Loss of SMARCB1/INI1 expression in poorly differentiated chordomas

Abstract

Chordomas are malignant neoplasms that typically arise in the axial spine and primarily affect adults. When chordomas arise in pediatric patients they are more likely to display unusual histological features and aggressive behavior. We noted the absence of SMARCB1/INI1 expression by immunohistochemistry in an index case of poorly differentiated chordoma of the sacrum, leading us to further examine SMARCB1/INI1 expression as well as that of brachyury, a highly specific marker of notochordal differentiation, in 3 additional poorly differentiated chordomas of the clivus, 10 typical chordomas, and 8 atypical teratoid/rhabdoid tumors (AT/RTs). All 4 poorly differentiated chordomas and all AT/RTs lacked nuclear expression of SMARCB1/INI1, while the 10 typical chordomas maintained strong nuclear SMARCB1/INI1 immunoreactivity. All 10 typical and 4 poorly differentiated chordomas expressed brachyury; all 8 AT/RTs were brachyury immunonegative. Cytogenetic evaluation utilizing FISH probes near the SMARCB1/INI1 locus on chromosome 22q was also performed in all of the poorly differentiated chordomas in this series. Three of the four poorly differentiated chordomas had evidence for deletion of this region by FISH. Analysis of the SMARCB1/INI1 gene sequence was performed using formalin-fixed paraffin-embedded tissue in all cases and no point mutations were observed. In summary, all poorly differentiated chordomas in this series showed the absence of SMARCB1/INI1 expression, and were reliably distinguished from AT/RTs, clinically by their characteristic primary sites of origin and pathologically by strong nuclear brachyury expression. Our findings reveal a likely role for SMARCB1/INI1 in a subset of chordomas with aggressive features.

Diffusion-Weighted MRI: Distinction of Skull Base Chordoma from Chondrosarcoma

“…This subtype, however, may be difficult to distinguish from other highly cellular neoplasms of the skull base, such as rhabdomyosarcoma and primitive neuroectodermal tumor, and requires a pathologic assessment with special stains such as those for brachyury and INI-1. 10 For tumors in general, variation in ADC may arise from heterogeneity in cell size and density, as well as microscopic hemorrhage or calcification. In our study, 2 hemorrhagic tumors were excluded because nonhemorrhagic tumor could not be defined for measurement, and in 1 case with MR imaging-visible focal calcification or blood product, region-of-interest placement and imaging section selection were conducted carefully to exclude this area from analysis.…”

“…7 While mitotic activity is rare in typical chordoma, poorly differentiated chordoma shows high mitotic activity and relatively high cell attenuation with a high nuclear-to-cytoplasmic ratio and prominent nucleoli. [8][9][10] The poorly differentiated chordoma is a particularly aggressive tumor with a predilection for the pediatric population. Chondrosarcoma, histologically distinct from chordoma, is composed of atypical chondrocytes with enlarged hyperchromatic nuclei set in an abundant cartilaginous matrix.…”

Roles of SWI/SNF Complex Genes in Breast Cancer

“…Furthermore, loss of Ini1 was redundant with loss of Rb function in the formation of pituitary tumors in Rb heterozygous mice and gave rise to the formation of large, atypical Rb(+/-) tumor cells lacking adrenocorticotropic hormone expression, confirming in vivo the relationship between Rb and Ini1 in tumor suppression [74]. Mutations and alterations of SNF5 were also reported in familial schwannomatosis and other cancer types [75][76][77][78][79][80][81][82][83][84]. Germ line mutations of SNF5 were detected in brain tumors and rhabdoid tumors, suggesting its link with familial cancers [85][86][87][88].…”

Bone Involvement in Atypical Teratoid/Rhabdoid Tumors of the CNS

“…11,19 Two children with AT/RT of clival location (similar to our patient 5) have been described, whose radiologic appearance also led to the suspicion of chordoma despite very low signal on T2-weighted images. 22,23 Indeed, in our patient, the possibility of "poorly differentiated chordoma" 24,25 was also discussed during neuropathologic evaluation but rejected in favor of AT/RT, because the tumor lacked any convincing chordoid differentiation. Patient 3 does not completely fit with the other cases because he probably had multifocal malignant rhabdoid tumors of the body in addition to the probable AT/RT.…”