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ORIGINAL ARTICLE
Year : 2019  |  Volume : 12  |  Issue : 1  |  Page : 22-27  

Hemophagocytosis in bone marrow aspirates: An indication of hidden pathologies


Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission17-Feb-2018
Date of Acceptance15-May-2018
Date of Web Publication18-Jan-2019

Correspondence Address:
Venkatesan Somasundaram
Department of Pathology, Armed Forces Medical College, Sholapur Road, Pune - 411 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_33_18

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  Abstract 


Background and Objectives: Hemophagocytosis in bone marrow aspirates is fairly common and can be observed in a spectrum of clinical conditions. This study aimed at evaluating the clinicopathological profile of patients showing hemophagocytosis on bone marrow aspirates examined for varied clinical indications. Materials and Methods: In this study, all those bone marrow aspirate smears sent with various clinical indications and which showed hemophagocytosis were included. Finally, 25 bone marrow aspirates were studied. Results: Of 25 patients, 18 (72%) were males and 7 (28%) were females. The age of the patients ranged from 2 to 73 years. Two common clinical indications with which bone marrow aspirates were sent were fever of unknown origin 10 (40%) and HIV-positive patients with cytopenias 7 (24%). Anemia was the most common cytopenias observed followed by cytopenias in other combinations. Microcytic hypochromic anemia was the common morphological type of the anemia encountered in these patients 17 (68%). Twenty-three (92%) of the bone marrow aspirates showed cellular bone marrow with features of hemophagocytosis. Bone marrow aspirate from a HIV-positive patient showed erythroid hyperplasia (78% early erythroids) with giant erythroblasts and features suggestive of parvovirus B19 infection and hemophagocytosis. Conclusions: Hemophagocytosis in the bone marrow aspirates should not be overlooked and always be documented and reported. The presence of hemophagocytosis may be the only clue to the underlying conditions such as systemic infections or hemophagocytic lymphohistiocytosis (HLH). It is therefore recommended that every case which shows hemophagocytosis needs to be reported and further workup be done to confirm the diagnosis of HLH.

Keywords: Bone marrow aspirates, cytopenias, hemophagocytosis, HIV positive


How to cite this article:
Srinivasagowda SK, Somasundaram V, Balraam V, Bharadwaj R. Hemophagocytosis in bone marrow aspirates: An indication of hidden pathologies. Med J DY Patil Vidyapeeth 2019;12:22-7

How to cite this URL:
Srinivasagowda SK, Somasundaram V, Balraam V, Bharadwaj R. Hemophagocytosis in bone marrow aspirates: An indication of hidden pathologies. Med J DY Patil Vidyapeeth [serial online] 2019 [cited 2019 Sep 18];12:22-7. Available from: http://www.mjdrdypv.org/text.asp?2019/12/1/22/250440




  Introduction Top


Hemophagocytosis is the pathologic process of engulfment of erythrocytes, leukocytes, platelets, and their precursors by the histiocytes, either in the bone marrow or in other parts of the reticuloendothelial system.[1] These syndromes result from macrophage activation with increased number of hemophagocytic macrophages and peripheral blood cytopenias.[2] The phenomenon of hemophagocytosis is a common pathologic feature observed in the bone marrow aspirates sent for examination with various clinical conditions. Many a times, its presence is overlooked and is not documented in the report.[3] Reporting of hemophagocytosis on the bone marrow aspirates becomes critical as the further management of the patient depends on the cause of hemophagocytosis.

Hemophagocytic syndromes occur commonly secondary to bacterial or viral infections. They either occur in previously healthy individuals or as a terminal complication in patients with altered immune response. The next common cause of hemophagocytic syndrome is hemophagocytic lymphohistiocytosis (HLH).[3] HLH is a disease which poses diagnostic and therapeutic challenges, and it occurs in primary and secondary forms. Distinguishing both is the most important prerequisite in the management. The primary form is a fatal disease with a median survival of <2 months after diagnosis if untreated.[4] The secondary form occurs as a result of strong immunological activation of the immune system.

Therefore, the index study was conducted with an aim to evaluate the clinicopathological profile of patients showing hemophagocytosis on the bone marrow aspirates examined for various clinical indications and to assist a clinician in carrying out further workup on such patients to differentiate primary and secondary causes of hemophagocytosis.


  Materials and Methods Top


This descriptive, cross-sectional study was carried out in the hematology section of the Department of Pathology, Armed Forces Medical College, Pune, India. All those bone marrow aspirate smears sent to the department with various clinical indications from June 2015 to May 2017 and which showed hemophagocytosis were included in the study. Finally, 25 bone marrow aspirates were included in the study. Clearance of the institutional ethical committee was obtained for the conduct of the study.

The bone marrow aspirate smears were fixed with methanol for 10 min, followed by staining being carried out with Giemsa-Wright stain as per the standard protocol. The aspirates were initially scanned for the cellular trail and for any obvious pathology, under low power ×4 and ×10 view. Later, 500 consecutive nucleated cells were counted under oil immersion objective ×100 for cytomorphological details and evidence of hemophagocytosis. Even a single histiocyte showing hemophagocytosis was considered positive; however, the phenomenon was not graded in this study. In the presence of hemophagocytosis, the aspirate smears were searched thoroughly for the presence of hemoparasites and for any hematolymphoid malignancies.

The demographic profile and the indication for the bone marrow aspirate were noted from an investigation requisition form sent along with the specimen. The peripheral blood sent along with the bone marrow aspirate was aspirated, and the complete blood count was obtained using Sysmex-XT 2000i fully automated hematology analyzer. Peripheral smears were prepared in 100% of the cases for the assessment of cytopenias; morphology of red blood cells, white blood cells, and platelets; identification of acute/chronic leukemias or any hemoparasites. The presence of hemophagocytosis was endorsed in the bone marrow aspirate reports, and the clinicians were advised to carry out further investigations to stratify the patients as primary versus secondary hemophagocytosis. The clinicopathological profile of the patients was tabulated and interpreted. Microsoft Excel was used for compiling the basic data and statistics.


  Results Top


We studied the peripheral blood counts, peripheral blood smear, and bone marrow aspirates of 25 patients who demonstrated hemophagocytosis in the marrow aspirates. Of the 25 patients, 18 (72%) were males and 7 (28%) were females. The age of the patients ranged from 2 to 73 years. Most of the patients 16 (64%) were in the age group of 21–60 years. Two common clinical indications with which bone marrow aspirates were sent for examination were fever of unknown origin 10 (40%) and HIV-positive patients with cytopenias 7 (24%), followed by the other causes [Table 1].
Table 1: Clinico-demographical profile of study patients

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Anemia was the most common cytopenias observed in these patients. All the 25 (100%) of the patients had anemia. Eight (32%) patients had only anemia. Eight (32%) patients had pancytopenia. Seven (28%) patients had anemia with thrombocytopenia, and two (8%) patients had anemia with leukopenia. Microcytic hypochromic anemia was the common morphological type of the anemia encountered in these patients 17 (68%), followed by normocytic normochromic anemia 8 (32%) [Table 2].
Table 2: Peripheral blood smear findings in study cases

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Twenty-three (92%) of the bone marrow aspirates showed cellular bone marrow with features of hemophagocytosis. Representative pictures of bone marrow aspirates of cases under study are depicted at [Figure 1]. Bone marrow aspirate from an HIV-positive patient showed erythroid hyperplasia (78% early erythroid) with giant erythroblasts and features suggestive of parvovirus B19 infection and hemophagocytosis. The clinician was advised to carry out the requisite diagnostic test to confirm the infection. One bone marrow aspirate from a known case of chronic lymphocytic leukemia on maintenance chemotherapy showed hypocellular bone marrow with hemophagocytosis. Fifteen (60%) of the patients showed increased bone marrow plasma cells (>3%). The plasma cell percentage ranged from 0% to 10% [Table 3].
Figure 1: Bone marrow aspirate smears showing hemophagocytosis. (a) Histiocyte showing multiple engulfed platelets in the cytoplasm; Wright- Giemsa, Oil immersion (100×). (b) Histiocyte with engulfed erythroid precursor and a lymphocyte in the cytoplasm; Wright-Giemsa, Oil immersion (100×). (c) Histiocyte with an engulfed lymphocyte in the cytoplasm; Wright-Giemsa, Oil immersion (100×). (d) Clustering of histiocytes with one of the enlarged histiocytes showing multiple engulfe RBCs; Wright-Giemsa, Oil immersion (100×)

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Table 3: Bone marrow aspirate findings: Index cases

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  Discussion Top


Hemophagocytosis is the pathologic process of engulfment of erythrocytes, leukocytes, platelets, and their precursors by the histiocytes, either in the bone marrow or in other parts of the reticuloendothelial system.[1] The syndrome of hemophagocytosis has to be first recognized as whether a primary disease or secondary to an underlying reactive process. This is critical for the line of management and has prognostic value. The causes of primary and secondary hemophagocytosis are listed in [Table 4]. The separation has to be done using the revised diagnostic guidelines HLH-2004.[4] The diagnostic criteria are reproduced in [Table 5]. Secondary HLH is more common to occur than primary HLH. The diagnosis of HLH can be made if there is a family history of HLH or evidence of genetic defects or if five of eight clinicopathological criteria are fulfilled.[5] The challenge of separating primary from secondary hemophagocytic lymphohistiocytosis (HLH) is always present.
Table 4: Causes of hemophagocytic lymphohistiocytosis

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Table 5: Revised diagnostic guidelines hemophagocytic lymphohistiocytosis -2004

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Hemophagocytosis could be seen in the bone marrow specimens sent for examination in various clinical indications. The presence of hemophagocytosis in the bone marrow leads to a varying degree of cytopenias. Some patients have severe transfusion-requiring cytopenias. Therefore, the early recognition of primary/secondary HLH becomes critical and life-saving in certain situations. Secondary HLH is associated with infections, collagen vascular disorders, and various hematolymphoid malignancies. Association with solid tumors is also known.[6] Many a times, the presence of hemophagocytosis in the bone marrow aspirates is overlooked and not reported routinely. This would lead to prolonged morbidity, delay in diagnosis, and fatal consequences if primary HLH is not diagnosed on time.[3],[7]

In our study, 25 bone marrow aspirates sent for examination for various clinical indications showed the presence of hemophagocytosis. The common presenting features in these patients were fever and cytopenias. All the patients had anemia. In a study of six patients with HLH by Goel et al., the presence of hemophagocytosis in the bone marrow had a sensitivity of 83% in detecting HLH.[5] The presence of hemophagocytosis in the bone marrow aspirates should be the guiding principle for further workup to rule out HLH. In our center, the bone marrow aspirates showing hemophagocytosis are reported with advice for carrying requisite tests required to satisfy the HLH-2004 criteria.

In our study, the second most common clinical diagnosis in which bone marrow aspirates showed hemophagocytosis was the HIV-positive status with cytopenias. Multiple previous studies also have acknowledged the occurrence of secondary hemophagocytosis in patients with HIV infection.[8],[9] The proposed pathogenetic mechanism in these patients is defective cytotoxic regulatory function of macrophages and natural killer cells, leading to the unregulated cytokine release and cell damage.[10] Hemophagocytosis is also associated with a variety of infectious diseases.[11],[12] In our study, 10 (40%) of the patients had a clinical presentation of fever of unknown origin. Peripheral blood smears and bone marrow aspirates were thoroughly examined for the presence of hemoparasites as hemoparasites are also associated with the presence of hemophagocytosis.[9],[13]

Other clinical diagnoses in which bone marrow aspirates showed hemophagocytosis were various hematolymphoid newly diagnosed malignancies and also those on chemotherapy (1 case of acute lymphocytic leukemia on maintenance chemotherapy, 1 case of chronic lymphocytic leukemia on maintenance chemotherapy, 1 freshly diagnosed case of chronic myelomonocytic leukemia-II, and 1 case of newly diagnosed case of diffuse large B-cell lymphoma). Multiple studies acknowledge the occurrence of secondary HLH in hematolymphoid malignancies and also as a consequence of chemotherapy.


  Conclusions Top


Hemophagocytosis is a fairly common phenomenon; however, it should not be overlooked and always be documented and reported. The presence of hemophagocytosis may be the only clue to the underlying conditions such as systemic infections or HLH. It is essential to suspect and diagnose HLH early as the condition can be life-threatening. Diagnosis of HLH requires clinical and laboratory criteria to be met. This study therefore concludes that every case which shows hemophagocytosis on the bone marrow needs to be reported and further workup be done to confirm the diagnosis of HLH so that the patients can be timely and appropriately managed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Favara BE, Jaffe R, Egeler RM. Macrophage activation and hemophagocytic syndrome in Langerhans cell histiocytosis: Report of 30 cases. Pediatr Dev Pathol 2002;5:130-40.  Back to cited text no. 1
    
2.
Bain BJ, Clark DM, Wilkins BS. Bone Marrow Pathology. 4th ed. Wiley-Blackwell; 2009.  Back to cited text no. 2
    
3.
Chandra H, Chandra S, Kaushik R, Bhat N, Shrivastava V. Hemophagocytosis on bone marrow aspirate cytology: Single center experience in North Himalayan region of India. Ann Med Health Sci Res 2014;4:692-6.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 4
    
5.
Goel S, Polski JM, Imran H. Sensitivity and specificity of bone marrow hemophagocytosis in hemophagocytic lymphohistiocytosis. Ann Clin Lab Sci 2012;42:21-5.  Back to cited text no. 5
    
6.
Oliveira C, Chacim S, Ferreira I, Domingues N, Mariz JM. Secondary hemophagocytic syndrome: The importance of clinical suspicion. Case Rep Hematol 2014;2014:958425.  Back to cited text no. 6
    
7.
George MR. Hemophagocytic lymphohistiocytosis: Review of etiologies and management. J Blood Med 2014;5:69-86.  Back to cited text no. 7
    
8.
Park KH, Yu HS, Jung SI, Shin DH, Shin JH. Acute human immunodeficiency virus syndrome presenting with hemophagocytic lymphohistiocytosis. Yonsei Med J 2008;49:325-8.  Back to cited text no. 8
    
9.
Campbell JI, Kanters S, Bennett JE, Thorlund K, Tsai AC, Mills EJ, et al. Comparative effectiveness of induction therapy for human immunodeficiency virus-associated cryptococcal meningitis: A network meta-analysis. Open Forum Infect Dis 2015;2:ofv010.  Back to cited text no. 9
    
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Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: Pathogenesis and treatment. Hematology Am Soc Hematol Educ Program 2013;2013:605-11.  Back to cited text no. 10
    
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Maakaroun NR, Moanna A, Jacob JT, Albrecht H. Viral infections associated with haemophagocytic syndrome. Rev Med Virol 2010;20:93-105.  Back to cited text no. 11
    
12.
Padhi S, Ravichandran K, Sahoo J, Varghese RG, Basheer A. Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis. Lung India 2015;32:593-601.  Back to cited text no. 12
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13.
Cançado GG, Freitas GG, Faria FH, de Macedo AV, Nobre V. Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis in late adulthood. Am J Trop Med Hyg 2013;88:575-7.  Back to cited text no. 13
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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