SMARCA4-Deficient Thoracic Sarcomatoid Tumors Represent Primarily Smoking-Related Undifferentiated Carcinomas Rather Than Primary Thoracic Sarcomas

Abstract

Introduction: Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non-small cell lung carcinomas (SD-NSCC).

Methods: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341-468 gene next-generation sequencing and other molecular platforms.

Results: The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30-50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers.

Conclusions: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.

Keywords: BRG1; Lung; Rhabdoid; SMARCA4; Sarcomatoid; Thoracic.

Figure 1.

Representative radiologic characteristics of SMARCA4-deficient thoracic sarcomatoid tumors. Axial (A) and coronal (B) Computed tomography images from “patient 11” illustrate large, central tumor extensively involving both pulmonary and mediastinal structures with unclear epicenter. Non-neoplastic lung shows marked emphysema in line with the patient’s history of heavy smoking. Subsequent molecular studies revealed presence of a smoking signature, supporting a lung origin.

Figure 2.

Histopathologic features of SMARCA4-deficient thoracic sarcomatoid tumors. A and B illustrate hallmark morphology: undifferentiated round to plasmacytoid cells with prominent nucleoli, discohesion, and overall monomorphism. Classic rhabdoid cells with hyaline cytoplasmic inclusions indenting the nuclei were present focally in most cases (A, B; black circles); in few cases they were a predominant feature (C; inset). Several cases showed increased pleomorphism, entering in close differential diagnosis with NSCC (D). Distinctive cells with compressed crescent-shaped peripheral nuclei were noted in most cases (blue circles). Typical immunohistochemical features included the loss of SMARCA4 (E) and SMARCA2 (F) with retained expression in normal inflammatory and stromal cells, lack of claudin-4 (G) and weak (or in other cases entirely negative) keratins (H).

Figure 3.

Histopathologic features of SMARCA4-deficient composite tumors (case #20). (A, B) Hematoxylin and eosin section showing an abrupt transition from cohesive NSCC (right) to discohesive undifferentiated round cell/rhabdoid histology (left; Undif). Cell-to-cell cohesion is evident in NSCC component (right inset) compared with discohesion of round cell/rhabdoid component (left inset). The transition is accompanied by a sharp loss of SMARCA2 (D), keratins (E) and claudin-4 (F), superimposed on SMARCA4 deficiency in both components (C). SMARCA4 and SMARCA2 positive cells within undifferentiated component in C and D represent lymphocytes and stromal cells. Undif, undifferentiated.

Figure 4.

Histopathologic features of SMARCA4-deficient composite tumors (case #22). Hematoxylin and eosin section (A, B) illustrates a tumor with predominantly undifferentiated round cell morphology with focal myxoid features containing scattered islands of NSCC with squamoid morphology. Transition between carcinomatous and undifferentiated areas is highlighted by the sharp loss of SMARCA2 (D), keratins (E), claudin-4 (F) and p40 (not shown) superimposed on homogeneous SMARCA4-deficiency in both components (C).

Figure 5.

Comparison of SMARCA4-deficient thoracic sarcomatoid tumors (SD-TST) versus SMARCA4-deficient NSCC (SD-NSCC). (A, B) Histologic features of SD-NSCC illustrating conventional acinar (A) or solid (B) morphology lacking undifferentiated round cell/rhabdoid features. Hallmarks include cellular cohesion and lack of monomorphism. Insets show the loss of SMARCA4 expression in tumor cells compared with entrapped benign cells. (C) Comparison of clinicopathologic features in SD-TSTs and SD-NSCCs. *Mosaic pattern of SMARCA2 expression (positive cells intermixed with low/negative cells) was seen in some SD-NSCCs but was not regarded as a loss. #Claudin-4 loss in SD-TSTs was diffuse in 16 cases, and near-diffuse (retained expression in < 5% of tumor cells) in six cases (see Supplementary Tables 3 and 5). ^All SD-NSCCs had diffuse or near-diffuse expression of claudin-4. (D) Comparison of overall survival for stage IV SD-TSTs (n = 19) versus SD-NSCCs (n = 40).

Figure 6.

Genomic profiles of SMARCA4-deficient thoracic sarcomatoid tumors. (A) OncoPrint illustrating recurrent genomic alterations in SD-TSTs. Key characteristics of patients and SMARCA4 locus analysis by FISH and FACETS are annotated. CN-LOH: copy-neutral LOH, HOM: homozygous deletion. For FISH, ++ indicates both alleles intact, ↓+ heterozygous loss/deletion, and ↓↓ homozygous loss/deletion. CT:? lung versus mediast denotes tumors with uncertain site of origin on initial imaging studies. (B) Comparison of genomic alterations in SD-TSTs and SD-NSCC. None of the parameters showed statistically significant differences. (C) Analysis of genomic smoking signature in 16 SD-TSTs versus 45 ST-NSCC versus 44 sarcomas, including soft tissue (n = 38) and thoracic (n = 6) sarcomas.

Figure 7.

A model for SMARCA4-mediated pathogenesis of thoracic tumors, depicting solitary SMARCA4 deficiency in conventional NSCC, and dual SMARCA4/A2 deficiency in sarcomatoid/undifferentiated tumors. The timing of SMARCA4/A2 may determine the presence and extent of carcinomatous components and likelihood of NSCC-type alterations (see Discussion). *denotes that SMARCA2-independent mechanisms may cooperate with SMARCA4 inactivation in a minority of cases.