Improving Recognition and Management of Systemic Mastocytosis

“The impact of systemic mastocytosis [SM] can be significant, even in patients with nonadvanced or indolent disease, and the treatment landscape truly is changing. We have several new options available for our patients, such that they are achieving outcomes and quality of life that were not previously possible for them,” Lauren Madigan, MD, said in a Dermatology Times Case-Based Peer Perspectives custom video series titled “Navigating Systemic Mastocytosis in Dermatology: Diagnostic Strategies and Personalized Treatment Approaches.”

Madigan, a dermatologist and assistant professor of dermatology at the University of Utah Hospital and the Huntsman Cancer Institute, reviewed the clinical spectrum of SM and highlighted the role that dermatology clinicians play in early recognition and multidisciplinary care.

Understanding the Disease Spectrum

SM is a heterogeneous clonal hematologic disorder characterized by the proliferation and accumulation of mast cells in multiple organs, resulting in varied systemic manifestations. According to Madigan, the disease encompasses a broad spectrum of subtypes.

The classification framework divides SM into nonadvanced and advanced forms. Nonadvanced disease includes bone marrow mastocytosis, indolent SM, and smoldering SM. Advanced variants include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia. These subtypes are differentiated by “B findings,” which reflect high mast cell burden or organ involvement without dysfunction, and “C findings,” which indicate overt organ damage.

Why SM Is Often Missed

Despite recognizable cutaneous manifestations, SM is frequently underdiagnosed. The condition’s multisystem presentation means patients often interact with numerous specialists before the underlying disorder is recognized.

“As the specialty that has a more specific disease manifestation—these fixed skin lesions that we biopsy and see abnormal mast cells in—we’re particularly positioned to help identify these patients at an earlier phase,” Madigan said.

Many systemic symptoms—including gastrointestinal distress, neurocognitive complaints, or flushing—may initially be attributed to more common disorders such as gastroesophageal reflux disease or irritable bowel syndrome, contributing to missed or delayed diagnoses.

Cutaneous Clues and Clinical History

Cutaneous involvement is often the key to recognition. Adults presenting with fixed maculopapular lesions consistent with mastocytosis in the skin should raise immediate suspicion for systemic disease.

Madigan highlighted a critical clinical point: “If a patient presents with the onset of fixed skin lesions at 18 years of age or older, the vast majority are going to meet current diagnostic criteria for [SM].”

Clinicians should also evaluate for systemic symptoms and triggers that suggest mast cell activation, including the following:

• Episodic flushing
• Pruritus or urticaria pigmentosa–like lesions
• Gastrointestinal symptoms such as abdominal cramping or diarrhea
• Anaphylaxis, particularly after insect stings
• Musculoskeletal symptoms or fragility fractures

Diagnostic Workup and Staging

Diagnosis relies on the integration of clinical features, laboratory findings, and pathologic confirmation. Skin biopsy may demonstrate mast cell infiltration, but definitive staging often requires bone marrow evaluation.

“A tryptase level greater than 20 is one of the minor criteria that we use to diagnose SM, but a tryptase level less than 20 does not exclude a diagnosis of SM,” Madigan said.

Molecular testing also plays a critical role. Approximately 95% of patients with nonadvanced disease harbor the activating KIT D816V mutation, which drives mast cell proliferation and represents a key therapeutic target.

Because most adult patients with cutaneous disease ultimately have systemic involvement, Madigan noted that bone marrow biopsy should generally be discussed as part of staging.

From Supportive Care to Targeted Therapy

Management of SM depends on disease subtype and symptom burden. For many patients with indolent disease, therapy initially focuses on symptomatic control.

First-line supportive measures may include antihistamines, mast cell stabilizers such as cromolyn sodium, and trigger avoidance. Importantly, patients should also be equipped with epinephrine autoinjectors because anaphylaxis is relatively common in this population.

Madigan noted that rates of anaphylaxis in indolent SM may approach 50% in some populations, demonstrating the importance of preventive counseling and preparedness.

When symptoms remain refractory or significantly impair quality of life, targeted therapies may be appropriate. One such option is avapritinib (Ayvakit; Blueprint Medicines), a selective inhibitor targeting the KIT D816V mutation.

Madigan described meaningful clinical improvements with the agent, noting that therapy can reduce mast cell burden while improving patient-reported outcomes. “The use of avapritinib can result in really significant, meaningful improvements in objective measures of disease, as well as patient-reported outcomes and quality-of-life metrics.”

Emerging targeted agents, including next-generation KIT inhibitors currently in clinical development, may further expand treatment options.

Multidisciplinary Care

Because SM affects multiple organ systems, optimal management typically involves collaboration across specialties. Dermatology, hematology-oncology, allergy and immunology, pathology, and other disciplines may all contribute to diagnosis and treatment planning.

“The diagnosis and management of [SM] truly is a team sport,” Madigan said.

Key Takeaway

Although rare, SM is a disease clinicians may encounter through its cutaneous manifestations. Recognizing fixed mastocytosis lesions in adults, investigating systemic symptoms, and coordinating multidisciplinary evaluation are essential steps in identifying affected patients earlier.