Thoracic SMARCA4-deficient undifferentiated tumor

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From the CAP Cytopathology Committee,
Jordan Paul Reynold, MD, Editor

Cytopathologic features, IHC, and molecular testing

Philip D. Hurst, MD
Derek B. Allison, MD

January 2024—Thoracic SMARCA4-deficient undifferentiated tumor (TSDUT), formerly known as SMARCA4-deficient thoracic sarcoma and SMARCA4-deficient thoracic sarcomatoid tumor, is a relatively newly defined entity with a distinct clinical history, morphology, immunohistochemical profile, molecular findings, and clinical behavior. The tumor was first described as a distinct diagnosis in the 2021 World Health Organization Classification of Thoracic Tumors, wherein it was defined as a high-grade malignant neoplasm of the thorax with an undifferentiated or rhabdoid phenotype and a deficiency in SMARCA4 protein expression. Importantly, TSDUT is a distinct entity from a non-small cell lung carcinoma with a SMARCA4 inactivating alteration.

First, TSDUT typically occurs in relatively young males (median age 48 years, range 27–90 years) with an extensive smoking history, which corresponds with coexisting bullous emphysema and a genomic smoking signature present in most cases. As a result, additional mutations in KRAS, STK11, and/or KEAP1, which are common in smokers, are seen in almost half of reported cases. As with many high-grade tumors, TP53 inactivating mutations are common. Interestingly, approximately 10 percent of reported cases have occurred in patients without a smoking history; however, these patients may also have bullous and interstitial lung disease, suggesting an alternative injurious pathway.

TSDUTs typically present as large masses with compressive symptoms in the mediastinum, pulmonary hilum, lung, or pleura. Most cases do have some degree of lung parenchymal involvement, but it can be challenging to determine where the primary site of disease is situated. In addition to compression of the lungs and superior vena cava, patients may develop weight loss and symptoms related to distant metastases, which are typical at presentation. Common sites for metastases include lymph nodes, bones, adrenal glands, brain, and abdominal/peritoneal cavity.¹ Unfortunately, TSDUTs are extremely aggressive, do not respond to cytotoxic chemotherapy regimens, and are associated with a median overall survival of four to seven months. Due to the fact that nearly all patients are clinical stage IV at presentation, these patients are not usually resection candidates. As a result, it is imperative to be aware of this entity because most patients will be diagnosed and treated based on fine-needle aspiration or a small core needle biopsy of the primary site of disease or distant metastasis.

As shown in Fig. 1, cytopathologic features of this tumor include variably discohesive clusters of large epithelioid cells with vesicular chromatin, prominent nucleoli, and indistinct cell borders. While nuclear pleomorphism can be seen, nuclei may be monotonous with round to ovoid contours. Cells tend to have an abundance of cytoplasm, which may be vacuolated or eccentric, and can invoke a plasmacytoid or rhabdoid appearance in some cases. Background features of tumor necrosis are often present, as are frequent typical and atypical mitoses.^1,2 Notably, there is a lack of diagnostic features consistent with another diagnosis, such as squamous, glandular, or other overt epithelial differentiation. These morphologic features correspond to what is seen in tissue samples. Of note, a small subset (five percent) have shown combined histology on resection with a conventional non-small cell lung cancer component and a clearly separate undifferentiated component; however, the morphology and immunohistochemical profiles are distinct in this scenario.

Immunohistochemistry and molecular testing play important roles in the classification of these tumors. On IHC, TSDUT cells show complete loss of cytokeratins or only focal or weak staining and are negative for claudin 4. CD34, SOX2, and SALL4 may be positive and a helpful clue to this diagnostic entity. BRG1, the surrogate marker for SMARCA4, is typically completely lost, though a quarter of cases may show diminished or weak staining. It is in these cases that confirmation with molecular testing, proving an inactivation alteration in the SMARCA4 gene, is most helpful. BRM, the surrogate marker for the SMARCA2 gene, may also be lost, due to the fact that BRM may have difficulty assembling onto the BAF chromatin-remodeling complex in the absence of a functional BRG1 protein. Evaluation for the presence of a SMARCA4 mutation by sequencing can be helpful if the diagnosis was not entertained initially or if the presentation is unusual; however, loss of staining with BRG1 by IHC is sufficient to make a definitive diagnosis.^1,2 This latter fact is important because these patients need a diagnosis as soon as possible and waiting several weeks for a molecular report is a loss of crucial time.

Fig. 1. High-power magnification of a modified Giemsa-stained smear shows variably rhabdoid, discohesive tumor cells with enlarged nuclei, variably prominent nucleoli, and nuclear smear artifact. Note the mitotic figure in the center of the field. On a medium-power H&E stain, note the discohesion, nuclear pleomorphism, and geographic necrosis. In both fields, note the lack of squamous, glandular, or epithelial differentiation, which was confirmed with additional immunohistochemistry. BRG1 was assessed in a well-preserved area and shows complete loss of staining, confirming the diagnosis.

Finally, it is important to differentiate these tumors from non-small cell carcinomas, neuroendocrine carcinomas, NUT carcinomas, mesotheliomas, germ cell tumors, melanomas, and epithelioid-appearing sarcomas. Furthermore, SMARCA4 alterations can be present in NSCLC, which means that this diagnosis cannot just be made based on BRG1 IHC or a molecular report. The diagnosis includes putting together a unique clinical history, morphology, and complete immunohistochemical profile.n

1. WHO Classification of Tumours Editorial Board. Thoracic Tumours. World Health Organization; 2021. WHO Classification of Tumours; 5th ed., vol. 5.
2. Kezlarian B, Montecalvo J, Bodd FM, et al. Diagnosis of thoracic SMARCA4-deficient undifferentiated tumor in cytology. Cancer Cytopathol. 2023;131(8):526–534.

Dr. Hurst is chief resident, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn. Dr. Allison is associate professor of pathology and urology and vice chair for research, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, and assistant director and quality officer, biospecimen procurement and translational pathology shared resource facility, Markey Cancer Center, UK HealthCare, Lexington. Drs. Allison and Hurst are members of the CAP Cytopathology Committee.