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Case Report/Case Series |

Pigment-Synthesizing Melanocytic Neoplasm With Protein Kinase C Alpha (PRKCA) Fusion

Armita Bahrami, MD1; Seungjae Lee, PhD1; Gang Wu, PhD2; Justin Kerstetter, MD3; Maral Rahvar, MD3; Xinmin Li, PhD4; John Easton, PhD2; Jinghui Zhang, PhD2; Raymond L. Barnhill, MD5
[+] Author Affiliations
1Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee
2Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee
3Department of Pathology, Loma Linda University, Loma Linda, California
4Department of Pathology, University of California–Los Angeles
5Department of Pathology, Institute Curie, Paris, France
JAMA Dermatol. 2016;152(3):318-322. doi:10.1001/jamadermatol.2015.2524.
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ABSTRACT

Importance  Melanocytic neoplasms with prominent pigment synthesis mimicking equine melanoma represent a rare variant of biologically indeterminate or low-grade malignant melanocytic tumors in which the molecular profile and exact histologic classification are not established. Tumors with these characteristics rarely occur as congenital lesions. We performed genomic analysis of a congenital pigment synthesizing melanocytic neoplasm with indeterminate biological potential.

Observations  The patient was a 5-month-old girl presenting with a 6-cm protuberant scalp mass, which had doubled in size since birth. Histologic examination showed heavily pigmented intradermal proliferation of large, epithelioid melanocytes with mild cytologic atypia, low mitotic activity, focal necrosis, and ulceration. RNA sequencing identified a novel ATPase, Ca2+ transporting, plasma membrane 4(ATP2B4)protein kinase C-alpha (PRKCA) fusion transcript. The fusion resulted in an in-frame linkage of the PRKCA catalytic domain with the N-terminal of ATP2B4 and high expression of the PRKCA kinase domain. Break-apart fluorescence in situ hybridization showed PRKCA rearrangement, and reverse transcriptase–polymerase chain reaction confirmed the presence of the fusion transcript. The patient was alive and well, with no evidence of recurrence, at the 1-year follow-up.

Conclusions and Relevance  To our knowledge, this is the first report of PRKCA fusions in melanocytic neoplasms. Future studies need to determine the frequency of PRKCA fusions in pigment-synthesizing melanocytic neoplasms.

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Figure 1.
Clinical and Pathological Findings

A, Protuberant mass on the scalp of a 5-month-old girl. B, Hyperdense, heterogeneous mass in the scalp invading the underlying calvarium. C, Skin overlying the mass is partially ulcerated and covered with crust over a 2.0 × 2.0-cm2 area. D, Uniform dark-brown cut surface of the mass.

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Figure 2.
Microscopic Examination

A, Intradermal atypical melanocytic neoplasm with prominent melanosis. B, Melanin-bleached section showing large polygonal epithelioid cells in confluent nests and sheets within the deep subcutaneous tissue.

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Figure 3.
Schematic of the ATP2B4-PRKCA Fusion

RNA-seq data showing chromosomal loci for the 2 genes participating in the translocation: ATP2B4 at 1q32.1 and PRKCA at 17q22-q23.2 (top lane). Exon 20 of ATP2B4 (NM_001684) was fused to exon 9 of PRKCA (NM_002737), yielding a 1378-amino acid chimeric product containing the intact kinase domain of PRKCA (middle lane). Sequence alignment of the ATP2B4-PRKCA breakpoint region by Sanger sequencing (bottom lane).

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Figure 4.
Identification of PRKCA Fusion by Fluorescence In Situ Hybridization (FISH) and Reverse Transcriptase–Polymerase Chain Reaction (RT-PCR)

A, Break-apart FISH for PRKCA shows gene rearrangement with loss of the green signal (pink arrowhead), suggestive of an unbalanced translocation. A subset of cells (yellow arrowhead) shows 1 or 2 extra red signals. B, Gel electrophoresis of ATP2B4-PRKCA RT-PCR fusion product. Amplicon spanning the location of the fusion was observed in the tumor (245 base pairs), but not in the control reactions for which RT was omitted. The amplicon was also absent in a control tumor sample (brain) predicted to be negative for the fusion. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) primers were included as an internal positive control. The identity of the fusion was confirmed by amplicon sequencing. M indicates 1-kb ladder.

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