Osteosarcomas with H3F3A mutation a clinicopathological and molecular genetic study of 7 cases with review of the literature.

Some studies have suggested that osteosarcomas with H3F3A mutations (OS-H3F3A‌) may represent a subtype of primary malignant giant cell tumor of bone (GCTB). Previous research has been limited in case number, highlighting the need for further investigation. In this study, we present seven cases of OS-H3F3A and review an additional 24 documented cases in the literature. Among 189 osteosarcoma cases, we identified seven (3.7%) with H3F3A mutations by surrogate immunohistochemistry and next-generation sequencing (NGS), including six (85.7%) with p.G35W and one (14.3%) with a p.G35R mutation. The cohort consisted of four males and three females with a mean age of 43 years (range: 20-66). The primary sites included the distal femur (n = 5), proximal tibia (n = 1) and sacrum (n = 1). Pain was the main clinical manifestation, lasting an average of 8.3 months (range: 1-48 months). Microscopically, tumors were classified into three types: spindle cell (n = 3; low-grade), epithelioid cell (n = 3; high-grade), and pleomorphic cell (n = 1; high-grade). A complete loss of H3K27me3 expression was observed in 3 of 6 cases, with concurrent mutant overexpression of p53 in 1 case. Clinical follow-up data were available for all patients over a mean period of 44 months (range: 5-110 months). At the last follow-up, one patient died from the disease, one was alive with the disease, and five were alive without evidence of the disease. Our findings support the hypothesis that OS-H3F3A may a distinct subtype of primary malignant GCTB. OS-H3F3A showed significant heterogeneity in morphological features and clinical behavior. We recommend routine screening for these tumors.