Recent Developments in the Field of Mast Cell Disorders: Classification, Prognostication, and Management

Abstract

Mast cell (MC) disorders are generally divided into MC neoplasms, including cutaneous mastocytosis (CM) and systemic mastocytosis (SM), MC activation disorders (MCADs), including MC activation syndromes (MCASs), and reactive MC hyperplasia.1Metcalfe D.D. Mast cells and mastocytosis.Blood. 2008; 112: 946-956Crossref PubMed Scopus (415) Google Scholar, 2Theoharides T.C. Valent P. Akin C. Mast cells, mastocytosis, and related disorders.N Engl J Med. 2015; 373: 163-172Crossref PubMed Scopus (285) Google Scholar, 3Valent P. Akin C. Hartmann K. Nilsson G. Reiter A. Hermine O. et al.Mast cells as a unique hematopoietic lineage and cell system: from Paul Ehrlich’s visions to precision medicine concepts.Theranostics. 2020; 10: 10743-10768Crossref PubMed Scopus (50) Google Scholar, 4Valent P. Akin C. Hartmann K. Nilsson G. Reiter A. Hermine O. et al.Advances in the classification and treatment of mastocytosis: current status and outlook toward the future.Cancer Res. 2017; 77: 1261-1270Crossref PubMed Scopus (161) Google Scholar, 5Reiter A. George T.I. Gotlib J. New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis.Blood. 2020; 135: 1365-1376Crossref PubMed Google Scholar During the past 25 years, diagnostic criteria and related classifications for MC disorders have been established by a consensus group that consists of experts from Europe (the European Union) and the United States and represents the relevant disciplines, including dermatology, hematology, immunology/allergy, laboratory medicine, and pathology.4Valent P. Akin C. Hartmann K. Nilsson G. Reiter A. Hermine O. et al.Advances in the classification and treatment of mastocytosis: current status and outlook toward the future.Cancer Res. 2017; 77: 1261-1270Crossref PubMed Scopus (161) Google Scholar,6Valent P. Horny H.P. Escribano L. Longley B.J. Li C.Y. Schwartz L.B. et al.Diagnostic criteria and classification of mastocytosis: a consensus proposal.Leuk Res. 2001; 25: 603-625Crossref PubMed Scopus (934) Google Scholar, 7Akin C. Valent P. Metcalfe D.D. Mast cell activation syndrome: proposed diagnostic criteria.J Allergy Clin Immunol. 2010; 126: 1099-1104Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 8Valent P. Akin C. Arock M. Brockow K. Butterfield J.H. Carter M.C. et al.Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.Int Arch Allergy Immunol. 2012; 157: 215-225Crossref PubMed Scopus (423) Google Scholar, 9Valent P. Akin C. Metcalfe D.D. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts.Blood. 2017; 129: 1420-1427Crossref PubMed Scopus (360) Google Scholar Subsequently, minimal diagnostic criteria, prognostic markers, and diagnostic assays have been standardized and validated.10Valent P. Akin C. Escribano L. Födinger M. Hartmann K. Brockow K. et al.Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria.Eur J Clin Invest. 2007; 37: 435-453Crossref PubMed Scopus (624) Google Scholar, 11Arock M. Valent P. Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives.Expert Rev Hematol. 2010; 3: 497-516Crossref PubMed Scopus (110) Google Scholar, 12Sperr W.R. Escribano L. Jordan J.H. Schernthaner G.H. Kundi M. Horny H.P. Valent P. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis.Leuk Res. 2001; 25: 529-536Crossref PubMed Scopus (178) Google Scholar, 13Lim K.H. Tefferi A. Lasho T.L. Finke C. Patnaik M. Butterfield J.H. et al.Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors.Blood. 2009; 113: 5727-5736Crossref PubMed Scopus (404) Google Scholar, 14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar, 15Zanotti R. Bonifacio M. Lucchini G. Sperr W.R. Scaffidi L. van Anrooij B. et al.Refined diagnostic criteria for bone marrow mastocytosis: a proposal of the European Competence Network on Mastocytosis.Leukemia. 2022; 36: 516-524Crossref PubMed Scopus (13) Google Scholar In addition, diagnostic algorithms and prognostic scoring systems have been established.16Alvarez-Twose I. González-de-Olano D. Sánchez-Muñoz L. Matito A. Jara-Acevedo M. Teodosio C. et al.Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms.Int Arch Allergy Immunol. 2012; 157: 275-280Crossref PubMed Scopus (107) Google Scholar, 17Pardanani A. Shah S. Mannelli F. Elala Y.C. Guglielmelli P. Lasho T.L. et al.Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models.Blood Adv. 2018; 2: 2964-2972Crossref PubMed Scopus (44) Google Scholar, 18Sperr W.R. Kundi M. Alvarez-Twose I. van Anrooij B. Oude Elberink J.N.G. Gorska A. et al.International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study.Lancet Haematol. 2019; 6: e638-e649Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 19Jawhar M. Schwaab J. Álvarez-Twose I. Shoumariyeh K. Naumann N. Lübke J. et al.MARS: mutation-adjusted risk score for advanced systemic mastocytosis.J Clin Oncol. 2019; 37: 2846-2856Crossref PubMed Scopus (53) Google Scholar, 20Muñoz-González J.I. Álvarez-Twose I. Jara-Acevedo M. Zanotti R. Perkins C. Jawhar M. et al.Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study.Lancet Haematol. 2021; 8: e194-e204Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar As a result, the diagnosis, prognostication, and management of patients with MC disorders has improved substantially over the past 20 years.An emerging concept in the prognostication and management of patients with various MC disorders is that several different predisposing conditions and comorbidities may be detected in the same patient and that these conditions and pathologies may act in concert to trigger disease evolution and manifestations.21Valent P. Sperr W.R. Schwartz L.B. Horny H.P. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms.J Allergy Clin Immunol. 2004; 114: 3-11Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 22Castells M.C. Mastocytosis: moving the field to precision and personalized medicine.Immunol Allergy Clin North Am. 2018; 38 (:xvii-xvii)Google Scholar, 23Valent P. Akin C. Gleixner K.V. Sperr W.R. Reiter A. Arock M. et al.Multidisciplinary challenges in mastocytosis and how to address with personalized medicine approaches.Int J Mol Sci. 2019; 20: 2976Crossref Scopus (46) Google Scholar, 24Castells M.C. Mast cell disorders: a framework of allergy and hematology symptoms leading to personalized treatments.Ann Allergy Asthma Immunol. 2021; 127: 403-404Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 25Zanotti R. Tanasi I. Crosera L. Bonifacio M. Schena D. Orsolini G. et al.Systemic mastocytosis: multidisciplinary approach.Mediterr J Hematol Infect Dis. 2021; 13e2021068Crossref PubMed Scopus (4) Google Scholar For example, a patient with SM may also suffer from an IgE-dependent allergy with extensive MC activation, and both conditions then contribute to the severity of mediator-related symptoms. In other patients with SM, severe osteoporosis or an associated hematologic neoplasm (AHN) may develop.Therefore, proper diagnosis, accurate prognostication, and optimal management require a multidisciplinary approach following the principles of personalized medicine.21Valent P. Sperr W.R. Schwartz L.B. Horny H.P. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms.J Allergy Clin Immunol. 2004; 114: 3-11Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 22Castells M.C. Mastocytosis: moving the field to precision and personalized medicine.Immunol Allergy Clin North Am. 2018; 38 (:xvii-xvii)Google Scholar, 23Valent P. Akin C. Gleixner K.V. Sperr W.R. Reiter A. Arock M. et al.Multidisciplinary challenges in mastocytosis and how to address with personalized medicine approaches.Int J Mol Sci. 2019; 20: 2976Crossref Scopus (46) Google Scholar, 24Castells M.C. Mast cell disorders: a framework of allergy and hematology symptoms leading to personalized treatments.Ann Allergy Asthma Immunol. 2021; 127: 403-404Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 25Zanotti R. Tanasi I. Crosera L. Bonifacio M. Schena D. Orsolini G. et al.Systemic mastocytosis: multidisciplinary approach.Mediterr J Hematol Infect Dis. 2021; 13e2021068Crossref PubMed Scopus (4) Google Scholar Indeed, in most patients with SM, multiple organ systems are involved and several different mechanisms and comorbidities may contribute to MC expansion and activation. In MCADs including MCASs, the most important comorbidities are allergic disorders. More recently, hereditary alpha tryptasemia (HαT) has been identified as a relevant genetic condition in these patients.26Greiner G. Sprinzl B. Górska A. Ratzinger F. Gurbisz M. Witzeneder N. et al.Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.Blood. 2021; 137: 238-247Crossref PubMed Scopus (62) Google Scholar,27Lyons J.J. Chovanec J. O’Connell M.P. Liu Y. Šelb J. Zanotti R. et al.Heritable risk for severe anaphylaxis associated with increased alpha-tryptase-encoding germline copy number at TPSAB1.J Allergy Clin Immunol. 2021; 147: 622-632Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar In those with advanced SM, such as aggressive SM, (aggressive) SM with an AHN, and MC leukemia, additional (often AHN-related) mutations in various driver genes (apart from KIT D816V) are considered to contribute to disease progression.28Schwaab J. Schnittger S. Sotlar K. Walz C. Fabarius A. Pfirrmann M. et al.Comprehensive mutational profiling in advanced systemic mastocytosis.Blood. 2013; 122: 2460-2466Crossref PubMed Scopus (176) Google Scholar, 29Jawhar M. Schwaab J. Schnittger S. Meggendorfer M. Pfirrmann M. Sotlar K. et al.Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis.Leukemia. 2016; 30: 136-143Crossref PubMed Scopus (140) Google Scholar, 30Muñoz-González J.I. Álvarez-Twose I. Jara-Acevedo M. Henriques A. Viñas E. Prieto C. et al.Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis.Blood. 2019; 134: 456-468Crossref PubMed Scopus (32) Google ScholarTo foster research and translation in the field of MCADs and mastocytosis and to develop and maintain standards in the diagnosis, prognostication, and management of disease in Europe (the European Union), in the United States, and ultimately worldwide, experts have established 2 interconnected competence networks, the European Competence Network on Mastocytosis (in 2002) and the American Initiative on Mast Cell Disorders (in 2019).31Valent P. Arock M. Bonadonna P. Brockow K. Broesby-Olsen S. Escribano L. et al.European Competence Network on Mastocytosis (ECNM): 10-year jubilee, update, and future perspectives.Wien Klin Wochenschr. 2012; 124: 807-814Crossref PubMed Scopus (23) Google Scholar,32Gotlib J. George T.I. Carter M.C. Austen K.F. Bochner B. Dwyer D.F. et al.Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference.J Allergy Clin Immunol. 2021; 147: 2043-2052Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Members of both networks are closely working together in multiple collaborative efforts and are organizing annual meetings and special working conferences to discuss new developments in the field, refinements in diagnostic criteria, and updates in the classification of MC disorders.In the Year 2020 Working Conference, experts discussed the current state of the art in the diagnosis, prognostication, and management of patients with MC disorders. In addition, a global classification of MC disorders was proposed (Table I).14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar Moreover, patients’ representatives from various countries were invited to share their concerns, requests, ideas, and recommendations with the scientific community. The conference-related project lasted from March 2020 until October 2021. In this project, topics were divided into 9 work packages (WPs), which are listed in Table II. WP-specific novel concepts and advancements in the field were discussed before, during, and after the conference and were then used to formulate consensus statements. These statements and a refined classification of MC disorders have recently been published.14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar A more detailed presentation of WP-related outcomes from the conference is provided in this theme issue.Table IGlobal classification of MC disorders including mastocytosis, MCADs, and predisposing conditionsCondition/disorderAbbreviationPathogenesis1. Conditions predisposing to MC activation and/or to MC expansionHereditary alpha tryptasemiaHαTExtra alpha tryptaseOther germline variants (often involving genes coding for cytokines or cytokine receptors)—Cytokine support2. MC hyperplasia—Induced by exogenous SCF—SCF-induced differentiation of MC progenitorsInduced by an underlying reactive disease (inflammation) or neoplastic disease (eg, NHL)—Cytokine-induced growth and differentiation of MC progenitors3. Mastocytosis (primary MC neoplasms)Growth and expansion of clonal MC progenitors triggered by mutant forms of the SCF receptor KIT and/or other oncogenic mechanismsCutaneous mastocytosisCMSystemic mastocytosisSMMast cell sarcomaMCS4. MC activation–related disordersMCADsMC activation induced by known or unknown triggersMC activation (disorder) unspecified/unconfirmedMCA(D)-NOSMast cell activation syndromesMCASs(in secondary MCAS: often IgE-dependent)Other mast cell activation disorder(s)MCADs∗Designated by general term used for all MCADs.5. Myeloid neoplasms with secondary MC expansionGrowth and expansion of clonal myeloid stem and progenitor cells that may differentiate into MCsMyelomastocytic leukemiaMMLOther myeloid neoplasms with MC lineage expansion—NHL, Non-Hodgkin’s lymphoma; NOS, not otherwise specified; SCF, stem cell factor.∗ Designated by general term used for all MCADs. Open table in a new tab Table IIWPs designated in the Year 2020 Working Conference on Mast Cell Disorders and Related TopicsWP no.Topics and objectivesReference∗References refer to the publications provided in the reference list of this editorial.WP1Pathology: histomorphology, immunohistochemical markers, pathologic staging in various organs (BM, skin, gastrointestinal tract, lymph nodes, spleen, liver, others)14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,33Sotlar K. George T.I. Kluin P. Reiter A. Schwaab J. Brockow K. et al.Standards of pathology in the diagnosis of systemic mastocytosis: recommendations of the EU-US Cooperative Group.J Allergy Clin Immunol Pract. 2022; 10: 1986-1998Abstract Full Text Full Text PDF Scopus (2) Google ScholarWP2Skin involvement in mastocytosis: skin infiltration patterns, symptomatology related to skin lesions, Darier’s sign, delineation between CM and SM14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,34Hartmann K. Escribano L. Grattan C. Brockow K. Carter M.C. Alvarez-Twose I. et al.Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology.J Allergy Clin Immunol. 2016; 137: 35-45Abstract Full Text Full Text PDF PubMed Scopus (211) Google ScholarWP3Major and minor diagnostic criteria of SM: definition of SM criteria, phenotypic markers (CD2, CD25, CD30), somatic KIT mutations, and serum tryptase levels14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,35Hoermann G. Sotlar K. Jawhar M. Kristensen T. Bachelot G. Nedoszytko B. et al.Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US Cooperative Group.J Allergy Clin Immunol Pract. 2022; 10: 1953-1963Abstract Full Text Full Text PDF Scopus (5) Google Scholar,36Valent P. Hartmann K. Schwaab J. Alvarez-Twose I. Brockow K. Bonadonna P. et al.Personalized management strategies in mast cell disorders: ECNM-AIM User’s Guide for Daily Clinical Practice.J Allergy Clin Immunol Pract. 2022; 10: 1999-2012Abstract Full Text Full Text PDF Scopus (3) Google ScholarWP4Molecular markers and genetic background: clinical impact of HαT, various KIT mutations, and additional mutations accumulated by myelomastocytic progenitor cells in patients with advanced SM26Greiner G. Sprinzl B. Górska A. Ratzinger F. Gurbisz M. Witzeneder N. et al.Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.Blood. 2021; 137: 238-247Crossref PubMed Scopus (62) Google Scholar,35Hoermann G. Sotlar K. Jawhar M. Kristensen T. Bachelot G. Nedoszytko B. et al.Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US Cooperative Group.J Allergy Clin Immunol Pract. 2022; 10: 1953-1963Abstract Full Text Full Text PDF Scopus (5) Google Scholar,37Lyons J. Greiner G. Hoermann G. Metcalfe D.D. Incorporating tryptase genotyping into the workup and diagnosis of mast cell diseases and reactions.J Allergy Clin Immunol Pract. 2022; 10: 1964-1973Abstract Full Text Full Text PDF Scopus (2) Google ScholarWP5Flow cytometry: application and diagnostic value of aberrantly expressed MC markers detected by flow cytometry, including CD2, CD25, and CD304Valent P. Akin C. Hartmann K. Nilsson G. Reiter A. Hermine O. et al.Advances in the classification and treatment of mastocytosis: current status and outlook toward the future.Cancer Res. 2017; 77: 1261-1270Crossref PubMed Scopus (161) Google Scholar,14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,38Blatt K. Cerny-Reiterer S. Schwaab J. Sotlar K. Eisenwort G. Stefanzl G. et al.Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis.Blood. 2015; 126: 2832-2841Crossref PubMed Scopus (35) Google ScholarWP6MC-derived mediators: clinical value of measuring the baseline serum tryptase levels in patients with CM, SM, and HαT; clinical value of event-related increase in serum tryptase in patients with MCASs; and possible clinical value of measuring other MC-derived mediators in MCAS-related events4Valent P. Akin C. Hartmann K. Nilsson G. Reiter A. Hermine O. et al.Advances in the classification and treatment of mastocytosis: current status and outlook toward the future.Cancer Res. 2017; 77: 1261-1270Crossref PubMed Scopus (161) Google Scholar,14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,39Butterfield J.H. Non-tryptase urinary and hematologic biomarkers of mast cell expansion and mast cell activation: status 2022.J Allergy Clin Immunol Pract. 2022; 10: 1974-1984Abstract Full Text Full Text PDF Google ScholarWP7MC activation and related disorders: diagnostic criteria and classification of MCASs, other MCADs (other MCADs), and suspected (unspecified) MCADs14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,39Butterfield J.H. Non-tryptase urinary and hematologic biomarkers of mast cell expansion and mast cell activation: status 2022.J Allergy Clin Immunol Pract. 2022; 10: 1974-1984Abstract Full Text Full Text PDF Google Scholar,40Valent P. Hartmann K. Bonadonna P. Gulen T. Brockow K. Alvarez-Twose I. Global classification of mast cell activation disorders: an ICD-10-adjusted proposal of the ECNM-AIM Consortium.J Allergy Clin Immunol Pract. 2022; 10: 1941-1950Abstract Full Text Full Text PDF Scopus (5) Google ScholarWP8Refinements in response criteria in advanced SM41Gotlib J. Schwaab J. Shomali W. George T.I. Radia D. Castells M. et al.Proposed ECNM-AIM response criteria in advanced systemic mastocytosis.J Allergy Clin Immunol Pract. 2022; 10: 2025-2038Abstract Full Text Full Text PDF Scopus (2) Google ScholarWP9Proposed response criteria in nonadvanced SM42Siebenhaar F. Pyatilova P. Akin C. Alvarez-Twose I. Arock M. Bonadonna P. Refined treatment response criteria for indolent systemic mastocytosis proposed by the ECNM-AIM Consortium.J Allergy Clin Immunol Pract. 2022; 10: 2015-2024Abstract Full Text Full Text PDF Scopus (1) Google Scholar∗ References refer to the publications provided in the reference list of this editorial. Open table in a new tab In WP1, refinements in the definition and application of histopathologic and immunohistochemical markers to bone marrow (BM) sections were discussed. A new specific marker of neoplastic MC in SM is CD30.14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,33Sotlar K. George T.I. Kluin P. Reiter A. Schwaab J. Brockow K. et al.Standards of pathology in the diagnosis of systemic mastocytosis: recommendations of the EU-US Cooperative Group.J Allergy Clin Immunol Pract. 2022; 10: 1986-1998Abstract Full Text Full Text PDF Scopus (2) Google Scholar,38Blatt K. Cerny-Reiterer S. Schwaab J. Sotlar K. Eisenwort G. Stefanzl G. et al.Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis.Blood. 2015; 126: 2832-2841Crossref PubMed Scopus (35) Google Scholar This marker is now recommended for addition to the diagnostic panel in SM (updated panel: CD2, CD25, CD30).14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google ScholarIn WP2, the various manifestations of skin involvement in CM and SM were discussed. An important aspect is that maculopapular skin lesions in adults are usually monomorphic and small-sized compared with the polymorphic and often larger lesions in children, and that in children with small-sized monomorphic skin lesions, these lesions are more likely to persist into adulthood.34Hartmann K. Escribano L. Grattan C. Brockow K. Carter M.C. Alvarez-Twose I. et al.Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology.J Allergy Clin Immunol. 2016; 137: 35-45Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Another important observation is that in most patients with World Health Organization–defined CM, neoplastic CD25+ and CD30+ MCs may be detected in the BM, even if SM criteria are not fulfilled.WP3 was dedicated to World Health Organization criteria for SM. Overall, major and minor SM criteria remain the same and only a few refinements were proposed. One is inclusion of CD30 as an additional phenotypic MC aberrancy that counts as a minor criterion of SM (apart from CD2 and CD25).14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar In addition, several different KIT mutations (not only D816V) are now regarded as minor SM criterion, provided that these variants are KIT-activating mutations.14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar Finally, the HαT carrier status has been discussed in the context of basal tryptase levels that count as minor SM criterion (≥20 ng/mL) or a B-Finding (≥200 ng/mL). Because carriers of HαT have elevated basal tryptase, a correction factor may be required for these criteria. Although the optimal correction approach remains under discussion, the faculty of the Working Conference concluded that a possible approach to consider would be to divide the basal serum tryptase level by the total copy number of the alpha tryptase gene (TPSAB1).14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,37Lyons J. Greiner G. Hoermann G. Metcalfe D.D. Incorporating tryptase genotyping into the workup and diagnosis of mast cell diseases and reactions.J Allergy Clin Immunol Pract. 2022; 10: 1964-1973Abstract Full Text Full Text PDF Scopus (2) Google ScholarIn WP4 (molecular markers), the diagnostic and prognostic impact of various KIT mutations and mutations in other genes was discussed. In most patients with indolent SM, smoldering SM, and SM with an AHN, the KIT mutation D816V is detected when a sensitive PCR technique is used. The recommended techniques are described in the current issue of this journal.35Hoermann G. Sotlar K. Jawhar M. Kristensen T. Bachelot G. Nedoszytko B. et al.Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US Cooperative Group.J Allergy Clin Immunol Pract. 2022; 10: 1953-1963Abstract Full Text Full Text PDF Scopus (5) Google Scholar In other patients, including some with MC leukemia and most SM cases with a well-differentiated MC morphology, other mutations in codon 816, mutations in other codons of KIT, or no KIT mutation may be found. In these patients, sequencing of the entire coding region of KIT is recommended.14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google Scholar,35Hoermann G. Sotlar K. Jawhar M. Kristensen T. Bachelot G. Nedoszytko B. et al.Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US Cooperative Group.J Allergy Clin Immunol Pract. 2022; 10: 1953-1963Abstract Full Text Full Text PDF Scopus (5) Google ScholarWP5 was dedicated to flow cytometry. A novel flow-cytometry–based diagnostic marker is CD30, which is specifically expressed on BM MCs in SM, including most patients with a well-differentiated MC morphology. This is important because neoplastic MCs in these patients often lack CD2 and CD25. All in all, CD30 is a new marker that counts as a minor SM criterion (in addition to CD2 and CD25) both in immunohistochemical and in flow cytometric assessments.14Valent P. Akin C. Hartmann K. Alvarez-Twose I. Brockow K. Hermine O. et al.Refined diagnostic criteria and classification of mast cell disorders: a consensus proposal.HemaSphere. 2021; 5: e646Crossref PubMed Google ScholarIn WP6, the diagnostic value and clinical implications of various MC-derived mediators, such as histamine, tryptase, or prostaglandin D2 (PGD2), were discussed. The preferred marker of marked systemic MC activation and thus MCAS remains tryptase.4Valent P. Akin C. Hartmann K. Nilsson G. Reiter A. Hermine O. et al.Advances in the classification and treatment of mastocytosis: current status and outlook toward the future.Cancer Res. 2017; 77: 1261-1270Crossref PubMed Scopus (161) Google Scholar, 5Reiter A. George T.I. Gotlib J. New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis.Blood. 2020; 135: 1365-1376Crossref PubMed Google Scholar, 6Valent P. Horny H.P. Escribano L. Longley B.J. Li C.Y. Schwartz L.B. et al.Diagnostic criteria and classification of mastocytosis: a consensus proposal.Leuk Res. 2001; 25: 603-625Crossref PubMed Scopus (934) Google Scholar, 7Akin C. Valent P. Metcalfe D.D. Mast cell activati