Systemic mastocytosis

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CHAPTER 26 Systemic mastocytosis

H-P. Horny

Definition

Systemic mastocytosis (SM) is a clonal disease derived from transformed bone marrow (BM) progenitor cells, histologically characterized by accumulations of atypical mast cells in various tissue sites. SM presents an unusually broad spectrum of morphological and clinical features. In approximately 30% of SM patients, a systemic mastocytosis-associated hematologic non-mast cell disorder (SM-AHNMD) is diagnosed simultaneously, before or after SM diagnosis.

Introduction

SM diagnosis is based on morphology and cannot be established on the basis of clinical findings alone. Therefore, the pathologist should be familiar with the diagnostic criteria defined for mastocytosis and also to recognize its mimickers.^1,² Important mimickers of mastocytosis are reactive states of mast cell hyperplasia and a few rare neoplastic hematological disorders such as tryptase-positive acute myeloid leukemia (AML) or myelomastocytic leukemia. Diagnostic criteria of SM are given in Box 26.1.

The major and two of four minor diagnostic criteria are morphology-based. Diagnosis of SM can be established if the major and one minor criterion are fulfilled. In cases lacking the major criterion, SM diagnosis can be established if at least three minor criteria are found.^1,² Most cases of SM can be easily diagnosed when focal compact infiltrates with a significant proportion of spindle-shaped mast cells are present. SM exhibiting exclusively round mast cells can be diagnosed after demonstration of an atypical immunophenotype with expression of CD25, which is not present in normal mast cells.³ If compact mast cell infiltrates are missing, diffusely scattered spindle-shaped mast cells with CD25 expression alone are not enough to establish a diagnosis of mastocytosis. In these patients, demonstration of the KIT^D816V mutation and/or chronically elevated serum tryptase enables diagnosis of mastocytosis since three of four minor criteria are fulfilled.^4,^5,⁶

BM is the main tissue where diagnosis of SM can be established. However, demonstration of compact mast cell infiltrates in extramedullary tissues like lymph node, spleen, liver and/or mucosa should also be regarded as strong indication for SM.^7,^8,⁹ Rarely, the diagnosis of mastocytosis is first established in the mucosa of the gastrointestinal (GI) tract and BM involvement is confirmed later. It is rather unlikely that pure GI form exists. In all patients with GI involvement, the meticulous investigation of the BM should be performed using immunohistochemistry and molecular biology. In a considerable proportion of SM patients, the degree of tissue infiltration is very low. The WHO 2008 classification of mastocytosis is given in Box 26.2.² The approach to the diagnosis of mastocytosis is complex and considering its relatively low incidence, the diagnosis is usually more difficult than in most other hematological malignancies. The different forms of SM can only be recognized when the pathologist is aware of important clinical findings, especially the so-called ‘B-findings’, including organomegaly, and ‘C-findings’, indicating organ dysfunction due to widespread mast cell infiltration (Box 26.2).

Box 26.2 Classification of mastocytosis (WHO 2008)²

1. Cutaneous mastocytosis (CM) includes urticaria pigmentosa/maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and solitary mastocytoma of the skin.

2. Systemic mastocytosis (SM) (meets criteria in Box 26.1)

i Indolent systemic mastocytosis (ISM) has no ‘C’ findings (see below). Includes BM mastocytosis (with no skin involvement) and smoldering SM (two or more B findings)

ii SM-associated hematologic non-mast cell disorder (SM-AHNMD)

iii Aggressive systemic mastocytosis (ASM) has one or more C findings but no evidence of mast cell leukemia.

iv Mast cell leukemia (MCL) must show 20% or more mast cells in BM smears

3. Mast cell sarcoma (MCS) is a unifocal mast cell tumor with high-grade cytology and destructive growth pattern.

4. Extracutaneous mastocytoma (ECM) is a unifocal mast cell tumor with low-grade cytology and no destructive growth pattern.

‘B’ findings

1. BM biopsy showing >30% infiltration of mast cells and/or serum tryptase level >200 ng/ml.

2. Signs of dysplasia or myeloproliferation in non-mast cell lineages but criteria for definitive diagnosis of AHNMD are not fulfilled.

3. Hepatomegaly without impairment of liver function and/or palpable splenomegaly without hypersplenisn and/or lymphadenopathy.

‘C’ findings

1. One or more cytopenia (ANC <1 × 10⁹/l, Hb<10 g/l, or platelets <100 × 10⁹/l) but no criteria for AHNMD.

2. Hepatomegaly with impairment of liver function, ascites and/or portal hypertension.

3. Skeletal involvement with osteolytic lesions and/or pathological fractures.

4. Splenomegaly with hypersplenism.

5. Malabsorption of weight loss due to GI mast cell infiltrates.

Molecular genetics aspects

Mast cells of most patients with SM carry the activating point mutation KIT^D816V of the c-kit gene.¹⁰ However, the frequency of KIT^D816V varies between subtypes of the disease. It has been found in almost 100% of patients with SM-AHNMD but only in about 50–60% of patients with aggressive SM and mast cell leukemia (MCL). Indolent SM assumes an intermediate position. Other than D816V point mutations of c-kit (e.g. D816Y or D816H) do occur but are rarely detected in SM.¹¹ A considerable number of patients with SM-AHNMD were found to carry KIT^D816V not only in the SM but also in the AHNMD compartment of the disease. The frequency of KIT^D816V depends on the subtype of hematological disorder. SM-associated chronic myelomonocytic leukemia (CMML) exhibits KIT^D816V in almost all cases. The mutation is found both in the SM and the AHNMD compartment of the disease, which underlines a close clonal relationship between SM and CMML in the setting of SM-AHNMD. In SM associated with a myeloproliferative neoplasm with eosinophilia (MPNEo), KIT^D816V is usually not found in the MPNEo. Very surprisingly, it is also lacking in the SM compartment, although compact infiltrates of CD25⁺ mast cells are present in a few cases thus enabling the morphological diagnosis of SM.¹² In other types of SM-AHNMD (SM with myelodysplastic syndrome (SM-MDS), SM-AML, and SM with myeloproliferative neoplasms (SM-MPN)), the incidence of KIT^D816V in the associated disorder varies between 20% and 60% of patients. Interestingly, it has been shown that in cases of SM-MPN (e.g. primary myelofibrosis), both mast cells and cells of neutrophilic lineage could carry both activating point mutations KIT^D816V and JAK-2^V617F, further indicating the close relationship between SM and ‘AHNMD’.¹³

Important messages

1. Indolent SM (ISM) is the most frequent subtype of the disease. In more than 90% of patients with long-standing adult-type cutaneous mastocytosis (CM), mostly urticaria pigmentosa, bone marrow trephine biopsies (BMTB) exhibit features of ISM when the sample is investigated with appropriate immunological and molecular methods.¹⁴

2. SM-AHNMD is the most frequent diagnosis in patients without cutaneous disease.^15,^16,¹⁷ In up to 10% of BMTB from patients with all myeloid neoplasms irrespective of the subtype (MDS, myelodysplastic/myeloproliferative neoplasms (MDS/MPN such as CMML), MPN, and AML) investigated with antibodies against tryptase, CD25 and CD117, atypical spindle-shaped CD25-expressing mast cells are found. Overt SM is present in about 5% of these patients. Almost all of SM-AHNMD patients carry the KIT^D816V mutation. In many of these patients, KIT^D816V mutation is not limited to the SM compartment but can be detected in a significant proportion of malignant cells of hematological disorder, especially when analyses are performed using microdissection technique.¹³

3. CMML is the hematological disorder most frequently associated with SM. Myeloid neoplasms, in particular AML and MPN, may even obscure SM, which is detected only after chemotherapy and remission of the basic disease (= ‘occult mastocytosis’).¹⁸

4. Juvenile patients almost exclusively present with CM without clinical signs of systemic involvement and a good chance of spontaneous regression at puberty.¹⁹ Adults with CM should be monitored for systemic spread of the disease (ISM), when the serum tryptase is chronically elevated and/or the cutaneous mast cells exhibit an atypical immunophenotype with expression of CD25. Detection of the KIT^D816V mutation in the skin should prompt suspicion of SM and investigation of a BMTB is strongly recommended in such patients.

Routine work-up of cases with suspected systemic mastocytosis

To be able to establish a proper diagnosis including classification of SM, the hematopathologist must be provided with clinical data concerning presence of urticaria pigmentosa or another mastocytosis-related rash, hepatosplenomegaly and/or lymphadenopathy, cytopenia or increase in blood cells such as thrombocytosis, allergy, and elevated serum tryptase.

Bone marrow trephine biopsy

The adequate BMTB specimen should be above 2 cm in length. Antibodies against CD25, CD117 and tryptase should be applied.^20,^21,^22,²³ In cases of suspected SM-AHNMD further immunohistochemical stainings with appropriate antibodies depending on the subtype of the hematological disorder should also be performed. The tissue can also be used for demonstration of the KIT^D816V mutation, which is best detected if the biopsy is fixed in 5% buffered neutral formalin and mildly decalcified in ethylenediaminetetraacetic acid (EDTA) overnight. Peripheral blood (PB) and BM smears are crucial for differential diagnosis between aggressive SM (ASM) and aleukemic MCL or aleukemic from leukemic MCL, respectively.

General morphological aspects of SM

Diagnosis of SM is usually established on the basis of BM findings. Investigation of a BMTB specimen is necessary in all cases with the exception of the very rare cases of MCL where evaluation of BM and blood smears is sufficient for diagnosis. There are various infiltration patterns that can be associated with the different subtypes of SM:

1. Multifocal infiltration. If the degree of involvement is low (5% or less of the section area), the most probable diagnoses are indolent SM or isolated SM of the bone marrow. However, mild multifocal involvement is also found in most cases of SM-AHNMD. In cases with more pronounced infiltration, smouldering SM or even ASM are the most probable diagnoses.

2. Diffuse compact infiltration is associated with aggressive or even leukemic SM.

3. Diffuse interstitial infiltration is usually associated with indolent or occult SM. However, the diagnosis of SM cannot be established here by morphology alone. The important major criterion is usually missing and only two of three required minor criteria are present, namely prominent spindling and aberrant immunophenotype of mast cells (expression of CD25). In these patients, it is crucial to detect at least one non-morphological minor criterion such as chronically elevated serum tryptase and/or the KIT^D816V point mutation to establish SM diagnosis.

Size and cytological composition of compact (diagnostic) mast cell infiltrates varies greatly. Mast cells are not always dominant and may be obscured by follicle-like aggregates of lymphocytes. The lymphocyte-dominated infiltrates may mimic lymphocytic lymphoma, which is almost always accompanied by an increase in reactive (round, strongly metachromatic) mast cells posing considerable differential diagnostic problems in some cases (Fig. 26.1A).²⁴ In contrast to mast cell hyperplasia, most SM cases exhibit at least one compact infiltrate consisting of slightly atypical often spindle-shaped and hypogranulated mast cells (Fig. 26.1B). Increased numbers of eosinophils are also usually found, admixed to lymphocytes and mast cells. Eosinophilic microabscesses are rarely detected. Focal increase in eosinophils within these compact infiltrates is only rarely accompanied by a significant eosinophilia in the hematopoietic islands. Stromal reaction shows almost always a dense network of reticulin fibers with the possibility to transform into collagen fibrosis. In some cases, the infiltrates may show striking variation in morphological appearance within the same biopsy specimen, ranging from large foci of collagen fibrosis with loosely scattered spindle-shaped mast cells to smaller lymphoid follicle-like structures with adjacent compact micronodules of round hypogranulated mast cells containing only slightly increased amounts of reticulin fibers. In larger infiltrates, there is also a significant angio-neogenesis with increase in small blood vessels. In most cases, mast cell infiltrates show a predominant peritrabecular localization leading to focal sclerosis of the adjacent bone. Cytomorphology of mast cells also varies greatly, ranging from cases with a predominance of spindle-shaped, markedly hypogranulated cells to cases containing exclusively round hypergranulated, mature-appearing mast cells, posing here the differential diagnosis of well-differentiated SM. The numbers of loosely scattered atypical mast cells are usually hard to estimate in Giemsa-stained sections (Fig. 26.2A), but they can be easily seen in CD25 immunostaining (Fig. 26.2B). It is crucial to apply all three antibodies: CD25, CD117 (KIT) and tryptase in all cases of suspected SM, in order to identify spindle-shaped, hypogranulated, fibroblast-like cells as mast cells, to recognize an aberrant immunophenotype with CD25-expression, and to be able to estimate the degree of the diffuse involvement of the BM aside from the compact mast cell infiltrates However, co-expression of tryptase and CD117 defines both normal/reactive and clonal-neoplastic mast cells of all stages of maturation and all degrees of atypia. Tryptase-expressing cells without CD117 are not mast cells but can be regarded as (neoplastic) basophils or myeloblasts. Such tryptase-positive CD117-negative cells are small to medium-sized and exclusively round. CD117-positive tryptase-negative cells are not mast cells but most likely BM progenitor cells of granulopoietic and/or erythropoietic lineage. Mast cells of high-grade subtypes like aggressive or leukemic SM may express some other aberrant markers like CD30 and/or CD33 that easily may lead to an erroneous diagnosis when the relevant mast cell-associated antibodies are not applied. In most patients with ISM or isolated SM of the bone marrow, the hematopoiesis is completely normal. Some signs of so-called inflammatory reaction like plasmacytosis, ceroid histiocytosis and eosinophilia are often present. In cases with aggressive SM or MCL, the hematopoiesis is often markedly reduced or almost completely effaced. It may be very difficult to assess or exclude the diagnosis of an ‘AHNMD’ (i.e., ASM-AHNMD or MCL-AHMD) in such cases. It is therefore strongly recommended to analyse BM and PB smears carefully in order not to miss an associated hematological malignancy. There are cases of ASM with subtotal involvement of the BM, where PB investigation revealed a diagnosis of CMML thus leading to the ultimate diagnosis of ASM-CMML. It is likely that ‘pure’ aggressive SM is a very uncommon disorder and ASM-AHNMD is the common setting (own unpublished observations).

Fig. 26.1 (A,B) (A) Mast cell hyperplasia. Giemsa stained bone marrow trephine biopsy shows extremely hypercellular bone marrow with diffuse compact infiltration by a non-Hodgkin`s lymphoma of lymphocytic subtype. A significant increase in loosely scattered, round, strongly metachromatic mast cells is almost always seen in this particular subtype of malignant lymphoma. This is the typical finding of a reactive increase in mast cells termed mast cell hyperplasia. (B) Systemic mastocytosis (focal infiltration of bone marrow). Giemsa stained bone marrow trephine biopsy with a focal compact infiltrate consisting of atypical spindle-shaped hypogranulated mast cells exhibiting elongated nuclei without inconspicuous nucleoli. The diagnosis of systemic mastocytosis is possible on the basis of this finding alone since the major criterion (compact mast infiltrate) and one minor criterion (predominance of spindle-shaped mast cells) are fulfilled, × 10, × 40 objective.

Fig. 26.2 (A, B) (A) Systemic mastocytosis with diffuse interstitial infiltration of bone marrow. Giemsa stained bone marrow trephine biopsy with an increase in loosely scattered atypical spindle-shaped hypogranulated mast cells before the background of a normal hemopoiesis. (B) Systemic mastocytosis with diffuse interstitial infiltration of bone marrow. Immunohistochemistry anti-CD25 (ABC method) reveals an aberrant phenotype of mast cells expressing CD25 (an antigen, which is not detected on normal/reactive mast cells). Note that CD25-positivity of megakaryocytes can be used as an internal control since CD25-expressing lymphoid cells are rarely found in the bone marrow. Such findings are seen in a considerable number of adults with long-standing urticaria pigmentosa (cutaneous mastocytosis). Since compact mast cell infiltrates are missing and only two of at least three minor criteria (prominent spindling, CD25-expression) are fulfilled, diagnosis of systemic mastocytosis cannot be established on the basis of morphology alone. An additional finding (activating point mutation KITD816V and/or chronically elevated serum tryptase), however, is sufficient for diagnosis of systemic mastocytosis, × 25, × 25 objective.

In cases of SM-AHNMD, each disease component has to be properly classified. Accordingly, the histological BM picture shows an extremely broad variation ranging from occult SM only detectable by a meticulous immunohistochemical investigation and additional molecular analysis, to aggressive or leukemic SM obscuring the associated neoplasm (AHNMD). The morphological aspects vary dependent on the subtype of the AHNMD, among which myeloid neoplasms are much more common than lymphatic tumors. Among myeloid neoplasms, CMML is most frequent, while among the lymphatic tumors plasma cell myeloma predominates.

TROCI-bm (= tryptase positive round cell infiltrate of the bone marrow)²⁵ is a recently described immunohistochemical phenomenon, defined as focal or diffuse but always compact tissue infiltrates consisting exclusively of tryptase-expressing round cells in the BM. TROCI-bm is only seen in some rare hematological neoplasms. Diffuse TROCI-bm is encountered in myelomastocytic leukemia, MCL or chronic basophilic leukemia. Focal TROCI-bm is seen in common type systemic mastocytosis, well-differentiated mastocytosis or chronic basophilic leukemia, as well as in accelerated phase of chronic myeloid leukemia (CML).

Bone marrow smears

In most cases, evaluation of BM smears is not sufficient for diagnosis of SM. However, cytomorphologic evaluation and differential count of BM smears is inevitable for differentiation of ASM from MCL.²⁶ If numbers of mast cells exceed 20% of nucleated BM cells, diagnosis of MCL is confirmed (Fig. 26.3A–C). Conversely, mast cell numbers are lower than 0.1% of nucleated cells in BM smears from patients with indolent SM and therefore it is challenging to search for mast cells and estimate their frequency. In patients with ISM, cytomorphological evaluation usually confirms mild atypia of mast cells. The mast cells here are often spindle-shaped and contain plump cigar-like nuclei together with a hypogranulated cytoplasm. The presence of such mast cells in patients with cutaneous mastocytosis (usually urticaria pigmentosa) must prompt suspicion of ISM and can be regarded as an indication for histological investigation of a BMTB specimen.

Fig. 26.3 (A–C) Mast cell leukemia. (A) Bone marrow trephine biopsy (H&E) reveals an extremely hypercellular bone marrow with subtotal reduction of fat cells and normal blood cell precursors. Note the prominent sinus-like structures. The picture is dominated by medium-sized to large sometimes bizarre and multinucleated blast-like cells forming dense infiltrates. A few groups of atypical grouped megakaryocytes can also be seen. Tryptase immunohistochemistry (B) reveals that blast cells are in fact atypical mast cells. A minor portion of mast cells co-express the activation antigen CD30, which is not found on normal/reactive mast cells and on mast cells of ‘low-grade’ systemic mastocytosis (C; author’s unpublished observation), × 10, × 25, × 25 objective.

Fig. 26.4 (A, B) Mast cell leukemia. Cytomorphology of smears (Pappenheim/Wright–Giemsa stain) reveals cellular bone marrow smears with marked increase in medium sized to large atypical mast cells often with vacuolated cytoplasm and scarce metachromatic granules. Some atypical neutrophils and megakaryocytes are intermingled leading to an ultimate diagnosis of SM-AHNMD in form of an aleukemic mast cell leukemia (aMCL) associated with a myeloid neoplasm which is nearly obscured by the MCL but can be diagnosed as myelodysplastic syndrome (aMCL-MDS), × 25, × 40 objective.

Blood smears

Apart from rare patients with MCL, blood findings are not indicative of SM.¹⁵ MCL shows a significant increase in circulating mast cells, which exhibit varying degrees of atypia. Some cases show mature round mast cells with abundant metachromatic granules leading to a correct diagnosis at first glance. Other MCL contain highly atypical hypogranulated circulating mast cells with pale large cytoplasm mimicking monocytoid or hairy cells. In most patients with indolent SM, PB exhibits no significant changes but some patients may show mild eosinophilia. Major alterations of blood cells are detected in most cases of SM-AHNMD, in particular those with associated myeloid leukemia. It has to be emphasized that sometimes a diagnosis of SM-AHNMD can only be established when a BMTB specimen and blood smears are investigated together because SM shows diffuse-compact BM infiltration thus obscuring the AHNMD. In every patient with aggressive SM or MCL, blood smears have to be analyzed in order not to overlook the AHNMD.

Morphology of the various defined subtypes of SM in the bone marrow

Main subtypes of SM

1. Indolent SM. Multifocal BM involvement, usually comprising 5% or less of the section area enables diagnosis of SM at first glance especially when there is prominent spindling and CD25-expression of mast cells. The hematopoiesis is intact with no signs of MDS or MPN. In cases with a slight diffuse increase of spindle-shaped CD25-expressing mast cells without any compact infiltrate, another minor criterion (KIT^D816V or elevated serum tryptase) is necessary to definitively establish the diagnosis.

2. SM-AHNMD. Here the morphological picture may be very difficult to interpret because in most cases the associated disorder dominates and even may obscure the SM (occult SM). Usually there is also multifocal BM involvement, comprising from <1% to 30% of the section area. In up to 10% of cases, SM is revealed only by using anti-tryptase and anti-CD25 immunostaining, thus enabling detection of even small compact infiltrates or a mere diffuse increase in atypical mast cells. Both compartments of the disease should be subcategorized. AHNMD in about 30–40% of the patients presents as CMML, while other disorders of the MDS/MPN group are rarely found. SM should also be further classified and usually presents as isolated BM mastocytosis, which is a subtype of indolent SM. SM-AHNMD is very heterogeneous not only morphologically but also on a molecular level (see above).

3. Aggressive SM.²⁷ In these patients, the BMTB is strongly infiltrated by large multifocal sometimes confluent sheets of mast cells (>30% of section area). In cases of ASM with diffuse-compact BM infiltration mast cell leukemia (MCL) can only be decided by investigation of BM and PB smears. In ASM, the BM smear contains <20% mast cells and the blood smear is without circulating mast cells. To establish a diagnosis of ASM, signs of organ dysfunction (‘C-findings’) should be present. ASM is almost always accompanied by significant cytopenia. Accordingly, the hematopoiesis is often markedly reduced and/or exhibits signs of dysplasia, which is indicative of an AHNMD (ASM-AHNMD).

4. Mast cell leukemia/MCL.²⁸ BM is usually diffusely infiltrated by sheets of mast cells (70% of section area or more). Numbers of fat cells and blood cell precursors are markedly reduced. Diagnosis of MCL, however, can only be established when more than 20% atypical mast cells are found in BM smears. Further classification (aleukemic versus leukemic MCL) depends on the presence of circulating mast cells (usually >10% of leukocytes). In aleukemic MCL, the BM smear shows >20% mast cells and PB is without evidence of circulating mast cells. In MCL, the BM smear shows >20% mast cells and blood smear shows circulating mast cells.

5. Mast cell sarcoma/MCS.^29,^30,³¹ MCS is extremely rare and almost always primarily involves extramedullary tissues. The terminal phase of the disease usually is a MCL.

Provisional entities

1. Smoldering systemic mastocytosis/SSM.^32,³³ SSM assumes an intermediate position between indolent and aggressive SM showing a more pronounced BM involvement (20% and more of the BMTB section area) and organomegaly (‘B findings’) while ‘C findings’ are missing. SSM usually exhibits expansion of the KIT^D816V mutation to non-mast cell lineages, usually neutrophils, but may also show minor degrees of dysplasia making the differential diagnosis to overt MDS (SM-MDS) very difficult in some of the cases.

2. Isolated BM mastocytosis morphologically presents like indolent SM but cutaneous (urticaria pigmentosa) involvement is missing. Isolated BM mastocytosis is usually found in patients with hymenoptera allergy and in some cases of SM-AHNMD.

3. Well-differentiated systemic mastocytosis³⁴ presents as exclusively round-cell type of the disease with compact multifocal infiltrates lacking expression of CD25. Since the demonstration of a point mutation outside codon 816 of c-kit (KIT^F522P) does not meet the defined minor criterion it is necessary to investigate the serum tryptase level of the patient. If serum tryptase is persistently elevated, a diagnosis of SM can be established.

4. ‘Occult’ mastocytosis can be used as a preliminary term for rare cases of SM that were initially obscured by a malignant hematological disorder in the setting of SM-AHNMD. After chemotherapy and disappearance of the associated neoplasm, typical compact mast cell infiltrates are disclosed.^18,¹¹ As a rule, appropriate investigation of the primary BMTB specimen enables to diagnose occult mastocytosis retrospectively, usually based on three minor criteria (spindling, CD25 expression and KIT^D816V). The term occult mastocytosis can also be used in rare patients, in whom previously examined tissue is available for re-evaluation. For example: in a patient with KIT^D816V-positive SM with multifocal BM infiltration, lymph nodes previously removed on the occasion of removal of cystadenolymphoma of the parotid gland lacked morphological signs of mastocytosis but demonstrated the molecular evidence of KIT^D816V mutation.¹¹

Differential diagnosis

Mastocytosis has to be strictly separated both from reactive states of mast cell hyperplasia and from neoplastic diseases exhibiting signs of mast cell differentiation. The so-called ‘monoclonal mast cell activation syndrome’ (MMAS) is only roughly defined until now with respect to morphology. MMAS can be applied to cases showing disseminated scattered mast cells carrying the KIT^D816V mutation but not fulfilling other criteria for mastocytosis, in particular missing compact infiltrates. MMAS is somewhat analogous to a monoclonal gammopathy of undetermined significance (MGUS, see Chapter 30) and at present is a preliminary description of a still ill-defined status.

The following neoplastic hematological disorders have to be included in the morphological differential diagnosis of mastocytosis:

1. Myelomastocytic leukemia^35,³⁶ represents an extremely rare type of AML with prominent signs of mast cell differentiation but not fulfilling criteria for SM, especially when compact mast cell infiltrates and the KIT^D816V mutation are missing. The histological picture is dominated by blast cells expressing myeloid and mast cell-associated antigens such as tryptase and/or chymase. A few cases exhibiting marked dysplastic features (similar to MDS of RAEB-2 type) have been encountered (author’s unpublished observation).

2. Tryptase positive acute myeloid leukemia³⁷ is also a rare subtype of AML, usually within the WHO categories of AML with minimal differentiation or AML without maturation, showing strong expression of tryptase but lacking other features of mastocytosis or myelomastocytic leukemia. Since serum tryptase is usually markedly elevated, it is possible to monitor the disease serologically. Similar to myelomastocytic leukemia, tryptase positive AML is only recognized when tryptase immunohistochemistry is applied.

3. Chronic basophilic leukemia (Fig. 26.5A–D) is a very rare myeloid leukemia usually presenting as secondary ‘basophilic crisis’ in preexisting BCR-ABL1+ CML. De novo/primary chronic basophilic leukemia is exceedingly rare but does exist. Since only neoplastic basophils express tryptase in immunohistochemically detectable amounts, it is important differentiate basophils from mast cells. Cytomorphologically basophils are small to medium-sized round cells while mast cells in SM are usually large and often spindle-shaped. Immunostaining with CD117 is crucial to confirm the mast cell nature of a tryptase+ round cell, since basophils in contrast to mast cells are always CD117 negative. Antibodies against basophil-associated antigens like CD123, 2D7 or BB1 can also be used in such cases.

4. Myeloproliferative neoplasm with eosinophilia (MPNEo)^38,¹² was formerly termed chronic eosinophilic leukemia/hypereosinophilic syndrome and is now regarded as a distinct group of disorders within myeloid neoplasms (see Chapter 25 for details). Morphologically more than 50% of cases with MPNEo exhibit a significant increase in spindle-shaped mast cells with an atypical immunophenotype and expression of CD25. However, criteria for diagnosis of SM, in particular SM-AHNMD, are not fulfilled in almost all cases since compact mast cell infiltrates are not present and the KIT^D816V mutation is not detectable.