We experienced the case of a young female with SMARCA4/BRG1-deficient lung cancer. Regrettably, a definitive diagnosis required approximately 2 years. The most frequent histology of SMARCA4/BRG1-deficient lung cancer has been reported to be solid adenocarcinoma, large cell carcinoma, and pleomorphic carcinoma with occasional rhabdoid features [6, 7, 10]. In our case, the major histological pattern was poorly differentiated carcinoma with malignant spindle cells in abundant hyalinous stroma according to the CT-guided needle biopsy; however, these morphological features have been seldom described in articles about SMARCA4/BRG1-deficient NSCLC. Although the undifferentiated round cell morphology and rhabdoid features seen in SMARCA4/BRG1-deficient neoplasms seem to be notable characteristics in several organs [5, 11, 12], the loss of SMARCA4/BRG1 has been found in more well-differentiated adenocarcinomas but not in squamous cell carcinoma of the lung [7, 10]. Immunohistochemistry for BRG1 in NSCLC of each histologic type should be performed not only to note SMARCA4/BRG1 loss but also because SMARCA4/BRG1-deficient NSCLC has been considered a peculiar subset with aggressive clinical behavior and the potential to benefit from targeted therapy. Differential diagnoses would be presented at that time and would include SMARCA4/BRG1-deficient thoracic neoplasms and lung metastasis of another SWI/SNF complex-related malignant neoplasm. Immunohistochemistry for BRG1 has been thought to have sufficient sensitivity and specificity for the diagnosis of SMARCA4/BRG1-deficient thoracic neoplasms [7, 10], although additional examination of SMARCA4 gene alterations ensures the diagnosis.
Radiologists suspected that the origin of the tumor in this case was the lung, but the tumor was distributed in the right lung apex, mediastinum, chest wall, and vertebra. Therefore, the possibility of mesothelioma, thymic carcinoma, and NUT carcinoma should be raised as differential diagnoses; moreover, SMARCA4/BRG1-deficient thoracic sarcoma should not be disregarded. The loss of SMARCA4/BRG1 was reported in some cases of mesothelioma [13] but has not been shown in thymic carcinoma and NUT carcinoma. Our case was negative for calretinin, CD5, and NUT by immunohistochemistry, and thus, these cancers were unlikely.
SMARCA4/BRG1-deficient thoracic sarcoma has been recently recognized as a peculiar disease with characteristics such as affected patients who are relatively young with a history of heavy smoking and emphysema/bullae in the lungs, the presence of large thoracic tumors, poor prognosis, and undifferentiated dyscohesive round cell morphology with rhabdoid features. We observed similar findings in our patients, such as younger age, smoking history, large thoracic mass in a bullous background, and poorly differentiated round cell morphology of the brain metastasis. We compared the findings of our case with those of SMARCA4/BRG1-deficient thoracic sarcoma/NSCLC. The results of this comparison are shown in Table 1 [7, 9, 10, 14–18]. We judged that our case was likely SMARCA4/BRG1-deficient NSCLC rather than a thoracic sarcoma considering the immunohistochemistry results, i.e., claudin-4 positivity and SOX2, CD34, and SALL4 negativity. Emperipolesis was observed in the brain metastasis in our case, which was reported in a previous article on SMARCA4/BRG1-deficient NSCLC [7], but this has not yet been described in SMARCA4/BRG1-deficient thoracic sarcoma. Emperipolesis in the tumor may be a clue that can be used for discrimination.
Table 1
Comparative analysis of the clinicopathological and genetic findings of SMARCA4/BRG1-deficient thoracic tumors including both the present case and published cases
| SMARCA4/BRG1-deficient thoracic sarcoma | SMARCA4/BRG1-deficient NSCLC | Present case |
Clinical feature | | | |
History of smoking, n (%) | 48/55 (87.2%) | 14/17 (82.4%) | Present |
Primary tumor location (n, %) | Abdominal cavity (1/12, 8.3%), axilla (1/12, 8.3%), chest wall (12/49, 24.5%), diaphragm (6/72, 8.3%), esophagus (2/36, 5.6%), heart (1/17, 5.9%), lung (38/60, 63.3%), mediastinum (35/41, 85.4%), pelvis (1/12, 8.3%), pericardium (2/19, 10.5%), retroperitoneum (1/12, 8.3%), pleura (16/36, 44.4%), vertebra (4/33, 12.1%) | Lung (37/37, 100%) | Lung, mediastinum, chest wall, vertebra, clavicle, brachial plexus |
Site of metastasis (n, %) | Adrenal gland (11/50, 22%), abdominal cavity (1/19, 5.3%), bone (14/49, 28.6%), brain (1/19, 5.3%), chest wall (1/17, 5.9%), dura (2/19, 10.5%), esophagus (1/17, 5.9%), kidney (3/36, 8.3%), liver (11/53, 20.8%), lung (8/29, 27.6%), lymph node (23/50, 46%), mesentery (2/36, 5.6%), omentum (1/17, 5.9%), ovary (1/12, 8.3%), pancreas (2/17, 11.8%), peritoneum/retroperitoneum (6/36, 16.7%), pleura (3/29, 10.3%), stomach (4/29, 13.8%), soft tissue (2/29, 6.9%), vertebra (7/29, 24.1%) | Abdominal wall (1/18, 5.5%), adrenal gland (5/18, 27.8%), bone (4/18, 22.2%), brain (2/18, 11.1%), liver (4/18, 22.2%), lung (3/19, 15.8%), lymph node (4/18. 22.2%), peritoneum (3/18, 16.7%), pleura (5/18, 27.8%), skin (1/18, 5.5%) | Brain |
Emphysema and/or bullae, n (%) | 33/49 (67.3%) | | Bullae |
Histology | | | |
Undifferentiated round cell, n (%) | 52/52 (100%) | 4/36 (11.1%) | Present |
Rhabdoid cell, n (%) | 23/52 (44.2%) | 5/36 (13.9%) | Present |
Spindle cell, n (%) | 2/14 (14.3%) | 1/40 (2.5%) | Present |
Non-small cell carcinoma, n (%) | 2/32 (6.3%) | 39/41 (95.1%) | Present |
IHC | | | |
BRG1 lost or reduced, n (%) | 52/52 (100%) | 41/41 (100%) | Negative (lost) |
BRM lost or reduced, n (%) | 43/46 (93.5%) | 23/85 (27.1%) | Present (reduced) |
CK positivity, n (%) | 28/52 (53.8%) | 23/24 (95.8%) | Positive |
TTF-1 positivity | 5/49 (10.2%) | 11/41 (26.8%) | Negative |
p40 positivity | 2/39 (5.1%) | 2/18 (11.1%) | Positive, a few |
Claudin-4 positivity | 0/27 (0%) | 56/52 (100%) | Positive, focal |
SOX2 positivity | 30/32 (93.8%) | 4/16 (25%) | Negative |
CD34 positivity | 31/52 (59.6%) | 0/17 (0%) | Negative |
SALL4 positivity | 19/32 (59.4%) | 5/78 (6.4%) | Negative |
p53 positivity | 10/14 (71.4%) | 2/2 (100%) | Negative |
Genetic alterations | | | |
SMARCA4 | 38/40 (95%) | 14/17 (82.4%) | Positive |
EGFR | 0/9 (0%) | 0/25 (0%) | Negative |
ALK/ROS1 | 0/9 (0%) | 0/17 (0%) | Negative |
TP53 | 27/33 (81.8%) | 15/17(88.2%) | Positive |
KRAS | 3/20 (15%) | 6/21(28.6%) | Negative |
STK11 | 5/20 (25%) | 3/12 (25%) | Negative |
KEAP1 | 3/20 (15%) | | Negative |
Abbreviations: ALK, anaplastic lymphoma kinase; BAF, BRG1/BRM-associated factors; BRG1, Brahma-related gene 1; BRM, Brahma; CT, computed tomography; CK, cytokeratin; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; NSCLC, non-small cell lung carcinoma; ROS1, ROS proto-oncogene 1; SALL4, Sal-like protein 4; SMARCA4, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4; SOX2, SRY-box 2; TTF-1, thyroid transcription factor 1. |
The absolute discrimination between SMARCA4/BRG1-deficient thoracic sarcoma and SMARCA4/BRG1-deficient NSCLC is difficult from a clinicopathologic perspective and also because of their genetic similarities; specifically, a thoracic mass may be distributed from the lung to the mediastinum/chest wall. Nowadays, alterations in SWI/SNF chromatin-remodeling complex genes, such as those in SMARCB1, SMARCA2, SMARCA4, and ARID1A, are believed to be associated with dedifferentiation of the carcinoma and epithelial–mesenchymal transition in several organs [11, 12, 15]. Rekhtman et al. [16] proposed that SMARCA4/BRG1-deficient thoracic sarcoma represents undifferentiated/dedifferentiated lung carcinoma associated with smoking history, which demonstrates the presence of smoking-related genetic alterations in the component of the NSCLC juxtaposed sarcomatoid area in SMARCA4/BRG1-deficient thoracic sarcoma. Dedifferentiated SMARCA4/BRG1-deficient NSCLC would likely be present in patients diagnosed with SMARCA4/BRG1-deficient thoracic sarcoma, but conversely, SMARCA4/BRG1-deficient thoracic sarcoma might be considered to be undifferentiated lung carcinoma. We wonder whether pure SMARCA4/BRG1-deficient thoracic sarcoma, which would be located only in the mediastinum and contain no lung lesions or epithelial elements, is a unique entity and whether there is an intermediate tumor type between thoracic sarcoma and dedifferentiated carcinoma that is yet to be defined (Fig. 4).
In this case, the alteration in SMARCA4 was located on exon22:c.3034C > T, Q1012, and was a stop-gain single nucleotide variant type, which is considered a truncating mutation. The same codon mutation in SMARCA4 was reported by Yoshida et al.15 in a patient with SMARCA4/BRG1-deficient thoracic sarcoma, who was a 40 year-old male smoker treated with surgery and chemotherapy but died after 7 months. His primary tumor was located in the axilla, and the metastatic sites were the lymph node, adrenal gland, and stomach. Remarkably, the lung lesion was not substantial in size during the disease period. An immunohistochemical analysis of his tumor revealed BRG1 loss, BRM positivity, CK AE1/AE3 positivity, CD34/SOX2/SALL4 negativity, and claudin-4 negativity. The diagnosis of SMARCA4/BRG1-deficient thoracic sarcoma was appropriate for that case; however, there were unusual findings, such as no bullous background, retention of BRM, and negativity of stem cell markers (CD34/SOX2/SALL4). These two cases with the same genetic alteration in SMARCA4 that also shared some similar clinical and immunohistochemical features were different in that one case was classified as SMARCA4/BRG1-deficient thoracic sarcoma, and the other was classified as SMARCA4/BRG1-deficient NSCLC; these diagnoses were made regardless of whether a lung mass, different carcinoma components, or the expression of epithelial markers, such as CK and claudin-4, was observed or not. We surmise that a relationship between SMARCA4/BRG1-deficient thoracic sarcoma and SMARCA4/BRG1-deficient NSCLC exists and might be influenced by the status of other factors including another SWI/SNF complex component (BRM) or TP53 [10, 15, 16].
In this case, the histology was not identical between the primary thoracic mass and the metastatic brain lesion, which was resected 2 years after presentation. Interestingly, the histological findings were more typical of a SMARCA4/BRG1-deficient neoplasm, such as a brain metastasis, than a lung tumor. The histological difference may represent some degree of dedifferentiation, or a peculiarity in each organ; likewise, an atypical teratoid/rhabdoid tumor of the central nervous system also frequently exhibits undifferentiated round cell tumor morphology with rhabdoid features, although the first biopsy specimen might represent a small portion of a larger heterogeneous tumor.
As molecular technology progresses, the detection of key gene mutations by NGS will increase such as in this case. An effective treatment of SMARCA4-deficient NSCLC has not yet been established. Recently, high TMB in SMARCA4/BRG1-deficient thoracic sarcoma/NSCLC was also detected by NGS, which suggests the possibility of a treatment strategy based on immune checkpoint inhibitors [8, 9].
In conclusion, we experienced a case of SMARCA4/BRG1-deficient NSCLC, which typically presents in young patients who are smokers and usually presents in a bullous background as a large tumor in the lung apex, along with aggressive behavior, and requires distinction from SMARCA4/BRG1-deficient thoracic sarcoma. SMARCA4/BRG1-deficient NSCLC has no specific morphology, which is the practical reason this disease is sometimes missed. Immunohistochemistry for BRG1 should be encouraged for the pathological examination of NSCLC with any histology, except for adenocarcinoma with a lepidic pattern. SMARCA4/BRG1-deficient NSCLC lacks targetable alterations in EGFR/ALK/ROS1, and therefore, further investigation is necessary to discover the potential of therapeutic personalization and improvement in prognosis.