Splenectomy as a diagnostic method in lymphoma-associated hemophagocytic lymphohistiocytosis of unknown origin

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Citation: Blood Cancer Journal (2017) 7, e534; doi:http://dx.doi.org/10.1038/bcj.2016.125

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LETTER TO THE EDITOR

Splenectomy as a diagnostic method in lymphoma-associated hemophagocytic lymphohistiocytosis of unknown origin

Blood Cancer Journal (2017) 7, e534; doi:http://dx.doi.org/10.1038/bcj.2016.125

Web End =10.1038/bcj.2016.125 ; published online 24 February 2017

Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a rare and life-threatening disease caused by a highly active but ineffective immune response.1 Uncontrolled immune activation results in the typical clinical characteristics and laboratory ndings of HLH, including high fever, pancytopenia, hepatosplenomegaly, liver dysfunction, coagulopathy, hyperferritinaemia and hemophagocytosis in the bone marrow or other organs. HLH may be divided into primary (familial) and secondary subtypes. Secondary HLH may develop following strong immunological stimuli such as a severe infection and malignancies especially lymphoma.2,3 Indeed, in a review on 162 adult patients with HLH, 56.8% were cases of lymphoma-associated hemophagocytic syndrome (LAHS).4 The prognosis of both HLH and LAHS is poor.5 Without hematopoietic stem cell transplantation, the survival rate of patients with HLH is 0%.6 Furthermore, in a study on 69 patients with HLH (16 of whom had LAHS), the median survival time of patients with LAHS was only 37 days.7 Early diagnosis of the underlying condition, and especially of lymphoma, leads to better outcomes. However, the diagnosis of LAHS is often difcult because of the frequent lack of lymphadenopathy or solid tissue masses amenable to biopsy. Many patients with LAHS only have splenomegaly or high standardized uptake values (SUVs) of the spleen on FDG-PET/CT to suggest the diagnosis, and in such situations, splenectomy may be the only choice to secure a histological diagnosis. However,

cytopenias and coagulopathy can make splenectomy a challenging and potentially hazardous undertaking. Here we report a retrospective analysis of 100 secondary HLH patients treated in two medical centers between 2012 and 2016. This study aimed to analyze the efciency and safety of splenectomy in patients with secondary HLH.

We retrospectively reviewed the patients who were given the clinical code D76.1 (hemophagocytic lymphohistiocytosis) between January 2012 and April 2016 in two medical centers.The ethics committee from Huadong Hospital and Huashan Hospital approved this study. All patients provided informed consent. Pre-treatment evaluation consisted of a standard history and physical examination. Various pre-treatment tests were also performed, including routine blood tests (peripheral blood examination, biochemical tests and coagulation check), blood immunology, virology, bacteriology, bone marrow morphology, ow cytometry, bone marrow or lymph node tissue immunohistochemical staining, karyotype analysis, and CT or PET/CT scan.The diagnostic criteria of HLH was according to guidelines.8,9 Sixty patients had neither palpable lymphadenopathy nor evidence of lymphoma in the bone marrow, but they all had a high FDG value of the whole spleen or some focus in the spleen. Among these patients, 25 underwent diagnostic splenectomy with blood product support in the form of plasma, platelet, and cryoprecipitate infusions, a further 35 patients rejected a splenectomy.Patients who did not undergo splenectomy were treated with etoposide and dexamethasone according to the international guidelines for the treatment of HLH 2004.9 Another 40 patients were diagnosed on the basis of lymph node biopsy or bone marrow biopsy and received standard chemotherapy.

Table 1. Clinical features of patients with HLH in the splenectomy and non-splenectomy groups

All patients (n = 100) Patients of unknown origin (n = 60)

Splenectomy Non-splenectomy P-value Splenectomy Non-splenectomy P-value

Sex, n (F/M) 17/8 40/35 0.20 17/8 14/21 0.051 Age, years (range) 45.8 (1966) 46.4 (267) 0.051 45.8 (1966) 49.0 (3467) 0.05 Temperature, C (range) 39.7 (38.040.4) 39.0 (38.340) 0.67 39.7 (38.040.4) 39.1 (38.540) 0.60 WBC, 109 cells/l (range) 2.75 (0.69.1) 3.66 (0.510.16) 0.071 2.75 (0.69.1) 4.68 (0.76.4) 0.031 PLT, 109 cells/l (range) 61.2 (4305) 51.4 (5197) 0.143 61.2 (4305) 44.1 (30.859) 0.057 TB, mol/l (range) 52.7 (7.4230.7) 49.0 (18.9332.7) 0.472 52.7 (7.4230.7) 43.7 (27332) 0.729

DB, mol/l (range) 37.3 (3.4218) 39.2 (11.8272.3) 0.286 37.3 (3.4218) 36.8 (13.4272) 0.414 TG, mmol/l (range) 3.23 (2.06.7) 3.21 (3.26.6) 0.284 3.23 (2.06.7) 3.0 (2.85.1) 0.425

Fbg, g/l (range) 1.78 (0.583) 1.32 (0.411.8) 0.773 1.78 (0.583) 1.2 (0.61.8) 0.228 Ferritin, ng/l (range) 3571 (24984956) 4448 (31516669) 0.556 3571 (24984956) 3676 (31515788) 0.640 LDH, U/l (range) 931 (681205) 2799 (10376044) 0.256 931 (6861205) 1239 (10373499) 0.118 Underlying diagnosis, n: 0.10EBV infection 2 9 2 UnkownAutoimmune disease 0 2 0 UnkownB-cell lymphoma 6 10 6 UnkownNKT cell lymphoma 7 7 7 UnkownT-cell lymphoma 10 12 10 UnkownUnknown origin 0 35 35PS (range) 1 (02) 1 (12) 0.57 1 (02) 1 (12) 0.30

Abbreviations: DB, direct bilirubin; EBV, EpsteinBarr virus; Fbg, brinogen; LDH, lactate dehydrogenase; PLT, platelet; PS, physical stage TB, total bilirubin; TG, triglycerides; WBC, white blood count.

Letter to the Editor

2

For splenectomized patients, all tests repeated on days 1, 3 and 7 postoperatively. All patients must have received virology tests, such as an EBV-DNA quantitative test. Patients with a diagnosis of lymphoma received chemotherapy appropriate to their underlying pathology 1 week after the surgery. In contrast, HLH patients with EpsteinBarr virus (EBV) infection are typically treated with immunoglobulin post-operatively. The comparisons of the clinical features of the splenectomy and non-splenectomy groups, and the changes before and after splenectomy were performed using the t-test and 2 test. Survival was assessed using the Kaplan Meier curve method, and survival between the groups was compared using the log-rank test. The analysis of prognostic factors was performed using a linear regression model. A Po0.05 was considered statistically signicant difference, SPSS software was explored to analyze the data.

The clinical features of patients in the splenectomy group and non-splenectomy group are comparable in Table 1. No signicant

differences of clinical features were evident (P40.05). Among the HLH patients of indenite underlying diseases, the white blood cell count was signicantly higher in the non-splenectomy group compared with the splenectomy group (P = 0.031), but no signicant difference was observed between the two groups in any of the other factors (Table 1, P40.05). Three days after splenectomy, many factors related to HLH got improvement, patients body temperature was signicantly lower (P = 0.001). ALT and AST measurements were also signicantly diminished (P = 0.006 and P = 0.01, respectively). The total white blood cell count was signicantly higher following surgery (P = 0.044), The TG level was lower (P = 0.002). Although splenectomy has frequently been rejected in the treatment of HLH due to the perceived operative risk, we analyzed patients death, which may be caused by operation in splenectomy group and nonsplenectomy group, the survival data was not signicantly different (P = 0.510). This indicates that splenectomy itself does not shorten the survival time of patients with HLH.

Figure 1. KaplanMeier overall survival (OS) and progression-free survival (PFS) curves of patients with HLH (a) KaplanMeier OS and PFS curves of patients of unknown origin with splenectomy (n = 25) and without splenectomy (n = 35) (P = 0.001, left, overall survival vs P = 0.000, right, progression-free survival). (b) KaplanMeier OS and PFS curves of all patients with HLH patients with splenectomy (n = 25) and without splenectomy (n = 75) (P = 0.203, left, overall survival vs P = 0.143, right, progression-free survival).

Blood Cancer Journal

Letter to the Editor

3

We analyzed the survival data of patients with HLH of unknown origin with splenectomy. The follow-up data were obtained from 60 patients, 25 of them underwent splenectomy to obtain a pathological diagnosis. In the splenectomy group, median overall survival time was 130 (74.0304.3) days, median progression free survival was 67 (11.67203.9) days. In the non-splenectomy group, the median survival time was 89 (64.994.3) days, the median progression-free survival was 13.3 (5.025.2) days, patients with HLH of unknown origin in the splenectomy group had signicantly improved overall survival compared with those in the nonsplenectomy group and improved progression free survival (Figure 1a, P = 0.001 vs 0.000). After splenectomy, a clear diagnosis could be determined: three patients were diagnosed with infection-associated HLH (two with underlying EBV infection, both of whom are still alive), six had underlying B-cell lymphoma (three of whom remain alive), seven had NKT cell lymphoma (two are still alive), and 10 had T-cell lymphoma (none survived, but one had a survival time exceeding three years). The 35 patients with HLH of unknown origin who did not undergo splenectomy all died. We performed a univariate analysis to evaluate the prognostic factors for HLH in the splenectomy group. The prognostic inuence of several factors (including age, sex, white blood cell count, hemoglobin levels, platelet count, liver function, bilirubin levels, LDH, TG, Fbg, serum ferritin and underlying diagnoses) were analyzed. Only a lower platelet count (r = 0.804, P = 0.000) and a lower serum ferritin level (r = 0.408, P = 0.002) were predictive of poorer survival in the splenectomy group. But when we analyzed the effect of splenectomy in all HLH patients in our study, including the patients who make clear the diagnosis by lymphocyte or bone marrow biopsy, patients in the splenectomy group did not show improved overall survival and progression-free survival compared with those without splenectomy (Figure 1b, P = 0.203 vs 0.143).

HLH is a serious condition with a high rate of mortality. Contemporary HLH treatment includes chemotherapy with etopo-side (100150 mg/m2 i.v.), and immunosuppressive drugs that specically target the hyperactivated macrophages (including corticosteroids and intravenous immunoglobulin) and T lymphocytes (including corticosteroids and ciclosporin A).9,10 However, immunochemotherapy is only temporarily effective in the control of HLH, determining the underlying cause of secondary HLH is necessary, but it is often difcult to secure the correct diagnosis as some patients do not have lymphomegaly, solid masses, or bone marrow involvement. Splenectomy was considered unsafe due to the poor clinical condition of HLH patients.11,12 In this study, we examined 100 patients with HLH, if a denitive diagnosis could be made from lymphocyte and bone marrow diagnosis, then splenectomy was not necessary. We found that with appropriate transfusion support (plasma and platelet infusions), splenectomy was relatively safe in the HLH patients. As both clinical and laboratory parameters showed improvement post-operatively, which may be related to a reduced cytokine storm. Moreover, splenectomy created more chances for patients with HLH of unknown origin to nd out the pathology. Splenectomy improved the survival of HLH patients with indenite underlying diseases, but it did not prolong the survival of all patients with HLH, especially those with denite diagnosis. The optimal time for splenectomy under such circumstances was in the initial stages of HLH, which is in concordance with the prognostic factors in our study. In conclusion, our data support the hypothesis that splenectomy is a valid and safe diagnostic approach for secondary HLH of unknown origin, especially for those only having foci in the spleen. But splenectomy itself does not prolong survival in all patients with HLH, particularly ones with a denitive diagnosis. This report provides a rationale for the further mechanistic investigation of the role of splenectomy in this condition.

CONFLICT OF INTEREST

The authors declare no conict of interest.

ACKNOWLEDGEMENTS

This work was supported by the Science and Technology Commission of Shanghai Municipality [grant number 15YF1403700]. This work was also supported by Shanghai Key Laboratory of Clinical Geriatric Medicine, (No.13DZ2260700), and Shanghai Key Developing Disciplines Program (No. 2015ZB0501).

J Ma1,5, Z Jiang2,5, T Ding3,5, H Xu1, J Song1, J Zhang4, Y Xie1 and W Wang2

1Department of Hematology, Huadong Hospital, Fudan University, Shanghai, China;

2Department of General Surgery, Huadong Hospital, Fudan University, Shanghai, China;

3Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China and

4Department of Infection, Huashan Hospital, Fudan University, Shanghai, China E-mail: mailto:[email protected]

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5These authors contributed equally to this work.

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Blood Cancer Journal