A Case of an SMARCB1 (INI1)-Deficient Intrathoracic Neoplasm That Did Not Respond to Chemotherapy for Non-Small Cell Lung Cancer and Rapidly Progressed

SWItch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complexes are involved in gene transcription, replication, and repair [1]. Mutations in SWI/SNF complex subunits, such as SMARC and ARID, have been found in approximately 20–25% of human tumors [1, 2] and are thought to be associated with poor prognosis and low tumor differentiation [3]. In the case of thoracic tumors, tumors associated with inactivation of SMARCA4 have attracted attention, and in the 2021 revision of the World Health Organization (WHO) classification, “SMARCA4-deficient undifferentiated tumor” was added as one of the “others” categories, separate from lung cancer, and established as an independent disease concept [4]. However, SMARCB1-deficient tumors, which are also components of the SWI/SNF complex, are rare and have poor prognosis in pediatric cancers, such as rhabdoid tumors and epithelioid sarcomas. These tumors are extremely rare in thoracic cancers, and there is insufficient accumulated knowledge about them [5]. In this report, we describe a case of a patient with an SMARCB1-deficient tumor who was treated with chemotherapy for non-small cell lung cancer (NSCLC) but had a fatal outcome. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000544167).

The patient was a man in his 60s who was in good health but had a history of smoking 15 cigarettes per day from the age of 20 years. A month before his first visit, he noticed a cough, blood in his phlegm, and shortness of breath when exerting himself, so he visited a local doctor. A chest X-ray revealed an infiltrative shadow in the right lower lobe, and the patient was referred to our department for further examination and treatment. At the time of his first visit, a physical examination revealed that he was underweight; however, no other abnormalities were noted. Blood tests revealed increased levels of C-reactive protein, neuron-specific enolase, and soluble interleukin-2 receptor. A chest contrast computed tomography (CT) performed at our hospital is shown in Figure 1a. A mass lesion with a maximum diameter of >10 cm was found in the lower right lobe, and right pleural effusion was noted. Besides the lesion in the lower right lobe, fluorodeoxyglucose positron emission tomography/CT showed accumulation in the hilar lymph nodes and ribs.

Transbronchial biopsy was performed on the right B9. Histologically, there was a dense proliferation of tumor cells with rhabdoid features (large tumor cells with eosinophilic spherical inclusions in the cytoplasm, a scattered foamy nucleus, and a prominent nucleolus) (Fig. 2). Immunostaining showed negative results for AE1/3+CAM5.2, TTF-1, p40, synaptophysin, chromogranin A, desmin, and myogenin, positive results for CD34 in some regions, and weakly positive results for SALL and EMA in some regions. The pathological diagnosis was an undifferentiated malignant tumor of unknown differentiation. Based on the fact that the pulmonary blood vessels and bronchi penetrated the tumor and that tumor tissue was extensively collected through a transbronchial biopsy, the primary site was considered to be the lung, and the patient was clinically diagnosed with NSCLC. Since the tumor was PD-L1 and driver gene mutation negative, we initiated treatment with carboplatin (CBDCA), nab-paclitaxel (nab-PTX), tremelimumab, and durvalumab as a relatively comprehensive approach.

Figure 1b shows a chest contrast-enhanced CT scan at the end of the second course. Rapid deterioration was observed, and the patient was hospitalized because of dyspnea. Additional immunostaining was performed using samples obtained before the start of treatment to re-evaluate the diagnosis. Figure 3 shows the immunostaining results for SMARC, and when SMARCB1 was deleted, SMARCA2 was reduced, and SMARCA4 was retained. Based on these results, the patient was diagnosed with SMARCB1 (INI1)-deficient intrathoracic neoplasm. Treatment for sarcoma was considered, but the patient died because of the deterioration of his general condition. The entire course was extremely rapid and lasted for over 2 months.

Here, we report a case of a patient with SMARCB1-deficient tumor that showed rapid progression and resulted in a fatal outcome. SMARCA4-deficient tumors are often seen in thoracic tumors and have been added to the WHO classification; SMARCB1-deficient tumors are extremely rare in thoracic tumors and are not listed in the WHO classification. In a genetic analysis conducted by Alessi et al., 555 patients (20.6%) were found to have SWI/SNF mutations, of which 27.4% were in SMARCA4 and only 0.7% were in SMARCB1 in NSCLC [6]. In a study conducted by Gu et al., 94 of 101 patients with SWI/SNF-deficient lung neoplasms identified by immunostaining were found to have SMARCA4 deficiency, whereas only 2 (2.0%) had SMARCB1 deficiency. Haberecker et al. [3] collectively reported thoracic tumors with SMARCB1 deficiency as SMARCB1 (INI1)-deficient intrathoracic neoplasms, and the clinical diagnoses included malignant rhabdoid tumors, epithelioid sarcomas, NSCLC, and malignant pleural mesothelioma [5]. SMARCA4-deficient tumors, which were reported in 2015 by Le Loarer et al. [7] as tumors that form mediastino-pulmonary masses, have a histogenetic relationship with NSCLC but are recognized as a unique disease concept due to their unique clinicopathologic characteristics [8]. Highly aggressive and undifferentiated round cell or rhabdoid morphology is a characteristic of this tumor. Compared to SMARCA4, SMARCB1-deleted tumors are rare in thoracic tumors, but SMARCB1-deficient tumors have been reported in soft tissue tumors, especially epithelioid sarcomas, which show rhabdoid features pathologically and are considered to have a poor prognosis due to their high degree of progression [9]. This patient was initially diagnosed with NSCLC and treated accordingly; however, owing to treatment resistance and rapid progression of the disease, this was not a typical case of NSCLC, and additional immunostaining was performed, leading to the diagnosis of SMARCB1 deficiency. Considering the clinicopathological features, including rhabdoid characteristics and the presence of a giant tumor, we deemed it appropriate to diagnose this case as an SMARCB1-deficient neoplasm, as reported by Haberecker et al. [5], rather than as NSCLC. For earlier diagnosis, malignant tumors with SWI/SNF complex defects generally have the pathological characteristics of being discoid or having a rhabdoid morphology, and it is desirable to investigate the presence or absence of these genetic abnormalities in such tumors.

Although there is no established treatment for SMARCA4 and SMARCB1-deficient thoracic tumors, it has been shown that immune checkpoint inhibitors may be effective. Naito et al. [10] reported that PD-L1 expression was high in NSCLC with SWI/SNF complex deficiency, with a tumor proportion score of ≥1%, and that tumor mutational burden also tended to be high [10]. As for SMARCA4-deficient NSCLC, Liu et al. [11] suggested that the combination of immune checkpoint inhibitors and local therapy significantly prolonged median progression-free survival. Furthermore, Gu et al. [3] reported that immunotherapy and radiotherapy significantly improved overall survival in thoracic tumors with mutations in SWI/SNF complex subunits, including SMARCB1-deficient tumors, and there remains the possibility that immune checkpoint inhibitors may be effective. However, SMARCB1-deficient tumors were rare in this study, and it remains difficult to sufficiently study them. In other types of cancer either, there are scattered case reports that suggest the efficacy of immunotherapy [12, 13]. In this patient, PD-L1 expression was tumor proportion score <1%; therefore, we performed a relatively comprehensive PD-L1 antibody + CTLA4 antibody + CBDCA + nab-PTX treatment for NSCLC, but no response was obtained. In the phase III randomized controlled trial POSEIDON, the response rate to this regimen was reported to be 46.3%, and median overall survival was reported to be 14.0 months [14]. As has been pointed out in previous reports on SMARCA4-deficient thoracic tumors [7], the course of this case was extremely poorer than the clinical trial data. As a treatment method other than immunotherapy, EZH2 activation is thought to be the carcinogenic mechanism caused by SMARCB1 deficiency. Tazemetostat, an EZH2 inhibitor, has been approved by the Food and Drug Administration for use in SMARCB1-deficient epithelioid sarcoma, and its efficacy has been evaluated in trials involving children [15]. Moreover, there is no information on whether it is effective against SMARCB1-deficient thoracic tumors. In any case, if the concept of this disease becomes more widely known and the number of patients increases, more appropriate treatment methods will be considered.

There were several limitations to this report. First, as it is a case report, it is unclear whether the findings observed in this case, such as the ineffectiveness of immunotherapy, can be generalized. In extremely rare diseases such as SMARCB1-deficient thoracic tumors, we believe that accumulating case reports like this is meaningful. Second, we investigated eight types of driver gene mutations covered by medical insurance in Japan, but we were unable to perform comprehensive cancer genome profiling that included SMARCB1. However, we evaluated SWI/SNF gene mutations using immunohistochemistry, as described in previous literature [3, 5]. Third, due to the extremely rapid progression of the disease, there was no time to consider other treatment methods. This further emphasizes the importance of early diagnosis of this disease.

In conclusion, we report a case of a patient with an SMARCB1 (INI1)-deficient thoracic neoplasm that rapidly progressed and failed to respond to chemotherapy for NSCLC and became fatal. The diagnosis of SMARCB1-deficient tumors, which are rare thoracic tumors, is difficult, but early and appropriate diagnosis using methods such as immunohistochemistry in cases that show pathological characteristics such as rapid tumor growth and rhabdoid features may be important for the accumulation of future clinical trials and the establishment of treatment methods.

We would like to express our deep gratitude to Dr. Yasushi Yatabe of the National Cancer Center Hospital for performing the immunostaining analysis in this study. We would like to thank Editage (www.editage.jp) for English language editing.

The patient in this case report died; therefore, it was not possible to obtain consent. However, we took sufficient ethical precautions to ensure that the individual could not be identified, and written informed consent was obtained from the patient’s next of kin for publication of the details of their medical case and any accompanying images. Approval was obtained from the Ethics Review Committee of Toyama Prefectural Central Hospital (Approval No. 66-47).

The authors have no conflicts of interest related to this study or its publication.

This study was not supported by any sponsor or funder.

Yutaro Moriyasu, Takeshi Tsuda, Kei Matsuyama, Isami Mizushima, Kenji Azechi, Yasuaki Masaki, and Hirokazu Taniguchi treated the patient. Hitoshi Abo evaluated the patient’s images. Akane Aikawa and Shin Ishizawa performed the histopathological analysis. Hirokazu Taniguchi reviewed the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.