RESUMEN
Objective: To summarize and analyze the clinical characteristics and prognosis of thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Methods: A retrospective analysis was conducted on the clinical data of 51 patients with SMARCA4-UT who were diagnosed in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023, and 52 patients with SMARCA4-intact non-small cell lung cancer (SMARCA4-iNSCLC) expression admitted during the same period were used as controls. The Kaplan-Meier survival analysis and log-rank test were used to analyze the survival difference between the two groups of patients, and the Cox regression model was used to explore the factors influencing the prognosis of the two groups of patients. Results: In the SMARCA4-UT group, there were 50 males and 1 female, with the age of (63.8±9.7) years. Compared to the SMARCA4-iNSCLC group, the SMARCA4-UT group exhibited a higher proportion of male patients and smokers, as well as a higher Ki-67 level (all P<0.05). SMARCA4-UT is mainly characterized by solid lesions with poor adhesion, and some of them exhibit rhabdomyoid morphology. Immunohistochemistry revealed negative results for BRG1, thyroid transcription factor-1, P40, NapsinA, and others were mostly negative, while some patients were positive for spalt-like transcription factor 4. There were a relatively large number of cases with Ki-67≥30% (47/51, 92%). Among the 10 patients in the SMARCA4-UT group who underwent next-generation sequencing genetic testing, 6 patients were found to have SMARCA4 mutations, often accompanied by TP53 (8/10, 80%), STK 11(3/10, 30%), KRAS(2/10, 20%), with fewer common driver gene mutations. The average tumor mutation burden was 16.12 mutations/Mb. Compared with SMARCA4-iNSCLC patients, the median overall survival of SMARCA4-UT patients was significantly shorter (12 months vs 45 months, P<0.001), and the median overall survival of patients with stage â ¢-â £ SMARCA4-UT treated with immunotherapy was longer than that of patients without immunotherapy (23 months vs 7 months, P=0.027). The results of the multivariate Cox regression model analysis indicated that SMARCA4 deficiency is a risk factor for prognosis in patients with SMARCA4-UT and SMARCA4-iNSCLC [HR=7.954(95%CIï¼ 2.764-22.890), P<0.001]. Conclusions: SMARCA4-UT is a rare undifferentiated tumour distinct from SMARCA4-iNSCLC, which is prevalent among elderly male smokers. It possesses high invasiveness and poor prognosis. The typical pathological characteristic is negative BRG1. Immunotherapy demonstrates a certain effect.
Asunto(s)
ADN Helicasas , Neoplasias Pulmonares , Proteínas Nucleares , Neoplasias Torácicas , Factores de Transcripción , Humanos , Masculino , ADN Helicasas/genética , Persona de Mediana Edad , Femenino , Factores de Transcripción/genética , Proteínas Nucleares/genética , Pronóstico , Estudios Retrospectivos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Torácicas/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Anciano , Mutación , Estimación de Kaplan-MeierRESUMEN
PURPOSE: Prognostic biomarkers remain necessary in sporadic desmoid tumor (DT) because the clinical course is unpredictable. DT location along with gene expression between thoracic and abdominal wall locations was analyzed. METHOD: Sporadic DT patients (GEIS Registry) diagnosed between 1982 and 2018 who underwent upfront surgery were enrolled retrospectively in this study. The primary endpoint was relapse-free survival (RFS). Additionally, the gene expression profile was analyzed in DT localized in the thoracic or abdominal wall, harboring the most frequent CTNNB1 T41A mutation. RESULTS: From a total of 454 DT patients, 197 patients with sporadic DT were selected. The median age was 38.2 years (1.8-89.1) with a male/female distribution of 33.5/66.5. Most of them harbored the CTNNB1 T41A mutation (71.6 %), followed by S45F (17.8 %) and S45P (4.1 %). A significant worse median RFS was associated with males (p = 0.019), tumor size ≥ 6 cm (p = 0.001), extra-abdominal DT location (p < 0.001) and the presence of CTNNB1 S45F mutation (p = 0.013). In the multivariate analysis, extra-abdominal DT location, CTNNB1 S45F mutation and tumor size were independent prognostic biomarkers for worse RFS. DTs harboring the CTNNB1 T41A mutation showed overexpression of DUSP1, SOCS1, EGR1, FOS, LIF, MYC, SGK1, SLC2A3, and IER3, and underexpression of BMP4, PMS2, HOXA9, and WISP1 in thoracic versus abdominal wall locations. CONCLUSION: Sporadic DT location exhibits a different prognosis in terms of RFS favoring the abdominal wall compared to extra-abdominal sites. A differential gene expression profile under the same CTNNB1 T41A mutation is observed in the abdominal wall versus the thoracic wall, mainly affecting the Wnt/ß-catenin, TGFß, IFN, and TNF pathways.
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Fibromatosis Agresiva , Mutación , Transcriptoma , beta Catenina , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Fibromatosis Agresiva/genética , Fibromatosis Agresiva/patología , Fibromatosis Agresiva/mortalidad , Fibromatosis Agresiva/metabolismo , Adolescente , Pronóstico , Adulto Joven , Anciano , Estudios Retrospectivos , Niño , Anciano de 80 o más Años , beta Catenina/genética , beta Catenina/metabolismo , Preescolar , Lactante , Biomarcadores de Tumor/genética , Neoplasias Abdominales/genética , Neoplasias Abdominales/patología , Neoplasias Abdominales/mortalidad , Perfilación de la Expresión Génica , Neoplasias Torácicas/genética , Neoplasias Torácicas/patología , Neoplasias Torácicas/mortalidadRESUMEN
The 5th WHO classification of thoracic tumours includes thoracic SMARCA4-deficient undifferentiated tumour (SMARCA4-UT) among the "other epithelial tumours of the lung" chapter. Herein, we present a case of undifferentiated thoracic neoplasm with retention of SMARCA4 expression, lack of NUT fusion protein and loss of SMARCB1/INI1 expression. After presenting the clinical and pathological features of the tumour, we carried out a review of the literature on the same topic. Albeit very rare, we believe this entity should be included in the heterogeneous group of undifferentiated neoplasms of the thorax.
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ADN Helicasas , Proteína SMARCB1 , Neoplasias Torácicas , Factores de Transcripción , Humanos , Proteína SMARCB1/deficiencia , Proteína SMARCB1/genética , Factores de Transcripción/genética , Factores de Transcripción/deficiencia , Neoplasias Torácicas/patología , Neoplasias Torácicas/genética , ADN Helicasas/deficiencia , ADN Helicasas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , Masculino , Femenino , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnósticoRESUMEN
Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)). Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens.
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Muerte Celular , Cobre , Inmunoterapia , Oxidación-Reducción , Humanos , Cobre/metabolismo , Neoplasias Torácicas/patología , Neoplasias Torácicas/genética , AnimalesAsunto(s)
Proteínas de Fusión Oncogénica , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma/patología , Proteínas Asociadas a Microtúbulos/genética , Masculino , Femenino , Neoplasias Torácicas/genética , Neoplasias Torácicas/patologíaRESUMEN
Nuclear protein of the testis carcinoma is an exceedingly rare and poorly differentiated carcinoma characterized by BDR4::NUTM1 gene translocation. Typically, the tumor affects young adults, and no standardized recommendations for therapeutic management have been available since 2022; the clinical course remains mostly dismal. We report the successful multimodal treatment of a 13-year-old boy affected by a primary chest NUT-carcinoma with a novel NUTM1 rearrangement that remains in complete continuous remission at 30 months from diagnosis.
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Proteínas de Neoplasias , Proteínas Nucleares , Proteínas de Fusión Oncogénica , Humanos , Masculino , Adolescente , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Neoplasias/genética , Neoplasias Torácicas/genética , Neoplasias Torácicas/patologíaRESUMEN
INTRODUCTIONS: The 2021 WHO Classification of Thoracic Tumors recognized SMARCA4-deficient undifferentiated thoracic tumors (SMARCA4-dUT) as a distinct entity that shows a striking overlap in demographic and molecular profiles with SMARCA4-deficient non-small lung cancer (SMARCA4-dNSCLC). The implications of SMARCA4 deficiency based on immunohistochemistry remain unclear. We aimed to investigate molecular characteristics of SMARCA4-deficient thoracic tumors (SDTT) and explore optimal therapeutics. METHODS: From June.15, 2018, to Nov.15, 2023, a large cohort including patients diagnosed with SMARCA4-deficient (N = 196) and SMARCA4-intact (N = 438) thoracic tumors confirmed by immunohistochemistry at SYSUCC were screened. Clinicopathologic and molecular characteristics were identified and compared. External SRRSH cohort (N = 34) was combined into a pooled cohort to compare clinical outcome of first-line therapy efficacy. RESULTS: SDTT is male predominance with smoking history, high tumor burden, and adrenal metastases. The relationship between SMARCA4 mutation and protein expression is not completely parallel. The majority of SMARCA4-deficient patients harbor truncating (Class-I) SMARCA4 mutations, whereas class-II alterations and wild-type also exist. Compared with SMARCA4-intact thoracic tumors, patients with SDTT displayed a higher tumor mutation burden (TMB) and associated with a shorter median OS (16.8 months vs. Not reached; P < 0.001). Notably, SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in these differences. SDTT is generally resistant to chemotherapy, while sensitive to chemoimmunotherapy (median PFS: 7.5 vs. 3.5 months, P < 0.001). In particular, patients with SMARCA4 deficient thoracic tumors treated with paclitaxel-based chemoimmunotherapy achieved a longer median PFS than those with pemetrexed-based chemoimmunotherapy (10.0 vs. 7.3 months, P = 0.028). CONCLUSIONS: SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in its characteristics of higher TMB and poor prognosis. Chemoimmunotherapy serves as the optimal option in the current treatment regimen. Paclitaxel-based chemoimmunotherapy performed better than those with pemetrexed-based chemoimmunotherapy.
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ADN Helicasas , Neoplasias Pulmonares , Proteínas Nucleares , Neoplasias Torácicas , Factores de Transcripción , Humanos , ADN Helicasas/genética , ADN Helicasas/deficiencia , Factores de Transcripción/genética , Masculino , Femenino , Neoplasias Torácicas/genética , Neoplasias Torácicas/patología , Neoplasias Torácicas/tratamiento farmacológico , Neoplasias Torácicas/terapia , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Anciano , Mutación , Pronóstico , Adulto , Biomarcadores de Tumor/genéticaRESUMEN
Molecularly defined neoplasms are increasingly recognized, given the broader application and performance of molecular studies. These studies allow us to better characterize these neoplasms and learn about their pathogenesis. In the thorax, molecularly defined neoplasms include tumors such as NUT carcinoma, SMARCA4-deficient undifferentiated tumor (DUT), primary pulmonary myxoid sarcoma with EWSR1::CREB1 fusion, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms. Overall, these tumors are rare but are now more often recognized given more widely available immunostains such as NUT (NUT carcinoma), BRG1 (SMARCA4-DUT), and INI-1 (SMARCB1-deficient neoplasm). Furthermore, cytogenetic studies for EWSR1 to support a hyalinizing clear cell carcinoma or primary pulmonary myxoid sarcoma are, in general, easily accessible. This enables pathologists to recognize and diagnose these tumors. The diagnosis of these tumors is important for clinical management and treatment. For instance, clinical trials are available for patients with NUT carcinoma, SMARCA4-DUT, and SMACRB1-deficient neoplasms. Herein, our current knowledge of clinical, morphologic, immunophenotypic, and molecular features of NUT carcinomas, SMARCA4-DUT, primary pulmonary myxoid sarcomas, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms will be reviewed.
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Neoplasias Torácicas , Humanos , Neoplasias Torácicas/genética , Neoplasias Torácicas/patología , Biomarcadores de Tumor/genética , Factores de Transcripción/genética , Proteína SMARCB1/genética , Proteína SMARCB1/deficiencia , ADN Helicasas/genética , Proteínas Nucleares/genética , Sarcoma/genética , Sarcoma/patología , Proteínas de NeoplasiasRESUMEN
A 56-year-old woman debuted with a palpable painless mass in the anterior thorax wall at the level of the second and third right parasternal intercostal space, which progressively increased in size over 5 months accompanied by localized skin rash, mild dyspnea and chest pain when changing position. Imaging studies showed a soft tissue mass measuring 75 × 62 mm and a density of 34 Hounsfield Units that had caused the lysis of the costal arches and grew expansively towards the anterior mediastinum, without identifying mediastinal adenopathies only by this imaging method. Core biopsy was performed, which was initially diagnosed as histiocytic sarcoma (HS); however, when the diagnostic panel was expanded to include molecular and NGS studies, the final diagnosis was anaplastic large cell lymphoma with ALK::ATIC fusion. Here, we report a very rare neoplasm with unusual clinical presentation, histopathology and molecular features.
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Sarcoma Histiocítico , Linfoma Anaplásico de Células Grandes , Humanos , Femenino , Persona de Mediana Edad , Sarcoma Histiocítico/patología , Sarcoma Histiocítico/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/diagnóstico , Quinasa de Linfoma Anaplásico/genética , Diagnóstico Diferencial , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Neoplasias Torácicas/patología , Neoplasias Torácicas/genéticaRESUMEN
SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option.
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ADN Helicasas , Proteína SMARCB1 , Factores de Transcripción , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , ADN Helicasas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , Pronóstico , Estudios Retrospectivos , Proteína SMARCB1/genética , Proteína SMARCB1/deficiencia , Neoplasias Torácicas/genética , Neoplasias Torácicas/terapia , Neoplasias Torácicas/patología , Factores de Transcripción/genéticaAsunto(s)
ADN Helicasas , Proteínas Nucleares , Factores de Transcripción , Humanos , Diagnóstico Diferencial , Factores de Transcripción/genética , ADN Helicasas/genética , Proteínas Nucleares/genética , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/genética , Neoplasias Torácicas/diagnóstico por imagen , Neoplasias Torácicas/patología , Masculino , Femenino , InflamaciónRESUMEN
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-metas-tasis (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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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Torácicas , Humanos , Masculino , Femenino , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios Retrospectivos , Neoplasias Pulmonares/diagnóstico por imagen , Biomarcadores de Tumor/genética , Neoplasias Torácicas/genética , ADN Helicasas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genéticaAsunto(s)
Sarcoma de Células Pequeñas , Humanos , Sarcoma de Células Pequeñas/patología , Sarcoma de Células Pequeñas/genética , Masculino , Neoplasias Torácicas/patología , Neoplasias Torácicas/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Femenino , Proteínas de Fusión Oncogénica/genéticaRESUMEN
SMARCA4-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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ADN Helicasas , Epigénesis Genética , Inmunoterapia , Neoplasias Torácicas , Factores de Transcripción , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Inmunoterapia/métodos , ADN Helicasas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias Torácicas/genética , Neoplasias Torácicas/terapia , Neoplasias Torácicas/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , PronósticoRESUMEN
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 might clinicopathologically mimic SCLC, which notably includes thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Multiomic reassessment of the presumed SCLC cell lines with high YAP1 expression reveals that nearly all of these tumors represent unsuspected SMARCA4-UT. See related article by Ng et al., p. 1846.
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ADN Helicasas , Neoplasias Pulmonares , Proteínas Nucleares , Carcinoma Pulmonar de Células Pequeñas , Factores de Transcripción , Humanos , ADN Helicasas/genética , ADN Helicasas/deficiencia , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Factores de Transcripción/genética , Factores de Transcripción/deficiencia , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Diagnóstico Diferencial , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/genética , Neoplasias Torácicas/patología , Línea Celular TumoralRESUMEN
OBJECTIVE: SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a highly malignant neoplasm with an undifferentiated or rhabdoid phenotype, posing a diagnostic challenge. This case report aims to create awareness about this rare neoplasm while dealing with cases presenting with undifferentiated morphology. CASE REPORT: A 55-year-old gentleman with constitutional symptoms and lymphadenopathy. Imaging revealed a mass lesion in the right upper lobe of the lung. A biopsy of the cervical lymph node showed diffusely effaced architecture replaced by sheets of undifferentiated pleomorphic cells with vesicular nuclei, prominent nucleoli, eosinophilic cytoplasm, and multiple necrotic foci. An extensive immunohistochemistry (IHC) panel was applied, which showed positivity for synaptophysin, vimentin, and focal CD34 and EMA expression. Other markers like pan-cytokeratin, p40, TTF1, CD56, INSM1, calretinin, CD45, SOX10, S100, CD30, CD117, SMA, and Desmin were negative, with INI1 retained. The IHC panel excluded the morphological differentials of carcinoma, lymphoma, rhabdomyosarcoma, melanoma, and germ cell tumor. Further literature review led to the possibility of the SMARCA4-UT entity, which had a morphology and IHC profile similar to the present case. Testing for SMARCA4 (BRG-1) by IHC showed a complete loss in the tumor cells, favoring the diagnosis of Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). CONCLUSION: SMARCA4-UTs are rare, highly aggressive, and poorly differentiated thoracic tumors. Recognizing them is vital as there is potential for therapeutic interventions such as immunotherapy and SMARCA4-targeted therapies, offering promising prospects for the future.
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Biomarcadores de Tumor , ADN Helicasas , Proteínas Nucleares , Factores de Transcripción , Humanos , Masculino , Factores de Transcripción/genética , Factores de Transcripción/deficiencia , Persona de Mediana Edad , ADN Helicasas/deficiencia , ADN Helicasas/genética , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Inmunohistoquímica , Neoplasias Torácicas/patología , Neoplasias Torácicas/genética , Neoplasias Torácicas/químicaRESUMEN
PURPOSE: SMARCA4-deficient thoracic tumors, characterized by distinct clinicopathological, morphological, immunohistochemical, and genetic features, differ significantly from conventional non-small-cell lung carcinomas (NSCLCs). This group encompasses both SMARCA4-deficient NSCLCs (SMARCA4-NSCLCs) and SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs). The efficacy of PD-1 inhibitors in treating SMARCA4-deficient thoracic tumors remains uncertain. METHODS: Medical records of 36 patients diagnosed with stage IIIB, IIIC, or IV SMARCA4-deficient thoracic tumors were analyzed. We assessed the clinical, pathological, and genetic features of these patients through immunohistochemistry (IHC) and a 68-gene panel next-generation sequencing (NGS). We compared the differences between SMARCA4-NSCLCs and SMARCA4-UTs, and evaluated the impact of chemotherapy and immunotherapy on patient outcomes. RESULTS: The majority of patients with SMARCA4-deficient thoracic tumors were heavy-smoking males, averaging 64.6 years in age. IHC predominantly showed weak or negative staining for markers such as TTF-1, CK5/6, p40, synaptophysin, chromogranin A, and CD56, which are often associated with adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors. The most common genetic mutations identified via NGS included TP53, CDKN2A, KRAS, STK11, NF1, and PTEN. No significant overall survival (OS) difference was observed between SMARCA4-NSCLCs and SMARCA4-UTs (p = 0.366). The median OS for patients treated with chemotherapy (n = 9) was 447 days, while the median OS for patients undergoing PD-1-inhibitor-based therapy (n = 16) was not reached (p = 0.105). CONCLUSION: SMARCA4-deficient thoracic tumors exhibit distinct characteristics from conventional NSCLCs, and PD-1 inhibitors show promise in treating advanced SMARCA4-deficient thoracic tumors.
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ADN Helicasas , Neoplasias Pulmonares , Proteínas Nucleares , Neoplasias Torácicas , Factores de Transcripción , Humanos , Masculino , ADN Helicasas/genética , ADN Helicasas/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/deficiencia , Persona de Mediana Edad , Femenino , Anciano , Neoplasias Torácicas/genética , Neoplasias Torácicas/patología , Neoplasias Torácicas/tratamiento farmacológico , Neoplasias Torácicas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , Resultado del Tratamiento , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Biomarcadores de Tumor/genética , Adulto , Estadificación de Neoplasias , Anciano de 80 o más Años , Secuenciación de Nucleótidos de Alto Rendimiento , Estudios Retrospectivos , Mutación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , InmunohistoquímicaRESUMEN
NUT carcinoma and thoracic SMARCA4-deficient undifferentiated tumour are unique entities in the 5th edition of the World Health Organisation (WHO) Classification of Thoracic Tumours, whose definitions include molecular genetic abnormalities. These aggressive tumours require rapid work-ups on biopsies, but a broad list of differential diagnoses poses challenges for practising pathologists. This review provides an update on their key clinicopathological and molecular characteristics, as well as controversies regarding tumour classification and diagnostic strategy. Phenotypical assessment plays a substantial role in diagnosis because recurrent and predictable clinicopathological findings exist, including robust immunohistochemical phenotypes. Accurate diagnosis is crucial for appropriate management and a clearer understanding of the disease.
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Carcinoma , Neoplasias Torácicas , Humanos , Factores de Transcripción/genética , Proteínas Nucleares/genética , ADN Helicasas/genética , Biomarcadores de Tumor , Carcinoma/diagnóstico , Carcinoma/patología , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/genética , Neoplasias Torácicas/patologíaRESUMEN
Thoracic SMARCA4-deficient undifferentiated tumor is a newly recognized disease entity characterized as a high-grade malignant neoplasm with an undifferentiated or rhabdoid phenotype. The tumor was initially identified as a subtype of thoracic sarcoma with SMARCA4 loss, but further investigation resulted in its classification as a subtype of epithelial malignancies in the current World Health Organization classification. SMARCA4-deficient undifferentiated tumor is highly aggressive and has a poor prognosis. Because of its rarity, an optimal treatment strategy has not yet been identified. In this review, we summarize the literature on SMARCA4-deficient undifferentiated tumor in terms of its clinical characteristics, diagnosis, treatment strategy and future perspectives.