Learning Resources

Diagnosing and Classifying Mast Cell Activation Syndrome (MCAS)

A diagnosis of mast cell activation syndrome (MCAS) is considered when a patient:^2,3

• Exhibits symptoms that do not meet the criteria for systemic mastocytosis
• Suffers from recurring and severe anaphylactic-like episodes that involve more than one organ system
• Has a positive response to mast cell stabilizing or mediator medications
• Experiences an increase of 20% or greater of blood serum tryptase levels from baseline between 3 and 4 hours after a mast cell reaction.

Monoclonal Mast Cell Activation Syndrome (MMAS)

Patients with MMAS will not meet the full criteria for systemic mastocytosis. A bone marrow aspirate or a peripheral blood test will reveal clonal mast cells with a KIT mutation, usually KIT D816V.²

Secondary Mast Cell Activation Syndrome (MCAS)

Most patients with MCAS will experience mast cell overstimulation to an IgE-dependent allergen or substance. Patients with MCAS present with an underlying allergic condition, inflammatory condition, or hypersensitivity disorder that causes mast cell activation. A bone marrow aspirate or a blood test will not reveal the presence of monoclonal mast cells.2,3

Idiopathic Mast Cell Activation Syndrome (IMCAS)

Patients with IMCAS meet the criteria for MCAS, including:

• Recurring and severe anaphylactic-like episodes that involve more than one organ system
• Positive response to mast cell stabilizing or mediator medications anaphylaxis-type symptoms

Patients with IMCAS do not present with an underlying allergic condition, inflammatory condition, or hypersensitivity disorder. A bone marrow aspirate or peripheral blood test does not reveal monoclonal mast cells or clonal mast cells with a KIT mutation.^2,3

Before diagnosing IMCAS, physicians should rule out other autoimmune diseases, such as:⁴

• Pheochromocytoma (a hormone-secreting tumor that generally develops in the adrenalglands)^5,6
• Neuroendocrine tumors and carcinoid syndrome (tumors that release the same mediators as mast cells and can mimic mast cell activation syndrome)^7-10

Diagnosing Hereditary Alpha-Tryptasemia (HαT)

Hereditary Alpha-Tryptasemia (HαT) is diagnosed with genetic testing on a peripheral blood sample to look for additional copies of the TPSAB1 gene. Since the HαT genetic trait can cause elevated tryptase serum levels, which can cause symptoms of mast cell activation, all individuals who have elevated tryptase serum levels should be tested for HαT. Keep in mind that only an estimated one-third of people with HαT experience symptoms of mast cell activation.^11,12

Diagnosing Cutaneous Mastocytosis

A diagnosis of cutaneous mastocytosis can generally be made with an examination of the skin. The three sub-types of cutaneous mastocytosis include:¹³

• Urticaria pigmentosa/maculopapular cutaneous mastocytosis (dark, itchy patches of skin that are tan or brown in color
• Solitary cutaneous mastocytoma (a nodule, papule, plaque, or module that is yellow-brown or reddish-brown in color)¹⁴
• Diffuse cutaneous mastocytosis

A punch skin biopsy can be used to confirm cutaneous mastocytosis, although it cannot confirm systemic mastocytosis. The skin biopsy should measure 3mm.¹⁵

Diagnosing and Classifying Systemic Mastocytosis

The World Health Organization outlines the standard for diagnostic criteria for mastocytosis. In 2019, the WHO updated these criteria.¹³

A diagnosis of systemic mastocytosis can be considered when:¹³

• The major criterion plus one minor criterion are met, or
• Three minor criteria are met

Major criterion

1. Multifocal, dense clusters of 15 or more mast cells in an extracutaneous organ (an organ other than the skin, such as the bone marrow, liver, spleen, lymph nodes, etc.).

Minor criteria

1. For bone marrow smears, greater than 25% of detected mast cells are either immature or atypical (abnormal size, shape, or color). For bone marrow and other organ biopsies, greater than 25% of mast cells seen in the biopsy have atypical morphology (abnormal shape, most commonly, a spindle shape).
2. Molecular testing reveals a KITD 816V mutation or any other KIT mutation in a sample from the blood, bone marrow, or another organ.
3. Flow cytometry and/or immunohistochemistry reveal abnormal mast cell CD25 markers (clusters of differentiation). May occur with or without CD2 markers.
4. A serum tryptase test with total tryptase blood levels greater than 20 ng/mL. This criterion is not valid if the patient has an associated myeloid neoplasm (a tumor of the bone marrow).

Classification of Systemic Mastocytosis

“B” and “C” findings are utilized to diagnose subtypes of systemic mastocytosis.¹³

“B” Findings

1. Greater than 30% infiltration of mast cells in a bone marrow biopsy and a serum tryptase test that shows total tryptase levels higher than 200 ng/mL.
2. Hepatomegaly (enlarged liver) that does not affect organ function, palpable splenomegaly (enlarged spleen) without hypersplenism (overactive spleen), and/or lymphadenopathy (swelling of the lymph nodes) that is identified either by palpation or imaging studies.
3. Indications of dysplasia (abnormal cell development) or myeloproliferation (abnormal blood cell growth within the bone marrow) with not enough evidence to make a definitive diagnosis of an associated hematological neoplasm (AHN). Blood tests show normal or only slightly abnormal blood counts.

“C” Findings

1. Hepatomegaly (enlarged liver) with organ function impairment, ascites (fluid build-up in the abdomen), and/or portal hypertension (elevated blood pressure in the major vein that leads to the liver).
2. Palpable splenomegaly (enlarged spleen) with hypersplenism (overactive spleen).
3. Weight loss due to malabsorption caused by mast cell infiltration of the gastrointestinal tract.
4. Neoplastic (cancerous) mast cell infiltration of the bone marrow that causes one or more cytopenia (low blood cell count). Cytopenia may manifest as an ANC (absolute neutrophil count) less than 1.0 × 109/L, hemoglobin (Hgb) less than 10 g/dL, and/or platelet count less than 100 × 109/L.
5. Osteolytic lesions (damaged bone) that may present with or without a pathological fracture. Pathological fractures associated with osteoporosis do not fit the criteria as a “C” finding

All sub-types of systemic mastocytosis must meet the criteria for systemic mastocytosis in addition to the criteria defined below.

Indolent systemic mastocytosis (ISM)

• Does not present “C” findings
• No evidence of associated hematological neoplasm

Smoldering systemic mastocytosis (SSM)

Presents the same criteria for ISM in addition to the following:

• Two or more “B” findings
• No “C” findings
• Generally, there is a high burden of mast cells

Systemic mastocytosis with an associated hematological neoplasm (SM-AHN)

In addition to meeting the criteria for systemic mastocytosis, also meets the criteria for an associated hematological neoplasm, per classification outlined by the WHO.

Aggressive systemic mastocytosis (ASM)

• Meets the systemic mastocytosis criteria
• Presents with one or more “C” findings
• Bone marrow aspirate smear: Less than 20% mast cell infiltration.
• Does not present with evidence of mast cell leukemia

Mast cell leukemia (MCL)

Diagnosed with the following studies:

• Bone marrow biopsy: Dense infiltration of atypical, immature mast cells.
• Bone marrow aspirate smear: 20% or greater mast cell infiltration.
• Peripheral blood test: Mast cells account for 10% or greater of the amount of peripheral blood white cells.
• Aleukemic MCL variant: Presents with less than 10% of circulating mast cells.

Mast cell sarcoma (MCS)

Mast cell sarcoma does not present with evidence of systemic mastocytosis. This diagnosis generally presents as a localized destructive growth pattern. MCS is diagnosed using high-grade cytology.

KIT Mutation Indications for Treatment

The KIT D816V mutation affects approximately 90% of patients with systemic mastocytosis.¹⁶

Knowing the patient’s KIT D816V mutation status is important because this mutation is resistant to certain therapies used to treat mast cell disease, such as:^17,18

• Imatinib mesylate (sold under the brand names Gleevec or Glivec)
• Nilotinib (sold under the brand name Tasigna)
• Tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib

Learn more about the treatment and management of mast cell disease.

When Should Patients Be Referred to a Specialist?

If a general practitioner suspects that a patient may have mast cell involvement, refer the patient to a board-certified allergist or immunologist.