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Mast cell disorders

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Mast Cell Disorders

Presented by Watt Mitthamsiri, MD.

September05, 2014

Published in: Health & Medicine
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Mast cell disorders

  1. 1. Mast Cell Disorders By Wat Mitthamsiri, MD. Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital
  2. 2. Previous issues • How long is the life span of mast cells in circulation (not in tissue)? J Hallgren and MF Gurich, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p14-28.
  3. 3. Previous issues • What is non-pathological, physiological role of mast cell? – One of the first responder in innate defense against infections • Location • Arrays of innate sensors: – PRRs: TLR1-7 and TLR9, NLRP3 – Complement products receptors – CRP, LPS-binding proteins, pentraxins, collectins – Sensors for other peptide signals from other cells CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  4. 4. Ligands that can activate MCs CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  5. 5. Ligands that can activate MCs CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  6. 6. Microbial sensors of MCs CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  7. 7. Previous issues • What is non-pathological, physiological role of mast cell? – One of the first responder in innate defense against infections • Arrays of weapons: – Mediators – Cytokines – Antimicrobial peptides: Beta-defensins, cathelicidin • Powerful response: Neutrophil recruitment CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  8. 8. Previous issues • What is non-pathological, physiological role of mast cell? – Protection against toxic substances • MC’s carboxypeptidase is required to limit effect of: – Endothelin-1 (ET-1) peptide from peritonitis – Pit viper venom – Honeybee (Apis mellifera) venom • MC’s proteases limit toxic effect of neurotensin, IL-6 CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  9. 9. Previous issues • What is non-pathological, physiological role of mast cell? – Enhance adaptive immune response • MC-deficient mice had impaired T-cell activation and had reduced DC migration • MCs remotely enhance lymphocytes sequestration in lymph nodes by using TNF-a • Using MC-activating compound as an adjuvant with some Ag can elicit protective immunity to the corresponding pathogen only in host with normal MC • MC activating compound can increase IgA secretion in mucosal challange CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  10. 10. Summary of MC’s defense model CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  11. 11. Summary of MC’s defense model CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
  12. 12. Mast Cell Disorders By Wat Mitthamsiri, MD. Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital
  13. 13. Outline • Classification and epidemiology • Pathogenesis • Clinical features • Pathology • Approach for diagnosis • Treatment • Prognosis
  14. 14. Classification and Epidemiology
  15. 15. Diseases of mast cells P Bradding, H Saito., Middleton’s Allergy 8th edition, 2013, 228-251. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. Excessive mast cell no/Fn • Localized mastocytosis • Systemic mastocytosis Mast cell deficiency • Never been found
  16. 16. Localized mastocytosis • Cutaneous mastocytosis – Urticaria pigmentosa/maculopapular cutaneous mastocytosis (UP/MPCM) – Diffuse cutaneous mastocytosis (DCM) – Solitary mastocytoma • Extracutaneous mastocytoma Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  17. 17. Systemic mastocytosis • Indolent Systemic Mastocytosis (ISM) • Systemic Mastocytosis with Associated Clonal, Hematologic Non–Mast Cell Lineage Disease (SM-AHNMD) • Aggressive Systemic Mastocytosis (ASM) • Mast Cell Leukemia (MCL) • Mast Cell Sarcoma (MCS) • Monoclonal mast cell activation syndrome (MMAS) • Mast cell activation syndrome (MCAS) Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  18. 18. Epidemiology • Unknown prevalence – Estimated 20,000-30,000 in the USA • Male/female ratio of 1 : 1 to 1 : 3 • Found in all ethnic backgrounds – More frequently reported in Caucasians • May occur at any age • Familial occurrence is unusual DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  19. 19. Pathogenesis
  20. 20. Pathogenesis KIT-dependent Apoptosis inhibition Other modifying mutation DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  21. 21. KIT-dependent AM Gilfillan and C Tkaczyk, Nature Reviews Immunology, 2006, 6:218-230
  22. 22. KIT-dependent Other names: • Mast/stem cell growth factor receptor (SCFR) • Proto-oncogene c-Kit • Tyrosine-protein kinase Kit • CD117 J Lennartsson and L Rönnstrand, Physiological ReviewsPublished 1 October 2012Vol. 92no. 4,1619-1649. AM Gilfillan and C Tkaczyk, Nature Reviews Immunology, 2006, 6:218-230
  23. 23. KIT-dependent J Lennartsson and L Rönnstrand, Physiological ReviewsPublished 1 October 2012Vol. 92no. 4,1619-1649. Chromosome image: http://ghr.nlm.nih.gov/gene/KIT Chromosome4 Position 12 (4q12)
  24. 24. KIT-dependent • Most common mutation = ASP 816 VAL (D816V) • Inheriable to next generation? No DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. Chromosome image: http://ghr.nlm.nih.gov/gene/KIT evidence • Other mutations: • V560G (MCL cell line) • D816Y, D816F, D816H, E839K (pediatric mastocytosis) • F522C • R815K, D820G, V533D, V559A, del419, K509I, and A533D (Exceedingly rare <1%)
  25. 25. Apoptosis inhibition FIP1L1-PDGFRA fusion PRKG2-PDGFRB fusion Anti-apoptotic proteins DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  26. 26. FIP1L1-PDGFRA Oncogene in pluripotential hematopoietic progenitor cells Results from ~800-kb interstitial deletion of chromosome 4q12 Patients: • ↑ Mast cells • Peripheral eosinophilia • ↑ Serum tryptase levels DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  27. 27. PRKG2-PDGFRB Systemic mastocytosis Chronic basophilic leukemia Rare DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  28. 28. Anti-apoptotic proteins AB Gustafsson and RA Gottlieb, American Journal of Physiology - Cell Physiology,1 January 2007Vol. 292no. 1, C45-C51
  29. 29. Clinical features
  30. 30. Clinical features Systemic symptoms Dermatologic symtoms GI symtoms Musculoskeletal symptoms Hepatosplenic symptoms Neuropsychiatric sypmtoms DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  31. 31. Systemic symptoms • Caused by mast cell’s mediators DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  32. 32. Systemic symptoms • Caused by mast cell’s mediators DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  33. 33. Systemic symptoms • Flushing and episodic hypotension • Hypotension may be provoked by – Alcohol – Aspirin – Insect stings – Infection – Exposure to iodinated contrast materials • No increased risk in bacterial, fungal, or viral infections DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  34. 34. Dermatologic symptoms • Urticaria pigmentosa (UP)/maculopapular cutaneous mastocytosis (MPCM) – Most common pattern of skin involvement in both adults and children – Found in >90% of ISM patients – Found in ~50% of SM-AHNMD or ASM patients DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  35. 35. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  36. 36. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  37. 37. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  38. 38. Urticaria pigmentosa • Tend to spare palms, soles, face, and scalp • Rubbing the lesions => urtication and erythema over and around the macules (Darier sign) • May be associated with pruritus exacerbated by: – Changes in temperature – Local frictionIngestion of hot beverages or spicy foods – Ethanol – Drugs • Petechiae, ecchymoses, or telangiectasias may be present in or adjacent to UP lesions DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  39. 39. Darier sign http://www.allergikos.gr/%CE%BC%CE%B1%CF%83%CF%84%CE%BF%CE%BA%CF%85%CF%84%CF%84%CE%AC%CF%81%CF%89%CF%83%CE%B7/
  40. 40. Diffuse cutaneous mastocytosis DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  41. 41. Both UP and DCM DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. • May have bullous eruptions with hemorrhage • Blisters may erupt spontaneously or in association with infection or immunization
  42. 42. Solitary mastocytomas • Fairly common cutaneous variant • May be present at birth but usually before age 3 months • Usually spontaneously involute during childhood • Solitary extracutaneous mastocytomas of the lung have been reported in adults DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  43. 43. Solitary mastocytomas (http://dermaamin.com/site/images/clinical-pic/m/mastocytoma-solitary_ mastocytoma/mastocytoma-solitary_mastocytoma1.jpg) DM Thappa,B. Jeevankumar, Indian Pediatrics 2005; 42:390
  44. 44. Mast cell sarcomas • Exceedingly rare • Characterized by a tumor consisting of highly atypical immature mast cells • Distant spread is possible • Leukemia phase may occur DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  45. 45. Telangiectasia macularis eruptiva perstans (TMEP) • Found <1% of mastocytosis patients • Reported only in adults • Characteristic skin lesion – Telangiectatic, red macule on a tan-brown background – 2-6 mm in diameter – No sharply defined borders • Pruritus, purpura, blister -> Uncommon • May become edematous when rubbed • Occasionally coexist with UP DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  46. 46. Telangiectasia macularis eruptiva perstans (TMEP) Ahmet AltinerMD, Julia Tzu MD, Rishi Patel MD, Shane Meehan MD, Miguel Sanchez, et al., Dermatology Online Journal 17 (10): 7
  47. 47. Telangiectasia macularis eruptiva perstans (TMEP) Ahmet AltinerMD, Julia Tzu MD, Rishi Patel MD, Shane Meehan MD, Miguel Sanchez, et al., Dermatology Online Journal 17 (10): 7
  48. 48. GI symptoms • 80% of patients had significant GI symptoms • Abdominal pain = Most common GI symptom – Followed by diarrhea and N/V – 70% of patients with dyspeptic pain had evidence of gastric acid hypersecretion – PU occured in 4-44% of all patients – Plasma concentration of histamine correlated with basal acid output • GI bleeding -> Uncommon DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  49. 49. GI symptoms DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. • Diarrhea, from: – Altered intestinal secretion – Structural disease of the small intestinal mucosa – Hypermotility or transit disorder • Malabsorption – Found in 31% of patients – Usually not severe – Primarily occurred as mild steatorrhea with impaired absorption of d-xylose or vitamin B12 – Diffuse, small intestinal mucosal dysfunction has been proposed as the cause
  50. 50. Musculoskeletal symptoms DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. • Uncertain etiology – Unless associated with osteopenia or osteoporosis • Osteoporosis leading to pathologic fractures – Back pain from osteoporosis – Vertebral compression fractures – May be the initial manifestation of mastocytosis
  51. 51. Hepatosplenic symptoms • ~60% of patients had evidence of liver disease – 24% -> Hepatomegaly – 54% -> Elevated ALP and GGT • ALP levels correlated with GGT levels, hepatomegaly, splenomegaly, and liver mast cell infiltration and fibrosis • In SM-AHNMD or ASM patients – Elevated ALP -> More frequently – Reported 5 cases of ascites or portal hypertension • Severe liver disease is uncommon – Except in patients with aggressive disease DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  52. 52. Neuropsychiatric symptoms DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. • In adults – Decreased attention span – Memory impairment – Irritability – May caused by therapeutic medicines as well as circulating mediators • In children – No clear excess pathology – No specific behavioral pattern implicating histamine overproduction was identified
  53. 53. Pathology
  54. 54. Pathology Dermatologic pathology Bone marrow pathology Radiologic pathology Liver pathology Spleen pathology Lymph nodes pathology DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  55. 55. Urticaria pigmentosa • Increased mast cells (>/= 10x of normal) within the papillary dermis • With variable extension throughout reticular dermis and into the subcutaneous fat • Absence of other pathology • Gross skin examination must be correlated with the number of mast cells in the skin DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  56. 56. Urticaria pigmentosa http://www.skinpathology.org/wp-content/uploads/Urticaria-Pigmentosa-Histopathology-1024x768.jpg
  57. 57. Urticaria pigmentosa http://www.skinpathology.org/wp-content/uploads/Urticaria-Pigmentosa-Histology-1024x768.jpg
  58. 58. Diffuse cutaneous mastocytosis DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  59. 59. TMEP Ahmet AltinerMD, Julia Tzu MD, Rishi Patel MD, Shane Meehan MD, Miguel Sanchez, et al., Dermatology Online Journal 17 (10): 7
  60. 60. Bone marrow pathology • Most common site of pathologic mast cell infiltrates in mastocytosis • Most useful Bx site for pathologic diagnosis • Majority of infiltrates are focal (may be diffuse in some cases) DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  61. 61. Bone marrow pathology • Often situated paratrabecularly • Consist of nodular aggregates of spindle-shaped mast cells, which may be accompanied by lymphocytes and eosinophils DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  62. 62. Bone marrow pathology • Hypercellular marrow, as a prognostic factor – With ↓percentage of fat cells = Significant predictor of poor prognosis – 1/3 of patients had associated hematologic disorders • Dysmyelopoietic syndromes • Myeloproliferative disorders • Acute leukemia • Malignant lymphoma • Chronic neutropenia • Had significantly reduced 5-year survival rates • In most patients, hematologic disorder is detected after mastocytosis is diagnosed DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  63. 63. Bone marrow pathology DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. • In mast cell leukemia – Diffuse infiltration by atypical, immature mast cells – Mast cells account >/= 10% of the peripheral WBC • In aggressive mastocytosis with a terminal leukemic phase – Circulating mast cells appear late in the disease course – Percentage of circulating mast cells is relatively low
  64. 64. Bone marrow pathology • BM Mast cell hyperplasia in non-mast cell diseases – Uremia – Osteoporosis – Hematologic conditions (lymphomas, preleukemias, leukemias) DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  65. 65. Radiologic pathology • Radiographically detectable BM infiltration are up to 70% of patients – Proximal long bones = Most often affected – Followed by the pelvis, ribs, and skull DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236. • Skeletal scintigraphy – More sensitive than radiographic surveys in detecting and locating active lesions – May aid in evaluating the extent of disease and disease progression
  66. 66. Liver pathology • Mast cell infiltration in liver – More severe in patients with SM-AHNMD or ASM – Correlates with hepatomegaly, splenomegaly, ALP levels, and GGT levels • Portal fibrosis correlates with mast cell infiltration and portal inflammation • Nodular regenerative hyperplasia, portal venopathy, and venoocclusive disease may contribute to portal hypertension DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  67. 67. Spleen pathology • Most common finding = Trabecular fibrotic thickening • Splenic mast cell lesions have been found in – Paratrabecular – Parafollicular – Follicular – Diffuse red pulp DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  68. 68. Spleen pathology http://www.webpathology.com/image.asp?case=385&n=2
  69. 69. LN pathology • Most common location of infiltration = Paracortical region • Less frequent – Parafollicular and follicular replacement – Medullary cord – Sinus infiltration • May resemble follicular and T cell lymphomas, monocytoid B cell hyperplasia and lymphoma, Kaposi sarcoma, hairy cell leukemia, and histiocytosis X DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  70. 70. LN pathology John Lazarchick, http://imagebank.hematology.org/Content/740/3803/3803_full.JPG
  71. 71. LN pathology John Lazarchick, http://imagebank.hematology.org/AssetDetail.aspx?AssetID=3804
  72. 72. Approach for diagnosis
  73. 73. Proposed algorithm P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  74. 74. Proposed algorithm P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  75. 75. Proposed algorithm P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  76. 76. Proposed algorithm P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  77. 77. Proposed algorithm = WHO’s criteria P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  78. 78. Classification of MCAS P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  79. 79. Classification of MC disorders P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.
  80. 80. Diagnosis (WHO’s criteria for Dx)
  81. 81. Cutaneous mastocytosis • Typical clinical findings of: – Urticaria pigmentosa/maculopapular cutaneous mastocytosis (UP/MPCM) – Diffuse cutaneous mastocytosis (DCM) – Or solitary mastocytoma • With typical infiltrates of mast cells in a multifocal or diffuse pattern on skin biopsy Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  82. 82. Systemic mastocytosis • 1 major+1 minor, or 3 minor criteria are required – Major Criterion • ≥15 foci of mast cells infiltrates in sections of bone marrow and/or another extracutaneous organ • (Confirmed by tryptase immunohistochemistry or other special stains) Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  83. 83. Systemic mastocytosis • 1 major+1 minor, or 3 minor criteria are required – Minor Criteria • >25% of mast cells are abnormal: – Spindle shape or atypical morphology (in Bx of BM/other extracutaneous organs) – Immature or atypical morphology (in BMA specimens) • Detection of activating point mutation at codon 816 of KIT in BM, blood, or another extracutaneous organ • Mast cells in BM, blood, or another extracutaneous organ express CD117 with CD2 and/or CD25 • Serum total tryptase persistently >20 ng/mL (without associated clonal myeloid disorder) Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  84. 84. Varients of mastocytosis • “B” findings – >30% infiltration by mast cells (focal, dense aggregates) in BMBx and/or serum total tryptase >200 ng/mL – Signs of dysplasia or myeloproliferation in non– mast cell lineages (but insufficient for Dx of a hematopoietic neoplasm) + normal/slightly abnormal blood counts – Hepatomegaly without impairment of LFT, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy. Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  85. 85. Varients of mastocytosis • “C” findings : – BM dysfunction: >/= 1 of • ANC <1.0 x109/L • Hb <10 g/dL • Platelets <100 × 109/L) • And no obvious non–mast cell hematopoietic malignancy – Palpable hepatomegaly + impaired LFT, ascites, and/or portal hypertension – Skeletal involvement + large osteolytic lesions and/or pathologic fractures – Palpable splenomegaly + hypersplenism – Malabsorption + Wt loss (from GI mast cell infiltrates) Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  86. 86. Varients of mastocytosis • Indolent Systemic Mastocytosis (ISM) – Meets criteria for systemic mastocytosis – No “C” findings – No evidence of an associated clonal, hematologic non–mast cell lineage disease (AHNMD) – In this variant the mast cell burden is low, and skin lesions are usually present • BM mastocytosis – ISM + BM involvement, but no skin lesions • Smoldering systemic mastocytosis – ISM, with >/=2 “B” findings and no “C” findings Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  87. 87. Varients of mastocytosis • Systemic Mastocytosis with Associated Clonal, Hematologic Non–Mast Cell Lineage Disease (SM-AHNMD) – Meets criteria for SM – And criteria for AHNMD • (MDS, MPN, AML, lymphoma, or other hematologic neoplasm that meets criteria for distinct entity in WHO classification) Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  88. 88. Varients of mastocytosis • Aggressive Systemic Mastocytosis (ASM) – Meets criteria for SM with one or more “C” findings – No evidence of mast cell leukemia. – Usually without skin lesions – Lymphadenopathic mastocytosis with eosinophilia – Progressive lymphadenopathy • With peripheral blood eosinophilia • Often with extensive bone involvement, and hepatosplenomegaly • Usually without skin lesions – Cases with rearrangement of PDGFRA are excluded Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  89. 89. Varients of mastocytosis • Mast Cell Leukemia (MCL) – Meets criteria for SM – BMBx: Diffuse infiltration by atypical, immature mast cells – BMA smears: >/= 20% mast cells + mast cells >/= 10% peripheral WBC • Variant: – Leukemic mast cell leukemia as above – <10% of WBC are mast cells – Usually without skin lesions Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  90. 90. Varients of mastocytosis • Mast Cell Sarcoma (MCS) – Unifocal mast cell tumor – No evidence of SM – Destructive growth pattern; high-grade cytology • Extracutaneous Mastocytoma – Unifocal mast cell tumor – No evidence of SM. – No skin lesions; nondestructive growth pattern; low-grade cytology Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  91. 91. Varients of mastocytosis • Proposed additional criteria – Monoclonal mast cell activation syndrome (MMAS) • BM examination to have met 1-2 minor diagnostic criteria for mastocytosis • But lack the full diagnostic criteria for systemic mastocytosis – Mast cell activation syndrome (MCAS) • Episodic allergy-like signs and symptoms (e.g., flushing, urticaria, diarrhea, wheezing) involving >/=2 organ systems • Without identifiable etiology DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  92. 92. Other surrogate markers • Serum histamine and 24-hr urinary histamine metabolites (N-methylhistamine, and methylimidazoleacetic acid) – Less often used – Disadvantages • Variability among healthy individuals and patients • Difficulty in assay standardization • False-positive • Easily altered result • Nonspecific DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  93. 93. Other surrogate markers • Metabolites of arachidonic acid – Urinary PGD-M or 9α,11β- dihydroxy-15-oxo- 2,2,18,19-tetranorprost-5-ene-1,20-dioxic acid – Plasma thromboxane B2 and its metabolites – Limitations • Source is not exclusively limited to mast cells -> insufficient specificity for diagnostic purposes • 24-hr urinary 5-hydroxyindoleacetic acid and urinary metanephrines – For R/O carcinoid tumor/pheochromocytoma DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  94. 94. Other W/U • Other tissue Bx • Bone scans or skeletal surveys • Abdominal U/S or CT scan • Upper GI series • Small bowel radiography • Endoscopy (to R/O PU or GERD) • Dual-energy x-ray absorptiometry (DEXA) scan (to monitor osteoporosis) DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  95. 95. Treatments
  96. 96. Treatments MC-mediated symptoms GI symptoms Osteoporosis Hematologic abnormality DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  97. 97. MC-mediated symptoms • Epinephrine – Rx episodes of systemic hypotension – Patients should be taught to administer this medication themselves – Intensive therapy as for anaphylaxis might be needed • H1 & H2 receptor antagonist – Mainly reduce flushing – Anti-H1 first, if inadequate response, then use anti-H2 • LTRA – Add on to antihistamines to help flushing DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  98. 98. MC-mediated symptoms • Disodium cromoglycate (cromolyn sodium) – Inhibits degranulation of mast cells – Relief of GI complaints – Not reduce plasma or urinary histamine levels • 8-methoxypsoralen with PUVA (or even natural sunlight in some cases) – Relieve pruritus&whealing in adult after 1-2 mo of Rx – Associated with transient decrease dermal mast cells – Pruritus relapsed in 3-6 months after discontinuation – Used only in patients with extensive cutaneous disease unresponsive to other therapy DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  99. 99. MC-mediated symptoms • Topical steroids with plastic wrap occlusion for 8 hr/day x 8-12 wks – Used to treat UP or DCM – Number of mast cells decreases as lesions resolve – Lesions recur after Rx discontinuation but may be last for up to 1 year DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  100. 100. GI symptoms • Gastric acid hypersecretion symptoms (peptic symptoms and PU) – H2 RA and PPI • Diarrhea – Anticholinergics -> partial relief • Severe malabsorption – Oral steroids • Ascites – Portacaval shunt DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  101. 101. Osteoporosis • Calcium supplementation • Estrogen replacement (postmenopausal women) • Bisphosphonates • Narcotic analgesics – May potentiate mast cell degranulation • Radiotherapy – Palliative role in decreasing bone pain in patients with aggressive forms of disease • IFN-α2b – Relieve musculoskeletal pain – Improve bone mineralization DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  102. 102. Hematologic abnormality • Managed as dictated by associated specific hematologic abnormality • IFN-α2b and 2-chloro-2-deoxyadenosine (cladribine, 2-CdA) – Potential first-line therapy for patients with aggressive forms • BMT – Good for associated hematologic disorders – Poor effect on mast cell hyperplasia DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  103. 103. Hematologic abnormality • Imatinib mesylate – Approved for Rx of aggressive forms of mastocytosis in patient without D816V mutation – May be useful in unusual presentations of mastocytosis, which are associated with novel mutations in c-kit – Patients with increased mast cells + peripheral eosinophilia + FIP1L1-PDGFRA fusion oncogene also respond – Mutational analysis of lesions are essential before Rx • Other tyrosine kinase inhibitors eg. midostaurin (PKC412) – Able to inhibit KIT with the D816V mutation in vitro – Now in clinical study DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  104. 104. Hematologic abnormality • Chemotherapy – Unable to produce remission – Unable to prolong survival in MCL – Has no place in the treatment of indolent mastocytosis – But may be considered for advanced disease DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  105. 105. Hematologic abnormality • Splenectomy – May improve survival times in mastocytotic patients with with poor prognosis • Radiotherapy – Used in the management of refractory bone pain in patients with aggressive disease • BMT – May be considered for extremely ill patients, – May yield a better prognosis if mast cell suppression is attempted before BM DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  106. 106. Prognosis
  107. 107. Prognosis • Patients with CM only = Best prognosis, followed by those with ISM • >50% of children with isolated UP resolve by adulthood • UP in adulthood may evolve into systemic disease • Occasionally, ISM converts to SM-AHNMD • Course depends largely on prognosis of specific hematologic disorder and response to Rx • Mean survival of MCL pt: <12 months • Survival time ASM pt: 2-4 years (with aggressive symptomatic management) DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
  108. 108. Take Home Message • Mast cell disorders vary greatly in clinical presentations • Primary pathomechanism is the activating mutation in KIT • Signs and symptoms are caused by: – Mast cell mediators – Increased mast cell burden – Associated hematologic disorder • Treatments – Symptomatic Rx for mastocytosis – Specific Rx for associated hematologic disorders
  109. 109. Thank you

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