WHO Criteria For Diagnosis
The Need For Criteria-based Diagnosis
As we already know, diagnosing mastocytosis is not an easy task. There are so many diverse, seemingly unrelated symptoms that patients can experience. And with many of these symptoms also being present in other conditions, diagnosing mastocytosis on the basis of its symptoms is virtually impossible.
During several decades of testing and diagnosing patients, some patterns began to emerge. Patients who were eventually diagnosed with mastocytosis presented some commonalities in their test results.
So, in 2001, the World Health Organisation, whose job it is to provide leadership on global health matters, as well as setting medical and clinical norms and standards, came up with a series of criteria which guided physicians into a method for mastocytosis diagnosis which is based on test results. The criteria was further refined by the WHO in 2008, based on new findings since 2001.
The WHO also structured a classification of mastocytosis, defining several different types and states of the disease.
The WHO Criteria For Diagnosing Mastocytosis
There are major and minor criteria to be considered during diagnosis. The importance of the major/minor criteria distinction will become clear in a minute. At this stage, please notice that the criteria have nothing to do with symptoms.
Let's describe the criteria first:
- Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ(s) (>15 mast cells in aggregate)
- Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (> 25%)
- c-KIT mutation at codon 816 in extracutaneous organ(s). (Activating mutations at codon 816; in most cases, c-kit D816V)
- Mast cells in bone marrow express CD2 and/or CD25
- Serum total tryptase > 20 ng/mL (does not count in patients who have associated hematologic clonal non-mast cell lineage disease)
Now, let's review the criteria in a bit more detail:
The major criterium looks at the result of a bone marrow biopsy and/or a biopsy of other organs (e.g., gastrointestinal tract biopsies, liver, spleen). And you'll have a pathologist looking at the biopsy slide under a microscope. That poor guy needs to find clusters (dense aggregates) of more than 15 mast cells within the field of view of his microscope. And the pathologist must find such a cluster in more than one place (multifocal) in his FOV.
Now, for the minor criteria:
- Twenty five percent of mast cells found by inspecting the biopsy must be oddly (spindly) shaped to score one minor criteria.
- If you have read the post What Are Receptors? , you know all you need to know to understand what minor criteria 2 means: you must exhibit ‘the' c-KIT mutation. Specifically, the one which is called D816V. (But you'll remember c-KIT can mutate in many different forms. Still, the D816V is the one specifically required to score that point.
- Criteria 3, about the CD2/CD25 stuff? That means the mast cells found in the biopsy must have two types proteins (called CD2 and CD25) sitting on the cell membrane. Apparently, these two proteins found on the cell surface at the same time is not a good thing. Score one more point if you have these 2 little critters (although research now shows that CD25 is the more important of the two. You could virtually score the point if CD25 was the only one present).
- And criteria 4 is easier to understand. Score one more point if your blood test shows that you have double the normal amount of tryptase (20 nanograms per milliliter of blood). BUT don't score that point if you have been diagnosed with a blood cancer of some sort ( associated hematologic clonal non-mast cell lineage)
Diagnosing systemic mastocytosis by WHO 2008 criteria requires you to either have those clusters of more than 15 mast cells in your biopsies or to have scored 3 points of the minor criteria category.
Now let's focus on the classification of the disease.
WHO Classification of Mastocytosis
In 2001, the World Health Organization developed a consensus classification system for mastocytosis.
This system separates mastocytosis into cutaneous mastocytosis (CM) and five main subtypes of systemic mastocytosis (SM).
CM is diagnosed by the presence of skin lesions and the absence of definitive systemic (meaning, in organ systems) involvement by mast cells. It is also known as Urticaria pigmentosa (UP) maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma.
As for SM, first, we have the form of indolent systemic mastocytosis (ISM), which is the vast majority of patients with SM. As distinct from UP, where no other organs than the skin is involved, SM exhibits enlarged liver or spleen. The GI tract may also be affected. Mediator-related symptoms are common in SM, but the grade of bone marrow infiltration is low, usually less than 5 percent.
Second, we have the form in which there is a associated hematologic non-mast cell lineage disorder (which basically means a blood cancer of some sort, like lymphoma or leukemia) associated with the mast cell disease (ISM-AHNMD). It is far more often the case that we recognize the lymphoma or leukemia and don’t see the underlying mast cell disease unless it happens to be picked up by chance in a bone marrow biopsy.
Third, we have the subvariant of SM called Smouldering Systemic Mastocytosis (SSM), where mast cells have infiltrated the bone marrow more than 30 percent and total tryptase levels greater than 200ng/mL. There is also a significant level of organ enlargement (liver, spleen, lymph nodes).
Fourth, aggressive systemic mastocytosis is the form of the disease in which the cells have actually infiltrated into a given organ (for example, the liver) and are causing significant organ dysfunction.
And finally, we have the extremely rare – and, for all intents and purposes, universally rapidly fatal – mast cell leukemia.
If you are new to this, no doubt you will be confused. It takes a while to sink in. Please join us in the forum and ask questions.
Here's a short video by Nancy Gould, recapping the diagnosis criteria in a hi-tech, lo-tech way.
Nancy Gould, a mast cell patient and registered nurse, was also a humanitarian who devoted her life to researching and helping mast cell patients get better. Nancy passed away 12/6/12.