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Background: Chordoma is a rare tumor most commonly arising in the sacrococcygeal region from notochord remnants. Usually, these tumors are locally invasive and recurrent, and they have a 5–43% ability to metastasize. A newly-described aggressive variant called poorly differentiated chordoma is different from conventional chordoma in that it does not have the well-differentiated histologic appearance of conventional chordoma and also exhibits the loss of SMARCB1/INI1. Herein, we describe a case of poorly differentiated chordoma with SMARCB1/INI1 loss, a concurrent TP53 mutation, and Rb1 loss. Methods: The patient is a middle-aged man with a history of previously resected sacrococcygeal chordoma, who was found to have new hepatic, lung, and adrenal lesions. Results: Biopsy of the liver lesion showed sheets of malignant epithelioid cells with vacuolated cytoplasm, areas of necrosis, and up to five mitoses in one high-power field. No physaliferous cytologic features or matrix material was seen. After reviewing an extensive panel of immunohistochemical markers, the origin of the metastatic tumor could not be determined; the tumor was only positive for Cam5.2, EMA, and CD56. Brachyury was performed due to the patient’s previous history and was positive. Genomic testing showed a SMARCB1 mutation, TP53 mutation, and RB1 loss. Additional markers were performed, and the tumor showed a Ki-67 proliferation index of approximately 80%, mutant p53 protein, loss of INI1, and strong expression of both the histone methyl transferase EZH2 and the chemokine receptor CXCR4. Conclusions: Poorly differentiated chordoma is a highly aggressive variant of chordoma with few cases reported. This case of SMARCB1/INI-deficient, poorly differentiated chordoma also showed a concurrent TP53 mutation and loss of RB1, which resulted in malignant transformation with upregulation of both prometastatic CXCR4 and the histone methyltransferase EZH2, causing aggressive behavior and metastasis.

Prometastatic CXCR4 and Histone Methyltransferase EZH2 Are Upregulated in SMARCB1/INI1-Deficient and TP53-Mutated Poorly Differentiated Chordoma