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1
Zhou, Ping, Yiyun Fu, Yuan Tang, Lili Jiang, and Weiya Wang. "Thoracic SMARCA4-deficient tumors: a clinicopathological analysis of 52 cases with SMARCA4-deficient non-small cell lung cancer and 20 cases with thoracic SMARCA4-deficient undifferentiated tumor." PeerJ 12 (February 16, 2024): e16923. http://dx.doi.org/10.7717/peerj.16923.
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Background Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a distinct clinicopathological entity with an aggressive clinical course. Additionally, SMARCA4/BRG1 deficiency can be observed in a few patients with non-small cell lung cancer (NSCLC). We aimed to compare the clinicopathological, immunohistochemical and prognostic features of SMARCA4-deficient NSCLC (SMARCA4-dNSCLC) with those of thoracic SMARCA4-UT. Methods Patients with BRG1-deficient tumors in the lung or thorax were enrolled in the study from the Department of Pathology of West China Hospital, Sichuan University, from January 2014 to June 2022. We retrospectively collected the clinicopathological and immunohistochemical features and outcomes of these patients. Results Seventy-two patients had tumors in the lung or thorax with BRG1-deficient expression, including 52 patients with SMARCA4-dNSCLC and 20 patients with thoracic SMARCA4-UT. Among the patients with SMARCA4-dNSCLC, 98.1% were male, 85.7% were smokers, and 79.5% (35/44) had tumor-node-metastasis (TNM) III-IV tumors. Among the patients with thoracic SMARCA4-UT, all were males who smoked, and 93.75% (15/16) had TNM III-IV tumors. Pure solid architecture and necrosis were the predominant pathological features. Rhabdoid morphology was observed in some SMARCA4-dNSCLCs (10/52, 19.2%) and thoracic SMARCA4-UTs (11/20, 55%). In most patients with thoracic SMARCA4-UT, the tumors exhibited scattered weak expression or negative expression of epithelial markers, and positive expression of CD34 and Syn. Overall survival (OS) and progression-free survival (PFS) were not significantly different between patients with SMARCA4-dNSCLC and patients with thoracic SMARCA4-UT (p = 0.63 and p = 0.20, respectively). Conclusions Thoracic SMARCA4-DTs include SMARCA4-dNSCLC and thoracic SMARCA4-UT. Both have overlapping clinicopathological features and poor prognosis. We hypothesize that thoracic SMARCA4-UT may be the undifferentiated or dedifferentiated form of SMARCA4-dNSCLC. However, further studies with larger cohorts and longer follow-up periods are needed.
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Longo, Vito, Annamaria Catino, Michele Montrone, Elisabetta Sara Montagna, Francesco Pesola, Ilaria Marech, Pamela Pizzutilo, et al. "Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go." International Journal of Molecular Sciences 25, no. 6 (March 13, 2024): 3237. http://dx.doi.org/10.3390/ijms25063237.
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Recently, the fifth edition of the WHO classification recognized the thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) as a separate entity from conventional non-small cell lung cancer with SMARCA4 deficiency because of the different clinicopathological characteristics of these two diseases. SMARCA4-UT mainly occurs in young to middle-aged adults and involves a large mass compressing the tissues surrounding the mediastinum and lung parenchyma. Unfortunately, SMARCA4-UT shows a high probability of recurrence after upfront surgery as well as radiotherapy resistance; moreover, chemotherapy has low efficacy. Moreover, given the recent classification of SMARCA4-UT, no data concerning specific clinical trials are currently available. However, several case reports show immunotherapy efficacy in patients with this disease not only in a metastatic setting but also in a neoadjuvant manner, supporting the development of clinical trials. In addition, preclinical data and initial clinical experiences suggest that inhibiting pathways such as CDK4/6, AURKA, ATR, and EZH2 may be a promising therapeutic approach to SMARCA4-UT.
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Lin, Juan, Qi Ren, and Binbin Liu. "SMARCA4-deficient undifferentiated tumor with high quality of life and far exceeding predicted survival: A case report." Medicine 103, no. 31 (August 2, 2024): e39045. http://dx.doi.org/10.1097/md.0000000000039045.
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Rationale: SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently reported rare malignancy that can rapidly metastasize to tissues and organs throughout the body. The tumor is characterized by a lower response to platinum-based chemotherapy. More regrettably, the mean survival time of patients with this disease after diagnosis is only 4 to 7 months. Patient concerns: A 58-year-old man was admitted to a hospital for fatigue, sudden syncope, and a mass-like shadow of his left upper lobe demonstrated by a pulmonary computed tomographic. Based on his subsequent clinical and pathological features, he was highly suspected of SMARCA4-UT. Diagnoses: Combined with next-generation sequencing genetic testing and immunohistochemical examination results, the patient was diagnosed with SMARCA4-UT. Interventions: The patient received a left upper lobectomy and lymph node dissection, four-course chemotherapy divided into 8 sessions with the use of paclitaxel simply, and a proper post-discharge self-care. Outcomes: The patient’s operation and chemotherapy were all successful and he maintained a high quality of life after surgery that far exceeded his predicted survival. Lessons: Early diagnosis, higher education level, attention to the disease and complications, reducing chemotherapy damage, adequate nutrient intake, relieving symptoms, controlling depression, and maintaining immunity and the ability to perform activities of daily living may all be the positive factors that can prolong the survival of patients with SMARCA4-UT.
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Jiang, Jiapeng, Zhixin Chen, Jiali Gong, Na Han, and Hongyang Lu. "Thoracic SMARCA4-deficient undifferentiated tumor." Discover Oncology 14, no. 1 (April 28, 2023). http://dx.doi.org/10.1007/s12672-023-00639-w.
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AbstractThoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described smoking-related malignancy. The pathogenesis of SMARCA4-UT is the mutational inactivation and loss of expression of a subunit encoding the mammalian switch/sucrose nonfermenting ATPase-dependent chromatin remodeling complex (which can be mobilized using adenosine triphosphate hydrolysis nucleosomes and regulate other cellular processes including development, differentiation, proliferation, and apoptosis), in particular SMARCA4 and SMARCA2. The dynamic activity of this complex plays an important role in regulating the activation and repression of gene expression programs. SMARCA4-UT exhibits morphological features similar to the malignant rhabdoid tumor (MRT), small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), and INI1-deficient tumor, but SMARCA4-UT differs from SCCOHT and MRT from a genomic perspective. SMARCA4-UT mainly involves the mediastinum and lung parenchyma, and appears as a large infiltrative mass that easily compresses surrounding tissues. At present, chemotherapy is a common treatment, but its efficacy is not clear. Moreover, the inhibitor of the enhancer of zeste homolog 2 showed promising efficacy in some patients with SMARCA4-UT. This study aimed to review the clinical characteristics, diagnosis, treatment, and prognosis of SMARCA4-UT.
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Gantzer, Justine, Guillaume Davidson, Bujamin Vokshi, Noëlle Weingertner, Antoine Bougoüin, Marco Moreira, Véronique Lindner, et al. "Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors." Oncologist, March 12, 2022. http://dx.doi.org/10.1093/oncolo/oyac040.
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Abstract Background Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. Materials and Methods Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non–small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. Results Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. Conclusion SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.
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Shen, Xiuling, Zhi Yang, and Nan Li. "68Ga-DOTA-FAPI-04 PET/CT in the Detection of Thoracic SMARCA4-Deficient Undifferentiated Tumor." Clinical Nuclear Medicine, October 17, 2023. http://dx.doi.org/10.1097/rlu.0000000000004910.
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Abstract Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare malignant disease. We present the case of a 56-year-old woman with thoracic SMARCA4-UT presenting as a mediastinal mass who underwent 68Ga-DOTA-FAPI-04 PET/CT imaging. Intense 68Ga-DOTA-FAPI-04 uptake was observed in the primary tumor and lymph node metastases. After 7 cycles of immune checkpoint inhibitor plus chemotherapy, the patient underwent mediastinal mass resection, and postoperative pathology confirmed a complete pathologic response. This case may provide valuable insights into the diagnosis and monitoring of the treatment response of thoracic SMARCA4-UT.
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Helmink, Austin J., Ahmad Alshomrani, Scott R. Lauer, and Ana Yuil-Valdes. "Thoracic SMARCA4-Deficient Undifferentiated Tumors With Unusual Presentations: A Case Series." International Journal of Surgical Pathology, October 30, 2023. http://dx.doi.org/10.1177/10668969231206350.
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Context Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described aggressive neoplasm of young smokers defined by SMARCA4 inactivating mutations and characterized by cells with rhabdoid morphology, high mitotic activity, and abundant necrosis. Objective Describe and compare 3 unusual presentations of SMARCA4-UT in older adults, including one presenting as a metastatic lesion mimicking a primary bone sarcoma. Discuss the molecular characteristics of SMARCA4-UT and their relationship to nonsmall-cell lung carcinomas with SMARCA4. Design Three patients with SMARCA4-UTs were identified utilizing a natural language search in CoPath. hematoxylin and eosin sections from all patients as well as Papanicolaou-stained slides and Diff-Quik-stained slides for the first patient were examined. A broad range of immunostains, including BRG1/SMARCA4, were evaluated. Molecular testing was performed via next-generation sequencing. Results The 3 patients were aged 58, 70, and 70 years. All had a significant smoking history. The first patient presented with an iliac bone mass and mediastinal lymphadenopathy, the second with mediastinal adenopathy, and the third with a paratracheal mass. All 3 tumors showed a diffuse proliferation of pleomorphic, rhabdoid cells with high mitotic activity and tumor necrosis. SMARCA4 was lost in all 3 tumors by immunohistochemistry. Molecular testing revealed SMARCA4 alterations in the first 2. Conclusions Thoracic SMARCA4-UT should be considered in the differential diagnosis of pleomorphic rhabdoid tumors in older adults with a smoking history. Although most present as lung and/or mediastinal masses, they may occasionally present as a metastasis and mimic an undifferentiated sarcoma, representing a potential diagnostic pitfall.
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Shi, Liyong, Lianshun Lin, Yin Ding, Yiming Zeng, and Xiaoyang Chen. "Case report: A rapid response to immunotherapy in a thoracic SMARCA4-deficient undifferentiated tumor with respiratory failure." Frontiers in Oncology 12 (November 1, 2022). http://dx.doi.org/10.3389/fonc.2022.1020875.
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Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is an extremely rare and poor-prognosis malignancy, which has recently been noted as a subtype of lung tumors. We presented a case of SMARCA4-UT in a 50-year-old man with progressively worsening respiratory failure. The tumor was the first reported to involve pulmonary artery, and 90% of tumor cells expressed programmed cell death ligand 1 (PD-L1). High tumor mutational burden (TMB, 23.93/Mb) and mutations in SMARCA4 were detected. It is the first reported case to receive Tislelizumab monotherapy with considerable improvement in clinical condition and no adverse events. As a result of our case, we highlight the importance of recognizing SMARCA4-UT as an individual entity, as well as the efficacy of immune checkpoint inhibitor therapy, particularly in patients with high levels of TMB and PD-L1 expression.
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Rekhtman, Natasha. "All that is small is not a small cell carcinoma: Thoracic SMARCA4 undifferentiated tumors masquerading as SCLC." Clinical Cancer Research, February 28, 2024. http://dx.doi.org/10.1158/1078-0432.ccr-24-0227.
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Abstract Small cell lung carcinoma (SCLC) cell lines have been widely utilized as a preclinical model of this highly aggressive disease. However, since their creation decades ago, novel tumor entities have been defined that may clinicopathologically mimic SCLC, which notably includes thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Multi-omic reassessment of the presumed SCLC cell lines with high YAP1 expression reveals that nearly all of these tumors represent unsuspected SMARCA4-UT.
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Duan, Ting, Mingxin Xu, Haibo Zhang, Shengchang Wu, Haochu Wang, and Zhenying Guo. "Long-term follow-up of combination therapy with pembrolizumab and anlotinib in thoracic SMARCA4-deficient undifferentiated tumor: a case report and molecular features." Frontiers in Oncology 14 (December 11, 2024). https://doi.org/10.3389/fonc.2024.1453895.
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Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs), recently recognized as a rare malignancy described in the 5th edition of the World Health Organization Classification of Tumors, are characterized by an inactivating mutation in SMARCA4, most commonly found in the mediastinum of male smokers. Despite the aggressive nature and poor prognosis associated with these tumors, which have a median survival time of approximately 4-7 months, no standardized treatment guidelines are currently established. There are currently no reported cases of extended progression-free survival (PFS) in SMARCA4-UT patients treated with surgery and immunotherapy. Here, we report the clinical features and genomic information of a SMARCA4-UT case in which the patient responded significantly to a combination therapy involving surgery, immunotherapy, and amlotinib. A 56-year-old male non-smoker presented with a mass in the superior lobe of left lung and left hilar adenopathy. A left upper lobectomy and lymphadenectomy were performed, and postoperative pathology confirmed that the tumor was Thoracic SMARCA4-UT. The patient subsequently received chemotherapy with pemetrexed and carboplatin. Five months post-operation, the disease progressed with left adrenal metastasis and mediastinal adenopathy. An adrenalectomy was performed, followed by whole exon sequencing (WES). SMARCA4, SMARCA2 and SMARCA1 gene mutations were detected in this case. Given a tumor proportion score (TPS) of 60% for programmed death-ligand 1(22C3)immunoexpression and high TMB(361.32 muts/Mb), a combination of Pembrolizumab plus anlotinib was initiated as a second-line approach. After 46 cycles, the patient demonstrated no disease progression with a PR lasting 31 months and long progression-free survival(PFS) of 43 months. The lung tumor was initially detected in September 2020, and the patient remained alive at the latest follow-up in November 2024. This case offers a long-term follow-up of the effectiveness and safety of combining pembrolizumab and anlotinib in advanced SMARCA4-UT, and substantiates the role of long-term immunotherapy in preventing radiographic/clinical recurrence following surgery. This case illustrates new potential efficacy of immunotherapy in combination with surgery as a treatment approach of SMARCA4-UT.
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Takei, Kensuke, Mitsuhiro Isaka, Junji Wasa, Takuya Kawata, Tatsuya Masuda, Shinya Katsumata, Koki Maeda, Hideaki Kojima, Hayato Konno, and Yasuhisa Ohde. "Surgical resection following chemoradiotherapy for thoracic SMARCA4-deficient undifferentiated tumor: a report of two cases." Surgical Case Reports 10, no. 1 (November 5, 2024). http://dx.doi.org/10.1186/s40792-024-02053-y.
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Abstract Background Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm with a poor prognosis. Most cases of SMARCA4-UT have extensive chest wall and mediastinum involvement. The efficacy of surgical resection has not been clearly established. Here, we report two surgical cases of SMARCA4-UT with chest wall invasion after chemoradiotherapy. Case presentation The first patient was a 40-year-old man with back pain. Computed tomography revealed a 6.8 cm mass in contact with the thoracic vertebrae near the intervertebral foramen, which was suspected to involve the third to fifth ribs. The patient was diagnosed with SMARCA4-UT with clinical T3N0M0 stage IIB. The tumor shrank after chemoradiotherapy, and conversion surgery combined with partial vertebrectomy was performed. Histopathological findings revealed 30% residual tumor in the tumor bed. Thirty-six days after surgery, the patient developed multiple liver metastases and peritoneal dissemination. Chemotherapy combined with immune checkpoint inhibitor treatment was performed, resulting in tumor shrinkage. However, peritoneal dissemination recurred within a short interval. The patient died 5 months postoperatively. The second patient was a 74-year-old man with chest pain. Computed tomography revealed a 7.4-cm mass in the left upper lobe with invasion of the third and fourth ribs. The patient was initially diagnosed with non-small cell lung cancer with clinical T4N1M0 stage IIIA. The tumor shrank after induction chemoradiotherapy, and a left upper lobectomy combined with the chest wall resection was performed. Based on histopathological findings, the patient was diagnosed with SMARCA4-UT. The residual tumor percentage was 3%. The patient was followed up for 12 months postoperatively without recurrence. Conclusions We performed the complete resection of SMARCA4-UT following chemoradiotherapy. The two surgical cases had different postoperative courses. Radical surgery after chemoradiotherapy is effective for local control. However, its long-term prognostic efficacy remains unclear. Multidisciplinary approaches and further investigations of novel therapeutic options are required.
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Zhou, Ping, Yiyun Fu, Weiya Wang, Yuan Tang, and Lili Jiang. "Gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT): a clinicopathological analysis of four rare cases." Orphanet Journal of Rare Diseases 19, no. 1 (June 14, 2024). http://dx.doi.org/10.1186/s13023-024-03244-4.
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Abstract Background SMARCA4, as one of the subunits of the SWI/SNF chromatin remodeling complex, drives SMARCA4-deficient tumors. Gastric SMARCA4-deficient tumors may include gastric SMARCA4-deficient carcinoma and gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Gastric SMARCA4-UT is rare and challenging to diagnose in clinical practice. The present report aims to provide insight into the clinicopathological characteristics and genetic alterations of gastric SMARCA4-UTs. Results We retrospectively reported four rare cases of gastric SMARCA4-UTs. All four cases were male, aged between 61 and 82 years. These tumors presented as ulcerated and transmural masses with infiltration, staged as TNM IV in cases 1, 2 and 4, and TNM IIIA in case 3. Pathologically, four cases presented solid architecture with undifferentiated morphology. Cases 2 and 3 showed focal necrosis and focal rhabdoid morphology. Immunohistochemical staining showed negative expression of epithelial markers and deficient expression of SMARCA4. Furthermore, positivity for Syn (cases 1, 2 and 3) and SALL4 (cases 1 and 2) were observed. Mutant p53 expression occurred in four cases, resulting in strong and diffuse staining of p53 expression in cases 1, 2 and 4, and complete loss in case 3. The Ki67 proliferative index exceeded 80%. 25% (1/4, case 4) of cases had mismatch repair deficiency (dMMR). Two available cases (cases 1 and 3) were detected with SMRACA4 gene alterations. The response to neoadjuvant therapy was ineffective in case 1. Conclusions Gastric SMARCA4-UT is a rare entity of gastric cancer with a poor prognosis, predominantly occurs in male patients. The tumors are typically diagnosed at advanced stages and shows a solid architecture with undifferentiated morphology. Negative expression of epithelial markers and complete loss of SMARCA4 immunoexpression are emerging as a useful diagnostic tool for rare gastric SMARCA4-UTs.
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Ng, Jin, Ling Cai, Luc Girard, Owen W. J. Prall, Neeha Rajan, Christine Khoo, Ahida Batrouney, et al. "Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies." Clinical Cancer Research, January 5, 2024, OF1—OF13. http://dx.doi.org/10.1158/1078-0432.ccr-23-2360.
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Abstract Purpose: The classification of small cell lung cancer (SCLC) into distinct molecular subtypes defined by ASCL1, NEUROD1, POU2F3, or YAP1 (SCLC-A, -N, -P, or -Y) expression, paves the way for a personalized treatment approach. However, the existence of a distinct YAP1-expressing SCLC subtype remains controversial. Experimental Design: To better understand YAP1-expressing SCLC, the mutational landscape of human SCLC cell lines was interrogated to identify pathogenic alterations unique to SCLC-Y. Xenograft tumors, generated from cell lines representing the four SCLC molecular subtypes, were evaluated by a panel of pathologists who routinely diagnose thoracic malignancies. Diagnoses were complemented by transcriptomic analysis of primary tumors and human cell line datasets. Protein expression profiles were validated in patient tumor tissue. Results: Unexpectedly, pathogenic mutations in SMARCA4 were identified in six of eight SCLC-Y cell lines and correlated with reduced SMARCA4 mRNA and protein expression. Pathologist evaluations revealed that SMARCA4-deficient SCLC-Y tumors exhibited features consistent with thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT). Similarly, the transcriptional profile SMARCA4-mutant SCLC-Y lines more closely resembled primary SMARCA4-UT, or SMARCA4-deficient non–small cell carcinoma, than SCLC. Furthermore, SMARCA4-UT patient samples were associated with a YAP1 transcriptional signature and exhibited strong YAP1 protein expression. Together, we found little evidence to support a diagnosis of SCLC for any of the YAP1-expressing cell lines originally used to define the SCLC-Y subtype. Conclusions: SMARCA4-mutant SCLC-Y cell lines exhibit characteristics consistent with SMARCA4-deficient malignancies rather than SCLC. Our findings suggest that, unlike ASCL1, NEUROD1, and POU2F3, YAP1 is not a subtype defining transcription factor in SCLC.
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Coconubo, Daniel Martinez, Sintawat Wangsiricharoen, Jason R. Pettus, Konstantinos Linos, Andre Pinto, Wei-Lien Wang, Darcy A. Kerr, and Jeffrey M. Cloutier. "A Subset of Thoracic SMARCA4-Deficient Undifferentiated Tumors Express GATA3." International Journal of Surgical Pathology, July 17, 2023. http://dx.doi.org/10.1177/10668969231188904.
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Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignant neoplasm characterized by high-grade undifferentiated morphologic features and recurrent inactivating mutations of SMARCA4. These tumors consistently exhibit loss of SMARCA4 (BRG1) while displaying variable expression of other nonspecific markers. Recently, we encountered a SMARCA4-UT demonstrating immunoreactivity for GATA3, and we sought to characterize this phenomenon in a larger series. A total of nine SMARCA4-UTs were examined from 3 large academic institutions. The clinicopathologic and molecular characteristics were studied and GATA3 immunohistochemistry was performed. The cohort included 5 male and 4 female patients, with a median age of 54 years and a median smoking history of 37 pack-years. At initial diagnosis, mediastinal lymph node involvement was observed in 5 patients (56%) while distant metastases were present in 7 patients (78%). The median survival was 6 months. Histologically, the tumors were characterized by sheets of undifferentiated epithelioid and/or rhabdoid cells, accompanied by frequent mitotic figures and necrosis. Immunohistochemically, all tumors displayed a complete loss of BRG1 expression. Notably, 4 of 9 tumors (44%) were positive for GATA3 expression, including one tumor that exhibited strong and diffuse immunoreactivity. GATA3 expression in SMARCA4-UT may pose diagnostic challenges, requiring differentiation from other GATA3-positive tumors. This distinction is crucial for accurate prognostication and treatment decisions.
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Chakrabarti, Rana, Sherman Lin, Hui Wang, and Matthew Cecchini. "SMARCA4-Deficient Undifferentiated Tumor of the Esophagus: Diagnostic Pitfalls in Immunohistochemical Profiles." International Journal of Surgical Pathology, March 18, 2024. http://dx.doi.org/10.1177/10668969241228290.
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SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are a newly described entity and are typically seen in the thoracic cavity. However, these tumors have been described in other body sites, including the esophagus. These tumors are rare, aggressive neoplasms, characterized by the loss of protein product of SMARCA4 (Brahma-related gene-1) and the preservation of INI1 (SMARCB1) expression. Here, we present two tumors of SMARCA4-UT of the esophagus with its microscopic appearance and immunohistochemical profile. We also include a literature review of SMARCA4-deficient tumors of the tubular gastrointestinal tract with their immunohistochemical and mismatch repair profiles for each specimen. Due to its non-specific histologic appearance and variable staining in expanded immunohistochemical panels, this tumor frequently overlaps with other tumor types, making the diagnosis of SMARCA4-UT challenging. These tumors are often associated with intestinal metaplasia of the esophagus and are thought to represent a high-grade undifferentiated transformation of a conventional esophageal adenocarcinoma. These tumors are typically associated with poor clinical outcomes and have poor response to conventional therapies. Currently, there are no standard guidelines for treatment of these tumors; however, palliative radiotherapy and systemic chemotherapy may provide benefit. More recently, immunotherapy and novel therapeutic targets have shown some promise for these patients.
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Yin, Cong, Zheng-jia Liu, Chao He, and Hai-xiang Yu. "A case of surgically treated non-metastatic SMARCA4-deficient undifferentiated thoracic tumor: a case report and literature review." Frontiers in Oncology 14 (June 6, 2024). http://dx.doi.org/10.3389/fonc.2024.1399868.
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SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT) is a rare malignant tumor characterized by inactivation of the SMARCA4 gene and the presence of undifferentiated or rhabdoid morphology in the tissue. This tumor is highly invasive, typically diagnosed at advanced stages III or IV, and commonly involves thoracic structures, such as the mediastinum and chest wall. Reported cases are limited and treatment guidelines have not yet been established. Here, we present a rare case of surgically treated non-metastatic SMARCA4-UT. The patient presented with blood-tinged sputum, dyspnea, and a history of heavy smoking, and underwent surgery after preoperative evaluation ruled out contraindications. The tumor was successfully removed along with the relevant lymph nodes; analysis determined it to be stage IIB T3N0M0. No recurrence was detected at two months post-surgery. However, four months after surgery, the tumor recurred and invaded the adjacent ribs. The diagnosis, differential diagnosis, and treatment of SMARCA4-deficient undifferentiated lung tumors is considered. The combination of chemotherapy and immunotherapy has shown efficacy, and other treatments such as anti-angiogenic drugs, histone deacetylase inhibitors (HDACi), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors, and oxidative phosphorylation (OXPHOS) inhibitors may also be beneficial in treating SMARCA4-UT.
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Wang, Yuanhang, Kelei Zhao, Jingjing Zhang, Xiaohan Yuan, Yanting Liu, Jinghang Zhang, Ping Lu, and Min Zhang. "Rapid Response to Penpulimab Combined With Anlotinib and Chemotherapy in a Thoracic SMARCA4‐UT Without PD‐L1 Expression: A Case Report and Review of Literature." Clinical Respiratory Journal 18, no. 12 (December 2024). https://doi.org/10.1111/crj.70036.
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ABSTRACTSMARCA4‐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.
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Lin, Ying, Bo Yu, Haifeng Sun, Hongyu Zhang, Zhihuang Hu, Yao Zhang, Zhenhua Wu, et al. "Promising efficacy of immune checkpoint inhibitor plus chemotherapy for thoracic SMARCA4-deficient undifferentiated tumor." Journal of Cancer Research and Clinical Oncology, April 28, 2023. http://dx.doi.org/10.1007/s00432-023-04806-y.
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Abstract 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.
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Kito, Yusuke, Keisuke Kawashima, Chiemi Saigo, Masayoshi Hasegawa, Shusuke Nomura, Takuya Mikamo, Yuki Hanamatsu, Yasuhiro Matsuo, and Tamostu Takeuchi. "Thorahcic SMARCA4-deficient undifferentiated tumors with ganglioneuroma and enchondroma: implications for SLC7A11 and ARID1A expression: a case report." Diagnostic Pathology 17, no. 1 (February 12, 2022). http://dx.doi.org/10.1186/s13000-022-01205-8.
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Abstract 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.
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Li, Xiang, Sen Tian, Hui Shi, Na Ta, Xiang Ni, Chenguang Bai, Zhanli Zhu, et al. "The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation." Cancer Gene Therapy, February 13, 2024. http://dx.doi.org/10.1038/s41417-024-00732-4.
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AbstractSMARCA4-deficient undifferentiated thoracic tumor is extremely invasive. This tumor with poor prognosis is easily confused with SMARCA4-deficent non-small cell lung cancer or sarcoma. Standard and efficient treatment has not been established. In this review, we summarized the etiology, pathogenesis and diagnosis, reviewed current and proposed innovative strategies for treatment and improving prognosis. Immunotherapy, targeting tumor microenvironment and epigenetic regulator have improved the prognosis of cancer patients. We summarized clinicopathological features and immunotherapy strategies and analyzed the progression-free survival (PFS) and overall survival (OS) of patients with SMARCA4-UT who received immune checkpoint inhibitors (ICIs). In addition, we proposed the feasibility of epigenetic regulation in the treatment of SMARCA4-UT. To our knowledge, this is the first review that aims to explore innovative strategies for targeting tumor microenvironment and epigenetic regulation and identify potential benefit population for immunotherapy to improve the prognosis.
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Wei, Xiaoling, Xiangju Xing, Wei Yao, Changzheng Wang, Yajie Xiao, and Xianzhi Du. "First-line combination therapy of immunotherapy plus anti-angiogenic drug for thoracic SMARCA4-deficient undifferentiated tumors in AIDS: a case report and review of the literature." Frontiers in Immunology 15 (January 9, 2025). https://doi.org/10.3389/fimmu.2024.1473578.
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BackgroundThoracic 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.Case presentationWe 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.ConclusionOur 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.
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Punjabi, Lavisha S., Kah Ling Lim, Chun Yuen Chow, Sangeeta Mantoo, and Angela Takano. "Three shades of an unusual mediastinal tumour." Diagnostic Cytopathology, August 17, 2023. http://dx.doi.org/10.1002/dc.25212.
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AbstractThoracic SMARCA4‐deficient undifferentiated tumour (SMARCA4‐UT) is an unusual and aggressive tumour. While there are approximately 100 cases of this tumour reported in the literature, there are very few detailed descriptions of its cytomorphologic characteristics, and only rare cases in which primary diagnosis was made on cytologic material. Herein we present a case with a detailed description of the appearance on three specimen types: transbronchial needle aspiration (TBNA) cytology, transbronchial needle biopsy (TBNB) and effusion cytology. Thoracic SMARCA4‐UT is an important diagnosis to clinch in modern pathology because of its prognostic and therapeutic implications. We discuss an integrated approach to clinching the diagnosis with reference to clinical, radiographic, morphologic and immunohistochemical features. We also discuss possible differential diagnoses, and how they can be excluded. Cytologic and/or small biopsy diagnosis is valuable in these cases as these tumours are typically not amenable to surgical resection. With the correct diagnosis, the patient may instead be a candidate for immune checkpoint inhibitors or experimental therapy targeting SWI/SNF deficiency.
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Popov, Petar, Oskar Steinbrecher, Anke Scharrer, Markus Raderer, Thomas Brodowicz, Matthias Preusser, and Wolfgang Lamm. "Alternating chemotherapy with VDC-IE as effective first-line treatment in a patient with SMARCA4-deficient undifferentiated tumor." memo - Magazine of European Medical Oncology, April 22, 2024. http://dx.doi.org/10.1007/s12254-024-00973-x.
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SummarySMARCA4-deficient undifferentiated tumor (SMARCA4-UTs) is an extremely rare and aggressive entity where no consensus on systemic treatment exists to date. We report the case of a 43-year-old woman with thoracic SMARCA4-UT who presented with rapid progression of disease after surgical resection and achieved complete radiologic remission under VDC-IE chemotherapy (vincristine, doxorubicin, and cyclophosphamide [VDC], alternating with ifosfamide and etoposide [IE]). The detailed case report is followed by a brief discussion and overview of current literature.
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Zalles, Nicole, Sanjay Mukhopadhyay, Swati Satturwar, Sigfred Lajara, Samer Khader, Liron Pantanowitz, and Tarik M. Elsheikh. "Fine‐needle aspiration and effusion cytology of thoracic SMARCA4–deficient undifferentiated tumor and SMARCA4‐deficient non–small cell lung carcinoma: A multi‐institutional experience with 27 patients." Cancer Cytopathology, November 18, 2024. http://dx.doi.org/10.1002/cncy.22919.
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AbstractBackgroundThoracic switch/sucrose nonfermentable–related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)–deficient (SD) malignancies, including SD undifferentiated tumor (SD‐UT) and SD non–small cell lung carcinoma (SD‐NSCLC), have been recently described. The cytologic features of these neoplasms in fine‐needle aspiration (FNA) and effusion specimens have rarely been reported in the literature. This study aimed to describe and compare the spectrum of cytologic, immunohistochemical, and clinical features of these high‐grade malignancies recently encountered at the participating institutions.MethodsThis study documented clinical and imaging characteristics of tumors from 27 patients. Sixteen cytomorphologic features and immunohistochemical findings were compared between SD‐UT and SD‐NSCLC samples.ResultsTwenty three FNAs, two bronchial brushings, and two pleural fluids were evaluated, including 17 SD‐UT cases (mean patient age, 70 years) and 10 SD‐NSCLC cases (mean patient age, 62 years). Both malignancies presented with large thoracic masses and/or hilar/mediastinal lymphadenopathy. All SD‐UT cytologic samples had a discohesive or mixed cohesive–discohesive architecture, and most (13 of 17) showed predominant rhabdoid or mixed rhabdoid–epithelioid features. Most SD‐NSCLC cytologic samples (nine of 10) were either cohesive or mixed cohesive–discohesive and had a predominantly epithelioid morphology (eight of 10). Keratins and claudin‐4 were negative or focally positive in SD‐UT samples, whereas they were diffusely positive in SD‐NSCLC samples. Both malignancies were negative for TTF‐1 and p40/p63 and showed loss of expression of SMARCA4.ConclusionsAlthough there is considerable clinical and cytopathologic overlap between SD‐UT and SD‐NSCLC, some key features allow for their distinction. SD‐UT is mostly discohesive with rhabdoid or mixed rhabdoid–epithelioid features, whereas SD‐NSCLC often has cohesive epithelioid morphology. The combination of clinical presentation, cytomorphology, and immunohistochemistry is essential for a definitive diagnosis.
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Li, Bin, and Xiao-Guang Li. "Iodine-125 Seed Implantation and Transarterial Chemoinfusion Combined with Immune Checkpoint Inhibitors for Thoracic SMARCA4-UT." Journal of Vascular and Interventional Radiology, October 2022. http://dx.doi.org/10.1016/j.jvir.2022.10.008.
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