Mastocytosis

Definition

Mastocytosis is a term collectively used for a group of disorders in which there is abnormal accumulation of mast cells in one or multiple organs.

Epidemiology

• cutaneous mastocytosis (CM): accounts for 80% of cases of mastocytosis. It most commonly seen in children, 80% of whom are less than 6 months old. In adults usually occurs in the third or fourth decade.

• systemic mastocytosis (SM); usually presents after the third decade of life.

Diagnostic criteria

• cutaneous mastocytosis: children, typical skin lesions with features of urticaria pigmentosa, diffuse cutaneous mastocytosis or solitary cutaneous mastocytoma, confirmed by a skin biopsy.

• systemic mastocytosis: any age, requires one major and one minor criterion, or three minor criteria.

major criterion: multifocal dense infiltrates of mast cells in extracutaneous biopsy, confirmed by special stains

minor criteria:

a: in an extracutaneous biopsy or bone marrow smear, more than 25% of the mast cells have a spindle-cell or atypical morphology

b: detection of c-kit mutation at codon 816

c: extracutaneous mast cells that co-express (CD2 or CD25) and CD117

d: serum total tryptase persistently >20ng/ml, in the absence of a myeloid disorder

• indolent systemic mastocytosis: no "B" or "C" findings and no associated clonal haematological disorder

"B" findings;

1. bone marrow shows >30% infiltration by mast cells OR serum total tryptase > 200 ng/ml.

2. signs of dysplasia/myeloproliferation in non-mast cell lineage but insufficient for a definite diagnosis of a haematopoietic neoplasm by WHO criteria.

3. hepatomegaly without impairment of liver function OR splenomegaly without hypersplenism OR lymphadenopathy.

"C" findings;

1. bone marrow dysfunction manifested by a cytopenia (ANC < 1.0.10⁹/l OR haemoglobin<10g/dl OR platelets <100.10⁹/l) but no frank non-mast cell haemopoietic neoplasm.

2. palpable hepatomegaly with impaired liver function, ascites or portal hypertension.

3. skeletal involvement with large foci of osteolysis or pathological fractures.

4. palpable splenomegaly with hypersplenism

5. malabsorption with weight loss due to gastrointestinal mastocytosis.

•  bone marrow mastocytosis: indolent SM with bone marrow involvement with no cutaneous involvement

• smouldering SM: SM with 2 or more "B" finding but no "C" findings.

"B" findings;

1. bone marrow shows >30% infiltration by mast cells OR serum total tryptase > 200 ng/ml.

2. signs of dysplasia/myeloproliferation in non-mast cell lineage but insufficient for a definite diagnosis of a haematopoietic neoplasm by WHO criteria.

3. hepatomegaly without impairment of liver function OR splenomegaly without hypersplenism OR lymphadenopathy.

"C" findings;

1. bone marrow dysfunction manifested by a cytopenia (ANC < 1.0.10⁹/l OR haemoglobin<10g/dl OR platelets <100.10⁹/l) but no frank non-mast cell haemopoietic neoplasm.

2. palpable hepatomegaly with impaired liver function, ascites or portal hypertension.

3. skeletal involvement with large foci of osteolysis or pathological fractures.

4. palpable splenomegaly with hypersplenism

5. malabsorption with weight loss due to gastrointestinal mastocytosis.

• SM with associated clonal haematological non-mast cell lineage disease (SM-AHNMD): SM associated with MDS, CMPD, AML or lymphoma with meets criterion for a distinct entity in WHO classification.

• aggressive SM: SM with one or more "C" findings but no associated clonal haematological disorder and no evidence of mast cell leukaemia

"C" findings;

1. bone marrow dysfunction manifested by a cytopenia (ANC < 1.0.10⁹/l OR haemoglobin<10g/dl OR platelets <100.10⁹/l) but no frank non-mast cell haemopoietic neoplasm.

2. palpable hepatomegaly with impaired liver function, ascites or portal hypertension.

3. skeletal involvement with large foci of osteolysis or pathological fractures.

4. palpable splenomegaly with hypersplenism

5. malabsorption with weight loss due to gastrointestinal mastocytosis.

• lymphadenopathic mastocytosis with eosinophilia: a blood eosinophilia, often with extensive bone involvement and hepatosplenomegaly but usually without cutaneous lesions.

• mast cell leukaemia: SM with a biopsy showing diffuse interstitial infiltration by atypical mast cells, a bone marrow aspirate with at least 20% mast cells and mast cells accounting for at least 10% of peripheral blood white cells.

  • aleukaemic mast cell leukaemia; as above but with mast cells accounting for less than 10% of peripheral blood white cells.

• extracutaneous mastocytoma: no evidence of SM, no skin lesions, unifocal mast cell tumour with a non-destructive growth pattern and low-grade cytology. This entity is exceedingly rare, most often affecting the lung.

• mast cell sarcoma: no evidence of SM, no skin lesions, unifocal mast cell tumour with a destructive growth pattern and high-grade cytology. There may be metastases or evolution to mast cell leukaemia.

Positivity for CD2 or CD25 on flow cytometry has been described as highly diagnostic of systemic mastocytosis⁵.

Clinical features

• cutaneous mastocytosis: the lesions of all forms may urticate and are commonly pigmented. There is no systemic involvement or organomegaly.

  • urticaria pigmentosa: the most common form and may be seen in children or adults

  • diffuse cutaneous mastocytosis: almost exclusive to children

  • mastocytoma of skin: usually occurs as a solitary lesion in infants.

•  

• systemic mastocytosis

signs and symptoms:

• constitutional; fatigue, fever, weight loss
  

• skin manifestations; urticaria, pruritus, dermatographia
  

• mediator-related; abdominal pain, flushing, syncope, hypertension or hypotension, headache, tachycardia, respiratory symptoms
  

• bone-related; pain, fractures, arthralgia
  

• splenomegaly, less often lymphadenopathy, hepatomegaly
  

• haematological; anaemia, leukocytosis or leukopenia, thrombocytosis or thrombocytopenia. eosinophilia may be extreme. In 20-30% of SM, there is an associated clonal non-mast cell haematopoietic disorder (AHNMD).

Histopathology

The infiltrating mast cells may be loosely scattered or form obvious clusters. Staining with Giemsa or for mast cell tryptase is strongly recommended for confirmation of their identity.

• cutaneous mastocytosis:

  • urticaria pigmentosa: in children, aggregates of spindled mast cells fill the papillary dermis and extend into the reticular dermis, often around vessels. In adults, the number of mast cells is smaller, so that on occasion multiple sections need to be examined to identify an increase above the normal number, and there is more often an association with telangestasia.

  • diffuse cutaneous mastocytosis; There is a band of mast cells in the papillary and upper reticular dermis. In nodular forms, it is indistinguishable form cutaneous mastocytoma.

  • mastocytoma of skin: sheets of mature mast cells fill the papillary and reticular dermis. They may extend into the he deep dermis and subcutis.

• bone marrow: There are usually multiple sharply demarcated aggregates of mast cells, which may be paratrabecular, perivascular or randomly distributed. Often the lesions consist of a central core of lymphocytes, surrounded by mast cells, with eosinophils at the periphery. In other cases, spindled mast cells are diffusely distributed, in association with marked fibrosis. An assessment of any associated haematological disorder must be made. In the context of mast cell leukaemia, there is a diffuse infiltrate of atypical mast cells, which may be poorly granulated, have lobated nuclei and prominent nucleoli.

• lymph node: the infiltrate may be generalized and diffuse or paracortical. It may be accompanied by hyperplasia of germinal centres and blood vessels, eosinophilia, plasmacytosis or fibrosis.

• spleen: the infiltrate may be in any compartment and may be accompanied by eosinophilia, plasmacytosis or fibrosis.

• liver; small aggregates of mast cells may be present, accompanied by fibrosis but very rarely full cirrhosis.

• skeletal; there is commonly osteosclerosis, but this may be combined with lytic lesions.

Immunohistochemistry

	reactive bone marrow	myelogenous neoplasms	myelomastocytic leukaemia
number of cases	545	165	55
CD2	negative5	negative5	negative5
CD25	negative5	negative5	negative5
CD117	positive5	minority positive5	positive5
chloroacetate esterase	positive5	majority positive5	positive5
Tryptase	positive5	negative5	positive5

	generally in mastocytosis	systemic indolent mastocytosis	systemic mastocytosis with associated clonal haemotologic non-mast cell lineage disease	aggressive systemic mastocytosis	mast cell leukaemia	isolated bone marrow mastocytosis
napthol ASD chloroacetate esterase	positive (may be negative poorly granulated neoplastic mast cells)0
tryptase	positive 2/23, 14/144 0	19/191			1/11	2/21
chymase	positive in a subpopulation0
lysozyme	positive 7/144
CD2	positive: negative in normal mast cells0, the proportion of positive cells is less than for CD255	13/191, 35/435	11/205	2/75	1/11, 2/35	2/21
CD14	negative0
CD15	negative 0/23, 0	0/191			0/11	0/21
CD16	negative0
CD20	negative 0/144
CD25	positive (negative in normal mast cells)0	42/43 (The one negative case also lacked a c-kit mutation, although fulfilling the morphological criteria for systemic mastocytosis.)5	20/205	7/75	3/35
CD29		7/171			1/11	0/11
CD30		0/181			0/11	0/11
CD31		0/171				0/11
CD33	positive0
CD34	negative 0/23, 0	0/181			0/11	0/21
CD45	positive0	18/181			1/11	2/21
CD51		7/141
CD56		0/141				0/21
CD68 (PG-M1)	positive 14/144, 0	18/181			1/11	2/21
CD117	positive 2/23,0	19/191			1/11	2/21
bcl-xL		18/181			1/11	2/21
bcl-2		0/171			<5% of cells positive1	0/21
HLA-DR		17/171			1/11	2/21
myeloperoxidase	negative 0/124	0/121			0/11	0/21

Cytogenetics

Point mutations in c-kit have been demonstrated in a very high proportion of cases of systemic mastocytosis⁵ and a new classification based on the type of mutation has been proposed. The predominant mutation in adult sporadic mastocytosis is Asp816Val, resulting in constitutive phosphorylation and activation of c-kit². This mutation is rarely seen in paediatric cutaneous mastocytosis; when it is, the presentation and course are atypical. Myeolmastocytic leukaemia lacks c-kit mutations⁵.

Differential diagnosis

reactive mast cell hyperplasia. Reactive mast cells are positive for tryptase but negative for CD2¹ and CD25⁵. CD25 Immunoreactivity in tissue sections has been proposed as highly reliable for the diagnosis of systemic mastocytosis⁵. Megakaryocytes and some T-lymphocytes stain faintly to moderately for CD25, giving an internal control⁵.

• differentiation of mast cells from basophils, especially in myelogenous malignancies with immature basophils: both are positive for tryptase but basophils are negative for CD117.

  myeloid neoplasms with clonal mast cells

• AML, may be positive for CD117²

Prognosis

• childhood cutaneous mastocytosis: usually regresses spontaneously before or during puberty.
  

• adult cutaneous mastocytosis: rarely regresses.
  

• systemic mastocytosis: not curable and of variable prognosis. Skin involvement is associated with an indolent course.

  • indolent mastocytosis: usually normal life expectance.
    
  • mast cell sarcoma and mast cell leukaemia: survival often very short.
    
  • with an associated haematological malignancy: course is that of the associated malignancy.

References

⁰World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

¹Jordan, J. H., Walchshofer, S., Jurecka, W., Mosberger, I., Sperr, W. R., Wolff, K., Chott, A., Buhring, H. J., Lechner, K., Horny, H. P., Valent, P. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L) Hum Pathol 2001;32:545-552.

²Gibson, P. C., Cooper, K. CD117 (KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol 2002;9:65-69.

³Sperr, W.R., Walchshofer, S., Horny, H.P., Fodinger, M., Simonitsch, I., Fritsche-Polanz, R., Schwarzinger, I., Tschachler, E., Sillaber, C., Hagen, W., Geissler, K., Chott, A., Lechner, K. and Valent, P. Systemic mastocytosis associated with acute myeloid leukaemia: report of two cases and detection of the c-kit mutation Asp-816 to Val. Br J Haematol 1998;103:740-9.

⁴Li, W.V., Kapadia, S.B., Sonmez-Alpan, E. and Swerdlow, S.H. Immunohistochemical characterization of mast cell disease in paraffin sections using tryptase, CD68, myeloperoxidase, lysozyme, and CD20 antibodies. Mod Pathol 1996;9:982-8.

⁵Sotlar, K., H. P. Horny, et al. (2004). "CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens." Am J Surg Pathol 28(10): 1319-25.

This page last revised 28.12.2002.