Multidisciplinary Collaboration Is Vital for Timely, Definitive Diagnosis of Indolent Systemic Mastocytosis

Despite advancements in diagnostic testing, patients with indolent systemic mastocytosis (ISM) often experience delays in diagnosis due to the disease’s heterogeneous presentation, highlighting the need for an integrative, multidisciplinary approach to improve early recognition of this condition and optimize patient care, according to Andrew Kuykendall, MD.

“The kind of nuanced approach different specialties take [when managing ISM] and the different [treatment] options that can be offered to make patients’ lives better is certainly encouraging,” said Kuykendall, who is an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida. “Also, knowing how tough it is to establish a multidisciplinary team is indicative of the challenges that patients face with this disease.”

In an interview with OncLive®, Kuykendall expanded on the diagnostic process in ISM, discussing the importance of biopsy, KIT mutation testing, and serum tryptase levels in diagnosing ISM. He also outlined the challenges posed by ISM’s heterogeneous presentation and underscored the need for a multidisciplinary approach due to the disease’s multisystem involvement.

OncLive: What is the diagnostic approach for ISM, and what key factors are used to confirm this diagnosis?

Kuykendall: ISM is a rare diagnosis, but it comes into my hands and our clinic in a variety of ways. From a diagnosis standpoint, how [the condition] presents directs us, as far as what we're looking for. When we think about the diagnostic criteria of systemic mastocytosis in general, one of the most critical things is [to obtain] a biopsy of an extracutaneous organ that shows these clusters of atypical mast cells. That’s quite important because those mast cells that are occurring in clusters are also going to show some atypical morphology. They may show some aberrant staining of CD2, CD25, and CD30.

We can also look for molecular signs where—and this is something we increasingly rely upon—[we are] checking for the presence of a KIT mutation. Importantly, that mutation can occur at very low levels. It's important to send this test to be done in a highly sensitive fashion. There are a couple of different options there, with droplet digital PCR [ddPCR] being one. [ddPCR] can assess down to a level of 0.03% in many cases, and [this method] can identify these low-level KIT mutations that come from the peripheral blood or the bone marrow. The bone marrow is probably a bit more accurate in assessing for those low-level mutations.

That kind of biopsy with the assessment of mast cell morphology is very important, [along with] KIT mutation testing. Then we [can conduct] peripheral blood testing of tryptase levels. This is often the first thing that's done to get a sense for whether we may be dealing with systemic mastocytosis because tryptase levels are often in excess of 20 ng/mL, with normal [levels] being less than approximately 11 ng/mL.

Where the biopsy is done [is based on] how a patient presents. If a patient's coming in with cutaneous mastocytosis or skin lesions, the first thing we might do is a bone marrow biopsy. However, if someone else is coming in with prominent gastrointestinal [GI] symptoms, the biopsy may come from the gastrointestinal [GI] tract with an endoscopy or colonoscopy.

Given that symptoms of ISM can emerge at different points in time, what are the key challenges in recognizing ISM as a potential diagnosis?

The biggest challenge is having that pre-test probability or clinical suspicion for this rare disease. The patients who get diagnosed [faster] are the ones that present with cutaneous lesions because we can see those on the skin. Patients are often seeing a dermatologist, and dermatologists often biopsy things. When that biopsy comes back showing cutaneous mastocytosis, the workup becomes relatively streamlined where that patient is then sent to see a hematologist, a bone marrow biopsy is performed, and we get the diagnosis.

Outside of [cutaneous presentation], the symptoms are a bit more vague or less readily apparent. Patients who are dealing with bloating, diarrhea, constipation, or frequent allergic reactions to various stimuli, and anaphylaxis could be easier [to identify]. Atypical anaphylaxis or recurrent anaphylaxis may raise a red flag, but it may not [be raised] if patients are just having more GI symptoms, itchiness, or hives that happen more frequently than one would [consider] normal. Oftentimes, those patients bounce around from a primary care doctor to perhaps an allergist, a pulmonologist, or a gastroenterologist. [All of these practitioners], myself included, are highly specialized, so we [tend to] see everyone through our lens. If someone comes in with diarrhea, a GI doctor is going to be focused just on the diarrhea [and will be less likely to consider] the possibility of something beyond that. It takes recurrent symptoms over years and years to sometimes [realize that] we need to look beyond common [diagnoses].

As patients may see multiple specialists before receiving a definitive diagnosis of ISM, what is the importance of multidisciplinary collaboration?

This is hugely important, but it can be a challenge. In today's world, medicine is very fragmented. When we're talking about a disease that can affect many different organ systems in somewhat uncommon ways, we have to be able to communicate with physicians and other specialists to get to the bottom of it. We've worked to create a network of allergists, gastroenterologists, and dermatologists who know we're a resource and can help in certain ways, and vice versa. If I am talking to a gastroenterologist and they are doing a colonoscopy or endoscopy, I will often urge them to check for mastocytosis. [We must] make sure that the pathologist who’s looking at this understands why we're doing this and what we may be looking for. What we've learned from this disease is that frequently, after we do get that diagnosis, we can find some of those older tissues and realize this was there all along, but the right assessments or studies weren't performed.

How have diagnostic methods for ISM evolved over time to ensure more timely and accurate identification of this condition?

Our advances in understanding the biology behind this disease and our ability to have more sensitive testing have allowed for an increase in diagnoses and awareness. People [are now far more] aware of what approach to take, what needs to be done, and some of the limitations with current treatments.

The main example would be KIT mutation testing. Here is a mutation that could provide some clarity on a disease process, as almost everyone [with systemic mastocytosis] has a KIT mutation. However, in the past, we didn't even have the technology to test to a level where we could rule this disease in or out. I can't tell you how many times I've had someone come in with very high concern for mastocytosis who was told their KIT mutation test was negative. However, when we look at the sensitivity [of the older technology], the test was only going to pick up a KIT mutation if it occurred in 10% or 15% of cells, and that's just not what we see.

With that, [we have a better] understanding of the tryptase values and some of these stains that need to be done on these cells, so we certainly have an enhanced ability to capture these patients.

[We] need a multidisciplinary approach. [I’ve] talked with folks in different fields who see [ISM] through a different lens, and we have talked about what different testing we do for these patients.