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Chapter 72 Mast Cells and Mastocytosis 1173

Diagnostic criteria for SM were initially formulated by a working
Germline Susceptibility to Mast Cell Disorders and group of MC disease experts at a consensus conference in Vienna in
Familial Mastocytosis 2000, and adopted by the WHO in both 2001 and 2008. In the
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2008 WHO Classification of hematolymphoid neoplasms, mastocy-
In general, mastocytosis behaves as an acquired, somatic disease. tosis was classified as one of the disease subtypes under the major
However, a few familial cases have been reported. In most of these category of “Myeloproliferative Neoplasms (MPNs)”. However, in
families, a KIT mutation (various codons affected) can be detected the revised 2016 WHO classification, mastocytosis is now classified
in the germline. However, in a few families, the KIT mutation was as its own major category distinct from MPNs. Minimal diagnostic
only expressed in hematopoietic cells, but not in the germline of the criteria for SM requires at least one major plus one minor criterion,
affected individuals, suggesting that predisposing germline factors or at least three minor criteria (Table 72.2). The major criterion is
may contribute to disease development. However, so far, little is the presence of multifocal dense aggregates of MCs (>15 MCs in
known about what gene polymorphisms serve as susceptibility alleles. aggregates) in sections of BM or other extracutaneous organ(s); minor
In one study, polymorphisms within certain cytokine genes have been criteria include: (1) >25% of the MCs in the infiltrate or in the BM
identified as exerting a potential predisposition to development of smear are of spindle shape or of otherwise atypical morphology; (2)
SM. In particular, a polymorphism in the promoter of the IL-13 gene, activating mutation at codon 816 in the KIT gene in an extracutane-
−1112C/T, was significantly more frequent in SM patients versus ous organ; (3) expression of CD2 and/or CD25 in/on MCs; and 4)
both cutaneous mastocytosis (CM) patients and healthy controls. In serum tryptase level >20 ng/mL, unless there is an associated myeloid
addition −1112C/T was associated with increased serum tryptase disorder that makes this parameter not valid.
levels and adult-onset disease. MCs express IL-13 receptors and SM is further divided into several subtypes that reflect the pres-
IL-13–containing medium provides enhanced support for the growth ence or absence of certain clinical or laboratory findings (Tables 72.3
of MCs. However, it remains unclear how −1112C/T relates to these and 72.4). The most common form of SM in adults is ISM, charac-
specific biologic findings. In contradistinction to the IL-13 −1112C/T terized by a slightly to markedly increased burden of neoplastic MCs
germline allele, the IL-4α chain receptor Q576 polymorphism was in the BM and/or other extracutaneous organ(s). By definition, ISM
associated with more limited forms of mastocytosis. IL-4 modulates patients do not exhibit MC-related organ damage or an associated
the growth and differentiation of MCs, and induces IgE receptor hematologic disorder, and life expectancy in this variant is similar to
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expression in MCs. Polymorphisms in the IL4 receptor have been that of an age-matched healthy population (Fig. 72.1). However,
implicated in allergic and inflammatory conditions. In a study of ISM patients often experience mediator symptoms related to MC
patients with cutaneous and systemic forms of mastocytosis, this degranulation (e.g., flushing, pruritis, diarrhea, abdominal cramping,
polymorphic allele was significantly more associated with cutaneous neuropsychiatric complaints). Although triggers may not always be
disease, childhood-onset disease, and lower levels of serum tryptase identifiable, known provokers of MC activation and/or anaphylaxis
and soluble CD117. The Q576 polymorphism in the IL4α chain include non-IgE and IgE-mediated causes: physical or emotional
receptor therefore appears to protect against MC hyperplasia and stress, exercise, hot or cold temperature stimuli, medications such as
more aggressive forms of the disease. The Asp358Ala polymorphism aspirin, NSAIDs, opioid analgesics, or antibiotics, alcohol, radiocon-
in the IL-6 receptor was associated with a 2.5-fold lower risk for trast dye, and IgE-mediated allergies. One critical comorbidity is
mastocytosis compared with those with the AC or CC genotypes. Hymenoptera venom allergy. In particular, these patients are at high
However, no association was found between the IL-6 174G/C risk of developing severe or even fatal anaphylaxis upon exposure to
polymorphism and increased susceptibility to SM. the venom. Cutaneous involvement usually develops in conjunction
with the ISM subtype, both in younger individuals as well as in older
EPIDEMIOLOGY AND CLASSIFICATION patients. Bony disease (e.g., localized bone pain, diffuse osteopenia,
osteoporosis with or without pathologic fractures, osteosclerosis) is
OF MASTOCYTOSIS also well described in ISM, but can cause morbid complications
across the spectrum of SM variants.
In 2008, SM was included in the WHO category of myeloprolifera- In the 2008 WHO classification, smoldering SM (SSM) was
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tive neoplasms (MPNs). However, based on the complex clinical designated as a subvariant of ISM. However, based on the current
picture, biology and pathology, SM has been again defined by the
WHO as a separate unique myeloid neoplasm in 2016. SM is an
orphan disease and sparse data exist regarding its incidence or other
epidemiologic features. A slight male predominance has been TABLE World Health Organization Diagnostic Criteria for
observed, and in one study, the median age at time of SM diagnosis 72.2 Systemic Mastocytosis a
was 55 years. A retrospective study from Denmark that canvassed the
years from 1997 to 2010 estimated the incidence of SM at 0.89 per Major criterion Multifocal dense infiltrates of mast cells (>15 mast
100,000 persons per year, with an estimated prevalence of 9.59 per cells in aggregates) detected in sections of bone
100,000 individuals. A Dutch analysis estimated the prevalence of marrow and/or other extracutaneous organ(s)
ISM to be 13 cases per 100,000 inhabitants. Minor criteria a. In biopsy sections of bone marrow or other
The first diagnostic checkpoint is to distinguish SM from CM, extracutaneous organs, >25% of the mast cells in
which is characterized by predominant skin involvement. Criteria to the infiltrate are spindle shaped or have atypical
diagnose SM are not fulfilled in these patients. However, in rare cases morphology or, of all mast cells in bone marrow
with CM, a discrete involvement of the BM by clonal cells may be aspirate smears, >25% are immature or atypical
detected, and serum tryptase levels may be slightly elevated. SM pri- b. Detection of an activating point mutation at
marily occurs in adults, whereas CM is more common in children and codon 816 in KIT in bone marrow, blood, or
its natural history is typically defined by spontaneous resolution of skin another extracutaneous organ
lesions usually at the time of puberty. CM variants include urticaria c. Mast cells in bone marrow, blood, or other
pigmentosa/maculopapular CM, diffuse CM, and solitary mastocy- extracutaneous organs express CD2 and/or CD25
toma of the skin. In the overwhelmingly majority of adults with cutane- in addition to normal mast cell markers
ous involvement, systemic disease (SM) is diagnosed. However, absence d. Serum total tryptase persistently exceeds 20 ng/
of skin lesions does not exclude the presence of SM. Skin involvement mL (unless there is an associated clonal myeloid
occurs in over 80% of all patients with adult SM. However, sometimes, disorder, in which case this parameter is not
no BM examination is performed for some time, especially when the valid)
patient has not been referred to a hematologist. In such cases, cutane- a Requires at least 1 major + 1 minor criteria or 3 minor criteria.
ous lesions are referred to as mastocytosis in the skin (MIS).