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Subtypes and Characteristics of Mastocytosis

Insights From: Hervé Dombret, MD, Institut Universitaire d’Hématologie; Richard M. Stone, MD, Dana-Farber Cancer Institute; Cem Akin, MD, University of Michigan
Published: Monday, May 01, 2017


Transcript:

Cem Akin, MD:
Mastocytosis is a rare disease. It is estimated to occur in about 1 in 10,000 to 20,000 individuals in the general population, and it’s a very heterogeneous disease. But in broad terms, we can separate it into 2 major classes. One is the cutaneous mastocytosis, which occurs primarily in children and is limited to skin. Those children have a self-limited disease. They usually grow out of it by the time they reach adolescence, and they are not candidates for cytoreductive treatment options because they have good prognosis.

The other major category is systemic mastocytosis. Those patients may or may not have skin lesions, but they always have bone marrow involvement. In those patients, when we do a bone marrow biopsy, we see collections of mast cells in the bone marrow in clusters, and they express abnormal markers, such as CD25, on their surface. They carry a mutation in a gene called KIT, and most of those mutations involve one particular area of the gene, codon-816; especially since one particular mutation, D816V, is seen in more than 90% of those patients.

Richard M. Stone, MD: The spectrum of mast cell diseases can have proteome manifestations in patients that have one or more of the subtypes. The most common clinical manifestation is skin disease, but in those with the more aggressive subtypes of mast cell disease, they can have fevers, severe anaphylactic reactions, and diarrhea due to infiltration of the mast cells in the GI mucosa. They can have liver abnormalities, which can even cause jaundice. They can have bone pain from localized mast cell infiltration in bone lesions. They can have infection, bleeding, and fevers from bone marrow failure engendered by too many mast cells. So, there can be a lot of different ways a person can come to medical attention with a mast cell disease.

Cem Akin, MD: Among the systemic mastocytosis patients, there are 5 different categories. The most common category in systemic mastocytosis is called indolent systemic mastocytosis. This is the benign version of the disease. Those patients will have bone marrow infiltrates of mast cells, but they have a comparable life expectancy to general population. They do suffer from mast cell mediator-related symptoms caused by mediators like histamine, prostaglandin, and cytokines. Those symptoms may include recurrent flushing of the face, stomach issues, nausea, vomiting, and diarrhea, which all come on episodically. Sometimes vasoactive symptoms occur: low blood pressure, passing out, and syncopal or pre-syncopal episodes. We generally treat those patients with anti-mast cell mediator treatment, such as antihistamine medications.

Then there are the advanced varieties of systemic mastocytosis that are associated with a worse prognosis and decreased life expectancy. Among those advanced categories, the first one is mastocytosis associated with a hematologic disorder. Those patients have mastocytosis plus another blood disorder in the bone marrow biopsy, and that disorder is usually a myeloproliferative or a myelodysplastic disorder. Those patients are at risk for progressing into acute myeloid leukemia, and the prognosis is determined by the course of that associated hematologic disorder.

The other advanced category of mastocytosis is called aggressive systemic mastocytosis. This category could be thought of as a cancer or as a malignant version of mast cell disease. Those patients generally have very high mast cell burdens, not only in their bone marrow, but also infiltrating other tissues—spleen, liver, lymph nodes, gastrointestinal tract—and causing disruption of the function of the tissue. For example, in a patient with liver infiltration, the mast cells might cause fibrosis and portal hypertension and that patient might experience ascites and the consequences of liver dysfunction.

In patients with very heavy mast cell involvement of the bone marrow, we see cytopenias, neutropenias, and anemias requiring transfusion; platelet problems; and thrombocytopenia requiring platelet transfusions. That’s another manifestation of aggressive systemic mastocytosis. Some of those patients may have extensive gastrointestinal tract infiltration resulting in low albumin, malabsorption, weight loss, and extensive diarrhea. Finally, another group might experience pathologic bone fractures because of the mast cell involvement of the cortical bone. All of those tissue dysfunction findings are called C-findings.

If the patient has any of those C-findings together with the diagnostic findings of mastocytosis, the patient is classified into an aggressive systemic mastocytosis category. Then there is the extremely rare variant of mast cell leukemia. That variety is diagnosed by showing more than 10% mast cells in circulation and peripheral blood or greater than 20% mast cells in the bone marrow aspirate. Aspirate is the key tissue here, not the biopsy. It wouldn’t be unusual to see a 20% infiltrate in the bone marrow biopsy of a patient with indolent mastocytosis, but they should not be in the aspirate portion of the biopsy because they tend to stick with the bone trabeculae, so they don’t become loose and get into the aspirate smear.

Those patients have very poor prognosis. The published case reports suggest a median survival time of less than 6 months after the diagnosis, whereas patients with aggressive systemic mastocytosis have a median survival time of around 3 years. There are more rapidly progressing and slowly progressing varieties among each category, but we are talking about just overall survival when we talk about those numbers. For the patients with an associated hematologic disorder, the prognosis depends on if and how fast they progress into AML or not.

Those are, in general, the broad categories that we see, most of them in clinical practice. There are other rare variances, such as mast cell sarcoma and another transitional group called smoldering mastocytosis, which is a group between the indolent and the malignant forms of mastocytosis. Those are rare patients, and we usually adopt treatment options for those patients based on what we know about patients with other advanced varieties.

Transcript Edited for Clarity
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Transcript:

Cem Akin, MD:
Mastocytosis is a rare disease. It is estimated to occur in about 1 in 10,000 to 20,000 individuals in the general population, and it’s a very heterogeneous disease. But in broad terms, we can separate it into 2 major classes. One is the cutaneous mastocytosis, which occurs primarily in children and is limited to skin. Those children have a self-limited disease. They usually grow out of it by the time they reach adolescence, and they are not candidates for cytoreductive treatment options because they have good prognosis.

The other major category is systemic mastocytosis. Those patients may or may not have skin lesions, but they always have bone marrow involvement. In those patients, when we do a bone marrow biopsy, we see collections of mast cells in the bone marrow in clusters, and they express abnormal markers, such as CD25, on their surface. They carry a mutation in a gene called KIT, and most of those mutations involve one particular area of the gene, codon-816; especially since one particular mutation, D816V, is seen in more than 90% of those patients.

Richard M. Stone, MD: The spectrum of mast cell diseases can have proteome manifestations in patients that have one or more of the subtypes. The most common clinical manifestation is skin disease, but in those with the more aggressive subtypes of mast cell disease, they can have fevers, severe anaphylactic reactions, and diarrhea due to infiltration of the mast cells in the GI mucosa. They can have liver abnormalities, which can even cause jaundice. They can have bone pain from localized mast cell infiltration in bone lesions. They can have infection, bleeding, and fevers from bone marrow failure engendered by too many mast cells. So, there can be a lot of different ways a person can come to medical attention with a mast cell disease.

Cem Akin, MD: Among the systemic mastocytosis patients, there are 5 different categories. The most common category in systemic mastocytosis is called indolent systemic mastocytosis. This is the benign version of the disease. Those patients will have bone marrow infiltrates of mast cells, but they have a comparable life expectancy to general population. They do suffer from mast cell mediator-related symptoms caused by mediators like histamine, prostaglandin, and cytokines. Those symptoms may include recurrent flushing of the face, stomach issues, nausea, vomiting, and diarrhea, which all come on episodically. Sometimes vasoactive symptoms occur: low blood pressure, passing out, and syncopal or pre-syncopal episodes. We generally treat those patients with anti-mast cell mediator treatment, such as antihistamine medications.

Then there are the advanced varieties of systemic mastocytosis that are associated with a worse prognosis and decreased life expectancy. Among those advanced categories, the first one is mastocytosis associated with a hematologic disorder. Those patients have mastocytosis plus another blood disorder in the bone marrow biopsy, and that disorder is usually a myeloproliferative or a myelodysplastic disorder. Those patients are at risk for progressing into acute myeloid leukemia, and the prognosis is determined by the course of that associated hematologic disorder.

The other advanced category of mastocytosis is called aggressive systemic mastocytosis. This category could be thought of as a cancer or as a malignant version of mast cell disease. Those patients generally have very high mast cell burdens, not only in their bone marrow, but also infiltrating other tissues—spleen, liver, lymph nodes, gastrointestinal tract—and causing disruption of the function of the tissue. For example, in a patient with liver infiltration, the mast cells might cause fibrosis and portal hypertension and that patient might experience ascites and the consequences of liver dysfunction.

In patients with very heavy mast cell involvement of the bone marrow, we see cytopenias, neutropenias, and anemias requiring transfusion; platelet problems; and thrombocytopenia requiring platelet transfusions. That’s another manifestation of aggressive systemic mastocytosis. Some of those patients may have extensive gastrointestinal tract infiltration resulting in low albumin, malabsorption, weight loss, and extensive diarrhea. Finally, another group might experience pathologic bone fractures because of the mast cell involvement of the cortical bone. All of those tissue dysfunction findings are called C-findings.

If the patient has any of those C-findings together with the diagnostic findings of mastocytosis, the patient is classified into an aggressive systemic mastocytosis category. Then there is the extremely rare variant of mast cell leukemia. That variety is diagnosed by showing more than 10% mast cells in circulation and peripheral blood or greater than 20% mast cells in the bone marrow aspirate. Aspirate is the key tissue here, not the biopsy. It wouldn’t be unusual to see a 20% infiltrate in the bone marrow biopsy of a patient with indolent mastocytosis, but they should not be in the aspirate portion of the biopsy because they tend to stick with the bone trabeculae, so they don’t become loose and get into the aspirate smear.

Those patients have very poor prognosis. The published case reports suggest a median survival time of less than 6 months after the diagnosis, whereas patients with aggressive systemic mastocytosis have a median survival time of around 3 years. There are more rapidly progressing and slowly progressing varieties among each category, but we are talking about just overall survival when we talk about those numbers. For the patients with an associated hematologic disorder, the prognosis depends on if and how fast they progress into AML or not.

Those are, in general, the broad categories that we see, most of them in clinical practice. There are other rare variances, such as mast cell sarcoma and another transitional group called smoldering mastocytosis, which is a group between the indolent and the malignant forms of mastocytosis. Those are rare patients, and we usually adopt treatment options for those patients based on what we know about patients with other advanced varieties.

Transcript Edited for Clarity
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