Seminars in Diagnostic Pathology
Volume 29, Issue 1 , Pages 19-30, February 2012

Mastocytosis and related disorders

  • April Chiu, MD

      Affiliations

    • Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
    • Corresponding Author InformationAddress reprint requests and correspondence: April Chiu, MD, Department of Pathology, Brigham and Women's Hospital, Amory 3-201, 75 Francis Street, Boston, MA 02115
    • ,
  • Attilio Orazi, MD, FRCPath

      Affiliations

    • Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York

Article Outline

Mastocytosis represents a heterogeneous group of disorders characterized by an abnormal accumulation of mast cells in one or more organ systems. Mastocytosis is further divided into different subtypes according to the sites of involvement, laboratory findings, and degree of organ impairment. Cutaneous mastocytosis is diagnosed in the presence of skin involvement and absence of extracutaneous disease, and is most commonly seen in the pediatric population. Systemic mastocytosis, the disease form most commonly seen in adults, is characterized by the presence of multifocal, compact (dense) mast cell aggregates in the bone marrow or other extracutaneous organs. The mast cells may display atypical, often spindle-shape morphology and/or aberrant CD2 and/or CD25 expression. Elevation of serum tryptase and/or presence of KIT D816V mutation are other common findings. Systemic mastocytosis is further divided into different subtypes based on a combination of clinical features and laboratory findings. Recent studies have indicated that CD30 is frequently expressed in aggressive systemic mastocytosis and mast cell leukemia but infrequently in indolent systemic mastocytosis, and may be a useful marker for distinguishing these subtypes of systemic mastocytosis from one another. A group of related myeloid disorders, collectively termed myelomastocytic overlap syndromes, may pose diagnostic difficulty because of their significant clinical and pathologic overlap with systemic mastocytosis, and these will also be discussed in this review.

Keywords:  Mastocytosis , Mast cell disease , Mast cell leukemia , Myelomastocytic overlap syndromes

 

Mastocytosis (mast cell disease) is a heterogeneous group of disorders characterized by the accumulation of morphologically and/or immunophenotypically abnormal mast cells in one or more organ systems.1 Recognizing that mast cells share a common progenitor with myeloid cells, mastocytosis is currently categorized under myeloproliferative neoplasms in the 2008 World Health Organization (WHO) classification. Mastocytosis is divided into cutaneous and systemic forms based on disease distribution and clinical manifestation. Specifically, whereas the diagnosis of cutaneous mastocytosis (CM) is reserved for cases with no systemic involvement, systemic mastocytosis (SM) typically involves multiple organs that almost always include the bone marrow (BM) and often the skin. Furthermore, although the diagnosis of mastocytosis is based on histologic confirmation of mast cell aggregates in tissue sections, further classification of SM into various subcategories requires correlation with a variety of clinical parameters and laboratory findings.2

The clinical presentation of patients with mastocytosis is diverse. Patients may have a history of urticaria pigmentosa (UP) of variable duration, followed by insidious onset of abdominal cramping, weight loss, bone pain, and hepatosplenomegaly.3, 4 Patients may also complain of episodes of mediator-related symptoms (e.g. flushing, hypotension, and diarrhea). Although in pediatric patients the mast cell lesions are generally limited to the skin, adults with UP-like skin lesions generally have evidence of systemic disease usually confirmed by BM biopsy, and meet the diagnostic criteria for SM.5

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Cutaneous mastocytosis 

Because various subtypes of SM frequently involve the skin, a diagnosis of CM requires exclusion of systemic involvement (e.g., lack of elevation of total serum tryptase, BM involvement, or organomegaly). CM has a predilection for onset in childhood and has a favorable prognosis with spontaneous regression frequently occurring around puberty. Adult-onset CM does not typically regress, and careful staging is warranted because many of these patients have underlying systemic involvement.6 In essence, the diagnosis of CM should not be made in adults without a BM examination because most patients would in fact have an underlying SM. However, the prognosis remains favorable because SM with skin involvement usually represents the indolent variant.

CM is further divided into three major variants–UP, diffuse CM, and mastocytoma. UP, or maculopapular CM, is the most common form, which may occur in children or adults. The mast cell infiltrate is more subtle in adults and may require examination of multiple biopsies and immunohistochemical analysis for diagnosis. Histologically, aggregates of spindle-shape mast cells are seen, which often show perivascular and periadnexal distribution in papillary and reticular dermis (Figure 1). Diffuse CM is extremely rare and presents almost exclusively in childhood. The skin is typically diffusely thickened and erythematous without distinct lesions. The mast cell infiltrate generally forms a band in the papillary and upper reticular dermis. Mastocytoma of skin presents as a single lesion, most often on the trunk or wrist of infants. Histologically, sheets of mature-appearing mast cells without atypia fill the papillary and reticular dermis and may extend into the deep dermis and subcutaneous adipose tissue.6

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Systemic mastocytosis 

A diagnosis of SM requires histologic detection of multifocal compact mast cell aggregates (≥15 mast cells), the major diagnostic criterion, as well as one of four minor diagnostic criteria: (1) >25% of the mast cells in the infiltrate are atypical with immature or spindle-shape morphology; (2) presence of D816V KIT-activating point mutation; (3) aberrant CD2 and/or CD25 expression by the mast cells; and (4) persistent elevation of serum tryptase (>20 ng/mL; see Table 1 for additional information). Alternatively, in the absence of mast cell aggregates in tissue sections, the fulfillment of at least three minor criteria is required.1

Table 1. WHO Classification criteria for systemic mastocytosis⁎
Major criterion
Multifocal, dense mast cell infiltrate (≥15 mast cells in aggregates) in tissue sections of bone marrow and/or other extracutaneous organ(s)
Minor criteria
1. In bone marrow or extracutaneous tissue sections or in bone marrow aspirate smears, >25% of the mast cells in the infiltrate are spindled shaped or have atypical morphology
2. Detection of KIT D816V mutation in bone marrow, blood, or other extracutaneous organ
3. Expression of CD2 and/or CD25 on mast cells
4. Serum total tryptase persistently exceeds 20 ng/mL (unless there is an associated clonal myeloid disorder, in which this parameter is not valid)

⁎ The diagnosis of systemic mastocytosis is met when one major and one minor criterion, or at least three minor criteria, are present.

The BM is the most common site where the diagnosis of SM is established, as it is almost always involved in adults with mastocytosis. Diagnostic material can also be obtained from other sites, although histologic criteria for extramedullary/extracutaneous organs are less established. Histologically, the BM typically shows multiple (i.e., at least two) lesions consisting of compact clusters of cohesive mast cell aggregates, often paratrabecular and/or perivascular in distribution (Figure 2A).1, 2 Occasionally, the mast cells may be individually dispersed rather than forming discrete aggregates. The mast cell lesions are characteristically associated with admixed eosinophils and small lymphocytes (Figure 2B). Most lesions also show marked reticulin fibrosis with the presence of collagen (stroma trichrome stain positive; Figure 3A and B) but, in contrast to most other fibrogenic neoplasms, are often poor in vascularity (Figure 3C).7 The adjacent trabecular bone may be variably osteosclerotic (Figure 3D). The proliferating mast cells are frequently spindled or fusiform shaped, although a variable number of round forms is also usually detected (Figure 4A and B). The nuclei may be oval or appear atypical with bi- or multilobation (Figure 4C). The presence of >25% mast cells displaying spindle-shape or atypical/immature features satisfies one of the minor criteria for a diagnosis of SM (Table 1). The cytoplasm may contain abundant metachromatic granules that obscure the nucleus, but more commonly are hypogranular with asymmetric cytoplasmic distribution. The presence of mast cells with marked cytologic atypia is seen more frequently in aggressive SM (ASM) and in mast cell leukemia (MCL).2 However, histologic features alone are insufficient for subclassification or prediction of clinical outcome. Careful examination of peripheral blood (PB) and BM aspirate smears, in addition to histology, is crucial to establish or rule out the simultaneous presence of another hematologic neoplasm (i.e., SM with associated clonal hematological nonmast cell lineage disease [SM-AHNMD]) or to confirm a diagnosis of MCL or myelomastocytic overlap syndrome. Furthermore, subclassification of SM into the indolent versus aggressive forms requires correlation of morphology with clinical and laboratory findings related to mast cell burden and organ dysfunction, designated as “B” or “C” findings (Table 2).

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  • Figure 2. 

    Systemic mastocytosis in bone marrow biopsy. The mast cell aggregate is sharply delineated and is present in the paratrabecular location (A). Within the mast cell lesion are many spindle-shape mast cells with admixed eosinophils, fibroblasts, and small lymphocytes (B).

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  • Figure 3. 

    The mast cells lesions typically show significant fibrosis with the presence of collagen, as shown by reticulin (A) and collagen (B) histochemical stains. In contrast with other fibrogenic myeloid neoplasms, the mast cell lesions are poor in vascularity as demonstrated by CD34 immunostaining (C). There is significant thickening (osteosclerosis) of the adjacent trabecular bone (D).

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  • Figure 4. 

    The neoplastic mast cells are often spindled shaped with asymmetric distribution of cytoplasmic metachromatic granules (A), although a variable number of round forms is usually also identified (B). Frequent atypical bi- or multilobated forms are seen in this case (C).

Table 2. B and C findings in systemic mastocytosis
“B” Findings
1. Bone marrow biopsy showing >30% mast cells confined in focal, dense aggregates and/or serum total tryptase level >200 ng/mL
2. Signs of dysplasia or myeloproliferation in non mast cell lineage(s), but insufficient criteria for definitive diagnosis of a hematopoietic neoplasm by WHO classification, with normal or only slightly abnormal blood counts
3. Hepatomegaly without impairment of liver function and/or palpable splenomegaly without hypersplenism and/or lymphadenopathy on palpation or with imaging
“C” findings
1. Bone marrow dysfunction manifested by one or more cytopenia (ANC < 1.0 × 109/L, Hb <10 g/dL, or platelets <100 × 109/L), but no obvious non mast cell hematopoietic malignancy
2. Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
3. Skeletal involvement with large osteolytic lesions and/or pathologic fractures
4. Palpable splenomegaly with hypersplenism
5. Malabsorption with weight loss caused by GI mast cell infiltrates

Indolent systemic mastocytosis 

Indolent systemic mastocytosis (ISM) is the most common subtype of SM, representing 46% of the cases in a recent study of 342 adult patients.8 ISM patients tend to be younger at presentation (median age 49 years). There are no “C” findings and no evidence of another hematologic malignancy. Skin lesions are almost invariably present and “B” findings are usually absent. To accommodate for exceptions, two variants of ISM are included in the 2008 WHO classification: isolated bone marrow mastocytosis (BMM) and smoldering systemic mastocytosis (SSM). BMM is defined as BM involvement without the presence of concurrent skin involvement or multiorgan lesions, whereas SSM is characterized by high mast cell burden as indicated by the presence of two or more “B” findings. Together, BMM and SSM constitute approximately one third of all ISM cases. Patients with ISM have significantly better prognosis than those with ASM or SM-AHNMD and have a life expectancy nearly identical to that of an age- and sex-matched U.S. control population (median 198 months).8 Patients with SSM tend to be significantly older (median age 64 years), with a significantly higher incidence of constitutional symptoms (fatigue, weight loss, fever, diaphoresis) and anemia and shorter survival (median 120 months) compared with other ISM patients.9

Systemic mastocytosis with associated clonal hematological nonmast cell lineage disease 

SM-AHNMD is the second most common type of SM, representing 40% of cases.8 SM-AHNMD meets the criteria for both SM and another hematologic malignancy by WHO classification.

The associated hematologic malignancy is usually a myeloid neoplasm (89% of cases) such as myeloproliferative neoplasm (MPN; including chronic eosinophilic leukemia (CEL), essential thrombocytosis, polycythemia vera, and primary myelofibrosis; Figure 5), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) such as chronic myelomonocytic leukemia (CMML), MDS, and acute myeloid leukemia (AML). Cytogenetic abnormalities, such as trisomy 8, monosomy 7, del(5q), and del(20q), are frequently identified in cases of SM associated with myeloid neoplasm.8 It is important to remember that in this diagnostic setting, elevation of serum tryptase level cannot be used as a minor criterion when the associated non mast cell disease is a myeloid neoplasm because elevation of serum tryptase level may be produced by the myeloid malignancy on its own. Less frequently there is an associated lymphoid neoplasm, such as hairy cell leukemia, plasma cell myeloma, and chronic lymphocytic leukemia, as well as other lymphomas.8, 10, 11, 12 In cases of SM-AHNMD, KIT mutation can be found both in the SM and in the myeloid (non mast cell) component, with the highest frequency seen in CMML followed by AML and MPN. In contrast, in cases of SM associated with a lymphoproliferative neoplasm, KIT mutation has never been documented to occur in the malignant lymphoid component.13

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  • Figure 5. 

    A case of primary myelofibrosis (cellular phase) with positive JAK-2 V617F point mutation marked by the presence of atypical, hyperlobated megakaryocytes forming clusters (A). The adjacent marrow shows an aggregate of mast cells (B) highlighted by mast cell tryptase immunostaining (C), indicating involvement by systemic mastocytosis with associated clonal hematological non mast cell lineage disease (SM-AHNMD/SM-PMF).

The overall median survival of SM-AHNMD is 24 months.8 The prognosis of patients with SM-AHNMD is usually dictated by the non mast cell disorder, with SM-MPN showing the best prognosis, whereas the worst survival is seen in SM-AML (median survival 31 months vs. 11 months, respectively).14

Aggressive systemic mastocytosis 

ASM represents 12% of SM cases.8 Patients with ASM have one or more “C” findings, indicating organ dysfunction caused by mast cell infiltration.1 Diagnostic criteria of SM are fulfilled, whereas MCL and AHNMD are excluded through BM and PB examinations. Patients with ASM usually show no skin involvement.2 A distinct subtype of ASM, termed lymphadenopathic mastocytosis with eosinophilia, presents with lymphadenopathy and blood eosinophilia and should be differentiated from CEL or myeloid/lymphoid neoplasms with platelet-derived growth factor recetor-α (PDGFRA) translocations.2, 15 ASM patients have a relatively short median survival of 41 months.8

Mast cell leukemia 

MCL is a rare (1%)8 form of SM characterized by leukemic spread of mast cells. Skin lesions are uncommon.16, 17 By definition, MCL meets the criteria for SM and is marked by the presence of immature/atypical mast cells, which may include a variable proportion of metachromatic blasts, accounting for at least 20% of all nucleated cells on the BM aspirate smear (Figure 6).1 However, it should be noted that it is important to obtain a truly average value in a uniformly spread marrow smear; counting of the mast cells in close proximity or within BM particles should be avoided. The aleukemic variant is rare and has fewer than 10% PB mast cells.17, 18 It should be noted that MCL is the only subtype of SM for which a cytologic diagnosis on a BM aspirate and PB smears is required to make the diagnosis.19 Serum tryptase is almost always elevated. Molecular biology studies identify the D816V KIT mutation in most patients. “C” findings such as persistent pancytopenia and transfusion dependence, as well as hypoalbuminemia, are frequently associated.19 In most cases, the mast cells express CD2 and/or CD25. As reported later, CD30 can be positive in a proportion of the mast cells.20, 21 Both forms have similar dismal prognosis, with survival of just a few months (median 2 months).8, 19

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  • Figure 6. 

    A case of mast cell leukemia showing a markedly increased number of atypical mast cells in the bone marrow aspirate smear (A) and peripheral blood involvement (B). The bone marrow biopsy shows diffuse infiltration by the neoplastic mast cells (C) that are highlighted by mast cell tryptase immunostain (D).

Mast cell sarcoma 

Mast cell sarcoma is an extremely rare entity characterized by the presence of a localized destructive tumor in the absence of systemic involvement. Only a few cases have been reported, and the sites of involvement include the larynx, colon, meninges, bone, and skin.22, 23, 24, 25 The mast cells are highly atypical and often appear immature or blast-like, or may have bi- or multilobated nuclei. Some patients may develop a terminal leukemic phase indistinguishable from MCL. The prognosis is dismal.

Extracutaneous mastocytoma 

Extracutaneous mastocytoma is a localized benign tumor composed of mature-appearing mast cells with abundant metachromatic granules and no significant cytologic atypia. In contrast to mast cell sarcoma, mastocytomas do not show a destructive growth pattern. Most of the cases occur in the lung without skin lesions or evidence of systemic disease. The prognosis is favorable and patients do not generally progress to systemic disease or leukemic involvement.26, 27, 28, 29

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Histochemical stains 

Mast cells are not easily identified by routine hematoxylin-and-eosin stain. Giemsa and toluidine blue stain may be useful to highlight mast cell metachromatic granules. However, abnormal mast cells are frequently hypogranular. Furthermore, mast cell granules may be further diminished during tissue processing, especially during decalcification. Mast cells can also be made visible by chloracetate esterase, although this enzyme is also present in neutrophils and their precursors.30 Because these stains are affected by variables such as decalcification and mast cell granularity, they are less informative than specific immunophenotypic studies.

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Immunophenotyping 

Mast cells in both neoplastic and reactive conditions generally express CD33, CD43, CD68, CD117 (KIT), and tryptase. Of these, tryptase (Figure 7A) is the most lineage-specific marker, but may show high background staining in some cases.31, 32, 33 In addition, basophils in some cases of acute basophilic leukemia, chronic basophilic leukemia, and chronic myelogenous leukemia may be positive for tryptase.30 CD117 (KIT; Figure 7B) is a sensitive but nonspecific marker for mast cells because it is also expressed by myeloblasts/early promyelocytes, erythroid progenitor cells, and nonhematopoietic cells such germ cells, melanocytes, and interstitial cells of Cajal in the gastrointestinal tract.34 KIT interacts with its ligand, stem cell factor, and thereby regulates mast cell proliferation, maturation, adhesion, chemotaxis, and survival.35

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  • Figure 7. 

    Immunohistochemistry in a case of systemic mastocytosis. The mast cells are positive for mast cell tryptase (A) and CD117 (KIT) (B) and show aberrant expression for CD25 (C) and CD2 (D).

Neoplastic mast cells also frequently express CD2 and/or CD25, two markers not expressed by normal mast cells or mast cells associated with other hematologic neoplasms.36, 37, 38, 39 Of these two markers, CD25 (Figure 7C) is more often expressed by neoplastic mast cells, while CD2 expression (Figure 7D) is less consistent and may be negative in aggressive forms of SM. Multicolor flow cytometry provides a sensitive method of detection of CD2 and/or CD25 expression in the CD117+ CD34− mast cell population in patients with SM.36, 40 In addition to flow cytometry, an immunohistochemical panel consisting of tryptase, CD117, CD2, and CD25 is recommended for the diagnostic workup of SM in tissue sections to confirm mast cell lineage of the proliferation and to potentially identify an aberrant immunophenotype.37, 39

Recently, strong CD30 expression by mast cells has been reported in aggressive subtypes of SM, including ASM and MCL, whereas CD30 expression is weak or absent in most cases of ISM.20, 21, 41 Therefore, CD30 may be a useful biomarker in screening for aggressive subtypes of SM and could be considered a potential target for monoclonal antibody–based therapy. However, CD30 may be expressed in a small number of ISM cases with stable clinical course, and thus its expression may not be invariably linked to adverse prognosis.20 Furthermore, when CD30 expression is detected, other CD30-positive neoplasms, such as Hodgkin lymphoma and anaplastic large cell lymphoma, should be excluded by applying appropriate morphologic and immunophenotypic criteria.

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Genetics 

Point mutations of the tyrosine kinase receptor gene KIT are the most common genetic abnormality seen in mastocytosis. Although most cases are acquired, rare familial cases with germline mutations of KIT have also been reported. The most common type of mutation, found in over 95% of patients with SM, is a gain-of-function mutation resulting from a substitution of valine for aspartate at codon 816 of exon 17 in the tyrosine kinase domain, termed Asp816Val or D816V.42, 43 This mutation is detected not only in mast cells but also in other myeloid cells, CD34+ progenitors, and lymphocytes.44 In addition, in cases of SM-AHNMD, especially in SM-CMML as previously mentioned, the mutation can be detected not only in the mast cells but also in the AHNMD component of the disease.45, 46 In this regard, SM may be considered a stem cell disease. Early studies indicated that KIT mutations are uncommon in pediatric and cutaneous mast cell tumors, suggesting that these may not be clonal disorders. However, more recent studies confirmed that childhood-onset mastocytosis is also clonal in nature and is associated with germline or acquired activating KIT mutations.47, 48 One larger study in children detected KIT mutation in 86% of the cases, with mutation of codon 816 (exon 17) found in 42% of cases and mutations outside exon 17 observed in 44%.47 Other activating KIT mutations, such as D816Y (tyrosine for aspartate), D816F (phenylalanine for aspartate), and E839K (lysine for glutamic acid at codon 839), have also been described.49 KIT mutations, however, are not specific for SM and have been reported in other diseases such as gastrointestinal stomal tumor50 and melanoma.51 Even the D816V KIT mutation is not specific to SM and may occur in some cases of seminoma52 and core binding factor acute myeloid leukemias (CBF-AML; e.g., inv(16) and t(8;21)).53 Therefore, the detection of KIT D816V mutation constitutes only a minor diagnostic criterion in the 2008 WHO classification.

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Therapy 

Patients with ISM are generally treated symptomatically given their excellent prognosis and normal life expectancy.54, 55 Patients should avoid triggers of mast cell activation, including exposure to extreme temperature variations, extreme exercise, and, in some patients, exposure to alcohol or some drugs. Anaphylactic reactions are treated with epinephrine, and prophylactic H1 and H2 antihistamines may be given. Medications that have been shown to alleviate secondary symptoms in SM include disodium cromoglycate for gastrointestinal cramping and diarrhea; ketotifen, glucocorticoids, and PUVA for pruritis, and nonsteroidal anti-inflammatory drugs for flushing. No curative therapies for ASM or MCL are available, and these patients may be candidates for experimental therapy. Some studies have reported success with interferon-α,56, 57 and cladribine (2-CdA)58, 59, 60 in reducing the mast cell burden. However, interferon-α may be poorly tolerated, whereas 2-CdA may cause myelosuppression and immunosuppression.61, 62 The KIT D816V mutation is resistant to imatinib. However, imatinib and other tyrosine kinase inhibitors directed at the KIT mutation may show some effects in the rare cases harboring other types of KIT mutations (e.g., F522C, K509I).63, 64 Ongoing trials with other tyrosine kinase inhibitors, such as dasatinib65, 66 and PKC412,67 are underway in the hope of directly impact the molecular defect of SM.

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The myelomastocytic overlap syndromes and related disorders 

Myelomastocytic leukemia (MML) and myelomastocytic myelodysplastic syndrome (MM-MDS) 

MML and MM-MDS are rare overlap diseases defined by the presence of an aggressive myeloid neoplasm associated with prominent secondary expansion of clonal mast cells.19, 68, 69, 70 Major differential diagnoses are MCL (Table 3), SM with associated MDS (SM-MDS) or AML (SM-AML), and basophilic leukemia.19, 70 MML and MM-MDS are defined by the presence of (a) an advanced myeloid neoplasm, most commonly AML or refractory anemia with excess blasts; (b) at least 10% immature/atypical mast cells and/or metachromatic blasts in BM or PB smears; and (c) the absence of a primary mast cell disease (i.e., SM criteria are not fulfilled in these cases).69, 70 In contrast to MCL and SM-MDS/AML, no multifocal mast cell aggregates are present; only a diffuse infiltration of the BM by immature/atypical mast cells is found in MML/MM-MDS.69, 70 In addition, no D816V KIT mutation is found in MML/MM-MDS, and the mast cells are usually negative for CD25 and CD2. MML/MM-MDS must and can be discriminated from basophilic leukemia by immunophenotyping, as mast cells are tryptase+ KIT+ 2D7– CD123– cells, while basophils are tryptase–/+ KIT– 2D7+ CD123+ cells. Similar to patients with MDS or AML without MML/MM-MDS, dysplastic features are seen in one or more myeloid cell lineages.68, 69, 71, 72, 73 Mature mast cells and basophils may also be observed. In most cases, the finding of immature/atypical mast cells and/or metachromatic blasts in the aspirate may suggest either MML/MM-MDS or MCL, as these types of cells are rarely observed in SM or SM-AHNMD. The diagnosis of MML/MM-MDS is then confirmed by the lack of dense mast cell aggregates in the biopsy and the lack of D816V KIT mutation.

Table 3. Clinicopathologic features of mast cell leukemia versus myelomastocytic leukemia/myelomastocytic myelodysplastic syndrome
MCLMML/MM-MDS
Clinical features
Skin lesions−−
Fulfill AML/HG-MDS criteria−+
Fulfill SM criteria+−
Mediator symptoms++/−
Organomegaly++/−
Peripheral blood findings
Circulating MCs+⁎+†
Circulating nonmetachromatic blasts−+/−
Bone marrow findings
Atypical/immature MCs≥20%‡≥10%‡
Metachromatic blasts++†
Multifocal dense MC aggregates+−
Nonmetachromatic blasts<5%‡≥5%‡
CD2 and/or CD25 expression by MCs+−
Molecular/laboratory findings
Elevated serum tryptase+§+§
KIT D816V mutation+−

Abbreviations: MCL, mast cell leukemia; MML, myelomastocytic leukemia; MM-MDS, myelomastocytic myelodysplastic syndrome; AML, acute myeloid leukemia; HG-MDS, high-grade myelodysplastic syndrome; SM, systemic mastocytosis; MC, mast cell.

⁎ ≥10% immature/atypical mast cells in typical cases of MCL (<10% in aleukemic variant). The immature/atypical mast cells may include metachromatic blasts.

† MML/MM-MDS is marked by the presence of ≥10% immature/atypical mast cells and/or metachromatic blasts in BM and/or PB smears.

‡ Value expressed as the percentage of the total marrow nucleated cells.

§ Usually >100 ng/mL.

AML with KIT D816V mutation 

KIT D816V mutation has also reported to be present in cases of AML with genetic alterations affecting CBF, particularly those associated with t(8;21) translocation involving CBFα, with incidence ranging from 1.7% to 6.9%.74, 75, 76, 77, 78, 79 KIT exon 8 mutation has also been found in cases of CBF-AML, particularly inv(16) involving CBFβ.53, 80 Although CBF-AMLs are typically associated with favorable prognosis, the concomitant presence of KIT D816V in these cases imparts an adverse prognosis with resistance to imatinib therapy.53, 78, 81 However, imatinib has shown clinical efficacy in cases of CBF-AML harboring the KIT exon 8 mutation.

In cases of AML with KIT D816V mutation, the leukemic blastic infiltrate may obscure a concomitant SM in which the mast cell infiltrate is either subtle or not apparent, thereby representing an “occult mastocytosis.” In a recent study, KIT D816V mutation was detected in 7 of 101 (6.9%) patients with AML, all of whom were found to have an associated SM by WHO classification criteria.79 Therefore, if the KIT D816V mutation is detected in a case of AML, the BM biopsy should be carefully examined in search for evidence of SM (e.g., by preparing additional levels). Immunohistochemistry for tryptase, CD2, and CD25 may facilitate detection of mast cells and their aberrant antigen expression. If diagnostic features for SM are met, these cases should be classified as SM-AHNMD. However, as mentioned previously, elevation of serum tryptase level per se cannot be used to fulfill the diagnostic criteria for SM-AHNMD, as elevation of serum tryptase may be seen in patients with de novo AML where the tryptase is produced by the leukemic myeloblasts.82

CD25+ mast cell infiltrate/mast cell hyperplasia 

Low numbers of scattered spindle-shaped CD25+ mast cells are occasionally incidentally detected in BM biopsies. These cases do not meet the major diagnostic criteria for SM because of a lack of compact mast cell aggregates. However, KIT D816V mutation may be detected in some cases, which would then meet the diagnostic criteria for SM-AHNMD because three minor criteria would have been met: presence of spindle-shaped mast cells, aberrant CD25 expression, and KIT D816V mutation.83 Cases without KIT D816V mutation may represent an occult mastocytosis with unclear biological behavior or clinical significance. Cases with an increased number of morphologically normal mast cells lacking CD25 and/or CD2 expression should be termed mast cell hyperplasia.

AML with tryptase+ blasts 

Cases of AML with tryptase+ blasts have been described in cases of AML, most commonly in French-American-British classification M0, M2, M3, and M4eo subtypes.84 There are no compact aggregates or other evidence of SM, and the biological significance of tryptase expression by the leukemic blasts is unclear.

SM with eosinophilia 

PB eosinophilia has been reported in 15% to 28% of patients with SM.3, 8, 85, 86 Interestingly, KIT D816V mutation has been demonstrated in mast cells as well as eosinophils of patients diagnosed with SM.86 Clinical outcome of SM patients is similar with or without eosinophilia.8

FIP1L1/PDGFRA+ myeloid neoplasms with increased mast cells 

FIP1L1/PDGFRA fusion tyrosine kinase has been described in a subset of patients with hypereosinophilia, thus demonstrating clonality and meeting the WHO diagnostic criteria of CEL.1, 87 In addition to the pronounced PB eosinophilia, the BM of these patients shows a myeloproliferative picture, frequently with increased number of mast cells (Figure 8) that may have spindle-shaped atypical morphology and/or CD25 expression.83, 85, 88 Serum tryptase is also often elevated in these patients. As with the KIT D816V mutation, the FIP1L1/PDGFRA fusion gene is detected in both eosinophils and mast cells. The significant clinical and pathologic overlap between SM with eosinophilia and FIP1L1/PDGFRA+ CEL often leads to perplexing nomenclatures and diagnostic dilemma. Yet the distinction has crucial therapeutic implications, as myeloid neoplasms with FIP1L1/PDGFRA fusion kinase, but not D816V KIT mutation, respond to imatinib therapy. Therefore, cases of myeloid neoplasm with PDGFRA rearrangement with BM mast cell hyperplasia but not meeting the diagnostic criteria for SM, including negative KIT D816V mutation, are best regarded as “myeloid neoplasm with eosinophilia and abnormalities of PDGFRA” by WHO classification. Rare cases of CEL with deletion of CHIC2 (a gene locus deleted in the FIP1L1/PDGFRA rearrangement) and also meeting diagnostic criteria for SM have been published; these cases would represent examples of SM-AHNMD in which the “AHNMD” is CEL (i.e., SM-CEL).13, 89, 90 In none of these cases, however, has a coexisting KIT D816V mutation been reported. Most of these cases have shown response to imatinib therapy, achieving complete remission as evidenced by regression of eosinophilia and molecular remission.89, 90

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Conclusions 

Mastocytosis consists of a group of heterogeneous disorders with diverse clinical and pathologic features. In addition, mastocytosis often exhibits significant clinical and/or pathologic overlap with other myeloid neoplasms, such as in SM-AHNMD or in cases of MML. Strict application of WHO classification criteria incorporating immunophenotyping and molecular genetic studies is crucial for correct diagnosis, which is critical for clinical management and treatment decisions.

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References 

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 Competing interests: The authors declare no conflict of interest.

PII: S0740-2570(11)00087-6

doi:10.1053/j.semdp.2011.06.002

Seminars in Diagnostic Pathology
Volume 29, Issue 1 , Pages 19-30, February 2012

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