SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity

Abstract

To more fully characterize the clinical and pathologic spectrum of a recently described tumor entity of the sinonasal tract characterized by loss of nuclear expression of SMARCB1 (INI1), we analyzed 39 SMARCB1-deficient sinonasal carcinomas collected from multiple medical centers. The tumors affected 23 males and 16 females with an age range of 19 to 89 years (median, 52). All patients presented with locally advanced disease (T3, n=5; T4, n=27) involving the sinuses (mainly ethmoid) with variable involvement of the nasal cavity. Thirty patients received surgery and/or radiochemotherapy with curative intent. At last follow-up, 56% of patients died of disease 0 to 102 months after diagnosis (median, 15), 2 were alive with disease, and 1 died of an unrelated cause. Only 9 patients (30%) were alive without disease at last follow-up (range, 11 to 115 mo; median, 26). The original diagnosis of retrospectively identified cases was most often sinonasal undifferentiated carcinoma (n=14) and nonkeratinizing/basaloid squamous cell carcinoma (n=5). Histologically, most tumors displayed either a predominantly basaloid (61%) or plasmacytoid/rhabdoid morphology (36%). The plasmacytoid/rhabdoid form consisted of sheets of tumor cells with abundant, eccentrically placed eosinophilic cytoplasm, whereas similar cells were typically rare and singly distributed in the basaloid variant. Glandular differentiation was seen in a few tumors. None of the cases showed squamous differentiation or surface dysplasia. By immunohistochemistry, the tumors were positive for pancytokeratin (97%), CK5 (64%), p63 (55%), and CK7 (48%); and they were negative for NUT (0%). Epstein-Barr virus and high-risk human papillomavirus was not detected by in situ hybridization. Immunohistochemical loss of SMARCB1 (INI1) expression was confirmed for all 39 tumors. Investigation of other proteins in the SWI/SNF complex revealed co-loss of SMARCA2 in 4 cases, but none were SMARCA4 deficient or ARID1A deficient. Of 27 tumors with SMARCB1 fluorescence in situ hybridization analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions. SMARCB1-deficient sinonasal carcinoma represents an emerging poorly differentiated/undifferentiated sinonasal carcinoma that (1) cannot be better classified as another specific tumor type, (2) has consistent histopathologic findings (albeit with some variability) with varying proportions of plasmacytoid/rhabdoid cells, and (3) demonstrates an aggressive clinical course. This entity should be considered in any difficult-to-classify sinonasal carcinoma, as correct diagnosis will be mandatory for optimizing therapy and for further delineation of this likely underdiagnosed disease.

Figure 1

MRT (case 3) revealed a mass in the right frontal sinus and anterior ethmoid cells abutting the anterior skull base. The lesion demonstrates inhomogeneous contrast enhancement with areas of necrosis on post-contrast T1w images (A and B). T2w images (C) help in differentiating tumor and surrounding sinonasal mucosa. The right eye globe is displaced latero-inferiorly.

Figure 2

While the surface epithelium overlying SMARCB1-deficient sinonasal carcinoma lacks conventional squamous dysplasia or carcinoma-in-situ, the tumors often exhibit spread into the epithelium in a pagetoid manner. This can be demonstrated by SMARCB1 immunohistochemistry which highlights absent expression in the tumor cells (inset).

Figure 3

The predominant histologic pattern of SMARCB1-deficient sinonasal carcinoma was basaloid, with nests of basophilic cells with high nuclear: cytoplasmic ratios growing in a desmoplastic stroma. Note also the presence of non-specific vacuoles within the tumor, a common finding (inset) (A). In some cases of basaloid SMARCB1-deficient sinonasal carcinoma, the tumor grows downward in an inverted growth pattern reminiscent of inverted Schneiderian papilloma (B). On close inspection, basaloid SMARCB1-deficient sinonasal carcinomas may demonstrate rare, singly-dispersed plasmacytoid or rhabdoid cells (arrow) (C). In one case, a basaloid SMARCB1-deficient sinonasal carcinoma became predominantly plasmacytoid/rhabdoid upon metastasizing to the lung (D).

Figure 4

The second most common appearance of SMARCB1-deficient sinonasal carcinoma was that of an eosinophilic tumor, often growing in a nested or solid pattern (A). This form of SMARCB1-deficient sinonasal carcinoma consisted of numerous cells with abundant, pink, eccentrically placed cytoplasm that were variably plasmacytoid or rhabdoid (B). Two cases grew in a multinodular, “pseudogranulomatous” manner at low power, reminiscent of epithelioid sarcoma (C), and two of the eosinophilic SMARCB1-deficient sinonasal carcinomas exhibited areas of glandular differentiation (D).

Figure 5

Two SMARCB1-deficient sinonasal carcinomas exhibited overt spindle cell (sarcomatoid) differentiation. In one case, the sarcomatoid areas (right) were seen in addition to the more common basaloid pattern (left) (A), while the other case was as pure sarcomatoid carcinoma (B).

Figure 6

SMARCB1-deficient sinonasal carcinomas were variably p63-positive (A; note perivascular rosette-like nuclei). A few cases expressed neuroendocrine markers like synaptophysin, typically focally (B).

Figure 7

As per definition, all tumors showed complete loss of SMARCB1 while normal stromal cells in the background stained strongly (A). SMARCA2 was frequently reduced (B) and occasionally lost. In contrast, SMARCA4 (C) and ARID1A (D) were entirely intact in all tested cases.

Figure 8

By fluorescence in situ hybridization, 13 SMARCB1-deficient sinonasal carcinomas demonstrated homozygous deletion of SMARCB1, with both SMARCB1 alleles deleted (red), while 2 copies of EWSR1 (green) are present. See in contrast normal cells having 2 copies of both green and red signals (top right) (A). Six SMARCB1-deficient sinonasal carcinomas exhibited heterozygous SMARCB1 deletion, with only one copy of SMARCB1 present (red) while 2 copies of EWSR1 (green) are seen.