is often difficult to diagnose. Much of the diagnosis requires clinical signs and symptoms and criteria have been established (see excellent Journal Article in Journal of Hematology and Oncology by Molderings et al.). However, Mast Cell Activation can also be a sequelae of other disease processes as seen recently in a patient with CD8 promoter genetic mutations where the Mast Cell Activation was a consequence of CD8 immune dysregulation.
So confirmation of Mast Cell Activation Disease is important. Often a diagnosis requires a tissue biopsy showing elevated numbers of Mast Cells. In many individuals the problem becomes that they may not have active disease at the time of biopsy or they are usually on anti-histamines or immunosuppressants by the time a need for a tissue diagnosis is required.
Recently, Ravi et al. published in the Journal of Allergy and Clinical Immunology, a paper showing that Mast Cell Activation Disease had differing levels of biomarkers and that a combination biomarker approach resulted in the most sensitive method for disease confirmation.
In their study, they evaluated patients with MCAD by measuring serum tryptase, and urine N-methyl-histamine (NMH) and 11B-prostaglandinF2 (PGF2A).
Tryptase levels were only elevated in about 40% of patients and NMH was elevated in less than 10% of patients. In contrast, PGF2A and Tryptase levels together were elevated in the majority of patients with MCAD.
Importantly, since PGF2A is in the inflammatory process, it highlights patients that may benefit from Aspirin as a means to block this pathway (More on this later).
Overall, the diagnosis should still require clinical criteria. However, tryptase and PGF2A can be used for confirmation in some patients. Most importantly, PGF2A can be used to identify patients with auto-inflammation in the prostaglandin pathway.
is based on finding histological (seen under the microscope) evidence of an increase of mast cells in tissues. However, it is often necessary to perform a Bone Marrow Biopsy, in order to rule out other immunodeficiency syndromes which have overlap of the phenotype of Mast Cell Activation Disorder. We recently saw a patient with a diagnosis of Mast Cell Activation Disorder, and Eosinophilic Esophagitis, who had atypical features. Review of a number of her immunological tests were more indicative of a possible primary immunodeficiency syndrome so a bone marrow biopsy, was performed. This allowed me to review bone marrow findings in Mast Cell Activation Disorder. Interestingly enough, there is very little medical literature on bone marrow findings in Mast Cell Activation Disorder. Most of the literature is related to the malignant form of Mast Cell Disease also known as Mastocytosis. To validate my literature search, I spoke to Dr. S., a hemopathologist with Florida Hospitals in Wesley Chapel, Florida. I did a keyword search of Mast Cell Activation Disorder and Bone Marrow on Medline. Histological findings include Mast Cell infiltrates on the core biopsy with prominent spindling of the cells. The infiltrates often have interspersed histiocytic cells, eosinophilic granulocytes and plasma cells. The lymphocytic component can be prominent and often lead to a mis-diagnosis of Non-Hodgkins’s Lymphoma. Many Mast Cell infiltrates can be hypogranulated (few granules) and escape detection on standard Giemsa and Toludine Blue staining. Immunohistochemical staining with anti-tryptase antibodies is often required. In many patients, there may be clonal Mast Cell populations. Subsequent staining of bone marrow should include the markers CD2. CD2 is usually only expressed on Mast Cells in systemic Mastocytosis. In addition to CD2, Patients should have staining for CD25 and C-Kit. If possible, C-Kit mutations should be tested for. Primary Mast Cell Activation Syndrome will have Mast Cell monoclonality proven by CD25+ Mast Cells and a higher level of CD25+ and C-Kit+ cells. Testing for the C-KIT D816V, can also assist in the diagnosis. Of note, there are other C-Kit mutatons and the medical literature shows numerous patients who have the alternative mutations of K509I, I817V and N819Y. So full C-Kit sequencing may be appropriate. Other cell types that assist in the diagnosis are CD3-, CD4+ and CD154+ cells.
Of course, to throw a wrench into these findings is a recent study in Journal of Allergy and Clinical Immunology from June 2015. Alvarez-Twose et al. from the Spanish Network on Mastocytosis report that in variants of Systemic Mastocytosis, only 27% of individuals with Well-Diferntiated Systemic Mastocytosis met the WHO criteria for Systemic Mastocytosis. Kit mutations were identified in only 30% of patients despite having other immunophenotypic patterns on bone marrow suggestive of the diagnosis. This study highlights the difficulties often found in interpreting data.
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