A Rare Cause of Duodenal Ulcer

Question: A 63-year-old female patient with epigastric pain, nausea, vomiting, and fever was admitted to our ward for two days. The patient had a history of right breast cancer, having undergone a right partial mastectomy and right axillary sentinel lymph nodes removal 6 years before. The initial stage of her breast cancer was T2N1M0, with special staining showing hormone receptor–positive and human epidermal growth factor receptor 2–negative results. She received hormone therapy with 2.5 mg letrozole after the operation. She had been taking atorvastatin for hypercholesterolemia and clopidogrel for the prevention of cardiovascular disease for 6 years. One month before this presentation, multiple metastases were discovered in the mediastinal lymph nodes, liver, and bones. Her carbohydrate antigen 15-3 level was 42.2 U/mL (normal range 0–37 U/mL). Ribociclib was subsequently added by the oncologist. However, 10 days after starting ribociclib, she presented with epigastric pain, nausea, vomiting, and fever. Abdominal computed tomography revealed findings as shown in Figures A, B (arrows), and endoscopy performed the next day revealed findings as shown in Figure C, including a biopsy from the duodenal ulcer. What is your diagnosis? Look on page 570 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. Biopsies for histologic diagnosis were performed, and the pathologic report revealed ulceration with multiple violet crystal-like materials and dense infiltration of lymphocytes, plasma cells, and neutrophils in the lamina propria (Figure D, arrows, hematoxylin and eosin stain, ×200). There was neither cryptitis nor crypt distortion. The most likely diagnosis is crystal-associated duodenal mucosal injury. Sodium polystyrene sulfonate, which is used to treat hyperkalemia in patients with chronic renal failure, is a well known cause for crystal-associated mucosal injury but this patient has never been exposed to sodium polystyrene sulfonate. Therefore, we explored other causes for crystal associated duodenal mucosal injury. Drug-related injury has been well established in all organ systems and presents in different patterns. Injury to the gastrointestinal tract is common but often under-recognized. Many drugs exhibit characteristic patterns of mucosal injury, whereas others have unclear mechanisms. For example, non-steroidal anti-inflammatory drugs can cause erosion and ulcers in the stomach and duodenum.1Parfitt J.R. Driman D.K. Pathological effects of drugs on the gastrointestinal tract: a review. Southern Ethiopia: a case-control study.Hum Pathol. 2007; 38: 527-536Crossref PubMed Scopus (169) Google Scholar Crystal deposition caused by certain medications (eg, ion-exchange resins) may result in gastrointestinal tract ulcers, but there are few case reports, and it remains under-recognized.2Abraham S.C. Bhagavan B.S. Lee L.A. et al.Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings.Am J Surg Pathol. 2001; 25: 637-644Crossref PubMed Scopus (160) Google Scholar Ribociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor that has shown significant promise in the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. As with many targeted therapies, the use of ribociclib has been associated with various adverse effects. One adverse event that has emerged in our clinical studies is duodenal ulcer associated with ribociclib.3Groot AF de Kuijpers C.J. Kroep J.R. CDK4/6 inhibition in early and metastatic breast cancer: a review.Cancer Treat Rev. 2017; 60: 130-138Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Understanding the mechanism of kayexalate-associated duodenal mucosal injury, which is well known for crystal-deposited duodenal ulcers, is crucial to begin the discussion. Kayexalate works by exchanging sodium ions for potassium ions in the intestines, leading to increased potassium excretion in the stool. However, in some cases, this can result in the formation of crystals that may damage the gastrointestinal tract.2Abraham S.C. Bhagavan B.S. Lee L.A. et al.Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings.Am J Surg Pathol. 2001; 25: 637-644Crossref PubMed Scopus (160) Google Scholar The exact mechanisms behind ribociclib-associated duodenal mucosal injury are not fully understood. However, it is thought that the inhibition of CDK 4/6 by ribociclib might play a role in impairing the cell cycle progression of gastrointestinal mucosal cells, leading to epithelial damage and vulnerability to injury.4Basile D. di Nardo P. Corvaja C. et al.Mucosal injury during anti-cancer treatment: from pathobiology to bedside.Cancers. 2019; 11: 857-879Crossref PubMed Scopus (75) Google Scholar Diagnosing ribociclib-associated duodenal mucosal injury requires a thorough evaluation of the patient's medical history, including a detailed account of ribociclib use. Endoscopy, which visualizes the duodenal ulcer, is the criterion standard for diagnosis. During endoscopy, biopsies can be taken for histopathologic examination to confirm the presence of crystal deposition in the duodenal mucosa. Symptoms and signs typically resolve after temporarily discontinuing ribociclib. Ribociclib-associated duodenal ulcers are an emerging adverse event associated with the use of this promising breast cancer therapy. Clinicians should be aware of its clinical presentation and potential mechanisms to promptly diagnose and manage affected patients. Collaborative efforts between oncologists and gastroenterologists are crucial to strike the right balance between optimal cancer treatment and minimizing the risk of gastrointestinal toxicity. Further research is warranted to better understand the underlying mechanisms and develop more effective preventive and therapeutic strategies for this complication.4Basile D. di Nardo P. Corvaja C. et al.Mucosal injury during anti-cancer treatment: from pathobiology to bedside.Cancers. 2019; 11: 857-879Crossref PubMed Scopus (75) Google Scholar All medications except dexlansoprazole were discontinued. She experienced no more nausea and vomiting the next day. The epigastric pain and fever subsided 3 days later. The patient was discharged without any adverse complications. She resumed ribociclib 2 days after discharge owing to her fear of breast cancer progression. However, she developed epigastric pain without fever and returned to our outpatient department. Ribociclib was changed to letrozole, and the epigastric pain subsided the following day. The diagnosis of ribociclib-associated duodenal mucosal injury was confirmed through patient self-rechallenge. She discontinued ribociclib and was prescribed a proton-pump inhibitor for one week. Subsequently, she no longer experienced epigastric pain, fever, or nausea. One month later, a follow-up endoscopy revealed complete resolution of the duodenal ulcer, and there was no evidence of Helicobacter pylori in the biopsy of the gastric antrum. An open and informed discussion about crystal-associated gastrointestinal tract ulcers related to ribociclib is crucial for health professionals and patients. By comprehending the risks and benefits of this treatment option and implementing appropriate monitoring and management strategies, we can enhance patient safety and outcomes.