January 2021 — Gastroenterology

A 75-year-old woman presented with severe abdominal pain, nausea, and gastrointestinal bleeding. Endoscopic ultrasound revealed a 13 cm circumferential, infiltrative mass within the distal body and antrum involving the serosa. A subtotal gastrectomy and omentectomy was performed for palliative purposes.

Figure 1. Histologic sections demonstrate an undifferentiated malignant neoplasm replacing the gastric wall and involving the serosa, with ulceration and extensive necrosis.
Figure 2. The tumor cells show rhabdoid features with abundant eosinophilic cytoplasm and eccentric, vesicular nuclei with prominent nucleoli (A). Increased mitotic activity (A, arrows) and lymphovascular invasion (B) are also present.
Figure 3. Immunohistochemical stains demonstrate BRG1 loss of expression within tumor cells (A). INI1 expression is retained (B).

What is the diagnosis?

  • Large cell neuroendocrine carcinoma
  • Metastatic alveolar rhabdomyosarcoma
  • Poorly differentiated adenocarcinoma, diffuse type
  • Undifferentiated/rhabdoid carcinoma

The correct answer is...

The correct answer is undifferentiated/rhabdoid carcinoma.

Undifferentiated rhabdoid carcinoma of the stomach is a rare entity. The undifferentiated phenotype is thought to be driven by abnormalities in various components of the switch/sucrose-nonfermenting (SWI/SNF) chromatin remodeling complex, that binds to DNA and histones to mobilize nucleosomes to enhance DNA accessibility for transcription, replication, and repair. As a regulator of chromatin structure and DNA transcription, SWI/SNF complex is involved in cell cycle progression and tissue-specific differentiation. At least eight genes encoding core subunits of the SWI/SNF complex have been identified to date, including SMARCB1 (INI1), SMARCA2 (BRM), and SMARCA4 (BRG1). SMARCB1 (INI1) is the most extensively studied. A variety of neoplasms are known to carry inactivating mutations in this gene, including atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system and its peripheral counterparts of the kidney and soft tissue. Moreover, mutations in other subunits of SWI/SNF complex, including BRG1 and BRM, have been identified in many other tumors that now constitute an expanding family known as SMARC-deficient neoplasms. Immunohistochemistry is widely used as a surrogate to recognize the genetic alterations and help diagnose this heterogenous group of tumors.

These tumors show significant variation in age of onset, clinical presentation, and radiographic or gross features. They arise from many organs including brain, lung, kidney, gastrointestinal (GI) tract, pancreas, liver, endometrium, and ovary. A common clinical feature of these tumors appears to be their highly aggressive biological behavior with poor prognosis and short-term survival. Histologically, they tend to be poorly differentiated or undifferentiated and frequently show rhabdoid features, hence the name of undifferentiated/rhabdoid carcinomas..

Undifferentiated/rhabdoid carcinomas with BRG1 loss in the GI tract more frequently affect the colon, followed by the small bowel, stomach, and esophagus. Histologically, they often form solid and diffuse sheets, show anaplastic cytomorphology with occasional pleomorphic tumor giant cells, and frequently display rhabdoid features characterized by abundant eosinophilic cytoplasm and eccentric, vesicular nuclei with prominent nucleoli. High mitotic activity, extensive necrosis, and lymphovascular invasion are common. The tumor cells are generally immunoreactive for pancytokeratin and vimentin, and show variable CK7, CK20, and CDX2 staining. They characteristically show loss of BRG1 and/or BRM by immunohistochemistry. Some tumors may show variable glandular component or areas of transition to adenocarcinoma, suggesting an origin via a dedifferentiation process.

There are ongoing studies for therapeutic interventions of SMARC-deficient tumors, such as PARP inhibitors or PI3K and AKT inhibitors. It is also worth noting that a subset of GI undifferentiated/rhabdoid carcinomas with BRG1 loss show overexpression of PD-L1, high tumor mutation burden and/or loss of mismatch-repair (MMR) proteins. Although further studies are needed, these findings indicate a potential role of immune checkpoint inhibitor therapy in treating the aggressive tumors.

1. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017 Apr;108(4):547-552.
2. Matsubara D, Kishaba Y, Ishikawa S, Sakatani T, Oguni S et al. Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. Cancer Sci. 2013 Feb;104(2):266-73.
3. Kolin DL, Quick CM, Dong F, Fletcher CDM, Stewart CJR et al. SMARCA4-deficient Uterine Sarcoma and Undifferentiated Endometrial Carcinoma Are Distinct Clinicopathologic Entities. Am J Surg Pathol. 2020 Feb;44(2):263-270.
4. Herpel E, Rieker RJ, Dienemann H, Muley T, Meister M et al. SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens. Ann Diagn Pathol. 2017 Feb;26:47-51.
5. Ramalingam P, Croce S, McCluggage WG. Loss of expression of SMARCA4 (BRG1), SMARCA2 (BRM) and SMARCB1 (INI1) in undifferentiated carcinoma of the endometrium is not uncommon and is not always associated with rhabdoid morphology. Histopathology. 2017 Feb;70(3):359-366.
6. Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A. SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol. 2016 Apr;40(4):544-53.
7. Horton RK, Ahadi M, Gill AJ, Said S, Chen ZE et al. SMARCA4/SMARCA2-deficient Carcinoma of the Esophagus and Gastroesophageal Junction. Am J Surg Pathol. 2020 Oct 6. doi: 10.1097/PAS.0000000000001599. Epub ahead of print. PMID: 33027072. ​

Photo of Maria (Adelita) Vizcaino Villalobos, M.D. Maria (Adelita) Vizcaino Villalobos, M.D.
Resident, Anatomic Pathology/Neuropathology
Mayo Clinic
Photo of Zong-Ming (Eric) Chen, M.D., Ph.D. Zong-Ming (Eric) Chen, M.D., Ph.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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