Multiple desmoplastic Spitz nevi with BRAF fusions in a patient with ring chromosome 7 syndrome

Abstract

Patients with non-supernumerary ring chromosome 7 syndrome have an increased incidence of hemangiomas, café-au-lait spots, and melanocytic nevi. The mechanism for the increased incidence of these benign neoplasms is unknown. We present the case of a 22-year-old man with ring chromosome 7 and multiple melanocytic nevi. Two nevi, one on the right ear and the other on the right knee, were biopsied and diagnosed as desmoplastic Spitz nevi. Upon targeted next-generation DNA sequencing, both harbored BRAF fusions. Copy number alterations and fluorescence in situ hybridization (FISH) for BRAF suggested that the fusions arose on the ring chromosome 7. Hence, one reason for increased numbers of nevi in patients with non-supernumerary ring chromosome 7 syndrome may be increased likelihood of BRAF fusions, due to the instability of the ring chromosome.

Keywords: BRAF fusion; BRAF gene; Spitz nevus; Spitz tumor; melanocytic nevi; melanocytic nevus; ring chromosome 7; ring chromosome seven; spitzoid.

Figure 1.

Histopathology of the Spitz nevus from the knee showing a predominantly dermal distribution of melanocytes, with nests and fascicles of melanocytes extending into the reticular dermis with a wedge-shaped profile. (1A,C: H&E) Large epithelioid melanocytes with abundant cytoplasm and prominent nucleoli are observed. The melanocytes demonstrated strong mosaic expression of p16 by immunohistochemistry with less expression in the deeper aspects of the nevus (a gradient pattern of expression) (1B,D).

Figure 2.

Molecular characterization of the two Spitz nevi. (A) Copy number profiles derived by next-generation DNA sequencing. In both tumors, there is loss of the identical distal portions of chromosome 7, reflecting the genomic material lost from the ring chromosome 7. Both tumors demonstrate amplified regions consistent with amplification of the BRAF fusion. (B) FISH with break-apart probes for the BRAF region showed two closely paired red and green signals in keratinocytes and several loosely paired signals in neoplastic melanocytes from the Spitz nevus on the ear. (C) The illustration shows the BRAF and TMEM106B loci, which are far apart on the opposing arms of chromosome 7. The location targeted by the red and green FISH probes flanking the BRAF locus are shown. The top panel illustrates how a TMEM106B-BRAF fusion would lead to widely split signals. The lower panel shows closer proximity of the BRAF and TMEM106B loci in the setting of a ring chromosome 7, and how a TMEM106B-BRAF fusion would result in loosely split FISH signals as seen in the neoplastic melanocytes of our case.