Systemic Mastocytosis: A Concise Clinical and Laboratory Review

Written By: Sam Savage

Published Date: May 18, 2007 Last Edited: May 18, 2007

By Patnaik, Mrinal M; Rindos, Michelle; Kouides, Peter A; Tefferi, Ayalew; Pardanani, Animesh

Context.-Systemic mastocytosis is characterized by abnormal growth and accumulation of neoplastic mast cells in various organs. The clinical presentation is varied and may include skin rash, symptoms related to release of mast cell mediators, and/or organopathy from involvement of bone, liver, spleen, bowel, or bone marrow.

Objective.-To concisely review pathogenesis, disease classification, clinical features, diagnosis, and treatment of mast cell disorders.

Data Sources.-Pertinent literature emerging during the last 20 years in the field of mast cell disorders.

Conclusions.-The cornerstone of diagnosis is careful bone marrow histologic examination with appropriate immunohistochemical studies. Ancillary tests such as mast cell immunophenotyping, cytogenetic/ molecular studies, and serum tryptase levels assist in confirming the diagnosis. Patients with cutaneous disease or with low systemic mast cell burden are generally managed symptomatically. In the patients requiring mast cell cytoreductive therapy, treatment decisions are increasingly being guided by results of molecular studies. Most patients carry the kit D816V mutation and are predicted to be resistant to imatinib mesylate (Gleevec) therapy. In contrast, patients carrying the FIP1L1-PDGFRA mutation achieve complete responses with low-dose imatinib therapy. Other therapeutic options include use of interferon-α, chemotherapy (2- chlorodeoxyadenosine), or novel small molecule tyrosine kinase inhibitors currently in clinical trials.

(Arch Pathol Lab Med. 2007;131:784-791)

The discovery of mast cells (MCs) in 1878 is credited to Paul Ehrlich, who first described cells that stained with metachromatic dyes such as toluidine blue, which he termed MCs. Since then, extensive work has been done on the physiology, pathology, and genetics of normal MCs and their pathologic counterparts in mast cell disease (MCD). It is now known that MCs are myeloid lineage cells that arise from bone marrow (BM) precursors, more specifically from CD34^sup +^ and Kit^sup +^ hematopoietic progenitors and not from monocytes or basophils as previously thought.1-5 The cytokine stem cell factor (also known as Kit ligand) plays a key role in inducing differentiation of MCs from their progenitors, in concert with other cytokines including interleukin 3.6-8 Normal MCs are round or oval cells, with a round, centrally located, nonlobated nucleus, and have abundant, uniformly distributed cytoplasmic granules. Immunophenotypic characterization of normal MCs typically reveals the presence of 2 characteristic surface markers, the CD117 antigen (c-Kit; the receptor for stem cell factor) and the high affinity receptor for immunoglobulin (Ig) E (FcεRI), neither of which, however, are MC specific.9,10 The typical profile of MCs in normal BM has been described as CD117^sup ++^/CD34^sup -^/CD38^sup – ^/CD138^sup -^/CD45^sup +^/FcεRI^sup +^. Mast cells play an integral role in type I hypersensitivity reactions implicated in bronchial asthma, urticaria, anaphylaxis, and other allergic conditions. Here, engagement of FcεRI receptors promotes MC degranulation and release of histamine and other mediators including proteases, heparin, prostaglandins, leukotrienes, cytokines, and chemokines that mediate many of the clinical features of MCD (reviewed by Castells11).

MAST CELL DISORDERS

Mastocytosis is characterized by the abnormal growth and accumulation of morphologically and immunophenotypically abnormal MCs in 1 or more organs. Neoplastic MCs, in contrast to normal MCs, are more variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with uneven distribution of fine granules and atypical nuclei with monocytoid appearance. 12-14 Immunophenotypic interrogation of MCs has revealed aberrant expression of several markers in patients of virtually all adult systemic mastocytosis (SM) categories. 15-17 Of these, MC expression of CD25 and/or CD2, as determined by either flow cytometry or immunohistochemistry, are the most relevant from the clinical standpoint and serve as a minor criterion for making the diagnosis of SM per World Health Organization (WHO) guidelines.18-20

Mast cells retain surface Kit expression at high levels on maturation, and the interaction between Kit and stem cell factor has been shown to promote the proliferation, maturation, adhesion, chemotaxis, and survival of MCs.8 Consequently, gain-of-function mutations in kit, particularly the D816V mutation, have been found to occur frequently in SM patients.21 The issue as to whether additional genetic “hits” are necessary for neoplastic transformation of MCs and for full expression of aggressive SM subtypes remains unsettled based on currently available data (reviewed by Pardanani et al22).

Furitsu et al23 first demonstrated constitutive phosphorylation of Kit receptor expressed on HMC-1 cells, an immature MC line derived from a patient with mast cell leukemia (MCL), and described the presence of 2 mutations in the kit gene (V560G and D816V) in this cell line. Soon after this report, Nagata et al24 published the first report of the kit D816V mutation in human SM. Since then, other kit mutations, either replacement of D816 with a nonvaline residue (eg, D816Y,25 D816F,25 D816H,26 and D820G27) or mutations in other domains (extracellular,28 transmembrane, 29,30 or juxtamembrane31,32) have also been identified in MCD. The latter mutations include F522C, A533D, K509I, del419, and V559A, many of which are representative of rare alleles detected in germline DNA in several cohorts of familial mastocytosis (reviewed by Akin33). Interestingly, several kindreds with combined familial gastrointestinal stromal tumors and mastocytosis, both of which are associated with gain-of-function kit mutations, have also now been described.28

The classification of mast cell neoplasms has evolved with time. The current WHO classification classifies MCD into 7 variants (Table 1)20,34: cutaneous mastocytosis (CM), indolent SM, SM with an associated clonal hematologic non-mast cell disorder, aggressive SM, MCL, and MC sarcoma. In addition, 2 provisional and relatively rare variants of SM with characteristic clinical and/or pathologic features have also been described-well-differentiated systemic mastocytosis (WDSM)30 and systemic mastocytosis without skin involvement associated with recurrent anaphylaxis.21

The WHO classification of SM mandates a number of staging investigations to define the exact subtype of disease. 20 Identification of “B” findings alone such as more than 30% BM MC burden or serum tryptase more than 200 ng/mL are indicative of a high systemic MC burden (ie, smoldering SM), whereas the additional presence of “C” findings (Table 2) such as cytopenias, pathologic fractures, hypersplenism, and so forth indicate impaired organ function directly attributable to MC infiltration and are diagnostic for presence of “aggressive” disease (ie, aggressive SM).

Non-MCD-related conditions including benign disorders associated with MC activation such as allergic (bronchial asthma) and atopic disorders, chronic urticaria, anaphylaxis, and other systemic disorders mimicking MCD (eg, VIPoma, adrenal tumors, gastrointestinal inflammatory disorders) must be excluded by appropriate testing prior to reaching a diagnosis of MCD.

CLINICAL FEATURES OF MAST CELL DISORDERS

Mast cell disease presents with varied clinical features that can be broadly grouped as follows:

Cutaneous Disease

There are 3 major forms of CM recognized by the WHO.20 The most common is urticaria pigmentosa (also referred to as maculopapular cutaneous mastocytosis), the others being diffuse CM and solitary mastocytoma of the skin. The skin lesions are typically yellow tan to reddish brown macules and may less frequently present as nodules or plaques. The lesions generally involve the extremities, trunk, and abdomen but spare the palms, soles, and scalp. The lesions commonly exhibit an urticarial response to mechanical stimulation such as stroking or scratching (Darier sign or dermographic urticaria).35,36 Biopsies of urticaria pigmentosa/maculopapular cutaneous mastocytosis lesions demonstrate multifocal MC aggregates mainly around blood vessels and around skin appendages in the papillary dermis.36,37 Children account for nearly two thirds of all reported cases of CM, with nearly 80% of these arising in infancy.38- 40 In contrast, most adult MCD patients with urticaria pigmentosa/ maculopapular cutaneous mastocytosis have systemic disease (often indolent) at presentation, which is most commonly revealed by a BM biopsy done as part of the diagnostic workup.41

MC-Mediator Release Symptoms With or Without Cutaneous Manifestations

Most adult patients with MC-mediator release symptoms have a low systemic MC burden, commonly exhibit CM lesions, and generally have indolent disease. Presenting symptoms include pruritus, urticaria, angioedema, flushing, bronchoconstriction, neuropsychiatric manifestations, and hypotension.42 Gastrointestinal features such as nausea, vomiting, abdominal pain, diarrhea, and malabsorption may be prominent in some patients. Histamine receptor stimulation increases gastric acid production, which may cause peptic ulcer diseasewith potential morbidity from a bleeding peptic ulcer and/or perforation.43,44 Presyncope, episodic vascular collapse, and sudden death represent the more dramatic clinical presentations of MCmediator release.45

Musculoskeletal Symptoms

Patients may have indolent or aggressive disease and present with poorly localized bone pain, diffuse osteoporosis or osteopenia, myalgias, arthralgias, pathologic fractures, skeletal deformities, and/or compression radiculopathies. In the absence of typical cutaneous lesions (urticaria pigmentosa/maculopapular cutaneous mastocytosis) or MC-mediator release symptoms, the diagnosis of SM may prove challenging and diagnosis is frequently delayed in this setting. Systemic mastocytosis, in this setting, must be distinguished from other disorders including osteoporosis, metastatic cancer, Paget disease, and multiple myeloma.

Systemic Disease

Systemic mastocytosis patients with systemic disease are generally older, are without CM lesions, frequently exhibit organomegaly and MC atypia (ie, high-grade morphology), and commonly have aggressive disease.13,46,47 Organ infiltration by neoplastic MCs may present as hepatomegaly (with or without liver dysfunction and ascites), splenomegaly (with or without hypersplenism), lymphadenopathy, large osteolyses with or without pathologic fractures, and malabsorption with hypoalbuminemia and weight loss. Extensive marrow involvement may result in anemia and eventually pancytopenia.

DIAGNOSIS OF MAST CELL DISORDERS

The diagnosis of SM is based on identification of neoplastic MCs by morphologic, immunophenotypic, and/or genetic (molecular) criteria in various organs. Per the WHO criteria for MCD classification, the diagnosis of SM requires fulfillment of 1 major and 1 minor criterion or, alternatively, of 3 minor criteria (Table 3).20 The diagnosis of SM is most commonly established by thorough histologic and immunohistochemical examination of a BM specimen (aspirate and biopsy). This is because the BM is almost universally involved in adult MCD, and histologic diagnostic criteria for non- BM organ involvement in SM have not been established and/or widely accepted as of yet.

BM Examination

Bone marrow examination is almost always necessary for the diagnosis of adult SM and helps establish whether an associated clonal non-MC lineage hematologic disorder is present. The pathognomonic lesion, which satisfies the WHO major diagnostic criterion, is the presence of multifocal, dense MC aggregates, frequently in perivascular and/or paratrabecular locations (Figure, A). These aggregates may be relatively monomorphic, composed mainly of fusiform MC, or may be polymorphic withMC admixed with lymphocytes, eosinophils, neutrophils, histiocytes, endothelial cells, and fibroblasts.12 Eosinophils are most commonly found distributed at the periphery of MC aggregates (often focally), but increased eosinophils may also be seen in noninfiltrated areas.13 Although irregular trabecular thickening is commonly noted, particularly when MC aggregates abut the trabeculae, other cases may be characterized by a marked thinning of BM trabeculae and osteopenia. Mast cell infiltrates are commonly associated with a dense network of reticulin fibers. In cases with diffuse BM infiltration by monomorphous, spindled MCs resembling fibroblasts, a diagnosis of idiopathic myelofibrosis may be erroneously made, especially when accompanied with a decrease in normal hematopoietic elements.

Three distinct histologic patterns of BM involvement in SM have been described.12,13 The commonest, type I, is frequently associated with urticaria pigmentosa and exhibits focal MC infiltration with normal distribution of fat cells and hematopoietic elements in the uninvolved marrow space. In contrast, type II pattern reveals significantly increased granulopoiesis in the marrow space not involved by MCs, and type III pattern is characterized by a diffuse marrow infiltration with morphologically atypical MCs, commonly with circulating MCs. The histologic pattern of BM MC involvement appears to be prognostically important, and this feature is reflected in the list of “B” findings in the WHO classification, which helps distinguish between various SM subtypes.13,20 Although MC cytologic atypia (large, irregularly shaped nuclei, increased mitotic activity, decreased numbers of metachromatic granules, etc) has been historically proposed by some authors as a criterion for “aggressive” MCD,47-50 such proposals have not been either broadly accepted or implemented in routine practice.

In general, MCs may not be readily recognized by standard dyes such as Giemsa, toluidine blue, or naphthol ASD chloroacetate esterase (Leder stain), particularly when associated with significant hypogranulation or with abnormal nuclear morphology, and may be confused with a variety of other cells that include fibroblasts, histiocytes, hairy cells, and monocytes.12,51 Furthermore, the metachromatic staining properties of MCs may be significantly diminished or lost with conventional tissue processing, particularly decalcification with acidic solutions that is necessary for sectioning of paraffin-embedded BM tissue.51 Among the immunohistochemical markers, staining for tryptase is considered the most sensitive, being able to detect even small-sized MC infiltrates (Figure, B).52,53 Given that virtually all MCs, irrespective of their stage of maturation, activation status, or tissue of localization, express tryptase, staining for this marker detects even those infiltrates that are primarily comprised of immature, nongranulated MCs.19 Tryptase immunostaining is particularly useful for the diffuse pattern of MC infiltration, in which a loose MC distribution, in lieu of the discrete MC aggregates, may be seen.52 It must be emphasized that neither tryptase nor other immunohistochemical markers such as chymase, c- Kit/CD117 (Figure, C), or CD68 can distinguish between normal and neoplastic MCs.18 In addition, abnormal basophils seen in some cases of acute and chronic basophilic leukemia and in chronic myeloid leukemia and blasts in some acute myeloid leukemia cases may be tryptase positive and may prove difficult to distinguish from MCs.54 In contrast, immunohistochemical detection of aberrant CD25 expression on BM MCs appears to be a reliable diagnostic tool in SM, given its ability to detect abnormal MCs in all SM subtypes, including the rare cases with a loosely scattered, interstitial pattern of MC involvement. 19 Finally, it should be pointed out that the MC burden in normal BM is very low (

MC Immunophenotyping

As mentioned previously, the qualitative and semiquantitative profiling of cell surface antigens by multiparametric flow cytometry can be extremely useful in distinguishing normal BM MCs from their pathologic counterparts in SM (reviewed by Escribano et al56). Normal MCs typically express c-Kit/CD117 and FcεRI, and the typical profile of normal MCs is CD117^sup ++^/FcεRI^sup +^/ CD34-/CD38-/CD33^sup +^/CD45^sup +^/CD11c^sup +^/CD71^sup +^. These cells do not express certain myeloid markers (CD14 and CD15) or lymphoid lineage markers except CD22.57 Neoplastic MCs in most SM subtypes usually express CD25 and/or CD2, and the abnormal expression of at least 1 of these 2 antigens counts as a minor criterion toward the diagnosis of SM per the WHO system.20 In general, the detection of CD25 on MCs, by either flow cytometry or immunohistochemistry, appears to be the more reliable marker (relative to CD2), although some authors have noted significant variation in the percentage of CD2^sup +^ cases by flow cytometry depending on the specific antibody-fluorochrome conjugate used.56 Consistent with flow cytometry data,17 it has been reported that screening for CD2 expression by immunohistochemistry may have relatively low diagnostic value because a significant proportion of cases stain negative, and CD2 expression on BM MCs is generally weak in the cases that are positive.18,19,53 Interval monitoring of CD25 expression on BM MCs may represent one approach for assessing presence of residual disease in patients undergoing MC cytoreductive therapy, generally for aggressive SM disease subtypes.17,58,59 Other aberrant immunophenotypic features of neoplastic MCs include abnormally high expression of complement-related markers such as CD11c,60 CD35,61 CD59,61 and CD88,61 as well as increased expression of the CD69 early-activation antigen,62 and the CD63 lysosomal- associated protein.63

Serum Tryptase Measurement

Measurement of tryptase (an MC enzyme with trypsinlike enzymatic activity) levels in biologic fluids (serum) has proven to be a useful disease-related marker in SM and is included as a minor criterion for the diagnosis of SM per WHO guidelines, provided that certain conditions are satisfied.20,64 There are 2 major forms of MC tryptase-alpha (subtypes alpha 1 and 2) and beta (subtypes beta 1, 2, and 3) (reviewed by Schwartz65). Mature beta 2 tryptase is stored in MC secretory granules and released only during granule exocytosis, thereby reflecting MC activation. In contrast, the precursor forms of both alpha and beta tryptase are constitutively secreted by MCs,66 and the combined “total” serum levels (including precursor and mature tryptase forms) are thought to reflect the total systemic MC burden.67 The commercially available fluoroimmunoenzymatic assay (Pharmacia, Uppsala, Sweden) measures total tryptase levels. In healthy individuals, levels range from 1 to 15 ng/mL, whereas in most patients with SM, total serum tryptase levels exceed 20 ng/mL. In cases of suspected SM, it is important that serum tryptase levels be \interpreted in the appropriate context. Elevated levels of serum tryptase have been documented in patients with non-SM myeloid malignancies, including acute myeloid leukemia,68,69 myelodysplastic syndrome,70 and chronic myeloid leukemia,71 which mandates exclusion of such non-SM myeloid disorders before reaching a diagnosis of SM. Furthermore, levels of total serum tryptase may also be transiently elevated during anaphylaxis or a severe allergic reaction.64

Molecular Studies

In SM patients, molecular studies are important from the diagnostic standpoint and, increasingly, from the therapeutic standpoint as well.

Recent studies underscore the high prevalence of the kit D816V gain-of-function mutation in SM patients, with high correlation between mutation detection and the proportion of lesional cells in the sample, as well as the sensitivity of the screening method used (reviewed by Akin33). Accordingly, the likelihood of mutation detection in peripheral blood mononuclear cells in a case of indolent systemic mastocytosis (with low probability of circulating clonal cells), using a low-sensitivity screening test (eg, direct DNA sequencing), is exceedingly low. Sensitivity of detection may be enhanced by enriching lesional MCs or other clonal cell populations (eg, neutrophils or eosinophils) by laser capture microdissection or magnetic beador fluorescence-activated cell sorter (FACS)-based cell sorting, respectively.72-74 Furthermore, use of higher sensitivity methods including allele-specific polymerase chain reaction,75 or polymerase chain reaction with peptide nucleic acid probes to “clamp” the wild-type allele combined with mutant allele detection with hybridization probes, dramatically enhance the probability of mutation detection in bulk cells (sensitivity, 10-3).21,76 Using the latter method, the D816V mutation was detected in virtually all patients with indolent systemic mastocytosis or aggressive systemic mastocytosis (93%) but less frequently in patients with WDSM (29%) in a recent study.21 Here, kit mutations (I817V and VI815-816) other than D816V were rarely detected (

Well-differentiated systemic mastocytosis may represent a distinct, albeit genetically heterogenous, subtype of SM.21 A subset of WDSM cases carry the F522C germline mutation, which is located in the kit transmembrane domain. 30 In contrast to other SM subtypes, MCs in WDSM do not express either CD2 or CD25 antigens and are mature in appearance.

Eosinophilia (BM and/or peripheral blood) commonly accompanies SM (in 20%-40% of cases-termed SMeos) 77-80 and is demonstrably clonal in a proportion of such cases.73 Up to one half of SM-eos patients carry the FIP1L1-PDGFRA fusion oncogene,81 which results from an ~800-kb interstitial deletion of chromosome 4q12, thereby generating a constitutively active PDGFRA tyrosine kinase. 82 These patients have a multilineage disorder with demonstrable presence of the FIP1L1-PDGFRA gene within cells of multiple hematopoietic lineages including MCs.83 These patients also exhibit clinical and histologic features of myeloproliferation and generally have an elevated serum tryptase level but may lack pathognomonic clusters of atypical MCs in the BM on routine staining. 81,84-86 FIP1L1-PDGFRA^sup +^ cases have been variably classified as a unique subtype of SM81,87 or a “myeloproliferative variant” of hypereosinophilic syndrome84,85 or as chronic eosinophilic leukemia88 or a myelomastocytic overlap syndrome89 in the literature. Given the sensitivity of this lesion to imatinib therapy (discussed later), it is currently recommended that all suspected SM-eos cases be screened for the FIP1L1-PDGFRA fusion by either fluorescence in situ hybridization or reverse transcriptase polymerase chain reaction.90,91

TREATMENT OF MAST CELL DISORDERS

Treatment of MCD patients is highly individualized. The abbreviated treatment guidelines provided below are for general reference only, and readers are referred to specialized hematology texts and literature sources for details.

Cutaneous Mastocytosis

Spontaneous regression is observed in the majority of pediatric- onset CM.40,92 In contrast, most patients with adult-onset CM have persistent disease, with a proportion exhibiting progression to SM. Treatment is symptomatic, and treatment considerations include use of psoralen ultraviolet A therapy and corticosteroids for severe cases.

Treatment of MC-Mediator Release Symptoms

The cornerstone of therapy in indolent cases is avoidance of identifiable triggers for MC degranulation such as animal venoms, extremes of temperature, mechanical irritation, alcohol, certain dyes, or medications (eg, aspirin, radiocontrast agents, certain anesthetic agents). Therapy is supportive, with use of histamine 1 and histamine 2 receptor blockers (pruritus, peptic symptoms) and cromolyn sodium (gastrointestinal symptoms).93 Corticosteroids are reserved for patients with recurrent or refractory symptoms related to MC-mediator release. It is recommended that patients with a history of vascular collapse or anaphylaxis carry an Epi-Pen for epinephrine self-adminstration.94

Management of Aggressive Systemic Mastocytosis (Organopathy Present)

In general, patients with aggressive systemic mastocytosis require effective MC cytoreductive therapy. Potential therapeutic options are interferon-, 2-chlorodeoxyadenosine, polychemotherapy, and molecularly targeted therapy.

Interferon-α. Interferon-α is frequently combined with prednisone and is commonly used as first-line cytoreductive therapy for SM.95 It ameliorates SM-related organopathy in a proportion of cases but is associated with considerable toxicity (flulike symptoms, myelosuppression, depression, hypothyroidism, etc), which may limit its use in SM (reviewed by Butterfield).96

2-Chlorodeoxyadenosine. 2-Chlorodeoxyadenosine is generally reserved for treatment of patients with aggressive systemic mastocytosis, who are either refractory or intolerant to interferon- α.97-99 Potential toxicities of 2-chlorodeoxyadenosine include significant and potentially prolonged myelosuppression and lymphopenia with increased risk of opportunistic infections. Despite its efficacy in the SM treatment, the precise indications and the optimal dose and schedule for this group of patients remains to be ascertained.

Polychemotherapy.-Polychemotherapy including intensive induction regimens of the kind used in treating acute myeloid leukemia, as well as high-dose therapy with stem cell rescue, represent investigational approaches restricted to rare SM patients, such as select patients with MCL.

Molecularly Targeted Therapy.-Molecularly targeted therapy for SM has recently been reviewed by Gotlib.100

Imatinib Mesylate (Gleevec).-Imatinib is an orally bioavailable, small molecule inhibitor of Kit, ABL, ARG, and PDGFR tyrosine kinases. The identification of gain-offunction mutations involving kit and PDGFRA genes (known imatinib targets) in the pathogenesis of SM has obvious therapeutic implications in this regard. Consistent with predictions from in vitro data,101,102 the limited clinical experience to date suggests that the majority of SM patients (kit D816V+) are likely to be refractory to imatinib therapy.103,104 In contrast, clinically meaningful responses have been observed for the rare patients with kit juxtamembrane mutations (eg, F522C, K509I), suggesting that this subgroup of patients has imatinib-responsive disease. 30,32 For SM patients with eosinophilia (SM-eos) who carry the FIPILI-PDGFRA mutation, complete clinical responses are virtually uniformly obtained with low-dose imatinib therapy, in the absence of mutations that confer imatinib resistance (eg, PDGFRA T764I), which may be seen with clonal evolution (reviewed by Pardanani). 81,82,87,105 Lastly, imatinib is predicted to be effective in SM with specific mutations such as V560G106 and del419,28 but this has not yet been clinically demonstrated.

Dasatinib (BMS-354825).-Dasatinib is an orally available, dual SRC/ABL inhibitor that has been shown to have activity against the imatinib resistant kit D816V mutation in preclinical studies and is currently in clinical trials for treatment of SM.107,108

PKC412.-PKC412 is a multitargeted kinase inhibitor with activity against FLT3, Kit, VEGFR2, PDGFR, and FGFR kinases.109-111 Cools et al112 demonstrated that PKC412 effectively inhibits myeloproliferation induced by the imatinib-resistant FIP1L1-PDGFRA T674I mutation in a murine model. Subsequently, after PK412 was shown to inhibit kit D816V in vitro at nanomolar concentrations, Gotlib et al were able to show a significant clinical and histologic response to PKC412 in a single patient with D186V^sup +^ MCL.112,113 This agent is currently under study for SM treatment in phase II trials.

Other Agents.-Other agents such as the ATP-based inhibitors AP23464 and AP23848,114 the quinazoline-based inhibitor MLN518,115 the indolinone compounds SU11652, SU11654, and SU11655,116 the aminopyrimidine-based inhibitor AMN107 (Nilotinib),117 and the thiophene-based inhibitor OSI-930118,119 have activity against at least some of the SM-associated kit mutants and may have a future role in the treatment of this disease.

Accepted for publication October 24, 2006.

From the Department of Medicine, University of Minnesota, Minneapolis (Dr Patnaik); the Departments of Pathology, University of Rochester School of Medicine (Dr Rindos) and Hematology, Rochester General Hospital (Dr Kouides), Rochester, NY; and the Division of Hematology, Mayo Clinic, Rochester, Minn (Drs Tefferi and Pardanani).

The authors have no relevant financial interest in the products or companies described in this article.

Table 1. World Health Organization Variants of Mastocytosis*

Cutaneous mastocytosis (CM)

Maculopapular \CM

Diffuse CM

Mastocytoma of skin

Indolent systemic mastocytosis (SM)

Smoldering SM

Isolated bone marrow mastocytosis

Systemic mastocytosis with an associated clonal hematologic non- mast cell lineage disease (MCD-AHNMD)

Aggressive systemic mastocytosis

With eosinophilia

Mast cell leukemia (MCL)

Aleukemic MCL

Mast cell sarcoma

Extracutaneous mastocytoma

* From Valent et al.20

Table 2. “C” Findings*

Cytopenia(s): absolute neutrophil count

Hepatomegaly with ascites and impaired liver function

Palpable splenomegaly with hypersplenism

Malabsorption with hypoalbuminemia and weight loss

Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures

Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast cells

* “C” findings are an indication of impaired organ function resulting from mast cell infiltration. From Valent et al.20

Table 3. World Health Organization Criteria for Diagnosis of Systemic Mast Cell Disease*

Major

Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organs (>15 mast cells aggregating)

Minor

Mast cells in bone marrow or other extracutaneous organs show an abnormal (spindling) morphology (>25%)

Codon 816 c-kit mutation D816V in extracutaneous organs

Mast cells in the bone marrow express CD2, CD25, or both

Serum tryptase > 20 ng/mL (does not count in patients who have an associated clonal hematologic non-mast cell disease [AHNMD])

* From Valent et al.20

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Mrinal M. Patnaik, MD; Michelle Rindos, MD; Peter A. Kouides, MD; Ayalew Tefferi, MD; Animesh Pardanani, MD, PhD

Reprints: Animesh Pardanani, MD, PhD, Mayo Clinic, Division of Hematology, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]).

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