Diagnostic Considerations

The three most important conditions in the differential diagnosis are carcinoid syndrome, VIPoma, and Zollinger-Ellison syndrome. Like systemic mastocytosis (systemic mast cell disease), each of these conditions causes diarrhea, abdominal pain, and some degree of malabsorption.

Urticaria pigmentosa can help distinguish systemic mastocytosis from the other disorders. Plasma hormone measurements can also help in identifying these disorders: Gastrin levels can be elevated in persons with Zollinger-Ellison syndrome, and serotonin levels can be elevated in persons with carcinoid syndrome. Other malabsorption syndromes, such as celiac sprue, are also in the differential diagnosis.

Three other disorders of mast cell activation with overlapping clinical and pathological features are monoclonal mast cell activation syndrome, idiopathic mast cell activation syndrome, and idiopathic anaphylaxis. Systemic mastocytosis is a histopathologic and genetic diagnosis and should not be based solely on clinical presentation.

Bone marrow involvement can have a differential diagnosis that includes primary myelofibrosis, reactive mastocytosis, and other myeloproliferative disorders, especially chronic eosinophilic leukemia. These disorders can be distinguished from systemic mastocytosis by differences on bone marrow biopsy as well as the presence or absence of characteristic clinical and laboratory features. Distinguishing lymph node involvement from a wide variety of lymphomas is based on histomorphology and staining. However, clinicians should remain aware that systemic mastocytosis can coexist with other primary hematologic disorders.

Differential Diagnoses

Workup

Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004. 55:419-32. [QxMD MEDLINE Link].
Bain BJ. Systemic mastocytosis and other mast cell neoplasms. Br J Haematol. 1999 Jul. 106(1):9-17. [QxMD MEDLINE Link].
Bunimovich O, Grassi M, Baer MR. Systemic mastocytosis: classification, pathogenesis, diagnosis, and treatment. Cutis. 2009 Jan. 83(1):29-36. [QxMD MEDLINE Link].
Pettigrew HD, Teuber SS, Kong JS, Gershwin ME. Contemporary challenges in mastocytosis. Clin Rev Allergy Immunol. 2010 Apr. 38(2-3):125-34. [QxMD MEDLINE Link].
Bonadonna P, Zanotti R, Pagani M, Caruso B, Perbellini O, Colarossi S. How much specific is the association between hymenoptera venom allergy and mastocytosis?. Allergy. 2009 Sep. 64(9):1379-82. [QxMD MEDLINE Link].
Weingarten TN, Volcheck GW, Sprung J. Anaphylactoid reaction to intravenous contrast in patient with systemic mastocytosis. Anaesth Intensive Care. 2009 Jul. 37(4):646-9. [QxMD MEDLINE Link].
Moura DS, Georgin-Lavialle S, Gaillard R, Hermine O. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am. 2014 May. 34 (2):407-22. [QxMD MEDLINE Link].
van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy. 2012 Mar. 67 (3):431-8. [QxMD MEDLINE Link].
Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009 Jun 4. 113(23):5727-36. [QxMD MEDLINE Link].
Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun. 14(3):641-57. [QxMD MEDLINE Link].
Ustun C, Corless CL, Savage N, et al. Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. Leuk Res. 2009 May. 33(5):735-41. [QxMD MEDLINE Link].
Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003 Nov 1. 102(9):3093-6. [QxMD MEDLINE Link]. [Full Text].
Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30. 374 (26):2530-41. [QxMD MEDLINE Link]. [Full Text].
Pieri L, Bonadonna P, Elena C, Papayannidis C, Grifoni FI, et al. Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients. Am J Hematol. 2016 Apr 7. [QxMD MEDLINE Link].
Ehrlich P. Beitrage zur Kenntnis der Anilinfarbungen und ihrer Verwendung in der mikroskopischen Technik. Arch mikr Anat. 1877. 13:263-7.
Parker RI. Hematologic aspects of systemic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun. 14(3):557-68. [QxMD MEDLINE Link].
Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999 Oct 1. 94(7):2333-42. [QxMD MEDLINE Link].
Mueller N, Wicklein D, Eisenwort G, Jawhar M, Berger D, Stefanzl G, et al. CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis. Blood. 2018 Jul 17. [QxMD MEDLINE Link].
Ho CL, Kito H, Squillace DL, Lasho TL, Tefferi A. Clinical correlates of serum pro-major basic protein in a spectrum of eosinophilic disorders and myelofibrosis. Acta Haematol. 2008. 120(3):158-64. [QxMD MEDLINE Link].
Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun. 14(3):579-623. [QxMD MEDLINE Link].
Kirsch R, Geboes K, Shepherd NA, et al. Systemic mastocytosis involving the gastrointestinal tract: clinicopathologic and molecular study of five cases. Mod Pathol. 2008 Dec. 21(12):1508-16. [QxMD MEDLINE Link].
Rossini M, Zanotti R, Orsolini G, Tripi G, Viapiana O, Idolazzi L, et al. Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis. Osteoporos Int. 2016 Feb 18. [QxMD MEDLINE Link].
[Guideline] Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19. 127 (20):2391-405. [QxMD MEDLINE Link]. [Full Text].
Schwaab J, Schnittger S, Sotlar K, Walz C, Fabarius A, Pfirrmann M, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013 Oct 3. 122 (14):2460-6. [QxMD MEDLINE Link].
Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009 May. 23(5):900-4. [QxMD MEDLINE Link].
Kondo R, Gleixner KV, Mayerhofer M, Vales A, Gruze A, Samorapoompichit P, et al. Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells. Blood. 2007 Jul 15. 110 (2):661-9. [QxMD MEDLINE Link].
Butterfield JH. Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 2009 Apr. 88(3-4):122-4. [QxMD MEDLINE Link].
Mital A, Prejzner W, Hellmann A. Acquired von Willebrand syndrome during the course of systemic mastocytosis - analysis of 21 cases. Pol Arch Intern Med. 2018 Jul 11. [QxMD MEDLINE Link]. [Full Text].
Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood. 2002 Mar 1. 99(5):1741-4. [QxMD MEDLINE Link]. [Full Text].
Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. 2003 Aug 16. 362(9383):535-6. [QxMD MEDLINE Link].
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006 Oct 1. 108(7):2366-72. [QxMD MEDLINE Link].
Jawhar M, Schwaab J, Horny HP, Sotlar K, Naumann N, Fabarius A, et al. Impact of Centralized Evaluation of Bone Marrow Histology in Systemic Mastocytosis. Eur J Clin Invest. 2016 Feb 23. [QxMD MEDLINE Link].
Donker ML, van Doormaal JJ, van Doormaal FF, Kluin PM, van der Veer E, de Monchy JG, et al. Biochemical markers predictive for bone marrow involvement in systemic mastocytosis. Haematologica. 2008 Jan. 93 (1):120-3. [QxMD MEDLINE Link]. [Full Text].
Lueke AJ, Meeusen JW, Donato LJ, Gray AV, Butterfield JH, Saenger AK. Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E₄: A marker of systemic mastocytosis. Clin Biochem. 2016 Feb 18. 264 (1):217-22. [QxMD MEDLINE Link].
Gilreath JA, Tchertanov L, Deininger MW. Novel approaches to treating advanced systemic mastocytosis. Clin Pharmacol. 2019. 11:77-92. [QxMD MEDLINE Link]. [Full Text].
Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. Am J Clin Pathol. 2009 Sep. 132(3):438-47. [QxMD MEDLINE Link].
Jawhar M, Schwaab J, Horny HP, Sotlar K, Naumann N, Fabarius A, et al. Impact of Centralized Evaluation of Bone Marrow Histology in Systemic Mastocytosis. Eur J Clin Invest. 2016 Feb 23. [QxMD MEDLINE Link].
Hahn HP, Hornick JL. Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. Am J Surg Pathol. 2007 Nov. 31 (11):1669-76. [QxMD MEDLINE Link].
Worobec AS. Treatment of systemic mast cell disorders. Hematol Oncol Clin North Am. 2000 Jun. 14(3):659-87, vii. [QxMD MEDLINE Link].
Pitt TJ, Cisneros N, Kalicinsky C, Becker AB. Successful treatment of idiopathic anaphylaxis in an adolescent. J Allergy Clin Immunol. 2010 Aug. 126 (2):415-6; author reply 416. [QxMD MEDLINE Link].
Slapnicar C, Trinkaus M, Hicks L, Vadas P. Efficacy of Omalizumab in Indolent Systemic Mastocytosis. Case Rep Hematol. 2019. 2019:3787586. [QxMD MEDLINE Link]. [Full Text].
van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy. 2012 Mar. 67(3):431-8. [QxMD MEDLINE Link].
FDA Approves Avapritinib for Advanced Systemic Mastocytosis. The ASCO Post. Available at https://ascopost.com/news/june-2021/fda-approves-avapritinib-for-advanced-systemic-mastocytosis/?utm_source=TAP%2DEN%2D061721%2DTrending%5FHeme&utm_medium=email&utm_term=046fca8ed7062b1f9d17ba521501b8c9?bc_md5=046fca8ed7062b1f9d17ba521501b8c9. June 17, 2021; Accessed: June 21, 2021.
Radia D, Deininger M, Gotlib J, et al. Avapritinib, a potent and selective inhibitor of KIT D816V, induces complete and durable responses in patients (pts) with advanced systemic mastocytosis (AdvSM). European Hematology Association. Available at https://library.ehaweb.org/eha/2019/24th/267413/deepti.radia.avapritinib.a.potent.and.selective.inhibitor.of.kit.d816v.induces.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1. June 15, 2019; Accessed: June 22, 2020.
Valent P, Sperr WR, Akin C. How I treat patients with advanced systemic mastocytosis. Blood. 2010 Dec 23. 116 (26):5812-7. [QxMD MEDLINE Link]. [Full Text].
Aichberger KJ, Sperr WR, Gleixner KV, Kretschmer A, Valent P. Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosis. Eur J Clin Invest. 2008 Nov. 38(11):869-73. [QxMD MEDLINE Link].
Dowse R, Ibrahim M, McLornan DP, Moonim MT, Harrison CN, Radia DH. Beneficial effects of JAK inhibitor therapy in Systemic Mastocytosis. Br J Haematol. 2016 Feb 5. [QxMD MEDLINE Link]. [Full Text].
Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014 Oct 10. 32 (29):3264-74. [QxMD MEDLINE Link]. [Full Text].
Chaar CI, Bell RL, Duffy TP, Duffy AJ. Guidelines for safe surgery in patients with systemic mastocytosis. Am Surg. 2009 Jan. 75(1):74-80. [QxMD MEDLINE Link].
Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009 Nov. 33(11):1481-4. [QxMD MEDLINE Link].
Yacoub A, Prochaska L. Ruxolitinib improves symptoms and quality of life in a patient with systemic mastocytosis. Biomark Res. 2016. 4:2. [QxMD MEDLINE Link]. [Full Text].
Gotlib JR, Radia D, DeAngelo DJ, et al. Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM): Analyses of Patient Reported Outcomes (PROs) from the Phase 1 (EXPLORER) Study Using the (AdvSM) Symptom Assessment Form (AdvSM-SAF), a New PRO Questionnaire for (AdvSM). Blood. 2018. 132 (Supplement 1):351. [Full Text].
Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009 Jun 4. 113(23):5727-36. [QxMD MEDLINE Link].
Pardanani A, Lim KH, Lasho TL, et al. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood. 2009 Oct 29. 114(18):3769-72. [QxMD MEDLINE Link].
Jawhar M, Schwaab J, Álvarez-Twose I, et al. MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. J Clin Oncol. 2019 Nov 1. 37 (31):2846-2856. [QxMD MEDLINE Link]. [Full Text].
Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J Invest Dermatol. 1991 Mar. 96(3 suppl):2S-4S; discussion 4S, 60S-65S. [QxMD MEDLINE Link]. [Full Text].
Akin C, Schwartz LB, Kitoh T, et al. Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology. Blood. 2000 Aug 15. 96(4):1267-73. [QxMD MEDLINE Link]. [Full Text].
Kumar S, Moody P. Mastocytosis. Pediatr Rev. 2001 Jan. 22(1):33-4. [QxMD MEDLINE Link].
Longley BJ, Metcalfe DD. A proposed classification of mastocytosis incorporating molecular genetics. Hematol Oncol Clin North Am. 2000 Jun. 14(3):697-701, viii. [QxMD MEDLINE Link].
Pauls JD, Brems J, Pockros PJ, et al. Mastocytosis: diverse presentations and outcomes. Arch Intern Med. 1999 Feb 22. 159(4):401-5. [QxMD MEDLINE Link].
Seitz S, Barvencik F, Koehne T, Priemel M, Pogoda P, Semler J, et al. Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis. Osteoporos Int. 2013 Feb 23. [QxMD MEDLINE Link].
Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000 Jun. 14(3):537-55, vi. [QxMD MEDLINE Link].
Sperr WR, El-Samahi A, Kundi M, Girschikofsky M, Winkler S, Lutz D. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology. Eur J Clin Invest. 2009 Oct. 39(10):914-23. [QxMD MEDLINE Link].
Swolin B, Rodjer S, Roupe G. Cytogenetic studies in patients with mastocytosis. Cancer Genet Cytogenet. 2000 Jul 15. 120(2):131-5. [QxMD MEDLINE Link].
Tefferi A, Li CY, Butterfield JH, Hoagland HC. Treatment of systemic mast-cell disease with cladribine. N Engl J Med. 2001 Jan 25. 344(4):307-9. [QxMD MEDLINE Link].
van Daele PL, Beukenkamp BS, Geertsma-Kleinekoort WM, et al. Immunophenotyping of mast cells: a sensitive and specific diagnostic tool for systemic mastocytosis. Neth J Med. 2009 Apr. 67(4):142-6. [QxMD MEDLINE Link]. [Full Text].
Cherner JA, Jensen RT, Dubois A, O'Dorisio TM, Gardner JD, Metcalfe DD. Gastrointestinal dysfunction in systemic mastocytosis. A prospective study. Gastroenterology. 1988 Sep. 95 (3):657-67. [QxMD MEDLINE Link].

Media Gallery

Systemic mastocytosis. Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bone marrow smear from a patient with systemic mastocytosis. Several mast cells are present in this photograph. These mast cells are larger than normal mast cells and have more irregularly shaped nuclear outlines and less densely packed mast cell granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Systemic mastocytosis. Bone marrow aspirate, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a toluidine blue stain of a bone marrow smear from a patient with marrow involvement by systemic mastocytosis. Five mast cells are present in this field. The mast cell granules are metachromatic with the toluidine blue reaction. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Systemic mastocytosis. Bone marrow biopsy, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cell infiltrate. This is a toluidine blue stain of a bone marrow biopsy from a patient with systemic mastocytosis. The mast cells are metachromatic with toluidine blue and contain numerous purple granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Systemic mastocytosis. Lymph node biopsy. Diagnosis is mastocytosis, morphology is mast cell infiltrate, and the organ is the lymph nodes. This is a lymph node biopsy from a person with systemic mastocytosis. The mast cells have a characteristic perifollicular distribution. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Systemic mastocytosis. Lymph node biopsy, chloroacetate esterase stain. Diagnosis is mastocytosis, and morphology is mast cell infiltrate. This is a portion of a lymph node biopsy from a patient with systemic mastocytosis. The mast cells are chloroacetate esterase positive, which is characterized by an orange granular appearance. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

of 5

Author

Devapiran Jaishankar, MBBS Professor of Medicine, Division Chief of Oncology-Hematology, Director of Oncology Fellowship Program, James H Quillen College of Medicine, East Tennessee State University

Devapiran Jaishankar, MBBS is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Sukesh Manthri, MBBS, MD Chief Fellow in Medical Oncology, East Tennessee State University, James H Quillen College of Medicine

Sukesh Manthri, MBBS, MD is a member of the following medical societies: American Medical Association, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Koyamangalath Krishnan, MD, FRCP, FACP Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Thomas H Davis, MD, FACP Associate Professor, Fellowship Program Director, Department of Internal Medicine, Section of Hematology/Oncology, Geisel School of Medicine at Dartmouth

Thomas H Davis, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Education, American College of Physicians, New Hampshire Medical Society, Phi Beta Kappa, Society of University Urologists

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Stephen J Smith, MD, Harsha G Vardhana, MD, and Guha Krishnaswamy, MD, to the development and writing of this article.