SMARCA4-Deficient Undifferentiated Carcinoma: A Report of 2 Cases

Introduction

SMARCA4-deficient undifferentiated carcinoma (SMARCA4-DUC) is a rare (fewer than 100 SMARCA4-DUC cases have been reported [1]) and aggressive malignancy driven by inactivation of the SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 4) gene, a critical component of the SWI/SNF chromatin-remodeling complex. This complex regulates gene expression by remodeling chromatin to ensure DNA accessibility for transcription, repair, and replication. SMARCA4 mutations disrupt these essential processes, impairing normal cell differentiation, development, and genomic stability, ultimately leading to tumorigenesis [2,3].

Initially identified in thoracic tumors, particularly in the mediastinum, SMARCA4-DUC is now increasingly recognized in extrathoracic sites, including the gastrointestinal tract, genitourinary system, and soft tissues [4,5]. Histopathologically, SMARCA4-DUC shows loss of BRG1 (the protein encoded by the SMARCA4) expression on immunohistochemistry and typically exhibits a high Ki-67 proliferation index, reflecting its aggressive biology.

Clinically, SMARCA4-DUC is characterized by rapid tumor progression, extensive local invasion, and poor prognosis due to its undifferentiated morphology and high proliferative potential. Patients often present symptoms such as pain, significant weight loss, and mass effect, reflecting the tumor’s aggressive and invasive nature. Among these, gastric SMARCA4-DUC is not only extremely rare, with SMARCA4 loss observed in less than 0.5% of gastric tumors, but also often mimics other malignancies such as poorly differentiated adenocarcinoma, gastrointestinal stromal tumor (GIST), lymphomas, metastatic melanoma, germ cell tumors, or sarcomas [6], making timely diagnosis and appropriate treatment particularly challenging.

Here, we report 2 rare cases of gastric SMARCA4-DUC with extensive local invasion and metastasis. These cases underscore the importance of early clinical suspicion, timely molecular diagnostics, and multidisciplinary management to prevent diagnostic delays and to guide appropriate therapeutic strategies for this rare gastric tumor.

Case Reports

CASE 1:

A 71-year-old woman presented with a 2-month history of nausea, dyspepsia, and significant weight loss. An initial gastroscopy at an outside hospital identified a 5-cm ulcerofungating mass at the gastroesophageal junction to the midbody along the greater curvature, raising suspicion for advanced gastric cancer. She received her last gastroscopy 2 or 3 years ago. Her medical history included hypertension and dyslipidemia, with a family history for her father’s gastric cancer. Endoscopic re-evaluation revealed a large ulcerofungating mass in the gastric cardia (Figure 1A). Computed tomography (CT) identified a 13.6×13.0×9.0 cm exophytic tumor suspected to be advanced gastric cancer (AGC) or a gastrointestinal stromal tumor (GIST), invading the pancreas and transverse colon, with suspicious regional LN metastasis (Figure 1B, 1C). Positron-emission tomography (PET) imaging suggested a large hypermetabolic gastric tumor with a nodule suggestive of pelvic seeding (Figure 1D).

Endoscopic biopsy revealed a malignant tumor composed of round-to-epithelioid cells arranged in solid sheets without evidence of glandular or squamous differentiation (Figure 2A). Immunohistochemically, the tumor cells were negative for cytokeratin (AE1/AE3) (Figure 2B), CD3, CD20, CD30, CD34, CD117, HMB45, S-100, and NUT, with a high Ki-67 proliferation index (>90%). BRG1 expression was lost in tumor cells but were retained in non-neoplastic elements (Figure 2C). Targeted next-generation sequencing identified a frameshift mutation in SMARCA4 (p.Ser478fs, c.1432delA), confirming the diagnosis of SMARCA4-deficient undifferentiated carcinoma.

The patient underwent total gastrectomy with lymph node dissection, distal pancreatectomy, and segmental colectomy. No pelvic seeding nodules were found during surgery. The postoperative course was complicated by transient bacteremia effectively managed with antibiotics and supportive care. A CT scan taken 1 week after surgery revealed multiple liver metastases (Figure 3A–3D), which had not been present on preoperative imaging, consistent with progressive disease (PD) based on RECIST 1.1 criteria. Postoperative pathology confirmed a SMARCA4-deficient undifferentiated carcinoma (SMARCA4-DUC). The tumor was staged as pT4b (direct invasion into the pancreas), N0 (0/12), M0. A multidisciplinary treatment discussion recommended systemic chemotherapy with paclitaxel and carboplatin. Despite the aggressive nature of the tumor, early imaging after the first cycle of chemotherapy demonstrated stable disease. However, the patient was unable to proceed to a second cycle due to poor general condition and was subsequently transferred to another hospital for hospice care.

CASE 2:

An 80-year-old man with a history of hypertension, diabetes mellitus, chronic kidney disease (CKD), benign prostatic hyperplasia (BPH), and a 6 pack-year smoking history visited Seoul National University Hospital following the incidental discovery of a gastric mass during routine health screening. He reported general fatigue and a 5 kg weight loss over 1 month but denied significant abdominal pain or other specific symptoms.

Gastroscopy performed at an outside hospital revealed a gastric tumor suspicious for Borrmann type III advanced gastric cancer (AGC) located in the gastric cardia (Figure 4A). Computed tomography (CT) demonstrated a 9.0×7.4×4.6 cm gastric tumor invading the pancreas tail without distant metastasis (Figure 4B, 4C). Severe anemia (Hb 7.9 g/dL) was found during preoperative evaluation. Positron-emission tomography (PET) imaging suggested a hypermetabolic mass in the stomach without distant metastasis (Figure 4D).

The patient underwent laparoscopic total gastrectomy, distal pancreatectomy, and splenectomy. Postoperative recovery was complicated by a loculated fluid collection in the distal pancreatectomy bed and mild pleural effusion, both of which were managed conservatively with antibiotics and supportive care. Postoperative pathology confirmed a SMARCA4-deficient undifferentiated gastric carcinoma with a poorly differentiated tubular adenocarcinoma component (20%). Immunohistochemical staining revealed complete loss of SMARCA4 expression in the undifferentiated component, while expression was retained in the adenocarcinoma component (Figure 5A–5C). The tumor was staged as pT4b (direct invasion into the pancreas), N2 (4/62), M0. Adjuvant XELOX chemotherapy (capecitabine and oxaliplatin) was initiated in January 2025, and he completed 5 cycles by April 2025. He remains under close surveillance without recurrence. A comparison of the 2 cases is presented in Table 1.

Discussion

SMARCA4-deficient undifferentiated carcinoma (SMARCA4-DUC) is a rare and underrecognized malignancy of the gastrointestinal tract, often leading to delayed diagnosis [1–5]. A definitive diagnosis requires either identification of pathogenic SMARCA4 gene alterations or confirmation of BRG1 loss by immunohistochemistry. However, these characteristic findings may not be evident in small or superficial biopsy specimens, highlighting the need for comprehensive clinicopathologic correlation and increased awareness among clinicians and pathologists.

Surgical resection remains the cornerstone of treatment; however, given the aggressive nature of SMARCA4-DUC, systemic therapy is generally required after surgery, even in resectable cases. While cytotoxic regimens such as paclitaxel-carboplatin and XELOX have shown potential for initial disease stabilization, no standardized treatment protocols have been established, and long-term outcomes remain unsatisfactory. Clinical courses vary considerably, as reflected in our 2 cases: one patient developed liver metastases shortly after surgery and was unable to proceed beyond the first cycle of chemotherapy due to poor general condition, whereas the other completed 5 cycles of adjuvant chemotherapy and remains recurrence-free under active surveillance. Interestingly, the latter case exhibited a 20% component of poorly differentiated tubular adenocarcinoma. Some undifferentiated carcinomas demonstrate focal glandular differentiation, implying a potential dedifferentiation from more differentiated gastric cancer subtypes. However, due to their rarity and aggressive nature, the prognostic implications of such histologic features remain poorly defined [6].

Recent molecular studies have identified potential vulnerabilities in SMARCA4-DUC, including synthetic lethality with inhibition of epigenetic regulators such as bromodomain and extra-terminal motif (BET) proteins and enhancer of Zeste homolog 2 (EZH2), which are currently under clinical investigation [4]. However, the rarity of this tumor presents challenges in clinical trial enrollment and robust data generation.

Accordingly, maintaining a high index of clinical suspicion and ensuring early referral for multidisciplinary evaluation are essential to improve diagnostic accuracy and therapeutic outcomes.

Conclusions

In cases where gastric tumors reveal an extensive and undifferentiated morphology, the differential diagnosis encompasses a broad spectrum of malignancies, including adenocarcinoma, GIST, lymphoma, melanoma, germ cell tumors, and sarcoma. SMARCA4-deficient undifferentiated carcinoma should be included as a potential entity, particularly in cases lacking lineage-specific features. BRG1 immunohistochemistry, along with clinicopathologic correlation, plays a key role in accurate identification. Multidisciplinary management should involve early consultation among surgeons, medical oncologists, pathologists, and radiologists to ensure accurate diagnosis, timely surgery, and initiation of systemic therapy and appropriate surveillance strategies.

We report 2 rare cases of SMARCA4-DUC of the stomach, which initially mimicked other malignancies, resulting in diagnostic ambiguity. Despite similar preoperative presentations, the clinical outcomes differed significantly. These cases are novel in highlighting the importance of early recognition and in proposing a practical diagnostic and tailored management workflow for this rare and aggressive tumor. Further studies are warranted to clarify the prognostic implications of tumor biology, including the potential role of histologic heterogeneity.