Ileal Signet Ring Adenocarcinoma in Crohn’s Disease: Unanticipated Diagnosis After Surgical Resection of a Symptomatic Stricture

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Clarke, Maria Christina Riascos, Mark S. Redston, Matthew J. Hamilton, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4731250/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Sep, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted 7 You are reading this latest preprint version Abstract We describe a rare case of small bowel signet ring adenocarcinoma that developed in the context of ileal Crohn’s disease. The patient had medically refractory, stricturing disease for several years, leading to obstructive symptoms necessitating resection, which ultimately led to the diagnosis. This case highlights the importance of considering malignancy in the differential and surgical referral earlier in the treatment paradigm for obstructive symptoms that do not respond to IBD-directed therapies. Since there currently are no screening guidelines for small bowel malignancy in CD, close clinical monitoring is recommended in an effort to reduce complications. Crohn’s disease ileal stricture ileal signet ring cell adenocarcinoma Figures Figure 1 Figure 2 Figure 3 Key points We describe a rare case of small bowel signet ring adenocarcinoma that developed in the context of ileal Crohn’s disease. The patient had medically refractory, stricturing disease for several years, leading to obstructive symptoms necessitating resection, which ultimately led to the diagnosis. This case highlights the importance of considering malignancy in the differential and surgical referral earlier in the treatment paradigm for obstructive symptoms that do not respond to IBD-directed therapies. Since there currently are no screening guidelines for small bowel malignancy in CD, close clinical monitoring is recommended in an effort to reduce complications. Case Background A 46-year-old woman with a history of stricturing ileal Crohn’s disease (CD) was evaluated in our Center following transfer of care due to persistent abdominal pain, constipation, and weight loss. She was diagnosed with ileal CD at 38 years of age during an evaluation for post-partum diarrhea; diagnostic colonoscopy revealed ileal CD for which she was treated with oral mesalamine but required intermittent budesonide courses for ongoing symptoms over a five year span, at which time infliximab was started. Video capsule endoscopy at one year showed erythema and ulceration in the jejunum and ileum. Colonoscopy showed an endoscopically normal colon and normal-appearing terminal ileal mucosa though with mild stenosis, which was traversable with an adult colonoscope. Due to these findings and ongoing symptoms of diarrhea, arthralgias, and fatigue, she was switched to ustekinumab in addition to a specific carbohydrate diet. One year later and just before transitioning to our care, she was admitted to an outside hospital with a partial small bowel obstruction at the level of the terminal ileum, and treated with intravenous steroids. At our Center, she complained of increasingly severe post-prandial abdominal pain, constipation, and was noted to have weight loss of 10 pounds. A course of budesonide was prescribed with minimal improvement in symptoms. A computed tomography (CT) enterography showed worsened ileal disease with wall thickening and a focal region of significant luminal narrowing and upstream small bowel dilation approximately 20 cm from the ileocecal valve. Additional findings included mild fat stranding and diffuse mucosal hyperemia extending distally from the stricture to the level of the ileocecal valve (Fig. 1). Laboratory evaluation was notable for hemoglobin 12.6 g/dL, albumin 4.4 g/dL, C-reactive protein 2.9 mg/L, fecal calprotectin of > 600 µg/g, ustekinumab level 5.5 µg/mL and ustekinumab antibody < 10 AU/mL (last dose four weeks prior). Due to medically refractory disease with an ileal stricture leading to obstructive symptoms, she was referred for surgery, undergoing an uncomplicated laparoscopic ileocecectomy. The gross specimen revealed focal thickening and ulceration with creeping fat in the short segment of distal ileum (Fig. 2). The histology unexpectedly showed poorly-differentiated mucinous signet ring cell adenocarcinoma, measuring 6 cm in greatest dimension and arising from a polypoid lesion with low- and high-grade dysplasia with extensive lymphovascular and perineural invasion and involvement of 18 of 39 lymph nodes (pT4, pN2, cM0; stage IIIB). There was chronic active enteritis without granulomas in the involved segment of ileum (Fig. 3). Immunohistochemistry for mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 revealed intact nuclear staining in the tumor cells. Genetic analysis was also negative for mutations. She was subsequently started on adjuvant chemotherapy with oxaliplatin, fluorouracil, and folinic acid for 12 cycles. Carcinoembryonic antigen (CEA) was 1.8 ng/mL at diagnosis and has remained normal throughout treatment. Case Discussion We present a case of poorly differentiated mucinous signet ring cell adenocarcinoma of the ileum in a patient with eight years of medically refractory and stricturing ileal CD. Small bowel malignancies are rare, comprising 0.1–0.3% of all malignancies. 1 Although 40% of small bowel malignancies are adenocarcinoma; of these, 20% arise from the ileum, 1 2 yet among patients with CD with small bowel adenocarcinoma, 75% occur in the ileum. 3 As these malignancies are often diagnosed at more advanced stages, prognosis tends to be poor. Risk factors for small bowel adenocarcinoma include longstanding CD and celiac disease in addition to genetic cancer syndromes including Lynch syndrome, Peutz-Jeghers syndrome, and familial adenomatous polyposis. 2 Crohn’s disease increases the risk of both small bowel and colonic neoplasms compared with the general population; though the incidence is difficult to determine based on the observational data available, the relative risk of small bowel malignancy in CD was reported to be 28.37 (95% CI 14.46–55.66) in one meta-analysis. 3 4 Proposed risk factors for the development of small bowel adenocarcinoma in CD include isolated small bowel CD, longstanding disease, a history of stricturoplasty or surgically bypassed bowel segments, hazardous occupational exposures including aromatic halogen compounds or asbestos, and the use of 6-mercaptopurine. 3 5 Small bowel adenocarcinoma in the setting of CD is also associated with an earlier age at diagnosis, between the fourth and fifth decades, compared with the sixth decade in the general population. 3 Signet ring cell adenocarcinoma, associated with younger age at diagnosis, portends an inferior prognosis compared with other types of adenocarcinomas irrespective of tumor location. 6 It is most commonly found in the stomach, though it can occur in several organs including the esophagus, small bowel, colon, pancreas, breast, bladder, ovaries, and lungs. 1 Signet ring cell adenocarcinoma contains intracytoplasmic mucin vacuoles that displace the nucleus to the periphery. 7 Whereas both signet ring cell and mucinous adenocarcinomas contain mucin, the latter contains > 50% extracellular mucin that is produced by acinar cells within the tumor. 6 Of several prior reported cases of signet ring cell adenocarcinoma associated with CD in the literature, one study estimated the mean age of diagnosis was 50.9 years, mean duration of CD was 20.4 years, with abdominal pain as the most common symptom at presentation in 89% of cases. 8 Additional symptoms of small bowel signet ring cell adenocarcinoma include nausea, vomiting, gastrointestinal bleeding, obstruction, fistula, or perforation 7 that may overlap with typical symptoms of CD. Radiologic images of small bowel malignancy are generally nonspecific, appearing similar to acute inflammatory or chronic fibrotic strictures in CD, increasing the diagnostic challenge. 3 In cases of suspected small bowel adenocarcinoma, a wide surgical resection, including the mesentery and lymph nodes, is recommended. Adjuvant chemotherapy is advised, though supporting data are limited. 7 In this case, the presence of dysplasia suggests a progression leading to adenocarcinoma, as typically seen in previously-reported cases of Crohn’s disease-associated intestinal malignancy. 9 Although inflammatory bowel disease (IBD) increases the risk for carcinogenesis, current screening guidelines are focused on the detection of colorectal dysplasia and cancer. Small bowel dysplasia may be difficult to diagnose endoscopically, especially in the setting of strictures. At present, since there are no surveillance guidelines for the detection of small bowel dysplasia in patients with small bowel CD, likely explaining why cases of adenocarcinoma are often diagnosed incidentally following bowel resection. 3 A prospective cohort study of patients with longstanding small bowel CD found a 4% prevalence of small bowel dysplasia or adenocarcinoma. 5 Due to the low sensitivity of endoscopic screening at 33%, the authors of this study concluded that there was insufficient evidence to recommend routine endoscopic surveillance for small bowel dysplasia or adenocarcinoma in patients with CD. 5 This patient had evidence of inflammatory and stricturing small bowel disease without prior imaging or colonoscopy with biopsy to suggest dysplasia or mass lesion. With the clinical progression of abdominal pain, weight loss, and bowel obstruction, repeat diagnostic studies including dedicated small bowel imaging prompted referral to surgery to establish the diagnosis. Adenocarcinoma of the small intestine should be considered in the differential diagnosis of patients with stricturing CD who present with new or worsened symptoms or disease manifestations including bowel obstruction. Declarations Authorship statement: (i) Guarantor of the article: Colleen R. Kelly (ii) All authors approved the final version of the manuscript for submission. Conflicts of interest: Authors' declaration of personal interests: LMC has no conflicts to declare. Ethics Statement: This report did not require approval from the Mass General Brigham Institutional Review Board. The authors received consent from the patient for the publication of this case report. Author Contribution LMC: writing original draft preparation, review, and editingMCR: preparation of pathology slides and figures, review and editing MSR: preparation of pathology slides and figuresMJH: original draft review and editing, supervisionCRK: original draft review and editing, supervision References Carvalho JR, Tavares J, Goulart I, et al. Signet Ring Cell Carcinoma, Ileal Crohn Disease or Both? - A Case of Diagnostic Challenge. GE Port J Gastroenterol. 2018;25(1). doi: 10.1159/000479590 Khosla D, Dey T, Madan R, et al. Small bowel adenocarcinoma: An overview. World J Gastrointest Oncol. 2022;14(2). doi: 10.4251/wjgo.v14.i2.413 Cahill C, Gordon PH, Petrucci A, Boutros M. Small bowel adenocarcinoma and Crohn’s disease: Any further ahead than 50 years ago? World J Gastroenterol. 2014;20(33). doi: 10.3748/wjg.v20.i33.11486 Von Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn’s disease. Dis Colon Rectum. 2007;50(6). doi: 10.1007/s10350-006-0848-z Simon M, Cosnes J, Gornet JM, et al. Endoscopic detection of small bowel dysplasia and adenocarcinoma in Crohn’s disease: A prospective cohort-study in high-risk patients. J Crohns Colitis. 2017;11(1). doi: 10.1093/ecco-jcc/jjw123 Hyngstrom JR, Hu CY, Xing Y, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the National Cancer Data Base. Ann Surg Oncol. 2012;19(9). doi: 10.1245/s10434-012-2321-7 Martins T, Umar J, Groudan K, Bharadwaj HS, Desilets D. Mucinous Signet-Cell Adenocarcinoma of the Ileum: A Diagnostic Challenge—Case Report and Review of the Literature. Case Rep Gastrointest Med. 2022;2022. doi: 10.1155/2022/5703407 Hammami MB, Aboushaar R, Musmar A, Azhar M. Ileal signet ring cell carcinoma masked by crohn disease. Ochsner Journal. 2020;20(3). doi: 10.31486/toj.19.0066 Sigel JE, Petras RE, Lashner BA, Fazio VW, Goldblum JR. Intestinal adenocarcinoma in Crohn’s disease: A report of 30 cases with a focus on coexisting dysplasia. American Journal of Surgical Pathology. 1999;23(6). doi: 10.1097/00000478-199906000-00003 Additional Declarations No competing interests reported. Supplementary Files LindsayClarkeAuthorProfile.docx Cite Share Download PDF Status: Published Journal Publication published 09 Sep, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Accepted 23 Aug, 2024 Reviews received at journal 23 Aug, 2024 Reviewers agreed at journal 23 Jul, 2024 Reviewers invited by journal 16 Jul, 2024 Editor assigned by journal 15 Jul, 2024 Submission checks completed at journal 13 Jul, 2024 First submitted to journal 12 Jul, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4731250","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":334369183,"identity":"783f0a39-1254-4ed4-aa3f-80812fbd6793","order_by":0,"name":"Lindsay M. Clarke","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBACPgYGxgMMDAkM/BIMbAyMDRBRCQYGZpxa2IAYrEVyBslaDG4QrUXs8IMDP/ekyRnf7jF7wLjDLt/g+NmHNxgqrBMbcGmRTjM42PMsx9jszhlzA8YzyZYbzqQbWzCcScejJYfhAM+BisRtN3K3STC2MRtINqSxARmH8Wo5+OdARf3mGWAt9QaS/c+AWv7h13KY50BOgoEEWMthA34JkC0N+LSkGRyWOZBmOOPO+W8SiW3HgVqeMVskHEs3xqWFXzr54cM3B5Ll+We3pUl8bKs2YONPY7zxocZaFpcWVJCAwRgFo2AUjIJRQBYAACnZV4FC/QDfAAAAAElFTkSuQmCC","orcid":"","institution":"Division of Gastroenterology, Hepatology and Endoscopy, Brigham \u0026 Women's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Lindsay","middleName":"M.","lastName":"Clarke","suffix":""},{"id":334369184,"identity":"ad4d7156-0aa6-47ee-ba56-682d8bb72837","order_by":1,"name":"Maria Christina Riascos","email":"","orcid":"","institution":"Division of Anatomic and Clinical Pathology, Department of Pathology, Mass General Brigham","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Christina","lastName":"Riascos","suffix":""},{"id":334369185,"identity":"36f9dbe3-ba42-44fa-8703-a88c61f80e12","order_by":2,"name":"Mark S. Redston","email":"","orcid":"","institution":"Division of Anatomic and Clinical Pathology, Department of Pathology, Mass General Brigham","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"S.","lastName":"Redston","suffix":""},{"id":334369186,"identity":"26a03a8a-a6ac-450a-92e9-3866d52974fe","order_by":3,"name":"Matthew J. Hamilton","email":"","orcid":"","institution":"Division of Gastroenterology, Hepatology and Endoscopy, Brigham \u0026 Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"J.","lastName":"Hamilton","suffix":""},{"id":334369187,"identity":"6ca1a135-78be-4839-bdbd-bd8b168d0d31","order_by":4,"name":"Colleen R. Kelly","email":"","orcid":"","institution":"Division of Gastroenterology, Hepatology and Endoscopy, Brigham \u0026 Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Colleen","middleName":"R.","lastName":"Kelly","suffix":""}],"badges":[],"createdAt":"2024-07-12 15:22:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4731250/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4731250/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-024-08621-4","type":"published","date":"2024-09-09T15:57:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62219250,"identity":"77e20329-be05-4401-be5a-829ea1189251","added_by":"auto","created_at":"2024-08-11 12:12:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137254,"visible":true,"origin":"","legend":"\u003cp\u003eComputed tomography enterographywith asymmetric ileal thickening and focal luminal narrowing with fat stranding, edema, and hyperemia.\u003c/p\u003e","description":"","filename":"DDSCTimage.png","url":"https://assets-eu.researchsquare.com/files/rs-4731250/v1/ded6ebc51a42adaa5b6a2d85.png"},{"id":62220304,"identity":"c11f1ea2-99c7-45e4-a744-f4a9a3806fa4","added_by":"auto","created_at":"2024-08-11 12:20:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":491189,"visible":true,"origin":"","legend":"\u003cp\u003eGross image of partial right colectomy including terminal ileum, cecum, appendix, and proximal colon. There was a 6.0 cm stricture area (inked green) in the terminal ileum. The mucosa within the area of stricture is tan-pink, granular, and focally ulcerated (spanning 7.2 x 5.0 cm) with a thickened, white fibrotic wall. The area of fibrotic tissue within the wall abuts the serosa and extends into the underlying soft tissue. The terminal ileum was markedly erythematous and with focal ulcerations.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-4731250/v1/fb980c281d86a3fa588a7213.png"},{"id":62219251,"identity":"80d0d1c4-bd25-44cb-910b-74ab98565f8e","added_by":"auto","created_at":"2024-08-11 12:12:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1447048,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathologic images of representative sections of stricture area of the surgical specimen: A. Hematoxylin and eosin (H\u0026amp;E) stain photomicrograph at 5× magnification of signet ring cell adenocarcinoma arising from a polypoid low and high-grade dysplastic lesion. B. H\u0026amp;E stain photomicrograph at 20× of signet ring cells (black arrows) with clear cytoplasm and crescent-shaped eccentric nuclei. C. H\u0026amp;E stain photomicrograph at 20× magnification of neoplastic cells infiltrating pericolonicfat and peritoneum. D. P53 immunohistochemical stain photomicrograph at 10× magnification of signet ring cells and background polyp with mutant overexpression of P53.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-4731250/v1/eff1ade21b233fffb45a9c07.png"},{"id":64619171,"identity":"9850bd21-9bd2-4687-920b-fd3b3b61b5f5","added_by":"auto","created_at":"2024-09-16 16:12:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2364477,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4731250/v1/6e2a39cb-9129-4c22-a03a-46aa5f0daa70.pdf"},{"id":62219253,"identity":"c33af58d-be6c-4436-a4be-b7339520b316","added_by":"auto","created_at":"2024-08-11 12:12:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13356600,"visible":true,"origin":"","legend":"","description":"","filename":"LindsayClarkeAuthorProfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-4731250/v1/db0b4f40fbe4c0038d11ac1e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ileal Signet Ring Adenocarcinoma in Crohn’s Disease: Unanticipated Diagnosis After Surgical Resection of a Symptomatic Stricture","fulltext":[{"header":"Key points","content":"\u003cp\u003eWe describe a rare case of small bowel signet ring adenocarcinoma that developed in the context of ileal Crohn’s disease. The patient had medically refractory, stricturing disease for several years, leading to obstructive symptoms necessitating resection, which ultimately led to the diagnosis. This case highlights the importance of considering malignancy in the differential and surgical referral earlier in the treatment paradigm for obstructive symptoms that do not respond to IBD-directed therapies. Since there currently are no screening guidelines for small bowel malignancy in CD, close clinical monitoring is recommended in an effort to reduce complications. \u003c/p\u003e"},{"header":"Case Background","content":"\u003cp\u003eA 46-year-old woman with a history of stricturing ileal Crohn\u0026rsquo;s disease (CD) was evaluated in our Center following transfer of care due to persistent abdominal pain, constipation, and weight loss.\u003c/p\u003e \u003cp\u003eShe was diagnosed with ileal CD at 38 years of age during an evaluation for post-partum diarrhea; diagnostic colonoscopy revealed ileal CD for which she was treated with oral mesalamine but required intermittent budesonide courses for ongoing symptoms over a five year span, at which time infliximab was started. Video capsule endoscopy at one year showed erythema and ulceration in the jejunum and ileum. Colonoscopy showed an endoscopically normal colon and normal-appearing terminal ileal mucosa though with mild stenosis, which was traversable with an adult colonoscope. Due to these findings and ongoing symptoms of diarrhea, arthralgias, and fatigue, she was switched to ustekinumab in addition to a specific carbohydrate diet. One year later and just before transitioning to our care, she was admitted to an outside hospital with a partial small bowel obstruction at the level of the terminal ileum, and treated with intravenous steroids.\u003c/p\u003e \u003cp\u003eAt our Center, she complained of increasingly severe post-prandial abdominal pain, constipation, and was noted to have weight loss of 10 pounds. A course of budesonide was prescribed with minimal improvement in symptoms. A computed tomography (CT) enterography showed worsened ileal disease with wall thickening and a focal region of significant luminal narrowing and upstream small bowel dilation approximately 20 cm from the ileocecal valve. Additional findings included mild fat stranding and diffuse mucosal hyperemia extending distally from the stricture to the level of the ileocecal valve (Fig.\u0026nbsp;1). Laboratory evaluation was notable for hemoglobin 12.6 g/dL, albumin 4.4 g/dL, C-reactive protein 2.9 mg/L, fecal calprotectin of \u0026gt;\u0026thinsp;600 \u0026micro;g/g, ustekinumab level 5.5 \u0026micro;g/mL and ustekinumab antibody\u0026thinsp;\u0026lt;\u0026thinsp;10 AU/mL (last dose four weeks prior).\u003c/p\u003e \u003cp\u003eDue to medically refractory disease with an ileal stricture leading to obstructive symptoms, she was referred for surgery, undergoing an uncomplicated laparoscopic ileocecectomy. The gross specimen revealed focal thickening and ulceration with creeping fat in the short segment of distal ileum (Fig.\u0026nbsp;2). The histology unexpectedly showed poorly-differentiated mucinous signet ring cell adenocarcinoma, measuring 6 cm in greatest dimension and arising from a polypoid lesion with low- and high-grade dysplasia with extensive lymphovascular and perineural invasion and involvement of 18 of 39 lymph nodes (pT4, pN2, cM0; stage IIIB). There was chronic active enteritis without granulomas in the involved segment of ileum (Fig.\u0026nbsp;3). Immunohistochemistry for mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 revealed intact nuclear staining in the tumor cells. Genetic analysis was also negative for mutations. She was subsequently started on adjuvant chemotherapy with oxaliplatin, fluorouracil, and folinic acid for 12 cycles. Carcinoembryonic antigen (CEA) was 1.8 ng/mL at diagnosis and has remained normal throughout treatment.\u003c/p\u003e"},{"header":"Case Discussion","content":"\u003cp\u003eWe present a case of poorly differentiated mucinous signet ring cell adenocarcinoma of the ileum in a patient with eight years of medically refractory and stricturing ileal CD.\u003c/p\u003e \u003cp\u003eSmall bowel malignancies are rare, comprising 0.1\u0026ndash;0.3% of all malignancies.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Although 40% of small bowel malignancies are adenocarcinoma; of these, 20% arise from the ileum,\u003csup\u003e1 2\u003c/sup\u003e yet among patients with CD with small bowel adenocarcinoma, 75% occur in the ileum.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e As these malignancies are often diagnosed at more advanced stages, prognosis tends to be poor. Risk factors for small bowel adenocarcinoma include longstanding CD and celiac disease in addition to genetic cancer syndromes including Lynch syndrome, Peutz-Jeghers syndrome, and familial adenomatous polyposis.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Crohn\u0026rsquo;s disease increases the risk of both small bowel and colonic neoplasms compared with the general population; though the incidence is difficult to determine based on the observational data available, the relative risk of small bowel malignancy in CD was reported to be 28.37 (95% CI 14.46\u0026ndash;55.66) in one meta-analysis. \u003csup\u003e3 4\u003c/sup\u003e Proposed risk factors for the development of small bowel adenocarcinoma in CD include isolated small bowel CD, longstanding disease, a history of stricturoplasty or surgically bypassed bowel segments, hazardous occupational exposures including aromatic halogen compounds or asbestos, and the use of 6-mercaptopurine.\u003csup\u003e3 5\u003c/sup\u003e Small bowel adenocarcinoma in the setting of CD is also associated with an earlier age at diagnosis, between the fourth and fifth decades, compared with the sixth decade in the general population.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSignet ring cell adenocarcinoma, associated with younger age at diagnosis, portends an inferior prognosis compared with other types of adenocarcinomas irrespective of tumor location.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e It is most commonly found in the stomach, though it can occur in several organs including the esophagus, small bowel, colon, pancreas, breast, bladder, ovaries, and lungs.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Signet ring cell adenocarcinoma contains intracytoplasmic mucin vacuoles that displace the nucleus to the periphery.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Whereas both signet ring cell and mucinous adenocarcinomas contain mucin, the latter contains\u0026thinsp;\u0026gt;\u0026thinsp;50% extracellular mucin that is produced by acinar cells within the tumor.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOf several prior reported cases of signet ring cell adenocarcinoma associated with CD in the literature, one study estimated the mean age of diagnosis was 50.9 years, mean duration of CD was 20.4 years, with abdominal pain as the most common symptom at presentation in 89% of cases.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Additional symptoms of small bowel signet ring cell adenocarcinoma include nausea, vomiting, gastrointestinal bleeding, obstruction, fistula, or perforation\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e that may overlap with typical symptoms of CD. Radiologic images of small bowel malignancy are generally nonspecific, appearing similar to acute inflammatory or chronic fibrotic strictures in CD, increasing the diagnostic challenge.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In cases of suspected small bowel adenocarcinoma, a wide surgical resection, including the mesentery and lymph nodes, is recommended. Adjuvant chemotherapy is advised, though supporting data are limited.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this case, the presence of dysplasia suggests a progression leading to adenocarcinoma, as typically seen in previously-reported cases of Crohn\u0026rsquo;s disease-associated intestinal malignancy.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Although inflammatory bowel disease (IBD) increases the risk for carcinogenesis, current screening guidelines are focused on the detection of colorectal dysplasia and cancer. Small bowel dysplasia may be difficult to diagnose endoscopically, especially in the setting of strictures. At present, since there are no surveillance guidelines for the detection of small bowel dysplasia in patients with small bowel CD, likely explaining why cases of adenocarcinoma are often diagnosed incidentally following bowel resection.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e A prospective cohort study of patients with longstanding small bowel CD found a 4% prevalence of small bowel dysplasia or adenocarcinoma.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Due to the low sensitivity of endoscopic screening at 33%, the authors of this study concluded that there was insufficient evidence to recommend routine endoscopic surveillance for small bowel dysplasia or adenocarcinoma in patients with CD.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis patient had evidence of inflammatory and stricturing small bowel disease without prior imaging or colonoscopy with biopsy to suggest dysplasia or mass lesion. With the clinical progression of abdominal pain, weight loss, and bowel obstruction, repeat diagnostic studies including dedicated small bowel imaging prompted referral to surgery to establish the diagnosis. Adenocarcinoma of the small intestine should be considered in the differential diagnosis of patients with stricturing CD who present with new or worsened symptoms or disease manifestations including bowel obstruction.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthorship statement:\u003c/p\u003e\n\u003cp\u003e(i) Guarantor of the article: Colleen R. Kelly \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(ii) All authors approved the final version of the manuscript for submission.\u003c/p\u003e\n\n\u003cp\u003eConflicts of interest:\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; declaration of personal interests:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cbr\u003eLMC has no conflicts to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthics Statement: This report did not require approval from the Mass General Brigham Institutional Review Board. The authors received consent from the patient for the publication of this case report.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLMC: writing original draft preparation, review, and editingMCR: preparation of pathology slides and figures, review and editing MSR: preparation of pathology slides and figuresMJH: original draft review and editing, supervisionCRK: original draft review and editing, supervision\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCarvalho JR, Tavares J, Goulart I, et al. Signet Ring Cell Carcinoma, Ileal Crohn Disease or Both? - A Case of Diagnostic Challenge. GE Port J Gastroenterol. 2018;25(1). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000479590\u003c/span\u003e\u003cspan address=\"10.1159/000479590\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhosla D, Dey T, Madan R, et al. Small bowel adenocarcinoma: An overview. World J Gastrointest Oncol. 2022;14(2). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4251/wjgo.v14.i2.413\u003c/span\u003e\u003cspan address=\"10.4251/wjgo.v14.i2.413\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCahill C, Gordon PH, Petrucci A, Boutros M. Small bowel adenocarcinoma and Crohn\u0026rsquo;s disease: Any further ahead than 50 years ago? World J Gastroenterol. 2014;20(33). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3748/wjg.v20.i33.11486\u003c/span\u003e\u003cspan address=\"10.3748/wjg.v20.i33.11486\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVon Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn\u0026rsquo;s disease. Dis Colon Rectum. 2007;50(6). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10350-006-0848-z\u003c/span\u003e\u003cspan address=\"10.1007/s10350-006-0848-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimon M, Cosnes J, Gornet JM, et al. Endoscopic detection of small bowel dysplasia and adenocarcinoma in Crohn\u0026rsquo;s disease: A prospective cohort-study in high-risk patients. J Crohns Colitis. 2017;11(1). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ecco-jcc/jjw123\u003c/span\u003e\u003cspan address=\"10.1093/ecco-jcc/jjw123\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHyngstrom JR, Hu CY, Xing Y, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the National Cancer Data Base. Ann Surg Oncol. 2012;19(9). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1245/s10434-012-2321-7\u003c/span\u003e\u003cspan address=\"10.1245/s10434-012-2321-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartins T, Umar J, Groudan K, Bharadwaj HS, Desilets D. Mucinous Signet-Cell Adenocarcinoma of the Ileum: A Diagnostic Challenge\u0026mdash;Case Report and Review of the Literature. Case Rep Gastrointest Med. 2022;2022. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2022/5703407\u003c/span\u003e\u003cspan address=\"10.1155/2022/5703407\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHammami MB, Aboushaar R, Musmar A, Azhar M. Ileal signet ring cell carcinoma masked by crohn disease. Ochsner Journal. 2020;20(3). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.31486/toj.19.0066\u003c/span\u003e\u003cspan address=\"10.31486/toj.19.0066\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSigel JE, Petras RE, Lashner BA, Fazio VW, Goldblum JR. Intestinal adenocarcinoma in Crohn\u0026rsquo;s disease: A report of 30 cases with a focus on coexisting dysplasia. American Journal of Surgical Pathology. 1999;23(6). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00000478-199906000-00003\u003c/span\u003e\u003cspan address=\"10.1097/00000478-199906000-00003\" 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":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Crohn’s disease, ileal stricture, ileal signet ring cell adenocarcinoma","lastPublishedDoi":"10.21203/rs.3.rs-4731250/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4731250/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"We describe a rare case of small bowel signet ring adenocarcinoma that developed in the context of ileal Crohn’s disease. The patient had medically refractory, stricturing disease for several years, leading to obstructive symptoms necessitating resection, which ultimately led to the diagnosis. This case highlights the importance of considering malignancy in the differential and surgical referral earlier in the treatment paradigm for obstructive symptoms that do not respond to IBD-directed therapies. Since there currently are no screening guidelines for small bowel malignancy in CD, close clinical monitoring is recommended in an effort to reduce complications.","manuscriptTitle":"Ileal Signet Ring Adenocarcinoma in Crohn’s Disease: Unanticipated Diagnosis After Surgical Resection of a Symptomatic Stricture","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-11 12:12:24","doi":"10.21203/rs.3.rs-4731250/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-08-23T16:09:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-23T04:05:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56157664922775284299254853515201026651","date":"2024-07-23T16:30:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-17T02:47:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-15T16:21:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-13T06:45:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2024-07-12T15:20:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d7e7a798-c134-4932-9847-4831570a6c15","owner":[],"postedDate":"August 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-16T16:03:35+00:00","versionOfRecord":{"articleIdentity":"rs-4731250","link":"https://doi.org/10.1007/s10620-024-08621-4","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2024-09-09 15:57:51","publishedOnDateReadable":"September 9th, 2024"},"versionCreatedAt":"2024-08-11 12:12:24","video":"","vorDoi":"10.1007/s10620-024-08621-4","vorDoiUrl":"https://doi.org/10.1007/s10620-024-08621-4","workflowStages":[]},"version":"v1","identity":"rs-4731250","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4731250","identity":"rs-4731250","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}