Higher stakes in systemic mastocytosis​

Patients enrolled in clinical trials at academic centers, Dr. George says, generally have two bone marrow biopsies—one remains in place locally and the other arrives at her lab for central pathology review. “So those pathologists are already seeing the results of those drugs,” she says. “It’s interesting, because what I’ve noticed is that as these mast cells go away, they also change their phenotype.” (See images.)

As they move from an abnormal shape to essentially a normal shape, their response to staining changes as well. While aberrant mast cells express CD25, normal ones don’t. As patients are treated, they’ll lose this expression in their cells, Dr. George says. “You have to be aware of those changes as a pathologist who’s reading bone marrows, so you’re properly diagnosing these patients and understanding what’s happening.”

Once physicians understand they’re working on a puzzling diagnosis, it’s easier to start putting the pieces together. “What often happens,” says Dr. Gotlib, “is patients get sent to me with random colon biopsies, and they haven’t done the mast cell stains. So for the non-bone marrows, the GI biopsies, we often have to ask for the extra stains to look for mast cell disease.”

He’d like to see pathologists take the lead on doing or suggesting additional stains. Depending on the clinical information, “I would hope the pathologist would go back to the gastroenterologist and say, ‘What do you think about adding on CD25, CD117, and tryptase to look for mast cells?’ There is absolutely a role for closer communication and collaboration between the subspecialist and the pathologist.” Dr. Duncavage says he and his colleagues on the heme-path service frequently consult with GI pathologists to sort out the molecular testing on suspected cases of mast cell disease.

Another place to dial up the chatter is when clinical symptoms and pathology findings don’t fit snugly into place. Advanced disease is often overcalled, Dr. Gotlib says, with diagnosis based on the presence of mast cells in the bone marrow as well as sclerotic bone lesions. But the diagnosis isn’t based solely on mast cell burden; it also requires the right clinical signs and symptoms, he says. “That’s where the pathologist and the clinician need to work together to know what type this is.” Is it indolent SM? Smoldering SM? Aggressive SM? “Advanced disease is often not only the pathology diagnosis but also frankly as much or more of a clinical diagnosis.”

(The only SM subtype that is a purely histopathologic diagnosis is mast cell leukemia, Dr. Gotlib says, which is based on the presence of 20 percent or more mast cells in the bone marrow aspirate—not a biopsy.)

Those who’ve been involved in the clinical trials for KIT inhibitors, says Dr. Gotlib, have observed that local pathologists (“and frankly, a lot of these are academic centers,” he says) don’t routinely identify the associated hematologic neoplasm in patients with mast cell disease involving the bone marrow. “They either find the mast cells and don’t comment,” he says, or they don’t discern between a myelodysplastic syndrome and a myeloproliferative neoplasm, or do not appreciate a possible overlap. “A significant proportion of those local reads did not comment on an AHN,” though it turned up when it was read centrally, by, for example, Dr. George.

“So I would say that undercalling AHNs in the bone marrow is highly prevalent,” Dr. Gotlib says. “That needs to be discussed and reviewed among the pathology community.”

The converse can also occur in cases such as a CMML, where physicians don’t realize there’s also a mast cell component. “That’s where the use of tryptase staining could be of value,” he says.

Though Dr. Ustun reports progress in SM diagnoses, he too expresses concern about ongoing gaps. He typically sees patients with either a cutaneous mastocytosis diagnosis or allergic reactions, with an elevated tryptase. “People order tryptase much more than in the past. And overall awareness is increasing, but it’s not great yet. Oncologists and hematologists think more common diseases when they see blood abnormalities in patients, such as MDS or AML.”

If they’re suspicious for AML, and a bone marrow biopsy confirms it, too often that’s where the matter ends. The diagnosis is correct but not complete. “They can miss that there is also occult SM. It’s minor, but it’s there.” But if neither the pathologist nor the clinician thinks to do additional stains, mast cells will be easily overlooked. “So we think some patients go without a diagnosis,” Dr. Ustun says.

The more common problem, though, is that patients with more common hematologic neoplasms—AML, MDS—may have an SM component. Finding a KIT mutation when working up a hematologic malignancy is a reason to look for SM. “It’s remarkable that quite a few patients have SM in this group,” Dr. Ustun says.

Another area to pay attention to is bone. “Not bone marrow—bone,” Dr. Ustun says. Oncologists may encounter patients with serious bone pain—an x-ray reveals osteolytic bone lesions, which are small and quite dense, says Dr. Ustun. The apparently obvious diagnosis is a cancer that metastasized to bone. But follow-up steps—interventional radiology, bone biopsy, CT scans to identify a primary cancer—may not turn up an explanation for the very real lesions. In such cases, it may turn out that the abnormal cells are mast cells, linked to SM. “This happens more frequently than people think,” he says.

The final area of concern is the liver. “Personally, I do more and more liver biopsies in patients with systemic mastocytosis already diagnosed to understand what is going on in their liver,” Dr. Ustun says. Blood tests aren’t adequate, in his opinion. “I have had almost completely normal liver function tests, and when I did liver biopsy I saw tremendous fibrosis in the liver, due to mast cells.”

Despite the seeming similarities, the differences are real and worth sorting out—like making the distinction between Prince Hal and Hal Prince.

So why do physicians short-sheet their diagnostic efforts? Dr. Gotlib has a few hunches. “It’s just one of those things if you make a diagnosis of a mast cell neoplasm, one may not consider the presence of a co-occurring neoplasm. Or,” he says, reciting the by-now familiar refrain, “it’s just a matter of, you need to think about it in order to work it up.”

The lapse may be understandable, but it comes at a cost, and not just in terms of quality of life. Dr. George estimates five to 10 percent of patients with indolent disease will progress to aggressive SM, though “we’re still trying to understand what is different about those patients,” she says.

“If the mutation burden of KIT D816V is relatively high,” Dr. Gotlib says, “or if additional mutations beyond KIT D816V are found, this could indicate disease beyond the indolent stage.” A high KIT D816V allele burden may reflect multilineage involvement of the KIT mutation, which means not only in the mast cells but in the granulocytic lineages—something that’s more likely to be seen in patients with smoldering or advanced disease. “Which means they’re already transitioning,” he says.

Dr. Ustun asks: “If we diagnose them earlier, can we prevent them from developing additional mutations?” No one knows how many progress, or why, he concedes. “From my experience, though, I do see patients start as indolent, and maybe a decade later they were really in trouble.”

Dr. Duncavage would like to head off such trouble sooner. “I suspect a lot of pathologists think of associated mast cell disorders as an esoteric diagnosis,” he says, thinking that may be furthered along because mast disease is considered indolent in most cases (quality of life issues notwithstanding). “Is it really something they should aggressively work up? Especially as a secondary disorder. But now that it’s treatable, it’s definitely something that should be considered and worked up appropriately.”

He and his colleagues will see a CMML once or twice a week. “We’re comfortable with that,” he says. “But it’s easy to overlook these other diseases that can co-occur with CMML. Because you’re very focused on, basically, the main diagnosis.”

The risk is that even when the CMML is treated successfully, the mast cell disease may continue to expand, says Dr. Duncavage. “The oncologist needs to be aware that there are two kinds of clonal processes going on.”

That’s probably the hardest challenge he and his colleagues see on the heme-path service, he says. “We’ve made one diagnosis. We think we’re done. And then all of a sudden we’re clued in to the fact, Gee, there’s a lot of mast cells here. We should work this up more.”

Clinicians may think about ordering a serum tryptase level; if it’s elevated, “certainly mast cell disease is on the differential,” Dr. Gotlib says.

The question then becomes: What meets the WHO criteria for a diagnosis of systemic mastocytosis?

The major criterion is multifocal aggregates of mast cells on an extracutaneous organ (which is almost always the bone marrow biopsy).

There are four minor criteria:

• Atypical mast cells (immature or spindle-shaped);
• CD25 expression on mast cells, with or without CD2;
• KIT D816V mutation; and
• Serum tryptase level above 20 ng/mL.

The diagnosis requires one major and one minor criterion or at least three minor criteria.

From a pathology standpoint, says Dr. Gotlib, “there are nuances to making sure that one correctly identifies these major/minor criteria.”

The GI pathology is incredibly challenging, says Dr. George, pointing to the considerable confusion about what mastocytosis looks like in the gut, compared with other diseases like irritable bowel syndrome, which can present with increased normal mast cells.

Naturally, mast cells can be increased in other disorders as well. With myeloid and lymphoid neoplasms with eosinophilia, says Dr. George, the presence of increased mast cells is well documented. They can even look spindle-shaped and thus mark aberrantly. And these, too, are rare diseases.

“This is where you have to do NGS,” Dr. George says. “You’ll often have to do FISH or PCR for PDGFRA, PDGFRB, or FGFR1 mutations. These are some really substantial workups.”

“Ultimately, if you’re going to make the WHO diagnostic criteria for systemic mastocytosis,” says Dr. Gotlib, “you need to do a bone marrow biopsy” to identify multifocal aggregates. Moreover, he notes, two of the minor criteria require a bone marrow biopsy. “You need to find the atypical mast cells and that they express CD25, and you can’t do that off of peripheral blood.” But to address sensitivity issues, he recommends that the KIT mutation assays be done with ddPCR or KIT allele-specific PCR.

“Having said that,” Dr. Gotlib continues, “it’s possible to do a ‘dirty’ screening test off the peripheral blood.” But unless the patient has mast cell leukemia, mast cells will not be circulating in the blood. Some subtypes of advanced mast cell disease, however, such as SM-AHN, will often carry the KIT mutation, which can be picked up in the blood. “But at the end of the day, if you’re going to be doing a bone marrow, then do it off the bone marrow.” With a nod to the infamous quote from bank robber Willie Sutton, he jokes, “That’s where the money is.”

“It’s the same thing with bone marrow,” he explains, where multifocal aggregates of mast cells can be found. In contrast, mast cells circulate in the blood only in rare cases of mast cell leukemia.

NGS does have advantages, Dr. Gotlib says. Patients with other types of advanced mast cell disease, particularly SM-AHN, have other myeloid mutations apart from KIT D816V, which are well known and easily picked up by NGS, such as those on the S/A/R panel.

But many other mutations are myeloid in nature, such as CBL, JAK2, and EZH2. Other mutations, including TET2 and DNMT3A, are more neutral, but clearly have been found in advanced mast cell disease.

NGS panels should be part of the standard workup, Dr. Gotlib says, “because they are now part of new diagnostic scoring systems to provide more nuanced evaluation of prognosis,” as well as identifying whether there’s an AHN.

The clinical treatments are very different. Patients with a myeloid neoplasm with eosinophilia but a PDGFRA mutation will respond “very, very well to very low doses of imatinib,” Dr. George says. “But you could have a patient with systemic mastocytosis—that looks very similar in the bone marrow because you also see eosinophils that accompany mast cells.” These patients will have a KIT D816V instead of a PDGFRA mutation. “There’s a number of ways pathologists can be misled if they don’t do or understand the entire workup.”

Clearly, much of this needs to land in a reference lab—most labs simply don’t offer this type of specialized testing. Dr. George is sympathetic.

“I’m at a reference lab, so I can get it all done,” she says. “But even so, it takes time to do all these tests.”

“There is a challenge, I think, on the pathology side,” she adds, “especially if you’re in a community practice. You’re so busy. I was in community practice when I first came out of training, and I remember: You’re busy. You’re seeing all sorts of different malignancies.”

Despite the seemingly endless frustrations, it’s worth persevering. “It’s uncommon in the sense that you’re not going to see it every day,” says Dr. Duncavage. But like snow in April, “It’s common enough that you’re going to see it eventually.” He calls these “dangerous diagnoses,” given the ease with which they can elude a physician’s awareness. “You’re not thinking about it in every case. But it’s not a total zebra that you’ll never see.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.