Atypical cartilage in type II germ cell tumors of the mediastinum show significantly different patterns of IDH1/2 mutations from conventional chondrosarcoma.

Neoplastic cartilage is a common component of teratomas in type II germ cell tumors. Although IDH1/2 mutations have been well-described in somatic cartilaginous tumors, ranging from benign enchondromas to highly aggressive dedifferentiated chondrosarcomas, the presence of IDH1/2 mutations in cartilaginous neoplasms arising from germ cell tumors has not been previously investigated. To better understand the relationship between these tumors and their bone/soft tissue counterpart, we studied the IDH1/2 mutational status of 20 cases of primary mediastinal mixed germ cell tumors with areas of readily identifiable cartilaginous differentiation. Our study found that cartilaginous lesions arising in germ cell tumors have a different frequency and distribution of IDH1/2 mutations compared to those at somatic sites. We identified IDH1/2 mutations in only 15% (3/20) of cases, compared to a frequency in the literature among differentiated chondroid tumors of bone and soft tissue of 54%, a highly significant decreased frequency (p = 0.0011; chi-square test). Furthermore, they were exclusively IDH2 R172 mutations that occurred at a non-significant, increased frequency in the germ cell tumor group compared to conventional chondrosarcoma (15% vs. 5%, respectively, p > 0.05, chi-square test). The unexpected finding, therefore, was entirely attributable to the absence of IDH1 R132 mutation in chondroid neoplasia of germ cell origin (p < 0.00001, Fisher exact test). Our results suggest that a subset of cartilaginous lesions arising within type II germ cell tumors have a similar oncogenic mechanism to their bone/soft tissue counterpart but that the majority form using different oncogenic mechanisms compared to their somatic counterparts.