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Advanced SM: Diagnosis and Initial Treatment Approach

Insights From: Hervé Dombret, MD, Institut Universitaire d’Hématologie; Richard M. Stone, MD, Dana-Farber Cancer Institute; Cem Akin, MD, University of Michigan
Published: Wednesday, May 03, 2017


Transcript:

Cem Akin, MD: Mastocytosis is diagnosed by a biopsy; it is a tissue diagnosis. In cutaneous versions of the disease, we observe the skin lesions and biopsy the skin. In systemic variants of the disease, we need to have a bone marrow biopsy, and that bone marrow biopsy will tell us whether or not the patient meets the WHO criteria for systemic mastocytosis.

To briefly go over those criteria, there’s 1 major and 4 minor criteria. The major criterion is a collection of mast cells in aggregates at multifocal locations in the bone marrow biopsy. Each collection should have at least 15 or more mast cells.

One of the 4 minor criteria is elevation and serum tryptase greater than 20 ng/mL. Serum tryptase is a marker of mast cell burden, and normal levels are around 5. We usually see levels greater than 20 in patients with systemic mastocytosis correlating with increased levels of mast cell burden.

Another minor criterion is the presence of a KIT mutation, and KIT is a tyrosine kinase receptor that binds stem cell factor and has very important functions in mast cell survival differentiation; it protects them from apoptosis. In mastocytosis, there’s a point mutation in codon 816 in the tyrosine kinase area of the gene that obviates the need for the receptor to bind stem cell factor. The receptor becomes independent of its ligand and is constantly turned on and that sends a message to the mast cell to proliferate and protect it from apoptosis.

In more than 90% of the patients, there’s this long mutation, D816V, associated with systemic disease. It is seen in all varieties—in indolent and advanced varieties.

Richard M. Stone, MD: Aggressive systemic mastocytosis needs to be diagnosed histologically. You need to find mast cells in an organ where they shouldn’t normally be, such as a bone, the bone marrow, the liver, or the GI tract. Furthermore, many patients with symptomatic aggressive systemic mastocytosis have elevations in their serum tryptase. Tryptase is one of the mast cell mediators that is often in high enough levels of the blood that you can actually measure it; you can track the course of the disease with it. It’s a combination of serum tryptase, but is mainly a biopsy of the affected organ to prove that there are mast cells there. These mast cells can look atypical, as well, under the microscope.

The risk assessment in aggressive systemic mastocytosis is based on the number of extracutaneous lesions that the patient has and the degree of infiltration. Again, there are C-findings, where you have bone involvement, GI tract involvement, profound skin involvement, or bone marrow involvement. Those with more of those things have a worse prognosis than those with less, but there’s not a great clinical staging system as there is in Hodgkin’s lymphoma or even non-Hodgkin’s lymphoma to account for prognosis.

Cem Akin, MD: Once we make the diagnosis of systemic mastocytosis, then we need to assign a variety, or subcategory, of systemic mastocytosis: whether or not it is indolent or the benign form; one of the more advanced forms, such as those associated with hematologic disorders or aggressive mastocytosis; or mast cell leukemia. Those are mainly determined by how the bone marrow biopsy looks, whether or not it meets criteria for another myeloproliferative disorder in addition to mastocytosis, or if the mast cells are present in aspirates greater than 20% to meet the criteria for mast cell leukemia. To diagnose aggressive systemic mastocytosis, we also need to look at the clinical findings: whether or not the patient has experienced a weight loss, if there’s severe diarrhea and malabsorption, and other laboratory finding like cytopenias, low albumin, and liver dysfunction. If any of those findings, C-findings, are present, then the patient is categorized into aggressive systemic mastocytosis.

Transcript Edited for Clarity
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Transcript:

Cem Akin, MD: Mastocytosis is diagnosed by a biopsy; it is a tissue diagnosis. In cutaneous versions of the disease, we observe the skin lesions and biopsy the skin. In systemic variants of the disease, we need to have a bone marrow biopsy, and that bone marrow biopsy will tell us whether or not the patient meets the WHO criteria for systemic mastocytosis.

To briefly go over those criteria, there’s 1 major and 4 minor criteria. The major criterion is a collection of mast cells in aggregates at multifocal locations in the bone marrow biopsy. Each collection should have at least 15 or more mast cells.

One of the 4 minor criteria is elevation and serum tryptase greater than 20 ng/mL. Serum tryptase is a marker of mast cell burden, and normal levels are around 5. We usually see levels greater than 20 in patients with systemic mastocytosis correlating with increased levels of mast cell burden.

Another minor criterion is the presence of a KIT mutation, and KIT is a tyrosine kinase receptor that binds stem cell factor and has very important functions in mast cell survival differentiation; it protects them from apoptosis. In mastocytosis, there’s a point mutation in codon 816 in the tyrosine kinase area of the gene that obviates the need for the receptor to bind stem cell factor. The receptor becomes independent of its ligand and is constantly turned on and that sends a message to the mast cell to proliferate and protect it from apoptosis.

In more than 90% of the patients, there’s this long mutation, D816V, associated with systemic disease. It is seen in all varieties—in indolent and advanced varieties.

Richard M. Stone, MD: Aggressive systemic mastocytosis needs to be diagnosed histologically. You need to find mast cells in an organ where they shouldn’t normally be, such as a bone, the bone marrow, the liver, or the GI tract. Furthermore, many patients with symptomatic aggressive systemic mastocytosis have elevations in their serum tryptase. Tryptase is one of the mast cell mediators that is often in high enough levels of the blood that you can actually measure it; you can track the course of the disease with it. It’s a combination of serum tryptase, but is mainly a biopsy of the affected organ to prove that there are mast cells there. These mast cells can look atypical, as well, under the microscope.

The risk assessment in aggressive systemic mastocytosis is based on the number of extracutaneous lesions that the patient has and the degree of infiltration. Again, there are C-findings, where you have bone involvement, GI tract involvement, profound skin involvement, or bone marrow involvement. Those with more of those things have a worse prognosis than those with less, but there’s not a great clinical staging system as there is in Hodgkin’s lymphoma or even non-Hodgkin’s lymphoma to account for prognosis.

Cem Akin, MD: Once we make the diagnosis of systemic mastocytosis, then we need to assign a variety, or subcategory, of systemic mastocytosis: whether or not it is indolent or the benign form; one of the more advanced forms, such as those associated with hematologic disorders or aggressive mastocytosis; or mast cell leukemia. Those are mainly determined by how the bone marrow biopsy looks, whether or not it meets criteria for another myeloproliferative disorder in addition to mastocytosis, or if the mast cells are present in aspirates greater than 20% to meet the criteria for mast cell leukemia. To diagnose aggressive systemic mastocytosis, we also need to look at the clinical findings: whether or not the patient has experienced a weight loss, if there’s severe diarrhea and malabsorption, and other laboratory finding like cytopenias, low albumin, and liver dysfunction. If any of those findings, C-findings, are present, then the patient is categorized into aggressive systemic mastocytosis.

Transcript Edited for Clarity
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