Extra-Axial Poorly Differentiated Chordoma: Clinicopathologic and Molecular Genetic Characterization.

Poorly differentiated chordoma (PDC) is an aggressive subtype of chordoma characterized by SMARCB1 (INI1) loss and a dismal prognosis. It typically involves the axial skeleton, most commonly the skull base and the cervical spine. To our knowledge, only five cases of extra-axial PDC (EAPDC) have been reported, and the natural history of these tumors is not fully understood. We studied six cases of extra-axial poorly differentiated chordoma, with the goal of better understanding these exceptionally rare tumors. The tumors occurred in four women and two men, ranging from 37 to 68 years of age (median 57.5 years) and involved or originated in the left knee joint (3 cases) and right knee joint (2 cases) and right wrist (1 case). Grossly, all were solid and lobulated, with areas of necrosis. Histologically, the tumors were identical to axial poorly differentiated chordoma, with sheets and lobules of overtly malignant-appearing epithelioid-to-rhabdoid cells with prominent nucleoli. Mitotic activity and necrosis were present. By immunohistochemistry, all cases expressed keratins and brachyury and were SMARCB1-deficient. Molecular genetic analysis identified SMARCB1 loss-of-function alterations in 4 of the tested cases, including mutations (2 cases) and copy number loss (2 cases). DNA methylation profiling of 4 cases of extra-axial poorly differentiated chordoma showed clustering with axial PDC. Clinical follow-up (6 patients; median 11.5 months; range 1-26 months) showed 4 patients to have received transfemoral amputation and one extra-articular resection. None received neoadjuvant radiotherapy; one received neoadjuvant chemotherapy, one adjuvant chemotherapy/immunotherapy. Local recurrences were seen in 2 patients at 7 and 8 months; 3 patients developed metastases 7-11 months after surgery. Two patients were alive with metastatic disease (at 7 and 13 months), one dead of disease (20 months) and three disease-free (1- 26 months). We conclude that extra-axial poorly differentiated chordoma are aggressive malignancies with an unusual predilection for the knee joint and unknown pathogenesis.