Mastocytosis

 

Epidemiology and Etiology:

    • Rare
    • Cutaneous mastocytosis (CM)
      • >50% of all cases
      • predominantly children (lesions usually present <8 months after birth)
    • Systemic mastocytosis (SM)
      • Adults often
    • Etiology is unknown

 

Common sites:

    • Skin usually (80%)
      • Solitary mastocytoma – trunk and wrist
    • Systemic in 10-20%
      • Bone marrow
      • Liver
      • Spleen
      • Lymph nodes
      • GI tract
    • Peripheral blood rarely shows circulating mast cells

 

Gross features:

    • Skin lesions:
      • Multiple papules and small plaques widely distributed on skin
      • Roud to oval
      • Red-brown
      • Nonscaling
      • Darier sign:
        • Localized area of dermal edema and erythema (wheal) occus when lesion skin is rubbed
    • Solitary mastocytomas:
      • One or several nodules
      • Pink to tan-brown
      • Pruritic maybe
      • Blister formation maybe

 

Histologic features:

    • Multifocal clusters or aggregates of mast cells are required for diagnosis
      • 15 or more mast cells in aggregates
      • confirmed by special stains
    • Normal mast cells (see below for morphology in mastocytosis):
      • Round to oval nucleus
        • Clumped chromatin
        • Low N:C ratio
        • Absent or indistinct nucleoli
      • Moderately abundant oval or polygonal-shaped cytoplasm
        • Small, faintly-visible, slightly eosinophilic granules
        • Deeply basophilic granules on Giemsa stain
    • Mast cells in mastocytosis – morphology is variable:
      • More spindle-shaped
      • Reniform or indented nuclei
      • Abundant cytoplasm with sparse granules
        • May resemble histiocytes or lymphocytes of hairy cell leukemia or monocytoid B cell lymphoma
        • Granules may not be present even with Giemsa stain
      • Bi- or multi-lobated nuclei (usually indicates an aggressive proliferation
        • Commonly observed in mast cell leukemia (very rare)
      • Mitoses scarse even in aggressive variants
    • Skin:
      • Mild:
        • Subtle increase in the numbers of mast cells around superficial dermal blood vessels
        • Cells are spindle-shaped and stellate
      • Heavy:
        • Large numbers of tightly packed mast cells in the upper to mid dermis
        • Cells are round to oval
      • Aggregates of elongated or spindle-shaped mast cells
      • Typically fill the papillary dermis and extend as sheets and aggregates in to the reticular dermis
      • Often cells follow the vasculature
      • May see:
        • Fibrosis
        • Edema
        • Small numbers of eosinophils
    • Bone marrow:
      • Sharply demarcated deposits of mast cells in peritrabecular or perivascular locations or randomly distributed
      • Lesions composed of various proportions of mast cells, lymphocytes, eosinophils, and fibroblasts
        • Often central core of lymphocytes surrounded by mast cells with reactive eosinophilia at the margins
      • Spindled mast cells that abut against or stream along the bony trabeculae
      • May appear similar to fibrosis with fibroblasts
      • Significant fibrosis and thickening of adjacent bone frequently
      • Note that normal mast cells sprinkled throughout the marrow may be seen in a number of hematological disorders
      • If mast cells comprise >20% of cells in bone marrow aspirate, mast cell leukemia can be suspected
        • Mast cells should account for >10% of peripheral white cells in mast cell leukemia
    • Lymph node:
      • Mast cell infiltration, often paracortical
      • Hyperplasia of germinal centres
      • Small blood vessel hyperplasia
      • Eosinophilia
      • Plasmacytoiss
      • Collagen fibrosis
    • Spleen:
      • Mast cell infiltration, any compartment
      • May see in areas of infiltration:
        • Eosinophilia
        • Fibrosis
        • Plasmacytosis
    • GI Tract:
      • Multifocal, dense infiltrates of mast cells (>= 15 mast cells per HPF, in aggregates) (major criteria of systemic mastocytosis)
        • Band-like subepithelial infiltrate is a typical finding
        •  
        • Mean 209 mast cells per HPF in one study
        • CD25+ (9 of 9 cases in one study)
      • Expansion of lamina propria by oval to spindle-shaped cells
        • Numerous intermixed eosinophils commonly
      • Mild crypt architectural distortion maybe
        • Irregular crypt spacing and crypt foreshortening
      • > 20 mast cells per HPF may be considered abnormal and evidence for mastocytic enterocolitis (rare, rule out systemic mastocytosis)
        • Normal colon shows 13.6 +/- 3 per HPF)

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 Toluidene blue (granules)

Note: may fail if cells are degranulated 

 

Giemsa (granules)

Note: may fail if cells are degranulated

 

Tryptase

 All

good

Napthol ASD chloroacetate esterase

Not good

CD117

Not good

CD68

 

Not good

Chymase

Some

CD2 (expressed on neoplastic mast cells but not normal mast cells)

CD25 (expressed in neoplastic mast cells but not normal mast cells)

MPO (neg)

CD45

CD33

CD14 (neg)

CD15 (neg)

CD16 (neg)

 

Molecular features:

    • c-KIT
      • Some cases involve a clonal proliferation of mast cells with a point mutation of c-KIT at codon 816
      • Causes activation of a tyrosine kinase involved in their growth and differentiation

 

Other features:

    • Diagnostic criteria:
      •  Cutaneous mastocytosis (CM)
        • Typical skin lesions clinically  (UP/MPCM)
        • Typical histological infiltrates of mast cells in a multifocal or diffuse pattern in an adequate skin biopsy
        • Absence of features/criteria sufficient for SM
      • Systemic Mastocytosis (SM)
        • Major criterion and one minor criterion, or at least 3 minor criteria
        • Major criterion:
          • Multifocal, dense infiltrates of mast cells (>= 15 mast cells in aggregates) in bone marrow and/or other extracutaneous organ(s)
        • Minor criteria:
          • > 25% of any one of the following features in a mast cell infiltrate in the bone marrow or other extracutaneous organs
            • Spindle-shaped
            • Atypical morphology
            • Immature or atypical
          • Activating mutation at codon 816 of KIT in bone marrow, blood, or other extracutaneous organ
          • CD2 and/or CD25 expression (in addition to normal mast cell markers) of mast cells in bone marrow, blood, or other extracutaneous organs
          • Serum total tryptase persistently > 20 ng/mL (unless there is an associated clonal myeloid disorder, in which case this parameter is not valid)
      • Indolent systemic mastocytosis (ISM)
        • Meets criteria for SM
        • No “C” findings
        • No evidence of an associated non-mast cell lineage clonal haematological malignancy/disorder (AHNMD)
        • (Mast cell burden is low and skin lesions are almost invariably present)
        • Bone marrow mastocytosis:
          • ISM with bone marrow involvement but no skin lesions
        • Smouldering systemic mastocytosis
          • ISM with 2 or more “B” findings but no “C” findings
      • SM with associated clonal haematological non-mast cell lineage disease (SM-AHNMD)
        • Meets criteria for SM
        • Meets criteria for an associated, clonal haematological non-mast cell lineage disorder
          • (MDS, MPN, AML, lymphoma, or other distinct entity in the WHO classification)
      • Aggressive systemic mastocytosis (ASM)
        • Meets criteria for SM
        • One or more “C” findings
        • No evidence of mast cell leukemia
        • (Usually without skin lesions)
        • Lymphadenopathic mastocytosis with eosinophilia
          • Progressive lymphadenopathy
          • Peripheral blood eosinophilia
          • (often with extensive BM involvement and hepatosplenomegaly)
          • (usually without skin lesions)
          • No PDGFRA rearrangement
      • Mast cell leukaemia (MCL)
        • Meets criteria for SM
        • Diffuse BM infiltration (usually compact) by atypical, immature mast cells
        • >= 20% mast cells in aspirate smears
        • (typically >= 10% mast cells in PB) (if not, it is aleukaemic variant)
        • (usually without skin lesions)
      • Mast cell sarcoma (MCS)
        • Unifocal mast cell tumour
        • No evidence of SM
        • No skin lesions
        • Non-destructive growth pattern
        • Low-grade cytology
      • “B” findings:
        • > 30% mast cells (focal, dense aggregates) in BM biopsy, AND/OR
          • Serum total tryptase level > 200 ng/mL
        • Dysplasia or myeloproliferation in non-mast cell lineage(s) AND
          • insufficient criteria for definitive diagnosis of a haematopoietic neoplasm (AHNMD) AND
          • normal or only slightly abnormal blood counts
        • Hepatomegaly without impairment of liver function, AND/OR
          • Palpable splenomegaly without hypersplenism, AND/OR
          • Lymphadenopathy on palpation or imaging
      • “C” findings:
        • One or more cytopenia (ANC < 1.0x109/L, Hb < 10 g/dL, or platelets < 100x109/L)
        • Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
        • Skeletal involvement with large osteolytic lesions and/or pathological fractures
        • Palpable splenomegaly with hypersplenism
        • Malabsorption with weight loss due to GI mast cell infiltrates
    • spectrum of disorders
    • associated clonal hematopoietic, non-mast cell lineage disorder (AHNMD) may be found in 20-30% of SM
    • Clinical features of systemic mastocytosis:
      • Constitutional symptoms – fatigue, weight loss, fever, sweats
      • Pruritus and flushing triggered by:
        • Certain foods
        • Temperature changes
        • Alcohol
        • Certain drugs (morphine, codeine, aspirin)
      • Watery nasal discharge
      • Results of release of histamine, eicosanoids, proteases, heparin
        • Peptic ulcer disease
        • diarrhea
        • GI or nasal bleeding (rare) (anticoagulant effects of heparin release)
        • Abdominal pain
        • Syncope
        • Hypertension
        • Headache
        • Hypotension
        • Tachycardia
        • Respiratory symptoms
      • Bone symptoms:
        • pain (osteoblastic and osteoclastic involvement)
        • Fractures
        • arthralgia
      • dermatographism
      • physical findings may include:
        • splenomegaly
        • lymphadenopathy
        • hepatomegaly
      • bloodwork:
        • serum total tryptase is useful (elevated in SM) (>20ng/ml)
        • anemia
        • leukocytosis or leukopenia
        • thrombocytopenia or thrombocytosis
        • bone marrow failure may occur
        • eosinophilia (may be marked and mimic hypereosinophilia syndrome)
    • prognosis
      • good with localized cutaneous disease
        • CM usually regresses spontaneously before or during puberty
      • may be poor with systemic disease
      • skin lesions when present usually imply an indolent course (major prognostic indicator)
      • mast cell leukemia is very aggressive

 

References:

    • Robbins 2005
    • WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2001, 2008)
    • Odze & Goldblum, eds.  Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, 3rd ed.  (2015)