Mast Cells and Mastocytosis

Origin and Development of Mast Cells

The marrow origin of MCs was first demonstrated by engrafting BM cells into irradiated mice. Human MCs can be generated from CD34 ⁺ hematopoietic stem and progenitor cells in response to stimulation with stem cell factor (SCF). In vitro MC differentiation models showed that circulating MC progenitors express CD13, CD34, and KIT, but lack CD14 and CD17. MC progenitors are released from the BM into the circulation in a primitive state and undergo terminal maturation and differentiation after their migration to tissues. Although shared histomorphologic and biologic features of MCs and basophils include cytoplasmic basophilic granules, expression of high-affinity immunoglobulin (Ig)E receptors (FcεRI), and release of histamine upon stimulation, basophils exhibit several distinctive characteristics. Basophils circulate as mature cells, which are incapable of proliferation, and subsequently undergo apoptosis after their recruitment and activation in the tissues. Differential expression of the transcription factor CCAAT-enhancer-binding protein (CEBP)α may be a primary determinant of whether development is skewed toward basophil progenitors (CEBPα present) or MC progenitors (CEBPα absent). Although eosinophils and basophils have been found to share a common bipotential progenitor in humans, definitive data for a similar progenitor giving rise to both basophils and MCs are lacking. Rather, based on in vitro colony assays, MCs are directly derived from multilineage and lineage-restricted progenitors, but not from such a bi-potent precursor cell. In line with this observation, evidence against a bilineage basophil/MC progenitor also came from tracking lineage involvement of KIT D816V in patients with SM, where KIT D816V was only found in basophils in a small subset of patients, namely those with multilineage involvement of the mutation. In addition, when highly enriched by cell sorting, neither mature blood basophils nor mature blood monocytes give rise to MCs in vitro.

Collectively, these data suggest that normal human MCs are derived from CD34 ⁺ stem and progenitor cells but not from a more mature myeloid cell and that MCs form a unique cell lineage in the hematopoietic cell system. Correspondingly, in 2019, Eisenwort and colleagues described that the leukemia-initiating stem cell in MCL resides within the CD34 ⁺ /CD38 ^- fraction, but not in CD34 ⁺ /CD38 ⁺ progenitors or bulk KIT ⁺ /CD34 ^- MCs.

Mast Cell Activation and Function

MCs commonly reside at the interface between the host and environment, usually in the skin, or in the mucosa lining the lungs or GI tract. Migration and homing of MCs to various sites is regulated by the interaction between surface expression of numerous types of chemokine receptors (e.g., CXC chemokine receptor 2) and integrins (e.g., α4β7, α4β1) on MCs to tissue-specific endothelial binding sites such as mucosal vascular address in cell adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In addition to playing a primary role in mediating allergic responses and inflammation, MCs act as one arm of the adaptive immune system by playing a role in host defense against pathogens such as bacteria, fungi, and viruses.

MCs serve as a rich source of a variety of biologically active molecules ( Table 75.1 ). These include preformed mediators such as vasoactive amines (histamine), anionic proteoglycans (heparin, chondroitin sulfate), and proteases (tryptase, chymase, and carboxypeptidase). Activated MCs also contribute to de novo synthesis of lipid-derived mediators that constitute the slow-reacting substance of anaphylaxis (SRS-A). These mediators include lipoxygenase-derived metabolites of arachidonic acid—the cysteinyl leukotrienes LTC4, LTD4, and LTE4, and cyclooxygenase-derived prostaglandin (PG)D2. These substances are involved in mediating vasodilation and vasopermeability, smooth muscle constriction, mucus secretion, and other proinflammatory sequelae. IgE- and non-IgE–dependent mechanisms (e.g., IgG, complement [C3a, C5a], neuropeptides, narcotics, physical stimuli, and activation of Toll-like receptors by bacterial products) can induce MCs to release a variety of cytokines (e.g., TNF-α, macrophage inflammatory protein [MIP]-1α and -1β, monocyte chemoattractant protein [MCP]-1, IFN-α, -β, and -γ, and various ILs) and growth factors (see Table 75.1 ) that are implicated in the aforementioned physiologic roles of inflammation, allergic responses, and host defense. MCs mediate early-phase (e.g., anaphylaxis, acute asthma) and late-phase allergic responses, as well as non–type I hypersensitivity reactions through their proinflammatory mediators. Furthermore, MCs mediate upregulation of Th2 responses and allergen-specific IgE biosynthesis, which contribute to host defense against parasitic infections. MCs have also been implicated in the pathogenesis of various nonallergic conditions such as infectious or autoimmune diseases (e.g., multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease), and also in repair after tissue injury, such as wound healing, thrombolysis, or tissue remodeling.

Coupling of MCs and eosinophils often occurs in the same tissue niches in allergic/inflammatory and neoplastic disorders such as eosinophilic esophagitis, chronic gastritis, GI neoplasms, parasitic infections, and inflammatory bowel disease. MCs can initiate the allergic inflammatory cascade, resulting in recruitment of eosinophils during the later phases of an allergen encounter. Both MCs and eosinophils express CCR3 and respond to eotaxins and RANTES (CCL5), leading to recruitment of both cell types into inflamed tissue (see Chapter 41, Chapter 41 ). Moreover, MC-derived heparin can bind and stabilize eotaxins. In addition, MCs and eosinophils can interact with each other through soluble mediators or via direct cell-to-cell contact. At least in the murine system, MCs can also be induced to produce IL-3 and IL-5, which can potentiate eosinophil recruitment in tissues. The two principal MC-derived proteases exert dual actions on eosinophils. For example, MC-derived chymase suppresses eosinophil apoptosis and induces release of IL-6, CXCL8, CCL2, and CXCL1 from eosinophils. In contrast, β-tryptase can cleave eotaxin and RANTES, and can limit eosinophil chemotaxis. Eosinophils in turn produce SCF, which can attract more tissue MCs and protect them from apoptosis.

IgE-mediated hypersensitivity reactions (e.g., allergic rhinitis or asthma, anaphylaxis) are mediated by binding of allergen-specific IgE to the high-affinity FcεRI receptor, which is constitutively expressed at a high level on MCs. Engagement of FcεRI leads to its inclusion in lipid rafts, and phosphorylation of its β- and γ-chain immunoreceptor tyrosine-based activation motifs (ITAMs) by Lyn kinase and subsequent activation of Syk kinase through its binding to the ITAMs. These proximal signaling events also activate Fyn kinase, which is important for phosphorylation of the adaptor protein Gab2 and activation of the PI3K pathway. Lyn kinase also regulates phosphorylation of the protein scaffolds LAT and NTAL, which coordinate multiple signaling pathways including Ras/MAP kinase, TEC family kinases, and PLCγ activation. PLCγ, in turn, is a critical mediator of MC cytokine production and degranulation. Experimental data indicate that the functions of KIT and FcεRI in MCs are interdependent. It has been observed that SCF enhances FcεRI-mediated MC degranulation, and that phosphorylation of the membrane adaptor molecule NTAL is a crucial link between the signaling cascades following KIT activation and FcεRI aggregation. In addition, BTK is a mediator of FcεRI-mediated MC degranulation and plays a critical role in the amplification of FcεRI activation by KIT.

Tools to Study Human Mast Cells

The challenges of studying MCs relate to heterogeneity in their morphology and function between different species, and also within different tissues of the same organism. Although several techniques, including flow cytometry-based cell sorting, exist for ex vivo isolation of BM MCs, yields are typically low, reflecting the low numbers of MCs in the BM and the difficulties in isolating them from other tissues, such as the lung. Ex vivo generation of human cord blood–derived or peripheral blood–derived MCs from their CD34 ⁺ or CD133 ⁺ progenitor cells using SCF and IL-6 can generate large numbers of functionally mature MCs that can be interrogated for various types of biologic investigations. Many studies of MCs and/or mastocytosis have relied on MC lines such as the SCF-dependent cell lines LAD1/LAD2, derived from patients with MC sarcoma (MCS) with KIT D816V (this cell line actually has normal KIT despite its origin, and is SCF-dependent); the LUVA cell line (derived from CD34 ⁺ cells, growth factor–independent, normal KIT , and tendency to lose FcεRI expression with long-term culture); and the SCF-independent human MC line HMC-1 derived from a patient with MCL. Two HMC-1 subclones are available—HMC-1.1, which contains the KIT V560G mutation, and HMC-1.2, which expresses both KIT V560G and D816V. Both clones have been useful for in vitro evaluation of the differential sensitivity of different small-molecule inhibitors of KIT. None of these human MC lines, however, express both a functional IgE receptor and KIT D816V. However, a human cord blood–derived cell line that is SCF-dependent and FcεRI ⁺ (ROSA ^{KIT WT} ) has been developed which converts to SCF independence and produces tumors with transfection by KIT D816V (ROSA ^{KIT D816V} ), and is widely used as a tool for studying the biology and pharmacologic aspects of mastocytosis. Other human MC lines that have been studied in the context of mastocytosis are LAD2, LADR, and MCPV-1.

Epidemiology and Classification of Mastocytosis

In 2008, SM was included in the WHO category of myeloproliferative neoplasms (MPNs). However, based on the complex clinical picture, biology, and pathology, SM was again defined by the WHO as a separate unique myeloid neoplasm in 2016. SM is an orphan disease and sparse data exist regarding its incidence or other epidemiologic features. A slight male predominance has been observed, and in one study, the median age at time of SM diagnosis was 55 years. A retrospective study from Denmark that canvassed the years from 1997 to 2010 estimated the incidence of SM at 0.89 per 100,000 persons per year, with an estimated prevalence of 9.59 per 100,000 individuals. A Dutch analysis estimated the prevalence of ISM to be 13 cases per 100,000 inhabitants.

The first diagnostic checkpoint is to distinguish SM from CM, which is characterized by predominant skin involvement. Criteria to diagnose SM are not fulfilled in these patients. However, in rare cases with CM, a discrete involvement of the BM by clonal cells may be detected, and serum tryptase levels may be slightly elevated. SM primarily occurs in adults, whereas CM is more common in children and its natural history is typically defined by spontaneous resolution of skin lesions usually at the time of puberty. CM variants include urticaria pigmentosa/maculopapular CM, diffuse CM, and solitary mastocytoma of the skin. In the overwhelming majority of adults with cutaneous involvement, systemic disease (SM) is diagnosed. However, absence of skin lesions does not exclude the presence of SM. Skin involvement occurs in over 80% of all patients with adult SM. However, sometimes no BM examination is performed for some time, especially when the patient has not been referred to a hematologist. In such cases, cutaneous lesions are referred to as mastocytosis in the skin (MIS).

Diagnostic criteria for SM were initially formulated by a working group of MC disease experts at a consensus conference in Vienna in 2000, and adopted by the WHO in both 2001 and 2008. In 2022, the WHO and International Consensus Classification (ICC) generated some minor modifications to the classification of SM and its variants. Minimal diagnostic criteria for SM requires at least one major plus one minor criterion, or at least three minor criteria ( Table 75.2 ). The major criterion is the presence of multifocal dense aggregates of MCs (>15 MCs in aggregates) in sections of BM or other extracutaneous organ(s); minor criteria include: (1) >25% of the MCs in the infiltrate or in the BM smear are of spindle shape or of otherwise atypical morphology; (2) activating mutation at codon 816 in the KIT gene (or other activating KIT mutation) in an extracutaneous organ; (3) expression of CD25 +/− CD2 or CD30 in/on MCs (2022 WHO and ICC modifications); and (4) serum tryptase level >20 ng/mL, unless there is an associated myeloid disorder that makes this parameter not valid.

SM is further divided into several subtypes that reflect the presence or absence of certain clinical or laboratory findings ( Tables 75.3 and 75.4 ). The most common form of SM in adults is ISM, characterized by a slightly to markedly increased burden of neoplastic MCs in the BM and/or other extracutaneous organ(s). By definition, ISM patients do not exhibit MC-related organ damage or an associated hematologic disorder, and life expectancy in this variant has been shown to be similar to that of an age-matched healthy population, with an analysis showing a 10-year overall survival (OS) of 93.5% ( Fig. 75.1 ). However, ISM patients often experience mediator symptoms related to MC degranulation (e.g., flushing, pruritis, diarrhea, abdominal cramping, neuropsychiatric complaints). Although triggers may not always be identifiable, known provokers of MC activation and/or anaphylaxis include non-IgE and IgE-mediated causes: physical or emotional stress, exercise, hot or cold temperature stimuli, medications such as aspirin, NSAIDs, opioid analgesics, or antibiotics, alcohol, radiocontrast dye, and IgE-mediated allergies. One critical comorbidity is Hymenoptera (e.g., wasps, bees, and ants) venom allergy. In particular, these patients are at high risk of developing severe or even fatal anaphylaxis upon exposure to the venom. Cutaneous involvement usually develops in conjunction with the ISM subtype, both in younger individuals as well as in older patients. However, those with advanced disease may also develop MIS. Interestingly, skin disease usually portends a decreased risk of anaphylaxis, especially due to Hymenoptera stings. Bony disease (e.g., localized bone pain, diffuse osteopenia, osteoporosis with or without pathologic fractures, osteosclerosis) is also well described in ISM, but can cause morbid complications across the spectrum of SM variants. Bone marrow mastocytosis (BMM) is defined similarly as ISM but without skin lesions and typically exhibits lower tryptase levels, e.g. <125 ng/mL. It is listed as a subtype of ISM the 2016 WHO diagnostic criteria, but as a separate category in the 2020 Working Conference consensus proposal of mastocytosis.

In the 2008 WHO classification, smoldering SM (SSM) was designated as a subvariant of ISM. However, based on the current classification proposed by the consensus group, SSM was included in the revised 2016 WHO classification as a separate variant of SM, which is meaningful because these patients exhibit a higher chance of progression to more advanced disease. SSM is defined by two or more “B” findings ( Table 75.5 ), for example, (1) hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging; (2) BM MC burden >30% and serum tryptase level >200 ng/mL; and (3) signs of dysplasia or myeloproliferation, in non-MC lineage(s), but insufficient criteria for definitive diagnosis of an additional hematopoietic neoplasm, with normal or only slightly abnormal blood counts. Compared with ISM, SSM patients often exhibit clonal multilineage involvement with the KIT D816V mutation, which is also a prognostically relevant variable. In the 2022 WHO classification, a KIT D816V variant allele frequency ≥10% qualifies as a “B” finding.

Advanced SM (AdvSM) is an umbrella term for three variants that are characterized by decreased life expectancy: SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), and MCL. SM-AHN comprises 30% of SM variants, and approximately two-thirds of advSM cases, although this figure may vary depending on referral patterns. In the revised 2016 WHO classification, the term “SM-AHN” can be used interchangeably with or in lieu of the prior term “SM-AHNMD” (SM with an associated hematologic non-MC lineage disease). The vast majority of AHNs are myeloid neoplasms: myelodysplastic syndrome (MDS), MPNs, MDS/MPN overlap disorders such as chronic myelomonocytic leukemia (CMML) or MDS/MPN-unclassifiable, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), and acute myeloid leukemia (AML). Rarely, lymphoid neoplasms such as chronic lymphocytic leukemia, myeloma, or lymphomas have been found in association with SM. Identifying a concomitant myeloid neoplasm may depend on several factors, including the expertise of the evaluating pathologist, and whether one disease is masked by the presence of another. For example, in cases of SM-AML, MC aggregates may only be unmasked after induction chemotherapy with achievement of BM hypoplasia, because neoplastic MCs may persist after such therapy. Distinguishing nonhematologic or hematologic organ damage due to the SM component versus the associated myeloid disease can be very difficult, if not impossible, in some patients. Even when a biopsy of the involved extramedullary organ is analyzed to elucidate the burden of neoplastic MCs versus associated myeloid neoplasm, it is sometimes impossible to define the relative impact of the SM versus AHN component on organ dysfunction, especially when both disease components are of an aggressive type.

Although the prognosis of SM-AHN frequently relates to the AHN component, the burden of SM as well as the type and stage of the associated myeloid neoplasm need to be considered on an individual basis. Treatment plans are tailored to the histopathologic and molecular findings and the clinical sequelae that are felt to be attributable to each disease component. A commonly cited therapeutic approach has been to treat the SM component as if the myeloid neoplasm were not present, and to treat the myeloid neoplasm as if SM were not present. Because the KIT D816V mutation may be present in the cells belonging to both disease compartments, small molecule inhibitors of dysregulated KIT may provide benefit for both the SM and AHN in selected cases.

ASM comprises 5% to 10% of SM variants and is defined by one or more “C findings” ( Table 75.6 ) reflecting organ dysfunction because of neoplastic MC infiltrates. Examples of C findings include marked cytopenias because of extensive BM involvement (defined by an absolute neutrophil count [ANC] <1 × 10 ⁹ /L, hemoglobin <10 g/dL, and/or platelet count <100 × 10 ⁹ /L) and/or hypersplenism; hepatomegaly with liver dysfunction, and/or portal hypertension or ascites; hypoalbuminemia, which may relate to liver dysfunction and/or gut infiltration by neoplastic MCs; weight loss; and severe bone disease manifested by large osteolyses (≥ 2 cm) and/or pathologic fractures. In a majority of patients with ASM, the percentage of MCs in the BM smear is below 5%, which is a favorable prognostic sign. Notably, in the less frequent ASM patients in whom MCs comprise ≥5% of all nucleated BM cells on a Giemsa-stained BM smear, the prognosis is poor, as many of these patients progress and transform to MCL or an ASM-AHN. Therefore these patients have recently been described as ASM in transformation (ASM-t; see later also under diagnostic evaluation of mastocytosis). As soon as the percentage of MCs in these patients increases to ≥20% in the BM smear, the diagnosis changes to MCL.

MCL is a very rare form of SM (~1% of SM variants) and is defined by MCs comprising ≥20% of nucleated cells on BM aspirate smears. On the core biopsy, MCs form a diffuse, compact infiltrate with usually low levels of fibrosis. High-grade cytologic features of MCs can be observed in MCL, including multilobed or clefted nuclei, clumping of metachromatic granules, metachromatic blasts (rare, more typical for myelomastocytic leukemia), and, rarely, mitotic figures. In MCL, circulating MCs (≥10% of nucleated cells) may be found; however, the aleukemic MCL variant (<10% MCs in the peripheral blood) is more common. MCL may arise de novo or progress from less advanced forms of SM, such as ASM with elevated MC counts on the BM aspirate. MCL typically has a dismal prognosis with a life expectancy of 6 months or less in most patients, but survival can be heterogeneous, extending to 1 to 2 years or longer, and can be adversely impacted by high-risk mutations involving SRSF2 , ASXL1 , and/or RUNX1 . A chronic form of MCL has also been described, wherein patients meet histopathologic criteria for the disease, but without C findings (see later). In these cases, MCs tend to show a more mature morphology, and may exhibit imatinib-sensitive JM KIT mutations. However, even those with the initially more indolent form of (chronic) MCL are expected to show progression over time with development of organ damage (transformation to acute MCL) and limited survival. In addition to the distinction of MCL into acute and chronic forms, and the historical convention of dividing MCL into leukemic and aleukemic variants, other useful subclassifications include MCL with or without an AHN, and primary (de novo) versus secondary MCL, the latter transformed from less advanced disease or MCS.

MCS is a rare MC tumor that can invade local tissues and has a high potential to develop advanced systemic disease with a fulminant course. In particular, most if not all patients with MCS progress to MCL within a relatively short time period. Vice versa, MCS-like tumors (“secondary MCS”) may develop during the course of SM, usually the advanced forms. Extracutaneous mastocytoma is another rare SM variant that typically follows a benign course. However, because of its rarity, this MC disease entity was eliminated from the last update of the WHO classification.

Well-differentiated SM (WDSM) is a more recently described rare variant of SM that is not yet formally recognized by the WHO (see later for histopathologic characteristics). The major reason for this is that the well-differentiated (WD) morphology of MCs can be found in all WHO subvariants of SM, including ISM, ASM, and MCL. Therefore the WD phenotype should be used as a descriptive term to complement the WHO diagnosis rather than as a tool to formulate a new entity.

Diagnostic Evaluation of Mastocytosis

Tissue biopsy in conjunction with clinical and pathology expertise are critical in establishing the diagnosis of SM. BM MC burden is best quantified by morphologic analysis and immunohistochemical stains such as tryptase, CD117 (KIT), and CD25 on the core biopsy. Multiparameter flow cytometric analysis of BM aspirates can also be used to quantify the percentage of MCs, and generally correlates with SM burden defined by morphologic/immunohistochemical evaluation. Morphologic evaluation of the BM aspirate is additionally important for evaluating dysplasia and excess myeloblasts, and most relevant to MCL, the number of atypical MCs. Based on this evaluation, the presence of MCL can be excluded or can be confirmed during the diagnostic work-up.

The most important morphologic feature of mastocytosis, in particular its systemic variants, is the presence of compact infiltrates consisting of densely packed atypical MCs. Compact MC infiltrates are almost never detected in reactive states, even in those with marked MC hyperplasia. Accordingly, compact MC infiltrates can be regarded as the only major criterion for diagnosis of mastocytosis, which also underlines the important role of the hematopathologist in making these diagnoses. Investigation of an adequate BM biopsy trephine specimen is crucial to assess or exclude a diagnosis of SM. In most patients a few compact infiltrates can be identified even by using conventional stains like Giemsa-Wright or toluidine blue, which both facilitate detection of the pathognomonic metachromatic granules. The MCs are round or spindle shaped, and often exhibit at least some hypogranulation. The nuclei are round or elongated depending on the shape of the cell. Prominent nucleoli are not seen. Almost always such compact infiltrates also contain mature eosinophils, histiocytes, and sometimes large follicle-like aggregates of lymphocytes that are polyclonal in nature. Reticulin fiber density is always increased with the exception of a few very small but diagnostic infiltrates. Larger compact and mixed infiltrates often show patchy collagen fibrosis. The degree of reticulin fibrosis in most cases of MCL is low, which can be used as a criterion that allows one to distinguish MCL from ASM, which usually exhibits marked reticulin or even collagen fibrosis ( Fig. 75.2 ). Immunohistochemistry should be performed in all cases in order to enumerate the numbers of loosely scattered MCs and to detect small but diagnostic compact infiltrates. The degree of MC infiltration should always be documented by the hematopathologist: it is recommended to refer to the section area and to the overall cellularity in this respect. This enables monitoring of the disease during and after therapy. MCs almost always coexpress tryptase and CD117; in most SM cases, MCs also aberrantly express CD25, whereas aberrant expression of other antigens such as CD2 is more rarely encountered and therefore of minor diagnostic importance ( Fig. 75.3 ). Interestingly, it could be shown that MCs may lose immunohistochemically detectable CD25 or tryptase expression during or after therapy with TK inhibitors such as midostaurin, and MCs in cases of intestinal involvement by SM may lack detectable tryptase expression at diagnosis (e.g., incomplete immunophenotype). However, it can be stated definitively that a cell lacking expression of CD117 (KIT) cannot be a MC. Although ISM and isolated mastocytosis of the BM (BMM) usually show a minor degree of BM involvement with multifocal compact infiltrates (<10% of the section area), smoldering and advSM but also MCL usually exhibit a more diffuse or packed infiltration occupying more than 30% and up to 100% of the section area. In a significant proportion of cases compact MC infiltrates are missing and the degree of tissue involvement may be very low (<1% regarding cellularity and section area). Accordingly, such cases could be termed “occult SM,” and are difficult to detect for the pathologists. Moreover, SM is a great mimicker with regard to morphologic and immunophenotypical features of MCs, and a broad spectrum of differential diagnoses should be considered. The following list only contains the main entities and is therefore incomplete:

• 1.

  monocytic leukemias (clear cell feature + CD14)

• 2.

  histiocytoses (clear cell feature + CD68)

• 3.

  clear-cell carcinomas (clear cell feature + epithelial antigens like keratin)

• 4.

  basophilic leukemias (metachromatic granules + tryptase but missing CD117)

• 5.

  myelomastocytic leukemia (metachromatic blasts + tryptase + CD117)

• 6.

  Hodgkin lymphoma (CD30)

• 7.

  hairy cell leukemia (clear cell feature + CD25)

• 8.

  granulation tissue and scars

Evaluation of blood and BM smears is crucial for both identification and subtyping of MCL and separation of MCL from a recently described subtype of ASM, namely ASM-t (see earlier). In almost all patients with ISM and SSM, but also in most cases with ASM, the MC numbers in BM smears are lower than 5%, in ISM and SSM usually even below 1%. Crushed particles with higher numbers of MCs must not be considered in this respect. In a few patients with ASM the number of MCs is unusually high, exceeding 5% but not 19% of all nucleated cells. It is this subgroup of patients that has a worse prognosis but do not fulfill criteria for MCL and have therefore been termed ASM-t.

Cytomorphologic findings in SM include atypically shaped MCs with spindled appearance (type I) on the one hand and round immature MCs with bilobated or monocytoid nuclei on the other (type II). Atypical type I MCs are usually encountered in ISM, SSM, and often also in ASM, but also in isolated BMM, whereas atypical type II MCs dominate the picture in most cases of MCL, and are often found also in patients with ASM and ASM-t. Exceedingly rare cases of MCL with predominance of spindle-shaped cells of type I are associated with a relatively good prognosis and the disease accordingly has been termed chronic MCL (see earlier) ( Fig. 75.4 ). There is one peculiar phenotypic variant of SM termed WDSM (see earlier) that consists exclusively of round hypergranular-appearing MCs that form the typical cohesive clusters in BM smears. Such MC clusters are not seen in all of the subvariants of SM. The feature of WDSM has been encountered in almost all defined subvariants of SM including MCL. WDSM usually lacks aberrant expression of CD25 and does also not show the typical activating point mutations at codon 816 of KIT , but instead the aforementioned JM KIT mutations which often exhibit sensitivity to imatinib ( Fig. 75.5 ). In addition, MCs in WDSM usually express CD30 which can be employed as additional disease indication (criterion) in these patients.

CD30 (Ki-1) is a cytoplasmic and membrane-bound antigen expressed by neoplastic cells in Hodgkin lymphoma and anaplastic large-cell lymphoma. However, CD30 has also been shown to be expressed by neoplastic MCs in SM. Although the antigen was originally reported as an immunohistochemical marker that is primarily expressed in the cytoplasm of MCs in more advanced forms of SM, other studies have detected CD30 by immunohistochemistry in less advanced forms of MC disease, including CM, as well as ISM and SSM. CD30 is not only expressed in the cytoplasm of neoplastic MCs but also on the cell surface, which has clinical implications as a CD30 antibody-toxin conjugate is available and was tested in a phase II trial of patients with CD30 ⁺ advSM. More recently, it was found that neoplastic MCs express higher levels of CD44 compared to normal MCs and that the levels of measurable CD44 on MC and in the plasma of patients with SM correlates with aggressiveness of the disease.

Altogether, a complete diagnosis of SM reported by the hematopathologist should read like this:

SM-AHN; SM shows a marked multifocal BM infiltration (>50% section area) and is best subtyped as ASM since there is a reported C-finding and MC numbers in BM smears are low; AHN is a myeloid neoplasm that cannot be subtyped with certainty but morphological features are consistent with a disorder of the MDS/MPN category (MDS/MPN-unclassifiable).

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