Mast Cell Disorders

From: <a href="https://tmsforacure.org/overview/">Overview & Diagnosis - TMS - The Mastocytosis Society :TMS – The Mastocytosis Society</a>

Mast cells (MC) are immune system cells that live in the bone marrow and in body tissues, internal and external, such as the gastrointestinal tract, the lining of the airway, and the skin. Everyone has mast cells in their body, and they play many complex and critical roles in keeping us healthy. The positive roles that they play include protecting us from infection, and helping our body by participating in the inflammatory process. However, mast cells are also involved in allergic reactions, from the tiny swelling that appears after a mosquito bite to a life threatening, full-blown anaphylaxis.

Mast cells have within them small sacs, or granules, surrounded by membranes. The sacs contain many different kinds of substances called mediators, which participate in all of the roles above, including allergic response and anaphylaxis.

The mediators are selectively released when there is an allergic or mast cell based reaction.1

There is a difference between someone who is healthy, with mast cells that are functioning normally, and someone with a mast cell disorder, whose mast cells may be activating inappropriately in response to triggers, or may also be proliferating and accumulating in organ tissues.

<h3>WHAT ARE MAST CELL DISORDERS?</h3>

Mast cell disorders are caused by the proliferation and accumulation of genetically altered mast cells and/or the inappropriate release of mast cell mediators, creating symptoms in multiple organ systems.2The two major forms of mast cell disorders are mastocytosis and mast cell activation syndromes (MCAS). Mast cell disorders can cause tremendous suffering and disability due to symptomatology from daily mast cell mediator release, and/or symptoms arising from infiltration and accumulation of mast cells in major organ systems. Although systemic mastocytosis is a rare disease,3 those suffering with MCAS have recently been increasingly recognized and diagnosed. As a result, patients with MCAS appear to represent a growing proportion of the mast cell disorder patient population.4, 5 It is important to note that the process of mast cell activation can occur in anyone, even without a mast cell disorder, as well as in patients with both mastocytosis and MCAS.6

<h3>MASTOCYTOSIS</h3>

Definition

Mastocytosis has been defined in the literature as an abnormal accumulation of mast cells in one or more organ systems. Previously classified by the World Health Organization (WHO) as a myeloproliferative neoplasm, mastocytosis is now classified in its own category under myeloid neoplasms.7 Broadly separated into three categories, cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma these diseases occur in both children and adults. CM is considered a benign skin disease representing the majority of pediatric cases. In 67-80% of pediatric cases seen, resolution will occur before or in early adulthood.8-10 In pediatric mastocytosis, symptoms of mast cell mediator release may occur systemically as a result of mast cell mediators released from skin lesions.10 This, however, does not necessarily indicate systemic disease. The incidence of systemic pediatric disease was previously unknown, but systemic forms have now been proven to exist in some children.8-10 The majority of adult patients are diagnosed with systemic disease. Skin involvement, typically maculopapular cutaneous mastocytosis/urticaria pigmentosa, is common in adult patients and can provide an important clue to accurate diagnosis.11, 12

Diagnosis and Classification13-17

CM is diagnosed by the presence of typical skin lesions and a positive skin biopsy demonstrating characteristic clusters of mast cells. The preferred method of diagnosing SM is via bone marrow (BM) biopsy. The WHO has established criteria for diagnosing SM, summarized18 as follows:

Major ª: Multifocal dense infiltrates of mast cells (MCs) (> 15 MCs in aggregate) in tryptase stained biopsy sections of the bone marrow or other extracutaneous organ

Minorª:

<ul>

<li>More than 25% of MCs in bone marrow or other extracutaneous organ(s) show <a href="https://tmsforacure.org/wp-content/uploads/Cytology-of-mast-cells_1.11_083016.pdf" target="_blank">abnormal morphology</a>(i.e. are atypical MC type 1 or are spindle–shaped MCs) in multifocal lesions in histologic examination</li>

<li>KIT mutation at codon 816b in extracutaneous organ(s) (in most cases bone marrow cells are examined)</li>

<li>KIT+MCs in bone marrow show aberrant expression of CD2 and/or CD25</li>

<li>Serum total tryptase > 20 ng/mL (does not count in patients who have ANHMD-type disease.)</li>

</ul>

Abbreviation Key:

ª If at least one major criterion and one minor criterion OR at least three minor criteria are fulfilled, the diagnosis of systemic mastocytosis can be established.

b Activating mutations at codon 816, in most cases, KIT D816V

<a href="https://tmsforacure.org/overview/cutaneous-mastocytosis-variants/">Cutaneous Mastocytosis Variants</a>

<a href="https://tmsforacure.org/overview/systemic-mastocytosis-variants-including-b-c-findings/">Systemic Mastocytosis Variants, including B and C findings and Mast Cell Leukemia</a>

<a href="https://tmsforacure.org/overview/mast-cell-sarcoma/">Mast Cell Sarcoma</a>

<h3>MAST CELL ACTIVATION SYNDROMES</h3>

Definition

Existence of a subset of mast cell disorder patients who experience episodes of mast cell activation without detectable evidence of a proliferative mast cell disorder was postulated over 20 years ago.19, 20Over the last two decades, with development of improved methodology for identification of abnormal mast cells,21-24 it became apparent that there were patients who exhibited symptoms of mast cell mediator release who did not fulfill the criteria for SM.25, 26 Thus began the evolution of discussions about other forms of mast cell disorders, both clonal and nonclonal, which became known as Mast Cell Activation Syndromes (MCAS).6, 27, 28

Diagnosis and Proposed Classification

Recognition by specialist physicians of the importance of mast cell activation in disease led to an international Mast Cell Disorders Working Conference emphasizing this topic in September of 2010. Consensus statements were published regarding classification of and diagnostic criteria for mast cell disorders,6 where mast cell activation plays a prominent role.

Mediators produced by mast cells have a considerable effect on specific symptomatology. Symptoms, including, but not limited to flushing, pruritis (itching), urticaria (hives), headache, gastrointestinal symptoms (including diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux), and hypotension (low blood pressure), allow a patient to meet the first of three required co-criterion for systemic mast cell activation when the patient exhibits symptoms involving two or more organ systems in parallel, which recur, or are chronic, are found not to be caused by any other condition or disorder other than mast cell activation, and require treatment or therapy.6, 28

The second required co-criterion for systemic mast cell activation depends on documentation that mast cells are directly involved in the symptomatology. An increase in the serum level of tryptase, above baseline and within a narrow (generally accepted as one to two hour) window of time after a symptomatic episode, is proposed as the preferred method for providing evidence of mast cell involvement according to these criteria.6, 28-30 The consensus article provides a method for calculating the required minimum rise in serum tryptase.6 After a reaction, a level of serum tryptase that is a minimum of 20% above the basal serum tryptase level, plus 2 ng/ml, will meet the second criterion listed above for a mast cell activation event (see <a href="https://tmsforacure.org/tests/">Tests</a> for further information). Consensus members also agreed that when serum tryptase evaluation is not available or when the tryptase level does not rise sufficiently to meet the required increase for the co-criterion, other mediator tests could suffice. A rise in urinary n-methyl histamine, prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α (24-hour urine test for any of the three), is considered an alternative for the co-criterion related to a requirement for a mast cell mediator level rise during a systemic mast cell activation event.6

Finally, the third co-criterion requires a response (based on response criteria15) to medications that inhibit the action of histamine.6 In addition, in those with typical mast cell activation symptoms, a “complete or major” response to drugs that inhibit other mediators produced by mast cells or block mast cell mediator release can be regarded as fulfillment of the third co-criterion for MCAS.6, 28

<a href="https://tmsforacure.org/mast-cell-activation-syndrome-variants/">Mast Cell Activation Syndrome Variants</a>