The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 59

73. Can mast cell disease cause organ damage?

  • Yes.
  • The term organ damage is tricky because people use it to mean a lot of things while providers and researchers often use it to mean one very specific thing. For providers and researchers, the term “organ damage” usually means a change in the organ that affects its structure, like it becomes misshapen or deformed in some way. Structural changes like this are often irreversible. This damage to the organ’s shape and structure usually affects how the organ works, called organ function.
  • When patients and laypeople talk about organ damage, they usually mean a change in the way the organ functions, even if the structure is not changed at all. This is different in a very important way: changes in an organ that do not affect its permanent structure can sometimes be reversible.
  • Both cutaneous and systemic mastocytosis cause organ damage in a way that damages the organ’s structure. When too many mast cells burrow into the tissue of an organ, it has to push other things out of the way. When you have mastocytosis, the mast cells like to stick together and form a big clump in the tissue. This punches holes in the tissue, affecting the organ’s structure and shape. This is called dense infiltration. It is one of the criteria for systemic mastocytosis and also happens in cutaneous mastocytosis.
  • In patients with mastocytosis, those mast cells clumping together cause a lot of the organ damage. This means that people who have the most mast cells usually have the worst organ damage. Patients with malignant forms of mast cell disease, like mast cell leukemia or aggressive systemic mastocytosis, often have organs that are riddled with TONS of mast cells.
  • Mast cells don’t live in the blood so when your body makes way too many mast cells, those mast cells will dive into whatever organ they can to get out of the bloodstream. This causes damage to the structure that you can see with scans or in biopsies.  People with mast cell leukemia and aggressive systemic mastocytosis suffer so much damage to the shape and function of their organs that the organs can totally stop working, called organ failure.
  • One of the key differences researchers and providers see between mastocytosis and mast cell activation syndrome is that mast cells don’t cause THIS TYPE of structural damage in mast cell activation syndrome patients.
  • We know this because in biopsies, they do not have mast cells clumped together to punch holes in the tissue. Sometimes they have lots of mast cells, but it is much less damaging to the tissue if they aren’t clumped together. Think of it like poking something with finger versus punching with your fist.
  • In MCAS, mast cells do not cause structural damage to organs IN THIS WAY. However, many people with MCAS do have structural damage to their organs. Many of them also have organs that do not function correctly even if the organs look normal.
  • Even if you don’t have mast cells punching holes in all your organs, they can still do a lot of damage. This is because mast cells cause lots of inflammation, which can stress out your organs. Over time, your organs can be damaged by the mast cells releasing too many mediators. While this is not always dangerous, it is certainly painful and frustrating.
  • Many MCAS and mastocytosis patients have a lot of damage to their GI tracts from years of vomiting, obstructions, diarrhea or constipation. Hives and mastocytosis spots can damage your skin, causing discoloration, scarring or sensitivity. Muscles can become weaker over time because of mast cell inflammation. Swelling can stretch out your skin and connective tissues. Nerves can be damaged significantly, affecting organ function. Bones can become brittle and break, or can become too dense because the body is making new bone when it shouldn’t.
  • All of these effects on organ function can be caused by mast cells. Major changes in organ function can also cause secondary conditions to arise.
  • Mast cell patients are also at an increased risk for anaphylaxis which can cause changes in organ function or organ damage.
  • Patients who have trouble breathing or low blood pressure may not be getting enough oxygen to their whole body. That can cause lasting damage if it goes on long enough.

For more detailed reading, please visit the following posts:

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 37

44. What is a myeloproliferative neoplasm? Is that what mast cell disease is?

First, let’s pull this term apart.

“Myelo” means marrow, like bone marrow. In this context, it refers to a specific group of blood cells that are made in the bone marrow. These cells are called myeloid or myelogenous cells. These cells all start as one kind of cell called a myeloid progenitor cell. Mast cells and eosinophils are myeloid cells. There are other myeloid cells, too.

“Proliferative” means making lots of cells quickly. In this case, it means making many cells too quickly. When too many cells are made too quickly, the cells are often not made correctly so they don’t work right.

“Myeloproliferative” means making too many myeloid cells very quickly, producing cells that often don’t work right.

“Neo” means new.

“Plasm” means the substance that makes up something living, like what makes up a cell or a tissue. “Plasm” is part of many words used in biology.

“Neoplasm” means the body growing new things, things that don’t belong there. For example, cancers are neoplasms. (Although not all neoplasms are cancers).

Myeloproliferative neoplasm means your body making too many myeloid cells that don’t work correctly.

Speaking generally, any condition where the body makes too many of these myeloid cells when they shouldn’t is a myeloproliferative neoplasm. This means all form of mastocytosis and mast cell tumors (mast cell sarcoma and mastocytoma) are myeloproliferative neoplasms.

However, when people ask if mast cell diseases are myeloproliferative neoplasms, they are usually asking about the WHO (World Health Organization) classification of mast cell disease, which is a little different.

The WHO puts out an exhaustive list of diseases for reference. They group similar diseases together under one category. This list is also revised periodically as new data becomes available or experts request it.

Under the 2008 WHO guidelines, mast cell diseases were classified as myeloproliferative neoplasms along with several other diseases. The other diseases also included in this category make too many myeloid cells too quickly, like essential thrombocythemia, in which the body makes too many platelets.

The mast cell diseases classified as myeloproliferative neoplasms were cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated hematologic disease (SM-AHD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); and mast cell sarcoma. Smoldering systemic mastocytosis (SSM) was mentioned as a provisional category rather than a formal category, meaning that the WHO did not agree that this diagnosis was different enough from ISM to warrant its own category. Neither monoclonal mast cell activation syndrome (MMAS) or mast cell activation syndrome (MCAS) were classified anywhere in the 2008 WHO Guidelines as they were not yet recognized by the WHO as diseases.

Last year, the WHO revised the classification of myeloproliferative neoplasms. It removed all forms of mast cell disease from the myeloproliferative neoplasm category and made a different category for mast cell diseases. This was done because the WHO recognized that mast cell diseases differed from the other myeloproliferative neoplasms in specific ways. They also recognized that mast cell activation syndrome has a ton in common with other mast cell diseases even though it’s not a neoplastic disease. (Mast cell activation syndrome is not from the body making too many mast cells).

So all mast cell diseases were put together. In the new category, the following mast cell diseases were included: cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); mast cell sarcoma; monoclonal mast cell activation syndrome (MMAS); and mast cell activation syndrome (MCAS).

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 26

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

34. What are the differences between the forms of systemic mastocytosis?

Indolent systemic mastocytosis

  • A form of SM in which the amount of mast cells produced in the bone marrow is excessive but not inherently dangerous to organ function.
  • Mast cells produced in the bone marrow are damaged.
  • These mast cells are released into the blood. While there are more mast cells than usual, there are not enough to overwhelm the blood.
  • There are fewer mast cells than in mast cell leukemia. There are often fewer mast cells than aggressive systemic mastocytosis or smoldering systemic mastocytosis.
  • The mast cells leave the blood and may enter organs inappropriately. Some patients do not have signs of too many mast cells being in an organ other than bone marrow.
  • The presence of mast cells in organ tissue can cause symptoms and medical signs but is not inherently dangerous to organ function.
  • It is not unusual for ISM patients to have typical mast cell symptoms and complications like anaphylaxis.
  • The lifespan for ISM is normal.
  • In indolent systemic mastocytosis, patients die from progressing to a more aggressive form of SM, such as MCL, ASM or SM-AHD.
  • Fatal anaphylaxis is always a risk with mast cell disease.

Smoldering systemic mastocytosis

  • A form of SM in which the amount of mast cells produced in the bone marrow is increasing to the point at which it might cause organ damage.
  • Mast cells produced in the bone marrow are damaged.
  • These mast cells are released into the blood. There are fewer mast cells than in mast cell leukemia. There are often fewer mast cells than aggressive systemic mastocytosis.
  • Mast cells leave the blood and enter organs in larger numbers than is normal. The presence of mast cells in these organs can cause symptoms and medical signs, like swelling of the liver.
  • Organ dysfunction can sometimes be corrected with surgery or certain medications.
  • It is not unusual for SSM patients to have typical mast cell symptoms and complications like anaphylaxis.
  • The lifespan for SSM is widely variable. One well known paper published survival of around ten years. However, many of the patients in this study were over 60 and age may have affected the average survival found in this group.
  • Patients with smoldering systemic mastocytosis are monitored to look for signs of significant organ dysfunction.
  • People with this diagnosis are considered to be possibly transitioning to a more serious form of systemic mastocytosis.
  • Smoldering systemic mastocytosis is the diagnosis that occurs between aggressive systemic mastocytosis and indolent systemic mastocytosis. It is thought of as the stage crossed when a patient with indolent systemic mastocytosis progresses to having aggressive systemic mastocytosis or mast cell leukemia.
  • In smoldering systemic mastocytosis, patients die from progressing to a more aggressive form of SM, such as MCL, ASM or SM-AHD.
  • Fatal anaphylaxis is always a risk with mast cell disease.

Aggressive systemic mastocytosis

  • A dangerous form of SM in which your bone marrow makes way too many damaged mast cells.
  • These mast cells are released into the blood. There are fewer mast cells than in the blood than in mast cell leukemia.
  • The mast cells leave the blood and go into various organs.
  • The presence and activation of the mast cells in the organs can affect organ function.
  • Over time, the presence and activation of mast cells in the organs can cause organ failure. This can sometimes be corrected with surgery or certain medications.
  • Typical mast cell mediator symptoms and complications like anaphylaxis are less common than in less serious types of SM.
  • The lifespan for ASM is much shorter than normal but is dependent upon response to treatment and which organs are involved. Older papers reference an average of 41 month survival but this has changed with more recent treatment options.
  • Generally, people with ASM live longer than those with MCL.
  • In aggressive systemic mastocytosis, patients die from the organ damage that has accrued over time by the presence and activation of mast cells in places they don’t belong.
  • Fatal anaphylaxis is always a risk with mast cell disease.

Mast cell leukemia

  • A very dangerous form of SM in which your bone marrow makes massive amounts of damaged mast cells.
  • These mast cells are released into the blood in overwhelming numbers.
  • The mast cells leave the blood and end up in various organs.
  • Specifically because of how many mast cells are present, mast cells invading the organs break up the organ tissue and cause severe organ damage.
  • The organ damage leads to organ failure, which leads to death.
  • Typical mast cell mediator symptoms and complications like anaphylaxis are less common than in less serious types of SM.
  • The lifespan for MCL is much shorter than normal.
  • Lifespan for MCL is usually quoted as being in the range of 6-18 months. However, there are more recent reports of some patients living 4+ years.
  • In mast cell leukemia, patients die from the organ damage caused by large amounts of mast cells entering and breaking up organ tissue.
  • Fatal anaphylaxis is always a risk with mast cell disease.
  • Of note, there is a newly described chronic form of mast cell leukemia. In this form, patients have stable mast cell disease despite having an overwhelming amount of mast cells in their bodies. The reason for this is unclear and long term survival is not yet known.

Systemic mastocytosis with associated hematologic disease

  • A form of SM in which the patient also has a separate blood disorder that produces too many cells of a different kind.
  • A patient with systemic mastocytosis with associated hematologic disease has too many mast cells and too many blood cells of a different kind. 
  • Previously called SM-AHNMD, systemic mastocytosis with associated clonal hematologic non mast cell lineage disease.
  • The two blood disorders, SM and the other disorder, are treated separately the same way they would be if the patient only had one or the other.
  • The lifespan for SM-AHD is wildly variable as it depends both on which type of SM the patient has as well as the type and severity of the other blood disorder.
  • An important thing to remember is if a patient has SM and another blood disorder that produces too many cells, they are classified as SM-AHD regardless of the type of SM they have. For example, if a patient who has ISM (normal lifespan) also has chronic myelogenous leukemia, they have SM-AHD. However, if the patient has ASM (shortened lifespan) and chronicle myelogenous leukemia, they still have SM-AHD even though the prognosis changes considerably.
  • In SM-AHD, patients die from having an aggressive form of SM, such as MCL or ASM, or as a result of their other blood disorder.
  • Fatal anaphylaxis is always a risk with mast cell disease.

For more detailed reading, please visit these posts:
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 15

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.
23. Is mast cell disease progressive?
No, mast cell disease is not inherently progressive. Many patients live their entire lives with the same diagnosis.
“Progressive” is not the same thing as “changing.” The way mast cell disease can change over time and often does.
• “Progressive” has a very specific meaning in this context. It means movement from one diagnostic category to another, essentially changing your diagnosis to a more serious form of mast cell disease.
We do not have studies yet on whether or not MCAS “becomes” SM. However, we know that many people live with MCAS for decades without evidence of SM.
• There are several subtypes of systemic mastocytosis. In order of increasing severity, they are: indolent systemic mastocytosis; smoldering systemic mastocytosis; systemic mastocytosis with associated hematologic disease; aggressive systemic mastocytosis; and mast cell leukemia.
• The relative danger of systemic mastocytosis with associated hematologic disease (SM-AHD) when compared with other forms of systemic mastocytosis varies wildly. SM-AHD is when you have SM and another blood disorder where your body makes way too many cells. The other blood disorder is an important factor in life expectancy and risk of organ damage so it is difficult to compare it to other forms of mastocytosis.
• For patients with indolent systemic mastocytosis, in the 5-10 years following diagnosis, about 1.7% of patients progressed to smoldering mastocytosis, aggressive systemic mastocytosis, or mast cell leukemia.
• For patients with indolent systemic mastocytosis, in the 20-25 years following diagnosis, about 8.4% of patients progressed to smoldering mastocytosis, aggressive systemic mastocytosis, or mast cell leukemia.
• For patients with indolent systemic mastocytosis, one study found that roughly 8% of patients progressed to smoldering systemic mastocytosis.
• For patients with indolent systemic mastocytosis, two studies found that roughly 3% and 4% of patients progressed to aggressive systemic mastocytosis.
• For patients with indolent systemic mastocytosis, about 0.6% of patients progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia)..
• For patients with smoldering systemic mastocytosis, about 18% of them progressed to aggressive systemic mastocytosis or mast cell leukemia.
• For patients with aggressive systemic mastocytosis, about 6.5% of them progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia).
• For patients with systemic mastocytosis with associated hematologic disease, about 13% of them progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia).

For more detailed reading, please visit these posts:

Progression of mast cell diseases: Part 2

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 2

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

3. What causes mast cell disease?

  • The cause of mast cell disease is not yet definitively known.
  • As mentioned yesterday, when the body makes too many copies of a broken cell, those cells are called ‘clonal’ cells. In clonal forms of mast cell disease, the bone marrow makes too many mast cells. Those mast cells also don’t work correctly. Examples of clonal mast cell diseases are systemic mastocytosis and cutaneous mastocytosis.
  • Patients with systemic mastocytosis often have a specific genetic mutation called the CKIT D816V mutation. About 80-90% of systemic mastocytosis patients have this mutation. This mutation is in mast cells and it tells the mast cells to stay alive WAY longer than they should. And mast cells already live for months or years, a very long time for cells to live in the body. So patients with this mutation can end up with way too many broken mast cells.
  • Despite the fact that we know that many patients have this mutation, we do not say that this mutation CAUSES the disease. The reason for this is that sometimes, mast cell patients don’t have the mutation when they get sick but they develop it later. Sometimes, mast cell patients have the mutation and then lose it later. So we are still looking for something that causes the disease.
  • Patients with non-clonal mast cell disease do not have a single major mutation like the CKIT D816V mutation. This makes it harder to diagnose. Researchers have found that many times, patients with MCAS DO have mutations similar to the ones systemic mastocytosis patients do. But the MCAS patients often have different mutations from each other. That’s why it’s not helpful yet for diagnosis.
  • Despite the fact that the mutations described here are not considered to be heritable, there is more and more evidence that mast cell disease can happen to many people in the same family. See the next question for more details.

4. Is mast cell disease heritable?

  • Mast cell disease often affects multiple members of the same family. Importantly, patients often have a different type of mast cell disease than their relatives. This implies that mast cell disease is more of a spectrum rather than several different diseases.
  • A survey found that 74% of mast cell patients interviewed reported at least one first degree relative that had mast cell disease. This same study found that 46% of those patients had mast cell disease that affected more than just their skin. This is called systemic disease.
  • The CKIT D816V mutation is the mutation most strongly associated with clonal mast cell disease. The CKIT D816V mutation is NOT heritable.
  • There are very rare instances of other heritable mutations in families that have mast cell disease. The significance of this is not clear.

5. Can mast cell disease be cured?

  • Generally speaking, there is no cure for mast cell disease.
  • Children who present with cutaneous mastocytosis sometimes grow out of their disease. Their lesions disappear. Their mast cell symptoms affecting the rest of the body may disappear. We do not know why this happens. It has been heavily researched with long term follow up of children with childhood mastocytosis (at least one paper followed them for 20 years).
  • Children with true systemic mastocytosis do not grow out of their disease.
  • There is not yet data on children with MCAS. Anecdotally, they do not seem to grow out of their disease like kids with cutaneous mastocytosis can. Importantly, this is just what it looks like to me. Again, there is no data.
  • People with adult onset mast cell disease have lifelong disease.
  • There is one notable exception to this scenario. There are reports of curing mast cell disease following hematopoietic stem cell transplant/bone marrow transplant.
  • Transplantation is EXTREMELY dangerous. The transplant is MUCH, MUCH more dangerous than mast cell disease. Many people do not survive the protocol necessary to prepare for transplant. Many die from complications, or from a disease they acquired after their transplant.
  • Rarely, people may have malignant forms of mast cell disease, aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL). A few patients with these diseases have tried transplants after everything else failed. While some did see improvement after transplant, no one has survived more than a few years.
  • Conversely, sometimes people with mast cell disease have these transplants for other reasons, like having another blood cancer or bone marrow disease that requires transplant. In this group of people, some see drastic improvement of their mast cell disease. Some see a full remission of mast cell disease. Some do not get any improvement. These findings are pretty recent so it’s hard to be more specific.

For more detailed reading, please visit these posts:

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Mast cell disease in families

Heritable mutations in mastocytosis

The Provider Primer Series: Natural history of SM-AHD, MCL and MCS

Natural history of systemic mastocytosis with associated hematologic disease (SM-AHD):

  • SM-AHD is defined by systemic mastocytosis in the presence of another clonal hematologic disease. SM-AHD is thought to comprise 30-40% of all mastocytosis cases[i].
  • In about 90% of cases, the associated blood disorder is a myeloid neoplasm such as myelodysplastic syndrome, myeloid leukemias, or myeloproliferative diseases such as polycythemia vera or essential thrombocythemia[i] . Janus kinase 2 (JAK2) V617F mutation, which has a known association with myeloproliferative neoplastic conditions such as essential thrombocythemia and polycythemia vera, is sometimes present in SM-AHD patients[vii].
  • In this condition, SM and the other blood disorder are treated as separate entities as if they did not co-occur[i]. The conditions are synchronous and the associated hematologic disease does not occur secondarily to SM or treatment thereof. Prognosis in SM-AHD depends almost exclusively upon the associated hematologic concern. In multiple studies, fatalities are reported as result of associated malignancies[ii].
  • Myeloid neoplasms are the most common AHD, including chronic myelomonocytic leukemia or other leukemias, myelodysplastic syndrome, or myeloproliferative diseases[i].
  • In a 138 patient cohort: about 1/3 demonstrated Hgb <100 g/L and platelets<100×109/L; 51% had elevated white cell count; 31% demonstrated frank eosinophilia <1.5×109/L[vii].
  • SM-AHD patients are at increased risk of leukemic transformation relative to other forms of systemic mastocytosis (excluding mast cell leukemia) with a frequency of 14% in a 138 patient cohort[vii].
  • The SM aspect of SM-AHD is diagnosed and staged according to the SM diagnostic algorithm. It is therefore possible for a patient with SM-AHD to have mast cell leukemia or any other subtype of SM[vii].

Natural history of mast cell leukemia (MCL):

Table 1: Diagnostic criteria for mast cell leukemia[iii] 
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 2: C findings present in acute MCL[iii] 

 

C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

  • Mast cell leukemia is defined by SM where ≥20% nucleated cells in marrow are mast cells. In leukemic variant, >10% of nucleated cells in blood are mast cells; in aleukemic variant, there are <10% mast cells[iii].
  • MCL can occur de novo or from a previous mast cell neoplastic condition such as aggressive systemic mastocytosis or mast cell sarcoma[iii].
  • CKIT D816V mutation is less common in MCL than in other forms of systemic mastocytosis (50-80%). Some patients have mutations elsewhere in the coding regions of CKIT or a non-D816V mutation at CKIT codon 816. An unusual feature of MCL is that when the disease progresses quickly, the patient may lose positivity for the D816V mutation[iv].
  • MCL patients do not typically demonstrate mastocytosis in the skin[iii].
  • In the absence of C findings, some MCL patients have stable disease without markers of progression. This is referred to as chronic MCL[iii] .
  • >90% mature mast cells is a positive prognostic indicator. Presence of mostly immature mast cells is associated with more aggressive disease[iii] .
  • Acute MCL rapidly causes catastrophic organ damage. Median survival in acute cases is six months, though some MCL patients live for years through the use of newer targeted therapies[iv].
  • Hematopoietic stem cell transplant (HSCT) is an experimental option for MCL patients. In one study, overall survival at the three year mark was 17% (2 of 12 patients)[viii].

Natural history of mast cell sarcoma:

  • Mast cell sarcoma is an exceedingly rare tumor with high grade cytology that can present in a variety of tissues[v].
  • Mast cells that comprise the tumor resemble neither morphologically normal mast cells or spindled cells often seen in SM. In mast cell sarcoma, mast cells are often bilobed and multinucleated tumor cells have been reported. Of note, mast cells compromising the sarcoma often express CD30[iv].
  • Mast cell sarcomas often have neither CKIT D816V mutation nor mutations elsewhere in CKIT coding regions[vi].
  • Mast cell sarcomas often induce only local symptoms at the time of diagnosis but systemic involvement rapidly follows. Mast cell sarcoma may progress to mast cell leukemia. Median survival is 12 months[vi].

References:

[i] Gotlib J. (2013). Approach to the diagnosis and management of mastocytosis. The Hematologist, 10(1). Retrieved from: http://www.hematology.org/Thehematologist/Ask/5960.aspx

[ii] Wang SA. (2013). Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): clinical significance and comparison of chromosomal abnormalities in SM and AHNMD components. Am J Hematol, 88(3), 219-224.

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.

[iv] Youk J. (2016). A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data. Blood Res, 51(1), 17-22.

[v] Ryan RJH, et al. (2013). Mast cell sarcoma: a rare and potentially underreecognized diagnostic eneity with specific therapeutic implications. Modern Pathology, 26, 533-543.

[vi] Georgin-Lavialle S, et al. (2013). Mast cell sarcoma: a rare and aggressive entity – report of two cases and review of the literature. JCO, 31(6), e50-e57.

[vii] Lim KH, et al. (2009). Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 113(23), 5727-5736.

[viii] Ustun C, et al. (2014). Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol, 32(29), 3264-3274.

Chronic mast cell leukemia: A new variant of systemic mastocytosis

Mast cell leukemia (MCL) is a variant of systemic mastocytosis (SM) marked by a significantly shortened lifespan.  In MCL, patients experience massive and devastating proliferation of immature mast cells.  The bone marrow is always affected and the huge amount of mast cells means there is no room for other types of blood cells. Usually, the bone marrow smear reveals over 20% of nucleated cells in bone marrow are atypical mast cells, as well as large quantities present in the blood.  In the aleukemic variant, less than 10% of all white cells in the blood are mast cells.

In most patients with MCL, C-findings (markers of organ infiltration and damage progressing to organ failure) are present.  These include such features as hypersplenism, liver damage, very low blood cell counts, and others.  However, in the last several years, a number of MCL patients described who do not have C findings.  These patients have over 20% mast cells in the nucleated cells of the bone marrow, but the mast cells are mostly mature, and most do not circulate in the blood stream.  This population often demonstrates stability rather than rapid progression toward death, as was previously seen in most MCL patients.  The term “chronic MCL” has been suggested to describe this group.

The more classic MCL presentation (now called acute MCL) has a number of differences from chronic MCL.  In acute MCL, most of the mast cells are not mature, with metachromatic blast cells.  In acute MCL, CD25 receptor is always present on the cells, while this only sometimes occurs in the chronic course.  Chronic MCL never expresses Ki-67 on the outside of the cells, while this is sometimes seen in acute MCL.  Both acute and chronic sometimes have CD2 and D816V mutation, but not always.  Spindle shaped mast cells are almost never present in acute MCL.  Swelling of the spleen is always seen in acute MCL, but only sometimes in the chronic form.  Chronic MCL patients have no C findings.  If they develop a C finding, they are reclassified as acute MCL.

Acute MCL has long been associated with very short survival times following diagnosis, most often less than a year.  This can be extended in some patients with the use of newer medications.  Remarkably, patients with chronic MCL demonstrate a largely stable clinical course comparable to smouldering SM.  In both of these conditions, tryptase levels are high but stable; the spleen is most often swollen; and mast cell burden is high.  Patients with chronic MCL usually have no mast cell skin lesions.

Chronic MCL patients can be stable for years, but can progress to acute MCL or MCL-AHNMD at any time.  Mediator release symptoms more often seen in indolent mast cell diseases are also common in chronic MCL, while less so in acute MCL.

Reference:

P. Valent et al. Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features. 23eukemia Research 39 (2015) 1-5.

MCAD, MCAS and the hierarchy of mast cell disease classifications

I have seen several posts recently expressing confusion about various mast cell diagnoses so I figured I would put up a post to clear things up.
Mast cell activation disorder (MCAD) is a catch-all term for mast cell disease (MCD.)  MCAD and MCD can be used interchangeably.  So if you have any mast cell disease, you have MCAD.  If you have SM, you have MCAD, because SM is a type of MCAD.  If you have UP, you have MCAD, and so on.  MCAD is an umbrella term.  It is non-specific.  It is similar to being told that you have heart disease when you have mitral valve prolapse.  It is true, but it is not precise enough to give all information needed to treat effectively.
Mast cell activation syndrome (MCAS) is the diagnosis you get if you do not meet the criteria for any of the defined mast cell diseases, but have mast cell mediator related symptoms.  You cannot have MCAS and another mast cell disease because, by its definition, MCAS is ONLY diagnosed if you do NOT meet the criteria for any other mast cell disease.  You cannot have UP and MCAS.  You cannot have SM and MCAS.  I think some people think that MCAS means you have mediator related symptoms.  This is not the case.  You can have mediator related symptoms with pretty much any mast cell disease. 
A paper was published a few years ago by a doctor who considers mast cell activation symptoms to be due exclusively to proliferation (like in SM.)  He wrote a paper that says that MCAS is found in people with SM.  This paper sort of confused the issue for a lot of people.  However, the mast cell community (including researchers and prominent doctors) do not consider this to be the case.  They agree that you cannot have SM and MCAS.
Also confusing is the fact that mast cell activation (MCA) is NOT the same as MCAS.  MCA just means that your mast cells are activated, which occurs in any mast cell disease.  MCA is not a diagnosis, it is a symptom.  So you can have MCA in SM.  But you still can’t have MCAS in SM.
So if you have SM and have lots of mediator related symptoms, you have SM.  If you want to speak broadly, you have SM.
If you test negative for SM and have no CM, but have mast cell symptoms and elevated mast cell markers, you have MCAS. 
If you have UP and then later develop SM, you have SM with skin involvement, or SM with UP. 
If you have UP or TMEP and have lots of mediator related systemic symptoms, you do NOT have UP and MCAS.  You have UP.  UP and TMEP (forms of CM) can cause systemic symptoms.  But you cannot have MCAS because you can only have MCAS if you do not meet the criteria for another mast cell disease.
Let’s review.
If you have UP: you have UP, you have CM, you have MCAD.
If you have TMEP: you have TMEP, you have CM, you have MCAD.
If you have SM: you have SM, you have MCAD.
If you have SM with UP: you have SM with skin involvement, you have UP, you have MCAD.
If you have SM with TMEP: you have SM with skin involvement, you have TMEP, you have MCAD.
If you have SM-AHNMD: you have SM-AHNMD, you have MCAD.
If you have ASM: you have ASM, you have MCAD.
If you have MCL: you have MCL, you have MCAD.

If you have MCAS: you have MCAD.

Reference:
Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.