A Case Report of Incomplete Carney Complex With SMARCA4-Decient Thoracic Sarcoma: Implications for the SLC7Aaa and ARID1A Expression

Background: SWI/SNF-related, matrix-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member (SMARCA4)-decient 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 specic genetic alterations. As an immunohistological feature, the tumors are decient in SMARCA4 and SMARCA2 and express the sex-determining region Y-box 2 (SOX2). In contrast, Carney’s triad is a syndrome that combines three rare soft tissue tumors: gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma, of which at least two are required for diagnosis. Both diseases are valuable case, and 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 his 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 rhabdoid-kile cells in some locations. Immunohistochemical analysis revealed that the tumor cells were positive for 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, suggesting an incomplete Carney complex. Conclusion: SMARCA4-DTS is a rare and recently established disease. While it is dicult to siagnose, it is necessary to distinguish undifferentiated carcinoma, large cell carcinoma, Ewing sarcoma, epithelioid sarcoma, etc. when diagnosing tumors involving the mediastinum, In addition, case with both an incomplete Carney complex and SMARCA4-DTS are very rare. We discuss and report about SMARCA4-DTS

Background SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)-de cient thoracic sarcoma (SMARCA4-DTS) is a new disease concept with characteristic clinical, pathological, and molecular features [1]. This tumor is caused by an abnormality in SMARCA4/BRG1, which is a chromatin remodeling mechanism [2][3][4]. This tumor has been reported in various organs, including small cell carcinoma of ovary, medulloblastoma, lung cancer, intrathoracic sarcoma, and paranasal sinuses [5]. Its clinical feature is its average age at onset, i.e., 40S to 50S, most often in men and smokers. SMARCA4-DTS is refractory to treatment, progresses rapidly, and has a poor prognosis. Its morphological features include monotonous epithelioid-like cells that proliferate in sheet form with loose connectivity [6]. The tumor cells have a large eosinophilic cytoplasm, appear as rhabdoid cells, and have large swollen nuclei and distinct nucleoli [7]. Among the immunohistological features are high positivity for SRY (sex-determining region Y)-box 2 (SOX2), Cd34, Sal-loke protein 4, and p53; keratin positive in half of the reported cases; and general negativity for BRG1/SMARCA4, Claudin4, transcription termination factor 1, desmin, and S100 calcium-binding protein P (S100P) [8].
In contrast, in 1977, Carney et al. reported a case in which two or more of the three lesions of gastric leiomyosarcoma, extra-adrenal ganglionoma, and pulmonary chondroma were observed as single disease group, irrespective of it being metachronous or simultaneous [9]. In 1977, Carney also reported the clinical features of 79 case of this syndrome with two or more signs as it may take years for all three signs to appear [10]. These cases are considered to correspond to the incomplete form of Carney's triad.

Case Presentation
A 43-year-old man visited our hospital because of respiratory distress. He was a heavy smoker. Computed tomography revealed large mass measuring 55 in the upper lobe of the right lung and front mediastinum, with multiple metastases in the surrounding lymph nodes. Lymph node biopsy was performed. The initial pathological diagnosis was non-small cell lung cancer and poorly differentiated adenocarcinoma.
Chemotherapy was administered. However, the tumor was refractory, and the patient died 6 months after admission. Subsequently, an autopsy was performed. Macroscopically, the tumor was 10 cm in size from the upper lobe of the right lung to the anterior mediastinum, with many lymph node metastases observed, the tumor was deeper than the submucosa and 10 cm in size, solid, opalescent, and necrotic. Histologically, the tumor showed a sheet-like growth pattern of monotonous epithelial-like cells. The tumor cells showed loose binding and distinct nucleoli, with rhabdoid-like cells observed in some places.
Based on the results of the immunohistochemical analysis and histological features, we concluded that this tumor was a SMARCA4-DTS. In this case, the histological and immunohistochemical ndings well representaed the characteristics of SMARCA4-DTS; if frozen material remains, genetic analysis may reveal SMARCA4 de ciencies or mutations.
An autopsy revealed a ganglioneuroma in the adrenal gland ( Fig. 2A) and an enchondroma in the left clavicle (Fig. 2B). In other words, two of the three signs of Carney's triad were found; therefore, the patient was diagnosed with an incomplete form of carney's triad.

Discussion And Conclusions
SMARCA4-DTS is a group of diseases rst reported by Le Loarer et al. in 2015 [1]. Their study investigated unclassi ed sarcoma by RNA sequencing and found that 19 cases showed inactivation of SMARCA4, which encodes the ATPase subunit of the BAF chromatin remodeling complex. SMARCA4-effective treatment is urgently needed. A SMARCA4 mutant lung cancer cell line was recently reported to show oxidative phosphorylation (oxphos) activity and sensitivity to its inhibitor IACS-010759 [11]. Thus, this drug may be an effective treatment for SMARCA4-DTS. In contrast, ARID1A was recently reported to promote the expression of SLC7A11 [12], which regulates the synthesis of antioxidant glutathione. Moreover, ARID1A-de cient cancers have lower glutathione levels owing to reduced SLC7A11 expression. Therefore, research is underway regarding the treatment of ARID1A-de cient cancer by inhibiting glutathione and its synthesis [12]. Therefore, since BRG1 is another factor responsible for the chromatin remodeling mechanism together with ARID1A, we hypothesized that SLC7A11 expression was decreased in SMARCA4-de cient tumors and ARID1A-di cient tumors. Subsequently, the expression levels of ARID1A and SLC11A were examined immunohistochemically. While a partial ARID1A de ciency was observed, SLC11A expression did not decrease. Thus, BRG1 de ciency was not directly related to SLC11A expression, and SLC11A expression requires the presence or absence of ARID1A de ciency.
A ganglioneuroma and enchondroma were found in the adrenal gland and left clavicle, respectively.
Carney's triad is a rare multiple neoplastic association of pulmonary chondroma, gastrointestinal stromal tumor, and paraganglioma [9]. At least two tumors are required for its diagnosis [10]. Therefore, this case was considered an incomplete Carney's triad. Ganglioneuroma and chondroma may be less associated with SMARCA4-DTS but may be a subtype of the Carney complex.
In conclusion, we encountered a rare case of SMARCA4-DTS that showed typical histopathological and immunostaining ndings. Further case reports nay help understand the pathobiological properties of SMARCA4-DTS and contribute to the general understanding of SMARCA4-DTS. More rarely, this case was accompanied by an incomplete form of Carney's triad consisting of chondroma and ganglioneuroma. This was a very rare in which two rare disease were combined. Abbreviations ARID1A: AT-rich interactive domain-containing protein 1A BRG1: SMARCA4 oxphos: oxidative phosphorylation S100P: S100 calcium-binding protein P SLC7A11: solute carrier family 7 member 11 SMARCA4: SWI/SNF-erlated, matrix-associated, actin-dependent regulator od chromatin, subfamily A, member 4 SMARCA4-DTS: SMARCA4-de cient thoracic sarcoma