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

Abstract

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.