial and at the time of the manuscript has shown no recurrence or progression of disease. This case expands the molecular landscape of PRKC fusion-driven melanocytic neoplasms by introducing a novel ARL6IP1–PRKCB variant. It highlights the utility of molecular characterization in pediatric melanoma for guiding diagnosis, prognostication, and therapeutic decision-making. Further investigation is warranted to clarify the clinical behavior of PRKC fusion-positive melanomas and their responsiveness to immune checkpoint inhibitors. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The report was prepared in accordance with the ethical standards of the University of Colorado Anschutz Medical Campus Institutional Review Board. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.