Mastocytosis
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Mastocytosis

Mastocytosis

Presented by Suparat Sirivimonpan, MD.

May3, 2013

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    Mastocytosis Mastocytosis Presentation Transcript

    • MastocytosisSuparat Sirivimonpan3/5/13
    • Outline• Introduction• Etiology and pathogenesis• Clinical features and classification• Diagnosis and evaluation• Management• Prognosis
    • Introduction• Mast cell disease, or mastocytosis : variety of disordersthat are characterized by clonal, neoplastic proliferationsof mast cells in one or multiple organs• The most remarkable pathologic features– mast cell hyperplasia in the skin, GI tract, bonemarrow, liver, spleen, and lymph nodes– frequent association of mast cell hyperplasia withhematologic disordersDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Hematol Oncol Clin N Am 25 (2011) 1067–1083
    • Introduction• Clinical features : pruritus, flushing, nausea, vomiting,diarrhea, abdominal pain, and vascular instability• The prevalence of the disease is unknown• Mastocytosis occurs in all ethnic groups• may present at any age• Cutaneous mastocytosis : children• Systemic mastocytosis : adultsDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • ETIOLOGY ANDPATHOGENESIS
    • Mast cell• Human mast cells develop from a bone marrow-derivedhematopoietic pluripotential precursor cell (CD34+, Kit[CD117]+)• complete maturation in vascularized peripheral tissues• During this maturation : downregulate CD34 but remainCD117+• Mature mast cells have– prominent cytoplasmic granules that contain histamine, andother chemical mediators, and– surface receptors that bind the Fc portion of IgE with high affinityDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Mast cell• Mast cells within tissues are often found adjacent toblood vessels and under epithelial surfaces– prominent in GI, respiratory tracts, lymphoid tissues, skin• Mature mast cells normally do not circulate, are long-lived, and appear to retain a limited capacity toproliferateDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Mast cell• SCF-Kit system plays a role in the development of mast cells• Stem cell factor (SCF) : mast cell growth• c-kit (protooncogene) encodes Kit (CD117) : transmembranetyrosine kinase receptor for SCFDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • Etiology : c-kit mutation• Activating point mutation of the c-kit gene• most common mutation consists of a substitution ofvaline for aspartic acid (ASP 816 VAL) (KIT D816V)– codon 816, exon 17 of the gene– more than 90% of patients with SM, including both indolent andaggressive subgroups– present in only one-third of pediatric patients• A clear phenotype– genotype correlation could not bedemonstratedHematol Oncol Clin N Am 26 (2012) 1143–1168Curr Allergy Asthma Rep (2011) 11:292–299
    • • cutaneous biopsies of50 children withmastocytosis• mutations in c-kit incodon 816 : 42%• outside exon 17: 44%J Invest Dermatol. 2010;130:804–15
    • J Invest Dermatol. 2010;130:804–15
    • Expert Rev. Hematol. 5(3), 261–274 (2012)
    • Expert Rev. Hematol. 5(3), 261–274 (2012)
    • Etiology• The downstream signal transduction pathwaysresponsible for oncogenesis by these point mutationsare not fully understood• play a role in ligand-independent growth andsuppression of apoptosisDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Etiology :inhibition of MCs apoptosis• A subset of patients with– increased mast cells and peripheral eosinophilia and– increase in serum tryptase levelshas been described that carry the Fip1-like-1-platelet-derived growth factor receptor (FIP1L1-PDGFRA) fusiononcogene in pluripotential hematopoietic progenitor cells,which results from an approximately 800-kb interstitialdeletion of chromosome 4q12Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Etiology• Disease associated with mutations in c-kit may bemodified by the genetic composition of the affectedindividual– a polymorphism in the gene for the IL-4 receptor α-chain : lessextensive mast cell involvement, with disease usually localizedto the skin– the bone marrow cells of patients with mastocytosis have beenfound to constitutively express the antiapoptotic proteins Bcl-XLand Bcl-2• This may explain the long survival of these cells andperhaps their resistance to chemotherapy-inducedapoptosisDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • PATHOLOGIC EFFECTS OF INCREASEDMAST CELLS• The pathologic changes observed in mastocytosis arethe result of the increased number of mast cells residingwithin tissues, and the release of mast cell-dependentmediators within tissues• Mast cell-derived mediators also circulate through thebloodstream and lymphatic system to produce biologiceffectsDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • CLINICAL FEATURES
    • Clinical feature• Skin, GI tract, lymph nodes, liver, spleen, bone marrow,and skeletal system : common• RS, Endocrine, Renal systems : seldom• Patients in every category of mastocytosis sometimesexperience flushing and/or episodic hypotension• Occasionally, hypotension may be provoked by alcohol,aspirin, insect stings, infection, or exposure to iodinatedcontrast materials• Patients with mastocytosis do not suffer from anincrease in bacterial, fungal, or viral infectionDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Mastocytosis2 main categories:• Cutaneous mastocytosis (CM)– MC infiltrate is confined to one or more lesions on the skin• Systemic mastocytosis (SM)– by MC infiltration of at least one extracutaneous organ with orwithout evidence of skin involvementHematol Oncol Clin N Am 26 (2012) 1143–1168
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • • The symptoms of SM are usually grouped into 4categories:(1) constitutional symptoms : fatigue, weight loss, sweats, and fever(2) skin symptoms(3) MC mediator-related symptoms(4) musculoskeletal symptoms, which include bone,muscle, and joint painHematol Oncol Clin N Am 26 (2012) 1143–1168
    • Am J Med Sci 2011;342(5):409–415
    • Skin• Urticaria pigmentosa (UP)/maculopapularcutaneous mastocytosis (MPCM)• Diffuse cutaneous mastocytosis (DCM)• Solitary mastocytoma of the skin
    • Urticaria pigmentosa(UP)• The most common skin manifestation of mastocytosis inboth children and adults• It is the most common pattern of skin involvement in CM• UP is also observed in– > 90% of ISM– 50% of SM-AHNMD or ASMDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.UP: small yellowish-tan to reddish-brown macules or slightly raised papulesraised nodulesPlaque like lesions
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • UP• Spare palms, soles, face, and scalp• Darier’s sign : rubbing of the lesions usually leads to urticationand erythema over and around the macules,• UP is sometimes associated with pruritus that isexacerbated by– changes in temperature, local friction, ingestion of hot beveragesor spicy foods, ethanol, and certain drugsDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Diffuse cutaneous mastocytosis (DCM)• extremely rare form of CM• diffuse mast cell infiltration in the dermis• no discrete lesions• entire cutaneous integument is involved• Onset < age of 3 years• The skin is normal to yellowish-brownand is thickened• may exhibit discoloration with a peaud’orange appearance• spontaneous resolution has usuallyoccurred before 5 years of ageDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • • Young children with UP or DCM may have bullous eruptions withhemorrhage• Blisters may erupt spontaneously or in association with infection orimmunization• Blisters may also occur at birth• CM is thus included in the differential diagnosis of neonatal disorderswith blistersDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Extensive diffuse skin involvement Bullous eruption
    • Solitary mastocytoma• presents in the first 3 months of life• 1-3 plaques or nodules , >1 cm indiameter• brown or orange• usually located on the extremities• spare the palms and soles of thefeet• usually spontaneously involuteduring childhoodDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • Telangiectasia macularis eruptiva perstans(TMEP)• < 1% of cases of mastocytosis• report only in adults• telangiectatic, red macule on a tan-brown background• Individual lesions are 2-6mm in diameter and are withoutsharply defined borders• TMEP may occasionally coexist with UP.Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • GI• Common(80%) : as frequent as pruritus(88%) or flushing (43%)• Abdominal pain is the most common GI symptom,followed by diarrhea, nausea, and vomiting• GI bleeding is uncommon• Peptic ulcer disease is relatively infrequent (4-44%)despite hyperhistaminemia• The pathogenesis of abdominal symptoms appearsmultifactorialDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Musculoskeletal• Musculoskeletal pain• associated with osteopenia or osteoporosis  pathologicfractures• osteoporosis or pathologic fractures, or both may be theinitial manifestation of mastocytosisDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Bone marrow• The bone marrow is the most common site of pathologicmast cell infiltrates– BM>spleen>liver>LN• Initial diagnosis– palpable splenomegaly 48%– Hepatomegaly 41%– lymphadenopathy 26%Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Bone marrow• BM biopsy– most useful biopsy site for diagnosis of systemic mastocytosis– important prognostic information– Immunohistochemical staining with antitryptase : visualize mastcells• The majority of infiltrates in the bone marrow are focal,• Focal mastocytosis lesions are most commonly situated– Paratrabecular > Perivascular > ParafollicularDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Fig. 60.8 (A) Paratrabecular aggregate of spindle-shaped mast cells. The hematopoieticmarrow is hypercellular, and the bone trabeculae are slightly thickened. This patient hasan aggressive form of systemic mastocytosis. (Hematoxylin-eosin stain; 20.)(B) Higher power demonstrates the spindle shape of the mast cells and the faint granularity ofthe cytoplasm. (Giemsa stain; plastic imbedded; 250).
    • Bone marrow• Early stage : MCs infiltrate(cellular)• Late stage : mast cells number may decrease and thelesions may become fibrotic• osteosclerotic or osteolytic changes in the bonetrabeculae• DDX:– granulomas, myelofibrosis, Hodgkin’s disease, metastaticcarcinoma, Kaposi’s sarcoma, and histiocytosis X– because these cells resemble fibroblasts and histiocytes.Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Bone marrow• Most sensitive and specific method to support thediagnosis of SM in BM– flow cytometry of bone marrow aspirates or byimmunohistochemical analysis of bone marrowbiopsies– The co-expression of CD2 and/or CD25 in CD117(Kit)-positive mast cellsDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • HEPATIC AND SPLENIC INVOLVEMENTSpleen• The most common finding is trabecular fibrotic thickening• found in a paratrabecular, parafollicular, follicular, or diffusered pulp distributionLymph node• The most common location is the paracortical region– Parafollicular and follicular replacement, medullary cord andsinus infiltration: less frequent• Mastocytosis infiltrates in the spleen and lymph nodes : DDx– follicular and T cell lymphomas, monocytoid B cell hyperplasiaand lymphoma, Kaposi’s sarcoma, hairy cell leukemia, andhistiocytosis XDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • HEPATIC AND SPLENIC INVOLVEMENTLiver• 61% of patients had evidence of liver disease– Hepatomegaly 24%,– elevated levels of ALP,AST,ALT,GGTP 54%• SM-AHNMD or ASM– Elevated ALP levels (frequently)– May developed ascites or portal hypertension• Mast cell infiltration– more severe in patients with SM-AHNMD or ASM– correlated with hepatomegaly, splenomegaly, alkalinephosphatase levels, and GGTP levels• Cirrhosis was not observedDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • NEUROPSYCHIATRIC ABNORMALITIES• Headache, dizziness• Seizures• Decreased attention span, memory impairment, and irritability• DepressionDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • DIAGNOSIS ANDEVALUATION
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Hematol Oncol Clin N Am 25 (2011) 1067–1083
    • Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Hematol Oncol Clin N Am 25 (2011) 1067–1083impaired organ function≥ 2 B findings, no C finding smoldering mastocytosis≥ 1 C  aggressive SM (ASM)
    • Systemic mastocytosis• Indolent systemic mastocytosis– involves skin and bone marrow– most common form of SM• Smoldering systemic mastocytosis– 2 or more “B findings” are present , no C finding– mainly affects older patients– more constitutional symptomsHematol Oncol Clin N Am 25 (2011) 1067–1083
    • Systemic mastocytosis• SM-AHNMD– usually a myeloid malignancy, but may also include lymphomasor plasma cell neoplasms– Symptoms and prognosis typically reflect the associated non–mast cell disease• Aggressive systemic mastocytosis– typically lacking skin lesions– presenting with one or more “C findings” that indicate organdysfunction owing to mast cell infiltrationHematol Oncol Clin N Am 25 (2011) 1067–1083
    • MCL• rare• characterized by circulating MCs and 20% or greaterMCs on the bone marrow aspirate smear• Most patients are adults• Cutaneous lesions are typically absent• present with– episodes of mediator-related symptoms– later develop constitutional symptoms, including weight loss andbone pain, and symptoms and signs of organomegalyHematol Oncol Clin N Am 26 (2012) 1143–1168
    • Expert Rev. Hematol. 5(3), 261–274 (2012)
    • Diagnosis• Mastocytosis should be suspected in patients withoutskin lesions if ≥1 of the following features is present:– unexplained ulcer disease or malabsorption– radiographic or technetium 99 bone scanabnormalities,– hepatomegaly, splenomegaly, lymphadenopathy– peripheral blood abnormalities– unexplained flushing or anaphylaxis BM biopsy and aspirationDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • InvestigationSkin biopsy• Cutaneous disease should be confirmed by skin biopsy• UP : increase mast cells in the dermal papillae,particularly near blood vessels– DDX : recurrent anaphylaxis, scleroderma, chronic urticaria,andprolonged antigenic contactDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • InvestigationBone marrow biopsy & aspiration• show multifocal, sharply demarcated, compact infiltrates of MCs• MCs are a mixture of both round and spindle shaped forms• Immunohistochemical and molecular studies are recommendedto distinguish reactive from malignant MC infiltrates• Antibodies to tryptase detect all MCs and MC progenitors,neoplastic MCs• malignant MC populations, which express tryptase/chymaseand CD117 and aberrantly coexpress CD2/CD25Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • MCs in Bone marrowHematol Oncol Clin N Am 26 (2012) 1143–1168
    • EvaluationSerum tryptase :• most commonly used surrogate marker for SM• Total tryptase >20 ng/mL : minor criterion (SM)• Tryptase levels < 20ng/mL– cutaneous mastocytosis– those with limited systemic disease• higher tryptase values  likelihood of multiorganinvolvement• increased serum tryptase levels are not specific for SM– also found in association with acute myeloid leukemia, chronicmyeloid leukemia, and myelodysplasiaDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • Evaluation• Other surrogate disease markers– serum histamine– 24-hour urine sampling for the urinary histamine metabolites N-methylhistamine, and methylmidazole acetic acid– less commonly used• Disadvantages– variability of histamine levels among healthy individuals andpatients– difficulty in assay standardization– false-positive results due to presumed synthesis of histamine bybacteria in the urinary tract and sampleDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Evaluation• Examination of other tissue specimens can help definethe extent of mast cell involvement– lymph nodes, spleen, liver, and GI mucosa– performed only when necessary• Identification of genetic markers– point mutations of c-kit, help support the diagnosis ofmastocytosis– In patients with coexisting eosinophilia, peripheral blood shouldbe examined for the presence of the FIP1L1/PDGFRA fusiongeneDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Evaluation• Additional diagnostic studies– bone scans or skeletal surveys– ultrasound or computed tomography scan of the abdomen– upper GI series– small bowel radiography– endoscopyDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Am. J. Hematol. 87:402–411, 2012
    • Treatment
    • Treatment• Counseling and education• Management of MC mediator-release symptoms• Cytoreductive treatement
    • Management of mediator-release symptoms• Most prominent among these are systemic hypotension,gastric hypersecretion, GI cramping, and pruritus• Antihistamine• Corticosteroid• Disodium cromolyn (cromolyn sodium)• Biphosphonates• UV light irradiation• Epinephrine• Leukotriene antagonisDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Antihistamine• H1-receptor antagonists– classic or non-sedating antihistamines– reduce pruritus and flushing• H2 antagonist– If H1 is insufficient– ranitidine, cimetidine or famotidine may be beneficial• Many patients continue to complain of musculoskeletalpain, headaches, and flushing– inability of histamine antagonists to block the effects of highlevels of histamine , presence of other mast cell mediators–  adding a leukotriene-modifying agent.Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • CorticosteroidsOral steroids• control malabsorption,abdominal pain, nausea andvomiting• prevention or treatment of anaphylaxis• should only be used for short periods as a second- orthird-line therapy  osteopenia or osteoporosisTopical steroids• treat UP or DCM• Lesions recur after discontinuation of therapyHematol Oncol Clin N Am 26 (2012) 1143–1168Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Disodium cromoglycate (cromolynsodium)• inhibits degranulation of mast cells and• relief of GI complaintsKetotifen• antihistamine with mast cell stabilizing properties• relieving the pruritus and whealing• no advantage over hydroxyzineDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Epinephrine• treat episodes of systemic hypotension• Self-administer IM epinephrineDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • UV light irradiation• Oral methoxypsoralen with UVA (PUVA)• relieve pruritus and whealing after 1-2 months oftreatment• Relapse occurs within 3-6 months after discontinuationof therapy• Photochemotherapy should be used only in instances ofextensive cutaneous disease unresponsive to otherforms of therapyDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Cytoreductive Therapy• Use in aggressive SM, SM-AHNMD,MCL• interferon-α2b and 2-chloro-2-deoxyadenosine (cladribine,2-CdA) are potential first- and second-line therapeuticoptions• In highly aggressive or relapsed cases : combinationchemotherapy followed by a hematopoietic stem celltransplant should be considered– cytarabine, fludarabine, and hydroxyureaHematol Oncol Clin N Am 26 (2012) 1143–1168Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Cytoreductive Therapy• Specific tyrosine kinase inhibitors– patients who are negative for D816V but have non–codon 816 mutations or wild-type KIT– such as imatinib, or other tyrosine kinase inhibitorsHematol Oncol Clin N Am 26 (2012) 1143–1168Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Bone marrow transplantation• treatment option for patients with advanced categories ofmastocytosis associated with poor survival in only a fewreported instances• may yield a better prognosis if mast cell suppression isattempted prior to the transplantationHematol Oncol Clin N Am 26 (2012) 1143–1168Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Curr Allergy Asthma Rep (2011) 11:292–299
    • PROGNOSIS
    • Hematol Oncol Clin N Am 26 (2012) 1143–1168
    • Prognosis• Patients with CM only have the best prognosis• For children with isolated UP, at least 50% of cases arereported to resolve by adulthood• UP in adulthood may evolve into systemic disease• Occasionally, ISM converts to SM-AHNMDDean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
    • Expert Rev. Hematol. 5(3), 261–274 (2012)
    • PrognosisExpert Rev. Hematol. 5(3), 261–274 (2012)
    • Take home messages• Mastocytosis is associated with a pathologic increase inmast cells in one or more organ systems• Most adult patients have an activating mutation in Kit• Serum tryptase is usually elevated• The signs and symptoms are due to release of mast cellmediators, the increase in mast cell burden, and, insome patients, an associated hematologic disorder• Treatment is largely symptomatic, with specific treatmentof any associated hematologic disorder
    • Thank you