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 known cases in humans. To be
clear, this is NOT the same as mastocytoma.
Mastocytomas are benign.
I think I got everything.
Any questions? Ask in the
comments.
You have once again cleared it all up! Thank you!
ReplyDeleteThank you for your blog... your information... your wisdom! One question here, what does a positive Darier's sign mean, or not mean? Thank you!
ReplyDeleteThis is a good question. I'll do a post on Darier's sign tomorrow.
ReplyDeleteJust signed up for the email subscription! :)
ReplyDeleteI started having allergic symptoms about 6 months ago. (Itching everywhere,Hives,Acid Reflux,and increased asthma attacks) the only relief I've had is taking 360mg. Of Alegra, proton pump inhibitors,Inhalors and prednisone) Though I still itch a bit and still have dermitagraphia. Not sure how much to read into this but my Alergist had my Dermatologist Re-Run one of my skin biopsies that previously had come back as "inconclusive" to look for mast cells and as it turns out there was a "Slight Increase" in Mast cells and added possible (T.E.M.P.) to the diagnosis which is a form of Mastocytosis apparently. Found a new Hemotologist to see me out of University of Chicago Cancer Centsr and they are saying they don't rem ever seeing this and are as curious as I am about this now! Just took C-Kit test along with 24 Hr. Urine as well as other blood work. Does any of this sound familiar and do you think the Skin Biopsy says anything? Just looking for any opinions...Hope everyone else is well!
ReplyDeleteI forgot to add I've had "IBS" issues for years as well along with blood tests a year ago indicating "High Liver function"
DeleteSorry, another correction. That diagnosis on the Biopsy was "T.M.E.P." I must be getting Dyslexia too.... Too much medical language for me.
ReplyDelete