The Challenge Of Getting A Proper Mast Cell Disease Diagnosis

There are many forms of mast cell disease, including several subtypes of mastocytosis and mast cell activation disorder/syndrome. I’ve even read there may be an autoimmune form of MCAS even though mast cell disease is not considered an autoimmune disease.

My own diagnosis, at least for insurance coding, is simply:

But which type of mast cell disease do I have? According to two hematologists and an immunologist who did all my tests, I have MCAS (mast cell activation syndrome) and, according to my own research possibly MMAS (monoclonal mast cell activation syndrome). Maybe a form of mastocytosis, even.

Honestly, though, we just don’t know. Why? According to the Mastocytosis Society:

Diagnosing these disorders is too often a long, complicated process involving many areas of specialty medicine. Many patients have suffered declining health for up to 10 years or longer before they were finally diagnosed. Those with skin or hematological involvement have the best chance of their physicians being able to definitively medically prove their illness. Anaphylaxis is more common; however, even anaphylaxis is often unrecognized or under-treated, but as a symptom on it’s own, it is easier to diagnose.

There are standard tests for mastocytosis. For mast cell activation and idiopathic anaphylaxis patients, the path to diagnosis involves many tests, many of which may be inconclusive. For all patients with mastocytosis, mast cell activation syndrome, or idiopathic anaphylaxis, none of the current diagnostic tests are reliable for every patient.

Some of these tests often return false-negatives. Some tests return positives outside the normal range, yet the patient experiences few symptoms and enjoys a normal unrestricted life. Many patients have completely normal test results (eg. Tryptase, Urine, Bone marrow) yet they are disabled by these disorders. The largest discrepancies reported by patients are those with positive skin biopsy of a cutaneous form of mastocytosis, yet negative test results proving systemic involvement; however, the patients exhibit all the classic symptoms of systemic mastocytosis. Physicians and patients worldwide are aware of this. The current diagnostic tests need refinement, and new tests need to be discovered, which are more reliable and definitive for these disorders. Researchers worldwide are constantly working to address these issues.

So, as you can see, it’s complicated.

Still, it is important for a proper diagnosis because it can determine your course of treatment. Here are some descriptions I found that break down mast cell disease into all of its categories to help better understand them, beginning with the newest one, MCAS or mast cell activation syndrome.

It is broken into two categories:

  • MCAS (mast cell activation syndrome) – an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a range of chronic symptoms, sometimes including anaphylaxis or near-anaphylaxis attacks
  • MMAS (monoclonal mast cell activation syndrome) – The term CMD comprises systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS). The common finding in these two conditions is the mast cells clonality; which can be proven by the detection of a codon 816 KIT mutation and/or occurrence of immunophenotypically aberrant mast cells expressing CD2 and/or CD25. In patients with MMAS, the WHO criteria for systemic mastocytosis are not met.

Next is mastocytosis. There are two general types according to Cancer.Net:

Cutaneous mastocytosis

Cutaneous mastocytosis is an increase of mast cells in the skin. About 90% of people with mastocytosis have the cutaneous type. Subtypes of cutaneous mastocytosis include:

  • Urticaria pigmentosa. This is the most common type of cutaneous mastocytosis. The main sign of urticaria pigmentosa is the appearance of tan or red-brown spots on the skin. These spots usually develop on the midsection of the body first and then spread over the rest of the body. A person with this type of mastocytosis may also experience nausea, vomiting, and diarrhea.
  • Solitary mastocytoma. This type of mastocytosis is more common in infants and children than in adults. It usually causes a large nodule, about 3 to 4 centimeters (cm) in diameter, to form on an arm or leg. This nodule is called a mastocytoma.
  • Diffuse erythrodermic mastocytosis. This type of mastocytosis is found most often in children younger than 3 years old. Diffuse erythrodermic mastocytosis may not be noticeable when a child is born, but it can later show up as a rapid thickening of the skin. Symptoms of systemic mastocytosis (see the Symptoms and Signs section) and blisters are also common.
  • Telangiectasia macularis eruptiva perstans. This type of cutaneous mastocytosis develops mainly in adults. The most common sign is lesions that do not itch and are smaller than those of urticaria pigmentosa.

Systemic mastocytosis

Systemic mastocytosis involves internal organs throughout the body, including the gastrointestinal tract, bone marrow, liver, spleen, and lymph nodes. Lymph nodes are tiny, bean-shaped organs that help fight infection. About 85% of the time, urticaria pigmentosa (see above) develops first.

Depending on the number of mast cells in an organ, the disease is classified as either indolent, which means it is slow growing, or aggressive, which means it is fast growing. As the number of mast cells builds up in an organ, the symptoms of the disease may get worse.

Systemic mastocytosis can become cancerous. The risk of systemic mastocytosis becoming cancerous is 7% when the disease begins in childhood and as much as 30% in adults. Mast cell leukemia involves the blood, while mast cell sarcoma involves the body’s soft tissues.

They simply list systemic as being either indolent or aggressive (or cancerous) but according to research, systemic mastocytosis can be further broken down as:

• Indolent systemic mastocytosis
• Isolated bone marrow mastocytosis
• Smoldering systemic mastocytosis
• Systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease
• Aggressive systemic mastocytosis

I know from experience that it can be incredibly confusing and frustrating for patients and doctors to narrow down the exact form of mast cell disease and sometimes it’s not easy to categorize a patient even with all the parameters in place for testing and labeling.

To complicate things, not all labs are able to handle the complicated testing we need to have done and, as noted above, the tests aren’t always reliable anyway.

Research into the disease (all forms of it) and experience with patients has been helpful in directing the testing, though, and Dr. Afrin discusses his personal views on this in his video Q&A here:

1:25:40 – What are your indications for recommending a bone marrow biopsy?

I actually did bone marrows in my first hundred MCAS patients and found no increased mast cells in any of them and only found molecular level evidence of disease in two of them. My approach is if the tryptase is persistently over 20 ng/mL OR if the pattern of presentation is much more consistent with what we expect in mastocytosis rather than MCAS then I am quick to do not just one BMB but two BMB’s since we know that one BMB will probably miss mastocytosis about 1/6 of the time.

What is the pattern that reflects mastocytosis?

Mastocytosis most commonly abruptly presents in middle or older age. Whereas in MCAS, patients can commonly trace symptoms reflective of mast cell activation back to at least adolescence, not uncommonly even back to childhood and occasionally even infancy.

So it’s a persistently high tryptase level along with the pattern of presentation that would lead me to recommend a BMB. Of course the other consideration is the fact that mast cell disease increases the risk for malignancy of all types, especially hematological malignancies, so if there is any hint in the patient that a hematological malignancy might be present, then absolutely a BMB needs to be done. But fortunately, preciously few patients who present suggestive of MCAS also have findings of hematological malignancy.

My doctor ordered a BMB even though my tryptase was low and it did find my mast cells expressing CD25, one of the minor criteria for diagnosing mastocytosis.

 

The other criteria weren’t met, thankfully, but I am glad I had it done to find out about the CD25 (something usually only seen in mast cell disease I was told) and also to rule out c-kit in case I need to access medicines like imatinib in the future.

Had Dr. Afrin been my doctor he wouldn’t have ordered a BMB on me to begin with, I’m sure. So it’s interesting and shows how complex diagnosing this equally complex disease really is, especially if you’re looking (or needing) to be put into a specific category.

It is important for a full diagnosis, though, in order to get the help we need.

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