Presentations

Leukemoid Reaction

Categories
Published
of 5
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Description
Leukemoid Reaction
Transcript
  Review article An update on the etiology and diagnostic evaluationof a leukemoid reaction Vissaria Sakka, Sotirios Tsiodras, Evangelos J. Giamarellos-Bourboulis, Helen Giamarellou ⁎ 4th Department of Internal Medicine, University General Hospital   “   ATTIKON  ”  , 1 Rimini Street, 124 62 Athens, Greece Received 28 November 2005; received in revised form 22 March 2006; accepted 27 April 2006 Abstract Persistent neutrophilic leukocytosis above 50,000 cells/  μ L when the cause is other than leukemia defines a leukemoid reaction. Thediagnostic work-up consists of the exclusion of chronic myelogenous leukemia (CML) and chronic neutrophilic leukemia (CNL) and thedetection of an underlying cause. The major causes of leukemoid reactions are severe infections, intoxications, malignancies, severehemorrhage, or acute hemolysis. The present article points out the difficulties in the differential diagnosis of a leukemoid reaction andsuggests an algorithm for a rational clinical and laboratory evaluation of this problematic entity.© 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.  Keywords:  Leukemoid reaction; Diagnosis; Chronic myelogenous leukemia; Chronic neutrophilic leukemia; Malignancy Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3942. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3953. Diagnostic evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3953.1. White blood cell count, differential count, and peripheral blood smear . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.2. Leukocyte alkaline phosphatase (LAP) score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.3. Serum vitamin B12 and vitamin B12-binding capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.4. Bone marrow aspiration and biopsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.5. Cytogenetic testing and molecular analysis of peripheral blood and bone marrow granulocytes . . . . . . . . . . . . . 3963.6. Immunophenotyping of peripheral blood and bone marrow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3973.7. Serum levels of hematopoietic growth factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3973.8. Human androgen receptor gene assay (HUMARA). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3973.9. Cultures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3973.10. Imaging studies and biopsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3974. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 1. Introduction A leukemoid reaction (LR) is a hematological disorder,defined by a leukocyte count greater than 50,000 cells/  μ L,caused by reactive causes outside the bone marrow [1,2]. It is European Journal of Internal Medicine 17 (2006) 394 – 398www.elsevier.com/locate/ejim ⁎  Corresponding author. Tel.: +30 210 5831989; fax: +30 210 5326446.  E-mail address:  hgiama@ath.forthnet.gr  (H. Giamarellou).0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.ejim.2006.04.004  characterized by a significant increase in mature neutrophilsin the peripheral blood and a differential count showingmarked left shift  [2]. The diagnosis of LR is based on theexclusion of chronic myelogenous leukemia (CML) andchronic neutrophilic leukemia (CNL). The absence of im-mature cells, basophilia or monocytosis, increased leukocytealkaline phosphatase (LAP), and the absence of the bcr/abltranslocation distinguishes LR from CML. CNL is a rare,distinct myeloproliferative syndrome with a poor prognosis[3]. The differential diagnosis between LR and CNL may bedifficult or even impossible because both conditions shareidentical morphological features, including a raised LAPscore and the absence of the bcr/abl translocation [3].The current review discusses the different causes of LR, pointing out the difficulties in the differential diagnosis.Moreover, a diagnostic approach to a rational clinical andlaboratory evaluation that mainly refers to an isolated LR is proposed. 2. Etiology The major causes of LRs are severe infections, intoxica-tions, malignancies, severe hemorrhage, or acute hemolysis(Table 1). A variety of infections, such as colitis due to Clostridium difficile , disseminated tuberculosis [4], andsevere shigellosis, have been associated with an LR.  C.difficile  colitis with an LR appears to be associated with amuch higher mortality rate ( ∼ 50%) [5]. A study of 111children with  Shigella dysenteriae  type 1 infection revealed25 patients with LR. Its presence indicates a poor prognosis because it may accompany or precede hemolytic – uremicsyndrome [6]. A leukemoid reaction can also follow expo-sure to a drug (e.g., corticosteroids, minocycline, recombi-nant hematopoietic growth factors [7]) or to a toxin (e.g.,ethylene glycol [8]). Other rare conditions that have beendescribed as causes of a LR are mesenteric inflammatory pseudotumor  [9], alcoholic steatohepatitis [10,11], and retroperitoneal hemorrhage [12].Granulocytosis with a modest elevation of the white blood cell count above 15,000 cells/  μ L, without infection or leukemia, is common in neoplasms and can be observed inseveral other conditions, such as smoking. Levels above50,000 cells/  μ L, or even above 100,000 cells/  μ L, constitutea rare, but well-documented, paraneoplastic syndrome.Leukemoid reactions can present simultaneously with themalignancy, late in the course of the disease, or precede thediagnosis by as many as 4 years [1]. Malignancy-associatedLRs are commonly observedin a variety of carcinomas, most notably lung and kidney cancer  [7,13,14]. In a study of 227 patients with carcinoma of the lung, 33 patients (14.5%)were diagnosed with tumor-related leukocytosis and 6 patients (2.6%) with LRs [14]. Only occasionally is an LR seen in association with other neoplastic conditions, such asHodgkin's lymphomas, melanomas, and sarcomas. Anumber of case reports have described an LR associatedwith melanoma [15], oropharyngeal [16,17], gastrointestinal [18,19], and genitourinary [1,20] tumors. The exact  mechanism of the generation of an LR in association witha neoplasm has not been fully elucidated. It is likely that various cytokines produced irregularly by the tumor cells,including granulocyte colony-stimulating factor (G-CSF),granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 6 (IL-6), may underlie the pathogen-esis of LR in such conditions [14 – 16,18,20,21]. Therapeuticstrategies for the neoplasm, like surgical excision [8,18,19],chemotherapy, and radiotherapy [1,21], frequently result in adecrease in the white blood cell count. Nevertheless, in such patients, LRs have been reported to correlate with anaggressive clinical course, lower survival time, occurringshortly before death [13]. 3. Diagnostic evaluation An LR is, by definition, diagnosed after the exclusion of amalignant hematological disorder. In the case of concomitant  polycythemia vera or thrombocytosis,a diagnostic approachconcerning general myeloproliferative diseases should bemade. However, the underlying cause of an LR is usuallyobvious. The clinician should obtain a clear history which,together with a good physical examination and limited imag-ing procedures, may provide significant clues to a diagnosis,such as a neoplasm or an infection. In this regard, it is impor-tant not to forget to ask about potentially important exposuresto drugs or toxins. Nevertheless, there are cases where the clinician maynot be able to exclude other significant causes of a LR without specific testing. The diagnostic work-up of an LR consists of the exclusion of a clonal disorder and specialtesting to identify other, more obscure, causes. White blood cell count and differential count, a peripheral bloodsmear, the leukocyte alkaline phosphatase (LAP) score,serum vitamin B12 levels, a bone marrow aspiration and Table 1Major causes of leukemoid reaction1. Infections (some major examples are listed)a.  Clostridium difficile  colitis b. Disseminated tuberculosisc. Severe shigellosis2. Malignanciesa. Carcinomas (lung, oropharyngeal, gastrointestinal, genitourinary) b. Hodgkin's lymphomac. Melanomad. Sarcoma3. Drugsa. Corticosteroids b. Minocyclinec. Recombinant hematopoietic growth factors4. Intoxicationa. Ethylene glycol5. Severe hemorrhage or acute hemolysisa. Retroperitoneal hemorrhage6. Miscellaneousa. Mesenteric inflammatory pseudotumor  b. Alcoholic steatohepatitis395 V. Sakka et al. / European Journal of Internal Medicine 17 (2006) 394  –  398   biopsy, cytogenetic studies, and immunophenotyping of  peripheral blood and bone marrow, as well as serum levelsof hemopoietic growth factors, may help in distinguishingLR from CML. Since CNL and LRs share identicalmorphological features, clonality studies of blood neutro- phils can help to demonstrate the monoclonality of neutrophils in CNL in contrast to a polyclonal LR (Table2). Further clinical evaluation and laboratory and imagingtests for an underlying infection or an occult tumor may benecessary. 3.1. Whitebloodcellcount,differentialcount,andperipheral blood smear  In LR, leukocyte counts are, by definition, greater than50,000 cells/  μ L and consist mostly of mature neutrophils.The differential count discloses a marked left shift, asevidenced by the presence of myelocytes and metamyelo-cytes [2]. An expert's review of the peripheral smear isnecessary to exclude a myeloproliferative syndrome. InCML, there are more immature cells, basophils, andeosinophils. In CNL, there is marked neutrophilia with noimmature cells and, in contrast to an LR, myelocytes,metamyelocytes, and nucleated red cells are infrequent.The peripheral smear may, in addition, disclose toxicgranulation, Doëhle bodies, and cytoplasmic vacuoles inthe neutrophils of patients with an LR attributed to aninfection [2]. 3.2. Leukocyte alkaline phosphatase (LAP) score LAP is an enzyme present in the cytoplasmic micro-somes of neutrophils, bands, metamyelocytes, and myelo-cytes, but not in lymphocytes or monocytes. Immatureneutrophils, such as those observed in CML, have decreasedLAP scores. The stimulated neutrophils of an LR haveincreased LAP scores [1]. In CNL, low LAP scores are theexception [22]. 3.3. Serum vitamin B12 and vitamin B12-binding capacity Vitamin B12 levels are usually elevated in CML andCNL, but they do not seem to be useful in differentiatingthese conditions from an LR. In fact, a recent observation of an LR due to G-CSF supplementation showed B12 levelsthat were just as high as the ones observed in CML [23]. 3.4. Bone marrow aspiration and biopsy Increased cellularity with myeloid hyperplasia is the principlepictureofanLR.Incontrasttoacuteleukemia,thereis marked proliferation and orderly maturation of all normalmyeloid elements with normal morphology. No fibrosis is present  [2]. Similar morphological features are present inCNL,butapackedbonemarrowbiopsy,togetherwithaslight increase in reticulin fibrosis, may help differentiate it from areactive process [1]. In CML, basophilia, eosinophilia,monocytosis, or even a minimum percentage of blasts andreticulin fibrosis are characteristic features. 3.5. Cytogenetic testing and molecular analysis of periph-eral blood and bone marrow granulocytes The presence of Philadelphia 1 chromosome in thekaryotype or the detection of t(9;22) translocation (creatingthe bcr/abl oncogene) by molecular techniques is the hall-mark for CML and excludes CNL. Still, in less than 10%,an atypical myeloproliferative disorder may be present. Insuch a case, the erythroid and megacaryocytic series may be involved. In a review, cytogenetic abnormalitiesoccurred in 37% of cases of CNL, the most frequent of which appeared to be involvement of chromosome 20, Table 2Differential diagnosis of leukemoid reaction, chronic myelogenous leukemia, and chronic neutrophilic leukemiaLeukemoid reaction Chronic myelogenous leukemia Chronic neutrophilic leukemiaPeripheral blood [2]Mature neutrophils,marked  “ left shift  ” Immature cells, basophils, and eosinophilsMarked neutrophilia, no immature cellsLAP score [1,22] High Low HighSerum vitaminB12 [23]Variable?, high High HighBone marrow[1,2]Myeloid hyperplasia, orderlymaturation, normal morphologyBasophilia, eosinophilia, monocytosis, slight increase in blasts and reticulin fibrosisSimilar morphology with LR, packed bonemarrow, slight increase in reticulinCytogeneticanalysis [22] No cytogenetic abnormalities bcr/abl translocation Cytogenetic abnormalities in 37% of casesImmuno- phenotyping [24]CD13 (+++), CD15 (+++), CD34 ( − )HLA-DR ( − )CD13 (+++), CD15 (+++), CD34( − )HLA-DR (+)CD13 (+++) CD15(+++), CD34 ( − )HLA-DR (+)Serum G-CSF[14 – 16,18,20 – 22]High a  Low LowClonalitystudies [3]Polyclonal Monoclonal Monoclonal(+++): high expression of the surface antigen. a  Only in G-CSF-producing tumors.396  V. Sakka et al. / European Journal of Internal Medicine 17 (2006) 394  –  398  whereas the majority of the cases recorded a normalkaryotype [22]. No karyotypic abnormalities are expectedin LRs. 3.6. Immunophenotyping of peripheral blood and bonemarrow Immunophenotypinghasnotbeenvalidatedasadifferentialdiagnostic tool in LRs, but it may exclude the presence of AMLortheprogressionofCMLtoablastcrisis[24].Itshould be stressed, however, that acute leukemias usually present completelydifferentlyandthe presenceofblasts above 20% iswhatischaracteristicoftheseconditionscomparedtotheother entitiesdiscussed.Theimmunophenotypeshowscharacteristicfindingsinleukemias.GatingshouldcomprisegranulocytesinFS/SS scattergrams of peripheral blood and granulocytes inSS/CD45 scattergrams of bone marrow. Mature neutrophilsexpresssurfaceantigensCD13andCD15atalevelhigherthan95% while, on the other hand, they are absolutely negative for CD34 and HLA-DR. Expression of CD34 would seem toimply the presence of acute leukemia or of a myelodysplasticsyndrome.CellsinCMLstainmaystainpositiveforHLA-DR,a finding not observed in LR. 3.7. Serum levels of hematopoietic growth factors Although G-CSF, GM-CSF, and IL-6 are not included inthe routine diagnostic work-up, their determination by anenzyme-linkedimmunosorbentassay(ELISA)havebeenused by several physicians to demonstrate an association between acytokine-producingtumorandthe development ofanLR [14 – 16,18,20,21]. These glycoproteins are normally secreted bymonocytes, macrophages, endothelial cells, and fibroblasts.Their functions include regulation of the growth and differ-entiation of hematopoietic progenitor cells and functional ac-tivation ofmature neutrophilsand macrophages [1]. LR due toa GM-CSF-producing tumor is characterized by markedeosinophilia [21]. CML and CNL patients have significantlylow G-CSF levels, suggesting that the neoplastic granulopoi-esis can exert a suppressor effect on G-CSF synthesis [22]. 3.8. Human androgen receptor gene assay (HUMARA) Bohm et al. have studied this method for the analysis of clonalityintissuesinfemalepatients.Theassayexaminestheinactivation patterns of the human androgen receptor geneon the X chromosome. In myeloproliferative syndromes,including CML and CNL, the neutrophils show monoclon-ality, whereas in reactive situations there is a polyclonal pattern [3]. 3.9. Cultures Searching for an underlying infection includes takingcultures of several fluids and tissues, especially blood, spu-tum, and bone marrow for common bacteria and mycobac-teria.Stoolculturesshouldnotbeoverlookedsincecolitisdueto Shigella spp.or  C.difficile isoneoftheclassicexamplesof an infection-associated LR. 3.10. Imaging studies and biopsies Ultrasound and computerized tomographic (CT) scans or magneticresonanceimages(MRI)ofthechestandabdomenshould be performed in order to reveal an occult infection or malignancy. As soon as a solid tumor is diagnosed, a biopsyshould be accompanied by special immunohistochemicalstaining to detect the possible expression of G- or GM-CSFreceptors that will confirm a cytokine-producing tumor. 4. Conclusions A LR is a rare condition that can be challenging and that may require a careful diagnostic work-up. The diagnosis isverified by a combination of the following: (i) a complete blood count with a peripheral blood smear that showsmarked mature neutrophilia with a left shift; (ii) a highleukocyte alkaline phosphatase (LAP) score; (iii) hypercel-lular bone marrow with intact maturation and morphology of all the elements; (iv) the absence of cytogeneticBox I Learning Points 1. A leukemoid reaction (LR) is defined by aleukocyte count greater than 50,000 cells/  μ L.2. By definition, it is diagnosed by theexclusion of a malignant hematological disorder,CML or CNL.3. The major causes of LRs are severeinfections, malignancies, intoxication, and se-vere hemorrhage or acute hemolysis.4. Careful history, good physical examination,and limited imaging studies may assist inrevealing the underlying cause.5. Diagnostic characteristics:a. marked mature neutrophilia with a left shiftb. ahigh leukocytealkaline phosphatase (LAP)scorec. hypercellular bone marrow with intactmaturation and morphology of all the elementsd. the absence ofcytogenetic abnormalities incytogenetic-molecular studiese. a mature granulocyte pattern by immuno-phenotyping of peripheral blood and bonemarrowf. a high serum level of hemopoietic growthfactorsinthecaseofacytokine-producingtumorg. a polyclonal pattern of blood neutrophils inclonality studies. 397 V. Sakka et al. / European Journal of Internal Medicine 17 (2006) 394  –  398
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks