© 2007 Foundation for Promotion of Cancer Research
Primary Bone Lymphoma: A New and Detailed Characterization of 28 Patients in a Single-Institution Study
1 Hematology and Stem Cell Transplantation
2 Orthopedic Surgery
3 Pediatric Oncology
4 Radiation Oncology
6 Clinical Laboratory Divisions, National Cancer Center Hospital, Tokyo
5 Diagnostic Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
For reprints and all correspondence: Takashi Watanabe, Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. E-mail: takawata{at}ncc.go.jp
Received August 21, 2006; accepted November 5, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: The incidence of primary bone lymphoma (PBL) is so rare that many of its aspects remain unknown. A number of studies have been reported from Western countries, but only a few reports are available from Asia.
Methods: We retrospectively analyzed 28 consecutive patients diagnosed with PBL initially treated at our hospital between 1995 and 2004. All patients underwent chemotherapy with half receiving radiotherapy as their initial treatment. A log-rank test was used in a univariate analysis to identify factors affecting overall survival.
Results: Fifteen (54%) patients were male and 13 (46%) female with a median age of 47 (range: 5–81). Although 19 (68%) patients had diffuse large B-cell lymphoma (DLBCL), other histopathological subtypes (three B-lymphoblastic lymphoma, two anaplastic large cell lymphoma, two indolent B-cell lymphoma, one NK/T-cell lymphoma (NTCL) and one Hodgkin lymphoma) were also included. The pelvis was the most frequently involved site (54%). While 68% of patients had stage IV disease, none of them showed bone marrow involvement at their initial diagnosis. Despite 61% high intermediate-risk and high-risk patients based on the International Prognostic Index, the estimated 3-year overall and progression-free survival rates were 84% and 77%, respectively. Only ‘histopathological subtype (immunoblastic variant of DLBCL or NTCL versus others)’ and ‘response to initial treatment (progression versus remission)’ were factors significantly affecting overall survival.
Conclusions: Although the total number of patients was relatively small, the detailed clinical data analyses presented here revealed several new characteristics of PBL and some aspects that may be unique to Japanese patients.
Key Words: primary bone lymphoma • DLBCL • radiotherapy • bone tumor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Primary bone lymphoma (PBL) is a rare disease that was first described by Oberling in 1928 (1). Parker and Jackson (2) published their series on ‘reticulum cell sarcoma of bone’ in 1939 and established PBL as a distinct clinical entity.
The incidence of PBL is 7% of all malignant bone tumors, 4–5% of all extranodal non-Hodgkin lymphoma (NHL) and less than 1% of all malignant lymphomas (3–5). Previous reports showed its particular tendency to affect senior adults although PBL can occur at any age. There is also a male predominance and the femur has been reported to be the most commonly involved location as a single site.
Many PBL patients have had early clinical stage diseases (3, 6–14) and the most important prognostic factor has been the disease stage (6, 15). Histopathologically, the majority of PBL cases have been diffuse large B-cell lymphoma (DLBCL) according to the World Health Organization (WHO) classification (16).
There are several problems, however, that should be noted with respect to the previous PBL reports: (i) the number of patients in each study was small; (ii) the definitions of PBL and the response criteria for PBL were heterogeneous and/or ambiguous in some of the reports; (iii) in most PBL studies, only patients with early stage disease were regarded as those meeting the criteria of PBL; (iv) treatment modalities were also heterogeneous; and (v) most of the case series were reported from Western countries with only a few studies available from Asia including Japan (17).
In an effort to help clarify the various uncertain aspects as to the character and nature of PBL, we now report the results of detailed clinicopathological analyses conducted on 28 consecutive patients with PBL who received their initial treatments at our hospital during the past 10 years.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients
We retrospectively analyzed 28 consecutive patients who were diagnosed with PBL and received their initial treatment at the National Cancer Center Hospital (NCCH) between April 1995 and September 2004. All pathological materials were obtained from surgical biopsies and the histopathological diagnoses were made according to the WHO classification. A number of clinical data were analyzed based on clinical records including age, gender, B symptoms, performance status according to the Eastern Cooperative Oncology Group (ECOG) scale, serum lactate dehydrogenase (LDH) level, clinical stage (CS), primary bone site, number of bone lesions, other involved sites with lymph-node lesions or extranodal lesions (except for the bone), maximal tumor diameter, treatment, response to initial treatment and histopathological subtype.
Definition of PBL
According to the WHO classification (3), lymphoma involving bone can be classified into four groups: Group 1, lymphoma with a single bone site with or without regional lymph-node involvement; Group 2, lymphoma with multiple bones involved, but no visceral or lymph-node involvement; Group 3, bone tumor with involvement of other visceral sites or lymph nodes at multiple sites; and Group 4, lymphoma involving any other sites and found by bone biopsy which was done to rule out possible involvement. We defined PBL in our study as consisting of WHO classification Groups 1 and 2 as well as Group 3 cases when the bone tumor was the largest lesion, which is supposed to be the initial site involved by lymphoma. This is because lymphomas with the same histology should have the same growth rate, and therefore we cannot expect lymphoma to spread more easily and rapidly inside the hard and compact bone than in other free space.
Clinical Staging
CS was determined according to the revised American Joint Committee on Cancer (AJCC) staging system for lymphoid neoplasms (18). All patients underwent chest X-ray; computed tomography (CT) scans of the neck, chest, abdomen and pelvis; magnetic resonance image (MRI) of bone lesions; histological examination of clot obtained by bone marrow aspiration or bone marrow biopsy; total body scintigraphy (Ga-67 scintigraphy [gallium scan], technetium-99 m bone scintigraphy or fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography [FDG-PET]); upper gastrointestinal tract endoscopy; blood smears; and physical examinations. All stage IIE disease was defined as lymph-node involvement adjacent to the bone lesion according to the AJCC staging system.
Response Criteria
For assessment of response, we used response criteria based on the International Workshop Response Criteria (IWRC) (19) combined with the MRI and total body scintigraphy findings. Complete response (CR) was defined as CR, CR-unconfirmed (CRu), partial response (PR) or stable disease (SD) in accordance with the IWRC without any abnormal accumulation as determined by either an FDG-PET or gallium scan. PR was defined as CR or CRu in accordance with the IWRC with either a positive FDG-PET or gallium scan or PR in accordance with the IWRC with or without evaluation by either an FDG-PET or gallium scan. SD was defined as SD in accordance with the IWRC with or without either a positive FDG-PET or gallium scan. Progressive disease (PD) was defined as PD in accordance with the IWRC with or without either an FDG-PET or gallium scan or the appearance of a new lesion by either an FDG-PET or gallium scan.
Statistical Analyses
For the full-set analysis (n = 28), overall survival (OS) was defined as the interval between the dates of diagnosis and death from any cause. Progression-free survival (PFS) was defined as the interval from the date of diagnosis to the date of disease progression, relapse or death from any cause. All survival curves were evaluated by the Kaplan–Meier analysis method. A log-rank test was used in a univariate analysis to identify factors affecting OS. A P value of 0.05 or less was considered to be indicative of a statistical significance. All statistical analyses were performed using SPSS version 11.0J (Dr. SPSS II for Windows).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Characteristics
The demographic and clinical characteristics of the 28 patients at the time of diagnosis are summarized in Table 1. The median age was 47 years (range: 5–81) with 15 male and 13 female patients. Seven (25%) patients had B symptoms, 23 patients (82%) showed elevated serum LDH levels, 19 (68%) had CS IV disease and 17 (61%) were high intermediate-risk or high-risk patients based on the International Prognostic Index (IPI) (20).
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The primary involved sites of the bone are shown in Fig. 1. Notably, the pelvis was the most frequently involved site (15 patients; 54%) rather than the extremities (six patients; 21%). The femur, which had been the most common site involved as a single PBL site in most of the previous reports (6, 7, 9–11, 13–15), was involved in only two (7%) patients. A total of 12 (43%) patients presented with a solitary lesion, nine (32%) had two lesions and seven (25%) had multifocal bone lesions. Nine male (32%) and nine female (32%) patients were classified as WHO Group 1 or Group 2 while six male (21%) and four (14%) female patients were classified as Group 3. In our study, there was no male preponderance although this had been the case in many previous reports (6, 8–12, 15, 17) in every category.
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Clinical Staging
Four (14%) patients presented with stage I disease, five (18%) patients with stage IIE, no patients (0%) with stage III and 19 (68%) patients with stage IV (Table 1). Nine of 19 patients with stage IV disease had multifocal bone lesions without visceral or lymph-node involvement (WHO classification Group 2) and other patients were classified as Group 3 when the bone tumor was the largest lesion. Three of 10 patients with a solitary bone lesion had either distant lymph node (two patients) or an extranodal site other than the bone (one patient, stomach). Seven of 10 patients with multifocal bone lesions had either distant lymph node (five patients) or some extranodal site involvement (one patient, stomach; one patient, skin). None of the 19 CS IV patients had bone marrow involvement at their initial diagnosis.
Histopathological Subtypes
The results of the histopathological diagnoses of all the bone lymphomas are summarized in Table 2. DLBCL was the most common histopathological PBL subtype (19 of 28 patients; 68%) as previously reported, but two of these 19 DLBCL patients revealed an immunoblastic variant.
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We also found a variety of histopathological subtypes other than DLBCL. Three patients (11%) had precursor B-lymphoblastic leukemia/lymphoma (B-ALL/LBL). Another patient (4%) had follicular lymphoma (FL), grade 1 without any transformed component in her bone biopsy sample. The bone biopsy sample that had been diagnosed as just ‘low grade B-cell lymphoma’ was considerably crushed so it was difficult to judge the precise histopathological subtype. An invasive and diffuse proliferation of a mixture of small-sized and medium-sized round cells was found in this sample and its immunohistochemical stainings showed that CD20, CD79a and Bcl-2 were positive and CD3, CD5, CD10, CD23, cyclin D1 and terminal deoxynucleotidyl transferase were negative. Two (7%) pediatric patients were diagnosed as anaplastic large cell lymphoma (ALCL). Both of them were positively stained with anaplastic lymphoma kinase with one positive and the other negative for CD56 stainings. One (4%) patient diagnosed as extranodal NK/T-cell lymphoma, nasal type (NTCL) did not have any nasal lesions, but had a bone lesion in the right tibia and regional lymph-node involvement while one (4%) other patient with lymphocyte-depleted Hodgkin lymphoma (LDHL) had multiple bone lesions accompanied by a skin lesion.
Initial treatment
All 28 patients underwent chemotherapy with most of them (21; 75%) receiving the CHOP regimen (cyclophosphamide [CPA], doxorubicin [DOX], vincristine [VCR] and prednisolone [PSL]). Two adult patients with B-ALL/LBL received a treatment regimen (Lymphoma Study Group of Japan Clinical Oncology Group 16) for acute lymphoblastic leukemia. The patient with FL had been previously diagnosed as having DLBCL in her former hospital so she received a dose-intensified third-generation regimen (MACOP-B) consisting of methotrexate, DOX, CPA, VCR, PSL and bleomycin (BLM). The patient with LDHL received the ABVD regimen (DOX, BLM, vinblastine and dacarbazine) and three pediatric patients (one B-ALL/LBL and two ALCL cases) received a regimen used in pediatrics for short-term intensive treatment. Fourteen (50%) of the 28 patients received combined modality treatment of sequential chemotherapy and radiotherapy with a median dose of 40 gray (Gy) (range: 30–50). The majority (11 patients) of them received chemotherapy followed by radiotherapy with the other three initially receiving radiotherapy.
Response to Treatment, Survival Rates and Statistical Analyses
All 28 patients could be evaluated for their response to initial treatment, OS and PFS. The median follow-up period was 31 months (range: 15–126). The overall response rate (ORR) for all the PBL patients was 89% as 19 patients (68%) achieved CR and six patients (21%) achieved PR. Three patients (11%) showed PD during initial treatment. For the patients classified as either WHO classification Group 1 or Group 2, the ORR was 88% (15 of 17 patients) and the ORR for the patients classified as Group 3 was 90% (10 of 11).
Twenty-five patients (89%) were alive at the time of the last follow-up and all remain in CR including 18 patients who achieved CR after initial treatment, four with PR following initial treatment and two patients who achieved CR after salvage chemotherapy but one patient who relapsed after achieving CR by salvage chemotherapy followed by radiotherapy. Six patients (21%) experienced recurrences of the lymph nodes (one patient), bone marrow (one patient), central nervous system (one patient) and bone (three patients). The three patients with bone relapses received chemotherapy followed by radiotherapy as the initial treatment and two of the recurrences occurred outside the radiation field. The bone relapse locus in the remaining patient was unclear because the patient was transferred to another hospital and detailed information was unavailable.
The median time to progression from the beginning of treatment was 21 months (range: 10–30). Histopathological subtypes for the six relapsed cases were DLBCL (three patients), the immunoblastic variant of DLBCL (two patients) and FL (one patient). Three patients (11%) showed PD during initial treatment and their histopathological subtypes were DLBCL, the immunoblastic variant of DLBCL and NTCL, respectively. The DLBCL patient with PD during first-line treatment achieved CR after salvage chemotherapy (CODOX-M/IVAC regimen (21) with rituximab) followed by radiotherapy. Subsequently, this same patient underwent high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) but his lymphoma relapsed in the central nervous system four months later. The second PD patient with the immunoblastic variant of DLBCL relapsed 10 months after achieving PR from an ESHAP salvage regimen (22) followed by radiotherapy and died of lymphoma progression. The third patient with NTCL had PD despite receiving an ESHAP salvage regimen and eventually died of lymphoma. It is important to note that the two PD patients diagnosed with either the immunoblastic variant of DLBCL or the NTCL both died of lymphoma progression.
The estimated 3-year OS and PFS rates were 84% and 77%, respectively (Fig. 2). The results of our univariate analysis of various factors affecting OS are shown in Table 3. Only two variables were found to be significant adverse factors related to OS: either the immunoblastic variant of DLBCL or the NTCL histopathological subtype and PD at initial treatment. OS classified according to patient response to their initial treatment is shown in Fig. 3. There was a significant difference between the two groups (P < 0.01). The estimated 3-year OS rate for patients in WHO classification Groups 1/2 and Group 3 was 84% and 91%, respectively.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The incidence of PBL is so rare that many aspects remain controversial, particularly the definition of PBL, appropriate treatment strategies, response criteria and prognostic factors.
There were a number of unique findings in our series compared with most of the previous reports. First, there was a divergence from DLBCL in histopathological subtypes. Second, the pelvis was the most commonly involved site compared to the majority of previous reports from Western countries identifying the femur as the most frequently involved site (Table 4). Horsman et al. reported that the most commonly presented site was the pelvis, although they described that the femur was the most frequently involved bone (13). Because another Japanese report also found that the pelvis was the most frequently involved site (17), this pelvic preponderance may be a characteristic peculiar to Japanese patients with PBL. Third, there was a predominance of advanced-stage disease despite defining PBL as including Group 3 of the WHO classification in any patient whose bone lesion was the largest, but neither the ORR to initial treatment nor the OS in this study was inferior to previously published reports. Fourth, there were no PBL patients with bone marrow involvement at the time of their initial diagnosis although stage IV disease was predominant in our study. Fifth, histopathological existence of either the immunoblastic variant of DLBCL or NTCL and response to initial treatment were both significant prognostic factors. Horsman et al. found that patients older than 60 years of age and other than complete response to initial treatment had a worse chance of survival (13), which is partially consistent with our results.
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According to the WHO classification, lymphoma involving the bone can be classified into four groups. The WHO classification and some previous reports have indicated that Groups 1 and 2 should be considered as PBL, but Group 3 should be excluded from PBL and considered to be systemic lymphoma regardless of the bone lesion size. An appropriate definition has not been established by verification, however, so the subject continues to be controversial. In clinical practice, we usually consider the largest lesion, which is supposed to be initially involved by lymphoma in cases with lymphomas in multiple lesions. In this study, therefore, we included Group 3 in our definition of PBL when the bone lesion was the largest as well as Groups 1 and 2 and found that there was no significant difference in the estimated 3-year OS rate between Groups 1/2 and Group 3 (P = 0.74).
Histopathologically, the previous studies reported that the majority of patients with PBL were DLBCL particularly the multilobated subtype (3, 6, 11, 23). In our series, there was a variety of diagnoses although the majority of histopathological subtypes were DLBCL (68%). It is important to note that PBL with certain specific histopathological subtypes had a poor prognosis despite the majority having a good prognosis. Heyning et al. found that patients older than 60 years of age and patients with the immunoblastic variant subtype had a worse chance of survival (6) which is partially consistent with our results. All the patients with either the immunoblastic variant of DLBCL or the NTCL died early of lymphoma progression in our study. Although ALCL as PBL is extremely rare, it has been reported that CD56-positive ALCL has had a tendency to involve the bone and its prognosis has been poor (24).
Several studies have suggested that a combination of chemotherapy and radiotherapy was the best treatment for patients with PBL (12, 25–27). Zinzani et al. conducted a retrospective analysis of 52 patients with stage I to stage IV PBL. The CR rates for patients treated by radiotherapy alone and chemotherapy with or without radiotherapy were 64% and 85%, respectively. The relapse rates between the two groups were 57% and 6%, respectively (9). These previous reports confirmed the superiority of chemotherapy to radiotherapy alone as the initial treatment for PBL patients. Beal et al. concluded that PBL patients treated with a combination of chemotherapy and radiotherapy were found to have a significantly better survival than the patients treated with single modality therapy (chemotherapy or radiotherapy alone), but the 5-year OS rate for patients treated with combined modality therapy versus chemotherapy alone was not significantly different (14). The addition of radiotherapy did not affect the survival rate in either the total of all PBL patients (Table 3) or those with early stage disease (data not shown) in our univariate analysis. Bacci et al. reported that four of six patients who underwent radiotherapy of less than 30 Gy had a relapse in their radiation fields and that a combination of chemotherapy and radiotherapy of more than 40 Gy was needed (27). Among the 28 patients in our study, three patients had relapses on the bone with each of them having received chemotherapy followed by radiotherapy. The patient transferred to another hospital received only 30 Gy while the others received more than 35 Gy as their initial treatment including two patients with bone relapses that occurred outside their radiation fields who then received additional radiotherapy. No bone marrow involvement at initial diagnosis might be beneficial to HDT/ASCT, however, PFS for most of PBL with DLBCL histology is quite good and only a few cases underwent HDT/ASCT. Additional studies will be necessary to help clarify the significance of this finding. Because the number of patients in this study was relatively small, further studies are needed to clarify the characteristics of PBL and its optimal treatment strategy.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgments |
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We wish to thank orthopedic surgeons, Hirokazu Chuman, Akira Kawai and Fumihiko Nakatani, of the Orthopedic Surgery Division at the National Cancer Center Hospital for performing surgical bone biopsies to obtain lymphoma diagnoses. This work was supported in part by a Grant-in-Aid for Cancer Research (15S-01) from the Ministry of Health, Labor and Welfare, Tokyo, Japan (to T.W.).
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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