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  2. 2. Introduction • Mature mast cells are 10μm in size with a life span of 6 months-1year • Mature mast cells have prominent cytoplasmic granules that contain histamine, and other chemical mediators, and surface receptors that bind the Fc portion of IgE with high affinity • Mast cell nuclei are round with surrounding ample cytoplasm producing a “FRIED EGG” appearance
  3. 3. MAST CELLS  Mast cells are the primary effector cells in immunoglobulin E (lgE) mediated inflammatory reactions.  Mast cells are widely distributed, long lived cells found predominately in connective and mucosal tissues and often in proximity to blood vessels, nerves, and lymphatic tissue  Mast cells are abundant in the skin, respiratory tract, gastrointestinal tract.  They are implicated in both acquired and innate immune responses, wound healing, fibrosis, angiogenesis, and autoimmune diseases.
  4. 4. Mast cells have been classified into two types 1. TC mast cells: Mast cells that contain tryptase and chymase are referred to as TC mast cells (MCTC)  Such cells tend to be located in submucosal tissues.  Increased numbers of these cells are found in fibrotic diseases 2. T mast cells: Mast cells that contain tryptase but not chymase are referred to as T mast cells(MCT)  are increased in allergic and parasitic diseases and decreased in the gastrointestinal mucosa in patients affected with HIV 
  5. 5. Development of Mast cells      Mast cells are derived from pluripotent CD34+ precursor cells in the bone marrow complete maturation in vascularized peripheral tissues c-kit (proto-oncogene) encodes Kit (CD117) : trans membrane tyrosine kinase receptor for SCF Cross linking KIT by stem cell factor (SCF) is essential for these precursor cells to differentiate into mast cells Other cytokines that regulate SCF-dependent mast cell differentiation and proliferation include interleukin 13 (lL-13), IL-4,-5, and interferon-ϒ (lFN-ϒ)
  6. 6. Mastocytosis  Definition: A heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells in the skin and sometimes in other organs(bones, GIT, liver, spleen)  Epidemiology:  Age: can present at the time of birth or develop anytime thereafter into late adulthood  sex: no gender preference and is reported in all races
  7. 7. History  The original description of mastocytosis was given by Nettleship and Tay on a 2 yr old girl with hyper pigmented papules that spontaneously urticated in 1869  Later in 1877, Paul Ehrlich discovered the mast cell  Unna was the first to demonstrate the mast cells were responsible for the cutaneous eruption in mastocytosis patients  In 1949, Ellis reported the first patient with systemic disease
  8. 8. Etiopathogenesis     Alteration in KIT structure and activity are central to the pathogenesis of mastocytosis Somatic point mutations in codon 816 of the c-kit proto-oncogene have been identified in adult mastocytosis without familial disease which causes constitutive activation of KIT leading to continued mast cell production(most commo mutation consists of a substitution of valine for aspartic acid (ASP 816 VAL)) Increased local concentrations of soluble SCF are believed to stimulate mast cell proliferation, melanocyte proliferation and melanin pigment production. Impaired mast cell apoptosis has been postulated to be involved as evidenced by up-regulation of the apoptosis preventing protein BCL-2 demonstrated in patients with mastocytosis
  9. 9. PATHOLOGIC EFFECTS OF INCREASED MAST CELLS  The pathologic changes observed in mastocytosis are the result of the increased number of mast cells residing within tissues, and the release of mast cell-dependent mediators within tissues  Mast cell-derived mediators also circulate through the bloodstream and lymphatic system to produce biologic effects
  10. 10. Mastocytosis  1. There are 2 main categories: CUTANEOUS MASTOCYTOSIS(CM): MC infiltrate is confined to one or more lesions on the skin 2. SYSTEMIC MASTOCYTOSIS(SM): MC infiltration of at least one extracutaneous organ with or without evidence of skin involvement
  11. 11. SYMPTOMS  The symptoms of SM are usually grouped into 4 categories: (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 pain
  12. 12. Skin  Urticaria pigmentosa (UP)/maculopapular cutaneous mastocytosis (MPCM)  Diffuse cutaneous mastocytosis (DCM)  Solitary mastocytoma of the skin  Telangiectasia macularis eruptiva perstans(TMEP)
  13. 13. URTICARIA PIGMENTOSA  Commonest form of mastocytosis  Onset: is generally before 2 years of age and a few infants born with few skin lesions , also seen in adults where it is more chronic and associated with systemic involvement  Lesion: multiple, monomorphic, oval, yellowish tan to reddish-brown macules and slightly elevated papules of variable size(1mm to several cm) with a characteristic border which is not sharp  Site: commonly on trunk but can occur anywhere central face, scalp, palms and soles are spared  Nodules and plaques are less common  A generalized blistering variety has been reported in patients less than 2 years which subsides spontaneously by 3-5 years
  14. 14.  Darier’s sign : rubbing of the lesions usually leads to urtication and erythema over and around the macules( due to local release of histamine from mast cells )  UP is sometimes associated with pruritus that is exacerbated by  changes in temperature, local friction, ingestion of hot beverages or spicy foods, ethanol, and certain drugs
  16. 16. Urticaria pigmentosa Typical lesions of urticaria pigmentosa in a child.
  17. 17. HISTOPATHOLOGY: Characterized by accumulation of mast cells in dermis particularly around the blood vessels Mast cells are basophilic, granular and they may appear elongated like fibroblast or cuboidal In macular and Papular lesions the infiltrate is relatively sparse and located in the upper dermis whereas in nodular lesions it is massive and tumor like In the bullous variety the blister is sub epidermal and the blister cavity often contains numerous eosinophils The epidemis shows increased melanization
  18. 18. DIFFUSE CUTANEOUS MASTOCYTOSIS        Extremely rare form of CM Characterized by diffuse infiltration of virtually the entire skin by mast cells Onset : children younger than 3 years , but also in adults Lesions: numerous erythematous to yellow tan papules and plaques with areas of confluence that have a leathery texture Skin may be normal or thickened with exaggerated skin markings Large blisters may develop on apparently normal skin spontaneously or following pressure or mild trauma Because of enormous mast cell load, serious complications such as hypotension, shock, GI bleeding, and severe diarrhea may occur
  19. 19. Diffuse cutaneous mastocytoma Spontaneous blister in an infant with diffuse cutaneous mastocytosis.
  20. 20. Extensive diffuse skin involvement Bullous eruption DIFFUSE CUTANEOUS MASTOCYTOSIS
  21. 21. HISTOPATHOLOGY: • Epidermis shows increased melanization • Full-thickness infiltration of skin or a band like involvement of the upper dermis are seen in diffuse cutaneous mastocytosis
  22. 22. SOLITARY MASTOCYTOMA  Onset: before the age of 6 months, but may appear at any age(extremely rare in adults)  Lesions: solitary, reddish brown or grayish yellow smooth surfaced plaques or nodules, often lobulated , up to 3-4 cm in diameter  Site: often appear at distal extremities but can occur in any location  Surface may have an orange peel appearance  They may be itchy, tender, or even asymptomatic  Darier’s sign is positive
  24. 24. Histopathology: • Epidermis shows increased melanization • Diffuse, dense interstitial infiltrate of mast cells around blood vessels are seen
  25. 25. Telangiectasia macularis eruptiva perstans         A rare form of mastocytosis seen < 1% of cases Age: usually appears in the adults Lesion: patients develop crops of numerous itchy, ill defined, telangiectatic, brown macules, 3-8mm in size Longstanding lesions develop hyperpigmentation It may co exist with Urticaria pigmentosa Darier’s sign and dermatographism are present Associated with bone lesions and peptic ulcers Site: primarily on the trunk(especially the chest), but also on the extremities
  26. 26. Telangiectasia macularis eruptiva perstans
  27. 27. Telangiectasia macularis eruptiva perstans
  28. 28. Telangiectasia macularis eruptiva perstans Multiple lesions composed of telangiectasias are present. Telangiectasia macularis eruptiva perstans
  29. 29. HISTOPATHOLOGY: • Mast cells are brick shaped or spindle shaped • The infiltrate tends to be predominantly perivascular and there is also vascular ectasia
  30. 30. Systemic mastocytosis(SM)  refers to the condition in which patients have an abnormal increase in mast cells in non cutaneous tissues  Usual sites affected: bone marrow, liver, spleen, lymph nodes , GIT, skeletal system but any tissue can be affected  CNS is not effected  Usually seen in adults but rarely seen in children
  31. 31. GIT symptoms  Most common chronic symptoms  It includes: 1. Abdominal pain: pain may be epigastric(due to hypersecretion of gastric juices due to elevated plasma histamine) or cramping , lower abdominal pain(due to bowel wall edema) 2. Diarrhea: episodic (caused by malabsorption, increased motility of the gut and hypersecretion) 3. GI hemorrhage: occurs secondary to gastritis or peptic ulcer
  32. 32. Skeletal system involvement        Occurs in 70% of patients It is common in adults , but rare in children Patients complain of localized bone pain(can be due to osteosclerosis or osteoporosis) The proximal long bones, pelvis, ribs, skull are most often effected Bone marrow is commonly involved in adult patients with mastocytosis There is increased number of spindle shaped bone marrow with focal perivascular, peritrabecular and/or intertrabecular accumulations Scattered lymphocytes and eosinophils have been associated with these mast cells leading to the term MEL(mast cell, eosinophil, lymphocytes) lesion which helps in differentiating mastocytosis from other hematological disorders such as myeloproliferative and myelodysplastic diseases
  33. 33. Other features       Hepatomegaly: is reported in up to 72% of patients but is of no consequences as liver function tests are normal Fibrosis, portal hypertension, and ascites can result from mast cell infiltration Splenomegaly is seen in 50-60% of the patients Lymph node enlargement is seen in patients with advanced systemic disease Hematological abnormalities like mild normochromic normocytic anemia, leukocytosis or leukopenia, eosinophilia, monocytosis, and thrombocytosis are seen(may be due to the involvement of bone marrow) Systemic mastocytosis may be associated with dysplastic and neoplastic disorders of myeloid cells
  34. 34. Malignant Mastocytosis  A rare condition which may be mistaken for systemic mastocytosis with or without the cutaneous signs  It is usually associated with a corresponding proliferation of atypical(malignant) mast cells in the bone marrow  Atypical cells have a larger nuclei, mitotic activity, fewer granules and increased toluidine metachromasia at a higher ph  Prominent constitutional symptoms, severe peptic ulcer disease, and hepatosplenomegaly are common features
  35. 35. Differential Diagnosis 1. Urticaria pigmentosa:  Histiocytosis  Secondary syphilis  Papular sarcoidasis  Xanthomas  Nevoxantho-endotheliomas Macular lesions of UP  Pigmented nevi, Multiple lentigens Bullous lesions of UP  Bullous insect bites, Epidermolysis bullosa, linear IgA disease and early incontinentia pigmenti
  36. 36. Differential Diagnosis 2. Mastocytoma:  Juvenile xanthogranuloma, pigmented nevi and connective tissue nevi 3. TMEP:  Hereditary hemorrhagic telangiectasia
  37. 37. Investigations  If the age of onset of mastocytosis is below 5 years , then skin biopsy is sufficient to determine the diagnosis  If systemic signs are present or later age of onset ,then 1. A complete blood count(anemia, leukocytosis, thrombocytopenia) 2. Serum tryptase levels (elevated in mastocytosis) 3. Bone marrow biopsy 4. USG Abdomen/CT Scan abdomen ( to rule out liver and spleen pathology) 5. Radiologic and endoscopic studies of GIT(if GI symptoms are present) 6. Radiological skeletal survey(if bone pain or h/o of fracture is present) 7. Liver Function tests 8. Urinary levels of major histamine metabolites(methylimidazoleacetic acid,MIAA) 9. Plasma or urinary histamine levels(2-3 times more in pts with mastocytosis)
  38. 38. Serum Tryptase Levels    1. 2. 3.  Normal range is 1-15ng/ml It is slightly elevated in patients with CM’s and isolated bone marrow mastocytosis It is significantly elevated(>20ng/ml) in case of multi organ involvement and also in other conditions like Acute and chronic myeloid leukemia Myelodysplastic disorders During a severe allergic reaction So, in adult patients with a persistently elevated tryptase, the likelihood of SM is significant, and a bone marrow examination warranted.
  39. 39. Bone marrow biopsy & aspiration  show multifocal, sharply demarcated, compact infiltrates of mast cells  Mast cells are a mixture of both round and spindle shaped forms  Immunohistochemical and molecular studies are recommended to distinguish reactive from malignant mast cell infiltrates
  40. 40. MCs in Bone marrow
  41. 41. Histamine Metabolites detection MIAA(1,4-methylimidazoleacetic acid) in urine  Markedly increased, especially in TMEP and SM.  They correlate well with the extent of systemic involvment and their periodic measurement can be used to monitor disease activity  Other indicators of mast cell degranulation are the mast cell granule associated tryptase, chronologically elevated urinary metabolite pf prostaglandin D2 and a prolonged PTT immediately after an attack
  42. 42. MANAGMENT Counseling the patient regarding the nature of the disease  Avoidance of factors provoking mediator release  Management of chronic symptoms like pruritis and gastric hypersecretion (mast cell mediator release symptoms)  Treatment of acute episodes of vascular collapse  Cytoreductive therapy to address the sequelae of disabling organ infiltration by mast cells 
  43. 43. Factors provocating mediator release         Alcohol intake Anticholinergic medications Aspirin NSAID’S Heat Friction Narcotics (morphine and codeine) Polymyxin B sulfate
  44. 44. Management of mediator release symptoms       Antihistamines Corticosteroid Disodium cromolyn (cromolyn sodium) Bisphosphonates UV light irradiation Epinephrine
  45. 45. Anti histamines          H1 receptor antagonists: classic or non-sedating antihistamines reduce pruritus and flushing H2 receptor antagonists: If H1 is insufficient, especially in cases of gastric hypersecretion Ex :ranitidine , cimetidine , famotidine Ketotifen fumarate:(dose :- 1-2 mg/day) has both antihistamine and mast cell stabilising properties Effective when combined with ranitidine.
  46. 46.  Disodium cromoglycate (oral cromolyn sodium):  dose:-400-800mg/day  Inhibits mast cell degranulation  may alleviate GI, cutaneous and CNS symptoms
  47. 47. UV light irradiation  Psoralen plus UVA (PUVA) can be given 4 times per week  Helps in controlling the pruritis and cutaneous whealing but does not alter other symptoms associated with this disorder  Photochemotherapy should be used only in instances of extensive cutaneous disease unresponsive to other forms of therapy
  48. 48.  Corticosteroids:  Topical steroids under occlusion for 6 weeks or more eliminates pruritis, cutaneous whealing , histamine levels and the no of lesional skin mast cells  Intralesional injection of Triamcinolone acetonide(30mg/ml) can also be given to clear mast cell infiltrates in the skin of mastocytosis patients  Systemic corticosteroids can be used in combination with cyclosporine in patients with aggressive mastocytosis
  49. 49.  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 inhibitors
  50. 50. Acute episodes of vascular collapse  Treated with self administered premeasured epinephrine preparations(EPIPEN)  Oral Prednisone(20-40mg/day for 2-4 days) can be given to prevent recurrence of episodes
  51. 51. Cytoreductive therapy  Given for aggressive SM, SM-AHNMD,MCL 1. interferon-α-2b(IFN-α-2b) has been used in treating more aggressive forms (dose -0.5×106 U/day)  side effects include hypothyroidism, thrombocytopenia, depression 2. Cladribine(2-chlorodeoxyadenosine) IV was effective in eliminating skin lesions and markedly reducing the no of bone marrow mast cells in patients with advanced systemic disease  In highly aggressive or relapsed cases : combination chemotherapy followed by a hematopoietic stem cell transplant should be considered  cytarabine, fludarabine, and hydroxyurea
  52. 52. Bone marrow Transplantation  treatment option for patients with advanced categories of mastocytosis associated with poor survival in only a few reported instances  may yield a better prognosis if mast cell suppression is attempted prior to the transplantation
  53. 53. Treatment at a glance
  54. 54. Prognosis      Patients with CM only have the best prognosis For children with isolated UP, at least 50% of cases are reported to resolve by adulthood UP in adulthood may evolve into systemic disease Occasionally, ISM converts to SM-AHNMD The prognosis appears to improve with aggressive symptomatic management