USP6 gene rearrangements occur preferentially in giant cell reparative granulomas of the hands and feet but not in gnathic location

Abstract

Giant cell reparative granulomas (GCRGs) are lytic lesions that occur predominantly in the gnathic bones and occasionally in the small bones of the hands and feet. They are morphologically indistinguishable from, and are regarded as synonymous with, solid variant of aneurysmal bone cysts (ABC) in extragnathic sites. Identification of USP6 gene rearrangements in primary ABC has made possible investigating potential pathogenetic relationships with other morphologic mimics. USP6 gene alterations in giant cell-rich lesions (GCRG/ABC) of small bones of the hands and feet have not been previously studied. We investigated USP6 gene alterations in a group of 9 giant cell-rich lesions of the hands and feet and compared the findings with morphologically similar lesions including 8 gnathic GCRGs, 22 primary ABCs, 8 giant cell tumors of bone, and 2 brown tumors of hyperparathyroidism. Overall, there were 49 samples from 48 patients including 26 females and 22 males. Of the 9 lesions of the hands and feet, 8 (89%) showed USP6 gene rearrangements, whereas no abnormalities were identified in the 8 gnathic GCRGs, 2 brown tumors, or 8 giant cell tumors of bone. Of the 22 primary ABCs, 13 (59%) showed USP6 gene rearrangements. In conclusion, most GCRGs of the hands and feet represent true ABCs and should be classified as such. The terminology of GCRG should be limited to lesions from gnathic location. Fluorescence in situ hybridization for USP6 break-apart is a useful ancillary tool in the diagnosis of primary ABCs and distinguishing them from GCRGs and other morphologically similar lesions.

Keywords: Giant cell reparative granuloma; Solid ABC; USP6.

Figure 1

GCRG of second metacarpal bone in a 16 year-old-female (Case 1). The Anterior-Posterior (AP) radiograph (A) shows an expansile lytic lesion (arrows) with a Codman’s triangle (arrowhead) in a second metacarpal bone. (B) The MRI axial STIR image of the hand shows multiple fluid levels (arrowheads) in the expansile second metacarpal lesion mimicking an ABC. (C) The spot view of the bone scan shows intense radiotracer uptake (arrow) in the second metacarpal bone. (R – right) (D) H&E sections showing a giant cell-rich lesion (100x) which at higher power (E, 200x) reveals a mixture of bland spindle cells and osteoclast-like giant cells. (F) FISH for USP6 gene break-apart assay showing an unbalanced rearrangement (arrows) with deletion of the telomeric (green) signal. (red – centromeric signal)

Figure 2

GCRG in the 4^th proximal phalanx of a 38 year-old-male (Case 6). (A) Anterior-Posterior radiograph of the 4^th finger shows an eccentric lesion (arrow) in the proximal phalanx. (B) MRI axial STIR image shows the lesion (arrows) eroding the bone. (C) MRI axial T1-weighted image shows an enhancing lesion (arrowhead) eroding the bone. (D) H&E section (200x) reveals lesional spindle cells with admixed osteoclast-like giant cells. (E) FISH showing an USP6 split apart signal (arrows) with associated deletion of the telomeric (green) signal. (red – centromeric signal)