Systemic Mastocytosis, a subcategory of mastocytosis, has many different extracutaneous manifestations including gastrointestinal (GI) tract involvement. While GI involvement can be deemed nonspecific due to generalized mast cell mediators from the disease, a mastocytic enterocolitis has only been recently described and studied. This case presents a 65-year old male with a six-month history of chronic diarrhea as well as severe allergic reactions who was diagnosed with mastocytic enterocolitis after endoscopy. A trial therapy with omalizumab was successfully used as treatment for both the GI and systemic manifestations of mastocytosis.

Introduction: Mastocytosis refers to a rare group of myeloproliferative disorders characterized by excessive mast cell proliferation in one or more tissues. It is subcategorized to either only involvement of the skin or the additional involvement of extracutaneous tissues, termed cutaneous mastocytosis (CS) and systemic mastocytosis (SM) respectively. Diagnosis of SM in particular frequently involves bone marrow biopsies which, through the guidelines set forth by the World Health Organization, use a combination of immunohistochemical, serologic, morphologic, and molecular findings.1 Gastrointestinal (GI) tract involvement, with presenting symptoms as vague as diarrhea and peptic ulcer pain, is seen in 70-80% of individuals diagnosed with SM.2,3 The exact explanation behind these symptoms is difficult to explain due to a multitude of different GI pathologies that have an increase in mast cell proliferation including inflammatory bowel disease, parasitic and bacterial infections.

GI symptoms may also be explained by the systemic effects of released mediators in SM making a pure diagnosis of extracutaneous involvement in the GI tract difficult.4 Diagnosis of a mastocytic enterocolitis has only recently been described and is without consistent clinical or histologic criteria. For that reason, a thorough understanding of the clinical picture in conjunction with the histologic evidence is necessary. Treatment options vary depending on extent of the disease, but multiple studies have shown the efficacy of omalizumab in the treatment of indolent SM.5 This case presents a patient with both the clinical and histological findings of mastocytic enterocolitis.

Case Presentation: A 65-year-old male presented with chronic intractable diarrhea over a six-month period. The patient described the stools as loose, watery and non-bloody. There were no new medications or dietary changes. Stool studies for clostridium difficile, Ova/Parasite and cultures. were all negative. Hydrogen breath testing and celiac antibody screening were also negative. His medical history was notable for a new onset of rashes, hives, urticaria, and episodes of anaphylaxis which have progressively worsened over the last 12 months. The patient has used cetirizine (Zyrtec) 20 mg twice a day as well as montelukast (Singulair) but did not show significant improvement. Pulmonary function tests were subsequently performed and yielded a forced expiratory volume (FEV1) 68% of the predicted value. There was also a 7% increase after the addition of a bronchodilator.

An esophagogastroduodenoscopy (EGD) and colonoscopy were performed to further evaluate his diarrhea. Biopsies were obtained from four different locations along the GI tract for histopathology, including CD117 (c-KIT) immunohistochemical (IHC) stain; (1) The fourth part of the small bowel showed approximately 25 mast cells/high power field (HPF), (2) The stomach body showed approximately 17-20 mast cells/HPF, (3) The terminal ileum showed approximately 30 mast cells/HPF, and (4) Random colon specimens showed approximately 30 mast cells/HPF. The pathology was otherwise negative for features such as celiac disease, eosinophila, microscopic colitis and inflammatory bowel disease. Using a criterion of greater than 20 mast cells by IHC/HPF, the findings supported a diagnosis of mastocytic enterocolitis. After coordination with an allergist, the patient was given omalizumab, an anti-IgE monoclonal antibody, which showed significant improvement in the patient’s systemic allergy response as well as his chronic diarrhea.

Discussion: When diagnosing SM, it is important to follow the WHO guidelines which require either the presence of one major and one minor criterion or the presence of three minor criteria. The major criterion is the presence multifocal, dense infiltrates of greater than or equal to 15 mast cells detected in sections of bone marrow and/or other extracutaneous organs through the use of tryptase or other special stains. The minor criteria are as follows; (1) Presence of greater than 25% atypical or spindle-shaped mast cells in extracutaneous organ(s), (2) Detection of the receptor tyrosine kinase KIT (CD117) mutation D816V in extracutaneous organ(s), (3) Expression of CD2 or/and CD25 in extracutaneous mast cells, and (4) Serum tryptase concentration > 20 ng/mL (with the exception of cases with associated clonal myeloid neoplasm).1 Tryptase and CD117 in particular are expressed in both normal and neoplastic mast cells which make them very useful in identifying and quantifying mast cells in tissue via immunohistochemistry.

While GI manifestations are extremely common in SM, other inflammatory disorders can also lead to increases in mast cells throughout the GI tract, making the diagnosis challenging in some cases. For this reason, the clinical history is paramount in deciding further steps. Endoscopy with biopsies is essential to not only cement a diagnosis but to also rule- out other potential causes of diarrhea. There are many different presentations of the mucosa including nodules, pigmented areas, neutrophilic cryptitis, crypt abscess formations, intraepithelial lymphocytosis, granulomas, or thickened folds, but the mucosa may even appear normal.

There are multiple conflicting reports on GI mast cell densities in patients diagnosed with SM. Some studies report aggregates of mast cells up to 100/HPF, while other studies have varied far more with scattered results ranging from diffusely increased all the way to decreased numbers of mast cells when compared to controls.6. Another study in 2006 found 20 mast cells/HPF in a group of patients with chronic intractable diarrhea who didn’t have evidence of mastocytosis or other inflammatory disease, subsequently labeling these patients with mastocytic enterocolitis.7 A more recent study in 2007 compared mast cells in biopsies from patients with mastocytosis to a control group of multiple inflammatory disorders. The results showed mast cells numbered at an average of 196/HPF in SM and aggregates of sheets of mast cells that were not seen in other biopsies. All other controls, excluding parasitic infections, were significantly less ranging between 3-70/HPF. 8

A recent article published in The Journal of Allergy and Clinical Immunology presented a study on 55 French patients with mast cell disorders. 9 The results of the study revealed 78.2% of patients had favorable results while on omalizumab therapy. Dramatic improvement in superficial, vasomotor, GI, urinary, and even partially in most neuropsychiatric symptoms were all evident within the first 2-6 months on therapy. Given our patients clinical history of chronic intractable diarrhea and allergies along with the results of the biopsies, omalizumab treatment was given and showed quite favorable results.

Conclusion: Mastocytic enterocolitis as a manifestation of SM should always be kept in the differential diagnosis in patients with chronic diarrhea with a clinical history closely resembling a mast cell disorder. Endoscopic assessment using immunohistochemical stains is necessary to further establish a diagnosis. While studies are still very limited and conflicting, more research needs to be done to enable better diagnostic criteria to aid in treatment of these patients.