Diagnosis and Classification
CM is diagnosed by the presence of typical skin lesions and a positive skin biopsy demonstrating characteristic clusters of mast cells. The preferred method of diagnosing is via bone marrow biopsy. The World Health Organization (WHO) has established criteria for diagnosing SM, restated below:
Multifocal dense infiltrates of mast cells (>15 in aggregate) in tryptase-stained biopsy sections of the bone marrow or of another extracutaneous organ.
1. In biopsy of bone marrow or other extracutaneous organ(s), more than 25% of the mast cells show abnormal morphology (that is, are atypical mast cell type I or are spindle-shaped) in multifocal lesions in histological examination.
2. Detection of a point mutation at codon 816 in the KIT receptor gene. This may be found in bone marrow, blood or other internal organ.
3. KIT-positive mast cells in bone marrow, blood, or other internal organs are found to express CD2 and/or CD25.
4. Serum total tryptase level persistently greater than 20 ng/mL. This criterion cannot be used if the patient has a clonal non-mast cell associated hematological disorder.
The presence of one major and one minor criteria or three minor criteria constitute the diagnosis of systemic mastocytosis. Diagnostic techniques differentiate mastocytosis into the following categories:
Urticaria pigmentosa (UP) --- also known as maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma.
Indolent Systemic Mastocytosis:
These patients fit the criteria for systemic mastocytosis and may have an enlarged liver or spleen. The GI tract may also be affected. The majority of adult patients fit into this category. Mediator-related symptoms are common, but the grade of bone marrow infiltration is low, usually less than 5 percent. Mast cells usually co-express CD2 and CD25 with KIT and contain the KIT mutation D816V. In most patients the serum tryptase concentration exceeds 20 ng/mL, but a normal level of tryptase does not rule out either mastocytosis or another mast cell activation disorder. Treatment usually includes mediator-targeting drugs, including antihistamines, but does not usually require cytoreductive agents, except for considering IFN-2b for severe osteoporosis.
Isolated Bone Marrow Mastocytosis (BMM) and Smouldering Systemic Mastocytosis (SSM) are subvariants of indolent SM. BMM is characterized by absence of skin lesions, lack of multiorgan involvement, and low or normal serum tryptase level. BMM patients may or may not require treatment for mediator-related symptoms. In SSM two or three of the following, which indicate high burden of mast cells may be observed:
1. Infiltration grade is greater than 30 percent in bone marrow and total tryptase levels greater than 200ng/mL.
2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for an MDS or MPD.
3. Organomegaly: Palpable hepatomegaly, splenomegaly, or lymphadenopathy (on CT or ultrasound) greater than 2 cm without impaired organ function.
Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast Cell Lineage Disease (AHNMD)
These patients for the criteria for systemic mastocytosis and they fit the WHO creiteria for myelodysplastic syndrome, myeloproliferative syndrome, acute myeloid leukemia, or non-Hodgkin’s lymphoma. These patients often do not have urticaria pigmentosa-like skin lesions. Successful treatment of the hematologic disorder has not been shown to change or improve their systemic mastocytosis.
Agressive Systemic Mastocytosis:
In this rare subvariant, these patients fit the criteria for systemic mastocytosis; and their bone marrow biopsy reveals abnormal blood cell formation that does not fit the WHO criteria for AHNMD as listed above. These patients are characterized by bone marrow aspirate smears showing less that 20% of the cells to be mast cells, no mast cells identified in the circulating blood, and the presence of at least one finding below:
1. An abnormal blood count;
2. An enlarged liver, and liver function is impaired;
3. An enlarged spleen, and its function is abnormal;
4. Malabsorption with weight loss is present and is due to mast cell infiltration in the GI tract that interferes with its normal function;
5. Bone involvement is seen with large areas of calcium loss and/or pathologic fractures; or
6. Other internal organs are affected by mast cell infiltrates with impairment of organ function.
Mast Cell Leukemia:
In this rare subvariant, these people fit the criteria for systemic mastocytosis, and a bone marrow aspirate smear shows that 20% or more of the cells are mast cells of 10% or more mast cells are seen in circulating blood. The shape of mast cells and their nuclei have malignant features.
Mast Cell Sarcoma:
Mast cell sarcoma is an extremely rare tumor. In three cases reported so far, the tumor has been located in the larynx, in the colon, and inside the skull. Prognosis is very poor. People with mast cell sarcoma have a single tumor made up of abnormal mast cells. They do not fit the criteria for systemic mastocytosis, they have no skin lesions, and pathological examination of the tumor shows it to be highly malignant with an aggressive growth pattern.
This is a very rare finding. Patients with extracutaneous mastocytoma do not fit the criteria for systemic mastocytosis, they have no skin lesions, and pathological examination of the lesion shows it to be made up of normal or nearly normal appearing mast cells with a non-aggressive growth pattern.
When aggressive disease or an associated hematological disorder is suspected, further evaluation of the patient may include:
1. X-ray or CT scan of the chest, looking for evidence of significantly enlarged lymph nodes (greater than 2 cm in diameter);
2. X-ray of the skeletal system, looking for osteoporosis, osteosclerosis, or areas where calcium has been completely lost from bone;
3. CT scan or ultrasound of the abdomen, looking for enlarged liver or spleen, enlarged lymph nodes, or the collection of fluid; and
4. Endoscopy and biopsy of the GI tract, looking for evidence of mast cell infiltration, ulcers, or areas of bleeding.
Other tests may be done, as indicated, if there is a suspected hematologic disorder or evaluate the individual patient’s symptoms. By contrast, further testing should be kept to a minimum when the disease seems to be confined to the skin, and in most pediatric cases.