Abstract
Gastric SMARCA4-deficient carcinosarcoma and sarcomatoid carcinoma are rare with poor prognosis. In the present study, two male patients were hospitalized due to abdominal manifestations, specifically abdominal pain and a sense of fullness and discomfort. Gastroscopic examination revealed huge raised lesions in the stomach of both individuals, subsequently leading to laparoscopic radical total gastrectomy. Histopathological analysis of surgical specimens obtained from both patients demonstrated the presence of carcinomatous and sarcomatous components. In Case 1, the sarcoma region was negative for the SMARCA4, epithelial markers cytokeratin (CK) and epithelial membrane antigen (EMA), CK, EMA, and SMARCA4 were positively expressed in the adenocarcinoma area, thereby warranting carcinosarcoma diagnosis. The sarcomatous component was identified as a tumor characterized by SMARCA4 deficiency. In Case 2, the tumor cells exhibited positive staining for CK and Vimentin, negative staining for SMARCA4, and the patient was positive for SMARCA4-deficient sarcomatoid carcinoma.
Introduction
SMARCA4 mutations occur in 7% of human tumors () and affect multiple organ systems. The mutation frequency of SMARCA4 varies significantly across different tumor types. It has been reported to be mutated in 15% of Burkitt’s lymphoma (), 10-35% of non-small-cell lung carcinoma (, ), 5-10% of medulloblastoma and melanoma (–). The mutation rate of SMARCA4 in gastric cancer is relatively low, approximately 2% ().SMARCA4-deficient tumors are typically poorly differentiated or undifferentiated, exhibit highly malignant and invasive characteristics, and show resistance to chemotherapy (). Histologically, adenocarcinoma is the most frequently observed cancer (), while sarcomatoid and carcinosarcomas variants are uncommon.
This study presents two cases of SMARCA4-deficient gastric tumors: one case of carcinosarcoma and one of sarcomatoid carcinoma. It elaborates on their histological similarities and differences and further explores potential therapeutic approaches for SMARCA4-deficient gastric tumors. The main clinicopathologic characteristics of these two patients are summarized in Table 1.
Table 1
| Clinical date | Case1 | Case2 |
|---|---|---|
| Age (years)/sex | 50/male | 68/male |
| Symptoms | Upper abdominal fullness and discomfort | Abdominal pain and belching |
| Location | Gastric fundus | Gastric fundus on the lesser curvature |
| Size | 6 × 7 cm | 10 x 8 cm |
| CT | Thickening of the gastric wall; mild enhancement | Thickening of the gastric wall; mild-to-moderate heterogeneous enhancement |
| Endoscopic finding | Protruding lesion; ulcerative | Protruding lesion; ulcerative |
| Borrmann | Type I | Type I |
| Pathologic diagnosis | SMARCA4-deficient Carcinosarcoma | SMARCA4-deficient sarcomatoid carcinoma |
| Histologic features | Moderately differentiated; glandular; rhabdoid | undifferentiated; rhabdoid |
| SMARCA4 expression | Positive in the adenocarcinoma, total loss in the sarcoma | total loss |
| TNM stage | pT4N2M0 | pT4N1M0 |
| Therapeutic approach | Resection | Resection; traditional Chinese medicine |
| Recurrence | liver | no |
| Duration after surgery | 24M | 25M |
| outcome | dead | alive |
The clinicopathologic features of gastric SMARCA4-deficient carcinosarcoma and sarcomatoid carcinoma.
Case presentation
Case1
A 50-year-old male patient was admitted to the hospital for upper abdominal fullness and discomfort lasting 6 months and difficulty in swallowing for more than 20 days. The patient had no specific medical or family history. Physical examination revealed deep tenderness in the upper abdomen. The serum tumor-related antigen was 99.47 U/mL (normal, 0–95 U/mL); all other laboratory results were normal. Enhanced computed tomography (CT) showed thickening of the gastric cardia wall in the lower esophageal segment with mild enhancement (Figure 1A); multiple hepatic cysts. Gastroscopy revealed a large protruding lesion on the gastric fundus mucosa with a ruptured surface, Borrmann type I (Figure 1C). Four biopsy specimens were taken from the edge of the ulceration. The biopsy pathology was diagnosed as tumor with SMARCA4 deficiency. Immunohistochemistry result: HMB-45(-), S-100(-), EMA(-), CAM5.2(-), ERG(-), INI-1(+), CK局灶(+), CK7(-), CK5/6(-), p40(-), Vimentin(+), SMARCA4(-), Ki-67(+,70-80%).
Figure 1
The patient underwent radical total gastrectomy with esophagojejunostomy, but declined postoperative adjuvant treatment. Lymph nodes no. 1, 2, 3, 5, 6, 7, 8, 9 and 11 were removed during the operation. The tumor measured approximately 7 cm × 6 cm. Histopathological analysis revealed a mixed tumor composed of moderately differentiated adenocarcinoma and sarcoma. In the adenocarcinoma region, cancer cells formed glandular tubular structures with fibrinoid necrosis. The boundary between the adenocarcinoma and sarcomatous areas was unclear. Sarcomatous cells were loosely arranged, spindle-shaped, uniform in size, and displayed bizarre nuclei, numerous mitotic figures, rich cytoplasm, eccentric nuclei, large nuclei, obvious nucleoli, and many inflammatory cell infiltrations (Figure 1E). The tumor invaded the entire thickness of the gastric wall and the nerve. Cancer emboli were observed in the vessels. There were three lymph node metastases: one was an adenocarcinoma, and two were sarcoma components. Immunohistochemistry revealed that CK (Figure 1G), EMA, and SMARCA4 (Figure 1K) were positively expressed in the adenocarcinoma area, whereas Vimentin (Figure 1I) was negative; CK (Figure 1G), EMA, SMARCA4 (Figure 1K), ERG, Desmin, CD34, HMB-45, S100, CK7, CK5/6, and p40 were negatively expressed in the sarcoma area, while Ki-67(+50–60%), Vimentin (Figure 1I), and INI-1 were positively expressed. The final diagnosis was carcinosarcoma with a SMARCA4 deficiency in the sarcoma area; pT4N2M0.
The patient underwent a re-examination 12 months after surgery. CEA, CA199, and CA125 were all within the normal ranges. Color ultrasound showed that the hypoechoic area in the left lobe of the liver was inclined to be a benign lesion, which required dynamic observation, and multiple cysts in the liver. Eighteen months after surgery, the patient was readmitted to hospital for liver metastasis detected by a CT scan at an out-of-town hospital, but refused further examinations and treatment. The patient ultimately survived for 24 months. The patient’s timeline of consultations is shown in Figure 2.
Figure 2
Case2
A 68-year-old male patient was admitted to the hospital for abdominal pain and belching lasting over 1 month. The patient had no specific medical or family history. Laboratory tests showed normal levels of CA19-9, carcinoembryonic antigen, and alpha-fetoprotein. Enhanced CT revealed thickening of the gastric lesser curvature at the cardia wall, with an irregular mass, and mild-to-moderate heterogeneous enhancement (Figure 1B). Gastroscopy showed a large protruding lesion near the gastric fundus on the lesser curvature, with ulceration on the oral side, Borrmann type I (Figure 1D). Six biopsy specimens were taken from the oral side. The biopsy pathology was diagnosed as adenocarcinoma of the gastric body with necrosis. The patient underwent radical total gastrectomy with esophagojejunostomy. Perigastric lymph nodes were removed during the operation.
The tumor measured approximately 10 cm × 8 cm. Microscopically, the tumor cells were arranged disorderly, without the structural hierarchy of normal tissues. They contained cancerous and sarcomatoid components. The cancerous component contained moderately differentiated epithelial-like nest cells, while the sarcomatoid component featured diffuse spindle growth cells invading the entire thickness of the gastric wall (Figure 1F). Cancer emboli were detected in the vessels. CK (Figure 1H), Vimentin (Figure 1J) and Ki-67 (>75%) were positive in the tumor cells, whereas SMARCA4 (Figure 1L), CD20, LCA, CD3, HMB-45, Melan-A, Epstein-Barr virus (EBV) were negative. Mismatch repair proteins were intact. The final diagnosis was SMARCA4-deficient sarcomatoid carcinoma; pT4N1M0.
After surgery, the patient refused chemotherapy and received traditional Chinese medicine (TCM) treatment at another hospital, with no recurrence or metastasis, during the 25-month telephone follow-up. The patient’s timeline of consultations is shown in Figure 3.
Figure 3
Discussion
The SWitch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex is a multi-protein complex consisting of 10–15 subunits, regulates gene activity through chromatin remodeling processes, maintains genomic stability, and controls cell growth, differentiation, and other biological behaviors. SMARCA4 is the primary SWI/SNF complex subunit that generates energy through the catalysis of ATP hydrolysis, which is essential for ensuring the normal function of the complex, thereby maintaining the normal cell physiological function and gene expression patterns ().
SMARCA4 mutations occur in almost all small cell carcinoma of the ovary hypercalcemic type () and 8% of non-small cell lung cancer cases (). Gastric SMARCA4-deficient carcinosarcoma and sarcomatoid carcinoma are particularly rare. In the literature review, we identified only 4 previously reported cases of SMARCA4-deficient gastrointestinal tumors with sarcomatoid components that had a definitive pathological diagnosis. These cases were designated as carcinosarcomas or sarcomatoid carcinomas (–). A summary of these cases is provided in Table 2. The patients ranged in age from 46 to 73 years (mean, 66.3 years) with a male-to-female ratio of 3:1. The tumors were located at the esophagogastric junction (1 case), rectum (1 case), and colon (2 cases), with sizes ranging from 3.5 to 17 cm. Including the 2 cases reported in the present study, 5 out of 6 patients underwent surgical resection, among whom 2 received other postoperative adjuvant therapies and achieved favorable outcomes. Detailed information is presented in Table 2. SMARCA4-deficient tumors with sarcomatoid components in the chest and rectum (, ) are often associated with claudin-4 and SMARCA2 deficiencies; they had larger primary tumor volumes and shorter survival times than other types of SMARCA4-deficient tumors.
Table 2
| NO. | References | Age (years) sex | Symptoms | Location | Size | CT | Endoscopic finding | Pathologic diagnosis | SMARCA4 expression | TNM stage | Therapeutic approach | Outcome (month) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | () | 73/male | dysphagia, odynophagi | gastro-esophageal junction and gastric fundus | 17cm | abnormal wall thickening in the proximal stomach | a gastric mass | SMARCA4-deficient sarcomatoid tumor | total loss | T4aN2M0 | Preoperative chemotherapy; resection | NA |
| 2 | () | 46/male | a prolapsing anal mass | lower rectum | 3.5x3cm | localized wall thickness | an irregular nodular elevated lesion | SMARCA4−deficient rectal carcinoma with a sarcomatoid component | total loss | T3N2bM0 | Resection; chemotherapy; radiation therapy | 12/alive |
| 3 | () | 79/female | NA | Transverse | NA | NA | NA | SMARCA4-deficient sarcomatoid carcinoma | total loss | NA | NA | 0/alive with disease in hospice |
| 4 | 67/male | NA | Sigmoid | 4.5cm | NA | NA | SMARCA4-deficient sarcomatoid carcinoma | SMARCA4-deficient sarcomatoid carcinoma | T4N2aM1b | Resection | 1/dead |
Reported cases: clinicopathologic features of SMARCA4-deficient gastrointestinal tumors with sarcomatoid components.
Carcinosarcomas and sarcomatoid carcinomas share some morphological overlap; however, they are distinct tumor entities (). The SMARCA4-deficient carcinosarcoma reported in this study is an unclassified pleomorphic sarcoma, which is immunoreactive to the stromal marker Vimentin but non-immunoreactive to the epithelial markers CK, EMA. The cancerous component is a moderately differentiated adenocarcinoma. There is no transitional zone between the two components. The SMARCA4-deficient sarcomatoid carcinoma is essentially a special type of epithelial-derived carcinoma, in which tumor cells undergo mesenchymal-like morphological transformation. Tumor cells express CK and Vimentin. The cancerous component manifests as nests of epithelial-like cells, and there is a distinct transitional zone between the two components.
The cases described in this study require differentiation from malignant rhabdoid tumors, lymphomas, epithelioid gastrointestinal stromal tumors, melanomas, undifferentiated gastric carcinomas, NUT midline carcinomas, and other neoplastic entities. Most of these differential diagnoses can be accomplished using specific immunohistochemical markers or molecular detection approaches. For example, malignant rhabdoid tumors predominantly affect infants and young children, primarily arising in the central nervous system or soft tissues, with occasional involvement of the gastrointestinal tract. Immunohistochemically, the tumor cells exhibit expression of Vimentin, CKpan, and EMA. Lymphoma cells characteristically express lymphoid markers such as LCA. Epithelioid gastrointestinal stromal tumor cells are arranged in a nest-like or sheet-like pattern with epithelioid morphology, and their identification can be confirmed by positive immunohistochemical staining for CD117 and DOG1. Melanomas show positivity for immunohistochemical markers including HMB45, MelanA, and S100. As an epithelial-derived neoplasm, undifferentiated gastric carcinoma typically expresses epithelial markers and generally lacks or rarely exhibits expression of mesenchymal markers (e.g., Vimentin). In NUT midline carcinoma, abrupt foci of squamous differentiation are frequently observed, and the tumor cells harbor detectable BRD-NUT fusion and positive NUT expression.
Surgical resection remains the main treatment for SMARCA4-deficient tumors. However, it is still necessary to combine other adjuvant therapies to delay the progression of the disease. SMARCA4/2 deficiency reportedly restricts the flow of calcium ions mediated by IP3R3 from cancer cells to the mitochondria, leading to resistance to chemotherapeutic drugs (). So most patients show poor responsiveness to chemotherapy (). For example, a case report of a 73-year-old male with gastric SMARCA4-deficient high-grade sarcomatoid carcinoma showed that the patient was unresponsive to chemotherapy (); however, a case report of a 59-year-old male with gastric SMARCA4-deficient sarcoma demonstrated that the patient had a good response to combined chemotherapy with doxorubicin and ifosfamide after surgery and remained alive during 49 months of follow-up (). Both patients in this article refused postoperative chemotherapy, making it impossible to evaluate the efficacy of chemotherapy.
As a homologous subunit of SMARCA4 in the SWI/SNF complex, SMARCA2 has emerged as an attractive therapeutic target for SMARCA4-deficient tumors through a synthetic lethal effect (). However, SMARCA2 is also mutated or inactivated in a variety of solid tumors. Previous studies have documented SMARCA2 mutations or deletion in 5-10% of non-small-cell lung carcinoma (, ), 10% of esophageal adenocarcinoma (), 5-9% of gastric cancer (, ), 1.3% of colorectal carcinoma (), 3% of clear cell renal cell carcinoma (), and 5% adenoid cystic carcinomas (). Notably, the loss of SMARCA2 has been observed in some tumors with SMARCA4 deficiency, such as 90-100% of small cell carcinoma of the ovary (hypercalcemic type) (, ), 67-80% of thoracic SMARCA4-deficient undifferentiated tumors (, ), 15-30% of SMARCA4-deficient non-small cell lung cancer (, ), 11% of SMARCA4-deficient gastric adenocarcinoma (), 15% of SMARCA4-deficient colorectal cancer (), 70% of undifferentiated endometrial carcinoma (). This phenomenon limits the application of SMARCA2-targeted synthetic lethal therapies. SMARCA2-induced synthetic lethality also requires the complete loss of SMARCA4 function () and is ineffective against tumors with reduced or heterogeneous SMARCA4 expression. Second-generation histone deacetylase inhibitors (HDACis) can reactivate the expression of SMARCA2-dependent IP3R3, reduce the limitation of IP3R3-mediated calcium ion flow to mitochondria caused by SMARCA4/2 deficiency, enhancing their response to chemotherapy (). However, they are unsuitable for SMARCA4-deficient tumors without SMARCA2 deletion. SMARCA4-deficient lung and ovarian cancer cells show increased sensitivity to the KDM6 inhibitor GSK-J4, which can be an effective treatment option after cisplatin resistance (). However, its effect on gastric cancer cells is unknown. Programmed death-ligand 1 (PDL1) immunotherapy remains the most effective therapeutic option and is not restricted by PDL1 expression levels (). In our study, TCM treatment after surgery has led to no recurrence or metastasis during the 25-month follow-up period. It indicates that TCM treatment can become another widely applicable postoperative adjuvant treatment method.
This study provides a comprehensive description of two rare cases of primary gastric SMARCA4-deficient carcinosarcoma and sarcomatoid carcinoma. Histologically, the difference was the distinct responses of the sarcomatous components to epithelial markers. TCM treatment may serve as a post-surgical treatment option. However, due to the small sample size in this study, further studies are needed to better characterize these two tumor subtypes and their response to chemotherapy.
Statements
Data availability statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.
Ethics statement
The studies involving humans were approved by the Ethical Committee of the Affiliated Hospital of Jining Medical University (No.2022-11-C017). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
RZ: Writing – review & editing, Data curation, Writing – original draft. JZ: Data curation, Writing – original draft. XZ: Resources, Writing – review & editing. RYZ: Writing – review & editing, Supervision. LL: Writing – review & editing, Conceptualization.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. This study was supported by the Jining Key Research and Development Program, Project No. 2024YXNS110.
Acknowledgments
The authors thanked the patients’ family members for their cooperation and regular follow-up. We would like to thank Editage (www.editage.cn) for English language editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Generative AI was used in the creation of this manuscript.
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Summary
Keywords
gastric tumor, SMARCA4-deficient, carcinosarcoma, sarcomatoid carcinoma, case report
Citation
Zhao R, Zhang J, Zhi X, Zhang R and Li L (2025) Primary gastric SMARCA4-deficient carcinosarcoma and sarcomatoid carcinoma: Two case reports. Front. Oncol. 15:1663811. doi: 10.3389/fonc.2025.1663811
Received
11 July 2025
Accepted
30 September 2025
Published
15 October 2025
Volume
15 - 2025
Edited by
Xiaojun Liu, Gansu Provincial Hospital, China
Reviewed by
Narendra Bharathy, Children’s Cancer Therapy Development Institute, United States
Genlin Lu, Longyou People’s Hospital, China
Teodor Florin Georgescu, Carol Davila University of Medicine and Pharmacy, Romania
Updates
Copyright
© 2025 Zhao, Zhang, Zhi, Zhang and Li.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lei Li, lilei@mail.jnmc.edu.cn
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.