Hodgkin's lymphoma associated with myelofibrosis: A case report

  • Authors:
    • Rong Fu
    • Hong Yu
    • Yu‑Hong Wu
    • Hui Liu
    • Zong‑Hong Shao
  • View Affiliations

  • Published online on: June 30, 2015     https://doi.org/10.3892/ol.2015.3438
  • Pages: 1551-1554
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Abstract

In the present study, the case of a patient with nodular sclerosing Hodgkin's lymphoma (NSHL) presenting with diffuse fibrosis of the bone marrow (BM) was reported. A 30‑year‑old male complained of fever for 1 year, as well as lumbago, lymph node swelling and night sweats for 3 months. A biopsy of the lymph nodes established a diagnosis of NSHL. Aspiration of BM was a dry tap, and the BM biopsy demonstrated marked myelofibrosis with increased proliferation of reticulin fiber. Multiple skeletal lesions were detected in the patient's vertebra, pelvis, sternum and bilateral femur by magnetic resonance imaging and computed tomography. Following numerous courses of chemotherapy and radiotherapy, remission of the lymphoma was achieved. Subsequently, the BM aspiration became possible, and BM biopsy demonstrated a reduction in fibrosis.

Introduction

Hodgkin's lymphoma (HL) accounts for ~30% of all lymphomas, presenting with generalized lymphadenopathy, hematological abnormalities and B symptoms (including fever, weight loss and night sweats) (1). Due to the development of highly active chemotherapy and radiotherapy strategies, patients with HL have an excellent prognosis following frontline therapy, and the 5-year progression-free survival rate can be as high as 75–80% (2). Myelofibrosis is a chronic myeloproliferative neoplasm characterized by clonal proliferation of myeloid hematopoietic cells and intramedullary fibrosis (3). Clinical manifestations of myelofibrosis include cytopenias, profound splenomegaly, bone pain, night sweats, weight loss, and fatigue (4). Secondary MF (SMF) is often observed in a number of hematological malignancies, including acute megakaryoblastic leukemia (5), chronic myeloid leukemia (6) and hairy cell leukemia (7); however, SMF is rare in lymphoid neoplasms. The present study reported a case of reversible MF associated with Hodgkin's lymphoma (HL), which was resolved following remission of lymphoma. Subsequent to a thorough review of the literature using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed), 7 reported cases of SMF accompanied by HL were identified (Table I); however, no HL cases with SMF have been previously reported in China. Previously reported lymphomas associated with MF were of various histological types, including T-cell lymphoma (812), B-cell lymphoma (13) and HL (1417).

Table I.

Hematological and clinical features of patients with HL with myelofibrosis.

Table I.

Hematological and clinical features of patients with HL with myelofibrosis.

Case (Ref.)Age/sexWBC (x109/1)Hb (g/1)Platelet (x109/1)Lymph nodeLiverSpleenBone marrow/invasionHistologic typeTreatmentSurvival time
1 (7)12/F  2.3115  41YesNoNoFibrosis/YesLPHLMOPP3 months
2 (7)50/M11.1141630YesNoYesFibrosis/NoNSHLBOPP10 years
3 (7)31/F  1.8  46100YesYesYesFibrosis/YesMCHLCOPP20 months
4 (7)20/F2.15  77100NoNoNoFibrosis/NoLPHLMOPP9 years
5 (8)37/M  2.5  41  50YesYesYesFibrosis/NoNSHLMOPP/BCVPP11 years
6 (9)31/M  6.0118250YesYesYesFibrosis/YesNSHLBCVPP4 years
7 (10)35/M  0.8  88122YesYesYesFibrosis/YesLDHLMOPP/ABVD/HDAC2 years

[i] HL, Hodgkin's lymphoma; WBC, white blood cell count; Hb, hemoglobin; F, female; M, male; LPHL, lymphocyte-predominant HL; NSHL, nodular sclerosis HL; MCHL, mixed cellularity HL; LDHL, lymphocyte-depleted HL; MOPP, mechloramine, vincristine, procarbazine and prednisone; BOPP, carmustine, oncovin, procarbazine and prednisone; COPP, cyclophosphamide, oncovin, procarbazine and prednisone; BCVPP, carmustine, cyclophosphamide, vinblastine, procarbazine, prednisone; ABVD, adriamycin, bleomycin, vinblastine, dacarbazine; HDAC, high-dose cytosine arabinoside.

Case report

A 30-year-old male presented to the Tianjin Medical University General Hospital (Tianjin, China) on October 10, 2012 with fever that had persisted for 1 year, night sweats and lumbago that had persisted for 3 months, and weight loss of 25 kg within 1 year. At the time of admission, the patient exhibited a high temperature of 40.2°C, a mild degree of pallor and palpable surface lymph nodes. Marked cervical, supraclavicular, axillary and inguinal lymphadenopathy had developed, with rubbery lymph nodes reaching 2–3 cm in size. The patient presented mild hepatomegaly and tender pain in the section of the lumbar vertebrae; however, no splenomegaly, adenopathy or skin eruptions were observed. A complete blood cell count revealed a normal white blood cell count (10.2×109 cells/l; normal, 4–10×109/l), 88% neutrophilic granulocytes and 10% lymphocytes, normocytic normochromic anemia (hemoglobin level, 81 g/l; normal, 120–160 g/l) and an increased platelet count (410×109/l; normal, 100–300×109/l). No teardrop-shaped red blood cells or erythroblasts were detected in the peripheral blood. The prothrombin time and activated partial thromboplastin time were found to be 12.1 sec and 37.1 sec (normal, 20–40 sec), respectively, while the fibrinogen level was 511 mg/dl (normal, 1.8–40 mg/dl) and the D-dimer level was 497 µg/l (normal, 0–500 µg/l). Blood chemistry studies demonstrated elevated levels of lactate dehydrogenase (253 U/l; normal, 94–250 U/l) and β2-microglobulin (1.41 mg/l; normal, 0.1–0.3 mg/l). The serum albumin level was 30 g/l (normal, 35–55 g/l), and the hepatic and renal functions were normal. Direct and indirect Coombs tests were negative, while hypergammaglobulinemia and monoclonal gammopathy were not detected and blood sample cultures failed to reveal any pathogens. The patient was serologically negative for Epstein-Barr virus, hepatitis virus, cytomegalovirus, parvovirus B19, toxoplasmosis, coccidiomycosis, brucellosis and human immunodeficiency virus. In addition, the erythrocyte sedimentation rate was 64 mm/h (normal, 0–15 mm/h), while immune screening, including autoantibody and complement, was negative. Finally, the CD4/CD8 ratio (1.01%; normal, 0.8–2.5%) was within the normal range.

A systemic computed tomography (CT) scan demonstrated multiple swellings of the bilateral cervical, supraclavicular, mediastinal, axillary, para-aortic, inguinal and mesenteric lymph nodes, an enlarged liver and no splenomegaly. A cranium CT scan demonstrated no lesions. A single-photon emission computed tomography bone scan revealed numerous areas of increased tracer uptake, indicating skeleton invasion. Fluorodeoxyglucose positron emission tomography was not performed at this time.

Biopsy of the cervical lymph node demonstrated disappearance of the normal architecture and neoplastic cells. Immunohistochemical staining demonstrated that the cells were positive for CD30, as well as for CD20 and CD3 in scattered cells, and negative for CD15. These findings were compatible with a diagnosis of NSHL (Fig. 1). Bone marrow (BM) aspirations of the sternum and iliac bone were dry taps, and biopsy of the BM from the iliac bone demonstrated diffuse MF, showing proliferation of fibroblasts and reticulin fiber, without an increase in megakaryocytes and without lymphomatous infiltration (Fig. 2).

Based on the aforementioned findings, the patient was diagnosed with an NSHL variant with MF. The lymphoma was classified as clinical stage IV (18). Subsequently, the patient underwent 4 courses of chemotherapy with ABVD (doxorubicin, 120 mg, days 1 and 15; bleomycin, 15 mg, days 1 and 15; vinblastine, 3 mg, days 1 and 15; and dacarbazine, 600 mg, days 1 and 15) achieving a partial response. The patient showed resolution of B symptoms with anemia improvement, and reduction in the size of the lymph nodes and liver. Aspiration of BM became possible and a BM biopsy demonstrated a hypocellular marrow without evidence of lymphoma and a reduction in fibrosis. Flow cytometric analyses of BM lymphocytes revealed that they were positive for CD7, CD3, CD5 and CD38, and negative for CD20, CD22, CD23, CD10, CD9, ZAP70 and CD79a. In addition, chromosome analysis of BM cells demonstrated a normal karyotype (46XY). A JAK2 mutation, V617F, was detected and immunoglobulin gene rearrangement was negative. However, small lymph nodes (1–2 cm in diameter) remained in the neck and supraclavicular after 4 courses of chemotherapy. Therefore, the patient was treated with 2 courses of BEACOPP (bleomycin, 15 mg, day 8; etoposide, 200 mg, days 1–3; doxorubicin, 80 mg, day 1; cyclophosphamide, 1,200 mg, day 1; vincristine, 4 mg, day 8; procarbazine, 700 mg, days 1 and 15; and prednisone, 80 mg, days 1–14) combined with local radiotherapy (2 Gy, days 1–20). Residual lesions were not observed on CT scans, and a BM biopsy demonstrated recovery of hematopoiesis and a disappearance of fibrosis. The patient was followed-up until relapse occurred after 2 years, and he was subsequently subjected to stem cell transplantation. Written informed consent was obtained from the patient prior to publication of this study.

Discussion

Primary or idiopathic MF is a myeloproliferative disorder characterized by myeloid metaplasia, evident splenomegaly, pancytopenia and a leukoerythroblastic peripheral blood smear. SMF occurs in a variety of systemic diseases, including tuberculosis, metastatic carcinoma, osteopetrosis and toxic marrow injury following irradiation or chemical exposure (19,20). SMF is also observed in a variety of hematological malignancies, including acute megakaryoblastic leukemia, chronic myeloid leukemia and hairy cell leukemia. However, SMF is uncommon in malignant lymphoma and reported cases of MF associated with HL are extremely rare.

In the present study, at the time of NSHL diagnosis, the patient's BM aspiration was a dry tap. A BM biopsy specimen demonstrated MF representing the proliferation of fibroblasts and reticulin fiber. No apparent increase in megakaryocytes was observed. Infiltration by lymphoma cells was not confirmed in the BM biopsy specimen or in the BM aspiration smear, when it became available. The fibrosis was reversible following successful chemotherapy for HL.

To the best of our knowledge, only 7 previous reports of MF associated with HL exist (Table I) (811). The patient ages were variable (median, 31 years; range, 12–50 years) and no significant difference in incidence based on gender was identified (male, 4; female, 3). The patients, with the exception of 1 case, exhibited pancytopenia without BM invasion by the lymphoma cells; in addition, 5 patients experienced bicytopenia and 3 patients had BM invasion by lymphoma cells. Furthermore, 6 of the 7 patients presented lymph node swelling, 5 demonstrated splenomegaly and 4 had hepatomegaly. The histological type of HL was reported to be of the nodular sclerosis subtype in 3 cases, lymphocyte-depleted in 2 cases, and of mixed cellularity or lymphocyte-predominant in one case each. All the patients were treated with chemotherapy, but survival times differed widely. Patients without marrow involvement presented a relatively good prognosis (survival, 9–11 years). However, marrow involvement was common, and those patients had an extremely poor prognosis (survival, 3 months to 4 years).

No specific association is known between MF and lymphoma, despite a few reported cases of MF complicated by concomitant or subsequent lymphoma (21). However, lymphoma is a recognized cause of MF, although it is uncommon. Gisselbrecht et al (22) reported that there were no patients with MF in a series of 1,883 patients with diffuse aggressive NHL. In addition, the pathogenesis of the fibrotic change in the BM of HL patients is unknown. Fibroblasts have been reported to be stimulated by certain cytokines, such as transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) (23). These cytokines are known to play an important role in the development of stromal proliferation. PDGF induces the proliferation of fibroblasts, while TGF-β induces the synthesis and accumulation of extracellular matrix proteins, including fibronectin and type I and III collagens (24). Megakaryocytes and monocytes have been reported to be sources of these cytokines. In cases of lymphoma with SMF, PDGF is expressed in monocytes (25). T cells are not known to secrete PDGF, which causes MF in myeloproliferative diseases; however, T cells secrete TGF, which can cause fibrosis. Plasma TGF-β levels were found to be elevated in cases of MF associated with peripheral T-cell (8), cytotoxic T-cell (12) and splenic marginal zone lymphomas (13). In addition, there is evidence that the nodular sclerosis of certain cases of Hodgkin's disease is due to the increased TGF levels (26,27).

In the present case, the patient developed MF and lymphoma simultaneously, and these regressed completely following chemotherapy. In conclusion, the disease status of MF was similar with that of HL, suggesting that HL plays an important role in the pathogenesis of MF. Certain cytokines are hypothesized to stimulate the growth of fibroblasts and synthesis of collagen in BM fibroblasts. Further studies and additional case reports will be required to clarify the pathogenesis of SMF and improve our understanding of the immunological dysregulation associated with lymphoma.

Acknowledgements

This study was supported by a grant from the Tianjin Cancer major special project (no. 12ZCDZSY18000).

References

1 

Younes A: Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology. 2009:507–519. 2009. View Article : Google Scholar

2 

Eichenauer DA, Böll B and Diehl V: Pharmacotherapy of Hodgkin lymphoma: standard approaches and future perspectives. Expert Opin Pharmacother. 15:1139–1151. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Tefferi A: Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol. 23:8520–8530. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Tefferi A: Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 89:915–925. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Niino D, Tsuchiya T, Tomonaga M, Miyazaki Y and Ohshima K: Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet-derived growth factor. Pathol Int. 63:141–149. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Aljinovic N, Bogusz AM, Kantarci S, Buck TP and Dewar R: An unusual case of Philadelphia chromosome-positive chronic myelogenous leukemia with trisomy 19 presenting with megakaryoblastosis and myelofibrosis. Arch Pathol Lab Med. 137:1147–1151. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Araki H, Matsunaga T, Murase K, Kuroda H, Kuribayashi K, Terui T and Niitsu Y: Successful induction and complete improvement of myelofibrosis and erythema nosodum with cladribine in a case of hairy cell leukemia. Gan To Kagaku Ryoho. 31:965–969. 2004.(In Japanese). PubMed/NCBI

8 

Okabe S, Miyazawa K, Lguchi T, Sumi M, Takaku T, Ito Y, Kimura Y, Serizawa H, Mukai K and Ohyashiki K: Peripheral T-cell lymphoma together with myelofibrosis with elevated plasma transforming growth factor-β1. Leuk Lymphoma. 46:599–602. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Kikukawa M, Umahara T, Kikawada M, Kanaya K, Sakurai H, Shin K, Mori M and Iwamoto T: Peripheral T-cell lymphoma presenting as myelofibrosis with the expression of basic fibroblast growth factor. Geriatr Gerontol Int. 9:395–398. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Matsui K, Adachi M, Tominaga T, Shinohara S and Kamei T: Angioimmunoblastic T cell lymphoma associated with reversible myelofibrosis. Int Med. 47:1921–1924. 2008. View Article : Google Scholar

11 

Rao SA, Gottesman SR, Nguyen MC and Braverman AS: T cell lymphoma associated with myelofibrosis. Leuk Lymphoma. 44:715–718. 2003. View Article : Google Scholar : PubMed/NCBI

12 

Abe Y, Ohshima K, Shiratsuchi M, Honda K, Nishimura J, Nawata H and Muta K: Cytotoxic T-cell lymphoma presenting as secondary myelofibrosis with high levels of PDGF and TGF-beta. Eur J Haematol. 66:210–212. 2001. View Article : Google Scholar : PubMed/NCBI

13 

Matsunaga T, Takemoto N, Miyajima N, Okuda T, Nagashima H, Sato T, Terui T, Sasaki H, Ohmi N, et al: Splenic marginal zone lymphoma presenting as myelofibrosis associated with bone marrow involvement of lymphoma cells which secrete a large amount of TGF-beta. Ann Hematol. 83:322–325. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Meadows LM, Rosse WR, Moore JO, Crawford J, Laszlo J and Kaufman RE: Hodgkin's disease presenting as myelofibrosis. Cancer. 64:1720–1726. 1989. View Article : Google Scholar : PubMed/NCBI

15 

Carroll WL, Berberich FR and Glader BE: Pancytopenia with myelofibrosis. An unusual presentation of childhood Hodgkin's disease. Clin Pediatr (Phila). 25:106–108. 1986. View Article : Google Scholar : PubMed/NCBI

16 

Vukelja SJ, Krishnan J, Ward FT and Redmond J III: Synchronous Hodgkin's disease and myelofibrosis terminating with granulocytic sarcoma and acute megakaryocytic leukemia. South Med J. 83:1317–1320. 1990. View Article : Google Scholar : PubMed/NCBI

17 

Viola MV, Kovi J and Nukhopadhyay M: Reversal of myelofibrosis in Hodgkin disease. JAMA. 223:1145–1146. 1973. View Article : Google Scholar : PubMed/NCBI

18 

Izumi T and Ozawa K: Clinical staging classification of non-Hodgkin's lymphoma. Nihon Rinsho. 58:598–601. 2000.(In Japanese). PubMed/NCBI

19 

Viallard JF, Parrens M, Boiron JM, Texier J, Mercie P and Pellegrin JL: Reversible myelofibrosis induced by tuberculosis. Clin Infect Dis. 34:1641–1643. 2002. View Article : Google Scholar : PubMed/NCBI

20 

Atasever T, Vural G, Yenidünya S, Ataoğlu O, Atavci S and Unlü M: Tc-99m MIBI bone marrow uptake in bone marrow fibrosis secondary to metastatic breast carcinoma. Clin Nucl Med. 22:655–656. 1997. View Article : Google Scholar : PubMed/NCBI

21 

Gabali AM, Jazaerly T, Chang CC, Cleveland R and Kass L: Simultaneous hepatosplenic T-cell lymphoma and myelofibrosis. Avicenna J Med. 4:34–36. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Gisselbrecht C, Gaulard P, Lepage E, Coiffier B, Brière J, Haioun C, Cazals-Hatem D, Bosly A, Xerri L, Tilly H, et al: Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA). Blood. 92:76–82. 1998.PubMed/NCBI

23 

Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med. 342:1255–1265. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Charni Chaabane S, Coomans de Brachène A, Essaghir A, Velghe A, Lo Re S, Stockis J, Lucas S, Khachigian LM, Huaux F and Demoulin JB: PDGF-D expression is down-regulated by TGFβ in fibroblasts. PLoS One. 9:e1086562014. View Article : Google Scholar : PubMed/NCBI

25 

Wang JC, Chang TH, Goldberg A, Novetsky AD, Lichter S and Lipton J: Quantitative analysis of growth factor production in the mechanism of fibrosis in agnogenic myeloid metaplasia. Exp Hematol. 34:1617–1623. 2006. View Article : Google Scholar : PubMed/NCBI

26 

Kadin ME, Agnarsson BA, Ellingsworth LR and Newcom SR: Immunohistochemical evidence of a role for transforming growth factor beta in the pathogenesis of nodular sclerosing Hodgkin's disease. Am J Pathol. 136:1209–1214. 1990.PubMed/NCBI

27 

Newcom SR and Tagra KK: High molecular weight transforming growth factor beta is excreted in the urine in active nodular sclerosing Hodgkin's disease. Cancer Res. 52:6768–6773. 1992.PubMed/NCBI

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APA
Fu, R., Yu, H., Wu, Y., Liu, H., & Shao, Z. (2015). Hodgkin's lymphoma associated with myelofibrosis: A case report. Oncology Letters, 10, 1551-1554. https://doi.org/10.3892/ol.2015.3438
MLA
Fu, R., Yu, H., Wu, Y., Liu, H., Shao, Z."Hodgkin's lymphoma associated with myelofibrosis: A case report". Oncology Letters 10.3 (2015): 1551-1554.
Chicago
Fu, R., Yu, H., Wu, Y., Liu, H., Shao, Z."Hodgkin's lymphoma associated with myelofibrosis: A case report". Oncology Letters 10, no. 3 (2015): 1551-1554. https://doi.org/10.3892/ol.2015.3438