Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas

Abstract

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis. Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares with other multiple schwannoma syndromes [sporadic schwannomatosis and neurofibromatosis 2 (NF2)] as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.

Figure 1

Immunohistochemical staining of INI1 in schwannomas. A. Solitary, sporadic schwannoma showing diffuse immunopositive staining. B. Schwannoma from a familial schwannomatosis patient showing a mosaic pattern with a subset of immunonegative tumor cells intimately intermixed with immunopositive nuclei. C. Negative control, atypical teratoid/rhabdoid tumor shows diffuse immunonegative tumor; immunopositive capillary endothelial cell nuclei provide an internal positive control (arrows).

Figure 2

Distribution of patterns of INI1 expression in schwannomas clinical subtypes. Most of the schwannomas of hereditary type, neurofibromatosis 2 (NF2) and familial schwannomatosis (familial SC) have a mosaic pattern of staining, in contrast to the diffuse pattern of solitary, sporadic schwannomas. Sporadic schwannomatosis (sporadic SC) tumors show both patterns of staining; SC = schwannomatosis.