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Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 559-562

Malignancy associated hemophagocytic lymphohistiocytosis in children

Department of Pediatrics, Division of Pediatric Oncology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication12-Jun-2018

Correspondence Address:
Dr. Rachna Seth
Department of Pediatrics, Division of Pediatric Oncology, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.188437

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 > Abstract 

Aim of Study: Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of immune dysregulation resulting in abnormal T-cell activation and inflammatory cytokine production which produces a constellation of clinical features unique to HLH. Pediatric secondary HLH is usually triggered by infection, malignancy, or rheumatological disorders. The diagnosis of malignancy-associated HLH (MA-HLH) poses a difficult challenge as clinical features may be attributed to the underlying disease or chemotherapy. Our study aimed to see the occurrence of this rare entity at our centre.
Materials and Methods: Data were collected from all pediatric oncology patient treated at our center with the diagnosis of MA-HLH from January 2012 to December 2014. Data were collected for age, sex, underlying disease, treatment protocol, stage of chemotherapy, any underlying infection, treatment given for HLH, and outcome.
Results: There were five patients with a diagnosis of MA-HLH in the study period. Age ranged from 18 months to 9 years. Of the five MA-HLH, two patients had acute lymphoblastic leukemia, two acute myeloid leukemia, and one had Hodgkin lymphoma. The three patients who had documented microbiological infection also did not improve after appropriate treatment. Two patients died during treatment. One patient improved completely on steroid alone. One patient received HLH 2004 induction.
Conclusion: The delay in the diagnosis of MA-HLH in pediatric patients may be due to decrease awareness about the condition the timely diagnosis of MA-HLH is crucial for a better outcome. Herein, we discuss our experience with this rare entity in pediatric oncology patients with review of literature.

Keywords: Childhood malignancy, cytokine storm, HLH 2004, immune dysregulation

How to cite this article:
Singh A, Dawman L, Seth R. Malignancy associated hemophagocytic lymphohistiocytosis in children. J Can Res Ther 2018;14:559-62

How to cite this URL:
Singh A, Dawman L, Seth R. Malignancy associated hemophagocytic lymphohistiocytosis in children. J Can Res Ther [serial online] 2018 [cited 2020 Aug 11];14:559-62. Available from: http://www.cancerjournal.net/text.asp?2018/14/3/559/188437

 > Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by cytokine storm from activated lymphocyte and macrophages. It was first recognized as “familial hemophagocytic reticulosis” in 1952.[1] It is either primary with an underlying genetic defect or secondary triggered by infection, malignancy, or rheumatological disorder. The genetic basis of HLH was proved by the discovery of perforin gene mutation in 1999.[2] The incidence of HLH is reported as 1.2 cases/million which appears to be an underestimate.[3] According to another study, a tertiary care pediatric hospital should see one case of HLH per 3000 inpatient admissions.[4] Malignancy-associated HLH (MA-HLH) is mainly reported in adult patients with lymphoma. Around 24 cases of HLH associated with B or precursor T acute leukemia are reported in pediatric patients.[4] The rarity of occurrence of HLH and its varied presentation makes the diagnosis of MA-HLH difficult. HLH being primarily a T-cell disorder, it is widely reported with peripheral T-cell/natural killer (NK-cell) lymphoma in adults, especially Epstein–Barr virus-positive lymphomas. Pediatric cases have been reported with varied types of malignancy. Data on pediatric HLH are lacking. With this background, we did a retrospective study to identify pediatric oncology patients diagnosed as MA-HLH at our center from 2012 to 2014 and to study their varied clinical presentation and outcome. The usefulness of HLH diagnostic criteria in these patients where some of the criteria may be present due to underlying disease was also studied. A better understanding of the pathogenesis of HLH and its relation with the underlying immune dysregulation seen in malignancy will help in early diagnosis of this entity and better outcome.

 > Materials and Methods Top

Data were collected from all pediatric oncology patient treated at our center with the diagnosis of MA-HLH from January 2012 to December 2014. Data were collected for age, sex, underlying disease, treatment protocol, stage of chemotherapy, any underlying infection, treatment given for HLH, and outcome. The usefulness of HLH diagnostic criteria in patients with underlying malignancy was also studied. The diagnosis of HLH was based on HLH 2004 guidelines.

 > Results Top

There were five patients with the diagnosis of MA-HLH in the study period. Age ranged from 18 months to 9 years. There were four males and one female patient in the group. The host and disease characteristics are explained in [Table 1]. The clinical features and laboratory parameters are mentioned in [Table 2]. Hemophagocytosis seen on bone marrow aspirate of the patient with Hodgkin disease is shown in [Figure 1]. The diagnosis of HLH was made on postmortem bone marrow aspirate of a patient with T-cell acute lymphoblastic leukemia (ALL). Two patients died on therapy within 2 weeks of starting on steroid. Case 5 had refractory thrombocytopenia and neutropenia on steroid and was started on HLH 2004 protocol. Two patients had skin manifestation in the form of a generalized maculopapular rash. All the patients had ferritin level >3000 ng/ml. Splenomegaly was present in all patients. HLH workup was incomplete for Case 2. NK-cell activity and sCD25 levels could not be done in all patients. The central nervous system (CNS) involvement was suspected in two patients clinically after ruling out CNS infections. Two patients died of disease. The cause of death in Case 1 was massive pulmonary hemorrhage and in Case 2 was a hepatic failure with multiple internal bleeds. Documented microbiological infection (Candida albicans, Aspergillus spp. and  Escherichia More Details coli) was present in three patients.
Table 1: Host and disease characteristic of patients diagnosed with malignancy-associated hemophagocytic lymphohistiocytosis

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Table 2: Clinical features and laboratory parameters of patients diagnosed as malignancy-associated hemophagocytic lymphohistiocytosis

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Figure 1: Bone marrow aspirate showing hemophagocytosis in a patient with underlying Hodgkin disease

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 > Discussion Top

All patient except one developed HLH during treatment. HLH is primarily a T-cell defect and has been reported with T-cell leukemia/lymphoma. The largest multicenter study on MA-HLH was published from Turkey by Celkan et al.[5] It reports HLH associated with ALL, acute myeloid leukemia (AML), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and Langerhans cell histiocytosis. In another study reporting series of six patient, two had ALL, two AML, one recurrent medulloblastoma, and one Ewing sarcoma.[6] There is a case report of HLH with B-cell ALL and Anaplastic large cell lymphoma.[7],[8] In our study out of five MA-HLH, two patient had ALL, two AML, and one had HL. In HLH, the cytotoxic T-cell and NK-cells fail to cause apoptosis of target cells and antigen presenting cell. There is an ineffective hyperimmune response. All the clinical features are due to hyperinflammation and present as a unique syndrome of clinical features.

The diagnosis of HLH was based on HLH 2004 guidelines [9] In HLH-2004, three additional criteria (low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels) are introduced to HLH 94 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). To make a diagnosis of HLH, five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. Primary HLH is an autosomal recessive condition with mutations in the perforin, the UNC13D, and the syntaxin 11 genes identified in approximately 50% of the patients.[10],[11] Genetic predispositions are recognized even with secondary HLH. Perforin has a role in preventing tumor growth and in immune surveillance. The genetic study was not done in any of our patients. HLH has many genotypes but one phenotype. Patients with secondary HLH have a tendency to develop a malignancy. Heterozygosity and polymorphisms of perforin gene are increasingly being recognized in secondary HLH.

All of our patients were investigated for HLH after they had prolonged fever and cytopenias not responding to chemotherapy withdrawal and appropriate empirical antibiotic cover. The three patients who had documented microbiological infection also did not improve after appropriate treatment. All the patients had splenomegaly compared to 13% of patients reported in the study from Turkey.[5] Ferritin levels were much higher than cutoff 500 ng/ml in all patients.

There is a delay in diagnosis of HLH in oncology patients due to clinical features attributed to either the disease or the chemotherapy. Sepsis and shock can cause similar clinical features. Decreased NK-cell activity and elevated sCD25 levels may help in differentiating HLH from sepsis. Fever, cytopenias, and hepatic dysfunction may all be explained by either the disease or the chemotherapy. In ALL, hypofibrinogenemia may be explained by L-asparaginase use.[12] The delay in diagnosis of this life-threatening disorder may be fatal. Malignancy is a common trigger for secondary HLH. The chemotherapy used can also predispose to infection (which is a most common trigger for S-HLH) and T-cell and NK-cell dysfunction which may trigger HLH. Basic pathogenesis in MA-HLH is predisposing immunodeficiency leading to significant immune activation by an infectious agent trigger leading to uncontrolled inflammation and disease manifestation. There should be a thorough search for an infection in any case of MA-HLH.[13] There was a delay in diagnosis in all the five patient with one patient diagnosed on postmortem bone marrow biopsy.

Two of our patients with ALL developed HLH in the second phase of Berlin-Frankfurt-Münster (BFM) ALL induction. The same observation was noted by Celkan et al. Steroid is not the part of the protocol in BFM induction Phase 2, and it is possible that steroid withdrawal heralds the onset of the hyperinflammatory condition.[5]

Once the diagnosis is made, the hyperinflammatory condition needs to be controlled with steroid or complete HLH 2004 protocol. Expert opinion is to withhold the chemotherapy till manifestations of HLH are brought under control. The same was done in our patients. Disease-specific immune chemotherapy can then be given, if steroids are not able to control immune dysregulation seen in HLH, patient may then need initiation of full HLH induction protocol. Intravenous immunoglobulin (IVIG) either as a part of HLH 2004 or with steroids only have been used in MA HLH. One of our patients received IVIG but succumbed early in the disease course.

The pro-inflammatory cascade characteristic of HLH may be due to cytokine production (interleukin-6, tumor necrosis factor alpha) by malignant cells and may mask the diagnosis of malignancy at presentation. One of our patients had HLH associated with AML-M7 at presentation and made the diagnosis challenging.

Out of all secondary triggers, MA-HLH seems to have the worst outcome. Approximately, 50% of secondary HLH patient die of irreversible multiorgan damage.[14] Two of our patient died during treatment. Only one patient recovered completely and one had to be started on HLH 2004 protocol. Progressively increasing transaminases, bilirubin, sCD25, ferritin, coagulopathy, and worsening respiratory status is recognized as poor prognostic signs of disease. Timely diagnosis is critical to improve outcome.

Hemophagocytosis observed on bone marrow is considered nonspecific and other biological markers like very high ferritin and sCD25 are of more value. About 1–10 hemophagocytes per 500 cells seen in bone marrow are considered positive.[1]

The risk of recurrence of HLH is poorly defined in MA-HLH. As triggers are extensive, the possible search for same is required. All primary HLH patients require allogeneic stem cell transplantation as the problem is genetic. Hemopoietic stem cell transplant is generally recommended in patients with recurrent/refractory disease, persistent NK-cell dysfunction, or CNS involvement. In MA-HLH, once symptoms are controlled, the disease-specific therapy for underlying malignancy should obviate the trigger and prevent recurrence.

The delay in diagnosis of MA-HLH in pediatric patients may be due to decrease awareness about the condition. The diagnostic criteria need to be studied on larger population of MA-HLH to define sensitivity and specificity of each criterion and identify features which have more positive predictive value for diagnosing MA-HLH. Genetic study in these patients will also identify genetic mutations which predispose to HLH in this subset of population. Bone marrow transplant may be ideal in some scenarios for treating both the underlying malignancy and HLH. The unavailability of matched donor is a hindrance to such approach. Infection needs to be ruled out in every case of MA-HLH. As we gather more information on this disease entity, clear guidelines for the treatment will emerge. The present approach of withholding disease-specific therapy poses a greater risk of recurrence of underlying malignancy. A better understanding of pathogenesis and characteristic immunopathology findings of HLH are required.

 > Conclusion Top

The diagnosis of MA-HLH is often delayed due to decreased awareness of this condition. The HLH 2004 criteria identify most of the cases but because of the overlap of symptoms due to underlying malignancy, diagnosis needs inclusion of more criteria.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.  Back to cited text no. 1
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957-9.  Back to cited text no. 2
Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991;80:428-35.  Back to cited text no. 3
Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227-35.  Back to cited text no. 4
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. 5
Lackner H, Urban C, Sovinz P, Benesch M, Moser A, Schwinger W. Hemophagocytic lymphohistiocytosis as severe adverse event of antineoplastic treatment in children. Haematologica 2008;93:291-4.  Back to cited text no. 6
Kelly C, Salvi S, McClain K, Hayani A. Hemophagocytic lymphohistiocytosis associated with precursor B acute lymphoblastic leukemia. Pediatr Blood Cancer 2011;56:658-60.  Back to cited text no. 7
Machaczka M, Nahi H, Karbach H, Klimkowska M, Hägglund H. Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation. Med Oncol 2012;29:1231-6.  Back to cited text no. 8
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. 9
Göransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, Söderhäll C, Samuelsson A, Janka G, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet 2001;68:590-7.  Back to cited text no. 10
zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 2009;85:482-92.  Back to cited text no. 11
Attarbaschi A, Mann G, Kronberger M, Witt V, Gadner H, Dworzak M. Effects of dose-reduced Medac L-asparaginase on coagulation in trial ALL-BFM 2000. Klin Padiatr 2003;215:321-6.  Back to cited text no. 12
O'Brien MM, Lee-Kim Y, George TI, McClain KL, Twist CJ, Jeng M. Precursor B-cell acute lymphoblastic leukemia presenting with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:381-3.  Back to cited text no. 13
Gurgey A, Secmeer G, Tavil B, Ceyhan M, Kuskonmaz B, Cengiz B, et al. Secondary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Infect Dis J 2005;24:1116-7.  Back to cited text no. 14


  [Figure 1]

  [Table 1], [Table 2]


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