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 30

38. What is the difference between the forms of cutaneous mastocytosis?

Cutaneous mastocytosis is a form of mast cell disease in which way too many mast cells are found only in the skin and not in other organs. Over 80% of patients with mastocytosis have mastocytosis in their skin.

Patients who have systemic mastocytosis have too many mast cells in organs that are not in the skin. However, many of them also have too many mast cells in their skin. These patients are said to have “systemic mastocytosis with mastocytosis in the skin (MIS).” This terminology distinguishes these patients from those who only have too many mast cells in the skin.

There are three categories of cutaneous mastocytosis:

Maculopapular cutaneous mastocytosis (MPCM):
Previously called urticaria pigmentosa (UP). Many patients and providers still use the term UP and the term MPCM is more commonly found in research work.
This is the most common form of cutaneous mastocytosis.
UP causes lesions on the skin, often called “spots” or “masto spots”. In adults, these spots are usually little red/brown lesions. Sometimes a small amount of skin is affected. Other times, a lot of the skin becomes covered in spots.
In adults, UP spots are usually permanent. Some people who need chemo find that the chemo makes some of their UP spots disappear.
In children, UP spots are often larger. The shape and number of spots may change as they get older.
In children, UP spots sometimes resolve over time and disappear.
There is a type of UP called telangiectasia macularis eruptiva perstans (TMEP). This used to be a separate diagnosis from UP but we now know that it is just a kind of UP that looks different from the common red/brown spots.
In TMEP, little blood vessels growth very close to the skin and look like little red or brown spots.

Diffuse cutaneous mastocytosis (DCM):
DCM almost exclusively starts in childhood.
DCM does not cause spots. Instead, it causes overall redness and thickening of skin. It can also cause blistering. The blisters and wounds sometimes bleed.

Solitary cutaneous mastocytoma:
The third form of cutaneous mastocytosis is a little misleading in classification. This form is called solitary cutaneous mastocytoma.                                                                      This is a benign mast cell tumor that grows on the skin.                                         Mastocytomas can grow elsewhere in the body. When they do, they are not considered a form of cutaneous mastocytosis.
While the term is “solitary cutaneous mastocytoma”, some people do have multiple mastocytomas on their skin.

The Provider Primer Series: Cutaneous mastocytosis/ Mastocytosis in the skin

Mast cell disease: Categories

  • Mast cell disease is the collective term given to several distinct conditions mediated by mast cell dysfunction.  Speaking broadly, mast cell disease has two forms: mastocytosis, a clonal disease marked by excessive proliferation and infiltration of mast cells; and mast cell activation syndrome (MCAS), a disease that presents similarly to mastocytosis but demonstrates no clear indication of excessive proliferation. In addition, monoclonal mast cell activation syndrome (MMAS) can be viewed as straddling the two groupings with markers of clonality but minimum evidence to suggest overproduction of mast cells[i].
  • Mastocytosis has two forms: cutaneous, in which excessive mast cell infiltration is confined to the skin; and systemic, in which an organ that is not skin that is affected by excessive mast cell infiltration. Patients with systemic mastocytosis (SM) often have cutaneous mastocytosis; in this instance, this is called systemic mastocytosis with mastocytosis in the skin[ii].

Mastocytosis in the skin

  • Cutaneous mastocytosis (CM) is a proliferative condition marked by increased mast cell infiltration of the skin.  There are three subvariants of cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), formerly known as urticarial pigmentosa (UP); diffuse cutaneous mastocytosis (DCM); and solitary mastocytoma of skin[ii].
  • Mast cell density in lesions is usually increased 4-8x above the density in healthy controls. However, some patients have mast cell density comparable to that in healthy controls[ii].
  • All forms of cutaneous mastocytosis can be found in children. Over 78% present by 13 months and some at birth[v]. Childhood onset CM often resolves by adolescence but not always[ii].
  • Most patients with mast cell lesions in childhood have CM rather than SM. Conversely, most patients who develop these macules in adulthood have systemic mastocytosis with mastocytosis in the skin[ii].
  • MPCM (UP) is overwhelmingly the dominant presentation of mastocytosis in the skin. Over 80% of all mastocytosis patients demonstrate the type of cutaneous involvement[ii].
  • In children, MPCM lesions are usually large and have variable morphology which may change over time. In adults, MPCM often occurs as small red/brown macules and may result in few lesions or cover the majority of the body[iii].
  • Telangiectasia macularis eruptive perstans (TMEP) is described as telangiectatic red macules generally found above the midtrunk. While previously thought to be a discrete entity, TMEP is now recognized as a form of MPCM[ii].
  • DCM is almost exclusively found in children with few adult onset cases. It does not present as discrete lesions but rather generalized erythema. Pachydermia may also be present, as well as darkening of the skin[ii].
  • DCM can be associated with formation of severe bullae from a variety of triggers, including rubbing the skin, infections and teething. Due to mast cell release of heparin, it is not unusual for skin wounds to bleed excessively[ii].
  • A mastocytoma is a low grade mast cell tumor most often found on the skin. It is frequently raised and yellow or brown in color. Touching the lesion usually evokes a strong wheal and flare reaction. Sweating may also occur. Blistering may be present[ii].

Diagnosis of mastocytosis in the skin

  • While a biopsy is the definitive diagnostic method, positive Darier’s sign is present in most children and many adults with mastocytosis in the skin. Use of antihistamines can suppress a positive Darier’s sign[ii].
  • Biopsies from lesional skin should be stained for mast cells using toluidine blue or Giemsa-Wright stain; evaluated for CD117, CD25 and CD2 using IHC; and evaluated for activating mutations in the CKIT gene using PCR or sequencing methods[i] .
Diagnostic criteria for cutaneous mastocytosis  (requires one major and one minor criterion)[iii]
Major Minor
Typical mast cell rash, usually maculopapular, or atypical rash with positive Darier’s sign Dense infiltration by tryptase positive mast cells, >15 mast cells/cluster or >20 mast cells/x40 magnification hpf if not clustered
Activating CKIT mutation detected in biopsy from skin lesion

 

Symptoms and treatment of mastocytosis in the skin

  • Common symptoms localized to the skin include flushing, itching, burning, hives and blistering[iv].
  • Mediator release symptoms can affect other organs regardless of whether or not they have systemic mastocytosis. Flushing, nausea, vomiting, diarrhea and low blood pressure have been reported among other symptoms. Wheezing, shortness of breath and rarely cyanosis may be present. Anaphylaxis can also occur[iii].
  • Treatment for cutaneous mastocytosis/mastocytosis in the skin relies upon histamine blockade with H1 inverse agonists and H2 antagonists; cromolyn sodium; leukotriene antagonists; and PUVA treatment in severe cases[v].
  • In treatment resistant cases, systemic glucocorticoids and topical cromolyn may be used.  In some instances, mastocytomas may be excisedi. Anaphylaxis should be treated with epinephrine per current guidelines[v].

[i] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol, 4(10), 10.1186/1756-8722-4-10

[ii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1), 35-45.

[iii] Valent P, et al. (2007). Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37, 435-453.

[iv] Carter MC, et al. (2014). Mastocytosis. Immunol Allergy Clin North Am, 34(1), 10.1016/j.iac.2013.09.001

[v] Castells M, et al. (2011). Guidelines for the diagnosis and treatment of cutaneous mastocytosis in children. Am J Clin Dermatol, 12(4), 259-270.

 

Take home points: October 2015

Childhood mastocytosis: Update

  • Cutaneous mastocytosis in children is the most common form of mastocytosis
  • True systemic mastocytosis is very rare in children
  • An NIH study of 105 children found 30-65% improved over time
  • Elevated baseline tryptase level and organ swelling were good indicators of SM
  • Serum tryptase should be measured every 6-12 months
  • Children with swelling of both liver and spleen were positive for CKIT D816V mutation
  • Swelling of liver and spleen together was linked to disease persisting into adulthood
  • Most children with UP with skin and minor GI issues had normal tryptase
  • Diffuse cutaneous mastocytosis patients had a much higher average tryptase but no organ swelling
  • Serum tryptase and IgE were inversely related (high tryptase with low IgE, low tryptase with high IgE)

Chronic mast cell leukemia: a new variant of systemic mastocytosis

  • Mast cell leukemia (MCL) has a significantly shortened lifespan
  • Usually over 20% of nucleated cells in bone marrow are atypical mast cells
  • Mast cells are present in large quantities on the blood
  • Cases where less than 10% of white blood cells in blood are mast cells are called aleukemic variant MCL
  • Cases where over 20% of nucleated cells in bone marrow are mature mast cells are called chronic MCL
  • Chronic MCL patients do not have any C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Chronic MCL patients have stable disease state but can progress to acute MCL at any time
  • Mediator release symptoms are more common in chronic MCL than acute MCL
  • Acute MCL is marked by immature CD25+ mast cells
  • Acute MCL patients do have C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Acute MCL has a very short survival time, usually less than a year

Childhood mastocytosis: Update

One of the more confusing aspects of mastocytosis is that childhood mastocytosis often bears little resemblance to adult-onset mastocytosis and has a very different natural history.  Cutaneous mastocytosis in children is the most common presentation of mastocytosis. True systemic mastocytosis (meeting WHO SM criteria) is quite rare in pediatric cases.

A recent paper describes the features of 105 children assessed at the NIH.  They found that the children in this group either had a stable disease state or improved, with 30-65% getting better over time.  None of the children received cytoreductive therapy.

They found that in this group, children with normal baseline tryptase levels had negative bone marrow biopsies.  A single elevated tryptase level was not determined to correlate well with to a positive bone marrow, rather an elevated baseline tryptase was a good indicator of SM. No children without systemic mastocytosis had organ swelling.

Likewise, all children with systemic mastocytosis had both elevated baseline tryptase and swelling of internal organs.  Bone marrow mast cell burden correlated well with tryptase value. The average tryptase for children with SM in this study was 111.5 ng/ml. Tryptase decreased over time in some SM children.  The researchers recommended evaluation of serum tryptase every 6-12 months.

All children with organ swelling were found to have SM. Children with swelling of both liver and spleen were found to be positive for the D816V CKIT mutation.  Swelling of both of these organs indicates that disease is more likely to persist into adulthood.  Of total 19 children with SM, 16 were positive for the CKIT D816V mutation.

In children with UP, the average tryptase value was 5.9 ng/ml. Twelve children with UP had tryptase values of 11-20, and six had values over 20. Children with UP most often saw significant decreases in tryptase levels over time.   Most UP children with skin and minor GI issues had normal tryptase values.

Children with DCM had much higher average tryptase values, with an average of 67. 85% of DCM children had tryptase over 20 ng/ml when diagnosed.  None of them had swelling of organs.

Of 105 children assessed in this study, 3 had elevated monocytes; 22 had elevated white blood cells; and 12 had elevated platelets.  All of these values returned to normal by the end of the study.  Seven had increased clotting time (PTT). Of those with longer clotting times, four had lupus antibodies and one had Factor VII deficiency. All seven PTT values returned to normal.  Two children with DCM and one with UP had iron deficiency anemia.  One patient had significant elevation of alkaline phosphatase, which resolved.  Researchers noted an inverse correlation between serum tryptase and IgE levels in this group.

Reference:

Carter et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol 2015.

Just a horse

This past spring, I started developing a rash on my back.  It was macular and itchy and swelled and turned red when I touched it. 
“It looks like urticaria pigmentosa except it’s not dark,” one doctor told me.  It’s important to note here that my rash pigmentation has been unusual for my entire life.  I have, on several occasions, had rashes misdiagnosed because they were “too pink” or “too faint.”  I don’t know the reason for this, but it happens.  “I’m sure it’s some kind of mast cell issue, your skin is very reactive,” he followed up.
“That is definitely urticaria pigmentosa,” another doctor told me.  He touched the spots and they puffed up and got itchy.  “See, it has a positive Darier’s sign.”  My skin will urticate will very little provocation so I was not convinced.  But I figured I was probably bound to have UP eventually, so I wasn’t very concerned.
“It is probably a mast cell rash, but you should get it biopsied just in case,” a third doctor told me.  By this point, the rash was all over my back and shoulders.  It was itchy, but not all the time.  I scheduled an appointment with a dermatologist. 
I saw the dermatologist on Thursday.  She took one look at it and said, “Oh, that’s not cutaneous mastocytosis.  That’s a harmless fungal rash.  It’s more common in people who are immunosuppressed.  I’ll give you a cream.”
We had a good laugh over the fact that when you have a rare disease, everyone assumes it is the cause of all your symptoms.  She told me a funny story about a patient with several rare diseases who had a “mysterious rash” that the residents couldn’t identify.  It was tinea versicolor, a very common fungal rash.  The residents had assumed it was something exotic and had not considered more mundane options.
Then there was a small fire in the building while I was dressed only in a gown, educating the visiting PCP about systemic mast cell symptoms from skin reactions.  I threw my clothes on and ran outside as the fire department arrived.  Always lively. 
Mast cell disease is hard to manage in part because it can cause so many problems.  But just because it can cause all of them doesn’t mean it does. 
Mast cell patients are zebras, often many times over.  But even zebras mingle with horses once in a while.

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.