Diagnosis of mast cell diseases

There seems to be a lot of confusion regarding diagnosis of mast cell diseases, so I figured I’d do a review.

Cutaneous mastocytosis (CM) is diagnosed by skin biopsy.  Urticaria pigmentosa (UP), also called maculopapullar cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM) and telangiectasia macularis eruptive perstans (TMEP) are types of cutaneous mastocytosis.  They each present with a rash and may have accompanying systemic symptoms. 
Mastocytoma of the skin is also diagnosed by skin biopsy.
Systemic mastocytosis (SM) has the following diagnostic criteria:
Major:
1.       Multifocal, dense infiltrates of mast cells (15 or more in an aggregate) detected in sections of bone marrow and/or extracutaneous organ. 
Minor:
1.       In biopsy sections, more than 25% of mast cells in infiltrated area are spindle-shaped or have atypical morphology; or, of all mast cells in bone marrow aspirate smears, more than 25% are immature of atypical. 
2.       Detection of Kit mutation at codon 816 in bone marrow, blood or other extracutaneous organ.
3.       Mast cells in bone marrow, blood or other extracutaneous organ that co-express CD117 with CD2 and/or CD25.
4.       Serum total tryptase persistently >20 ng/mL (if there is not a clonal myeloid disorder.)
SM is diagnosed if a patient has either one major and one minor criteria, or three minor criteria.  So let’s look at how this plays out.
A patient with mast cell symptoms gets a bone marrow biopsy.  It shows more than 25% abnormal mast cells in the section.  They are CKIT negative, have a serum tryptase of 2, and do not express CD2/CD25.  They are diagnosed with SM.
A patient has a biopsy that does not show dense infiltrates.  All their mast cells are shaped normally.  In blood tests, their mast cells are found to express CD2.  They are CKIT+, also from blood.  Their serum tryptase is 28.  They are diagnosed with SM.
A patient has a biopsy that shows dense infiltrates, but they have less than 25% abnormal mast cells and their mast cells do not express CD2/CD25.  They are CKIT- and have a serum tryptase of 18.  They are not diagnosed with SM.
A few things to keep in mind:
Most people with SM are diagnosed by bone marrow biopsy, but a biopsy from any non-skin organ showing mast cell infiltration as described above can be used.  This means if you have a positive lung biopsy, liver biopsy, whatever, you may not necessarily need a bone marrow biopsy. 
It can take up to six bone marrow biopsies to diagnose SM in a patient who has had it the entire time.  This is because there is no way to know where the mast cells will cluster.  A negative bone marrow biopsy does not necessarily mean that you do not have SM.  Hence the minor criteria.
The CKIT test looks for a specific mutation, the D816V mutation.  There are other mutations found in codon 816.  You may have a mutation but test CKIT- because you do not have the D816V mutation.  Also, the blood test for CKIT is not always reliable.  The test way to test this is from a bone marrow sample.  You could test CKIT- in blood and then test CKIT+ in bone marrow.
The serum tryptase criterion refers to persistent baseline level tryptase, not reaction level tryptase. 
So let’s say you have a negative bone marrow biopsy and a blood test that shows you are CKIT+ and have mast cells expressing CD2/CD25.  What do you have?  You have monoclonal mast cell activation syndrome (MMAS.)  MMAS is diagnosed in patients who have one or two of the minor criteria for systemic mastocytosis.
Let’s say you have a negative bone marrow biopsy and blood work that shows normal mast cells and tryptase below 20, but you have systemic symptoms.  What do you have?  You probably have MCAS (mast cell activation syndrome.)  There are some other tests for that.  24 hour urine tests are usually done to measure the levels of histamine metabolites and prostaglandin D2 metabolites.
The following are the diagnostic criteria for MCAS:
1.       Episodic symptoms consistent with mast cell mediator release affecting two or more organ systems: skin (urticarial, angioedema, flushing); GI (nausea, vomiting, diarrhea, cramping); cardiovascular (fainting or near fainting due to low blood pressure, rapid heartbeat); respiratory (wheezing); naso-ocular (itching, nasal stuffiness, red eyes.)
2.       A decrease in frequency or severity; or resolution of symptoms with antihistamines, leukotriene inhibitors or mast cell stabilizers.
3.       Evidence of elevation of urinary or serum marker of mast cell activation: Documentation of elevation of marker during a symptomatic period on at least two occasions, or if baseline tryptase is persistently above 15 ng.  This includes urinary histamine and prostaglandin D2.
4.       Clonal and secondary disorders of mast cell activation ruled out.
MCAS is a diagnosis of exclusion.  It is the diagnosis you receive if you have mast cell symptoms that are ameliorated with mast cell medications if you do not meet the criteria for any other mast cell disease.
Back to SM.  Let’s say you’re positive for SM.  Now what?
They will determine if you have other important markers of disease severity.  These are called B and C findings.  They are as follows:
B findings:
1.       Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/ml).
2.       Hypercellular marrow, signs of overproduction or abnormal development of blood cells, normal or slightly abnormal blood counts that are not abnormal enough to be considered an associated hematologic disorder.
3.       Swelling of the liver that can be felt manually, no free fluid or signs of dysfunction, persistently swollen glands, swelling of the spleen that can be felt manually without signs of dysfunction.
If you have two or more B findings, you have SSM (smoldering systemic mastocytosis.) 
C findings:
1.       Unusual blood counts (low ANC, low Hb, low platelets)
2.       Swelling of the liver that can be felt manually, with impaired liver function, free fluid and/or portal hypertension.
3.       Large osteolytic lesions and/or pathological fractures.
4.       Swelling of the spleen with impaired function.
5.       Malabsorption with weight loss and/or low albumin.
If you have one or more C finding, you have ASM (aggressive systemic mastocytosis.)
How are these B and C findings identified?  Bone marrow biopsy, blood tests and imaging (ultrasounds, MRI, etc.) 
If you have SM and one B finding, or no B findings, you have indolent systemic mastocytosis (ISM.) 
If your bone marrow biopsy shows significant overproduction or abnormal development of a cell type that is not a mast cell, you may be diagnosed with SM-AHNMD (systemic mastocytosis with associated hematologic non-mast cell lineage disease.)  People with this type of SM also have another blood disorder, such as chronic myelogenous leukemia, myelodysplasia, etc.  In these patients, serum tryptase is not reliable to assess mast cell burden.  
Mast cell leukemia (MCL) is extremely rare.  It is diagnosed by >20% mast cells on the bone marrow aspirate smear.   
Mast cell sarcoma is a very aggressive form of sarcoma.  It is diagnosed by biopsy of the tumor.  People with these tumors quickly developed mast cell leukemia.  There have only been three cases reported in literature.  To be clear, this is NOT the same as mastocytoma.  Mastocytomas are benign.
I think I got everything.  Any questions?  Ask in the comments.