Mastocytosis Flashcards
Classification
CUTANEOUS MASTOCYTOSIS (mainly children)
Maculopapular cutaneous mastocytosis
- Urticaria pigmentosa
- Telengiectasia macularis eruptiva perstans
Mastocytoma
Diffuse cutaneous mastocytosis
SYSTEMIC MASTOCYTOSIS
Indolent systemic mastocytosis (mostly adults)
- Smoldering indolent systemic mastocytosis
Systemic mastocytosis with an assoc clonal haem non-mast cell disease
Aggressive systemic mastocytosis
Mast cell leukaemia
Mast cell sarcoma
Extracutaneous mastocytoma
Pathogenesis
Symptoms of mastocytosis primarily d/t mast cell mediator release
Mast cells accumulate in tissues as a direct consequence of acquiring a gain-of-function KIT mutation
KIT activation —> survival, migration of tissue mast cells
Epidemiology
Uncommon
1/3 cases presents in childhood
Majority childhood mastocytosis presents within 1st 2 years of life
Adults present between 3rd and 6th decades
Familial cases reported
- Urticaria pigmentosa
- Telengiectasia madularis eruptiva perstans (TMEP) —> AD inheritance
Associated diseases
SYSTEMIC MASTOCYTOSIS
Anaphylaxis
Osteoporosis —> presents with vertebral fractures esp in men
Risk of potential non-mast cell haem disorder
Histo
SKIN
Increased mast cell numbers in the papillary dermis
Mainly around blood vessels and skin appendages
Increased melanin pigmentation in the epidermis
Otherwise Normal epidermis
Mast cells usually oval or spindle shaped “fried egg appearance”
Granules stain metachromatically -
- Toluidine blue
- Giemsa
- Tryptase
- Chloroacetate esterase
TMEP
- Mast cells confined ro superficial capillaries and dilated venules
- May be only slightly increased over the numbers seen in normal skin
Mastocytomas and diffuse cutaneous mastocytosis
- Full thickness infiltration of the skin vs band-like involvement of the upper dermis
BONE MARROW Focal aggregates of mast cells vs diffuse infiltration Accompanied by increased numbers of - - Neuts - Phagocytosing macrophages - Eos - Lymphocytes - Fibrosis
IHC
CD25 and/or CD2 with tryptase
CD 117
Biopsy of suspected mastocytosis in skin
Careful technique to minimise mast cell degranulation
Atraumatic Injection of LA around the lesion (ring block) —> yields higher number of stainable mast cells
4mm PBx of lesional skin
Place in formalin for histo (H&E) and mast cell stains - Toluidine blue Giemsa Tryptase Chloroacetate esterase
Cutaneous mastocytosis - maculopapular cutaneous mastocytosis
URTICARIA PIGMENTOSA
Commonest cutaneous mastocytosis in adults and children
Onset -
- Children within 1st 2 yrs of life
- Adults 20-40 yrs
Numerous reddish brown or pale monomorphic maculopapules, plaques, nodules
Symmetrical distribution
Anywhere on the body —> highest concentration on trunk and thighs
EXCEPT palms and soles
Unusual for face to be affected
+/- hairline in children
+/- neck of adults
In infancy/childhood —> lesions may blister —> heals without scarring
Urticate within mins of gentle rubbing in children —> Darier’s sign (localised itch, redness, wealing) —> subsides within an hour
Gentle skin stroking does NOT produce wealing between lesions
Darier sign illustration/selective wealing within lesions by stroking lesional and perilesional skin can be a substitute for skin biopsy in very young children
Darier sign not always demonstrable in the following scenarios -
Adult urticaria pigmentosa with long hx of disease
Child with resolving lesions
Darier sign not 100% specific for cutaneous mastocytosis, can also be demonstrated in -
- Juvenile xanthogranuloma
- Acute lymphoblastic leukaemia of neonates
Associated symptoms
- Flushing (common)
- Headache (common)
- Depression (common)
- ETOH intolerance
- Itch
- Heat or cold intolerance
- Wheezing (rare)
- Syncope (presentation of anaphylaxis)
- Acid dyspepsia
- Recurrent diarrhoea
- Urinary frequency
Associated diseases (adults)
- Indolent systemic mastocytosis ? 90 - 95%
- Clonal mast cell disease
Course/prognosis
50% of children clear by adolescence
Outlook for paed cases that do not remit is the same as for adults with indolent systemic mastocytosis —> progression to sognificant haem disorders is rare, even with proven systemic mastocytosis
10% adults spontaneous resolution
Cutaneous mastocytosis - maculopapular cutaneous mastocytosis
TELENGIECTASIA MACULARIS ERUPTIVA PERSTANS (TMEP)
Fixed erythema predominant clinical feature
Adults with persistent red macules
May or may not show obvious telengiectasia esp on the trunk
On rubbing —> flush, but do not urticate
Excess mast cells on skin bx will confirm dx, but madt cells may mot be numerous
Pure TMEP ? Better prognosis vs extensive urticaria pigmentosa with marked telengiectatic component
Persistent
Not responsive to Rx
Cutaneous mastocytosis - mastocytoma
Infancy/early childhood
Red, pink, yellowish nodules/plaques
3-4cm in diameter
Usually solitary
If multiple —> difficult to differentiate from nodular urticaria pigmentosa
When rubbed —>
- tend to blister esp in napkin area of infants —> bullous mastocytoma d/t intense subepidermal oedema resulting from mast cell degranulation
- Flushing attacks
Involutes over 1st few years of childhood
Systemic disease very unlikely
Reasonable to avoid skin bx to confirm clinical dx if there is convincing Darier’s sign
Cutaneous mastocytosis - diffuse cutaneous mastocytosis
Rare
Presents in neonatal period
Itch may be intense
Mast cells infiltrate entire skin diffusely
Skin tends to be thickened and doughy in consistency
May be smooth
Skin colour normal or almost red
Pigmentation usually absent
Blistering after minor trauma/scratching common —> bullous mastocytosis d/t intense subepidermal oedema resulting from mast cell degranulation
Epidermis may be lost over large area —> resemble impetigo
COMPLICATIONS
At risk of systemic disease
Anaphylaxis
Diarrhoea
COURSE/PROGNOSIS
Resolves spontaneously
Systemic mastocytosis
WHO CRITERIA 1 major + 1 minor OR 3 minor on bone marrow bx
Major
- Multifocal aggregates of at least 15 mast cells in bone marrow or another organ (pther than the skin)
Minor
- > 25% of mast cells in infiltrates are spindle shaped (bone marrow bx, or other tissue other than skin) OR > 25% of mast cells in bone marrow aspirate smears are immature or atypical
- Activating mutations in KIT i.e. codon 816 (bone marrow, blood, tissue other than skin)
- Co-expression of CD117 with CD2 and/or CD25 (bone marrow mast cells, blood, tissue other than skin)
- Serum tryptase > 20 ug/L (unless assoc with clonal myeloid disorder)
CLINICAL FEATURES
Not all patients with proven bone marrow involvement will be symptomatic
Symptoms d/t release of skin mast cell mediators which have distant effects, partly local effects of mast cell infilration in other tissues i.e. GIT -
- N & V & D
- Fatigue
- “Brain fogginess”
- Headache
- Syncope
- Hypotension
- Palpitations
- Dyspnoea
- Wheezing
- Bone pain
- Bone cysts
- Osteoporosis, osteosclerosis, spontaneous fractures
Majority of adults with urticaria pigmentosa investigated —> will have indolent systemic mastocytosis
IX (bone marrow involvement) Persistent Serum tryptase > 20 ug/L (however this is not specific for mastocytosis, can be elevated in other conditions) Urinary MIMA (methyl imidazole acetic acid) or methylhistamine
COMPLICATIONS
Risk of progression of indolent systemic mastocytosis —> systemic mastocytosis with an assoc haem clonal non-mast cell disease, or aggressive systemic mastocytosis UNUSUAL —> no reliable marlers to identify who is at greatest risk flr this progression
Causes for persistent;y raised serum tryptase without skin lesions
HAEM Systemic mastocytosis CML MDS Myeloproliferative neoplasm Eosimiphilic and basophilic leukaemias
NON-HAEM REACTIVE
Chronic urticaria
Atopic disorders
OTHER
Renal failure
Normal healthy ppl
Monoclonal mast cell activation syndrome
Evidence of clonality on bone marrow bx, but do NOT meet criteria for systemic mastocytosis i.e. less than 3 minor criteria
Implies these patients are at risk of developing systemic mastocytosis
Patients should receive ongoing review
Mast cell activation syndrome
Patients who increasingly present with symptoms of mast cell mediator release but do NOT meet criteria for mastocytosis
Dx of exclusion
Mast cell mediator symptoms in at least 2 body systems
- Skin
- Resp
- CVS
- GI
Respond to anti-mediator therapies
Have evidende of mast cell mediator release during an episode
- Rise and fall in serum tryptase
- Increase in urinary breakdown products i.e. methylhistamine, MIMA, prostaglandin
Diagnostic work-up of children with suspected mastocytoma/urticaria pigmentosa
Don’t require extensive Ix if well
INITIAL ASSESSMENT Hx Examine for LN and HSM FBC + diff LFT Serum tryptase Skin bx to confirm clinical dx (if convincing Darier’s sign in very young children, solitary mastocytoma —> delay bx, observation is appropriate)
