Fibroma-Like PEComa as an Early Indicator of Tuberous Sclerosis Complex: Confirmed With Strong GPNMB Expression and TSC2 Germline Mutation

Abstract

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms defined by co-expression of melanocytic and smooth muscle markers, with fibroma-like PEComa representing a novel and recently described subtype strongly associated with tuberous sclerosis complex (TSC). This article reports the eighth documented example of fibroma-like PEComa, occurring in the subcutaneous wrist tissue of a 6-year-old girl with no prior clinical or family history of TSC. Histopathological examination revealed a hypocellular to moderately cellular proliferation of bland oval, spindle to stellate cells within dense collagenous stroma, accompanied by focal myxoid change and scattered mature adipose tissue. Immunohistochemically, the tumor exhibited diffuse strong glycoprotein nonmetastatic melanoma protein B (GPNMB) expression and focal positivity for HMB45, melan-A, and desmin. DNA-based target next-generation sequencing identified a germline TSC2 nonsense mutation (c.268C > T, p.Q90*) with a variant allele frequency of 83%, confirmed via peripheral blood testing, leading to a definitive diagnosis of TSC. A review of all 8 reported tumors confirms that fibroma-like PEComa occurs predominantly in children and young adults, shows a female predilection (5:3), and favors extremity locations. These tumors typically demonstrate benign behavior with no recurrences or metastases reported. Our report highlights that fibroma-like PEComa can serve as an early indicator of occult TSC and underscores the diagnostic utility of GPNMB immunohistochemistry as a surrogate marker of TSC1/2/MTOR pathway activation. Comprehensive clinical and genetic evaluation for TSC is recommended upon diagnosis of this rare tumor.