SMARCA4-Deficient Undifferentiated Esophageal Carcinoma: A Clinical Case Series and Literature Review

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Deficiency in SMARCA genes, critical for chromatin regulation, has been observed in cases of UEC. Research in UEC is sparse, however, and we present a case series along with a comprehensive review of the literature. Case Series Case 1 is a 47-year-old female with abdominal pain and dysphagia and esophagogastroduodenoscopy (EGD) showing a friable mass at GE junction. Biopsies showed a poorly differentiated neoplasm and immunohistochemistry showed loss for SMARCA4. With metastatic disease, she agreed to undergo palliative chemotherapy and radiation, passing away at 4 months. Case 2 is an 85-year-old male with dysphagia, nausea, vomiting, and distal esophageal mass with biopsy showing a malignancy with loss of SMARCA4 expression. Due to extensive metastases, he was counseled on hospice care. Case 3 is a 50-year-old male with extensive alcohol and smoking history presenting with hematemesis, passing away shortly. Posthumous histopathology consistent with undifferentiated SMARCA4-deficient carcinoma. Results of literature review indicates higher in males (73.9%) and variable age range (39-86 years). Majority (80.0%) reported in the distal esophagus. Metastatic disease common at presentation. Average survival was 2.35 months. Some managed with chemotherapy and radiation. Conclusions Research in SMARCA-deficient UEC is very limited. It is more common in men, age is variable, and associated with Barret’s esophagus. Further research is necessary to better understand it and to establish treatment guidelines; however, it is clear that SMARCA4-deficient UEC carries a significantly poor prognosis. Esophageal Cancer Undifferentiated Carcinoma Chemoradiation SMARCA genes Histopathology Figures Figure 1 Figure 2 Figure 3 Introduction As of 2020, esophageal cancer (EC) was reported to rank seventh in incidence and sixth in overall mortality among cancers worldwide [ 1 ]. Esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) are the two main types with 80% of cases being ESCC, which can develop through all regions of the esophagus [ 2 ]. It is estimated that the incidence of EAC will continue to increase in countries of higher income, while the incidence of ESCC is projected to decrease in predilected countries [ 2 ]. Tobacco smoke and alcohol are well-known risk factors for ESCC, while gastroesophageal reflux disease (GERD) and Barrett’s esophagus are the greatest risk factors for EAC. Management of esophageal cancer depends on stage and can include endoscopic resection, stent placement, esophagectomy, radiation therapy, and chemotherapy. Prognosis and survival for patients with esophageal cancer, however, remains poor [ 3 ]. Undifferentiated carcinoma of the esophagus is a rare subset of esophageal cancer reported mainly in case reports and case series and was at least initially associated with an especially aggressive course and worse outcomes [ 4 ]. Research into undifferentiated esophageal carcinoma (UEC) is ongoing, and here we present a series of three cases and briefly review some of the most pertinent literature to enhance understanding of its clinical presentation, histopathological findings, treatment challenges, and outcomes. Case Series Case 1: The patient is a 47-year-old female with a remote history of endometrial cancer, status post hysterectomy, and GERD who presented to the ED with a 3-week history of abdominal pain and dysphagia but left before being evaluated. Later that month she had an appointment with outpatient gastroenterology. An esophagogastroduodenoscopy (EGD) showed a friable mass at the GE junction within an area of possible Barrett’s esophagus. Biopsies showed necrotic debris and Candidal pseudohyphae. She followed up with oncology and had a repeat EGD with biopsies taken (Fig. 1 ), which this time showed a poorly differentiated malignant neoplasm with extensive necrosis. The focal intact neoplasm demonstrated large cells with irregular vesicular nuclei, often with a prominent nucleolus, and moderate eosinophilic cytoplasm. Immunohistochemistry for SMARCA4 showed loss of nuclear expression in the neoplastic cells. Notably, intestinal metaplasia was noted in one of the biopsy fragments. Additionally, immunohistochemistry (IHC) for HER2 (ERBB2) was equivocal and reflex FISH testing for HER2 (ERBB2) showed a non-amplified result. Immunohistochemistry for PD-L1 showed a combined positive score (CPS) of < 1. Mismatch repair (MMR) testing was not performed in this case. An initial plan was made for neoadjuvant chemotherapy and radiation therapy followed by surgery with curative intent. She began having worsening dysphagia and severe epigastric pain and was admitted. A PET/CT was obtained which showed possible metastatic disease in the left axillary lymph node and right gluteus muscle. Imaging guided biopsies of both lesions were obtained and showed findings that were histologically identical to her esophageal carcinoma. She agreed to undergo chemotherapy and radiation therapy with palliative intent. Complications including severe pain and lymphadenopathy compressing her port site interfered with the remainder of her treatment. She received a few palliative radiation treatments. A few weeks later she was hospitalized for pneumonia and sepsis, progressing to respiratory failure for which she was intubated. Discussion was held with her family before extubation, and the patient passed away shortly thereafter, approximately 4 months after diagnosis. Case 2: The patient is an 85-year-old male with extensive history, but pertinently including colon cancer and GERD, who presented to the ED with worsening shortness of breath. He was worked up and hospitalized for pneumonia when he began experiencing dysphagia, nausea, and vomiting. A chest X-ray showed a large hiatal hernia and an EGD was performed. A large friable mass was noted in the distal esophagus and biopsies were taken. Histopathology showed an invasive high grade epithelioid malignancy with sheet-like pattern of somewhat discohesive cells in a background of Barrett’s esophagus with high grade glandular dysplasia (Fig. 2 ). The tumor cells showed moderate amounts of eosinophilic cytoplasm with focal features suggestive of rhabdoid morphology. SMARCA4 immunohistochemistry showed loss of nuclear expression in the tumor cells (Fig. 3 ). Overall, the pathologic findings were consistent with a poorly differentiated carcinoma with SMARCA4 deficiency. HER2 testing by immunohistochemistry was positive (score 3+). Mismatch repair testing by IHC showed a proficient result. Immunohistochemistry for PD-L1 showed a CPS of < 1. A later CT showed possible metastatic disease in the liver, which was biopsied and showed identical histological findings. A pleural effusion was sampled and found to also consist of malignant cells. He was not considered a good candidate for surgical intervention, chemotherapy, or radiation therapy and counseled on hospice care. He was eventually discharged to home on total parenteral nutrition and comfort care measures, where he passed away shortly thereafter, approximately 1 month after diagnosis. Case 3: The patient is a 50-year-old male with history of daily alcohol averaging 3–4 drinks per day and 15 pack year history of smoking who presented outpatient with 2-month history of fatigue, abdominal pain, vomiting, decreased appetite, and roughly 20 lbs. weight loss. Right upper quadrant ultrasound showed multiple discrete lesions in the liver concerning for metastatic disease. CT showed severe wall thickening of the distal esophagus suspicious for esophageal carcinoma as well as innumerable liver nodules and calcified lung nodules both suspicious for metastases. An EGD was performed and biopsies were taken. A few days later he presented to the ED with severe abdominal pain and hematemesis. He was hospitalized and passed away the next day due to respiratory failure. Posthumous histopathological exam of the esophageal biopsies was consistent with undifferentiated SMARCA4-deficient carcinoma. Because the patient was deceased at the time the pathology report was finalized, ancillary testing for HER2, PD-L1 and MMR was not performed. A meticulous search of the current literature on this topic yielded the articles summarized in Table 1 . Results of the literature review indicates males made up most cases (73.9%), with a variable age range (39–86 years). Majority of patients (80.0%) had lesions in the distal esophagus. EGD and CT typically showed a friable or ulcerating and/or esophageal thickening. Liver metastasis was common on presentation. Average survival following diagnosis is dismal at 2.35 months. Some patients were offered chemotherapy and radiation, although many passed away shortly after diagnosis. Table 1 Previous reported cases of SMARCA4/ SMARCA2-deficient Undifferentiated esophageal carcinoma. Authors Disease n Patient age Patient sex Location Stage / Sites of metastasis Procedures / Treatment Outcome Special Notes Cui et al. 2023 SMARCA4-deficient undifferentiated esophageal carcinoma 4 Case 1: 68 Case 2: 47 Case 3: 45 Case 4: 55 3 male, 1 female (Case 1) Mid-distal esophagus (1), Distal (3) Case 1: Stage IVB, liver metastasis Case 2: Stage IVB, liver metastasis Case 3: Stage III Case 4: Stage III Case 1: EGD, stent placement Case 2: EGD, Clinical trial CT, panitumumab Case 3: EGD, FOLFOX induction, carboplatin, paclitaxel, radiation, subsequent esophagectomy Case 4: EGD, FOLFOX Case 1: Death at 72 days Case 2: Death at 78 days Case 3: Death at 8 mo. Case 4: Death at 3 mo. Neil et al., 2023 Loss of SMARCA4 expression in gastroesophageal carcinomas 8 NR NR NR NR NR NR Pathological study of both esophageal and gastric carcinoma Ahmed et al 2022 SMARCA4-deficient undifferentiated esophageal carcinoma 2 Case 1: 39 Case 2: 64 2 male Distal (2) Case 1: Stage IVB, liver metastasis Case 2: Stage IVB, liver metastasis EGD, no further treatment Death at 1.5 mo. after initial presentation and at 3 mo. after initial presentation Horton et al. 2021 SMARCA4/ SMARCA2-deficient Undifferentiated esophageal and GEJ carcinoma 14 Mean age 73.1+/-7.2 years 10 male, 4 female GEJ (2), Distal (5), Mid (4), unspecified (4) N/A – see special notes N/A – see special notes Limited follow-up available, 3 patients noted to have died at 0.6, 2, and 7 months after diagnosis Most cases seen in consultation with limited follow-up and complete clinical information of course unavailable Agaimy et al. 2016 SMARCA2-deficient Undifferentiated GEJ carcinoma 1 54 male GEJ Liver, lung, mediastinal Neoadjuvent CT, resection, palliative CT Alive at 1 year Series of 13 cases of UC of GI tract EGD: esophagogastroduodenoscopy; NR: not reported; GEJ: gastroesophageal junction; CT: chemotherapy; FOLFOX: folinic acid, fluorouracil, and oxaliplatin; UC: undifferentiated carcinoma Discussion 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 – 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 – 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 2–4 months, though slighter lower, is still comparable to what has been reported in the past [ 4 – 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 acts 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. describes 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. reports a case series of 4 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 time of diagnosis, 2 of 4 of this cohort was 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 one 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 reports 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 twelve (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 toward 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 3 patients, Her2 testing would appear to be useful to identify patients that may benefit from trastuzumab (Herceptin) therapy. 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 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 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. Declarations This manuscript has not been published elsewhere in any language, nor is it under consideration for publication by another journal. No new data were generated or analyzed in support of this research, as this is a case report. However, the data underlying the case is available in the article and more information can be shared on reasonable request to the corresponding author. The authors acknowledge that there isn’t any grants or financial support to declare with regards to publication of this manuscript. No funding was received to assist with the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Faris Shweikeh, Gordon Hong, Jacob Walter, Jason Lane. The first draft of the manuscript was written by Faris Shweikeh, Gordon Hong, and Jacob Walter and all authors commented on previous versions of the manuscript. Primary conception and design: Faris Shweikeh, Jason Lane, and Mohamad Mouchli. Acquisition of Data: Faris Shweikeh and Jason Lan. Analysis and Interpretation of Data: All authors. Critically revising the article: Anthony Lembo, Matthew Hoscheit, Jason Lane, and Mohamad Mouchli. All authors read and approved the final version of the manuscript. Compliance with Ethical Standards The authors declare that this research is performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its subsequent amendments. Institutional Review Board (IRB) approval was not required according to the Cleveland Clinic IRB review board, given the number of subjects researched. The subjects involved gave their informed consent prior to their inclusion in this case series. The authors declare that there are no conflicts of interest with regards to the publication of this article. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. 10.3322/caac.21660 . Sheikh M, Roshandel G, McCormack V, Malekzadeh R. Current Status and Future Prospects for Esophageal Cancer. Cancers (Basel). 2023;15(3):765. 10.3390/cancers15030765 . Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509. 10.1056/NEJMra1314530 . Horton RK, Ahadi M, Gill AJ, Said S, Chen ZE, Bakhshwin A, Nichols M, Goldblum JR, Graham RP. SMARCA4/SMARCA2-deficient Carcinoma of the Esophagus and Gastroesophageal Junction. Am J Surg Pathol. 2021;45(3):414–20. 10.1097/PAS.0000000000001599 . Ahmed OT, Nam GH, Shui Y, Villavicencio J, Vaziri H. Case Series of SMARCA4-Deficient Undifferentiated Esophageal Carcinoma. Cureus. 2022;14(10):e30874. 10.7759/cureus.30874 . Cui M, Lemmon K, Jin Z, Uboha NV. Esophageal carcinoma with SMARCA4 mutation: Unique diagnostic challenges. Pathol Res Pract. 2023;248:154692. 10.1016/j.prp.2023.154692 . Singhi AD, Seethala RR, Nason K, Foxwell TJ, Roche RL, McGrath KM, Levy RM, Luketich JD, Davison JM. Undifferentiated carcinoma of the esophagus: a clinicopathological study of 16 cases. Hum Pathol. 2015;46(3):366–75. 10.1016/j.humpath.2014.11.021 . Tian Y, Xu L, Li X, Li H, Zhao M. SMARCA4: Current status and future perspectives in non-small-cell lung cancer. Cancer Lett. 2023;554:216022. 10.1016/j.canlet.2022.216022 . Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A. SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol. 2016;40(4):544–53. 10.1097/PAS.0000000000000554 . Karnezis AN, Wang Y, Ramos P, et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J Pathol. 2016;238(3):389–400. 10.1002/path.4633 . Chang B, Sheng W, Wang L, Zhu X, Tan C, Ni S, Weng W, Huang D, Wang J. SWI/SNF Complex-deficient Undifferentiated Carcinoma of the Gastrointestinal Tract: Clinicopathologic Study of 30 Cases With an Emphasis on Variable Morphology, Immune Features, and the Prognostic Significance of Different SMARCA4 and SMARCA2 Subunit Deficiencies. Am J Surg Pathol. 2022;46(7):889–906. 10.1097/PAS.0000000000001836 . Schallenberg S, Bork J, Essakly A, et al. Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma. BMC Cancer. 2020;20(1):12. 10.1186/s12885-019-6425-3 . Neil AJ, Zhao L, Isidro RA, Srivastava A, Cleary JM, Dong F. SMARCA4 Mutations in Carcinomas of the Esophagus, Esophagogastric Junction, and Stomach. Mod Pathol. 2023;36(6):100183. 10.1016/j.modpat.2023.100183 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Apr, 2024 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted Editorial decision: Revision requested 16 Mar, 2024 Reviews received at journal 16 Feb, 2024 Reviewers agreed at journal 14 Feb, 2024 Reviewers invited by journal 12 Feb, 2024 Editor assigned by journal 12 Feb, 2024 Submission checks completed at journal 08 Feb, 2024 First submitted to journal 08 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3939459","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":271752528,"identity":"511f1293-a0db-4b0d-9833-614f2d5c187a","order_by":0,"name":"Faris Shweikeh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYDACCSBOOCAnx8DA+IAkLcbGDAzMBiRoYThgnNhAtBb52T2GDx6cMUjvbz/MwPBxTy1hLQZ3zhgbJNwwyJ1xJpmBccaz40RokcjdJpHw4U/uBgn+A8w8B44R4bAZudt/JHwwSDeQYGYgTgvDjdxtDECHJUC11BDhsBv5nyUSzhgYgvxycMaBA8Q4LC3x449jBvL87YcZH3w4UEeEw5AB0IrDJGoBAlJtGQWjYBSMgpEAALmYPe9yWcvdAAAAAElFTkSuQmCC","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":true,"prefix":"","firstName":"Faris","middleName":"","lastName":"Shweikeh","suffix":""},{"id":271752529,"identity":"4bc49e89-f634-4105-a8b8-853428a5ba1f","order_by":1,"name":"Gordon Hong","email":"","orcid":"","institution":"University Hospitals Cleveland Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Gordon","middleName":"","lastName":"Hong","suffix":""},{"id":271752530,"identity":"23100976-4512-4bf7-bb83-8fae2e7e562d","order_by":2,"name":"Jacob Walter","email":"","orcid":"","institution":"Northeast Ohio Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jacob","middleName":"","lastName":"Walter","suffix":""},{"id":271752531,"identity":"c2849416-a201-44e5-abc3-366b37d83da5","order_by":3,"name":"Matthew Hoscheit","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Hoscheit","suffix":""},{"id":271752532,"identity":"9df30fd9-443a-4afe-bb05-ed05e3162873","order_by":4,"name":"Anthony Lembo","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Lembo","suffix":""},{"id":271752533,"identity":"f50140a0-7aed-4bb8-8d7b-e6d221413f4b","order_by":5,"name":"Jason Lane","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"","lastName":"Lane","suffix":""},{"id":271752534,"identity":"adb62d54-ebb2-47c6-884e-3b46fc2b0c29","order_by":6,"name":"Mohamad Mouchli","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Mohamad","middleName":"","lastName":"Mouchli","suffix":""}],"badges":[],"createdAt":"2024-02-08 09:29:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3939459/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3939459/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12029-024-01060-4","type":"published","date":"2024-04-24T23:38:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51023398,"identity":"4e3d2fd0-14de-4eef-8fd0-ce91733e8088","added_by":"auto","created_at":"2024-02-12 21:18:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":229844,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopy from Case 1 showed a necrotic friable, hard mass extending from 30 cm to 38 cm. Salmon colored mucosa noted in the background in combination with the mass suggested malignancy in the background of Barrett’s esophagus.\u003c/p\u003e","description":"","filename":"Figure1Endoscopy.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3939459/v1/ed8563ab25ccaef9f876f50d.jpg"},{"id":51023397,"identity":"f5fe6a1a-b8b2-40b2-849a-a8a7f4d8bd63","added_by":"auto","created_at":"2024-02-12 21:18:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":587221,"visible":true,"origin":"","legend":"\u003cp\u003eH\u0026amp;E-stained sections of tumor from case 2 showed an invasive high grade epithelioid malignancy with sheet-like pattern of growth infiltrating below benign glandular epithelium (40x total magnification). Separate biopsy fragments demonstrated Barrett’s esophagus with glandular dysplasia (inset, 100x).\u003c/p\u003e","description":"","filename":"Figure2Pathology1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3939459/v1/8cc7bb62a44563bbdf195cac.jpg"},{"id":51023399,"identity":"70f780d3-2f9a-4ed1-ac0d-1dd605b91833","added_by":"auto","created_at":"2024-02-12 21:18:23","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":423231,"visible":true,"origin":"","legend":"\u003cp\u003eHigh magnification (400x) H\u0026amp;E-stained section from case 2 showed discohesive cells with moderate amounts of eosinophilic cytoplasm and focal features suggestive of rhabdoid morphology (center of image). The tumor nuclei were enlarged and somewhat monomorphic with prominent nucleoli and mitotic activity was brisk. SMARCA4 immunohistochemistry (inset, 100x) showed loss of nuclear expression in the tumor cells while retained within the benign glandular epithelium and inflammatory cells which served as a positive internal control.\u003c/p\u003e","description":"","filename":"Figure3Pathology2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3939459/v1/80a023233841dd456a049114.jpg"},{"id":55696594,"identity":"0c566438-3a04-4cda-86c1-e535231b0c05","added_by":"auto","created_at":"2024-05-02 01:46:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1077683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3939459/v1/61c45d58-5d79-43ec-a6a8-bd2367deaadd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"SMARCA4-Deficient Undifferentiated Esophageal Carcinoma: A Clinical Case Series and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAs of 2020, esophageal cancer (EC) was reported to rank seventh in incidence and sixth in overall mortality among cancers worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) are the two main types with 80% of cases being ESCC, which can develop through all regions of the esophagus [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It is estimated that the incidence of EAC will continue to increase in countries of higher income, while the incidence of ESCC is projected to decrease in predilected countries [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Tobacco smoke and alcohol are well-known risk factors for ESCC, while gastroesophageal reflux disease (GERD) and Barrett\u0026rsquo;s esophagus are the greatest risk factors for EAC. Management of esophageal cancer depends on stage and can include endoscopic resection, stent placement, esophagectomy, radiation therapy, and chemotherapy. Prognosis and survival for patients with esophageal cancer, however, remains poor [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Undifferentiated carcinoma of the esophagus is a rare subset of esophageal cancer reported mainly in case reports and case series and was at least initially associated with an especially aggressive course and worse outcomes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Research into undifferentiated esophageal carcinoma (UEC) is ongoing, and here we present a series of three cases and briefly review some of the most pertinent literature to enhance understanding of its clinical presentation, histopathological findings, treatment challenges, and outcomes.\u003c/p\u003e"},{"header":"Case Series","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase 1:\u003c/h2\u003e \u003cp\u003eThe patient is a 47-year-old female with a remote history of endometrial cancer, status post hysterectomy, and GERD who presented to the ED with a 3-week history of abdominal pain and dysphagia but left before being evaluated. Later that month she had an appointment with outpatient gastroenterology. An esophagogastroduodenoscopy (EGD) showed a friable mass at the GE junction within an area of possible Barrett\u0026rsquo;s esophagus. Biopsies showed necrotic debris and Candidal pseudohyphae.\u003c/p\u003e \u003cp\u003eShe followed up with oncology and had a repeat EGD with biopsies taken (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), which this time showed a poorly differentiated malignant neoplasm with extensive necrosis. The focal intact neoplasm demonstrated large cells with irregular vesicular nuclei, often with a prominent nucleolus, and moderate eosinophilic cytoplasm. Immunohistochemistry for SMARCA4 showed loss of nuclear expression in the neoplastic cells. Notably, intestinal metaplasia was noted in one of the biopsy fragments. Additionally, immunohistochemistry (IHC) for HER2 (ERBB2) was equivocal and reflex FISH testing for HER2 (ERBB2) showed a non-amplified result. Immunohistochemistry for PD-L1 showed a combined positive score (CPS) of \u0026lt;\u0026thinsp;1. Mismatch repair (MMR) testing was not performed in this case.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAn initial plan was made for neoadjuvant chemotherapy and radiation therapy followed by surgery with curative intent. She began having worsening dysphagia and severe epigastric pain and was admitted. A PET/CT was obtained which showed possible metastatic disease in the left axillary lymph node and right gluteus muscle. Imaging guided biopsies of both lesions were obtained and showed findings that were histologically identical to her esophageal carcinoma. She agreed to undergo chemotherapy and radiation therapy with palliative intent.\u003c/p\u003e \u003cp\u003eComplications including severe pain and lymphadenopathy compressing her port site interfered with the remainder of her treatment. She received a few palliative radiation treatments. A few weeks later she was hospitalized for pneumonia and sepsis, progressing to respiratory failure for which she was intubated. Discussion was held with her family before extubation, and the patient passed away shortly thereafter, approximately 4 months after diagnosis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase 2:\u003c/h3\u003e\n\u003cp\u003eThe patient is an 85-year-old male with extensive history, but pertinently including colon cancer and GERD, who presented to the ED with worsening shortness of breath. He was worked up and hospitalized for pneumonia when he began experiencing dysphagia, nausea, and vomiting. A chest X-ray showed a large hiatal hernia and an EGD was performed. A large friable mass was noted in the distal esophagus and biopsies were taken.\u003c/p\u003e \u003cp\u003eHistopathology showed an invasive high grade epithelioid malignancy with sheet-like pattern of somewhat discohesive cells in a background of Barrett\u0026rsquo;s esophagus with high grade glandular dysplasia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The tumor cells showed moderate amounts of eosinophilic cytoplasm with focal features suggestive of rhabdoid morphology. SMARCA4 immunohistochemistry showed loss of nuclear expression in the tumor cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Overall, the pathologic findings were consistent with a poorly differentiated carcinoma with SMARCA4 deficiency. HER2 testing by immunohistochemistry was positive (score 3+). Mismatch repair testing by IHC showed a proficient result. Immunohistochemistry for PD-L1 showed a CPS of \u0026lt;\u0026thinsp;1. A later CT showed possible metastatic disease in the liver, which was biopsied and showed identical histological findings. A pleural effusion was sampled and found to also consist of malignant cells. He was not considered a good candidate for surgical intervention, chemotherapy, or radiation therapy and counseled on hospice care.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHe was eventually discharged to home on total parenteral nutrition and comfort care measures, where he passed away shortly thereafter, approximately 1 month after diagnosis.\u003c/p\u003e\n\u003ch3\u003eCase 3:\u003c/h3\u003e\n\u003cp\u003eThe patient is a 50-year-old male with history of daily alcohol averaging 3\u0026ndash;4 drinks per day and 15 pack year history of smoking who presented outpatient with 2-month history of fatigue, abdominal pain, vomiting, decreased appetite, and roughly 20 lbs. weight loss. Right upper quadrant ultrasound showed multiple discrete lesions in the liver concerning for metastatic disease. CT showed severe wall thickening of the distal esophagus suspicious for esophageal carcinoma as well as innumerable liver nodules and calcified lung nodules both suspicious for metastases. An EGD was performed and biopsies were taken. A few days later he presented to the ED with severe abdominal pain and hematemesis. He was hospitalized and passed away the next day due to respiratory failure.\u003c/p\u003e \u003cp\u003ePosthumous histopathological exam of the esophageal biopsies was consistent with undifferentiated SMARCA4-deficient carcinoma. Because the patient was deceased at the time the pathology report was finalized, ancillary testing for HER2, PD-L1 and MMR was not performed.\u003c/p\u003e \u003cp\u003eA meticulous search of the current literature on this topic yielded the articles summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Results of the literature review indicates males made up most cases (73.9%), with a variable age range (39\u0026ndash;86 years). Majority of patients (80.0%) had lesions in the distal esophagus. EGD and CT typically showed a friable or ulcerating and/or esophageal thickening. Liver metastasis was common on presentation. Average survival following diagnosis is dismal at 2.35 months. Some patients were offered chemotherapy and radiation, although many passed away shortly after diagnosis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrevious reported cases of SMARCA4/ SMARCA2-deficient Undifferentiated esophageal carcinoma.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatient age\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatient sex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStage / Sites of metastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProcedures / Treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSpecial Notes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCui et al. 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSMARCA4-deficient undifferentiated esophageal carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase 1: 68 Case 2: 47 Case 3: 45 Case 4: 55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 male,\u003c/p\u003e \u003cp\u003e1 female (Case 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMid-distal esophagus (1), Distal (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCase 1: Stage IVB, liver metastasis\u003c/p\u003e \u003cp\u003eCase 2: Stage IVB, liver metastasis\u003c/p\u003e \u003cp\u003eCase 3: Stage III\u003c/p\u003e \u003cp\u003eCase 4: Stage III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCase 1: EGD, stent placement\u003c/p\u003e \u003cp\u003eCase 2: EGD, Clinical trial CT, panitumumab\u003c/p\u003e \u003cp\u003eCase 3: EGD, FOLFOX induction, carboplatin, paclitaxel, radiation, subsequent esophagectomy\u003c/p\u003e \u003cp\u003eCase 4: EGD, FOLFOX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCase 1: Death at 72 days\u003c/p\u003e \u003cp\u003eCase 2: Death at 78 days\u003c/p\u003e \u003cp\u003eCase 3: Death at 8 mo.\u003c/p\u003e \u003cp\u003eCase 4: Death at 3 mo.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeil et al., 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoss of SMARCA4 expression in gastroesophageal carcinomas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePathological study of both esophageal and gastric carcinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAhmed et al 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSMARCA4-deficient undifferentiated esophageal carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase 1: 39\u003c/p\u003e \u003cp\u003eCase 2: 64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDistal (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCase 1: Stage IVB, liver metastasis\u003c/p\u003e \u003cp\u003eCase 2: Stage IVB, liver metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEGD, no further treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDeath at 1.5 mo. after initial presentation and at 3 mo. after initial presentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHorton et al. 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSMARCA4/ SMARCA2-deficient Undifferentiated esophageal and GEJ carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean age 73.1+/-7.2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 male, \u003c/p\u003e \u003cp\u003e4 female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGEJ (2), Distal (5), Mid (4), unspecified (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A \u0026ndash; see special notes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A \u0026ndash; see special notes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLimited follow-up available, 3 patients noted to have died at 0.6, 2, and 7 months after diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMost cases seen in consultation with limited follow-up and complete clinical information of course unavailable\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAgaimy et al. 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSMARCA2-deficient Undifferentiated GEJ carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGEJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiver, lung, mediastinal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNeoadjuvent CT, resection, palliative CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAlive at 1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSeries of 13 cases of UC of GI tract\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eEGD: esophagogastroduodenoscopy; NR: not reported; GEJ: gastroesophageal junction; CT: chemotherapy; FOLFOX: folinic acid, fluorouracil, and oxaliplatin; UC: undifferentiated carcinoma\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eUndifferentiated carcinoma of the esophagus with SMARCA4 and/or SMARCA2 deficiency is a rare tumor associated with a very poor prognosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Two out of the three cases we presented herein were males, coinciding with what previous authors have suggested \u0026ndash; a predilection towards male sex [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. 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 [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. 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\u0026ndash;4 months, though slighter lower, is still comparable to what has been reported in the past [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. As a result, treatment outcomes were very dismal in all three of our cases.\u003c/p\u003e \u003cp\u003eUndifferentiated 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 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. SMARCA4 and SMARCA2 are two important genes in the field of cancer genetics [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]; the protein products of the mutated genes form a SWI/SNF complex acts together as a functional unit [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Importantly, SMARCA4 mutations typically signal a bleak prognosis and difficult clinical course [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne 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\u0026rsquo;s, and all patients dying at last follow-up [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the largest case series to date, Horton et al. describes the pathologic findings and clinical features of UEC with SMARCA4 and/or SMARCA2 deficiency in a case series of 14 patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. 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\u0026rsquo;s esophagus, a precursor lesion that notably is also more likely to be found in males.\u003c/p\u003e \u003cp\u003eCui et al. reports a case series of 4 patients with SMARCA4-deficient UEC and similarly, the majority of these cases were male (3/4) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This cohort is notably younger, at ages 45, 47, 55, and 68. At time of diagnosis, 2 of 4 of this cohort was 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 one 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\u0026ndash;10 standard drinks per week. Ahmed et al. also reports a small case series of two male patients with SMARCA4-deficient UEC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eMore recently, molecular characterization of these tumors on a large number of cases was reported in two studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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 twelve (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 toward 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 3 patients, Her2 testing would appear to be useful to identify patients that may benefit from trastuzumab (Herceptin) therapy.\u003c/p\u003e \u003cp\u003eIn 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 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 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eThis manuscript has not been published elsewhere in any language, nor is it under consideration for publication by another journal.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNo new data were generated or analyzed in support of this research, as this is a case report.\u0026nbsp; However, the data underlying the case is available in the article and more information can be shared on reasonable request to the corresponding author.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge that there isn\u0026rsquo;t any grants or financial support to declare with regards to publication of this manuscript.\u003c/p\u003e\n\u003cp\u003eNo funding was received to assist with the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAuthor Contributions\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Faris Shweikeh, Gordon Hong, Jacob Walter, Jason Lane. The first draft of the manuscript was written by Faris Shweikeh, Gordon Hong, and Jacob Walter and all authors commented on previous versions of the manuscript. Primary conception and design: Faris Shweikeh, Jason Lane, and\u0026nbsp;Mohamad Mouchli. Acquisition of Data:\u0026nbsp;Faris Shweikeh and Jason Lan. Analysis and Interpretation of Data: All authors. \u0026nbsp;Critically revising the article: Anthony Lembo,\u0026nbsp;Matthew Hoscheit, Jason Lane, and\u0026nbsp;Mohamad Mouchli. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eCompliance with Ethical Standards\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that this research is performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its subsequent amendments. Institutional Review Board (IRB) approval was not required according to the Cleveland Clinic IRB review board, given the number of subjects researched. The subjects involved gave their informed consent prior to their inclusion in this case series.\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest with regards to the publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol. 2016;40(4):544\u0026ndash;53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/PAS.0000000000000554\u003c/span\u003e\u003cspan address=\"10.1097/PAS.0000000000000554\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarnezis AN, Wang Y, Ramos P, et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J Pathol. 2016;238(3):389\u0026ndash;400. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/path.4633\u003c/span\u003e\u003cspan address=\"10.1002/path.4633\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang B, Sheng W, Wang L, Zhu X, Tan C, Ni S, Weng W, Huang D, Wang J. SWI/SNF Complex-deficient Undifferentiated Carcinoma of the Gastrointestinal Tract: Clinicopathologic Study of 30 Cases With an Emphasis on Variable Morphology, Immune Features, and the Prognostic Significance of Different SMARCA4 and SMARCA2 Subunit Deficiencies. Am J Surg Pathol. 2022;46(7):889\u0026ndash;906. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/PAS.0000000000001836\u003c/span\u003e\u003cspan address=\"10.1097/PAS.0000000000001836\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchallenberg S, Bork J, Essakly A, et al. Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma. BMC Cancer. 2020;20(1):12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12885-019-6425-3\u003c/span\u003e\u003cspan address=\"10.1186/s12885-019-6425-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeil AJ, Zhao L, Isidro RA, Srivastava A, Cleary JM, Dong F. SMARCA4 Mutations in Carcinomas of the Esophagus, Esophagogastric Junction, and Stomach. Mod Pathol. 2023;36(6):100183. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.modpat.2023.100183\u003c/span\u003e\u003cspan address=\"10.1016/j.modpat.2023.100183\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Esophageal Cancer, Undifferentiated Carcinoma, Chemoradiation, SMARCA genes, Histopathology","lastPublishedDoi":"10.21203/rs.3.rs-3939459/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3939459/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUndifferentiated carcinoma of the esophagus (UEC) is a rare malignancy. Deficiency in SMARCA genes, critical for chromatin regulation, has been observed in cases of UEC. Research in UEC is sparse, however, and we present a case series along with a comprehensive review of the literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Series\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCase 1 is a 47-year-old female with abdominal pain and dysphagia and esophagogastroduodenoscopy (EGD) showing a friable mass at GE junction. Biopsies showed a poorly differentiated neoplasm and immunohistochemistry showed loss for SMARCA4. With metastatic disease, she agreed to undergo palliative chemotherapy and radiation, passing away at 4 months. Case 2 is an 85-year-old male with dysphagia, nausea, vomiting, and distal esophageal mass with biopsy showing a malignancy with loss of SMARCA4 expression. Due to extensive metastases, he was counseled on hospice care. Case 3 is a 50-year-old male with extensive alcohol and smoking history presenting with hematemesis, passing away shortly. Posthumous histopathology consistent with undifferentiated SMARCA4-deficient carcinoma. Results of literature review indicates higher in males (73.9%) and variable age range (39-86 years). Majority (80.0%) reported in the distal esophagus. Metastatic disease common at presentation. Average survival was 2.35 months. Some managed with chemotherapy and radiation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch in SMARCA-deficient UEC is very limited. It is more common in men, age is variable, and associated with Barret’s esophagus. Further research is necessary to better understand it and to establish treatment guidelines; however, it is clear that SMARCA4-deficient UEC carries a significantly poor prognosis.\u003c/p\u003e","manuscriptTitle":"SMARCA4-Deficient Undifferentiated Esophageal Carcinoma: A Clinical Case Series and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-12 21:18:18","doi":"10.21203/rs.3.rs-3939459/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-17T01:00:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-16T17:22:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51f89d53-4704-493a-97be-0cb24966383a","date":"2024-02-14T20:43:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-12T20:50:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-12T20:45:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-08T11:08:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Gastrointestinal Cancer","date":"2024-02-08T09:21:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4ab7be55-7de6-4e19-9eb5-9c596c430967","owner":[],"postedDate":"February 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T23:38:51+00:00","versionOfRecord":{"articleIdentity":"rs-3939459","link":"https://doi.org/10.1007/s12029-024-01060-4","journal":{"identity":"journal-of-gastrointestinal-cancer","isVorOnly":false,"title":"Journal of Gastrointestinal Cancer"},"publishedOn":"2024-04-24 23:38:51","publishedOnDateReadable":"April 24th, 2024"},"versionCreatedAt":"2024-02-12 21:18:18","video":"","vorDoi":"10.1007/s12029-024-01060-4","vorDoiUrl":"https://doi.org/10.1007/s12029-024-01060-4","workflowStages":[]},"version":"v1","identity":"rs-3939459","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3939459","identity":"rs-3939459","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}