Undifferentiated carcinoma of the esophagus with SMARCA4 and/or SMARCA2 deficiency is a rare tumor associated with a very poor prognosis [4]. Two out of the three cases we presented herein were males, coinciding with what previous authors have suggested—a predilection towards male sex [4,5,6,7]. As the age range previously reported varies, we similarly report a variable age range with a patient as young as 47 years. In terms of localization, the cancer occurred in the distal esophagus or GE junction with our cases, in line with what others have reported previously [4,5,6]. We find that all cases either initially presented with or shortly thereafter developed metastatic disease. The range of survival after presentation or diagnosis was between 2 and 4 months, though slighter lower, and is still comparable to what has been reported in the past [4,5,6]. As a result, treatment outcomes were very dismal in all three of our cases.

Undifferentiated esophageal carcinoma is challenging to diagnose given the rarity of this disease, lack of established diagnostic criteria, and absence of microscopic features typically used to characterize other malignancies. Deficiency in SMARCA genes, critical for chromatin regulation, has been observed in cases of undifferentiated neoplasms at other anatomic sites [8]. SMARCA4 and SMARCA2 are two important genes in the field of cancer genetics [4]. These genes encode subunits of the SWI/SNF chromatin remodeling complex, and loss-of-function mutations in these genes often act as the molecular basis for oncogenesis [4]; the protein products of the mutated genes form a SWI/SNF complex act together as a functional unit [9]. Mutations in these genes have been shown to play a key role in the development of certain malignancies, specifically rhabdoid tumors, small cell carcinoma of the ovary, hypercalcemic type, and non-small cell lung cancer [4, 8]. Importantly, SMARCA4 mutations typically signal a bleak prognosis and difficult clinical course [8, 10, 11].

One of the first reports of UEC tumors in the esophagus was reported in 2015 by Singhi et al., which reported male predominance, mean age of 65.5 years, 75% association with Barrett’s, and all patients dying at last follow-up [7]. Details with regards to SMARCA4 deficiency were not reported. The following year, Agaimy and colleagues reported on cases throughout the GI tract with one in the esophagus having SMARCA2 loss [9]. In the largest case series to date, Horton et al. describe the pathologic findings and clinical features of UEC with SMARCA4 and/or SMARCA2 deficiency in a case series of 14 patients [4]. In their report, the majority of cases were found among men (10/14), age at diagnosis ranged from 63 to 86 years, and half of cases originated from the distal esophagus or gastroesophageal junction. Patient follow-up in their series is significantly limited; however, they report known mortality of 3 patients from their cohort at 0.6, 2, and 7 months after diagnosis. The authors note the tumor cells of this malignancy as having enlarged nuclei, prominent nucleoli, and moderate eosinophilic cytoplasm, with 9 of 14 cases showing extensive necrosis, and 4 of 14 cases showing cells with rhabdoid morphology. Additionally, 8 of 14 cases showed adjacent intestinal epithelium with goblet cells, suggesting an association with Barrett’s esophagus, a precursor lesion that notably is also more likely to be found in males.

Cui et al. report a case series of four patients with SMARCA4-deficient UEC and similarly, the majority of these cases were male (3/4) [6]. This cohort is notably younger, at ages 45, 47, 55, and 68. At the time of diagnosis, two of four of this cohort were found to have stage III disease with locally advanced cancer whereas the other half were found to be at stage IVB, both with metastatic disease to the liver. Among the patients with stage III disease, one was treated with chemotherapy followed by esophagectomy while the other received chemotherapy alone. Both patients however were found to have progression to metastatic disease and eventual death less than 1 year after diagnosis. Patients with metastatic disease at diagnosis in this cohort underwent palliative measures, with death observed at 72 days and 78 days after diagnosis. Regarding risk factors, all patients denied smoking history and only one of four patients reported notable alcohol consumption at 5–10 standard drinks per week. Ahmed et al. also report a small case series of two male patients with SMARCA4-deficient UEC [5]. Interestingly, one of these patients was particularly young at 39 years of age while the other was 64 years old. Similarly, both patients presented with stage IVB disease with hepatic metastasis. Mortality in these patients was observed at 1.5 months and 3 months after initial presentation.

More recently, molecular characterization of these tumors on a large number of cases was reported in two studies [12, 13]. One specifically looked at all the GE junction carcinomas at a single institution which had molecular analysis performed and identified which ones had SMARCA4 mutation [13]. Then, from that subset they identified by histology which cases were undifferentiated versus well, moderate, or poorly differentiated. Subsequently, they identified the specific types of mutations occurring in the SMARCA4 gene (i.e., protein truncating versus missense) and correlated that with protein expression. Eight of 12 (75%) of cancers with protein-truncating SMARCA4 variants demonstrated a loss of SMARCA4 protein expression by IHC, whereas none of the seven cancers with pathogenic missense SMARCA4 variants demonstrated a loss of SMARCA4 protein expression. Although a more detailed clinical description of these individual cases was not provided in the article their survival analyses showed that patient outcome was associated with stage. Interestingly, not all carcinomas with SMARCA4 truncating variants demonstrated an undifferentiated phenotype, and a range of morphologic features were observed which did trend towards higher histologic grade: 37% were moderately differentiated, 53% were poorly differentiated, and 11% were undifferentiated. While the authors propose SMARCA4-deficient gastroesophageal carcinomas may not represent a unique tumor subtype, a more complete understanding of the full spectrum of SMARCA4 mutations will help define the patient population that may benefit from drug development. Further, the authors report that HER2 (ERBB2) gene amplification was observed in 5 (12%) of 42 carcinomas with pathogenic SMARCA4 mutation. Since we identified a single positive HER2 result in our series of three patients, HER2 testing would appear to be useful to identify patients that may benefit from trastuzumab (Herceptin) therapy.

Currently, no systemic chemotherapy regimen has proven to be effective in treating SWI/SNF-deficient malignancies, which include SMARCA2/SMARCA4-deficient tumors such as the cases described in this report. Thus, there is clearly a clinical need for effective treatment. The first step however is to accurately diagnose these tumors. Widespread availability and utilization of SWI/SNF immunohistochemistry in surgical pathology practices would be a good first step in screening for these tumors. However, as highlighted earlier, protein-truncating variants demonstrate a loss of SMARCA4 protein expression by IHC, whereas pathogenic missense SMARCA4 variants typically show retained expression thus masking the underlying mutation. Molecular testing would be a useful ancillary test to identify both types of mutations more accurately. Few commercial as well as academic laboratories have begun to include SWI/SNF-related genes (e.g., SMARCA4, SMARCB1) in their next-generation sequencing (NGS) panels. If initial screening by IHC is inconclusive but suspicion remains, these NGS panels would be a logical next step in the diagnostic algorithm. Improved therapies will hopefully follow the increase in identification and accurate diagnosis of these tumors.

Immune checkpoint inhibitors (ICIs) have been identified as a potentially promising treatment approach for SWI/SNF deficient tumors. Response to ICI therapy has been associated with the presence of key predictive biomarkers such as expression status of PD-1 and its ligand PDL-1, high tumor mutation burden, and presence of mismatch repair deficiency. Because this class of tumor remains rare, clinical cases of response to immune checkpoint inhibitors remain anecdotal [14, 15]. In addition to identifying mutations in SWI/SNF genes for diagnostic purposes, due to the large number of genes surveyed in some panels, another useful application is the identification of other targetable mutations that tumors may harbor. In regard to targeted therapy, the inhibitor of the enhancer of zeste homolog 2 (EZH2) when identified by NGS testing has been identified as a targetable mutation for EZH2 inhibition. A phase I clinical trial data using the EZH2 inhibitor tazemetostat in INI1 (SMARCB1)-negative or SMARCA4-negative solid tumors has shown encouraging results, with some patients achieving a complete or partial response and some with prolonged stable disease of greater than 2 years [16].

In conclusion, SMARC-deficient UEC represents a very rare subset of esophageal carcinoma,and thus, research in this disease has been limited. From the available literature, however, it appears that it is more commonly observed in men with age ranges varying. Further research is necessary to better understand this disease and to establish treatment guidelines. While these tumors may not be more aggressive than other esophageal adenocarcinomas when matched stage for stage, it appears from the reported cases that they present at an advanced stage. Additionally, while it may not represent a unique tumor subtype, testing for SMARC deficiency by immunohistochemistry or molecular means may be of clinical utility given the advent of molecularly targeted treatment strategies. In that same vein, HER2 testing would also be advisable for these patients.