Mastocytosis
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This document provides an overview of mast cells, mast cell activation disorders, and mastocytosis. It discusses the development, mediators, and receptors of mast cells. It also covers the epidemiology, pathogenesis, classification, clinical features, diagnosis, and treatment of mast cell activation disorders and mastocytosis. Key points include that mast cells develop from bone marrow stem cells and require stem cell factor for survival, and that mastocytosis is rare and commonly involves the skin and gastrointestinal system.
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Mastocytosis
- 2. • Mast cells • Mast cell activation disorders • Mastocytosis • Epidemiology • Pathogenesis and etiology • Classification and Diagnosis • Clinical features • Patient evaluation • Algorithm approach mastocytosis • Treatment • Prognosis
- 3. Mast cells
- 4. Mast cell development and survival Mast cells develop from pluripotent hematopoietic bone marrow stem cells. Release into the systemic circulation as CD34+, Kit (CD117)+ mononuclear cells. Mature under the control of the local cytokine milieu, the tissue matrix, and resident cells such as fibroblasts Stem cell factor (SCF, Kit ligand,steel factor) is an obligate mast cell growth factor Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 5. • Kit (CD117) is a transmembrane tyrosine kinase receptor for SCF, encoded by the proto-oncogene c-kit. • SCF that is derived from many cellular sources, including epithelial and mesenchymal cells. • Removal of SCF leads to rapid mast cell apoptosis. • Several cofactors enhance or inhibit the effects of SCF • Enhance: Nerve growth factor (NGF), IL-3, IL-6, IL-9, and IL-10 • Inhibit: GM-CSF, retinoids, and transforming growth factor-β (TGF-β) Mast cell development and survival Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 7. Komi DEA et al. Clinic Rev Allerg Immunol. 2018; 54: 397–411
- 10. Mast cell activation disorders Primary Mastocytosis Monoclonal mast cell activation syndrome (MMAS) Secondary IgE-mediated Drugs Mast cell hyperplasia Idiopathic Idiopathic anaphylaxis Idiopathic mast cell activation syndrome (MCAS) - Cutaneous mastocytosis (CM) - Systemic mastycytosis (SM) Food Drugs Insects Vancomycin Opioids - Infection - Neoplasia - Autoimmune Akin. J Allergy Clin Immunol 2017; 140: 349-55 M. Picard et al. Clin Ther 2013; 35: 548–562
- 12. • Rare disease • The actual prevalence is unknown. • Estimate from a recent population-based study is 1case per 10,000 persons.1 • 20,000 – 30,000 in USA • Male : female = 1:1 to 1:3 • More frequent in Caucasians • May occur at any age • Familial occurrence is unusal. Epidemiology 1. Cohen SS et al. Br J Haematol 2014; 166: 521- 8 Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 13. • The interaction between KIT and SCF seems to play an essential role in the development of mastocytosis. • Loss-of-function mutations in KIT: Piebaldism • Gain-of-function point mutations in KIT: Systemic mast cell proliferative disorders • The most common mutation consists of a substitution of valine for aspartic acid (ASP 816 VAL). • augment mast cell proliferation and survival • present in most adults, less common in children • no convincing evidence that mutation is passed from generation to generation Pathogenesis and etiology Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 14. • Other c-kit mutations including V560G, D816Y, D816F, D816H, and E839K have been identified in mast cell lines, MCL, and pediatric mastocytosis. • A subgroup of patients who present with hypereosinophilic syndrome have the FIP1L1/PDGRFA fusion tyrosine kinase. • increase mast cells in the bone marrow, an increase tryptase level, and peripheral eosinophilia Pathogenesis and etiology Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 18. • Increase mast cells present in tissue and the degree of release of mast cell mediators. • Local tissue and distal inflammation (released in to the bloodstream) • Skin, GI tract, lymph nodes, liver, spleen, bone marrow, and skeletal system contribute the most significant management problems. • The respiratory tract and endocrine and renal systems are seldom. Clinical features Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 20. • The most common organ site of involvement • Often the 1st sign of diseases • Highly heterogeneous, localized and disseminated form • Symptoms: pruritus, flushing, blistering (uniquely seen in children) • Darier’s sign: whealing and reddening of lesions upon mechanical stroking or rubbing Cutaneous patterns of mastocytosis Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Hartmann et al. J Allergy Clin Immunol 2016;137: 35-45
- 22. Cutaneous patterns of mastocytosis • Cutaneous mastocytosis: (WHO 2008) • Maculopapular cutaneous mastocytosis (MPCM) or urticaria pigmentosa (UP) • Diffuse cutaneous mastocytosis (DCM) • Mastocytoma of skin Hartmann et al. J Allergy Clin Immunol 2016;137: 35-45
- 24. Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Peter Bradding and Hirohisa Saito, Middleton 8th edition Urticarial pigmentosa in adult vs children Diffuse cutaneous mastocytosis in adult vs children Solitary mastocytoma in children Bullous eruption in children
- 28. • Testing for Darier’s sign in mastocytoma or nodular lesions can develop a systemic reaction, including hypotension, • testing should be avoided or be performed with caution • Children: a final diagnosis of CM without performing a bone marrow biopsy • Adult: complete staging, including a bone marrow biopsy. Cutaneous patterns of mastocytosis Hartmann et al. J Allergy Clin Immunol 2016;137: 35-45
- 29. • Highly prevalent • The most common symptoms were diarrhea and bloating, followed by nausea and abdominal pain. • Abdominal pain • peptic ulcer disease: increase gastric acid secretion • edema of the GI tract, or motility dysfunction • GI peptides: pathogenesis of diarrhea and abdominal pain • vasoactive intestinal peptide, neurotensin, substance P or motilin, and gastrin. • No correlation was found between histologic findings of mast cell infiltration in GI biopsies and GI symptoms. Gastrointestinal symptoms Hartmann et al. J Allergy Clin Immunol 2016;137: 35-45
- 30. • Uncertain etiology • Osteopenia or osteoporosis à pathologic fractures • proximal long bones >pelvis >ribs >skull • Initial manifestation of mastocytosis • Radiographically detectable lesions in up to 70% of patients. • Skeletal scintigraphy is more sensitive than radiographic surveys • detect and locate active lesions • evaluate the extent of disease and disease progression Musculoskeletal involvement Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 31. • Frequently involves especially in patients with aggressive diseases • Spleen (paratrabecular compartment) >liver >LN (paracortex) • Severe liver disease is uncommon. • morbidity and mortality • SM-AHNMD or ASM: Hepatomegaly, splenomegaly, and liver mast cell infiltration and fibrosis. • Elevate ALP, GGT • Ascites, portal hypertension Hepatic and splenic involvement Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 32. • Adults: decrease attention span, memory impairment, and irritability. • Medicines administered to patients with mastocytosis as well as circulating mediators may contribute to these findings. • Children: no clear excess pathology. • No specific behavioral pattern • implicating histamine overproduction was identified. Neuropsychiatric abnormalities Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 33. • The most common site of pathologic mast cell infiltrates in systemic mastocytosis. • Systemic mastocytosis is usually diagnosed by bone marrow histopathology outlined by WHO 2008 consensus. • Immunohisto- chemical (IHC) staining of the bone marrow biopsy with anti- tryptase is the method of choice to visualize mast cells in paraffin- imbedded decalcified specimens. Bone marrow pathology Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 34. • CD2 and CD25 in CD117 (KIT)– positive mast cells by flow cytometry of bone marrow aspirates or by IHC analysis of bone marrow biopsies is generally accepted as the most sensitive and specific method to support the diagnosis of SM in bone marrow. • Poor prognosis: • hypercellularmarrow with a decreased percentage of fat cells • hematologic disorders • Atypical or poorly differentiated mast cells may be identified in the bone marrow aspirates of patients with MCL and with aggressive forms of mastocytosis. Bone marrow pathology Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 35. • A progressive clonal mast cell disorder that in the future may meet the diagnostic criteria for systemic mastocytosis. • 1 or 2 minor diagnostic criteria for mastocytosis • Idiopathic anaphylaxis, anaphylaxis to stinging insects • Lab: Tryptase levels < 20 ng/mL • Treatment: under guidelines for anaphylaxis • Follow-up: yearly and include • Physical examination: organomegaly, lymphadenopathy • Serum tryptase: expand mast cell compartment • CBC: evolve hematologic disorder Monoclonal mast cell activation syndrome (MMAS) Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 36. • Hyperreactivity of mast cells, activate spontaneously • Extensive medical evaluation has failed to identify an etiology. • Vigilance must be maintained so that one of the diagnoses eliminated during the initial evaluation does not reach the level of diagnosis. Mast cell activation disorder/syndrome (MCAS) Akin. J Allergy Clin Immunol 2017;140:349-55 Peter Bradding and Hirohisa Saito, Middleton 8th edition
- 37. • Chronic urticaria, angioedema, and upper airway swelling • almost never associated with mastocytosis • a feature of secondary (IgE- and non–IgE-mediated) and idiopathic mast cell activation syndromes • identifying or ruling out such possible causes. • A baseline serum tryptase level should be measured • all patients with hypotensive anaphylaxis • systemic reactions to Hymenoptera • The presence of hypotension during anaphylaxis increases the odds of clonal mast cell disease. • refer for a bone marrow biopsy, regardless of tryptase levels, if an IgE- mediated cause does not explain all episodes. Mast cell activation disorders: Clinical pearls Akin. J Allergy Clin Immunol 2017; 140: 349-55
- 38. • History, clinical manifestations, histopathology, laboratory investigation • Cutaneous mastocytosis: confirm by skin biopsy • Systemic mastocytosis: fulfilling the major criterion, consisting of multifocal dense mast cell aggregates, and 1 minor criterion; or 3 minor criteria • bone marrow biopsy and aspiration • serum tryptase level • analysis for an activating mutation in KIT • Pediatric-onset disease • A bone marrow biopsy is not recommended unless there is evidence of systemic disease, as shown by hepatosplenomegaly, lymphadenopathy or unexplained peripheral blood abnormalities. Patient evaluation and Diagnosis Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196
- 39. • Adult-onset disease: The diagnosis should be considered when a patient, primarily in the adult population, presents with 1 or more the following (even in the absence of classic skin lesions) • Unexplained ulcer disease or malabsorption • Unexplained hypotensive episodes, syncope • Radiographic or bone scan abnormality • unexplained osteoporosis especially in men patients • Hepatomegaly • Splenomegaly • Lymphadenopathy • Peripheral blood abnormalities Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Theoharides TC et al. N Engl J Med 2015; 373(2): 163-72 Patient evaluation and Diagnosis
- 40. Akin. J Allergy Clin Immunol 2017; 140: 349-55 Serum tryptase • Formula: 20% baseline tryptase plus 2 ng/mL is suggested as a meaningful increase indicative of mast cell activation. • Peak in 1 hrs • Return to baseline within 4 hours Serum histamine • not recommended because they are often derived from basophils at baseline • influence by a variety of factors, including obtaining and storing the blood sample.
- 41. • The most useful stain for mast cells uses a monoclonal antibody to tryptase. • Immunohistochemistry to identify CD25+ mast cells is of value • Express on most clonal mast cells in mastocytosis • Other tissue specimens, such as those from lymph nodes, spleen, liver, and GI mucosa, may help determine the extent of mast cell involvement, but are not typically necessary. • Carcinoid tumor or pheochromocytoma should be ruled out. Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Patient evaluation and Diagnosis
- 46. Diagnostic algorithm for mastocytosis in adult M. Lange et al. Acta Derm Venereol 2016; 96: 292–297
- 47. Treatment • Avoidance of triggers: • An allergy workup can be used as guidance to avoid food, medication, and inhalational triggers of mast cell activation. • Patients with systemic venom reactions: venom immunotherapy indefinitely. • Immunotherapy to inhalant allergens can be considered on a case-by-case basis depending on the risk/benefit ratio for each patient. • Emotional stress should be managed appropriately by using pharmacologic or nonpharmacologic methods. • Epinephrine should be prescribed to • all patients with a history of anaphylactic episodes • consider for those with mastocytosis, even if they do not have a history of anaphylaxis. Akin. J Allergy Clin Immunol 2017; 140: 349-55
- 48. • No treatment that results in permanent resolution of the skin lesions associated with CM or SM. • H1 antihistamine (hydroxyzine, cetirizine, fexofenadine, loratadine), +/- H2 antihistamine (ranitidine, famotidine) à pruritus and flushing • Cysteine-leukotriene-receptor antagonists (Montelukast), 5-lipoxygenase inhibitor (Zileuton) à conjunction with H1 and H2 antihistamine • Psoralen + ultraviolet light type A (PUVA) or narrow-band ultraviolet B: alleviate itching, fade lesion temporarily • Topical corticosteroids + occlusive dressing à transient reduction the number of dermal mast cell • Omalizumab: an adjunctive treatment to allow tolerance of venom immunotherapy Mast cell-mediated therapies Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Theoharides TC et al. N Engl J Med 2015; 373(2): 163-72
- 49. • H2 antihistamine: inhibit gastric secretion • Proton pump inhibitors • Cromolyn sodium: reduce GI cramping • Systemic corticosteroids: severe hepatosplenomegaly and ascites GI manifestations Osteoporosis and fractures • Calcium supplement, bisphophonate, estrogen replacement in postmenopausal woman: mild osteoporosis • Interferon alpha-2b and 2-chlorodeoxyadenosine (cladribine/2-CdA): aggressive disease Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196
- 50. • IFN- alpha-2b and cladribine (2-CdA) • patients with advanced variants of mastocytosis, • associated hematologic disorders and aggressive systemic mastocytosis or mast cell leukemia • rare occasions in patients with indolent mastocytosis with life-threatening mast cell activation episodes • Imatinib (Gleevac): a tyrosine kinase inhibitor, • beneficial therapeutic effect primarily on patients who do not carry the D816V mutation • effective in a patients with FIP1L1/PDGRFA fusion mutation. Mast cell cytoreduction Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Akin. J Allergy Clin Immunol 2017; 140: 349-55
- 51. • Midostaurin: a multikinase inhibitor • activity against D816V KIT • approved recently by the US FDA • reduction in mast cell activation symptoms, increases quality of life. • side effects: N/V, cytopenias • not approved for patients with indolent mastocytosis or nonclonalmast cell disorders. • Masitinib: inhibitor of wild-type (not D816V mutated) KIT and LYN • improve symptoms in a phase III trial in patients with indolent systemic or smoldering mastocytosis • side effects: diarrhea, rash, and asthenia Mast cell cytoreduction Gotlib J et al. N Engl J Med 2016; 374: 2530-41 Lortholary O et al. Lancet 2017; 389: 612-20
- 52. Hematopoietic stem-cell transplantation • Allogeneic hematopoietic stem cell transplantation • Patients: advanced systemic mastocytois • Parameters:the percentage of bone marrow MCs, serum tryptase levels, and organ involvement • Results: the median bone marrow MC percentage in biopsies and the levels of serum tryptase showed a significant decrease after transplantation • Conclusion: alloHCT can confer long-term overall survival Ustun C et al. J Clin Oncol Off J Am Soc Clin Oncol 2014; 32(29): 3264–3274
- 53. • Differ for each category of mastocytosis. • Poor survival: • advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts • Children: • more favorable prognosis • total or major disease regression by late adolescence (90%) • Adults: clinical skin symptoms may not indicate disease regression • CM, ISM: the life expectancy parallels that of the general population. • SM-AHNMD: depend on the prognosis of hematologic disorder and response to aggressive therapy • ASM: the survival time 2-4 years with aggressive therapy • CML: the survival time usually less than 12 months Prognosis Carter MC et al. Immunol Allergy Clin N Am 2014; 34: 181–196 Peter Bradding and Hirohisa Saito, Middleton 8th edition