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Year : 2022  |  Volume : 18  |  Issue : 3  |  Page : 774-776

Acute lymphoblastic leukemia masquerading as hemophagocytic lymphohistiocytosis

Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission16-Jul-2020
Date of Decision29-Aug-2020
Date of Acceptance14-Oct-2020
Date of Web Publication01-Mar-2022

Correspondence Address:
Anshul Gupta
Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_679_20

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 > Abstract 

Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by immunological imbalance due to inappropriate activation of macrophage, T/NK cells resulting in hypercytokinemia and subsequent tissue damage. We present an interesting case of acute lymphoblastic leukemia (ALL) who presented to us with clinical and laboratory features of HLH. High index of suspicion for malignancy based on clinical history and bone marrow examination led us to reach at definitive diagnosis of ALL.

Keywords: Chemotherapy, hemophagocytic lymphohistiocytosis, malignancy

How to cite this article:
Mathiyazhagan G, Gupta A, Rahman K, Nityanand S. Acute lymphoblastic leukemia masquerading as hemophagocytic lymphohistiocytosis. J Can Res Ther 2022;18:774-6

How to cite this URL:
Mathiyazhagan G, Gupta A, Rahman K, Nityanand S. Acute lymphoblastic leukemia masquerading as hemophagocytic lymphohistiocytosis. J Can Res Ther [serial online] 2022 [cited 2022 Oct 7];18:774-6. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/774/338860

 > Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by excessive activation of macrophage, T, and NK cells, thereby leading to proinflammatory cytokine hypersecretion and hemophagocytosis resulting from defective cytotoxicity. Malignancy is one of the important triggers for precipitating HLH in children and accounts for 1.2%–24% of all HLH cases in several case series.[1],[2],[3] The diagnosis and treatment of the primary malignancy is crucial in the successful management of HLH. However, in leukemia, especially acute lymphoblastic leukemia (ALL)-associated HLH, the primary diagnosis is often delayed due to overlapping clinical picture of both these entities and poses a serious diagnostic challenge to the clinician.[4]

 > Case Report Top

A 12-year-old male child presented with the complaints of fever off and on for the past 1 month along with abdominal distention for 15 days. There was a history of receiving over-the-counter pain relief medications including oral steroids before admission for his disease symptoms. There was no history of jaundice, pedal edema, visible lumps, or swellings noted by the parents. Clinical examination on admission revealed severe pallor, petechial spots over the trunk and limbs, hepatomegaly (5 cm below costal margin), and splenomegaly (4 cm below costal margin). The initial laboratory workup revealed that pancytopenia with hemoglobin level of 35 gm/L, white cell count 0.43 × 109/L, and platelet count 0.12 × 109/L with no immature cells (blasts) in the peripheral smear. The clinical chemistry was conspicuous for deranged liver function test (serum bilirubin 3.4 mg/dl; direct bilirubin 2.8 mg/dl, aspartate aminotransferase 144 IU/dl, alanine aminotransferase 156 IU/dl, alkaline phosphatase 756 IU/dl, raised serum ferritin (3500 ng/ml) and serum triglycerides 324 mg/dl, and low serum fibrinogen (43 mg/dl). In view of his disease symptoms, bone marrow aspiration, and biopsy was done which revealed that florid proliferation of histiocyte with some displaying active hemophagocytosis against a background of extensive marrow necrosis [Figure 1]. The viral polymerase chain reaction samples for Epstein–Barr virus, Cytomegalovirus, parvovirus, and Herpes simplex virus were sent that were all negative. A diagnosis of HLH was made as it fulfilled five of the eight essential laboratory and clinical HLH 2004 criteria needed for the diagnosis.[5] However, there was a strong index of suspicion for acute leukemia in view of the history of intake of oral steroids before admission for the alleviation of his disease symptoms that could have masked the primary diagnosis. The patient was managed conservatively with intravenous antibiotics, IVIG, and transfusion support. His clinical condition improved though pancytopenia persisted and he remained transfusion dependent. In the background of this clinical scenario and the presence of extensive marrow necrosis in initial bone marrow aspirate which is an indirect pointer to malignancy, a repeat bone marrow was done on day 14 of his hospital admission that showed the presence of atypical lymphoid cells with blastic morphology. Flow cytometric immunophenotyping showed these blasts to be positive for CD19 (bright), CD10 (bright), CD34 (partial), CD20 (dim and heterogeneous), and CD45 (dim) confirming them to be B blast [Figure 2]. In conjunction with morphological, immunophenotypic, and clinical history, he was diagnosed as a case of partially treated B-cell ALL and was started on ALL chemotherapy. At present, he is tolerating chemotherapy well and has achieved complete remission (minimal residual disease-negative) postinduction chemotherapy.
Figure 1: Upper panel shows the marrow at presentation. Aspirate smears were paucicellular and showed histiocytes (A1, MGG, ×1000) with some showing active phagocytosis (A2, MGG, ×1000). Biopsy showed large areas of necrosis (B, H and E, ×40) along with some scattered foamy histiocytes (C, H and E, ×100).The lower panel shows the repeat marrow aspirate smears displaying scattered blasts (D, MGG, ×400). Bone marrow biopsy showed a monotonous population of cells (E, H, and E, ×40). Higher magnification shows these cells to be medium size and mononuclear cells high N:C ratio (blasts) (F, H and E, ×400)

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Figure 2: Abnormal B-cells (Purple color) showed positivity for CD19, CD10 (Bright), CD34 (partly), CD20 (Moderate heterogeneous), and dim to negative CD45 expression; suggesting them to be B Blasts. Normal mature B cells are shown in blue

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 > Discussion Top

The prevalence of malignancy-associated HLH (M-HLH) in children varies from 1.2% to 24% and hematological neoplasms that include B and T-cell lymphomas/leukemias contribute to the majority of cases of M-HLH in the pediatric population. The cause of malignancy-associated HLH is postulated to be immune dysregulation secondary to cytokines such as interleukin-6 and tumor necrosis factor-α from malignant cells.[6],[7] Perforin gene which is frequently mutated in genetic FHL is implicated in immune surveillance of abnormal hematopoietic clones. This has been well described in perforin A91V polymorphism which leads to reduced perforin protein expression and its occurrence at an increased frequency in children with ALL.[8],[9]

Broadly, M-HLH comprises two distinct subgroups: First malignancy triggered HLH in which the HLH is the initial presenting feature of the underlying malignancy. Second, it can be secondary to chemotherapy-induced myelosuppression, thereby leading to infection (usually viral) which is the precipitating cause for HLH. Often the latter contributes to the majority of cases of M-HLH in clinical practice. Strenger et al., in their series of 22 cases of pediatric M-HLH, 20 cases were associated with chemotherapy-induced myelosuppression and secondary infection related HLH.[2] The diagnosis of the primary malignancy (particularly acute leukemias) in the background of HLH still remains a challenge for the pediatric oncologist as the primary disease is often obscured by the clinical and laboratory features of HLH. Our case presented with a similar diagnostic dilemma with features of HLH masking the underlying malignancy at the initial presentation. However, on close follow-up and repeat bone marrow examination after an interval of 14 days led to the establishment of the diagnosis (B-ALL) and initiation of the definitive treatment. Lehmberg et al. in their study reported four cases of ALL (T-ALL = 3; B-ALL = 1) who had HLH at initial disease presentation. All four patients received HLH-2004 based initial therapy with dismal outcomes (two died and two relapsed), thereby highlighting the importance of timely initiation of anti-leukemic therapy for optimal response and outcome.[3] Similarly, Pan et al. reported 09 (40.9%) ALL cases in their series of 22 M-HLH who developed HLH as initial disease presentation, and majority were treated with HLH based chemotherapy protocols with modestly better outcomes (overall response rate - 68.2%; complete remission rate - 40.9%; and partial remission rate - 27.3%).[10] Thus, the optimal treatment approach of malignancy triggered HLH, especially acute leukemia has to be individualized. However, a high index of suspicion and careful follow-up holds the key to clinch the diagnosis of primary malignancy in the setting of M-HLH and thereby improving the disease outcome.

 > Conclusion Top

A possibility of primary malignancy as a trigger should always be considered toward managing HLH in children since there is an overlap in the clinical features of acute leukemia and HLH. A good clinicopathological correlation is needed for establishing the diagnosis in such scenario.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Celkan T, Berrak S, Kazanci E, Ozyürek E, Unal S, Uçar C, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in pediatric cases: A multicenter study from Turkey. Turk J Pediatr 2009;51:207-13.  Back to cited text no. 1
Strenger V, Merth G, Lackner H, Aberle SW, Kessler HH, Seidel MG, et al. Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience of 20 years. Ann Hematol 2018;97:989-98.  Back to cited text no. 2
Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Müller I, Suttorp M, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol 2015;170:539-49.  Back to cited text no. 3
Singh A, Dawman L, Seth R. Malignancy associated hemophagocytic lymphohistiocytosis in children. J Cancer Res Ther 2018;14:559-62.  Back to cited text no. 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. 5
Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:435-44.  Back to cited text no. 6
Trebo MM, Attarbaschi A, Mann G, Minkov M, Kornmüller R, Gadner H. Histiocytosis following T-acute lymphoblastic leukemia: A BFM study. Leuk Lymphoma 2005;46:1735-41.  Back to cited text no. 7
Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Aricò M. A single amino acid change A91V in perforin: A novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica 2005;90:697-8.  Back to cited text no. 8
Busiello R, Fimiani G, Miano MG, Aricò M, Santoro A, Ursini MV, et al. A91V perforin variation in healthy subjects and FHLH patients. Int J Immunogenet 2006;33:123-5.  Back to cited text no. 9
Pan H, Huo Y, Sun L. Comparison between clinical features and prognosis of malignancy- and non-malignancy-associated pediatric hemophagocytic lymphohistiocytosis. BMC Pediatr 2019;19:468.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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