Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts

Abstract

Ubiquitin-specific peptidase 6 (USP6) is a hominoid-specific gene residing on chromosome 17p13 and serves as a deubiquitinating enzyme with a diverse set of functions including intracellular trafficking, inflammatory signaling, cell transformation and protein turnover. USP6 rearrangements were first identified in aneurysmal bone cysts, resulting in promoter swapping and over-expression of wild type USP6. Several morphologically overlapping fibroblastic/myofibroblastic tumors are known to harbor USP6 rearrangements, including nodular fasciitis, cellular fibroma of tendon sheath, myositis ossificans and fibro-osseous pseudotumor of digits. Over the past few years, fusions involving the USP6 gene and various partner genes have been described in these neoplasms. The current World Health Organization Classification of Tumors of Soft Tissue suggests that USP6-rearranged lesions are typically benign and usually self-limited in their growth. This review provides an updated overview of the clinical, histological and molecular genetic features of USP6-associated fibroblastic/myofibroblastic tumors and discusses how these lesions should be best classified.

Keywords: Nodular fasciitis; USP6; fibro-osseous pseudotumor of digits; fibroma of tendon sheath; myositis ossificans; review.

Figure 1. Histological and immunohistochemical features of nodular fasciitis. A: Nodular fasciitis consists of plump spindle-shaped cells with a vague fascicular and storiform pattern. Extravasated erythrocytes and lymphocytes can be observed (hematoxylin and eosin staining, original magnification ×100). B: The neoplastic cells are diffusely positive for smooth muscle actin (original magnification ×200).

Figure 2. Histological and immunohistochemical features of classical and cellular variants of fibroma of tendon sheath. A: Classical fibroma of tendon sheath consists of bland spindle cells in a dense collagenous stroma. Slit-like vessels can be seen (hematoxylin and eosin staining, original magnification ×100). B: Cellular fibroma of tendon sheath contains areas of increased cellularity composed of spindled-to-stellae cells arranged in a vague fascicular pattern (hematoxylin and eosin staining, original magnification ×100). C: The tumor cells are positive for smooth muscle actin (original magnification ×100).

Figure 3. Radiographical and histological features of myositis ossificans. A: Lateral radiograph shows a densely mineralized mass in the posterior aspect of the distal thigh. B: Myositis ossificans shows a distinct zonal pattern with a central spindle cell proliferation surrounded by a peripheral bone formation. Skeletal muscle is entrapped (hematoxylin and eosin staining, original magnification ×20). C: Myositis ossificans is composed of (myo)fibroblasts and foci of osteoid formation (hematoxylin and eosin staining, original magnification ×100).

Figure 4. Histological features of fibro-osseous pseudotumor of digits. A: Fibro-osseous pseudotumor of digits involves the subcutaneous tissue. Mature bone is present at the periphery of the lesion (hematoxylin and eosin staining, original magnification ×20). B: Fibro-osseous pseudotumor of digits shows a (myo)fibroblastic proliferation and mature woven bone formation (hematoxylin and eosin staining, original magnification ×100). C: The central portion is composed of (myo)fibroblasts with a storiform pattern, resembling nodular fasciitis (hematoxylin and eosin staining, original magnification ×200).