SMARCB1 (INI-1)-deficient carcinomas of the sinonasal tract

Abstract

SMARCB1 (INI-1) is a tumor-suppressor gene located on chromosome 22q11.2. Its gene product is ubiquitously expressed in nuclei of all normal tissues. SMARCB1 gene inactivation has been implicated in the pathogenesis of a diverse group of malignant neoplasms that tend to share "rhabdoid" cytomorphology. This group of SMARCB1-deficient tumors is now further expanded by a subset of carcinomas arising in the sinonasal tract. SMARCB1 immunostaining was performed on 142 sinonasal carcinomas. Tumors that showed loss of expression were further characterized for SMARCB1 deletions by fluorescence in situ hybridization. Nine of 142 (6%) primary sinonasal carcinomas showed loss of SMARCB1 expression by immunohistochemistry. Five patients were women, and patients ranged in age from 33 to 78 years (mean 59 y). The SMARCB1-deficient tumors were characterized by nests, sheets, and cords of cells without any histologic evidence of specific (eg, squamous or glandular) differentiation. The tumors comprised varying proportions of basaloid and rhabdoid cells. The SMARCB1-deficient carcinomas had been diagnosed as nonkeratinizing squamous cell carcinomas (n=3), sinonasal undifferentiated carcinomas (n=2), myoepithelial carcinoma (n=2), nonintestinal adenocarcinoma (n=1), and carcinoma, not otherwise specified (n=1). Fluorescence in situ hybridization analysis revealed SMARCB1 deletions in 6 of 8 (75%) carcinomas. The SMARCB1-deficient carcinomas did not harbor human papillomavirus or NUT-1 alterations. Six patients presented with T4 disease, 5 patients developed local recurrences and/or distant metastases, and 4 died of their disease. Inactivation of the SMARCB1 tumor-suppressor gene appears to be involved in the pathogenesis of a subset of sinonasal carcinomas, further expanding the family of SMARCB1-deficient neoplasms and further delineating a bewildering group of poorly/undifferentiated, aggressive carcinomas arising at this site. The ability to detect SMARCB1 loss by immunohistochemistry, particularly when dealing with poorly differentiated carcinomas with basaloid or rhabdoid features, should facilitate a more comprehensive understanding of these sinonasal carcinomas including clinical behavior and response to targeted therapies.

Figure 1

Most of the carcinomas were composed of basaloid nests and lobules with intervening desmoplastic stroma (A, X200, case 3). All tumors exhibited complete loss of SMARCB1 immunostaining, with stromal and inflammatory cells serving as a internal positive control (B, X400, case 3).

Figure 2

Each SMARCB1 deficient sinonasal carcinoma exhibited a component of rhabdoid cells, but their distribution was variable. In some cases, the rhabdoid cells were individually dispersed among the basaloid tumor cells (A, X400, case 2), while in others the rhabdoid cells predominated (B, X400, case 6).

Figure 3

Two cases of SMARCB1 deficient sinonasal carcinoma lacked prominent nucleoli and had more evenly dispersed chromatin, imparting a plasmacytoid appearance to the tumors. These neoplasms were originally diagnosed as myoepithelial carcinoma on the basis of the plasmacytoid appearance (X400, case 7).

Figure 4

FISH showing loss of both red signals (SMARCB1), showing only two green signals (EWSR1) in the tumor cells. On the right side few normal cells with retained two green/two red signals as an internal control (A, case 1). FISH showing most cells lost one copy of the red signal (SMARCB1), while retaining two green copies (EWSR1) (B, case 6).

Figure 5

Most of the SMARCB1 deficient sinonasal carcinomas exhibited aggressive clinical behavior. This tumor extended from the right sinonasal tract to involve the orbit and brain (T2-weighted magnetic resonance imaging).