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The chronic leukemias of myeloid origin.

Chronic leukemias of myeloid origin (CLMO) disorders are the second major category of chronic leukemias. The first major category of chronic leukemias, leukemias of lymphoid origin, was discussed in part one of this two-part series (see MLO, November 1998, p. 26). This group of neoplastic disorders involves myelomonocytic hematopoietic cell lines and is characterized by persistence of maturation, at least until the terminal phase of the cell's natural history. Excluded from this discussion are polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia, which are also considered myeloproliferative disorders along with CLMO, but are generally not leukemic.

The approach to diagnosis of CLMO is similar to that for chronic leukemias of lymphoid origin and is based on the complete blood count (CBC), morphologic examination of the peripheral blood smear, special stains, cytogenetic data, and clinical correlation. Bone marrow examination is part of the work-up in most cases. Flow cytometric analysis has a more limited role in the evaluation of these disorders and is often not necessary.

Chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disorder originating from the hematopoietic stem cell. First described in 1845, CML is primarily a disease of adults. However, about 10% of the 3,400 new cases seen each year in the US develop in children and infants. The natural history of CML evolves through a chronic and accelerated phase and terminates in blast crisis. Clinical presentation may occur at any time during this metamorphosis. Splenomegaly is frequently present at diagnosis, and is accompanied by leukocytosis, anemia, and thrombocytosis.

Chronic phase CML. Most patients with CML are diagnosed during the chronic phase. At this time, the myeloid proliferation noted in the peripheral blood and bone marrow aspirate may appear strikingly similar. Leukocytosis is invariably present at diagnosis with less than 5% myeloblasts and varying numbers of promyelocytes, myelocytes, metamyelocytes, basophils, and neutrophils (Slide 1).

Basophilia is often prominent and is very helpful in separating this disorder from other causes of leukocytosis. Eosinophilia is present in more than 90% of cases. In the majority of patients, platelets are increased and giant forms are often present. Mild normochromic normocytic anemia is usually present. Abnormalities of red cell morphology or granulocytic dysplasia may be a harbingers of myelofibrosis or transformation.

Bone marrow findings. Bone marrow aspiration and biopsy should be performed at the time of diagnosis. in addition to morphologic information, the aspirate provides the best material for cytogenetic studies. The core biopsy is useful in establishing a baseline for reticulin fibrosis, increases of which may reflect progression of the disease.

In the chronic phase of CML, the bone marrow is predominantly myeloid and hypercellular. Myeloblasts are less than 5% of all cells, and maturing granulocytes are readily identified. Eosinophils and mast cells may be increased. Megakaryocytes are usually increased but lack the excessive nuclear lobulation and abuttment often present in essential thrombocythemia. Erythroid precursors occasionally reveal megaloblastoid nuclear maturation. Pseudo-Gaucher cells may be present. These macrophages are laden with products of cell breakdown such as ceroid and iron. Early reticulin fibrosis may be detected by silver impregnation of the core biopsy.

Laboratory studies. Ancillary studies are generally performed as part of the diagnostic evaluation. One of the more useful and inexpensive procedures is the leukocyte alkaline phosphatase (LAP) test. This is performed on peripheral blood smears and can help differentiate between reactive granulocytosis or leukemoid reactions from CML. The former reveal strong LAP activity. in contrast, the LAP score in CML is decreased in 95% of untreated patients and may return to normal following successful therapy. However, definitive diagnosis is established by the presence of the Philadelphia chromosome (discussed later in this article).

Accelerated phase and blast crisis

Approximately 3 years after the diagnosis of chronic phase CML, metamorphosis through periods of accelerated growth and blast crisis occur. Accelerated phase refers to a period of clinical and hematologic deterioration without a marked increased in the blast percentage. During this period, the bone marrow myeloblast count increases to 5 to 30%. Progressive splenomegaly, anemia, and thrombocytosis invariably accompany this metamorphosis; and additionally, fever and resistance to therapy often manifest.

In blast crisis, CML becomes acute with blasts exceeding 30% of marrow cellularity. Morphologic and immunological features of blasts in blast crisis may be discordant. While in the majority of cases the picture is acute myeloblastic, in about 30% of cases, it is acute lymphoblastic (Slide 2).[1,2] Since these different types of blast crises are treated with different chemotherapeutic regimens, immunophenotyping by flow cytometry is important for precise classification.

Occasionally, extramedullary forms of blast crisis (chloroma) may be the first manifestation of CML (Slide 3). Chloromas may develop in lymph nodes, skin, breast, bone, nervous system serous membranes, and the gastrointestinal tract and are composed of a myeloblastic proliferation with interspersed eosinophilic myelocytes. Chloromas can closely resemble large cell lymphoma. A battery of stains, including immunostaining for CD43 (cluster designation 43), specific esterase (Leder) stain, and anti-myeloperoxidase are most effective in differentiating this entity from lymphoma.

During accelerated phase and blast crisis, additional chromosomal abnormalities develop. These include an increase in modal chromosome numbers to between 47 and 50, acquisition of a second Philadelphia chromosome (Ph), and an isochromosome for the long arm of chromosome 17 [i(17q)], -8(trisomy 8), -19, and t(15;17). Rarely, chromosome loss, such as -7 and Y chromosomal deletion may be observed.[3]

The Philadelphia chromosome. Until 1960 when Hungerford and Nowell first described the Philadelphia chromosome, the pathogenesis of CML was unknown.[4] In 1973, Rowley determined that this results from a reciprocal translocation between genetic material on the long arm of chromosome 9 (proto-oncogene c-abl) and a portion of the BCR gene on the long arm of chromosome 22 [ILLUSTRATION OMITTED].[5] The resulting Ph chromosome is therefore due to the formation of chimeric BCR-ABL gene on chromosome 22 and is present in all hematopoietic elements. Transcription of a hybrid 8.5-kb messenger ribonucleic acid (mRNA), which is controlled by the chimeric BCR-ABL gene results in the production of a p210 Bcr-Abl protein with enhanced tyrosine kinase activity. This has been associated with production of granulocyte-colony stimulating factor (G-CSF), platelet-derived growth factor (PDGF), and possibly other growth-regulating properties and appears to be responsible for increasing the granulocyte pool up to 150 times normal in CML.[3]

Over the past few years, a new generation of methodologies in molecular diagnostics has enhanced our ability to detect and precisely ascertain subtypes of the chimeric gene in CML. These newer methods are DNA- or RNA-based technologies and include Southern blot, polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH) analysis.[6]

Discussion of these molecular diagnostic techniques is beyond the scope of this review, but a few practical points can be made:

* Conventional karyotyping is the current method of choice and allows for detection of additional or unexpected cytogenetic abnormalities. Potential drawbacks of cytogenetic analysis are its lower sensitivity, a relatively high cost, and the requirement for live cells.

* Molecular methods are rapid and sensitive, and small samples can be evaluated. The techniques can be applied to live or formalin-fixed material. However, these methods are generally used to look for a single, specific abnormality, and individual testing costs remain relatively high. Molecular methods should be considered in cases of apparent Ph chromosome negative CML, when dilute or limited specimens are obtained, and for the detection of minimal residual disease.

* In terms of their sensitivities, Southern blot analysis will detect the BCR/ABL chimeric gene in 98% of Philadelphia positive (Ph+) cases of CML and in 10-50% of Philadelphia negative (Ph-) cases.[7] However, at least 5% of abnormal cells need to be present in the sample.

* FISH and reverse transcriptase polymerase chain reaction (RT-PCR) are considered screening methodologies and are rapid, more cost effective, and less technically difficult.[8] Using FISH, the chimeric gene is detected in 80-100% of Ph- cases and is highly sensitive for the detection of minimal residual disease. RT-PCR detects the chimeric gene in 70-100% of Ph- cases, and is considered the most sensitive method.[9,10]

Differential diagnosis. The differential diagnosis of CML includes granulocytic leukemoid reactions, chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), and reactive causes of eosinophilia, basophilia, and monocytosis.

Chronic myelomonocytic leukemia

CMML is an irreversible hematopoietic disorder with trilineage dysplasia that invariably terminates in acute myeloid leukemia. Although CMML usually develops in persons older than 50 years, a rarer juvenile form has been recognized. In 1982, the French-American-British (FAB) working group included CMML as part of the family of myelodysplastic disorders.[11] Similar to other types of myelodysplasias, CMML may present with cytopenias, variable degrees of nuclear and cytoplasmic abnormalities (dysplasia), and variable circulating blasts with the additional feature of monocytosis (Slide 4). However, some cases of CMML present with elevated peripheral counts and little or no dysplasia and are classified by some authorities as myeloproliferative. Knowledge of these variable appearances is important in recognition of this disorder.

Clinical and hematologic findings. Greater than 75% of patients with CMML are over the age of 60 years. Clinical onset is frequently insidious with weakness, infections, or bleeding. Splenomegaly and hepatomegaly are present in about 40% of patients. Acceptable criteria for diagnosis include monocytosis with less than 5% circulating blasts. In the marrow, blast forms are less than 20%. Dysplasia in maturing hematopoietic elements may be present. During transformation to acute leukemia, the blast count increases to 20-30%. Increased lactate dehydrogenase (LDH) and lysozyme activity has been reported, and polyclonal hypergammaglobulinemia is present in about 30% of cases.

Leukocytosis is present in about 65% of patients, and counts as high as 100 x [10.sup.9]/L have been reported. Monocytosis is frequently a dominant abnormality, and according to the FAB working group, an absolute monocytosis of 1.0 x [10.sup.9]/L is considered necessary to establish a diagnosis. Circulating granulocytes frequently have bilobed nuclei with decreased or absent granularity and are referred to as pseudo-Pelger-Huet or "Pelgeroid" (Slide 5a). In some patients, neutrophils with ring nuclei have been observed. Thrombocytopenia may be present at diagnosis in about 25% of patients, and anemia with anisocytosis, stippling, polychromasia, and circulating nucleated red cells may be observed. Macro-ovalocytosis with a normal serum folate and vitamin [B.sub.12] level is often a clue to an underlying myelodysplastic disorder.

Bone marrow findings, The bone marrow aspirate in CMML reveals myeloid and monocytic predominance, with blast forms variably increased up to 20%, and a decrease in other hematopoietic elements. When the blast count is between 20 and 30% of the nucleated cells, the process is designated CMML in transformation (CMML-T). Cells with dual cytoplasmic myelomonocytic properties may be observed and are referred to as paramyeloid. The paramyeloid myelomonocytic nature of biastic and promonocytic forms as well as maturing myeloid elements are better delineated by cytochemical stains. Because primary and secondary granules are decreased in CMML, the staining intensity for these granules may be decreased. Dysmegakaryocytopoieisis with discrete megakaryocyte nuclei lacking lobation ("pawn ball" nuclei) and dwarf megakaryocytes may be observed (Slide 5b). Megaloblastoid erythropoiesis with abnormal nuclear division (dyskinesis) and ringed sideroblasts are also present (Slides 5c, 5d, respectively). In bone marrow biopsies, hypercellularity is evident in most cases, and abnormally located immature myeloid precursors (ALIP) are often abnormally grouped away from bony trabeculae. Occasionally, non-paratrabecular benign lymphoid aggregates may be present, and in most instances, myelofibrosis does not develop.

Immunophenotypic analysis. If performed, flow cytometric analysis often identifies an increased percentage of monocytes. An increased blast count is suggested by an increased percentage of CD34-positive cells. In most cases, morphologic and cytochemical stains provide sufficient information for diagnosis.

Cytogenetic abnormalities. Cytogenetic abnormalities are found in about 30% of patients at diagnosis. Monosomy 7 is the most frequently encountered defect, often occurring in younger patients and heralding a poor prognosis.[12] Next in frequency are trisomy 8, iso(17q), and a 12p anomaly with breakpoints at p11 or p12. Patients with trisomy 8 are often elderly and are at a high risk of evolution to acute myelogenous leukemia, FAB subtypes M-4 (AML-M4) and M-5 (AML-M5). The ABL/BCR translocation abnormality does not occur in CMML. However, a t(5;12)(q31;12) defect has been observed and is associated with an overexpression of the K-ras oncogene. Additionally, terminal or interstitial deletions of the long arm of chromosome 11, trisomy 11, a 5q-abnormality with terminal or interstitial deletions at p11, and other rarer abnormalities have also been reported. None of the chromosomal abnormalities detailed above are specific for CMML.[13]

Prognosis. With a view to prognostication and staging of patients with CMML, several scoring systems have been proposed. These include the Bournemouth score, which is based on the severity of the cytopenias and the percentage of marrow blasts; the Dusseldorf score, which additionally factors increases in levels of serum LDH; the Spanish score, which also considers the age of the patients; and the FAB score, which is the most complex. Since patients with CMML frequently have neutropenia, Worsley et al. have modified the original Bournemouth score to provide a practical and simple system.[14] Accordingly, one point is assigned for each of the following:

* hemoglobin less than 10.0 g/dL

* absolute neutrophil count less than 2.5 x [10.sup.9]/L or more than 16.0 x [10.sup.9]/L

* Platelet count less than 100.0 x [10.sup.9]/L

* bone marrow blasts [greater than] 5% of marrow cellularity.

Median survival for CMML patients with a score of 0-1 is 32 months, and for those with a score of greater than 2 is 9 months. All factors considered, the percentage of bone marrow blasts remains the most important prognostic factor. CMML eventually transforms into AML in most instances. However, transformation to acute lymphoblastic leukemia (ALL) has now been reported in at least 13 cases.[15] This additionally suggests that CMML develops from a pleuripotential stem cell.

Differential diagnosis. In the differential diagnosis of CMML, entities that should be considered include CML, AML-M4, AML-M5, other reactive causes of monocytosis, and the other forms of myelodysplasia. In most instances, the cause of CMML remains obscure. However, 10-20% of patients have a history of exposure to chemical carcinogens, chemotherapy, or irradiation. The role of the ras mutation which has been observed in 30-50% of patients is uncertain, and is in contrast to cases of Ph- "atypical CML," in which situation ras mutation is unusual.

Recently, abnormal chromatin clumping in leukocytes syndrome (ACCLS) has been reported by Vellejo et al.[16] It shares clinical and biological features with myelodysplastic and myeloproliferative disorders (MDS and MPD). Some authors consider ACCLS a new type of MDS that has much in common with CMML. Others maintain that it is a Ph-IBCR-ABL negative chronic myeloid leukemia. Additional cases are needed to more clearly classify this disorder.

Idiopathic hypereosinophilia and chronic eosinophilic leukemia

Eosinophils normally comprise 1-6% of circulating white cells. An absolute eosinophil count greater than 600/[mm.sup.3] is therefore considered abnormal. Increased eosinophils may be observed in peripheral blood or in tissue samples, and may develop in a remarkably heterogeneous group of disorders. In some of these it is believed that transforming growth factor-alpha (TGF-alpha) production, which is regulated by interleukin 3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) is unbalanced.(17) Eosinophilia may be observed in: (1) benign reactive eosinophilia, (2) eosinophilia of miscellaneous malignant disorders, and (3) sustained idiopathic eosinophilia, including idiopathic hypereosinophilic syndrome and eosinophilic leukemia.

Benign reactive eosinophilia. Benign reactive eosinophilia may develop in association with allergic and hypersensitivity disorders, drug reactions, parasitic infestations, chronic inflammation, and collagen vascular disorders. The eosinophilia in these conditions is frequently transient, and either abates or disappears following appropriate treatment.

Eosinophilia associated with malignant disorders. Eosinophilia of blood and tissues may develop in a variety of myeloid, lymphoid, and miscellaneous epithelial neoplasms, such as AML-M4Eo (with abnormal eosinophils), CML, Hodgkin's disease and infiltrating carcinoma. With the exception of AML-M4Eo and CML where fusion transcripts from their respective abnormal chromosomal translocations have been detected within eosinophils, the process appears to be reactive.

Hypereosinophilic syndrome. Sustained idiopathic eosinophilia may manifest at any age. Local and generalized forms of disease have been described, and this entity was designated the hypereosinophilic syndrome (HES) by Hardy and Anderson in 1968.(18) HES is characterized by idiopathic eosinophilia greater than 1.5 x [10.sup.9]/L that is sustained for at least 6 months

Hematologic findings. The eosinophils of HES may demonstrate dysmorphism, with increased cell size, [TABULAR DATA FOR TABLE 1 OMITTED] increased nuclear lobation, or tinged forms, and cytoplasmic vacuolation (Slide 6). Hypocellular and dysplastic eosinophils with Pelgeroid nuclei may be a harbinger of leukemia transformation. The bone marrow is often hypercellular in HES, and demonstrates increased numbers of eosinophils, some with basophilic granules. Myelofibrosis may develop in some cases.

Course and prognosis. In some instances of HES, an 80% survival rate has been reported at 5 years.[19] Progressive eosinophilia with widespread organ involvement may be observed with death from cardiac morbidity. Increased eosinophilic myelocytes and myeloblasts have been interpreted as eosinophilic leukemia,[20,21] and a valuable prognostic grading system has been described by Schooley.[22] Cases terminating as AML, acute mixed phenotype leukemia, and acute lymphoblastic leukemia have also been reported.[23-26]

Eosinophilic leukemia. EL was first reported by Stillman in 1912.[27) Since then, acute and chronic forms have been described. EL is rare and more frequently develops as a primary disease rather than secondary to HES. Since eosinophilic granules are secondary, and eosinophilic blasts and promyelocytes do not have distinctive structural features, a diagnosis of EL should be considered only when absolute idiopathic eosinophilia is present with increasing myeloid immaturity in the marrow. In such patients, thrombocytopenia, anemia, and hepatosplenomegaly are often supportive features.

In EL, eosinophils may appear similar to those in HES, and terminally, blast forms may be observed in the peripheral blood. Myelofibrosis is generally absent. Cytochemical analysis of eosinophils variably demonstrates periodic acid-Schiff stain positivity and arylsulphatase, acid phosphatase, and peroxidase activity. On electron microscopy, eosinophilic promyelocytes without internal crystalloids have been observed. In both HES and EL, tissue damage from eosinophils is believed to result from the products of eosinophil granules, particularly major basic protein and eosinophilic cationic protein.

Distinguishing between HES and EL is difficult, and several reported cases demonstrate overlapping features between HES and EL as well as with other disorders.[25] Recently, Juneja et al. reported a case with overlapping features of HES and MPD.[28] Their patient developed lytic lesions of the tibia and was classified and treated as chronic eosinophilic leukemia, a myeloproliferative disorder, rather than HES or atypical CML. Duell et al. reported on a case initially diagnosed with HES in the presence of a clonal translocation t(4,7) with peripheral leukocytosis, severe thrombocytopenia, and anemia at first presentation.[29] Ten months later, the patient died of diffuse leukemic tissue and organ infiltration resulting in paraplegia. We believe that cases with clonal abnormalities should be classified as eosmophilic leukemia from the start. However, no specific karyotypic abnormality has been reported in eosinophilic leukemia. Such cases emphasize the difficulty and confusion in separating HES and EL.

Chronic neutrophilic leukemia

Chronic neutrophilic leukemia (CNL) is a rare and fatal myeloproliferative disease, first described by Tuohy in 1920.[30] No more than 70 cases have been reported. A diagnosis of CNL should be made with caution, and only when granulocytic leukemoid reactions and chronic myeloid leukemia have been carefully excluded.[31]

Clinical findings. In most instances, patients with CNL have splenomegaly and are generally above 50 [TABULAR DATA FOR TABLE 2 OMITTED] years of age. Isolated instances of CNL have been preceded by polycythemia vera, thorotrast injection, plasmacytoma and refractive anemia with excess blasts (RAEB).[32-35] Cases of coexistent myelodysplasia and multiple myeloma have also been recognized, and rarely, myeloma has succeeded CNL.[36.37] In some instances, CNL has terminated in myelodysplasia, RAEB, blast crisis, AML-M1, AML-M4, AML-M5, and myelofibrosis.[38,39] Despite the association of CNL with MDS, neutrophilia is not a feature of MDS. Extensive leukemic infiltration of parenchymal organs is usually present, and has been reported in the liver, spleen, lung, lymph nodes, bone marrow, and in epidural tissues.[40] Survival has ranged between 5 and 80 months.

Hematologic findings. Sustained neutrophilia with counts in excess of 30 x [10.sup.9]/L are frequently present, and mature granulocytes may constitute 99% of all circulating white cells (Slide 7). The LAP score is increased in CNL, and although this helps to exclude CML, it does not exclude a leukemoid reaction. Dohle bodies and toxic granules have been described, as have hypogranular and hyposegmented myelodysplastic features with ring nuclei and myelocytes and metamyelocytes in some instances. In contrast to CML, eosinophilia, basophilia, and monocytosis are absent. Since CNL may terminate in AML, appropriate sequential CBC, peripheral smear examinations, and other procedures such as bone marrow examination, cytochemistry, immunophenotyping, and karyotyping should be considered. Thrombocytopenia and anemia may be variably present in CNL.

Bone marrow findings. The bone marrow in CNL is hypercellular and myeloid, and usually has an myeloid to erythroid cell ratio that varies between 5:1 and 25:1 (normal ratios are 2:1 to 5:1). Myeloblasts are generally less than 5%, and mature granulocytes predominate. Megakaryocytopoiesis and erythropoiesis are usually unremarkable. Myelofibrosis generally does not develop in CNL.

Cytogenetic abnormalities. The classic Philadelphia chromosome, p210 BCR-ABL gene major breakpoint cluster region (g-bcr) of CML, and the p190 BCR-ABL minor break point cluster region (m-bcr) break point abnormality of Ph+ ALL are absent in CNL. However, a p230 BCR-ABL gene ([micro]-bcr) breakpoint abnormality has been described.[41] Also, long arm abnormalities of chromosome 20 have been recently reported.[42] Whether these represent consistent and classic abnormalities of CNL awaits elucidation. Recently, a neutrophilic predominant CML with a rare type of BCR/ABL rearrangement with a breakpoint between exons c3 and c4 of the BCR gene (corresponding to BCR exons 19 and 20) has been detected with hybridization with an oligonucleotide probe, and spans the c3/a2 region.[43] The presence of a chromosomal abnormality does help in excluding reactive neutrophilia and leukemoid reactions.

Differential diagnosis. In patients with transient neutrophilia and in those with an apparent cause for reactive neutrophilia or a leukemoid reaction, CNL should not be a valid consideration. For comparative parameters of reactive neutrophilia, CML and CNL, see Table 1.

Chronic monocytic leukemia

Chronic monocytic leukemia (CMoL) is a poorly documented, rare disease. Hence, no universal criteria for diagnosis are established, and several contemporary texts do not mention this entity. In 1981, Bearman et al. reviewed CMoL and added five of their own cases to the data that have accrued since the initial description of CMoL by Reschad and Schilling-Torgau in 1913.[44,45] Most patients are adults, and present with fever, left upper quadrant pain, and hepatomegaly. Splenomegaly has been a consistent manifestation.

Hematologic findings. CMoL is the only form of human leukemia that usually does not initially appear to present with abnormal circulating cells or an infiltrated marrow, but does so following splenectomy.[46] Thrombocytopenia and anemia may be present. Absolute monocytosis may be detected immediately following splenectomy, or as late as 24 months thereafter. Monocytes in the peripheral blood have a ground glass or slate grey cytoplasm with a variable number of vacuoles and magenta granules (Slide 8). Nuclei may reveal delicate chromatin, and may be round, oval, or reniform. Nuclear folds may be variable. Nucleoli are usually absent or inconspicuous, but are more prominent in promonocytes. Auer rods and blast forms are absent, and platelet phagocytosis and emperipolesis may be apparent. Leukemic monocytes are fluoride sensitive, alpha naphthyl acetate esterase positive, alpha naphthyl butyrate esterase positive, and Leder stain negative. The Sudan black B and myeloperoxidase reactions are variably positive.

Bone marrow findings. Bone marrow samples may be unremarkable at initial diagnosis, but in post-splenectomy samples, a focal or diffuse monocytic infiltrate may progressively replace normal hematopoietic tissues. In the bone marrow, monocytic elements may be somewhat less mature than in the peripheral blood, and phagocytosis of platelets, other white cells, and erythroid cells may be apparent. Megaloblastoid changes may be observed, and megakaryocytes are reduced with increased marrow infiltration. Myelofibrosis does not appear to develop.

Cytogenetic abnormalities. No specific chromosomal abnormality appears to be present in CMoL, and the Philadelphia chromosome is absent. An extra chromosome 20 has been observed in a case of CMoL with biastic transformation.[47]

Differential diagnosis. Widespread parenchymal leukemic infiltrates have been observed in CMoL, and the differential diagnosis includes AML-M4, AML-M5, CMML, hairy cell leukemia (HCL), and malignant histiocytosis. The absence of myelodysplastic changes in CMoL helps to distinguish it from CMML.

Despite its rarity, CMoL is believed to be a distinct clinicopathologic entity, and the development of splenomegaly before marrow involvement has prompted consideration that CMoL may originate in the spleen.[44,48] Since spleen weights of as much as 2160.0 grams have been reported, the cytopenias of CMoL appear to be primarily a manifestation of hypersplenism with sequestration. CMoL is a fatal disease, and its etiology and pathogenesis are not understood. No long-term curative outcome is reported, and nothing new has been written regarding this very rare and controversial clinicopathological entity.

Mast cell leukemia

Mast cell leukemia (MCL) is an unusual and rare form of chronic leukemia, and only a few well documented cases are reported. At this time, the diagnostic criteria are considered less than perfect. In most cases however, features of systemic mastocytosis are apparent, and MCL is considered an aggressive form of mastocytosis. In contrast to indolent mastocytosis, which may arise in infancy and childhood, and may improve or resolve by puberty, MCL is progressive and fatal.[49]

Clinical findings. Constitutional symptoms are frequently present in patients with MCL, and may include peptic ulcer disease, diarrhea, hypotensive episodes, urticarial skin rash, and hepatosplenomegaly. In some cases of systemic mastocytosis, occasional mast cells have been observed in the peripheral blood. However, if mast cells are less than 10% of the total leukocyte count, this may not constitute a diagnosis of leukemia. Furthermore, since the number of circulating mast cells may neither reflect tumor burden nor survival, clinical correlation is paramount.

Hematologic findings. Normal and reactive mast cells do not circulate in the peripheral blood. However, in MCL, absolute mast cell counts as high as 50.0 x [10.sup.9]/L have been reported. Leukemic mast cells are readily identified in a Wright-Giemsa stained peripheral blood smear, and reveal characteristic round to oval nuclei, and variably tinctorial cytoplasmic granules which may be increased and resemble AML-M3 (Slide 9). Auer rods are absent.

Bone marrow findings. Since the marrow is frequently involved in indolent mastocytosis, a positive biopsy does not necessarily support a diagnosis of MCL. Aspirate samples may reveal varying numbers of atypical mast cells, and these are more numerous than those observed in reactive mastocytosis, as in Waldenstrom's macroglobulinemia, low grade B-cell lymphoma, and chronic myeloid leukemia. Myelofibrosis is frequently observed in the bone marrow biopsy, and mast cell proliferations may be focal or diffuse. Associated eosinophilia may be present, and examples of focal disease have been hitherto designated as the eosinophilic fibrohistiocytic lesion.

In an attempt to classify mast cell lesions in the bone marrow, Horny et al.[50] have recommended a classification into 3 types:

Type 1. Lesions are characterized by focal and polymorphous infiltrates that are either paratrabecular or perivascular and are accompanied by reticulin fibrosis. Such lesions best correlate with indolent and cutaneous disease, and are frequently associated with the best prognostic group.

Type 2. Lesions reveal sheets of mast cells which are often paratrabecular or perivascular, and often are associated with myelofibrosis and osteosclerosis. The marrow between intervening lesions is frequently hyperplastic and myeloid predominant. Type 2 lesions are mostly associated with AML, AMML, or CML.

Type 3. Lesions are diffuse, and are usually associated with MCL. Type 3 lesions are observed in the worst prognostic group.

Ancillary studies. Mast cells appear to be derived from a bone marrow progenitor, and are metachromatic, and reveal activity with the periodic acid-Schiff stain, Sudan black B, histamine, tartrate resistant acid phosphatase (TRAP), and Leder stains. Peripheral blood and bone marrow mast cells are positive for CD117 and immunoglobulin E (IgE) and express a variety of myeloid cell and other hematopoietic markers.[51] Cytochemical and immunohistochemical stains have been used to detect TRAP, tryptase, CD68, myeloperoxidase, lysozyme, and CD20 activity in mast cells.[52,53] One of the most useful cytochemical stains for mast cells is mast cell tryptase. It is highly specific and works well in decalcified bone marrow biopsy specimens. Membrane bound granules may be seen on electron microscopy, and scroll-like inclusions may be absent.[53] The Philadelphia chromosome is absent, and no specific chromosomal abnormality appears to be present.

Differential diagnosis The differential diagnosis of MCL in the bone marrow includes HCL, idiopathic myelofibrosis, Hodgkin's disease, hypergranular AML-M5 and CML.


The chronic leukemias are a diverse group of disorders that are challenging to both clinicians and laboratory. Knowledge of clinical and morphologic profiles of these various disorders is essential in a diagnostic work-up. Selection of appropriate ancillary studies can be done in a cost effective manner once careful morphologic evaluation is performed in most cases (see Table 2).


1. Dorfman DM, Longtine JA, Weinberg DS, et al. T-cell blast crisis in CML Immunophenotype and biologic findings. Am J Clin Pathol. 1997; 107:168-176.

2. Colovic M, Jankovic G, Lazrevic V. Burkitt-like blast crisis in CML. Med Oncol. 1996; 13:119-120.

3. Schumacher HR, Cotelingam JD. Chronic myeloid leukemia. Case #1. In Chronic Leukemia: Approach to Diagnosis. New York, New York, Igaku-Shoin; 1993:187-200.

4. Nowell Pc, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497.

5. Rowley JD. A new consistent chromosomal abnormality in CML identified by quinacrine fluorescence and Giemsa banding. Nature. 1973;243:248.

6. Sinclair PB, Green AR, Grace C. Improved sensitivity of BCR-ABL detection: A triple-probe 3 color FISH system. Blood. 1997; 90:1395-1402.

7. Cortes JE, Talpaz M, Beran M, et al. Phl chromosome negative CML with rearrangement of BCR. Long term follow up. Cancer. 1995; 75:464-470.

8. Lion T. Clinical implications of qualitative and quantitative polymerase chain reaction in the monitoring of patients with chronic myelogenous leukemia. Bone Marrow Transplantation. 1994;14:505-509.

9. Abdelghani T, Petty J, Sreenan JJ, et al. Comparative analysis of interphase FISH and RT-PCR to detect bcr-abl translocation in CML and related disorders. Am J Clin Pathol. 109:16-23, 1998.

10. Cox MC, Maffei L, Buffolino S, et al. A comparative analysis of FISH, RT-PCR and cytogenetics for diagnosis of bcr-abl positive leukemias. Am J Clin Pathol. 1998;109:24-31.

11. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189-199.

12. Kerer J, Ruutu T. de la Chapelle A. Monosomy 7 in granulocytes and monocytes in myelodysplastic syndromes. N Engl J Med. 1987;316:499

13. Schumacher HR, Cotelingam JD. Chronic myelomonocytic leukemia, Case #11. In: Chronic leukemia: Approach to diagnosis. New York: Igaku-Shoin; 1993: 303-314.

14. Worsley A, Oscier DG, Stevens J, et al. Prognostic features of chronic myelomonocytic leukemia: A modified Bournemouth score gives the prediction of survival. Br J Haematol. 1988;68:17-21.

15. Kovides PA, Bennett JM. Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: Case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome. Am J Hematol. 1995; 49:157-162.

16. Vallejo C, Garcia-Marcos MA, Del Canizo MC, et al. Syndrome of abnormal chromatin clumping in leucocytes with a high fraction of bone marrow cells in S-phase and in vitro autonomous growth. Medicina Clinica. 1997;109:340-342.

17. Brach MA, Scott C, Keihntopf M, et al. Expression of the transforming growth factor-alpha gene is regulated by interleukin-3, by interleukin-5, and granulocyte-macrophage colony-stimulating factor. Europ J Immunol. 1994; 24:646-650, 1994.

18. Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann. Int Med. 1969;68:1220-1229.

19. Fauci AS, Harley JD, Roberts WC, Ferrans, VJ, Gralnick HR, Bjomson BH. NIH Conference. The idiopathic hypereosinophilic syndrome: Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. 1982;97:78-92.

20. Brunning RD. The hypereosinophilic syndrome. pp 246-254. In Rosai J, ed: Tumors of the Bone Marrow. Armed Forces Institute of Pathology Fascicle #9, Third series. Washington D.C.: AFIP; 1994: 246-254.

21. Kueck BD, Smith RE, Parkin J, Peterson LC, Hanson CA. Eosinophilic leukemia: A myeloproliferative disorder distinct from the hypereosinophilic syndrome. Hematol Pathol. 1991;5:195-205.

22. Schooley RT, Flaum MA, Gralnick HR, Fauci AS. A clinicopathologic correlation of ideopathic hypereosinophilic syndrome. II. Clinical Manifestations. Blood. 1981;58:1021-1026.

23. Guitard AM, Horschowski N, Mozziconacci MJ, et al. Hypereosinophilic syndrome in childhood: Trisomy 8 and transformation to mixed acute leukemia. Nouvell Revue Franscaise d' Hematologie. 1994;35:555-559.

24. Schumacher HR, Cotelingam JD. HES Terminating in AML-M5a. Case #6. In: Chronic Leukemia: Approach to Diagnosis. New York, New York. Igaku-Shoin; 1993:245-259.

25. Higuchi W, Koike T, Ihizumi T, et al. Hypereosinophilic syndrome terminating in acute myelogenous leukemia. Acta Hematologica. 1993;90:165-166.

26. Blatt J, Pronjansky R, Horn M, et al. Idiopathic hypereosinophilic syndrome terminating in acute lymphoblastic leukemia. Pediat Hematol Oncol. 1992;9:151-155.

27. Stillman RG. A case of myeloid leukemia with predominance of eosinophilic cells. Med Res. 1912;81:594-595.

28. Juneja S, Stewart J, McKenzie A, et al. Hypereosinophilic syndrome or chronic eosinophilic leukemia: Report of a case with a lyric bone lesion. Leukemia. 1997;11:765-766.

29. Duell T, Mittermuller J, Schmetzer HM, et al. Chronic myeloid leukemia associated hypereosinophilic syndrome with a clonal t(4;7) (q11;q32). Cancer Gen and Cytogen. 1997;94:91-94.

30. Tuohy EL. A case of splenomegaly with polymorphonuclear neutrophil hyperleukocytosis. Am J Mec Sci. 1920;160:18-25.

31. Schumacher HR, Cotelingam JD. Chronic neutrophilic leukemia. Case #4. In: Chronic leukemia: Approach to diagnosis. New York: Igaku-Shoin; 1993:223-231.

32. Lewis MJ, Oelbaum MH, Coleman M, et al. An association between chronic neutrophilic leukemia and multiple myeloma with a study of cobalamin-binding proteins. Br J Haematol. 1986;63:173-180.

33. Boggs DR, Kaplan SS. Cytobiologic and clinical aspects in a patient with chronic neutrophilic leukemia after thorotrast exposure. Am J Med. 1986;81:905-910.

34. Lugassy G, Farhi R. Chronic neutrophilic leukemia associated with polycythemia vera. Am J Hematol. 1989,31:300-301.

35. Cervantes F, Rozman M, Vives-Corrons J-L, et al: Chronic neutrophilic leukemia with dysplastic features. Acta Haematol. 1990;84:109.

36. Franchi F, Seminara P, Giunchi G. Chronic neutrophilic leukemia and myeloma: Report on long survival. Tumori. 1984;76:105-107.

37. Rovira M, Cervantes F, Nomdedeu B, et al. Chronic neutrophilic leukemia preceding for seven years the development of multiple myeloma. Acta Haematol. 1990;83:94-95.

38. Shindo T, Sakai C, Shibata A: Neutrophilic leukemia and blast crisis. Ann Intern Med 1977;87:66-67.

39. Cervantes F, Marti JM, Rozman C et al. Chronic neturophilic leukemia with marked myelodysplasia terminating in blast crisis. Blut. 1988;56:75-78.

40. Yamaya T, Kamata Y, Nasai K, et al. An autopsy case of chronic neutrophilic leukemia and review of Japanese literature. Rinsho Ketsueki. 1982;23:1808-1810.

41. Christopoulos C, Kottoris K, Mikraki V et al. Presence of the bcr/abl rearrangement in a patient with CNL J Clin Pathol. 1996; 49:1013-1015.

42. Matano S, Nakamura S, Kobayashi K, et al. Detection of long arm of chromosome 20 in CNL Am J Hematol. 1997;54:72-75.

43. Pane F, Ferdinando F, Sidona M, et al. Neutrophilic CML; A distinct disease with a specific marker (BCR/ABL with a C3/A2 junction). Blood. 1996;88:2410-2414.

44. Bearman RM, Kjeldsberg CR, Pangalis GA, et al. Chronic monocytic leukemia in adults. Cancer. 1981;48:2239-2255.

45. Reschad H, Schilling-Torgau V. Uber eine neue Leukamie durch echte Ubergangsformen (Splenozytenleukamie) und ihre Bedeutung fur die Selbstandigkeit dieser Zellen. Munchen Med Wchnschr. 1913;60:1981-1984.

46. Schumacher HR, Cotelingam JD. Chronic monocytic leukemia. Case #7. In: Chronic leukemia: Approach to diagnosis New York, NY. Igaku-Shoin. 1993;261-268.

47. Wahlin A, Nordenson I, Roos G. Chronic monocytic leukemia terminating in blastic transformation. Blut. 1986;53:405-409.

48. Vardiman JW, Byrne GE, Rappaport H: Malignant histiocytosis with massive splenomegaly in asymptomatic patients. A possible chronic form of disease. Cancer. 1986;36:419-427.

49. Travis WD, Li C-Y, Hoagland HC, et al. Mast cell leukemia. Report of a case and review of the literature. Mayo Clin Proc 1986;61:957-966.

50. Horny HP, Parwaresch MR, Lennert K. Bone marrow findings in systemic mastocytesis Hum Pathol. 1985;16:808-814.

51. Escribano L, Orfao A, Villarrubia J, et al. Sequential immunophenotypic analysis of mast cells in a case of systemic mast cell disease evolving to a mast cell leukemia. Cytometry. 1997;30:98-102.

52. Li WV, Kapadia SB, Sonmez-Alpan E, et al. Immunohistochemical characterization of mast cell disease in paraffin sections using tryptase, CD68, myeloperoxidase, lysozyme, and CD20 antibodies. Modern Pathology. 1996;9:982-988.

53. Brunning RD, McKenna RW. Mast cell disease. In Rosai J, ed: Tumors of the bone marrow. Armed Forces Institute of Pathology. Fasicle #9, Third series. Washington D.C.: AFIP; 1994: 419-437.

James T. Rector is head of hematopathology at the National Naval Medical Center in Bethesda, MD. Diana M. Veillon is clinical associate professor of pathology at Louisiana State University Medical Center in Shreveport, LA. Harold Shumacher is head of hematopathology and professor of pathology at the University of Cincinnati Medical Center in Cincinnati, OH. James O. Cotelingam is head of hematopathology and clinical laboratories and professor of pathology at Louisiana State University Medical Center in Shreveport, LA.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
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Title Annotation:part 2
Author:Rector, James T.; Veillon, Diana M.; Schumacher, Harold R.; Cotelingam, James D.
Publication:Medical Laboratory Observer
Date:Dec 1, 1998
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