Mast Cell Disease

Pathogenesis

MCs are derived from CD34 ⁺ precursor cells arising in the bone marrow and circulate as monocytic cells. Circulating mast cell precursors in the blood express CD34, the tyrosine kinase KIT (CD117), and FcγRII, but not high-affinity IgE receptors (FcεRI). KIT is a type III tyrosine kinase that is expressed on MCs, melanocytes, primitive hematopoietic stem cells, primordial germ cells, and interstitial cells of Cajal. Activation of KIT induces cellular growth and extends cell survival by preventing apoptosis. The ligand for KIT is stem cell factor (SCF), which is important for mast cell growth. SCF is produced by bone marrow stromal cells, fibroblasts, keratinocytes, endothelial cells, and reproductive Sertoli and granulosa cells. Under normal conditions, once mast cell precursors enter tissues they become KIT ⁺ /CD34 ⁻ /FcγRII ⁻ /FcεRI ⁺ and develop characteristic cytoplasmic granules.

Alterations in c-KIT structure have been implicated in the pathogenesis of mast cell disease. Specifically, somatic mutations in codon 816 of the c-KIT proto-oncogene have been identified in adults and children with mastocytosis. The result is a substitution of the amino acid aspartic acid (D) with valine (V) or another amino acid; examples include D816V, D816Y, D816F, D816I, and D816H. This mutation causes constitutive activation of KIT, thereby leading to continued mast cell development. Additional mutations in c-KIT (del419, K509I, F522C, V533D, A533D, V559A, V560G, R815K, I817V, D820G, E839K) also have been reported in adults and children with mastocytosis, but are more rare. Frequently these mutations are detected in mRNA not DNA. In a recent study of 50 children with mastocytosis, ranging in age from 0 to 16 years, activating mutations were detected in 86% of the patients. Forty-two percent were in codon 816 and the remainder were within the gene that encodes the proximal extracellular region (fifth immunoglobulin-like domain). All the c-KIT mutations except M541L found in these children were associated with constitutive KIT activation. Interestingly, an inactivating mutation (e.g., E839K) also has been described in a child with mastocytosis, In the extremely rare familial mast cell disease, c-KIT mutation detection has been variable, ranging from none to the expression of K509I and A533D mutations. The finding of inactivating or no c-KIT mutations in some patients and families with mastocytosis suggests that factors beyond an abnormal KIT receptor play a role in this disease. In fact, additional gene mutations have been identified in some adult patients with more advanced mastocytosis and include the tumor suppressor gene TET2 as well as ASCL1 , JAK2 , SRSF2 , DNMT3A , RUNX1 , and CBL . Taken together, these observations suggest that mutations in c - KIT lead to the development of mastocytosis but that additional gene mutations occur and may be necessary for life-long disease.

Classification of Mast Cell Disease

The classification of mast cell disease has been defined by the World Health Organization (WHO) with the following disease categories: cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), isolated bone marrow mastocytosis (IBMM), systemic mastocytosis with an associated clonal hematologic nonmast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), mast cell sarcoma, and extracutaneous mastocytoma ( Table 42-1 ). Patients with CM and ISM represent the largest groups, and include most children with CM and many adults with CM or ISM. All CM patients and many ISM patients have cutaneous lesions. Cutaneous involvement in mast cell disease is defined by typical lesions of mastocytosis (see “Clinical Manifestations”), and pathological changes that demonstrate either monomorphic mast cell clusters (>15 MCs/cluster) or scattered MCs at more than 20 MCs/high-power field (hpf). Systemic mast cell disease is defined by major and minor criteria in which the major criteria are represented by multifocal dense mast cell infiltrates (15 MCs/aggregate) in the bone marrow or other extracutaneous organs, and the minor criteria include the presence of >25% spindle-shaped or atypical-appearing MCs in tissue sections or a bone marrow aspirate smear, the presence of a c-KIT mutation at codon 816, the expression of CD2 and/or CD25 by MCs and a persistent total serum tryptase level of >20 ng/mL ( Table 42-2 ). The diagnosis of SM is established in patients having the major and one minor criteria or three minor criteria. Whereas most patients with SM have indolent disease, a smaller subset has been recognized as SSM because of greater disease burden, e.g., hepatosplenomegaly, lymphadenopathy, serum tryptase levels >200 ng/mL. Another recognized group of SM patients is one with an associated clonal hematologic nonmast cell disorder. Hematologic diseases associated with this SM group include: polycythemia rubra vera, myelodysplastic syndrome, chronic eosinophilic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, lymphocytic leukemia, acute erythroblastic leukemia, megaloblastic leukemia, and non-Hodgkin’s lymphoma. Patients with SM-AHNMD may or may not have skin lesions, but frequently have liver, spleen, and/or lymph node involvement. They often are older adults, and many have constitutional symptoms such as fever, anorexia, weight loss, and generalized malaise. Aggressive systemic mast cell disease is characterized by lymphadenopathy with or without peripheral blood eosinophilia. Patients with this rare disorder often lack cutaneous lesions, but frequently have mast cell infiltrates involving the bone marrow, gastrointestinal tract, liver, spleen, and lymph nodes. MCL is an extremely rare condition, and the diagnosis is established by demonstrating MCs in the peripheral blood and/or >20% MCs in a bone marrow aspirate smear. Most MCL patients do not have cutaneous lesions, but frequently experience fever, weight loss, abdominal pain, diarrhea, nausea, and vomiting. These patients also have detectable hepatosplenomegaly and lymphadenopathy resulting from extensive mast cell infiltration of these organs. Bone marrow biopsies from MCL patients demonstrate increased MCs, which are often spindle-shaped or morphologically atypical. Mast cell sarcomas and extracutaneous mastocytomas are extremely rare, with only a few isolated case reports.

Clinical Manifestations