Page 1333 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 72 Mast Cells and Mastocytosis 1179

myeloid neoplasm, including evaluation of MC content. Other
causes of effusion should be excluded including infection, heart 1
failure, and drugs such as dasatinib that have been used to treat
advanced SM. 2
Del417-418-419insNA ±
3 Del417-418-419insI ±
Hematologic Organ Involvement Ig 1 Del417-418-419insY ±
4 Del419 ±
The etiology of cytopenias in advanced SM includes compromise of Ig 2 InsFF419 ±
normal marrow reserve by infiltration with neoplastic MCs (often 5 C443Y ±
seen in ASM and MCL), ineffective hematopoiesis in the context of S451C ±
SM with an associated myeloid neoplasm, hypersplenism, and other 6 S476I ±
causes such as recent myelosuppressive therapy or gastrointestinal Ig 3 ITD501-502 +
bleeding. The coexistence of another myeloid neoplasm (AHN) often 7
makes it difficult to ascertain the specific cause of the low blood ITD502-503 +
counts. This distinction is not relevant to ISM, where the relatively Ig 4 8 ITD504 ±
lower MC burden is not expected to contribute to the development ITD505-508 ±
of cytopenias. 9 K509I ±
Ig 5 F522C ±
Molecular Features of SM 10 A533D ±
TM 11 K550N ±
Following the discovery of the somatic KIT D816V mutation in MC V559I ±
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neoplasms in the mid-1990s, it has become evident that this JM 12 V560IG ±
molecular abnormality is found in approximately 80% to 90% of SM Del564-576 ±
patients. KIT D816V serves as a minor diagnostic criterion for the D572A ±
disease, and is considered a major driver of SM pathogenesis. Rare 13 R634W ±
codon 816 variants such as D816F/H/I/Y have also been described L799F ±
and are considered functionally equivalent to D816V. Mutations TK1 14 InsVI815-816 ±
affecting codon 816 are located in exon 17 and affect the second TK ∗
domain (TK2) that contains the phosphotransferase site and activa- 15 D816Y ±
tion loop of KIT. Other mutations that have been identified in exon D816F ±
17, for example in cases of ASM and MC sarcoma, include D820G 16 D816I ± ∗
and N822K. KIT mutations in exons 8–9 of the extracellular region D816V +++
(del419, S451C, ITD 502–503) and the TM region (exon 10; e.g., 17 D816H ±
F522C), and JM domain (exon 11; e.g., V560G/I) comprise some TK2 I817V ±
of the additional rare mutations in KIT that have been observed (Fig. 18 V819Y ±
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72.6). With a few exceptions (e.g., V559I), mutations affecting D820G ±
these domains are more likely to exhibit sensitivity to imatinib, 19
whereas codon 816 variants are imatinib resistant. Contrary to other N822I/K ±
SM subtypes, MCL less frequently exhibits the KIT D816V muta- 20 E839K ±
tion; in a review of MCL, D816V was found in 13 of 28 (46%) S840N ±
evaluable patients. MCL patients may exhibit other variants within 21 S849I ±
KIT, or sequencing of the entire KIT gene may reveal no mutations.
Increasingly sensitive assays, such as allele-specific quantitative PCR Fig. 72.6 STRUCTURE OF THE KIT GENE AND MUTATIONS IN
for KIT D816V, are now available and can detect KIT D816V in the MASTOCYTOSIS. Representation of the structure of KIT, illustrating the
peripheral blood of almost all adult patients with SM. Where avail- localization of the more frequently observed mutations in the KIT sequence
able, it has been recommended that such sensitive assays be used as in pediatric and adult patients with mastocytosis. The receptor is presented
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a valuable screening test for patients with suspected SM. However, under its monomeric form, whereas its WT counterpart dimerizes upon
a low MC burden or the presence of other rare KIT or non-KIT ligation with SCF before being activated in normal cells. In children, the KIT
mutations could lead to negative results; therefore a full workup with D816V PTD mutant (in red) is found in nearly 30% of the patients, whereas
BM biopsy is warranted in typical cases where clinical symptoms and the ECD mutants (in blue) are found in nearly 40% of the affected children,
findings are highly suggestive of the presence of SM. the most frequent being the deletion 419. In adults, depending of the category
In a large cohort of pediatric mastocytosis patients, 36% exhibited of mastocytosis, the KIT D816V mutant (in red) is found in at least 80% of
KIT D816V mutations, and three (6%) patients had other codon 816 all patients. The complete list of KIT mutants retrieved in the literature for
mutations (D816Y [n = 2] and D816I [n = 1]). Another 42% mastocytosis is depicted here. In children, the structure of KIT is found WT
demonstrated KIT mutations outside exon 17, with half of these being in ~25% of the patients analyzed, whereas in adults, KIT is found WT in
located in exons 8 and 9 (D417-418, D419Y, C443Y, S476I, <20% of all patients analyzed so far. Some of the mutations are found only
ITD502-503, K509I) and exon 11 (D572A). When these data were in a very few number of patients. The symbols indicate the following:
combined with a cohort from Dubreil and colleagues, 76% of the ±, mutation found in <10% of the pediatric or adult patients; +, mutations
pediatric patients were found to have alterations in KIT, all of which found in 1%–5% of pediatric patients; ++, mutation found in 5%–20% of
resulted in constitutive activation of the TK. Multiple families with pediatric patients; +++, mutation found in ~30% of pediatric patients and
hereditary mastocytosis, typically manifesting as cutaneous disease, in >80% of all adult patients. *Mutation also found in children at low fre-
were found to have germline KIT mutations, including K509I, quency. Del, Deletion; ECD, extracellular domain; Ig, immunoglobulin;
A533D, N822I, M835K, S849I, or deletion of amino acids 419 or Ins, insertion; ITD, internal tandem duplication; JM, juxtamembrane
559–560). domain; KI, kinase insert; PTD, phosphotransferase domain; TK, tyrosine
SM-AHN cases commonly harbor molecular abnormalities related kinase; TM, transmembrane domain. (From Arock M, Sotlar K, Akin C, et al:
to the myeloid disease component in addition to KIT D816V. For KIT mutation analysis in mast cell neoplasms: recommendations of the European
example, JAK2 V617F has been found in SM with myelofibrosis; Competence Network on Mastocytosis. Leukemia 29:1223, 2015.) 21
BCR-ABL1 in rare cases of concurrent SM-CML; and in SM-AML,