Original ArticlesDistinct Small Intestine Mast Cell Histologic Changes in Patients With Hereditary Alpha-tryptasemia and Mast Cell Activation SyndromeHamilton, Matthew J. MD*; Zhao, Melissa MD†; Giannetti, Matthew P. MD‡; Weller, Emily BA‡; Hufdhi, Raied MD‡; Novak, Peter MD§; Mendoza-Alvarez, Lybil B. MD∥; Hornick, Jason MD, PhD†; Lyons, Jonathan J. MD¶; Glover, Sarah C. DO#,**; Castells, Mariana C. MD, PhD‡; Pozdnyakova, Olga MD, PhD† Author Information *Division of Gastroenterology, Hepatology, and Endoscopy ‡Division of Allergy and Clinical Immunology, Mastocytosis Center Departments of †Pathology §Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA ∥Department of Pediatrics, Division of Pediatric Gastroenterology #Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL ¶Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD **Department of Medicine, Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MI M.C.C. and O.P. contributed equally. Conflicts of Interest and Source of Funding: Supported in part by a combined grant from the Mastocytosis Society and American Academy of Allergy, Asthma, and Immunology (M.J.H.), the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine (S.C.G.), extramural NIH fund 1R21TR002639-01A1 (M.J.H. and S.C.G.), and the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH (J.J.L.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Matthew J. Hamilton, MD, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 (e-mail: [email protected]). The American Journal of Surgical Pathology 45(7):p 997-1004, July 2021. | DOI: 10.1097/PAS.0000000000001676 Buy Metrics Abstract Mast cells (MCs) are important in intestinal homeostasis and pathogen defense but are also implicated in many of the clinical manifestations in disorders such as irritable bowel syndrome. The utility of specific staining for MCs to quantify and phenotype them in intestinal biopsies in patients with gastrointestinal (GI) symptoms is controversial and is not a widely adopted practice. Whether or not intestinal MCs are increased or have a unique phenotype in individuals with hereditary alpha-tryptasemia (HαT), who have extra copies of the MC tryptase gene TPSAB1 and typically elevated baseline serum tryptase levels >8 ng/mL is not known. We examined the duodenal biopsies of 17 patients with HαT and compared them to 15 patients with mast cell activation syndrome who had baseline serum tryptases <8 ng/mL (MCAS-NT) and 12 GI-controls. We determined that the HαT subjects had increased MCs in the duodenum compared with MCAS-NT and GI-controls (median=30.0; interquartile range [IQR]: 20.0 to 40.0 vs. median=15.0; IQR: 5.00 to 20.0; P=0.013 and median=15.0; IQR: 13.8 to 20.0; P=0.004, respectively). These MCs were significantly found in clusters (<15 MCs) and were located throughout the mucosa and submucosa including the superficial villi compared with MCAS-NT and GI-control patients. Spindle-shaped MCs were observed in all groups including controls. These data demonstrate that HαT is associated with increased small intestinal MCs that may contribute to the prevalent GI manifestations observed among individuals with this genetic trait. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.