SMARCB1/INI1-deficient lung cancer with lymph node metastasis: a case report and literature review

Introduction

Switch/Sucrose non-fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), also known as integrase interactor 1 (INI1), is currently considered a tumor suppressor gene (1). Located in the 11.2 region of the long arm of chromosome 22, SMARCB1 represents a core component of the chromatin remodeling complex SWI/SNF (2) and is universally expressed in all normal mammalian nucleated cells (3). SMARCB1 plays key roles in gene regulation, cell cycle and signaling, and transcriptional activation and inhibition. SMARCB1/INI1 deletion has been recognized as a marker, and it’s highly aggressive malignant tumors by more and more basic and clinical studies, and is detected in malignant rhabdomyosarcoma, epithelioid sarcoma, medullary carcinoma of the kidney, schwannoma, chordoma, myoepithelial carcinoma, sinus carcinoma and synovial sarcoma, etc. (4). However, SMARCB1/INI1-deficient lung cancer, as far as we know, has only been reported by Rickard (5) and Fujita (6). SMARCB1/INI1-deficient lung cancer is considered a highly aggressive malignant tumor with low differentiation and poor prognosis, with frequent missed diagnoses. At present, its clinical manifestations, prognosis and treatment are still unclear. Here, we report a case of SMARCB1/INI1-deficient lung cancer with lymph node metastasis to provide a reference for similar cases in the later stage. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-276/rc).

Case presentation

A 54-year-old man was admitted to our hospital in October 2022 due to “weakness for 4 months, cough and chest pain for 1 month”. He presented with 30 years of smoking history (20 cigarettes/day), and have quit smoking 1 month, 20 years of painting and woodworking history and no family history of tumors. The patient had no previous special diagnosis and treatment. Positive signs included: multiple enlarged lymph nodes that could be palpated on both sides of the supraclavicular area, not easily movable, and reduced respiratory sound in the right lower lung. Auxiliary tests indicated normal blood routine, liver and kidney functions and blood sugar. Tumor markers for lung cancer were negative, including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), pro-gastrin-releasing peptide (Pro-GRP), cytokeratin fragment 21-1 (Cyfra21-1) and neuron-specific enolase (NSE). The performance status (PS) score was 0 point. Chest enhanced computed tomography (CT) (2022-10-25) revealed an uneven density mass in the lower lobe of the right lung, measuring 4.1 cm × 2.7 cm in size, with spiculation sign and pleural indentation, multiple enlarged lymph nodes in bilateral hilum and mediastinum and partial fusion (Figure 1). Neck magnetic resonance imaging (MRI) (2022-10-19) showed multiple enlarged lymph nodes at the root of the neck (about 2.9 cm × 2.6 cm) (Figure 2). Abdominal and pelvic enhanced CT showed no abnormal lesions. Cranial enhanced MRI also showed no abnormal lesions. CT-guided percutaneous pulmonary mass biopsy was performed on 2022-10-26, and preliminary pathological results on the second day showed heterotypic cells nested in a sheet arrangement, with large nuclei, deep staining, obvious atypia, infiltrated growth, more central cells and plasma cells infiltrated in the interstroma, and poorly differentiated carcinoma (Figure 3). After repeated communication with pathologists, immunohistochemical markers such as common adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumor could not be clearly diagnosed. Later, rare tumor markers such as SMARCA4 and INI1 were examined. Finally, on 2022-10-28, pathology and immunohistochemical results showed negative SMARCB1/INI1, cytokeratin 5/6 (CK5/6), smooth muscle actin (SMA), S100 protein (S100), Sex determining region y-box transcription factor 10 (SOX10), tumor protein p40 (P40) and thyroid transcription factor-1 (TTF-1) and positive cytokeratin 7 (CK7) (partial +), tumor protein p63 (P63) (individual +), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), Epithelial membrane antigen (EMA), MutL homolog 1 (MLH1), MutS homolog 6 (MSH6), MutS homolog 2 (MSH2) and Postmeiotic segregation increased 2 (PMS2). Programmed cell death ligand 1 (PD-L1) (SP263) tumor proportion score (TPS) was about 30%, and Ki-67 was about 90% (Figure 3). Combined with morphological and immunohistochemical findings, the diagnosis of SMARCB1/INI1-deleted carcinoma was made. Due to the heterogeneity of the tumor, lymph node puncture biopsy was performed, and pathological results showed that abnormal cells were glandular tubular or papillary arranged in lymphohistiocytes. Immunohistochemistry showed negative CK5/6, TTF-1, Napsin A, ventana anaplastic lymphoma kinase (ALK) (D5F3), SMARCB1/INI, GATA-binding protein (GATA3), chromogranin A (CgA), cluster of differentiation 56 (CD56), Sal-like protein 4 (SALL4) and Epstein-Barr virus encoded ribonucleic acid (EBER). In in situ hybridization, CK7 and vimentin (partial positive), P40, P63, synaptophysin (SYN) (focus +), SMARCA4, claudin 4 and cytokeratin (CK) (AE1/AE3) were positive; PD-L1 (SP263) TPS was about 60%, and Ki-67 was about 95% (Figure 4). Morphological and immunohistochemical data confirmed that SMARCB1/INI1-deficient carcinoma was diagnosed. SMARCB1/INI1-deficient lung cancer with lymph node metastasis was diagnosed based on biopsy pathology and evaluation results of lung mass and neck’s (supraclavicular area) enlarged lymph nodes, the stage was T2bN3M0IIIB. Next generation sequencing (NGS) indicated a tumor protein 53 (TP53) mutation abundance of 22.18% and cyclin-dependent kinase 4 (CDK4) amplification (copy number of 4.30), and there was no clear and effective targeted drug. Currently, SMARCB1/INI1-deficient lung cancer is rare, and no standardized treatment plan is available. Because of financial concerns, the high cost of treatment, and therapeutic adverse reaction, the patient refused radiotherapy and chemotherapy. Considering the high expression of PD-L1, the patient was advised to undergo treatment with anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors. Unfortunately, the patient and his family gave up treatment for lack of financial resources to support medical expenses and went home for oral Chinese medicine therapy. The patient passed away 3 months after diagnosis. We also present several previously reported cases of INI1-deleted pleural and lung tumors (Table 1). All procedures performed in this study were in accordance with the ethical standards of the institutional (The First Affiliated Hospital of the Air Force Military Medical University) research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s family for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Chest enhanced CT revealed an uneven density mass (indicated by the red arrows) in the lower lobe of the right lung, and multiple enlarged lymph nodes (indicated by the green arrows) in bilateral hilum and mediastinum. CT, computed tomography.

Figure 2 Head and neck MRI. (A) Sagittal plane of the neck MRI shows no abnormal lesions; (B) transverse plane of the neck MRI shows multiple enlarged lymph nodes (indicated by the green arrows) at the base of the neck; (C) brain MRI shows no abnormal lesions. MRI, magnetic resonance imaging.

Figure 3 Pathological and immunohistochemical results of lung biopsy tissue. The first and second images show the results of hematoxylin-eosin staining of lung biopsy tissue, magnifications are ×20 (the first image), ×40 (the second image). The remaining images are typical biomarkers of lung tumor by immunohistochemical staining (+)/(−) on the upper right stand for positive or negative according to IHC staining. Magnifications: ×40. IHC, immunohistochemistry.

Figure 4 Pathological and immunohistochemical results of lymph node biopsy tissue. The first and second images show the results of hematoxylin-eosin staining of lymph node biopsy tissue, magnifications are ×20 (the first image), ×40 (the second image). The remaining images are typical biomarkers of lung tumor by IHC staining (+)/(−) on the upper right stand for positive or negative according to IHC staining. Magnifications: ×40. IHC, immunohistochemistry.

Discussion

As one of the notable subunits of the adenosine triphosphate (ATP)-dependent chromatin remodeling SWI//SNF complex, SMARCB1/INI1 is considered a tumor suppressor (1,3). It was first reported in malignant rhabdomyoma and has been detected in a variety of human tumors (2). The incidence of SMARCB1/INI1 deficiency in malignant rhabdomyoma and renal medullary carcinoma is 100%, versus 80–90% for epithelioid sarcoma, 50% for malignant peripheral schwannoma, 40% and 10% for pediatric and adult medullary carcinoma, respectively, and 17% for extra-skeletal myxoid chondrosarcoma (8,9). Its incidence in lung cancer is very rare: The American Association for Cancer Research (AACR) project Genomics Evidence Neoplasia Information Exchange (GENIE) registry showed that among all lung cancer patients (10,974 cases), only 3 had homozygous SMARCB1/INI1 deficiency (10), and only two SMARCB1/INI1-deficient lung cancer cases have been reported in the literature (5,6).

In 2022, Rickard et al. first reported a case of SMARCB1/INI1-deficient lung cancer with liver metastasis, and the present case was SMARCB1/INI1-deficient lung cancer with multiple lymph node metastases, indicating that this type of lung cancer is very rare. The patient reported by Rickard et al. was a 60-year-old male with no history of smoking or family tumors, who presented with “cough”. Chest CT showed a mass of 86 mm. SMARCB1/INI1-deficient lung cancer with liver metastasis was confirmed by liver and lung histology and characterized by lamellar or nestlike tumor cells with little cytoplasm and obvious mitosis (5). In 2023, Fujita et al. reported a case of a 77-year-old male patient with a 3-year history of plasma cell myeloma. During chemotherapy for plasma cell myeloma, chest CT showed a lung mass in the right middle lobe, lymphatic enlargement of hilar and mediastinum, right pleural effusion, and the lung mass expanded from 32 to 51 mm within 1 week, causing “cough, hemoptysis, and fever”. The patient died 2 weeks later due to severe respiratory symptoms and was diagnosed with SMARCB1 (INI1)-deficient lung cancer with intrapulmonary, lymph node, pleural, and adrenal metastases after pathology of pleural effusion and subsequent autopsy (6). In terms of medical history, all three cases were male patients, but this case had a long history of smoking. In terms of tumor-node-metastasis (TNM) staging, both published medical records revealed distant metastasis with late staging. In addition to the primary lesion of the lung, we mainly reported multiple lymph node metastases, including bilateral hilar, mediastinum and neck, and no other organ metastases were observed. Similar findings were obtained by histopathology, which also showed that tumor cells were nested in a lamellar arrangement with large nuclei and deep staining. The diagnosis of SMARCB1-deficient lung cancer requires immunohistochemical staining. Both histopathologic and immunohistochemical analyses of our case and Rickard’s and Fujita’s cases indicated INI1 deletion. In 2021, the World Health Organization (WHO) indicated rare lung malignancies include sarcomatoid carcinoma, nuclear protein in testis (NUT) midline carcinoma and undifferentiated tumors with SMARCA4 deletion in the chest, etc. SMARCB1-deficient cancer has not been included, but has been clinically detected. According to the preliminary experience of the three cases reported, if the tumor shows low histological differentiation in the preliminary pathological examination of lung cancer and is difficult to be classified as a common thoracic tumor by immunohistochemistry, such as adenocarcinoma (CK7, TTF-1, Napsin A) and squamous cell carcinoma (P40, P63, CK5/6), conventional tumor markers such as neuroendocrine tumors (CD56, SYN) or sarcoma (SMA) should be further considered as markers of SMARCB1. Because such cases are extremely rare, they may be subject to missed diagnosis in the diagnosis process, and are likely to be diagnosed as poorly differentiated carcinoma or other tumors by inexperienced clinical or pathologists. According to a registration study, some cases have been diagnosed as small cell carcinoma, neuroendocrine tumor and adenocarcinoma (10). For example, our case was a poorly differentiated cancer at the time of initial diagnosis. After repeated communications with pathologists, immunohistochemical markers of rare tumors were added, e.g., SMARCA4 and SMARCB1/INI1, and it was finally confirmed that the patient had an undifferentiated tumor with SMARCB1 deletion in the chest. This also suggests that thoracic oncologists need to engage in multidisciplinary discussion when they see pathology reports without clear guidance for diagnosis and treatmAlmost all SMARCB1/INI1-deficient tumors are highly aggressive and have a poor prognosis (11). As reported previously, malignant rhabdomyoma usually occurs in children below 3 years old and has a 5-year survival rate of 15–20% (4). The average survival of atypical teratoid/rhabdomyoma is 20 months (12). The survival time of patients with kidney medullary carcinoma is generally below 12 months (13,14). The same is true for SMARCB1/INI1-deficient lung cancer. The survival time reported by Fujita et al. was 2 weeks, while Rickard et al. reported less than half a year. The SMARCB1/INI1-deficient lung cancer reported here also died 3 months after diagnosis. There is no standardized treatment yet. In previous medical records, chemotherapy, surgery, radiotherapy and other treatment tools have been applied, but their effects were poor and survival time was short. For example, Yoshida reported a patient with SMARCB1/INI1-deficient squamous cell carcinoma in the pleura treated with cisplatin plus gemcitabine chemotherapy and Teghio, who died 10 months after diagnosis (7). Rickard’s case underwent immunotherapy with ipilimumab and nivolumab combined with carboplatin and paclitaxel, as well as gemcitabine/carboplatin chemotherapy, and the survival time was less than half a year (5). After treatment with isophosphamide and anthracycline chemotherapy and disease progression, the patient participated in a clinical trial of the zeste homologous activation enhancer 2 (EZH2) inhibitor tazemetostat. Imaging improvement was achieved after 4 cycles of treatment, but unfortunately, the patient died 2 months later, indicating a survival of about 6 months (15). There is an urgent need for new treatment options for this type of tumor. With the growing understanding of SMARCB1, targeted therapies such as tyrosine kinase inhibitors platelet-derived growth factor receptor α/β (PDGFRα/β) and fibroblast growth factor receptor 2 (FGFR2) initially provide a favorable direction, which may block the PDGFRα/β and FGFR2 signaling pathways in rhabdomyosarcoma, thereby inhibiting tumor growth (16). The mouse double minute 2/4 (MDM2/4) inhibitors idasanutlin and ATSP-7041 reduced the growth of rhabdomyoma cells (17). Zemetostat, an EZH2 inhibitor, was approved by the Food and Drug Administration (FDA) for the treatment of SMARCB1-deficient epithelioid sarcoma in 2020 (18). Another study has also confirmed the clinical benefit of immune checkpoint inhibitors in SMARCB1-deficient tumors (19). Meanwhile, it has also been clinically demonstrated that in another rare lung tumor, SMARCA4-deficient lung cancer, immune checkpoint inhibitors alone or combined with antiangiogenic drugs and chemotherapy can prolong patient survival (20,21).

In conclusion, the histomorphological and immunohistochemical results support the diagnosis of SMARCB1/INI1-deficient lung cancer in the current case, which is a highly aggressive malignancy with poor prognosis. Currently, there is no unified or standardized treatment plan, and EZH2 inhibitors, immune checkpoint inhibitors combined with chemotherapy and antiangiogenic therapy are expected to be effective treatment options. Clinicians need to pay attention to this type of lung cancer and develop new therapies for the affected patients.

Conclusions

Herein we present an extremely rare case of SMARCB1/INI1-deficient lung cancer with lymph node metastasis, clinicians and pathologists often have limited understanding of this disease. We combining clinical symptoms, signs, imaging data and literature findings, clinicians and pathologists may better understand the disease to avoid misdiagnosis of such patients, as well as provide reference for treatment decisions of similar cases.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-276/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-276/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 81601989) and Key research and development program of Shaanxi (No. 2019SF-097).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-276/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional (the First Affiliated Hospital of the Air Force Military Medical University) research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s family for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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