Continuing Education Activity

Systemic mastocytosis is an aggressive disorder characterized by the release of numerous vasoactive cell mediators due to excessive activity of mast cells, which results in a wide variety of symptoms. Symptoms include anaphylaxis, flushing, nonspecific GI as well as neuropsychiatric complaints. This activity outlines the evaluation and management of systemic mastocytosis and reviews the roles of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of systemic mastocytosis.
• Review the history, physical, and evaluation of systemic mastocytosis.
• Outline the treatment and management options available for systemic mastocytosis.
• Summarize interprofessional team strategies for improving care coordination and communication to enhance the care of patients with systemic mastocytosis and improve outcomes.

Introduction

Mastocytosis is a constellation of disorders where there are excessive proliferation and accumulation of pathologic mast cells in the tissues. It can involve only skin, which is known as cutaneous mastocytosis, or it can involve extracutaneous tissues which is known as systemic mastocytosis. Cutaneous mastocytosis usually has a benign presentation. Systemic mastocytosis, in particular, is an aggressive form of the disorder characterized by the release of numerous vasoactive cell mediators due to excessive activity of mast cells, which can result in a wide variety of symptoms. The most frequent symptoms associated with the disease include pruritis, flushing, itching, diarrhea, and anaphylaxis.[1][2]

Etiology

Mast cells are immune cells derived from myeloid lineage. They are usually located in the connective tissues. They are activated through immunoglobulin (Ig)E mediated and non-IgE mechanisms and thus act as effector cells in hypersensitivity and allergic reactions.[1] In the IgE mediated mechanism, the allergen forms a cross-link with the IgE receptor, which then activates the mast cells, resulting in degranulation. Non-IgE mediated mechanisms include emotional and physical stimuli, food, drugs like opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, heat, exercise, cytokines, venoms, and hormones. The most common mediators released are histamines, proteases, cytokines, growth hormones, tumor necrosis factors, and phospholipases. Tryptases and chymases form an abundant portion of the mast cell granules. Tryptase is almost always secreted by mast cells and therefore it is used as an important diagnostic factor.[1][3][4]

Epidemiology

Systemic mastocytosis is a rare disorder with unknown incidence. It affects males and females equally.[5] Most of the cases of mastocytosis are limited to the skin, and 80 percent of them appear during childhood. By adolescence, the majority of them improve or resolve completely.[6][7][8] Systemic mastocytosis accounts for more than 95 percent of the adult cases and usually persists for a longer time.[9]

Pathophysiology

The pathogenesis of all types of mastocytosis is the result of chronic and episodic discharge of mast cell mediators and excessive accumulation of mast cells in one or more tissues. Mast cells contain a range of vasoactive mediators and usually operate by releasing these chemicals to produce inflammatory reactions to safeguard the body from microbial invaders and other insults. The signs and symptoms connected with the sudden and widespread release of the mast cell mediator are comparable to allergic and anaphylactic reactions.

Mast cell production is under the regulation of a gene named KIT, which encodes CD117 transmembrane tyrosine kinase. CD117 helps in the growth, survival as well as the migration of mast cells. Once the progenitors get produced, they migrate to various tissue and acquire different phenotypes specific to the tissues. Activating and inactivating mutations of KIT are implicated in the pathogenesis of systemic mastocytosis.[10][11][12][13] The precise mechanism by which KIT-activating mutations improve signaling is not thoroughly understood, but these errors lead to stem cell factor (SCF)-independent activation.[14] KITD816V is the most common driver mutation for systemic mastocytosis. KIT mutations are mostly somatic, so they don't seem to be inherited although, they might be present at birth.[15][16] They are rarely present in the germline cells, hence not passed down to the next generation.[17] FIP1L1-PDGFRA mutation is associated with eosinophilia. Other mutations, namely TET2, IgE, JAK2V617F, and RAS, have associations with systemic mastocytosis as well.

Histopathology

Hematoxylin-eosin stained specimens from bone marrow demonstrate diffuse cohesive or multifocal infiltrates of atypical mast cells or spindle-shaped morphology. Atypical features include immature chromatin or multinucleation.

History and Physical

Systemic mastocytosis involves different organ systems due to the release of vasoactive mediators. 

1. Episodic mediator release and anaphylaxis — Acute release of mast cell mediators can result in episodes of vasodilation, hypotension, flushing, pruritus, syncope, abdominal pain, nausea, vomiting, diarrhea, fatigue, and headache.
2. Anaphylaxis is observable in both cutaneous mastocytosis and systemic mastocytosis. Symptoms typically include flushing, syncope, gastrointestinal symptoms, and vascular collapse. Urticaria and angioedema occur less frequently.[18] These reactions may result from either IgE-mediated allergy or nonspecific activation of mast cells.
3. Gastrointestinal complaints — Gastrointestinal dysfunction caused by the release of mast cell mediators is an observation in systemic mastocytosis.[19] Gastrointestinal symptoms can be precipitated by the same triggers that cause systemic symptoms. Signs and symptoms include abdominal pain, diarrhea, nausea, vomiting, peptic ulcer disease, and gastrointestinal bleeding.[20]
4. Neuropsychiatric symptoms — Neuropsychiatric manifestations, including depression, mood changes, lack of concentration, short memory span, increased somnolence, irritability, as well as emotional instability, are commonly witnessed in adult patients with mastocytosis.[21][22] These symptoms sometimes have the name of "mixed organic brain syndrome."
5. Musculoskeletal symptoms — Diffuse musculoskeletal pain of the long bones and a pain syndrome resembling fibromyalgia may appear in patients with systemic mastocytosis.
6. Osteopenia and osteoporosis — A subset of patients with systemic mastocytosis appears to be at increased risk of developing osteopenia and osteoporosis.[23][24][25] A bone densitometry measurement is recommended to evaluate for osteoporosis in all patients with systemic mastocytosis.
7. The most common hematologic abnormality is mild-to-moderate anemia, which occurs in up to 50 percent of patients.[26] Eosinophilia is present in 25 percent of patients.
8. Peptic ulcer disease, malabsorption, steatorrhea, and liver enlargement commonly present when mast cell infiltration occurs in the intestine or the liver in aggressive systemic mastocytosis (ASM).[20][27][28] Liver function tests may become elevated.
9. Lymphoid tissues and spleen — The lymph nodes and spleen commonly have infiltrates in all types of systemic mastocytosis.[29]
10. Central and peripheral lymphadenopathy occurs in 20 to 60 percent of patients with indolent systemic mastocytosis (ISM) and a higher proportion in those with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), ASM, and mast cell leukemia (MCL).[30]
11. Splenomegaly can present in 50 percent of patients with ISM and over 70 percent of those with SM-AHN, ASM, and MCL.

Evaluation

Basic Evaluation

The initial evaluation should target establishing the diagnosis and identification of the clonal origin of the disease. At diagnosis, a complete medical history is necessary. A comprehensive symptomatic assessment is pertinent, and triggers of mast cell activation symptoms require documentation (NSAIDs, heat, opioids, anesthetics, friction, contrast, anxiety, stress, vaccines, dextrans, and insect bites). Note any previous history of anaphylaxis to any particular food, medications, or other triggers requiring epinephrine.[2]

Includes the following workup:

• Laboratory evaluation includes a complete blood count, renal and hepatic function panel, serum tryptase, albumin, and calcium. 
• Bone marrow aspiration and biopsy should have immunophenotyping for CD25, tryptase, and KIT mutations. 
• Bone densitometry is a recommendation as systemic mastocytosis patients are at increased risk for bone loss. 

Advanced Evaluation

Based on the clinical presentation, the following additional studies are performed:

• Abdominal computed tomography (CT) scan is indicated for abnormal white blood cell counts, hepatosplenomegaly, or lymphadenopathy. 
• Gastrointestinal endoscopy and biopsies are indicated for patients with GI symptoms.
• Biopsies of liver and lymph nodes are indicated with the elevation of liver function tests or if patients experience any localizing symptoms, respectively. 

Criteria for diagnosis of Systemic Mastocytosis:[4]  As per the World Health Organization (WHO) diagnostic criteria for systemic mastocytosis:

1. Major criterion:

• Presence of multifocal clusters of abnormal mast cells (greater than 15% of mast cells in clusters) in the bone marrow or extracutaneous tissues. 

2. Minor criterion:

• Elevated serum tryptase level (over 20 ng/ml)
• Abnormal mast cell CD25 expression
• Presence of KITD 816V mutation
• Presence of greater than 25% atypical mast cells. 

Diagnosis of systemic mastocytosis requires one major and one minor criterion or three minor criteria.

Evaluation for Organ Dysfunction: It consists of B and C findings.[4]

B findings include:

• Bone marrow biopsy over 30% of mast cells or abnormally high serum tryptases
• Hepatomegaly or splenomegaly or lymphadenopathy

C findings include: 

• Bone marrow biopsy shows cytopenias 
• Palpable hepatomegaly as well splenomegaly 
• Osteolytic lesions or pathologic fractures
• Malabsorption resulting from mast cell infiltration of the GI tract

Treatment / Management

Management for systemic mastocytosis has its basis in symptoms and subtypes.[4]

Symptom Specific Management

The following therapies may be necessary for symptomatic patients with any subtype of systemic mastocytosis (SM). 

Antihistamines — Initial pharmacologic treatment includes the use of H1 and H2 antihistamines. H1 antihistamines are administered to prevent flushing and itching. H2 antihistamines may help with abdominal pain, heartburn, cramping, and/or diarrhea.

Antileukotriene drugs — Antileukotriene agents may be an option in patients with flushing, itching, or abdominal cramping unresponsive to H1 and H2 antihistamines.[31]

Recurrent anaphylaxis — For patients with systemic mastocytosis who experience recurrent anaphylaxis or mast cell activation symptoms with hemodynamic instability despite trigger avoidance, maximized doses of anti-mediator agents (H1 and H2 antihistamines and anti-leukotriene drugs) may provide benefit. These patients should also have injectable epinephrine with them at all times.

Omalizumab — Omalizumab (anti-IgE), a humanized monoclonal antibody that inhibits the binding of IgE to mast cells, reduced the frequency of anaphylaxis in a few patients with SM or monoclonal mast cell activation syndrome.[32][33]

Flushing — In patients with prominent flushing not responsive to antihistamines, aspirin may be helpful, provided the patient is known to tolerate NSAIDs.[34]

Gastrointestinal symptoms — Gastrointestinal symptoms in patients with systemic mastocytosis may respond to oral cromolyn sodium, H2 antihistamines, and proton pump inhibitors (PPIs). Orally administered glucocorticoids are helpful for patients with aggressive systemic mastocytosis (ASM) and severe malabsorption or ascites.[35]

Osteoporosis and fractures — Appropriate daily intake of calcium and vitamin D should be maintained. For patients with osteoporosis-related fractures, treatment with the combination of pamidronate and low-dose interferon-alfa has been reported to be helpful.[36]

Refractory symptoms - In patients who are unresponsive to anti-mediator therapies and omalizumab, low-dose maintenance glucocorticoids or cytoreductive measures (such as interferon-alfa, cladribine, or a tyrosine kinase inhibitor [TKI] depending on KIT mutational status) can be considered as second-line approaches.

Subtype-specific Management

Indolent Systemic Mastocytosis or Smoldering Systemic Mastocytosis: Treatment with cytoreductive therapy is also appropriate for select patients with ISM or smoldering systemic mastocytosis (SSM) who suffer from recurrent anaphylaxis that remains uncontrolled with anti-mediator treatments, although this is only appropriate when all other options have been exhausted.[37]

Aggressive SM: Management of aggressive forms of systemic mastocytosis is with cladribine, midostaurin, interferon-alpha, or TKI inhibitors (imatinib) based on mutation status along with bone marrow transplant. Treatment of advanced systemic mastocytosis is indicated to mitigate organ dysfunction and improve the quality of life. For those patients eligible for hematopoietic cell transplantation (HCT), the goal is to control symptoms and prevent progression until a donor can be found.

SM-AHN: Treatment in this subtype focuses on the associated hematopoietic disorder. After the initial salvage therapy, HCT should be a consideration for maintenance.[4]

Mast cell Leukemia: There is no standard treatment to treat mast cell leukemia. It has a poor prognosis overall. 

In patients with venom allergy, treatment with venom immunotherapy is helpful to reduce further episodes of anaphylaxis.

Differential Diagnosis

 Differentials are broad for systemic mastocytosis.

• Carcinoid syndrome 
• VIPoma
• Zollinger-Ellison syndrome
• Acute urticaria
• Inflammatory bowel disease
• Irritable bowel syndrome
• Malabsorption
• Myeloproliferative disease

Pertinent Studies and Ongoing Trials

Numerous drugs are undergoing clinical trial investigations. Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3 kinase (PI3K) target downstream KIT signaling. A study evaluating the effect of multi-kinase inhibitor DCC-2618 on proliferation indicated a promising result that the agent can reduce the proliferation and survival of neoplastic mast cells. Therefore it can play a role in advanced systemic mastocytosis.[2]

Staging

WHO (World Health Organization) classification of systemic mastocytosis include:[4]

• Indolent systemic mastocytosis (ISM)
• Smoldering systemic mastocytosis (SSM)
• Aggressive systemic mastocytosis (ASM)
• Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)
• Mast cell leukemia (MCL)

SM-AHN subtype subclassifies into: 

• SM with acute myeloid leukemia
• SM with myelodysplastic syndrome
• SM with a myeloproliferative disorder
• SM with chronic myelomonocytic leukemia
• SM with hypereosinophilic syndrome

Prognosis

The disease subtype is one of the strongest prognostic predictors in systemic mastocytosis.

Certain clinical features are associated with an increased risk of death due to disease progression, independent of the category of systemic mastocytosis present. These features include the following:[1][38][39][40]

• Low platelet count (less than 150 × 10/l)
• Low serum albumin (under 35 g/L)
• Low hemoglobin levels (less than 100 g/L or red blood cell transfusion dependence)
• Elevated lactate dehydrogenase (LDH)
• Older age at onset of systemic symptoms (age over 60)
• High alkaline phosphatase
• Hepatosplenomegaly 
• Ascites 
• Excess bone marrow blasts
• Weight loss
• ASXL1 mutation

Complications

Systemic mastocytosis is associated with many disorders, such as:

1. Monoclonal gammopathy 
2. Hairy cell leukemia 
3. Non-Hodgkin lymphoma
4. Polycythemia vera 
5. Primary thrombocythemia 
6. Anemia 
7. Hepatosplenomegaly 
8. Hypereosinophilic syndrome 
9. Castleman syndrome 
10. Coagulopathy
11. Recurrent anaphylaxis

Consultations

Newly diagnosed patients with systemic mastocytosis need the following consultants:

• Hematologist 
• Dermatologist
• Immunologist 
• Gastroenterologist

Deterrence and Patient Education

All patients with mastocytosis should carry epinephrine-filled syringes at all times and should receive education regarding the administration of epinephrine in cases of emergency. They should understand the avoidance of triggers such as exposure to heat or cold, medications such as aspirin, strenuous activity, alcohol, spicy foods, anesthesia, surgery, or endoscopy. Clinicians need to administer premedications before any surgery, minor procedures, or radiocontrast dye to avoid anaphylaxis. Premedications include diphenhydramine, ranitidine, montelukast, and prednisone. Insect stings (Hymenoptera) could also precipitate anaphylaxis in patients who developed IgE-mediated sensitivity. Patients should have testing for venom allergy and, if positive, should be treated with venom immunotherapy to decrease subsequent anaphylaxis to insect stings.[41][42][43]

Enhancing Healthcare Team Outcomes

The unique clinical profile of systemic mastocytosis combined with diagnostic and pharmacological advancements poses a challenge for many clinicians; thus, an interprofessional approach is necessary.

Primary care clinicians should obtain a detailed history as well as a physical evaluation of the patient with recurrent allergies. If systemic mastocytosis is suspected, referral to an immunologist, and hematologist is recommended.

Close coordination of care amongst allergists, immunologists as well as hematologists is crucial to prevent any delay in diagnosis and management.

Clinicians, including nursing staff and pharmacists, play an essential role in identifying symptoms of anaphylaxis and the immediate administration of epinephrine. The pharmacist should educate the patient about the importance of epinephrine. Pharmacists also need to reconcile medications for possible drug interactions, as well as verifying dosing, and report any concerns to nursing or the managing clinician. Nursing can monitor medication compliance, and also report any potential adverse effects to the physician or the pharmacist. This collaborative approach between members of the interprofessional healthcare team is essential for optimal patient outcomes. [Level 5]

The patient should be told to wear an ID bracelet, which reveals his or her medical condition. They should be educated about avoidance of triggers such as exposure to heat or cold, medications such as aspirin, strenuous activity, alcohol, spicy foods, anesthesia, surgery, or endoscopy. 

Patients with systemic mastocytosis should undergo next-generation sequencing (NGS) to identify potential genetic carriers, which might predispose them to a poor prognosis. NGS is very new and is underutilized. Patients with uncontrolled symptoms, diagnostic difficulties, and advanced disease should obtain a referral to centers that specialize in mast cell disorders in the advent of multiple clinical trials. [Level 5]

Outcomes

The outcomes of patients with systemic mastocytosis are guarded, and the quality of life is poor. The symptoms can come on at any time and lead to severe distress; hence, most patients have a restricted lifestyle. For those with more severe disease, the outcomes are the worst.[44] [Level 5]