Translational Windows in Chordoma: A Target Appraisal

Figures

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  Figure 1. (A) Conventional chordoma showing classic histologic features of large, epithelioid tumor cells with eosinophilic cytoplasm containing multiple vacuoles arranged in nests and cords in an overall lobular growth pattern. Tumor cells are reliably positive for (B) keratins and (C) EMA. S100 staining may be seen in select cases but is not ubiquitous (not shown). (D) Nuclear positivity for brachyury is highly specific and observed in the vast majority of cases. (E) Physaliphorous cells (arrows) display abundant, “bubbly” cytoplasm with small, round nuclei on higher magnification. Large and small cells can be seen in the background of blue, myxoid stroma.

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  Figure 2. (A) Chondroid chordoma characteristically contains regions forming hyaline cartilage with tumor cells distributed individually in lacunar spaces that greatly resemble (B) low-grade chondrosarcoma, which classically feature hypercellular hyaline cartilage lobules with a permeative growth pattern. Chondrosarcomas of the skull base in particular have variably prominent myxoid areas (arrow) that resemble chondroid chordoma. (C) Brachyury nuclear positivity confirms the diagnosis of chordoma, while being (D) consistently negative in chondrosarcoma.

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  Figure 3. (A) Dedifferentiated chordoma contains regions of high-grade sarcoma, frequently juxtaposed with regions of conventional chordoma (B). (C) Brachyury positivity is often negative in the dedifferentiated component (arrow). (D) Poorly differentiated chordoma exhibits higher cellularity than conventional chordoma and occasionally shows rhabdoid morphology. (E) Brachyury is reliably positive, and (F) SMARCB1 (INI-1) loss in tumor cells is characteristic of this entity.

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  Figure 4. Immune checkpoint pathways implicated in chordoma pathogenesis and survival. (A) Interferon-gamma released from natural killer (NK) cells and helper CD4+ T (Th1) cells was found to upregulate programmed death ligand (PD-L1) expression in chordomas. (B) PD-L1 binds the programmed cell death protein 1 (PD-1) on cytotoxic T cells, inducing T cell anergy. (C) Chordomas also induce immunosuppression via the Gal9 immune-checkpoint protein binding to TIM3 on cytotoxic T cells.

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  Figure 5. Growth factor signaling pathways implicated in chordoma pathogenesis. The PI3K/AKT and the RAS pathways lie downstream of EGFR, PDGFR, and IGF-1R and have been implicated in cancer promotion and progression. Upregulation of PI3K/AKT was associated with high brachyury expression in chordomas and may also regulate tuberous sclerosis comorbidity with chordomas. IGF-1R is a novel target whose activation was associated with poorer prognosis and increased tumor volume in chordomas.