The World Health Organization (WHO) system uses peripheral blood counts and smear analysis, bone marrow morphology, and cytogenetic and molecular genetic tests in order to classify myeloid malignancies into five major categories (Table 135e-4). In this chapter, we focus on chronic neutrophilic leukemia; atypical chronic myeloid leukemia, BCR-ABL1 negative; chronic myelomonocytic leukemia; juvenile myelomonocytic leukemia; chronic eosinophilic leukemia, not otherwise specified; mastocytosis; myeloproliferative neoplasm (MPN), unclassifiable (MPN-U); myelodysplastic syndrome (MDS)/MPN, unclassifiable (MDS/MPN-U); refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T); and myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. This chapter also includes histiocytic and dendritic cell neoplasms, transient myeloproliferative disorders, and a broader discussion on primary eosinophilic disorders including hypereosinophilic syndrome (HES).
TABLE 135e-4World Health Organization Classification of Myeloid Malignancies ||Download (.pdf) TABLE 135e-4World Health Organization Classification of Myeloid Malignancies
1. Acute myeloid leukemia (AML) and related precursor neoplasmsa
2. Myeloproliferative neoplasms (MPN)
2.1. Chronic myelogenous leukemia, BCR-ABL1 positive (CML)
2.2. BCR-ABL1-negative MPN
2.3. Chronic neutrophilic leukemia
2.4. Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)
2.6. Myeloproliferative neoplasm, unclassifiable (MPN-U)
3. Myelodysplastic syndromes (MDS)
3.1. Refractory cytopeniab with unilineage dysplasia (RCUD)
3.1.1. Refractory anemia (ring sideroblasts <15% of erythroid precursors)
3.1.2. Refractory neutropenia
3.1.3. Refractory thrombocytopenia
3.2. Refractory anemia with ring sideroblasts (RARS; dysplasia limited to erythroid lineage and ring sideroblasts ≥15% of bone marrow erythroid precursors)
3.3. Refractory cytopenia with multilineage dysplasia (RCMD; ring sideroblast count does not matter)
3.4. Refractory anemia with excess blasts (RAEB)
3.5. MDS associated with isolated del(5q)
3.6. MDS, unclassifiable (MDS-U)
4. MDS/MPN overlap
4.1. Chronic myelomonocytic leukemia (CMML)
4.2. Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML)
4.3. Juvenile myelomonocytic leukemia (JMML)
4.4. MDS/MPN, unclassifiable (MDS/MPN-U)
5. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1c
5.1. Myeloid and lymphoid neoplasms with PDGFRA rearrangement
5.2. Myeloid neoplasms with PDGFRB rearrangement
5.3. Myeloid and lymphoid neoplasms with FGFR1 abnormalities
CHRONIC NEUTROPHILIC LEUKEMIA
Chronic neutrophilic leukemia (CNL) is characterized by mature neutrophilic leukocytosis with few or no circulating immature granulocytes. CNL is associated with activating mutations of the gene (CSF3R) encoding for the receptor for granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3 (CSF3). Patients with CNL might be asymptomatic at presentation but also display constitutional symptoms, splenomegaly, anemia, and thrombocytopenia. Median survival is approximately 2 years, and causes of death include leukemic transformation, progressive disease associated with severe cytopenias, and marked treatment-refractory leukocytosis. CNL is rare, with less than 200 reported cases. Median age at diagnosis is approximately 67 years, and the disease is equally prevalent in both genders.
CSF3 is the main growth factor for granulocyte proliferation and differentiation. Accordingly, recombinant CSF3 is used for the treatment of severe neutropenia, including severe congenital neutropenia (SCN). Some patients with SCN acquire CSF3R mutations, and the frequency of such mutations is significantly higher (~80%) in patients who experience leukemic transformation. SCN-associated CSF3R mutations occur in the region of the gene coding for the cytoplasmic domain of CSF3R and result in truncation of the C-terminal-negative regulatory domain. A different class of CSF3R mutations is noted in ~90% of patients with CNL; these are mostly membrane proximal, with the most frequent being a C-to-T substitution at nucleotide 1853 (T618I). About 40% of the T618I-mutated cases also harbored SETBP1 mutations. CSF3R T618I induces a lethal myeloproliferative disorder in a mouse model and is associated with in vitro sensitivity to JAK inhibition.
Diagnosis of CNL requires exclusion of the more common causes of neutrophilia including infections and inflammatory processes. In addition, one should be mindful of the association between some forms of metastatic cancer or plasma cell neoplasms with secondary neutrophilia. Neoplastic neutrophilia also occurs in other myeloid malignancies including atypical chronic myeloid leukemia and chronic myelomonocytic leukemia. Accordingly, the WHO diagnostic criteria for CNL are designed to exclude the possibilities of both secondary/reactive neutrophilia and leukocytosis associated with myeloid malignancies other than CNL (Table 135e-5): leukocytosis (≥25 × 109/L), >80% segmented/band neutrophils, <10% immature myeloid cells, <1% circulating blasts, and absence of dysgranulopoiesis or monocytosis. Bone marrow in CNL is hypercellular and displays increased number and percentage of neutrophils with a very high myeloid-to-erythroid ratio and minimal left shift, myeloid dysplasia, or reticulin fibrosis.
TABLE 135e-5World Health Organization Diagnostic Criteria for Chronic Neutrophilic Leukemia (CNL); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative (aCML); and Chronic Myelomonocytic Leukemia (CMML) ||Download (.pdf) TABLE 135e-5World Health Organization Diagnostic Criteria for Chronic Neutrophilic Leukemia (CNL); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative (aCML); and Chronic Myelomonocytic Leukemia (CMML)
|Variables ||CNL ||aCML ||CMML |
|PB leukocyte count ||≥25 × 109/L ||≥13 × 109/L || |
|PB segmented neutrophils/bands ||>80% || || |
|PB immature granulocytesa ||<10% ||≥10% || |
|PB blast count ||<1% || || |
|PB monocyte count ||<1 × 109/L ||<1 × 109/L ||>1 × 109/L |
|PB increased neutrophils or precursors with dysgranulopoiesis ||No ||Yes || |
|PB basophil percentage || ||<2% || |
|PB monocyte percentage || ||<10% || |
|Bone marrow || |
↑Neutrophils, number and %
Normal neutrophilic maturation
Megakaryocytes normal or left shifted
Granulocytic dysplasia ± erythroid/megakaryocyte dysplasia
Dysplasia in ≥1 myeloid lineages
Clonal cytogenetic/molecular abnormality
|BCR-ABL1 ||No ||No ||No |
|PDGFRA, PDGFRB, or FGFR1 mutation ||No ||No ||No |
|PB and BM blasts/promonocytes ||<20% ||<20% ||<20% |
|Hepatosplenomegaly ||± ||± ||± |
|Evidence for other MDS/MPN ||No ||No ||No |
|Evidence for other MPN ||No ||No ||No |
|Evidence for reactive leukocytosisb or monocytosis ||No ||No ||No |
Current treatment in CNL is largely palliative and suboptimal in its efficacy. Several drugs alone or in combination have been tried, and none have shown remarkable efficacy. As such, allogeneic stem cell transplantation (ASCT) is reasonable to consider in the presence of symptomatic disease, especially in younger patients. Otherwise, cytoreductive therapy with hydroxyurea is probably as good as any treatment, and a more intensive combination chemotherapy may not have additional value. However, response to hydroxyurea therapy is often transient, and some have successfully used interferon α as an alternative drug. Response to treatment with ruxolitinib (a JAK1 and JAK2 inhibitor) has been reported but has not been confirmed.
ATYPICAL CHRONIC MYELOID LEUKEMIA
Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is formally classified under the MDS/MPN category of myeloid malignancies and is characterized by left shifted granulocytosis and dysgranulopoiesis. The differential diagnosis of aCML includes chronic myeloid leukemia (CML), which is distinguished by the presence of BCR-ABL1; CNL, which is distinguished by the absence of dysgranulopoiesis and presence of CSF3R mutations; and chronic myelomonocytic leukemia, which is distinguished by the presence of monocytosis (absolute monocyte count >1 × 109/L). The WHO diagnostic criteria for aCML are listed in Table 135e-5 and include granulocytosis (WBC ≥13 × 109/L), neutrophilia with dysgranulopoiesis, ≥10% immature granulocytes, <20% peripheral blood myeloblasts, <10% peripheral blood monocytes, <2% basophils, and absence of otherwise specific mutations such as BCR-ABL1. The bone marrow is hypercellular with granulocyte proliferation and dysplasia with or without erythroid or megakaryocytic dysplasia.
The molecular pathogenesis of aCML is incompletely understood; about one-fourth of the patients express SETBP1 mutations, which are, however, also found in several other myeloid malignancies, including CNL and chronic myelomonocytic leukemia. SETBP1 mutations in aCML were prognostically detrimental and mostly located between codons 858 and 871; similar mutations are seen with Schinzel-Giedion syndrome (a congenital disease with severe developmental delay and various physical stigmata including midface retraction, large forehead, and macroglossia).
In a series of 55 patients with WHO-defined aCML, median age at diagnosis was 62 years with female preponderance (57%); splenomegaly was reported in 54% of the patients, red cell transfusion requirement in 65%, abnormal karyotype in 20% (20q– and trisomy 8 being the most frequent), and leukemic transformation in 40%. Median survival was 25 months. Outcome was worse in patients with marked leukocytosis, transfusion requirement, and increased immature cells in the peripheral blood. Conventional chemotherapy is largely ineffective in the treatment of aCML. However, a favorable experience with ASCT was reported in nine patients; after a median follow-up of 55 months, the majority of the patients remained in complete remission.
CHRONIC MYELOMONOCYTIC LEUKEMIA
Chronic myelomonocytic leukemia (CMML) is classified under the WHO category of MDS/MPN and is defined by an absolute monocyte count (AMC) of >1 × 109/L in the peripheral blood. Median age at diagnosis ranges between 65 and 75 years, and there is a 2:1 male predominance. Clinical presentation is variable and depends on whether the disease presents with MDS-like or MPN-like phenotype; the former is associated with cytopenias and the latter with splenomegaly and features of myeloproliferation such as fatigue, night sweats, weight loss, and cachexia. About 20% of patients with CMML experience serositis involving the joints (arthritis), pericardium (pericarditis and pericardial effusion), pleura (pleural effusion), or peritoneum (ascites).
Clonal cytogenetic abnormalities are seen in about one-third of patients with CMML and include trisomy 8 and abnormalities of chromosome 7. Almost all patients with CMML harbor somatic mutations involving epigenetic regulator genes (e.g., ASXL1, TET2), spliceosome pathway genes (e.g., SRSF2), DNA damage response genes (e.g., TP53), and tyrosine kinases/transcription factors (e.g., KRAS, NRAS, CBL, and RUNX1). However, none of these mutations are specific to CMML, and their precise pathogenetic contribution is unclear.
Reactive monocytosis is uncommon but has been reported in association with certain infections and inflammatory conditions. Clonal (i.e., neoplastic) monocytosis defines CMML but is also seen with juvenile myelomonocytic leukemia and acute myeloid leukemia with monocytic differentiation. The WHO diagnostic criteria for CMML are listed in Table 135e-5 and include persistent AMC >1 × 109/L, absence of BCR-ABL1, absence of the PDGFRA or PDGFRB mutations, <20% blasts and promonocytes in the peripheral blood and bone marrow, and dysplasia involving one or more myeloid lineages.
The bone marrow in CMML is hypercellular with granulocytic and monocytic proliferation. Dysplasia is often present and may involve one, two, or all myeloid lineages. On immunophenotyping, the abnormal cells often express myelomonocytic antigens such as CD13 and CD33, with variable expression of CD14, CD68, CD64, and CD163. Monocytic-derived cells are almost always positive for the cytochemical nonspecific esterases (e.g., butyrate esterase), whereas normal granulocytic precursors are positive for lysozyme and chloroacetate esterase. In CMML, it is common to have a hybrid cytochemical staining pattern with cells expressing both chloroacetate and butyrate esterases simultaneously (dual esterase staining).
A meta-analysis showed median survival of 1.5 years in CMML. Numerous prognostic systems have attempted to better define and stratify the natural history of CMML. One of these, the Mayo prognostic model, assigns one point each to the following four independent prognostic variables: AMC >10 × 109/L, presence of circulating immature cells, hemoglobin <10 g/dL, and platelet count <100,000/mL. This model stratified patients into three risk groups: low (0 points), intermediate (1 point), and high (≥2 points), translating to median survival times of 32, 18, and 10 months, respectively.
A French study incorporated ASXL1 mutational status in 312 CMML patients. In a multivariable model, independent predictors of poor survival were WBC >15 × 109/L (3 points), ASXL1 mutations (2 points), age >65 years (2 points), platelet count <100,000/mL (2 points), and hemoglobin <10 g/dL in females and <11 g/dL in males (2 points). This model stratified patients into three groups: low (0–4 points), intermediate (5–7 points), and high risk (8–12 points), with median survival times of not reached, 38.5 months, and 14.4 months, respectively.
Current treatment consists of hydroxyurea and supportive care, including red cell transfusions and use of erythropoiesis-stimulating agents (ESAs). The value of hydroxyurea was reinforced by a randomized trial against oral etoposide. No other single or combination chemotherapy has been shown to be superior to hydroxyurea. ASCT is a viable treatment option for transplant-eligible patients with poor prognostic features. Given the MDS/MPN overlap phenotype and the presence of MDS-like genetic/methylation abnormalities in CMML, hypomethylating agents such as 5-azacitidine and decitabine have been used with limited efficacy.
JUVENILE MYELOMONOCYTIC LEUKEMIA
Juvenile myelomonocytic leukemia (JMML) is primarily a disease of early childhood and is included, along with CMML, in the MDS/MPN WHO category. Both CMML and JMML feature leukocytosis, monocytosis, and hepatosplenomegaly. Additional characteristic features in JMML include thrombocytopenia and elevated fetal hemoglobin. Myeloid progenitors in JMML display granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity that has been attributed to dysregulated RAS/MAPK signaling. The latter is believed to result from mutually exclusive mutations involving RAS, PTPN11, and NF1. A third of patients with JMML that is not associated with Noonan’s syndrome carry PTPN11 mutations, whereas the incidence of NF1 in patients without neurofibromatosis type 1 and RAS mutations is approximately 15% each. Drug therapy is relatively ineffective in JMML, and the treatment of choice is ASCT, which results in a 5-year survival of approximately 50%.
The WHO classifies patients with morphologic and laboratory features that resemble both MDS and MPN as MDS/MPN overlap. This category includes CMML, aCML, and JMML, which have been described above. In addition, MDS/MPN includes a fourth category referred to as MDS/MPN, unclassifiable (MDS/MPN-U). Diagnosis of MDS/MPN-U requires the presence of both MDS and MPN features that are not adequate to classify patients as CMML, aCML, or JMML. MDS/MPN includes the provisional category of RARS-T.
RARS-T is classified in the MDS/MPN category because it shares dysplastic features with RARS and myeloproliferative features with essential thrombocythemia (ET). In one study, 111 patients with RARS-T were compared with 33 patients with RARS. The frequency of SF3B1 mutations in RARS-T (87%) was similar to that in RARS (85%). JAK2 V617F mutation was detected in 49% of RARS-T patients (including 48% of those mutated for SF3B1) but none of those with RARS. In RARS-T, SF3B1 mutations were more frequent in females (95%) than in males (77%), and mean ring sideroblast counts were higher in SF3B1-mutated patients. Median overall survival was 6.9 years in SF3B1-mutated patients versus 3.3 years in unmutated patients. Six-year survival was 67% in JAK2-mutated patients versus 32% in unmutated patients. Multivariable analysis identified younger age and JAK2 and SF3B1 mutations as favorable factors.
In one series, 85 patients with non-RARS-T MDS/MPN, median age was 70 years, and 72% were males. Splenomegaly at presentation was present in 33%, thrombocytosis in 13%, leukocytosis in 18%, JAK2 mutations in 30%, and abnormal karyotype in 51%; the most frequent cytogenetic abnormality was trisomy 8. Median survival was 12.4 months and favorably affected by thrombocytosis. Treatment with hypomethylating agents, immunomodulators, or ASCT did not appear to favorably affect survival.
MYELOPROLIFERATIVE NEOPLASM, UNCLASSIFIABLE (MPN-U)
The category of MPN-U includes MPN-like neoplasms that cannot be clearly classified as one of the other seven subcategories of MPN (Table 135e-4). Examples include patients presenting with unusual thrombosis or unexplained organomegaly with normal blood counts but found to carry MPN-characteristic mutations such as JAK2 and CALR or display bone marrow morphology that is consistent with MPN. It is possible that some cases of MPN-U represent earlier disease stages in polycythemia vera (PV) or ET that fail to meet the threshold hemoglobin levels (18.5 g/dL in men or 16.5 g/dL in women) or platelet counts (450 × 109/L) that are required by the WHO diagnostic criteria. Specific treatment interventions might not be necessary in asymptomatic patients with MPN-U, whereas patients with arterial thrombotic complications might require cytoreductive and aspirin therapy and those with venous thrombosis might require systemic anticoagulation.
TRANSIENT MYELOPROLIFERATIVE DISORDER (TMD)
TMD constitutes an often but not always transient phenomenon of abnormal megakaryoblast proliferation, which occurs in approximately 10% of infants with Down’s syndrome. TMD is usually recognized at birth and either undergoes spontaneous regression (75% of cases) or progresses into acute megakaryoblastic leukemia (AMKL) (25% of cases). Almost all patients with TMD and TMD-derived AMKL display somatic GATA1 mutations. TMD-associated GATA1 mutations constitute exon 2 insertions, deletions, or missense mutations, affecting the N-terminal transactivation domain of GATA-1, and result in loss of full-length (50-kDa) GATA-1 and its replacement with a shorter isoform (40-kDa) that retains friend of GATA-1 (FOG-1) binding. In contrast, inherited forms of exon 2 GATA1 mutations produce a phenotype with anemia, whereas exon 4 mutations that affect the N-terminal, FOG-1-interactive domain produce familial dyserythropoietic anemia with thrombocytopenia or X-linked macrothrombocytopenia.
Eosinophilia refers to a peripheral blood absolute eosinophil count (AEC) that is above the upper normal limit of the reference range. The term hypereosinophilia is used when the AEC is >1500 × 109/L. Eosinophilia is operationally classified as secondary (nonneoplastic proliferation of eosinophils) and primary (proliferation of eosinophils that is either neoplastic or otherwise unexplained) (Table 135e-6). Secondary eosinophilia is by far the most frequent cause of eosinophilia and is often associated with infections, especially those related to tissue-invasive helminths; allergic/vasculitic diseases; drugs; and metastatic cancer. Primary eosinophilia is the focus of this chapter and is considered when a cause for secondary eosinophilia is not readily apparent.
TABLE 135e-6Diagnosis of Chronic Eosinophilic Leukemia and Hypereosinophilic Syndrome ||Download (.pdf) TABLE 135e-6Diagnosis of Chronic Eosinophilic Leukemia and Hypereosinophilic Syndrome
|Required: Persistent eosinophilia ≥1500/μL in blood, increased marrow eosinophils, and myeloblasts <20% in blood or marrow. |
|1. Exclude all causes of reactive eosinophilia: allergy, parasites, infection, pulmonary disease (e.g., hypersensitivity pneumonitis, Loeffler’s), and collagen vascular diseases |
|2. Exclude primary neoplasms associated with secondary eosinophilia: T-cell lymphomas, Hodgkin’s disease, acute lymphoid leukemia, mastocytosis |
|3. Exclude other primary myeloid neoplasms that may involve eosinophils: chronic myeloid leukemia, acute myeloid leukemia with inv(16) or t(16;16)(p13;q22), other myeloproliferative syndromes, and myelodysplasia |
|4. Exclude T-cell reaction with increased interleukin 5 or other cytokine production |
|If these entities have been excluded and no evidence documents a clonal myeloid disorder, the diagnosis is hypereosinophilic syndrome. |
|If these entities have been excluded and the myeloid cells show a clonal chromosome abnormality or some other evidence of clonality and blast cells are present in the peripheral blood (>2%) or are increased in the marrow (but <20%), the diagnosis is chronic eosinophilic leukemia. |
Primary eosinophilia is classified as clonal or idiopathic. Diagnosis of clonal eosinophilia requires morphologic, cytogenetic, or molecular evidence of a myeloid neoplasm. Idiopathic eosinophilia is considered when both secondary and clonal eosinophilias have been ruled out as a possibility. HES is a subcategory of idiopathic eosinophilia with persistent AEC of ≥1.5 × 109/L and associated with eosinophil-mediated organ damage (Table 135e-7). An HES-like disorder that is associated with clonal or phenotypically abnormal T cells is referred to as lymphocytic variant hypereosinophilia (Table 135e-7).
TABLE 135e-7Primary Eosinophilia Classification ||Download (.pdf) TABLE 135e-7Primary Eosinophilia Classification
|Variables ||PDGFRA-,PDGFRB-, or FGFR1-Mutated Eosinophilia ||Chronic Eosinophilia, Not Otherwise Specified ||Lymphocytic Variant Hypereosinophilia ||Hypereosinophilic Syndrome |
|Absolute eosinophil count ||>600 ×109/L ||>1500 × 109/L ||>1500 × 109/L ||>1500 × 109/L |
|Peripheral blood blast >2% ||Yes or no ||Yes or no ||No ||No |
|Bone marrow blast >5% ||Yes or no ||Yes or No ||No ||No |
|Abnormal karyotype ||Yes or no ||Yes or no ||No ||No |
|PDGFRA, PDGFRB, or FGFR1 mutation ||Yes ||No ||No ||No |
|BCR-ABL1 ||No ||No ||No ||No |
|Abnormal T lymphocyte phenotype or clonal T-cell clones ||No ||No ||Yes ||No |
|Eosinophil-mediated tissue damage ||Yes or no ||Yes or no ||Yes or no ||Yes |
Examples of clonal eosinophilia include eosinophilia associated with acute myeloid leukemia (AML), MDS, CML, mastocytosis, and MDS/MPN overlap. Myeloid neoplasm-associated eosinophilia also includes the WHO MPN subcategory of chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) and the WHO myeloid malignancy subcategory referred to as myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor (PDGFR) α/β or fibroblast growth factor receptor 1 (FGFR1).
The diagnostic workup for clonal eosinophilia that is not associated with morphologically overt myeloid malignancy should start with peripheral blood mutation screening for FIP1L1-PDGFRA and PDGFRB mutations using fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction. This is crucial because such eosinophilia is easily treated with imatinib. If mutation screening is negative, a bone marrow examination with cytogenetic studies is indicated. In this regard, one must first pay attention to the presence or absence of 5q33, 4q12, or 8p11.2 translocations, which, if present, would suggest PDGFRB-, PDGFRA-, or FGFR1-rearranged clonal eosinophilia, respectively. The presence of 5q33 or 4q12 translocations predicts favorable response to treatment with imatinib mesylate, whereas 8p11.2 translocations are associated with aggressive myeloid malignancies that are refractory to current drug therapy.
CEL-NOS is considered in the presence of cytogenetic/morphologic evidence of a myeloid malignancy that is otherwise not classifiable. Specifically, CEL-NOS is distinguished from HES by the presence of either a cytogenetic abnormality or greater than 2% peripheral blood blasts or greater than 5% bone marrow blasts (Table 135e-7). HES or idiopathic eosinophilia is considered in the absence of both morphologic and molecular evidence of clonal eosinophilia. However, before making a working diagnosis of HES, one has to exclude lymphocytic variant hypereosinophilia by excluding the presence of phenotypically abnormal T lymphocytes (by flow cytometry) and clonal T-cell gene rearrangements.
Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL-NOS)
CEL-NOS is a subset of clonal eosinophilia that is neither molecularly defined nor classified as an alternative clinicopathologically assigned myeloid malignancy. We prefer to use the term strictly in patients with an HES phenotype who also display either a clonal cytogenetic/molecular abnormality or excess blasts in the bone marrow or peripheral blood. The WHO defines CEL-NOS in the presence of an AEC ≥1.5 × 109/L that is accompanied by either the presence of myeloblast excess (either >2% in the peripheral blood or 5–19% in the bone marrow) or evidence of myeloid clonality. Cytogenetic abnormalities in CEL, other than those that are associated with molecularly defined eosinophilic disorders, include trisomy 8 (the most frequent), t(10;11)(p14;q21), and t(7;12)(q11;p11). CEL-NOS does not respond to imatinib, and treatment strategies are often not different from those used in other similar MPNs and include ASCT for transplant-eligible patients with poor risk factors and participation in experimental treatment protocols otherwise.
Both platelet-derived growth factor receptors α (PDGFRA located on chromosome 4q12) and β (PDGFRB located on chromosome 5q31-q32) are involved in MPN-relevant activating mutations. Clinical phenotype in both instances includes prominent blood eosinophilia and excellent response to imatinib therapy. In regard to PDGFRA mutations, the most popular is FIP1L1-PDGFRA, a karyotypically occult del(4)(q12) that was described in 2003 as an imatinib-sensitive activating mutation. Functional studies have demonstrated transforming properties in cell lines and the induction of MPN in mice. Cloning of the FIP1L1-PDGFRA fusion gene identified a novel molecular mechanism for generating this constitutively active fusion tyrosine kinase, wherein a ~800-kb interstitial deletion within 4q12 fuses the 5′ portion of FIP1L1 to the 3′ portion of PDGFRA. FIP1L1-PDGFRA occurs in a very small subset of patients who present with the phenotypic features of either systemic mastocytosis or HES, but the presence of the mutation reliably predicts complete hematologic and molecular response to imatinib therapy.
The association between eosinophilic myeloid malignancies and PDGFRB rearrangement was first characterized and published in 1994 when fusion of the tyrosine kinase–encoding region of PDGFRB to the ets-like gene, ETV6 [ETV6-PDGFRB, t(5;12)(q33;p13)] was demonstrated. The fusion protein was transforming to cell lines and resulted in constitutive activation of PDGFRB signaling. Since then, several other PDGFRB fusion transcripts with similar disease phenotypes have been described, cell line transformation and myeloproliferative disease (MPD) induction in mice has been demonstrated, and imatinib therapy was proven effective when used.
The 8p11 myeloproliferative syndrome (EMS) (also known as human stem cell leukemic/lymphoma syndrome) constitutes a clinical phenotype with features of both lymphoma and eosinophilic MPN and characterized by a fusion mutation that involves the gene for fibroblast growth factor receptor 1 (FGFR1), which is located on chromosome 8p11. In EMS, both myeloid and lymphoid lineage cells exhibit the 8p11 translocation, thus demonstrating the stem cell origin of the disease. The disease features several 8p11-linked chromosome translocations, and some of the corresponding fusion FGFR1 mutants have been shown to transform cell lines and induce EMS- or CML-like disease in mice depending on the specific FGFR1 partner gene (ZNF198 or BCR, respectively). Consistent with this laboratory observation, some patients with BCR-FGFR1 mutation manifest a more indolent CML-like disease. The mechanism of FGFR1 activation in EMS is similar to that seen with PDGFRB-associated MPD; the tyrosine kinase domain of FGFR1 is juxtaposed to a dimerization domain from the partner gene. EMS is aggressive and requires combination chemotherapy followed by ASCT.
Hypereosinophilic Syndrome (HES)
Blood eosinophilia that is neither secondary nor clonal is operationally labeled as being idiopathic. HES is a subcategory of idiopathic eosinophilia with persistent increase of the AEC to ≥1.5 × 109/L and presence of eosinophil-mediated organ damage, including cardiomyopathy, gastroenteritis, cutaneous lesions, sinusitis, pneumonitis, neuritis, and vasculitis. In addition, some patients manifest thromboembolic complications, hepatosplenomegaly, and either cytopenia or cytosis.
Bone marrow histologic and cytogenetic/molecular studies should be examined before a working diagnosis of HES is made. Additional blood studies that are currently recommended during the evaluation of HES include serum tryptase (an increased level suggests systemic mastocytosis and warrants molecular studies to detect FIP1L1-PDGFRA), T-cell immunophenotyping, and T-cell receptor antigen gene rearrangement analysis (a positive test suggests an underlying clonal or phenotypically abnormal T-cell disorder). In addition, initial evaluation in HES should include echocardiogram and measurement of serum troponin levels to screen for myocardial involvement by the disease.
Initial evaluation of the patient with eosinophilia should include tests that facilitate assessment of target organ damage, including complete blood count, chest x-ray, echocardiogram, and serum troponin level. An increased level of serum cardiac troponin has been shown to correlate with the presence of cardiomyopathy in HES. Typical echocardiographic findings in HES include ventricular apical thrombus, posterior mitral leaflet or tricuspid valve abnormality, endocardial thickening, dilated left ventricle, and pericardial effusion.
Glucocorticoids are the cornerstone of therapy in HES. Treatment with oral prednisone is usually started at 1 mg/kg per day and continued for 1–2 weeks before the dose is tapered slowly over the ensuing 2–3 months. If symptoms recur at a prednisone dose level of >10 mg/d, either hydroxyurea or interferon α is used as steroid-sparing agent. In patients who do not respond to usual therapy as outlined above, mepolizumab or alemtuzumab might be considered. Mepolizumab targets interleukin 5 (IL-5), a well-recognized survival factor for eosinophils. Alemtuzumab targets the CD52 antigen, which has been shown to be expressed by eosinophils but not by neutrophils.
Mast cell disease (MCD) is defined as tissue infiltration by morphologically and immunophenotypically abnormal mast cells. MCD is classified into two broad categories: cutaneous mastocytosis and systemic mastocytosis (SM). MCD in adults is usually systemic, and the clinical course can be either indolent or aggressive, depending on the respective absence or presence of impaired organ function. Symptoms and signs of MCD include urticaria pigmentosa, mast cell mediator release symptoms (e.g., headache, flushing, lightheadedness, syncope, anaphylaxis, pruritus, urticaria, angioedema, nausea, diarrhea, abdominal cramps), and organ damage (lytic bone lesions, osteoporosis, hepatosplenomegaly, cytopenia). Aggressive SM can be associated with another myeloid malignancy, including MPN, MDS, or MDS/MPN overlap (e.g., CMML), or present as overt mast cell leukemia. In general, life expectancy is near normal in indolent SM but significantly shortened in aggressive SM.
Diagnosis of SM is based on bone marrow examination that shows clusters of morphologically abnormal, spindle-shaped mast cells that are best evaluated by the use of immunohistochemical stains that are specific to mast cells (tryptase, CD117). In addition, mast cell immunophenotyping reveals aberrant CD25 expression by neoplastic mast cells. Other laboratory findings in SM include increased levels of serum tryptase, histamine and urine histamine metabolites, and prostaglandins. SM is associated with KIT mutations, usually KIT D816V, in the majority of patients. Accordingly, mutation screening for KIT D816V is diagnostically useful. However, the ability to detect KIT D816V depends on assay sensitivity and mast cell content of the test sample.
Both indolent and aggressive SM patients might experience mast cell mediator release symptoms, which are usually managed by both H1 and H2 histamine receptor blockers as well as cromolyn sodium. In addition, patients with propensity to vasodilatory shock should wear a medical alert bracelet and carry an Epi-Pen self-injector for self-administration of subcutaneous epinephrine. Urticaria pigmentosa shows variable response to both topical and systemic glucocorticoid therapy. Cytoreductive therapy is not recommended for indolent SM. In aggressive SM, either interferon α or cladribine is considered first-line therapy and benefits the majority of patients. In contrast, imatinib is ineffective in the treatment of PDGFR-unmutated SM.
DENDRITIC AND HISTIOCYTIC NEOPLASMS
Dendritic cell (DC) and histiocyte/macrophage neoplasms are extremely rare. DCs are antigen-presenting cells, whereas histiocyte/macrophages are antigen-processing cells. Bone marrow myeloid stem cells (CD34+) give rise to monocyte (CD14+, CD68+, CD11c+, CD1a–) and DC (CD14–, CD11c+/–, CD1a+/c) precursors. Monocyte precursors, in turn, give rise to macrophages (CD14+, CD68+, CD11c+, CD163+, lysozyme+) and interstitial DCs (CD68+, CD1a–). DC precursors give rise to Langerhans cell DCs (Birbeck granules, CD1a+, S100+, langerin+) and plasmacytoid DCs (CD68+, CD123+). Follicular DCs (CD21+, CD23+, CD35+) originate from mesenchymal stem cells. Dendritic and histiocytic neoplasms are operationally classified into macrophage/histiocyte-related and DC-related neoplasms. The former includes histiocytic sarcoma/malignant histiocytosis and the latter Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating DC sarcoma, and follicular DC sarcoma.
Histiocytic Sarcoma/Malignant Histiocytosis
Histiocytic sarcoma represents malignant proliferation of mature tissue histiocytes and is often localized. Median age at diagnosis is estimated at 46 years with slight male predilection. Some patients might have history of lymphoma, MDS, or germ cell tumors at time of disease presentation. The three typical disease sites are lymph nodes, skin, and the gastrointestinal system. Patients may or may not have systemic symptoms including fever and weight loss, and other symptoms include hepatosplenomegaly, lytic bone lesions, and pancytopenia. Immunophenotype includes presence of histiocytic markers (CD68, lysozyme, CD11c, CD14) and absence of myeloid or lymphoid markers. Prognosis is poor, and treatment is often ineffective. The term malignant histiocytosis refers to a disseminated disease and systemic symptoms. Lymphoma-like treatment induces complete remissions in some patients, and median survival is estimated at 2 years.
Langerhans Cell Histiocytosis
Langerhans cells (LCs) are specialized DCs that reside in mucocutaneous tissue and upon activation become specialized for antigen presentation to T cells. LC histiocytosis (LCH; also known as histiocytosis X) represents neoplastic proliferation of LCs (S-100+, CD1a+, and Birbeck granules on electron microscopy). LCH incidence is estimated at 5 per million, and the disease typically affects children with a male predilection. Presentation can be either unifocal (eosinophilic granuloma) or multifocal. The former usually affects bones and less frequently lymph nodes, skin, and lung, whereas the latter is more disseminated. Unifocal disease often affects older children and adults, whereas multisystem disease affects infants. LCH of the lung in adults is characterized by bilateral nodules. Prognosis depends on organs involved. Only 10% of patients progress from unifocal to multiorgan disease. LCH of the lung might improve upon cessation of smoking.
Langerhans cell sarcoma (LCS) also represents neoplastic proliferation of LCs with overtly malignant morphology. The disease can present de novo or progress from antecedent LCH. There is a female predilection, and median age at diagnosis is estimated at 41 years. Immunophenotype is similar to that seen in LCH, and liver, spleen, lung, and bone are the usual sites of disease. Prognosis is poor, and treatment is generally ineffective.
Interdigitating Dendritic Cell Sarcoma
Interdigitating DC sarcoma (IDCS), also known as reticulum cell sarcoma, represents neoplastic proliferation of interdigitating DCs. The disease is extremely rare and affects elderly adults with no sex predilection. Typical presentation is asymptomatic solitary lymphadenopathy. Immunophenotype includes S-100+ and negative for vimentin and CD1a. Prognosis ranges from benign local disease to widespread lethal disease.
Follicular Dendritic Cell Neoplasm
Follicular DCs (FDCs) reside in B-cell follicles and present antigen to B cells. FDC neoplasms (FDCNs) are usually localized and often affect adults. FDCN might be associated with Castleman’s disease in 10–20% of cases, and increased incidence in schizophrenia has been reported. Cervical lymph nodes are the most frequent site of involvement in FDCN, and other sites include maxillary, mediastinal, and retroperitoneal lymph nodes; oral cavity; gastrointestinal system; skin; and breast. Sites of metastasis include lung and liver. Immunophenotype includes CD21, CD35, and CD23. Clinical course is typically indolent, and treatment includes surgical excision followed by regional radiotherapy and sometimes systemic chemotherapy.
Hemophagocytic syndrome (HPS) represents nonneoplastic proliferation and activation of macrophages that induce cytokine-mediated bone marrow suppression and features of intense phagocytosis in bone marrow and liver. HPS may result from genetic or acquired disorders of macrophages. The former entail genetically determined inability to regulate macrophage proliferation and activation. Acquired HPS is often precipitated by viral infections, most notably Epstein-Barr virus. HPS might also accompany certain malignancies such as T-cell lymphoma. Clinical course is often fulminant and fatal.