October 2022 – Pulmonary

Thoracic SMARCA4-deficient undifferentiated tumor.

Thoracic SMARCA4-deficient undifferentiated tumor is an aggressive malignancy that may arise in the lung, pulmonary hilum, mediastinum, or pleura.^1,2 It predominantly occurs in middle-aged adults, but may occur in a wide age range. The vast majority patients with this tumor have a history of smoking.³ Metastases are frequently present at the time of diagnosis. SMARCA4-deficient undifferentiated tumors may also be primary to extra-thoracic organs (e.g., stomach, pancreas, kidney, ovary, and uterus), such that clinical correlation is critical for determination of the primary site.

On histology, these tumors are typically composed of sheets of relatively monotonous epithelioid cells with focal rhabdoid morphology, large round nuclei, vesicular chromatin, and prominent nucleoli. Mitotic figures are abundant and necrosis is often present, in keeping with a high-grade malignancy. The cells may appear discohesive, raising suspicion for a hematolymphoid neoplasm. On morphology, the differential diagnosis may also include pulmonary and thymic carcinoma, NUT midline carcinoma, melanoma, germ cell tumor, malignant rhabdoid tumor, epithelioid sarcoma, and other sarcomas. 

On immunohistochemistry, these tumors are negative for NUT and typically do not express melanoma or lymphoid markers. Keratin expression is typically weak and focal but may be negative.³ Diffuse strong expression of keratin is not in keeping with this entity. A negative claudin-4 may also be helpful in ruling out carcinoma. TTF1 and p40 may rarely be focally positive.³ CD34 and SALL4 are often expressed in these tumors,^2,4 but they may be distinguished from germ cell tumors and sarcomas by loss of BRG1 immunoreactivity. BRG1 loss is a defining feature of these tumors, reflecting biallelic inactivation of the chromatin remodeling gene SMARCA4.⁵ Approximately one quarter of cases show a severe reduction rather than full loss of BRG1 immunostaining.^2,3  Immunoreactivity for INI1, encoded by SMARCB1, is retained in these tumors, helping to distinguish them from malignant rhabdoid tumors and epithelioid sarcomas.

Importantly, the presence of any morphologic features definitive for carcinoma (e.g., gland formation, papillary architecture, or keratinization) excludes this diagnosis. However, approximately 5% of thoracic SMARCA4-deficient undifferentiated tumors are associated with adjacent areas of non-small cell lung carcinoma (NSCLC), raising the possibility that these tumors are undifferentiated or poorly differentiated carcinomas arising from epithelial precursors.³ In keeping with this notion, both thoracic SMARCA4-deficient undifferentiated tumors and pulmonary carcinomas tend to have a genomic smoking signature. Cases with definitive morphologic features of carcinoma in the SMARCA4-deficient areas are best classified as SMARCA4-deficient NSCLC, and represent about 5% of conventional NSCLC.^6-8 The prognosis of SMARCA4-deficient undifferentiated tumor is worse than that of SMARCA4-deficient NSCLC, with a median survival of only 4-7 months.^3,5  

References

1. Sauter JL, Graham RP, Larsen BT, Jenkins SM, Roden AC, Boland JM. SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior. Mod Pathol.2017;30:1422-32.
2. Yoshida A, Kobayashi E, Kubo T, Kodaira M, Motoi T, Motoi N, Yonemori K, Ohe Y, Watanabe SI, Kawai A, Kohno T, Kishimoto H, Ichikawa H, Hiraoka N. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol. 2017;30:797-809.
3. Rekhtman N, Montecalvo J, Chang JC, Alex D, Ptashkin RN, Ai N, Sauter JL, Kezlarian B, Jungbluth A, Desmeules P, Beras A, Bishop JA, Plodkowski AJ, Gounder MM, Schoenfeld AJ, Namakydoust A, Li BT, Rudin CM, Riely GJ, Jones DR, Ladanyi M, Travis WD. SMARCA4-deficient thoracic sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas. J Thorac Oncol.2020;15:231-47.
4. Perret R, Chalabreysse L, Watson S, Serre I, Garcia S, Forest F, Yvorel V, Pissaloux D, Thomas de Montpreville V, Masliah-Planchon J, Lantuejoul S, Brevet M, Blay JY, Coindre JM, Tirode F, Le Loarer F. SMARCA4-deficient thoracic sarcomas: clinicopathologic study of 30 cases with an emphasis on their nosology and differential diagnoses. Am J Surg Pathol. 2019;43:455-65.
5. Le Loarer F, Watson S, Pierron G, de Montpreville VT, Ballet S, Firmin N, Auguste A, Pissaloux D, Boyault S, Paindavoine S, Dechelotte PJ, Besse B, Vignaud JM, Brevet M, Fadel E, Richer W, Treilleux I, Masliah-Planchon J, Devouassoux-Shisheboran M, Zalcman G, Allory Y, Bourdeaut F, Thivolet-Bejui F, Ranchere-Vince D, Girard N, Lantuejoul S, Galateau-Sallé F, Coindre JM, Leary A, Delattre O, Blay JY, Tirode F. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet.2015;47:1200-5.
6. Dagogo-Jack I, Schrock AB, Kem M, Jessop N, Lee J, Ali SM, Ross JS, Lennerz JK, Shaw AT, Mino-Kenudson M. Clinicopathologic Characteristics of BRG1-Deficient NSCLC. J Thorac Oncol. 2020;15:766-76.
7. Herpel E, Rieker RJ, Dienemann H, Muley T, Meister M, Hartmann A, Warth A, Agaimy A. SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens. Ann Diagn Pathol. 2017;26:47-51.
8. Nambirajan A, Singh V, Bhardwaj N, Mittal S, Kumar S, Jain D. SMARCA4/BRG1-deficient non-small cell lung carcinomas: a case series and review of the literature. Arch Pathol Lab Med. 2021;145:90-8.