Current classification and diagnosis of systemic mastocytosis, and its distinction from other myeloid malignancies associated with bone marrow mastocytosis, remain challenging for both clinicians and hematopathologists. In its upcoming revision, due out in 2008, the World Health Organization (WHO) classification system for myeloid malignancies considers mast cell disease as a myeloproliferative neoplasm and systemic mastocytosis as a subcategory of mast cell disease with bone marrow involvement.1 At the same time, the WHO document distinguishes the usually KIT-mutated systemic mastocytosis from myeloid neoplasms associated with bone marrow mastocytosis and PDGFR mutations (e.g. FIP1L1-PDGFRA, PRKG2-PDGFRB).2–6 The latter are often associated with eosinophilia or basophilia and sensitive to treatment with imatinib. WHO-defined systemic mastocytosis is sometimes associated with a clonally-related second myeloid neoplasm,7–11 which is not surprising considering its origin as a stem cell disease with multilineage clonal involvement.12–16 Conversely, an otherwise well-defined myeloid malignancy, such as myelodysplastic syndrome or a non-mast cell disease myeloproliferative neoplasm, might harbor neoplastic mast cells.17
Our approach to diagnosis in systemic mastocytosis starts with bone marrow examination with tryptase staining and mast cell CD25 immunophenotyping. The former enhances morphologic and the latter immunophenotypic distinction between normal (round and CD25-negative) and abnormal (spindle-shaped and CD25-positive) mast cells.18,19 Bone marrow examination also allows detection of a second hematologic neoplasm, if present.7,9 In addition, in the presence of blood eosinophilia, we screen for FIP1L1-PDGFRA, using either FISH or RT-PCR.20 By contrast, we rely on conventional cytogenetics to identify cases of bone marrowmastocytosis associated with a PDGFRB rearrangement (i.e. chromosomal translocations involving 5q31-32).6 In general, we consider mutation screening for KITD816V and measurement of serum tryptase or urinary histamine metabolites as being complementary for the diagnosis of mast cell disease.21–23 It is to be noted that the likelihood of detecting a KIT mutation is significantly higher with the use of both highly sensitive PCR-based assay and mast cell-enriched test samples.24,25
After establishing the presence of abnormal bone marrow mast cells, we strictly follow the revised WHO criteria in assigning the specific diagnosis of myeloid neoplasm associated with PDGFR rearrangement, in the presence of either a PDGFRA or PDGFRB mutation.1 In all other instances, we use the term systemic mastocytosis, provided bone marrow mastocytosis is the prominent feature in terms of both bone marrow histology and clinical presentation. Drug therapy has not been shown to favorably affect survival in systemic mastocytosis and the experience with allogeneic stem cell transplantation has been too limited to allow discussion.26 Therefore, current therapy in WHO-defined systemic mastocytosis is palliative and directed at mast cell degranulation symptoms (e.g. pruritus, urticaria, angioedema, flushing, nausea, vomiting, abdominal pain, diarrhea, episodic anaphylactoid attacks), skin disease such as urticaria pigmentosa, and/or organ dysfunction from mast cell tissue infiltration. In general, antihistamines and cromolyn sodium are equally effective (or ineffective) in controlling mast cell degranulation symptoms.27 Urticaria pigmentosa and pruritus respond modestly to topical corticosteroids or ultraviolet A phototherapy with (PUVA) or without (UVA1) psoralen.28–31 We also consider interferon-α therapy for mast cell degranulation symptoms and urticaria pigmentosa that are refractory to usual therapy.32
The presence of organ dysfunction (e.g. symptomatic hepatosplenomegaly, clinically-significant liver function test abnormalities, ascites, cytopenias, osteoporosis or osteolysis, diarrhea associated with weight loss) distinguishes indolent from aggressive systemic mastocytosis. In general, we try to avoid the use of cytoreductive agents in patients with indolent systemic mastocytosis, where survival is usually long and disease course non-progressive.33–35 By contrast, cytoreductive therapy is usually employed in aggressive systemic mastocytosis with the intention to decrease mast cell burden. Here, interferon-α and cladribine are the first-line drugs of choice and we expect response rates of >50% with each drug.36,37 Treatment with either interferon-α or cladribine has the potential to benefit all aspects of disease, including mast cell degranulation symptoms, urticaria pigmentosa, symptomatic organomegaly and ascites. In the presence of osteoporosis or lytic bone lesions, we recommend, in addition, bisphosphonate therapy (e.g. pamidronate 90 mg IV monthly).38,39
Unfortunately, current therapy for patients with systemic mastocytosis who fail treatment with either interferon-α or cladribine is inadequate and we highly recommend that such patients participate in experimental treatment protocols. In this setting, in vitro activity against KITD816V or KITD814Y has been demonstrated for several kinase inhibitors such as PKC412,40,41 dasatinib,42,43 EXEL-0862,44 SU5416,45 SU6577,46 MLN51847 and other drugs including 17-AAG (binds heat-shock protein 90),48 IMD-0354 (an NF-κB inhibitor)49 and rapamycin (an mTOR inhibitor).50 Of relevance to the latter agent, PI3K/Akt signaling has been implicated in mutant KIT-associated cell transformation and rapamycin has been shown to induce apoptosis in D816V-positive mast cell lines, inhibit survival of D816V-positive but not wild-type primary cells from patients with systemic mastocytosis, and suppress ligand-independent growth of KITD814V-expressing cell lines.50–52 Phase II clinical trials in systemic mastocytosis involving several of the aforementioned drugs (e.g. dasatinib, PKC412, and RAD001, a rapamycin analog) are currently ongoing.53
References
- Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2007. Google Scholar
- Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003; 348:1201-4. PubMed|https://doi.org/10.1056/NEJMoa025217|Google Scholar
- Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Ketterling RP, Lasho TL. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004; 104:3038-45. PubMed|https://doi.org/10.1182/blood-2004-03-0787|Google Scholar
- Dalal BI, Horsman DE, Bruyere H, Forrest DL. Imatinib mesylate responsiveness in aggressive systemic mastocytosis: novel association with a platelet derived growth factor receptor beta mutation. Am J Hematol. 2007; 82:77-9. PubMed|https://doi.org/10.1002/ajh.20833|Google Scholar
- Lahortiga I, Akin C, Cools J. Haematologica. 2008; 93:49-56. PubMed|https://doi.org/10.3324/haematol.11836|Google Scholar
- Walz C, Metzgeroth G, Haferlach C, Schmitt-Graeff A, Fabarius A, Hagen V. Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor β gene. Haematologica. 2007; 92:163-9. PubMed|https://doi.org/10.3324/haematol.10980|Google Scholar
- Travis WD, Li CY, Yam LT, Bergstralh EJ, Swee RG. Significance of systemic mast cell disease with associated hematologic disorders. Cancer. 1988; 62:965-72. PubMed|https://doi.org/10.1002/1097-0142(19880901)62:5<965::AID-CNCR2820620520>3.0.CO;2-M|Google Scholar
- Pullarkat V, Bedell V, Kim Y, Bhatia R, Nakamura R, Forman S. Neoplastic mast cells in systemic mastocytosis associated with t(8;21) acute myeloid leukemia are derived from the leukemic clone. Leuk Res. 2007; 31:261-5. PubMed|https://doi.org/10.1016/j.leukres.2006.03.006|Google Scholar
- Horny HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol. 2004; 57:604-8. PubMed|https://doi.org/10.1136/jcp.2003.014860|Google Scholar
- Sperr WR, Drach J, Hauswirth AW, Ackermann J, Mitterbauer M, Mitterbauer G. Myelomastocytic leukemia: evidence for the origin of mast cells from the leukemic clone and eradication by allogeneic stem cell transplantation. Clin Cancer Res. 2005; 11:6787-92. PubMed|https://doi.org/10.1158/1078-0432.CCR-05-1064|Google Scholar
- Sotlar K, Marafioti T, Griesser H, Theil J, Aepinus C, Jaussi R. Detection of c-kit mutation Asp 816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia. Mol Pathol. 2000; 53:188-193. PubMed|https://doi.org/10.1136/mp.53.4.188|Google Scholar
- Taylor ML, Sehgal D, Raffeld M, Obiakor H, Akin C, Mage RG. Demonstration that mast cells, T cells, and B cells bearing the activating kit mutation D816V occur in clusters within the marrow of patients with mastocytosis. J Mol Diagn. 2004; 6:335-42. PubMed|Google Scholar
- Pardanani A, Reeder T, Li CY, Tefferi A. Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia. Leuk Res. 2003; 27:883-5. PubMed|https://doi.org/10.1016/S0145-2126(03)00065-1|Google Scholar
- Tefferi A, Lasho TL, Brockman SR, Elliott MA, Dispenzieri A, Pardanani A. FIP1L1-PDGFRA and c-kit D816V mutation-based clonality studies in systemic mast cell disease associated with eosinophilia. Haematologica. 2004; 89:871-3. PubMed|Google Scholar
- Afonja O, Amorosi E, Ashman L, Takeshita K. Multilineage involvement and erythropoietin-"independent" erythroid progenitor cells in a patient with systemic mastocytosis. Ann Hematol. 1998; 77:183-6. PubMed|https://doi.org/10.1007/s002770050439|Google Scholar
- Kocabas CN, Yavuz AS, Lipsky PE, Metcalfe DD, Akin C. Analysis of the lineage relationship between mast cells and basophils using the c-kit D816V mutation as a biologic signature. J Allergy Clin Immunol. 2005; 115:1155-61. PubMed|https://doi.org/10.1016/j.jaci.2005.02.030|Google Scholar
- Dunphy CH. Evaluation of mast cells in myeloproliferative disorders and myelodysplastic syndromes. Arch Pathol Lab Med. 2005; 129:219-22. PubMed|Google Scholar
- Pardanani A, Kimlinger T, Reeder T, Li CY, Tefferi A. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res. 2004; 28:777-83. PubMed|https://doi.org/10.1016/j.leukres.2003.10.035|Google Scholar
- Li WV, Kapadia SB, Sonmez-Alpan E, Swerdlow SH. Immunohistochemical characterization of mast cell disease in paraffin sections using tryptase, CD68, myeloperoxidase, lysozyme, and CD20 antibodies. Mod Pathol. 1996; 9:982-8. PubMed|Google Scholar
- Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib therapy. Blood. 2003; 102:3093-6. PubMed|https://doi.org/10.1182/blood-2003-05-1627|Google Scholar
- Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A. 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; 108:2366-72. PubMed|https://doi.org/10.1182/blood-2006-04-015545|Google Scholar
- Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987; 316:1622-6. PubMed|https://doi.org/10.1056/NEJM198706253162603|Google Scholar
- Keyzer JJ, de Monchy JG, van Doormaal JJ, van Voorst Vader PC. Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites. N Engl J Med. 1983; 309:1603-5. PubMed|Google Scholar
- Zhao W, Bueso-Ramos CE, Verstovsek S, Barkoh BA, Khitamy AA, Jones D. Quantitative profiling of codon 816 KIT mutations can aid in the classification of systemic mast cell disease. Leukemia. 2007; 21:1574-6. PubMed|https://doi.org/10.1038/sj.leu.2404680|Google Scholar
- Corless CL, Harrell P, Lacouture M, Bainbridge T, Le C, Gatter K. Allele-specific polymerase chain reaction for the imatinib-resistant KIT D816V and D816F mutations in mastocytosis and acute myelogenous leukemia. J Mol Diagn. 2006; 8:604-12. PubMed|https://doi.org/10.2353/jmoldx.2006.060089|Google Scholar
- Nakamura R, Chakrabarti S, Akin C, Robyn J, Bahceci E, Greene A. A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis. Bone Marrow Transplant. 2006; 37:353-8. PubMed|https://doi.org/10.1038/sj.bmt.1705245|Google Scholar
- Frieri M, Alling DW, Metcalfe DD. Comparison of the therapeutic efficacy of cromolyn sodium with that of combined chlorpheniramine and cimetidine in systemic mastocytosis. Results of a double-blind clinical trial. Am J Med. 1985; 78:9-14. PubMed|Google Scholar
- Barton J, Lavker RM, Schechter NM, Lazarus GS. Treatment of urticaria pigmentosa with corticosteroids. Arch Dermatol. 1985; 121:1516-23. PubMed|https://doi.org/10.1001/archderm.1985.01660120042017|Google Scholar
- Lavker RM, Schechter NM, Guzzo C, Lazarus GS. Aggressive topical corticosteroid therapy: a novel approach to mast-cell-dependent cutaneous disorders. Dermatologica. 1987; 175:213-6. PubMed|Google Scholar
- Godt O, Proksch E, Streit V, Christophers E. Short- and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997; 195:35-9. PubMed|Google Scholar
- Gobello T, Mazzanti C, Sordi D, Annessi G, Abeni D, Chinni LM. Medium- versus high-dose ultraviolet A1 therapy for urticaria pigmentosa: a pilot study. J Am Acad Dermatol. 2003; 49:679-84. PubMed|https://doi.org/10.1067/S0190-9622(03)01483-X|Google Scholar
- Simon J, Lortholary O, Caillat-Vigneron N, Raphaël M, Martin A, Brière J. Interest of interferon α in systemic mastocytosis. The French experience and review of the literature. Group AFIRMM (Association française pour les initiatives de recherche sur le mastocyte et les mastocytoses). Pathol Biol (Paris). 2004; 52:294-9. PubMed|Google Scholar
- Kors JW, Van Doormaal JJ, Breukelman H, Van Voorst Vader PC, De Monchy JG. Long-term follow-up of indolent mastocytosis in adults. J Intern Med. 1996; 239:157-64. PubMed|https://doi.org/10.1046/j.1365-2796.1996.440787000.x|Google Scholar
- Horan RF, Austen KF. Systemic mastocytosis: retrospective review of a decade's clinical experience at the Brigham and Women's Hospital. J Invest Dermatol. 1991; 96:5S-13S. PubMed|https://doi.org/10.1111/1523-1747.ep12468899|Google Scholar
- Lawrence JB, Friedman BS, Travis WD, Chinchilli VM, Metcalfe DD, Gralnick HR. Hematologic manifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis. Am J Med. 1991; 91:612-24. PubMed|https://doi.org/10.1016/0002-9343(91)90214-I|Google Scholar
- Hauswirth AW, Simonitsch-Klupp I, Uffmann M, Koller E, Sperr WR, Lechner K. Response to therapy with interferon α-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res. 2004; 28:249-57. PubMed|https://doi.org/10.1016/S0145-2126(03)00259-5|Google Scholar
- Kluin-Nelemans HC, Oldhoff JM, van Doormaal JJ, Van 't Wout JW, Verhoef G, Gerrits WB. Cladribine therapy for systemic mastocytosis. Blood. 2003; 102:4270-6. PubMed|https://doi.org/10.1182/blood-2003-05-1699|Google Scholar
- Marshall A, Kavanagh RT, Crisp AJ. The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis. Br J Rheumatol. 1997; 36:393-6. PubMed|https://doi.org/10.1093/rheumatology/36.3.393|Google Scholar
- Laroche M, Bret J, Brouchet A, Mazieres B. Clinical and densitometric efficacy of the association of interferon alpha and pamidronate in the treatment of osteoporosis in patients with systemic mastocytosis. Clin Rheumatol. 2007; 26:242-3. PubMed|https://doi.org/10.1007/s10067-006-0369-0|Google Scholar
- Gleixner KV, Mayerhofer M, Aichberger KJ, Derdak S, Sonneck K, Böhm A. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood. 2006; 107:752-9. PubMed|https://doi.org/10.1182/blood-2005-07-3022|Google Scholar
- Gotlib J, Berubé C, Growney JD, Chen CC, George TI, Williams C. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005; 106:2865-70. PubMed|https://doi.org/10.1182/blood-2005-04-1568|Google Scholar
- Shah NP, Lee FY, Luo R, Jiang Y, Donker M, Akin C. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006; 108:286-91. PubMed|https://doi.org/10.1182/blood-2005-10-3969|Google Scholar
- Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006; 66:473-81. PubMed|https://doi.org/10.1158/0008-5472.CAN-05-2050|Google Scholar
- Pan J, Quintás-Cardama A, Kantarjian HM, Akin C, Manshouri T, Lamb P. EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood. 2007; 109:315-22. PubMed|https://doi.org/10.1182/blood-2006-04-013805|Google Scholar
- Kosmider O, Denis N, Dubreuil P, Moreau-Gachelin F. Semaxinib (SU5416) as a therapeutic agent targeting oncogenic Kit mutants resistant to imatinib mesylate. Oncogene. 2007; 26:3904-8. PubMed|https://doi.org/10.1038/sj.onc.1210159|Google Scholar
- Ma Y, Carter E, Wang X, Shu C, McMahon G, Longley BJ. Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells. J Invest Dermatol. 2000; 114:392-4. PubMed|https://doi.org/10.1046/j.1523-1747.2000.00888.x|Google Scholar
- Corbin AS, Griswold IJ, La Rosee P, Yee KW, Heinrich MC, Reimer CL. Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood. 2004; 104:3754-7. PubMed|https://doi.org/10.1182/blood-2004-06-2189|Google Scholar
- Fumo G, Akin C, Metcalfe DD, Neckers L. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood. 2004; 103:1078-84. PubMed|https://doi.org/10.1182/blood-2003-07-2477|Google Scholar
- Tanaka A, Konno M, Muto S, Kambe N, Morii E, Nakahata T. A novel NF-κB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood. 2005; 105:2324-31. PubMed|https://doi.org/10.1182/blood-2004-08-3247|Google Scholar
- Gabillot-Carre M, Lepelletier Y, Humbert M, de Sepuvelda P, Hamouda NB, Zappulla JP. Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells. Blood. 2006; 108:1065-72. PubMed|https://doi.org/10.1182/blood-2005-06-2433|Google Scholar
- Munugalavadla V, Sims EC, Borneo J, Chan RJ, Kapur R. Genetic and pharmacologic evidence implicating the p85{α}, but not p85{β}, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis. Blood. 2007; 110:1612-20. PubMed|https://doi.org/10.1182/blood-2006-10-053058|Google Scholar
- Shivakrupa R, Bernstein A, Watring N, Linnekin D. Phosphatidylinositol 3'-kinase is required for growth of mast cells expressing the kit catalytic domain mutant. Cancer Res. 2003; 63:4412-9. PubMed|Google Scholar
- Quintas-Cardama A, Aribi A, Cortes J, Giles FJ, Kantarjian H, Verstovsek S. Novel approaches in the treatment of systemic mastocytosis. Cancer. 2006; 107:1429-39. PubMed|https://doi.org/10.1002/cncr.22187|Google Scholar