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. 2025 Jun;52(6):432-441.
doi: 10.1111/cup.14801. Epub 2025 Mar 20.

Genomic and Transcriptomic Characterization of Protein Kinase C Fusion Melanocytic Neoplasms With Distinctive Hypopigmented Histomorphology: A Single-Institution Study

Aofei Li  1 , Brandon Umphress  1 , Carina Dehner  1 , Ryan Jones  2 , Keller Toral  2 , Simon Warren  1   3 , Ahmed K Alomari  1   3
Affiliations

Genomic and Transcriptomic Characterization of Protein Kinase C Fusion Melanocytic Neoplasms With Distinctive Hypopigmented Histomorphology: A Single-Institution Study

Aofei Li et al. J Cutan Pathol. 2025 Jun.

Abstract

Background: Genomic fusions involving Protein Kinase C (PKC or PRKC) have been classically identified in a subset of melanocytic neoplasms with heavy melanin pigmentation as described in older series. They were recently reclassified from the pigmented epithelioid melanocytoma (PEM) category to the blue nevus (BN) category in the fifth edition of the World Health Organization (WHO) Classification of Skin Tumors.

Methods: Herein, we report a series of eight mostly hypopigmented PRKC fusion melanocytic tumors with novel comprehensive molecular characterization. Clinical, histopathologic, and immunohistochemical findings were reviewed. Next-generation sequencing (NGS) data on genomic and transcriptomic levels were explored.

Results: Histomorphology showed a biphasic pattern with hypercellular areas and hypocellular areas with dense fibrotic stroma and collagen trapping. The clinical courses were uncomplicated after excisions. NGS revealed three cases of PRKCB fusion and five cases of PRKCA fusions. RNA differential analysis against six blue nevi showed a group of genes with significantly higher transcription levels and strong enrichment in the direct p53 effectors gene set. PRKC fusion tumors also demonstrated significantly stronger p53 IHC staining.

Conclusion: We further expand the morphologic spectrum of PRKC fusion melanocytic tumors and provide insight into their morphologic identification. Our novel transcriptome-level findings provide insight into the nuanced molecular events and new evidence for classification.

Keywords: Protein Kinase C; melanocytic neoplasm; molecular pathology.

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Conflict of interest statement

Brandon Umphress is a consultant pathologist for Tempus Labs, however, unrelated to this work. No other conflicts to disclose.

Figures

FIGURE 1
FIGURE 1
Representative histomorphology of PRKC fusion tumors (Case 2). (A) Low power view shows dermal melanocytic proliferation with biphasic hypercellular and hypocellular areas (20×, H&E). (B) High power view shows hypercellular areas with epithelioid cells and light melanin pigment (200×, H&E). (C) High power view shows hypocellular areas with spindle cells and collagen trapping (200×, H&E). (D) Schematic showing ATP2B4::PRKCA in‐frame fusion with retained kinase domain.
FIGURE 2
FIGURE 2
Representative histomorphology of PRKC fusion tumors (Case 3). (A) Low power view shows dermal melanocytic proliferation with a band‐like distribution, as well as biphasic hypercellular and hypocellular areas (20×, H&E). (B) High power view shows hypercellular areas with epithelioid cells and light melanin pigment (200×, H&E). (C) High power view shows hypocellular areas with spindle cells and collagen trapping (200x H&E). (D) Schematic showing PTPRJ::PRKCB in‐frame fusion with retained kinase domain.
FIGURE 3
FIGURE 3
Representative histomorphology of PRKC fusion tumors (Case 4). (A) Low power view shows dermal melanocytic proliferation with biphasic hypercellular and hypocellular areas (20×, H&E). (B) High power view shows hypercellular areas with epithelioid cells and minimal melanin pigment (200×, H&E). (C) High power view shows hypocellular areas with spindle cells (200×, H&E). (D) Schematic showing SLC44A1::PRKCA in‐frame fusion with retained kinase domain. (E) High power view shows diminished patchy p16 immunohistochemistry.
FIGURE 4
FIGURE 4
Unusual histomorphology and clinical findings of PRKC fusion tumors (Cases 6 and 8). (A) Case 6:lw power view shows dermal melanocytic proliferation with a band‐like distribution, as well as biphasic hypercellular and hypocellular areas (20×, H&E). (B) Case 6: high power view shows prominent smooth muscle hyperplasia and biphasic melanocytic architectural pattern, light melanin pigment (200×, H&E). (C) Case 6: desmin immunostain highlights smooth muscle hyperplasia. (D) Case 6: high power view shows hypocellular area with collagen trapping pattern. (E) Case 8: low power view shows dermal nodular melanocytic proliferation with biphasic hypercellular and hypocellular areas (20×, H&E). (F) Case 8: high power view shows heavy melanin pigment in both melanocytes and melanophages (400×, H&E). (G) Clinical findings of Case 8: 6‐cm dark brown plaque on left scalp with central nodularity.
FIGURE 5
FIGURE 5
Transcriptomic comparison of PRKC fusion tumors against blue nevi. (A) Volcano plot showing numerous statistically significant differentially expressed genes after false discovery adjustment (vertical axis indicates raw p‐value on a Log10 scale; horizontal axis indicates transcript fold change on a Log2 scale), (B) Heatmap showing top significant differentially expressed genes (adjusted p‐value < 0.05).
FIGURE 6
FIGURE 6
Comparative p53 IHC of PRKC fusion tumors against blue nevi. (A, B) Representative PRKC fusion tumors (Cases 3 and 4) show patchy nuclear p53 staining. (C, D) Representative blue nevi show diffusely negative p53 staining (uniformly enhanced digitally). (E) Boxplot showing eight PRKC fusion tumors (left) with significantly higher p53 staining scores compared against six blue nevi (right) (mean 24.8 vs. 3.2, *p < 0.0023).
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