Primary cutaneous SMARCB1-deficient carcinoma

Abstract

Background: SMARCB1-deficient malignancies can arise in various sites. We describe a novel primary SMARCB1-deficient carcinoma of skin (SDCS) and characterize SMARCB1 mutations in non-melanoma skin cancers (NMSC).

Methods: Cases underwent immunophenotyping and targeted exome sequencing (MSK-IMPACT) assay interrogating somatic mutations in 468 cancer-related genes. The MSK-IMPACT database from 2014 to 2020 encompassing 55, 000 cases was searched for NMSC with SMARCB1 mutations.

Results: SDCS arose on the scalp of an 18-year-old woman showing homozygous SMARCB1 deletion with a LATS2 G963E variant. Another case arose on the temple of a 76-year-old man harboring a SMARCB1 W206* mutation associated with loss of heterozygosity (LOH), 59 concurrent mutations, and a UV mutation signature (UV-MS). Both tumors exhibited INI1 loss, positive CK5/6, p40, p63, and claudin-4 with negative CD34. Of 378 NMSC cases, including 370 carcinomas, 7 SMARCB1-mutated tumors were identified: 3 squamous cell, 3 Merkel cell, and one basal cell carcinoma. Six showed UV-MS. Five INI1-interrogated cases retained protein expression suggesting they were SMARCB1-proficient.

Conclusions: SDCS can be clinically aggressive, harbor SMARCB1 homozygous deletions or truncating SMARCB1 mutations associated with LOH, and can occur with or without UV-MS. Overall, SMARCB1 mutations in NMSC are rare with most being of undetermined significance and associated with retained INI1 and UV-MS.

Keywords: BAF47; INI1; SMARCB1; epithelioid sarcoma; squamous cell carcinoma.

Figure 1.

SMARCB1-deficient carcinoma involving scalp of an 18-year-old female. The tumor cells infiltrate dermis in the form of nests and cords intersected by variably thick, dense collagenous stroma and is associated with lymphoid aggregates at the tumor periphery [A, H&E, scanning magnification]. The tumor cells surround adnexal structures and no connection to the overlying epidermis was identified [B, H&E, 200x magnification]. Perineural invasion is seen (arrow). The tumor cells are of intermediate size and show smooth cell borders. No prominent rhabdoid features are seen although in areas, they do have a subtle plasmacytoid appearance. The nuclear/cytoplasmic ratio is high and the nuclei are round with finely dispersed chromatin and one or multiple conspicuous nucleoli [C, H&E, 400x magnification]. A cytologic preparation reveals clusters of cells with indistinct nuclear borders and scant delicate cytoplasm, vesicular chromatin and prominent nucleoli [D, Papanicolaou stain, 600x magnification]. Immunohistochemistry revealed loss of nuclear INI1 expression [E, 400x magnification] and positive staining for claudin-4 [F, 400x magnification], p40 [G, 400x magnification], with patchy CK 5/6 expression throughout the tumor [H, 400x magnification]. A CNA plot of Case 1 shows homozygous deletion of SMARCB1 (green arrow). The Y-axis depicts copy number changes expressed as the log2 transformed tumor/normal ratio by their genomic positions indicated on the x-axis. The blue dots represent individual exons and red dots indicate a ≥2-fold tumor/normal ratio [I]. FACETS analysis shows deletion of both SMARCB1 alleles as indicated by the total integer copy number 0 (black line, y-axis). A red line indicates a minor allele. SMARCB1 genomic position on chromosome 22 is indicated by the vertical green line [H]. Abbreviations: FACETS, Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing; CNA, copy number alterations.

Figure 2.

SMARCB1-deficient carcinoma involving the temple skin of a 75-year-old man. Infiltrative undifferentiated tumor cells in dermis are surrounded by collagenous and myxoid stroma [A, H&E, scanning magnification, inset 200x magnification]. Areas of necrosis were present, and apoptotic bodies and mitotic figures are notable. The tumor cells are variably sized, show high nuclear/cytoplasmic ratio, small to moderate amount of eosinophilic, focally very dense/pink cytoplasm [B, H&E, 200x magnification]. The undifferentiated tumor cells show no distinct rhabdoid features. Nuclei are round to oval with open or speckled chromatin, with one or multiple, focally prominent nucleoli [C, H&E, 400x magnification]. A cytologic preparation shows dishesive cells with moderate cytoplasm, prominent nucleoli and multinucleation [D, Diff-Quik stain, 400x magnification]. Immunohistochemistry also revealed loss of nuclear INI1 expression [E, 400x magnification] and positive staining for claudin-4 [F, 400x magnification], p40 [G, 400x magnification], and CK 5/6 [H, 400x magnification]. A CNA plot for Case 2 shows multiple gains and losses including homozygous CDKN2A deletion on chromosome 9p [red dots, I], which is confirmed by FACETS as the total copy number 0 [blue arrow, J]. LOH in SMARCB1 (green line) is indicated as the total copy number of 1 [J]. Abbreviations: FACETS, Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing; CNA, copy number alterations; LOH, loss of heterozygosity.