Systemic mastocytosis (SM) is a clonal disorder characterized by abnormal proliferation of mast cells in various organs.1 While SM commonly affects the skin, gastrointestinal involvement is also frequent, presenting as chronic diarrhea, abdominal pain, malabsorption, and peptic ulcers.2 Diagnosis requires histopathologic evaluation with immunohistochemical staining for mast cell markers. Abnormal endoscopic findings with biopsy-confirmed SM involvement have rarely been reported. Herein, we report a case of SM with chronic diarrhea and unique endoscopic findings of nodular lesions in the terminal ileum and colon. While such lesions are frequently associated with SM, they are often overlooked because of their subtle nature. We also highlight the diagnostic and management challenges in this case.
A 64-year-old man from Petchaburi, Thailand, with no significant medical history, presented with chronic diarrhea lasting two months. Four months earlier, he developed an itchy, brownish rash on his back, trunk, and limbs, which progressed to multiple hyperpigmented lesions. He subsequently experienced large amounts of loose, watery bowel movements 7 to 8 times daily, including nocturnal episodes, accompanied by significant weight loss, from 60 to 50 kg. He denied having fever, chronic cough, abdominal pain, flushing, or jaundice. The patient was a regular smoker but did not consume alcohol. Despite treatment with oral and intravenous antibiotics, his symptoms persisted.
Physical examination revealed cachexia, multiple discrete hyperpigmented papules, rubbery inguinal and cervical lymph nodes up to 2 cm in size, and hepatosplenomegaly. Laboratory investigations showed a hemoglobin level of 12 g/dL, leukocytosis (36,500 cells/mm3) with band forms, promyelocytes, and myelocytes, as well as thrombocytopenia (78,000 cells/mm3). The patient also had pre-renal acute kidney injury, with a blood urea nitrogen of 38.4 mg/dL and creatinine of 1.12 mg/dL, alongside mild hyponatremia, hypokalemia, and wide anion gap metabolic acidosis. Liver chemistry revealed an elevated alkaline phosphatase level of 709 U/L, with normal albumin and slightly elevated globulin levels (3.5 and 3.9 g/dL, respectively). Serological tests for hepatitis B, hepatitis C, and human immunodeficiency virus were negative. Chest X-ray was unremarkable. Stool examinations, including bacterial cultures and fresh smears for parasite analysis, yielded negative results. Abdominal computed tomography confirmed hepatosplenomegaly and multiple intra-abdominal lymphadenopathies up to 3 cm in size without abnormal bowel segments.
Differential diagnoses included hematologic malignancy or chronic infections, such as disseminated mycobacterial infection. Bone marrow biopsy showed hypercellular marrow with a prominent myeloid series but was non-diagnostic. Bidirectional endoscopy revealed diffuse mild gastroduodenopathy and ulcers in the gastric antrum and second part of the duodenum. Colonoscopy showed multiple nodular lesions throughout the terminal ileum, right-sided colon, and rectum but no ulcers or erosions (Fig. 1). A gastric biopsy revealed ulcerated mild gastritis without mast cell infiltration. However, biopsy of the right colon demonstrated monocytoid and spindle cells with eosinophilic granules (Fig. 2A). Immunohistochemical staining for CD117 and CD25 confirmed mast cell involvement (Fig. 2B, C). Tryptase staining was equivocal. These findings were consistent with the involvement of SM. An inguinal lymph node biopsy also confirmed SM involvement. Serum tryptase was elevated at 93.3 µg/L (>20 µg/L), confirming an aggressive type of SM due to organ dysfunction. Owing to limited access to midostaurin, the patient was treated with imatinib and received symptomatic management with antihistamines. Next-generation sequencing of bone marrow identified KIT D816V, SRSF2, and TET2 mutations. Imatinib was continued, but symptom improvement was minimal. After discussions with his family, the patient was referred for supportive care.
SM is characterized by the abnormal accumulation of mast cells in various organs. A classic skin manifestation includes small, round, brown, or red monomorphic lesions, typically appearing on the thighs, with biopsies demonstrating an increased number of mast cells. Other clinical manifestations, such as hepatosplenomegaly, portal hypertension, and osteolytic bone lesions, vary according to the site of infiltration. End-organ dysfunction indicates an aggressive subcategory of SM.3
Gastrointestinal involvement occurs in up to 65% of the patients.2,4 Mast cells in the intestinal lamina propria mediate gastrointestinal function by secreting histamine, tryptase, and various cytokines. A gain-of-function mutation in the KIT gene causes aberrant autophosphorylation and activation of the KIT/CD117 tyrosine kinase receptor. This activation causes mast cell proliferation and overactivation, disrupting the intestinal barrier and dysregulating mucosal immunity. The resulting effects include diarrhea, abdominal pain, esophagitis, and peptic ulcer.1 While diarrhea is usually watery due to cytokine secretion, significant infiltration may result in malabsorption.2 External stimuli, such as stress, allergens, or environmental exposures, can activate mast cells, though no such triggers were evident in this patient.
Benign-appearing gastric and duodenal ulcers are reported in 11% to 44% of cases due to histamine-induced acid hypersecretion.2 A notable finding in this case was mucosal nodularity along the small and large intestines, corresponding to massive mast cell infiltration, primarily in the lamina propria, adjacent to nerve terminals where they are activated by secreted neuropeptides. This aligns with the results of Doyle et al.,5 who reported abnormal endoscopic findings in 60% of patients with SM, primarily mucosal nodularity and granularity. The colon is the most frequently involved site (95%), followed by the ileum (86%), duodenum (80%), and stomach (54%). Other endoscopic findings include villous atrophy, esophageal varices, esophagitis, and intestinal telangiectasia.2 As these findings are subtle, accurate diagnosis necessitates a thorough endoscopic examination with particular attention. Due to deep infiltration of mast cells in the lamina propria, only 66% of biopsy specimens can detect this condition.5 Diagnostic yield can be improved by obtaining 6 to 10 specimens with adequate depth using the bite-on-bite technique or jumbo forceps, particularly for deeper layers and submucosal lesions.6 It is crucial to consult with specialized pathologists, and specific immunohistochemical staining must be performed. Additionally, a comprehensive evaluation of organ dysfunction and serum tryptase measurement is essential.7
Treatment should target mast cell stabilization using leukotriene antagonists, cromolyn sodium, or monoclonal antibodies such as omalizumab.3 Potential triggers of mast cells should be avoided. Gastrointestinal symptoms are managed with histamine-2 receptor antagonists, proton pump inhibitors, or systemic corticosteroids.4 Aggressive SM requires targeting mast cell proliferation with tyrosine kinase inhibitors.8 Two approved agents targeting specific KIT mutations are midostaurin and avapritinib. Imatinib has limited benefits and is best reserved for patients with unknown KIT mutations. Without specific agents, cytoreductive therapies such as cladribine, peginterferon alfa, or hydroxyurea may be considered. Due to the aggressive nature of SM, the long-term prognosis remains unsatisfactory, highlighting the need for novel therapies to improve treatment outcomes.
As most symptoms are non-specific, gastrointestinal involvement in SM should be suspected in patients with chronic diarrhea accompanied by typical skin lesions, hepatosplenomegaly, lymphadenopathy, or hematological abnormalities. Evidence of acid hypersecretion without an obvious cause should further raise suspicion. Prompt recognition of subtle endoscopic findings and adequate biopsies are essential for diagnosing this condition. Informed consent was obtained for this case report.
Conflicts of Interest
The authors have no potential conflicts of interest.
Funding
None.
Author Contributions
Conceptualization: UK, TC; Data curation: all authors; Investigations: TC, RK, SN, WVC, UK; Writing–original draft: TC, PW, SP, WVC, UK; Writing–review & editing: RK, SN, AK, UK.
Fig. 1.Endoscopic findings in systemic mastocytosis. Esophagogastroduodenoscopy revealed ulcers surrounded by erythematous, edematous mucosa in the gastric antrum (A) and the second part of the duodenum (B). Colonoscopy showed diffuse nodular mucosa in the terminal ileum (C) and focal nodular infiltrations along the ascending colon under white light (D), enhanced using narrow-band imaging (E), and erosive nodular infiltrations in the rectum (F).
Fig. 2.The histopathology of right colon demonstrated foci of monocytoid and spindle cells with occasional eosinophilic granules (hematoxylin and eosin stain, ×200) (A). Mast cells were highlighted by immunohistochemical stains, CD117 (×200) (B) and CD25 (×200) (C), consistent with systemic mastocytosis involvement.
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