Background: Hodgkin lymphoma usually presents with sequential enlargement of peripheral lymph nodes, and bone marrow invasion rarely occurs (approximately 3–5%). However, several cases have been reported as “primary” bone marrow Hodgkin lymphoma, especially among patients with human immunodeficiency virus and the elderly. This type of Hodgkin lymphoma is characterized by no peripheral lymphadenopathies and has been reported to have poorer prognosis. Case presentation: A 38-year-old Japanese man was admitted to our hospital because of fever of unknown origin and pancytopenia without lymphadenopathies. Bone marrow examination revealed Hodgkin cells mimicking abnormal cells. These were positive for CD30, EBER-1, CD15, PAX-5, and Bob-1 and negative for Oct-2, CD3, CD20, surface immunoglobulin, CD56. On the basis of systemic evaluation and bone marrow examination, he was diagnosed with primary bone marrow Hodgkin lymphoma. We initiated therapy with DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) therapy, but remission was not achieved. Then, the patient was treated with brentuximab vedotin combined with systemic chemotherapy (Adriamycin, vinblastine and dacarbazine), which was effective. Conclusions: There is no established treatment strategy for Hodgkin lymphoma, and therapeutic outcomes using ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine)-like or CHOP (cyclophosphamide, Adriamycin, vincristine, and prednisone)-like regimens are reportedly poor. Only a few patients have been reported to achieve long-term remission. Through this case report, we suggest an alternative therapeutic option for primary bone marrow Hodgkin lymphoma. Keywords: Epstein-Barr virus, Primary bone marrow Hodgkin lymphoma Background 3–5%)and typicallyonlyinthose with advanced dis- Hodgkin lymphoma (HL), one of the most common ease . However, Shah et al.  reported a rare case lymphoproliferative diseases, characteristically presents of a patient with “primary bone marrow” Hodgkin lymph- with progressive and sequential enlargement of per- oma (PBMHL) with human immunodeficiency virus ipheral lymph nodes . Bone marrow (BM) invasion (HIV). PBMHL has also been reported in both HIV- rarely occurs in patients with HL (approximately positive and HIV-negative patients. Epstein-Barr virus (EBV) is believed to play a causa- * Correspondence: email@example.com tive role in HIV-associated HL . Use of in situ Department of Hematology and Oncology, Suzuka General Hospital, Mie, hybridization or immunohistochemical staining has Japan 2 revealed that approximately 40% of patients with non- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan HIV-associated HL and 75–78% of patients with Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nagaharu et al. Journal of Medical Case Reports (2018) 12:151 Page 2 of 6 HIV-associated HL are EBV-positive [4, 6]. The precise Case presentation mechanism by which EBV contributes to development A 38-year-old Japanese man was admitted to our hospital of HL remains unclear. EBV infection has no influence because of progressive fever and thrombocytopenia for on the prognosis of children with HL . However, more than 1 month. His medical history included Burkitt some researchers have reported a higher relapse rate lymphoma (negative for EBV-encoded small ribonucleic after primary treatment in middle-aged patients with acid (RNA)), and he had been treated with hyper-CVAD EBV-associated HL than in those with non-EBV- (cyclophosphamide, vincristine, doxorubicin, and dexa- associated HL . In patients with refractory HL, dose- methasone) 12 years before admission. He had achieved dense systemic chemotherapy, brentuximab vedotin complete remission. He was a daily smoker (18 pack- (BV), and autologous hematopoietic stem cell trans- years) and took no daily medications. He had a family his- plant are considered salvage treatments. BV, which is a tory of hypertension and denied having any malignancies. CD30-directed antibody conjugated with monomethyl The patient’s physical examination findings were nor- auristatin E, is an approved treatment for patients with mal except for small papules on his upper back. Labora- relapsed or refractory HL , and it has safely been tory tests showed pancytopenia, high C-reactive protein, combined with systemic chemotherapy . In this re- and a negative result for HIV (Table 1). Computed tom- port,wepresent acaseofapatientwithEBV- ography (CT) revealed moderate pulmonary emphysema associated PBMHL who was successfully treated with with no evidence of infection or inflammation. Positron BV-containing combination chemotherapy. emission tomography/CT was unavailable for financial Table 1 Laboratory findings on admission Complete blood count Coagulation Biochemistry WBC 3300/μl APTT 32.2 s TP 6.2 g/dl IgG 1145 mg/dl Neu 77.00% PT 60% Alb 3.8 g/dl IgA 194 mg/dl Lym 12.00% FDP 8.4 μg/μl AST 18 IU/L IgM 28 mg/dl Mo 5.00% Fibrinogen 442 mg/dl ALT 17 IU/L sIL-2 receptor 7020 U/ml Eos 0.00% LDH 273 IU/L β -MG 1.4 μg/dl Bas 0.00% γ-GTP 28 IU/L IL-6 20.6 pg/ml Aty lym 5.00% T-Bil 1.3 mg/dl IFN-γ 6.3 IU/ml RBC 331 × 10 /μl BUN 13.7 mg/dl TNF-α Negative Hb 10.6 g/dl Cre 0.68 mg/dl Procalcitonin 0.06 ng/ml Hct 31.00% Na 135 mEq/L HIV antibody Negative MCV 93.7 fl K 4.4 mEq/L Parvovirus IgM Negative 4 − Plt 10.6 × 10 /μlCl 102 mEq/L Parvovirus IgG Positive CD4 T cells 220/μl CRP 5.87 mg/dl HHV-6 IgM Negative Fe 46 mg/dl HHV-6 IgG Positive Ferritin 771 ng/ml C7-HRP Negative EB EA IgG Negative (EIA index = 0.4) EB VCA IgM Negative (EIA index = 0.5) EB VCA IgG Positive (EIA index = 12.1) EBNA IgG Positive (EIA index = 2.5) EBV DNA 4200 copies/ml Abbreviations: WBC White blood cells, APTT Activated partial thromboplastin time, TP Total protein, IgG Immunoglobulin G, Neu Neutrophils, PT Prothrombin time, Alb Albumin, IgA Immunoglobulin A, Lym Lymphocytes, FDP Fibrinogen degradation product, AST Aspartate aminotransferase, IgM Immunoglobulin M, Mo Monocytes, ALT Alanine aminotransferase, sIL-2 Soluble interleukin 2, Eos Eosinophils, LDH Lactate dehydrogenase, β -MG β -microglobulin, Bas Basophils, γ-GTP γ- 2 2 Glutamyltransferase, IL-6 Interleukin 6, Aty lym Atypical lymphocytes, T-Bil Total bilirubin, IFN-γ Interferon-γ, RBC Red blood cells, BUN Blood urea nitrogen, TNF-α Tumor necrosis factor-α, Hb Hemoglobin, Cre Creatinine, Hct Hematocrit, HIV Human immunodeficiency virus, MCV Mean corpuscular volume, Plt Platelets, CRP C- reactive protein, HHV-6 Human herpesvirus 6, C7-HRP Cytomegalovirus antigenemia, EB EA IgG Epstein-Barr virus early antigen immunoglobulin G, EB VCA Epstein- Barr virus viral capsid antigen immunoglobulin M, EIA Enzyme immunoassay, EBNA Epstein-Barr nuclear antigen Nagaharu et al. Journal of Medical Case Reports (2018) 12:151 Page 3 of 6 reasons. A skin biopsy of his rash revealed no malignant later. A second BM sample showed infiltration with Reed- change. BM examination revealed hemophagocytosis Sternberg (RS)-like cells (Fig. 1a, b) that were positive for without abnormal cells. Plasma viral deoxynucleic acid CD30 (Fig. 1c), EBER-1 (Epstein-Barr encoding region 1) (DNA) was investigated to identify possible causes of (Fig. 1d), CD15 (Fig. 1e), Bob-1 (Fig. 1d), and PAX-5 (Fig. hemophagocytosis, and the patient was found to be EBV 1e) but negative for Oct-2, CD3, CD20, surface immuno- DNA-positive (170,000 copies/ml). globulin, and CD56. Another CT examination showed As recommended by a previous report, the patient’sEBV- neither lymphadenopathy nor hepatosplenomegaly. The associated hemophagocytic lymphohistiocytosis (HLH) was patient was eventually diagnosed with PBMHL (Ann Arbor treated with chemotherapy comprising etoposide and dexa- stage IVB, International Prognostic Index high-intermediate methasone . Shortly after initiation of chemotherapy, risk). Previous reports have indicated that PBMHL pro- his white blood cell count recovered to within the normal gresses rapidly and that combination chemotherapy (Adria- range, and his plasma EBV DNA became undetectable. mycin, bleomycin, vinblastine and dacarbazine [ABVD]-like However, his EBV DNA turned positive (290 copies/ml), or cyclophosphamide, Adriamycin, vincristine and prednis- and his white blood cell count declined again 7–9 weeks one [CHOP]-like regimens) is ineffective, as shown in Fig. 1 Histopathological findings in bone marrow on presentation. Representative photomicrographs of hematoxylin and eosin (HE) and immunohistochemically stained sections of bone marrow. Rectangular area in (a) (HE, × 40) is shown at higher magnification in (b) (HE, original magnification × 400). Reed-Sternberg cell-like cells are present (arrowhead). These cells are positive for CD30 (c, original magnification × 400), Ep- stein-Barr encoding region in situ hybridization (EBER-ISH) (d, original magnification × 400), CD15 (e, original magnification × 400), Bob-1 (f, original magnification × 400), and PAX-5 (g, original magnification × 400). The small rectangulars in d–g show expression of CD30 in the same field. Arrowheads in f and g identify the CD30 positive malignant cells Nagaharu et al. Journal of Medical Case Reports (2018) 12:151 Page 4 of 6 Table 2. Because some patients with EBV-associated Because a third BM examination revealed residual RS lymphoproliferative disease express P-glycoprotein, cells, the patient’s disease was considered refractory to which is a multidrug resistance 1 (MDR1) gene product DeVIC therapy. After giving informed consent, he was , the poor prognosis of PBMHL may be related to further treated with BV (1.2 mg/kg) and AVD (Adria- the presence of the MDR1 gene. DeVIC (dexametha- mycin, vinblastine, and dacarbazine) as described in a sone, etoposide, ifosfamide, and carboplatin) includes previous report . His peripheral blood cell count re- ifosfamide and carboplatin, which are MDR-unrelated covered without support of medication, and the RS anticancer agents. cells disappeared. After four courses of combined In addition, because of coexisting pulmonary emphy- chemotherapy, BV monotherapy was continued for sema, DeVIC therapy was initiated at 12 weeks from 8 months, during which both soluble interleukin (IL)-2 onset. Although DeVIC therapy induced transient re- receptor and plasma EBV DNA titers remained within covery of pancytopenia, it recurred with high plasma the normal range. The patient declined autologous EBV DNA titers (2300 copies/ml) after the second hematopoietic stem cell transplant. To date, no evi- course of DeVIC therapy (19–20 weeks from onset). dence of relapse has been detected. Table 2 Compilation of published reports of patients with primary bone marrow Hodgkin lymphoma Patient background Age (years) Sex CD4 count CD15 CD30 EB virus Therapies Survival (months) Reference Non-HIV 20 F No data ND ND ND MOPP 9  Non-HIV 72 F No data + + EBER1 THP-COP 1  Non-HIV 64 M No data + + ND ABVD 1  b + Non-HIV 50 M No data + + LMP1 ABVD 1  a + Non-HIV 66 F No data + + EBER1 A(B)VD 15  a + Non-HIV 68 M No data ND + EBER1 ND 1  Non-HIV 89 F No data – + Negative ND ND  AIDS 58 M 20 + + ND ABVD 2  AIDS 36 M 31 + + ND ABVD 4 AIDS 31 M 549 + + ND ABVD 18 AIDS 49 M 54 + + ND ABVD 114 AIDS 33 M 104 + + ND EBV 4 AIDS 34 M 86 + + ND ABVD 3 AIDS 29 M 193 ND ND ND MOPP 31  AIDS 55 M 14 ND ND ND ND ND  AIDS 43 M 179 + + ND ABVD ND  AIDS 26 M No data + + ND ND ND  AIDS 29 F No data + – ND ND ND AIDS 27 M 195 + + ND ND ND AIDS 34 M 17 + + Negative ND ND AIDS 26 M 39 + + ND ND ND AIDS 31 M 123 + + ND ND ND AIDS 49 M 52 + + ND ND ND AIDS 40 M 56 + + ND ND ND AIDS 35 M 104 + + LMP1 ND ND AIDS 41 M 237 + + ND ND ND AIDS 51 M 282 + + LMP1 ND ND AIDS 42 M 198 + + ND ND ND Abbreviations: AIDS Acquired immunodeficiency syndrome, HIV Human immunodeficiency virus, MOPP Mechlorethamine, vincristine, procarbazine, and prednisone, THP-COP Pirarubicin, cyclophosphamide, vincristine, and prednisolone, ABVD Adriamycin, bleomycin, vinblastine and dacarbazine, ND No data, EBER1 Epstein-Barr virus-encoded RNA 1, LMP1 Latent membrane protein 1, EB Epstein-Barr virus Leukocytopenia (under 3500/μl) but no CD4 count available Lymphocytopenia (under 1000/μl) but no CD4 count available Nagaharu et al. Journal of Medical Case Reports (2018) 12:151 Page 5 of 6 Discussion occurred earlier than the increase in soluble IL-2 recep- The overall incidence of BM involvement in HL is re- tor titer. Plasma EBV DNA titers may be helpful for portedly 5% . However, approximately 40–50% of pa- early detection of recurrence of PBMHL. tients with HIV-associated HL have BM invasion, and these patients commonly present with an advanced stage Conclusions of disease (mainly stage IV). PBMHL is characterized by We present a rare case of a patient with PBMHL with- solitary BM invasion with HL. PBMHL has been re- out HIV infection. More experience is needed to estab- ported in patients with and without HIV infection lish the optimum treatment for this disease. On the (Table 2). Our review of published reports revealed that basis of our patient’s progress, we propose that com- patients with acquired immunodeficiency syndrome or bined therapy with BV and AVD could be a therapeutic older patients are more likely to develop PBMHL. Al- option for PBMHL. though our patient was HIV-negative, his number of Abbreviations CD4 T cells was low (200/μl). As shown in Table 2, low ABVD: Adriamycin, bleomycin, vinblastine and dacarbazine; AIDS: Acquired CD4 T-cell counts (or lymphocytopenia) are common immunodeficiency syndrome; Alb: Albumin; ALT: Alanine aminotransferase; APTT: Activated partial thromboplastin time; AST: Aspartate aminotransferase; in patients with PBMHL, especially in those with HIV- Aty lym: Atypical lymphocytes; AVD: Adriamycin, vinblastine, and associated PBMHL, in whom CD4 T-cell counts are re- dacarbazine; Bas: Basophils; BM: Bone marrow; BUN: Blood urea nitrogen; portedly 133 ± 130/μl (range 14–549/μl, median 103/μl). BV: Brentuximab vedotin; C7-HRP: Cytomegalovirus antigenemia; CHOP: Cyclophosphamide, Adriamycin, vincristine, and prednisone; Our patient developed HLH as the first symptom of Cre: Creatinine; CRP: C-reactive protein; CT: Computed tomography; HL. Although HL-associated HLH is rare, a previous DeVIC: Dexamethasone, etoposide, ifosfamide, and carboplatin; retrospective study showed that EBV was frequently de- EB: Epstein-Barr virus; EB EA IgG: Epstein-Barr virus early antigen immunoglobulin G; EB VCA: Epstein-Barr virus viral capsid antigen tected in patients with HL-associated HLH . Patients immunoglobulin M; EBER: Epstein-Barr-encoding region; EBER1: Epstein-Barr with HIV-associated HL, in whom HLH is more com- virus-encoded RNA 1; EBNA: Epstein-Barr nuclear antigen; EBV: Epstein-Barr mon, also exhibit a high prevalence of EBV. These find- virus; EIA: Enzyme immunoassay; Eos: Eosinophils; FDP: Fibrinogen degradation product; γ-GTP: γ-Glutamyltransferase; Hb: Hemoglobin; ings suggest that patients with HL-associated HLH Hct: Hematocrit; HHV-6: Human herpesvirus 6; HIV: Human might have an unclear underlying immune disturbance immunodeficiency virus; HL: Hodgkin lymphoma; HLH: Hemophagocytic for EBV. Our patient’s case indicates that clinicians lymphohistiocytosis; IFN-γ: Interferon-γ; IgA: Immunoglobulin A; IgG: Immunoglobulin G; IgM: Immunoglobulin M; IL-6: Interleukin 6; should perform BM biopsies to check for PBMHL in pa- LDH: Lactate dehydrogenase; LMP1: Latent membrane protein 1; tients with (1) pancytopenia, (2) low CD4 T-cell counts Lym: Lymphocytes; MCV: Mean corpuscular volume; MDR1: Multidrug (or lymphocytopenia), and (3) EBV DNA positivity. resistance 1; β -MG: β -microglobulin; Mo: Monocytes; 2 2 MOPP: Mechlorethamine, vincristine, procarbazine, and prednisone; ND: No As for the prognosis of PBMHL, only a few patients data; Neu: Neutrophils; PBMHL: Primary bone marrow Hodgkin lymphoma; achieve long-term remission (Table 2). When our pa- Plt: Platelets; PT: Prothrombin time; RBC: Red blood cells; RS: Reed-Sternberg; tient’s PBMHL proved refractory, we selected BV with sIL-2: Soluble interleukin 2; T-Bil: Total bilirubin; THP-COP: Pirarubicin, cyclophosphamide, vincristine, and prednisolone; TNF-α: Tumor necrosis AVD as salvage therapy for the following reasons. First, factor-α; TP: Thymidine phosphorylase; WBC: White blood cells because of its rarity, there is no established treatment strategy for this disease, and therapeutic outcomes using Acknowledgements We thank Dr. Trish Reynolds, MBBS, FRACP, of Edanz Group ABVD- or CHOP-like regimens are reportedly poor (as (www.edanzediting.com/ac) for editing a draft of the manuscript. shown in Table 2). Second, bleomycin was contraindi- cated for our patient because of his coexisting moderate Authors’ contributions emphysema. Third, a combination of BV with AVD was KN, YK, TY, RI, and KK were responsible for the clinical management of the patient. MI evaluated the pathological examinations. MM and NK supervised significantly superior to BV with ABVD . Fortu- the writing of the manuscript. All authors read and approved the final nately, our patient completed his planned therapy with- manuscript. out relapse. To the best of our knowledge, this is the Ethics approval and consent to participate first reported case of successful treatment of HIV- This case report was approved by the Suzuka General Hospital Ethics negative PBMHL with BV. Committee on 30 Nov 2017 (approval number 176). The association of EBV and HL has been investigated; Consent for publication however, the exact mechanism involved remains unclear. Written informed consent was obtained from the patient for publication of Approximately 40% of patients with non-HIV-associated this case report and any accompanying images. A copy of the written HL are EBV-positive ; the rate of EBV positivity is consent is available for review by the Editor-in-Chief of this journal. much higher in patients with HIV-associated HL [4, 6]. Competing interests In addition to in situ hybridization and histopathological The authors declare that they have no competing interests. staining, plasma EBV DNA titers are also a useful bio- marker for monitoring prognosis in patients with EBV- Publisher’sNote associated HL . In our patient, an increase in EBV Springer Nature remains neutral with regard to jurisdictional claims in published DNA titer preceded recurrence of pancytopenia and maps and institutional affiliations. Nagaharu et al. Journal of Medical Case Reports (2018) 12:151 Page 6 of 6 Author details associated with hemophagocytosis as the initial symptom: a case report Department of Hematology and Oncology, Suzuka General Hospital, Mie, and review of the previous literature. Intern Med. 2015;54(11):1393–6. Japan. 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Published: May 30, 2018
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