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Purpose Thoracic SMARCA4-deficient undifferentiated tumor (SD-UT) is a highly aggressive disease that is nosologically related to but distinct from SMARCA4-deficient non-small cell lung cancer (SD-NSCLC). No standard treatment guidelines were established for SD-UT. This research explored the efficacy of different treatments in SD-UT, and the prognostic, clinicopathologic and genomic difference between SD-UT and SD-NSCLC. Materials and methods Information of 25 SD-UT and 22 SD-NSCLC patients diagnosed and treated in Fudan University Shanghai Cancer Center from January, 2017 to September, 2022 was analyzed. Results SD-UT was similar to SD-NSCLC in characteristics of onset age, male prevalence, heavy smoking history and metastatic pattern. SD-UT showed a rapid relapse pattern after radical therapy. For Stage IV SD-UT patients, immune checkpoint inhibitor (ICI) plus chemotherapy significantly improved median progression-free survival (PFS) compared to traditional chemotherapy as first-line treatment (26.8 vs. 2.73 months, p  = 0.0437), while objective response rates of two arms were comparable (71.4% vs. 66.7%). No significant survival differences were observed between SD-UT and SD-NSCLC under similar treatment settings. SD-UT or SD-NSCLC patients receiving ICI in the first line had significantly prolonged OS than those with ICI in the latter lines or without ICI treatment throughout clinical courses. Genetic study found frequent SMARCA4, TP53 and LRP1B mutations in SD-UT. Conclusion To the best of our knowledge, this is the largest series to date to compare the efficacy of ICI-based treatment to chemotherapy and document frequent mutations of LRP1B in SD-UT. ICI plus chemotherapy is an effective strategy for Stage IV SD-UT.

Background SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4-deficient thoracic sarcoma (SMARCA4-DTS) is a rare disease that has recently been described as an entity. It is characterized by an aggressive clinical course and specific genetic alterations. As an immunohistological feature, the tumors are deficient in SMARCA4 and SMARCA2 and express sex-determining region Y (SRY)-box 2 (SOX2). Occasionally, there are cases that are less frequent and difficult to distinguish from SMARCA4-deficient non-small cell lung carcinoma (SMARCA4-dNSCLC). Therefore, the 5th edition of the World Health Organization (WHO) classification describes thoracic SMARCA 4-deficient undifferentiated tumors (SMARCA4-UT). In contrast, Carney’s triad is a syndrome that combines three rare soft tissue tumors: gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) has been proposed as the causative gene. Both diseases are valuable cases; moreover, there have been no previous reports of their coexistence. Case presentation A 43-year-old man visited our hospital because of respiratory distress. Computed tomography revealed a large mass measuring 55 mm in the upper lobe of the right lung and front mediastinum, with metastases in the surrounding lymph nodes. Needle biopsy was performed for diagnosis, and histological examination of the samples revealed monotonous epithelioid-like cells with loose binding and sheet-form proliferation. The tumor cells had distinct nuclei with some rhabdoid-like cells. Immunohistochemical analysis revealed that the tumor cells were positive for AE1AE3, SOX2, CD34, and p53 and negative for SMARCA4 and SMARCA2. The patient died 6 months after admission, without any treatment. Autopsy revealed ganglioneuroma and enchondroma suggestive of an incomplete Carney complex. Conclusion SMARCA4-UT is a rare and recently established disease. While it is difficult to diagnose, it is necessary to distinguish undifferentiated carcinoma, large cell carcinoma, Ewing sarcoma, and epithelioid sarcoma when diagnosing tumors involving the mediastinum. Moreover, cases of SMARCA4-UT with ganglioneuroma and enchondroma are very rare. We discuss and report a case of SMARCA4-UT in which we also examined ARID1A and SLC7A11expression.

Background SMARCA4 -deficient undifferentiated tumor ( SMARCA4 -UT) is a rare and highly malignant primary tumor characterized by the loss of SMARCA4 expression. Despite advancements in oncology, diagnosing and treating SMARCA4-UT remain significant clinical challenges. Case demonstration A 67-year-old male with a history of smoking presented to the hospital with complaints of abdominal distention and pain lasting for more than four days. Abdominal computed tomography (CT) revealed a high-density mass measuring approximately 41 × 37 mm in the right lower quadrant. Additionally, chest CT identified a high-density mass measuring 63 × 48 mm in the upper lobe of the right lung. The patient underwent partial small bowel resection, and postoperative pathological examination confirmed a diagnosis of SMARCA4 -UT originating in the small mesentery. Unfortunately, the patient succumbed to respiratory failure 21 days after the diagnosis. Conclusion SMARCA4 -UT is an exceedingly rare and aggressive undifferentiated tumor. This case highlights a presentation of SMARCA4 -UT with abdominal pain and distention as initial symptoms. Clinicians should consider SMARCA4 -UT in middle-aged or elderly male patients with a history of smoking who present with large masses. Comprehensive chest imaging is essential to exclude the thoracic primary disease in such cases.

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are rare malignancies characterized by resistance to chemotherapy and poor clinical outcomes. While immunotherapy have shown promise, especially in the first-line treatment, effective therapeutic strategies for patients with PD-L1-negative tumors and complex genomic profiles remain undefined. We report a case of chemorefractory SMARCA4-UT in a patient presenting with cervical mass. CGP revealed pathogenic SMARCA4 , TP53 , and CDKN2A mutations. Despite PD-L1 negativity, the tumor exhibited TMB-H and a dominant smoking signature. Guided by precision oncology targeting both immunogenic profile and cell-cycle dysregulation, the patient was treated with dual immunotherapy (pembrolizumab plus ipilimumab) combined with the CDK4/6 inhibitor palbociclib. This novel regimen elicited a metabolic partial response within 1.5 months, which has been sustained for over 4 months. To our knowledge, this is the first report demonstrating the efficacy of dual checkpoint blockade plus CDK4/6 inhibition in SMARCA4-UT. This case highlights potential of biomarker-driven therapies to overcome resistance in rare thoracic neoplasms.

Introduction: Thoracic SMARCA4-deficient Undifferentiated Tumors (SMARCA4-UT) are rare and aggressive malignancies. This case is unique as it describes the first gingival metastasis from thoracic SMARCA4-UT, emphasizing the diagnostic role of dental professionals. Observation : A 71-year-old man, heavy smoker (50 pack-years), presented with chest pain, dyspnea, weight loss, and a gingival lesion. Oral examination revealed poor oral health with severe periodontitis, trismus, halitosis, pain on palpation, and a 3 cm friable gingival tumor in sector 2. Premolars showed grade 3 mobility and loss of vitality. 3D imaging confirmed tumor extension. CT, PET-CT, revealed thoracic, adrenal masses and multiple metastases. Histopathology confirmed SMARCA4-UT with gingival metastasis. Outcome : The patient's condition deteriorated rapidly, and he died before treatment could be initiated. Conclusion : Dental professionals play a key role in suspecting systemic disease from oral manifestations. This case underscores the importance of considering metastasis in atypical oral tumors.

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) exhibit a notably aggressive phenotype, which is associated with poor patient survival outcomes. These tumors are generally resistant to conventional cytotoxic chemotherapy, thereby limiting the availability of effective treatment options. We describe a 69-year-old AIDS patient who initially presented with a fused, enlarged lymph node on the right clavicle and mild, unexplained pain under the right axilla that worsened with severe coughing episodes. An initial chest CT scan revealed multiple nodular and mass shadows in the mediastinum and multiple nodules in both lungs, as well as a small amount of pericardial effusion. Additionally, serum biomarkers of lung cancer were abnormal as follows: carcinoembryonic antigen (CEA) at 13.74 ng/mL, cytokeratin 19 fragment (CYFRA21-1) at 6.82 ng/mL, neuron-specific enolase (NSE) at 25.49 ng/mL, and progastrin-releasing peptide precursor (ProGRP) at 89.35 pg/mL. Subsequent pathology confirmed SMARCA4-deficient undifferentiated tumors. Considering that the weak immune status and intermediate PD-L1 level, the patient was treated with a first-line combination therapy of immunotherapy and anti-angiogenic drug instead of chemo-immunotherapy. The patient responded well to immunotherapy combining anti-angiogenic drugs and achieved an overall survival for more than 22 months. Our study presented a rare case of thoracic SMARCA4-deficient undifferentiated tumors and AIDS, suggesting that first-line immunotherapy plus anti-angiogenic drugs as a potential therapeutic option for SMARCA4-UT patients under specific conditions.

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), as a rare and highly malignant neoplasm associated with a high mortality risk, is easily confused with SMARCA4-deficient nonsmall-cell lung cancer (NSCLC). To date, no standard and effective protocol for thoracic SMARCA4-UT has been established. Immunotherapy has demonstrated efficacy in advanced NSCLC, achieving unprecedented survival benefits. However, immune-related adverse events (irAEs) remain a significant clinical challenge. Here, we reported the first case of thoracic SMARCA4-UT with immune-related cystitis and hypothyroidism, in which the patient benefited from first-line immune checkpoint inhibitor (ICI)-based combination therapy, achieving a remarkable overall survival of over 100 weeks. Furthermore, we performed a review and analysis of the diagnosis, differential diagnosis, immunotherapy, and prognosis of thoracic SMARCA4-UT, proposing that first-line therapy combining immunotherapy with platinum-based chemotherapy (induction and maintenance phases) with or without radiotherapy, may improve the prognosis of such patients. Additionally, we hypothesized a potential role of macrophages in the pathogenesis of immune-related cystitis for the first time and detailed the clinicopathological characteristics and evidence-based management of this irAE.

SMARCA4‐deficient undifferentiated tumor (SMARCA4‐UT) in the chest is a high‐grade malignant tumor that grows rapidly and often carries a poor prognosis. Unfortunately, there are currently no effective treatment available until now. Here, we report a case of SMARCA4‐UT in a patient who showed a swift response to a combination treatment of penpulimab, anlotinib, and chemotherapy. A 55‐year‐old man was diagnosed with thoracic SMARCA4‐UT along with metastases to multiple lymph nodes, the pleura, and bones. Immunohistochemical (IHC) testing indicated the absence of PD‐L1 expression in tumor cells. He was given sintilimab and anlotinib as first line treatment. However, a follow‐up chest CT revealed progressive disease (PD) after the first cycle treatment. Subsequently, the second line regimen was modified to etoposide and cisplatin (EP) combined with anlotinib and penpulimab. The effectiveness evaluation revealed partial remission (PR) following two cycles of the second‐line regimen treatment. Notably, the patient's progress‐free survival (PFS) exceeds 7 months and the overall survival up to 12 months. Our case implies that a combination of chemotherapy, anlotinib, and penpulimab might offer a promising therapeutic approach for PD‐L1‐negative thoracic SMARCA4‐UT. A 55‐year‐old male with advanced thoracic SMARCA4‐deficient undifferentiated tumor (SMARCA4‐UT) and no PD‐L1 expression achieved a durable partial response with second‐line therapy combining etoposide‐platinum chemotherapy, anlotinib, and penpulimab. Maintenance therapy and palliative radiotherapy provided temporary disease control before progression at 12 months. This case highlights the potential of multimodal therapy targeting SMARCA4 and TP53 mutations in improving outcomes for this rare, aggressive malignancy.

Thoracic SMARCA4‐deficient undifferentiated tumour (SMARCA4‐dUT) is a rare and highly aggressive malignant tumour with poor response to conventional chemotherapy and a poor prognosis, for which there is currently no standard treatment. This article details a case of SMARCA4‐dUT in which next‐generation sequencing (NGS) revealed a frameshift mutation in SMARCA4 (N259Tfs44), along with high PD‐L1 expression (tumour proportion score, TPS 90%) and a high tumour mutational burden (TMB, 24.58 mutations/Mb). The patient achieved a progression‐free survival (PFS) of over 32 months following treatment with pembrolizumab combined with conventional chemotherapy. However, the tumour eventually recurred and transformed into SMARCA4‐deficient squamous cell carcinoma (SMARCA4‐dSCC). To our knowledge, this is the first reported case of histological transformation in SMARCA4‐dUT. Immunotherapy may represent a potential treatment option for SMARCA4‐dUT, particularly in patients with high TMB and PD‐L1 expression. We present the first confirmed SMARCA4‐dUT progression to SMARCA4‐dSCC in a patient achieving durable re‐mission with ICIs. This observation challenges the conventional view of SMARCA4‐dUT and SMARCA4‐dNSCLC as entirely distinct entities, suggesting potential pathogenic continuity.

SMARCA4‐deficient undifferentiated thoracic tumors are a rare phenomenon. A 40‐year‐old male was newly diagnosed with SMARCA4‐deficient undifferentiated non‐small cell lung cancer. He had a history of heavy smoking and job‐related exposure to metal dust and melted nickel. CT imaging showed numerous right‐sided pleural masses and soft tissue plaques, but no metastases. CT‐guided biopsy of a pleural mass confirmed the diagnosis. He was prescribed six cycles of carboplatin paclitaxel, and follow‐up imaging showed largely stable disease. Treatment was changed to nivolumab due to shortness of breath, and he received one cycle of nivolumab without considerable side effects. Unfortunately, during the second cycle of his nivolumab, the patient presented with new weakness. Imaging showed spinal cord metastasis and he underwent a laminectomy; he was subsequently followed up as an outpatient. The objective of this publication was to explore SMARCA4‐deficient undifferentiated thoracic tumors, other related SMARCA4‐deficient tumors, and their overall pattern of presentation. The genetic aberrations of this case are compared to recent publications that also discuss genetic aberrations commonly occurring with this disease process, with an ultimate goal of hastening detection and adding to the library of treatment results. SMARCA4 deficient tumors are rare and can present in multiple organ systems.This case report of a SMARCA4 deficient lung cancer exemplifies how to hasten diagnostic detection and how to navigate treatment options.