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Chronic Myelomonocytic Leukemia: the Role of Bone Marrow Biopsy Immunohistology

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Chronic Myelomonocytic Leukemia: the Role of Bone Marrow Biopsy Immunohistology Modern Pathology (2006) 19, 1536–1545 & 2006 USCAP, Inc All rights reserved 0893-3952/06 $30.00 www.modernpathology.org Chronic myelomonocytic leukemia: the role of bone marrow biopsy immunohistology Attilio Orazi1, Ronald Chiu1, Dennis P O’Malley1, Magdalena Czader1, Susan L Allen1, Caroline An1 and Gail H Vance2 1Clarian Pathology Laboratory, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA and 2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA The World Health Organization criteria for diagnosing chronic myelomonocytic leukemia (CMML) are largely based on findings observed in the peripheral blood and bone marrow aspirate. A specific diagnostic role for the bone marrow biopsy has not been adequately explored. We examined whether bone marrow biopsy supplemented by immunohistochemistry may be helpful in distinguishing CMML from cases of chronic myelogenous leukemia and atypical chronic myeloid leukemia (aCML). We immunostained 25 cases of CMML with paraffin reactive antibodies which included CD68 (KP1), CD68R (PG-M1), and CD163, and compared the results with those observed in six cases of chronic myelogenous leukemia and in three cases of atypical CML. In addition, we examined whether CD34 immunohistochemistry could be useful in separating cases of CMML with less than 10% blasts (type-1) from cases of CMML with blasts accounting for 10–19% (type-2), and cases of CMML in acute transformation to acute myeloid leukemia (blastsZ20%). The presence of nodules of plasmacytoid monocytes was investigated by CD123 staining. CD42b was used to highlight abnormal megakaryocytes. Our results demonstrate significant differences between the groups. CD34 analysis allowed separating CMML type-1 from type-2 and the former from CMML in acute transformation. CD123-positive plasmacytoid monocyte nodules were found only in CMML and not in the other two disease groups. Overlap between CMML and the other two groups were observed with CD68 immunostaining. CD68R was more restricted to bone marrow macrophages and monocytes than CD68, but the differences between CMML and chronic myelogenous leukemia or atypical CML were still not significant. Although CD42b immunostaining facilitated the detection of dwarf megakaryocytes often present in CMML, the distinction between those and the small forms seen in chronic myelogenous leukemia was still problematic. Modern Pathology (2006) 19, 1536–1545. doi:10.1038/modpathol.3800707; published online 13 October 2006 Keywords: chronic myelomonocytic leukemia; acute transformation; chronic myelogenous leukemia; atypical chronic myeloid leukemia; immunohistochemistry; plasmacytoid monocyte Chronic myelomonocytic leukemia (CMML) is a changes may be minimal and limited to the clonal hematopoietic malignancy which is charac- monocytes; mild anemia is usually seen. terized by hybrid features, of both a myeloprolifera- The bone marrow of CMML is usually hyper- tive and a myelodysplastic syndrome.1–4 According cellular and in most cases, demonstrates a signifi- to the World Health Organization (WHO) criteria, cant degree of granulocytic proliferation.1–3 Erythroid the diagnosis of CMML requires a persistent peri- precursors and megakaryocytes may demonstrate pheral blood monocytosis of more than 1 Â 109/l, prominent dysplastic changes, but these cell types with a percentage of monocytes greater than 10% of are often normal in appearance. the white blood cell count (WBC). The peripheral Several studied have shown the importance of blood may demonstrate dysplastic changes typical blast enumeration in CMML, their excess being of the myelodysplastic syndromes, or dysplastic associated with a poorer prognosis.3,5 On the basis of these studies, the WHO classification scheme sub- divides CMML into two subcategories, depending Correspondence: Dr A Orazi, MD, FRCPath (UK), Clarian on the number of blasts found in the peripheral Pathology Laboratory, Department of Pathology and Laboratory blood and bone marrow. These include: CMML Medicine, Indiana University School of Medicine, 350 West 11th type-1 with blasts o5% in the blood or o10% in the Street, Room 5034, Indianapolis, IN 46202-5200, USA. E-mail: [email protected] bone marrow, and CMML type-2 which is character- Received 6 February 2006; revised 25 August 2006; accepted 29 ized by blasts 5–19% in the blood or 10–19% in the August 2006; published online 13 October 2006 bone marrow, or when Auer rods are present and the Bone marrow biopsy in chronic myelomonocytic leukemia A Orazi et al 1537 blast count is less than 20% in blood or marrow. and three cases of atypical CML. Additionally, a If blasts and promonocytes account for Z20% of series of seven cases of CMML in acute transforma- the bone marrow differential count, the diagnosis tion to acute myeloid leukemia were also included. should be acute myeloid leukemia rather than For the purpose of this study, CMML in acute CMML.1 transformation to acute myeloid leukemia was Besides the assessment of the blast number and defined by the presence of Z20% marrow blasts in the presence and amount of dysplasia, it is unclear a patient with a previously documented diagnosis of how bone marrow morphology can be useful in CMML. distinguishing CMML from other myeloid neo- The cases were obtained from the files of the plasms, chronic myelogenous leukemia (CML) and Department of Pathology, Indiana University School atypical chronic myeloid leukemia (aCML) in of Medicine/Clarian Health Partners, Indianapolis, particular. The two latter entities are also character- Indiana. All cases were consecutively diagnosed ized by a degree of myeloid proliferation similar to within a period of approximately 10 years. Only ‘de that seen in most cases of CMML.1,8,9 novo’ (ie non-therapy-related) myeloid neoplasms Although the presence of monocytosis in peri- were included. Peripheral blood smear, bone mar- pheral blood is necessary for the diagnosis of row aspirate smear, and paraffin-embedded bone CMML, a similar criterion has not been proposed marrow biopsy and/or particle sections were avail- for the bone marrow, in spite of the assumption than able for all cases used in this study. The diagnostic monocytic proliferation is present in the marrow as categorization of these cases was based on a well. The rationale of this is that the presence of comprehensive multiparametric evaluation, which pronounced granulocytic proliferation makes it included a combination of clinical characteristics, difficult to distinguish the monocytic population morphology, immunohistochemistry, and when from the granulocytic precursors, myelocytes, and available, flow cytometry and cytogenetics, in metamyelocytes in particular.1 To overcome this accordance with the diagnostic guidelines for difficulty, the use of cytochemical stains for mono- CMML, chronic myelogenous leukemia, and atypical cytes such as naphtyl butyrate esterase, or naphtyl CML outlined in the current WHO classification.1 acetate esterase has been advocated.1,6 The role of bone marrow biopsy in this condition is even less clear than that of the marrow aspirate. Peripheral Blood and Bone Marrow Aspirate Besides the detection of an increased marrow Evaluation cellularity owing to myeloid proliferation and the A Wright-stained peripheral blood smear was eval- identification of fibrosis, additional diagnostic roles uated and the percentage of circulating blasts as well have not been explored. Bone marrow biopsy could as the absolute value and relative proportion of be potentially more useful than the bone marrow monocytes determined. Bone marrow aspirate aspirate in the presence of marrow fibrosis, which smears were examined and a 300 cells differential may cause a spurious dilution of the marrow count obtained. In 17 cases, naphtyl butyrate cellularity owing to ‘contamination’ of the sample esterase was performed and used to assess the with peripheral blood.7 Potentially, immunohisto- frequency of bone marrow monocytes. chemistry applied to the bone marrow biopsy should provide a reliable tool for the ‘in situ’ identification of monocytes and monocytic cells, as Histologic Evaluation well as facilitate the identification of plasmacytoid monocytes nodules, a relatively common finding in In each case, hematoxylin–eosin-stained sections of CMML.1 the bone marrow biopsy and/or clot preparation was In this study, we examined whether bone marrow examined. In histology sections, blasts were defined histology, supplemented by immunohistochemistry as cells with high nuclear:cytoplasmic ratio, dis- for monocytic markers may be helpful in distin- persed nuclear chromatin, and scant cytoplasm. A guishing CMML from chronic myelogenous leuke- comparison ‘side by side’ with a corresponding mia and atypical CML. We have also investigated section stained with CD34 (see below) was parti- CD34 immunostaining of bone marrow biopsy as a cularly helpful in confirming the increased marrow tool to separate CMML type-1 from cases of CMML blast percentage seen in the aggressive cases of type-2 and CMML in acute transformation to acute CMML (ie CMML type-2 and CMML in acute myeloid leukemia (Figures 1–3). transformation). In addition, in each case, a section of the bone marrow biopsy was stained with Gomori and the degree of reticulin fibrosis was measured, Materials and methods according to the system originally proposed by Manoharan et al10 on a scale of 0–3 þ . It should be The materials studied included 25 cases of CMML,
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