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.