Leukemia & Lymphoma, August 2014; 55(8): 1796–1799 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.853298
ORIGINAL ARTICLE: CLINICAL
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The clinical features, management and prognosis of primary and secondary indolent lymphoma of the bone: a retrospective study of the International Extranodal Lymphoma Study Group (IELSG #14 study) Silvia Govi1*, David Christie2*, Silvia Mappa1, Emerenziana Marturano1, Marta Bruno-Ventre1, Carlo Messina1, Elías A. Gracia Medina3, David Porter4, John Radford5, Dae Seog Heo6, Yeon Park7, Barbara Pro8, Jayasingham Jayamohan9, Nick Pavlakis10, Emanuele Zucca11, Mary Gospodarowicz12 & Andrés J. M. Ferreri1; for the International Extranodal Lymphoma Study Group (IELSG) 1Unit of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy, 2Premion
and Bond University, Tugun, Australia, 3Servicio de Oncología Médica, Instituto Nacional de Oncología y Radiobiología, La Habana, Cuba, 4Auckland Hospital, Auckland, New Zealand, 5Christie Hospital, Manchester, United Kingdom, 6Seoul National University Hospital, Seoul, Korea, 7Korea Cancer Center Hospital, Seoul, Korea, 8M. D. Anderson Cancer Center, Houston, TX, USA, 9Westmead Hospital, Sydney, Australia, 10Royal North Shore Hospital, Sydney, Australia, 11Oncology Institute of Southern Switzerland, Bellinzona, Switzerland and 12Department of Radiation Oncology, Princess Margaret Hospital, Ontario Cancer Institute, Toronto, Canada
Introduction
Abstract Indolent lymphomas primarily involving the skeleton (iPBL) represent ⬍ 1% of all primary bone lymphomas. The management and prognosis have not been previously described. Patients with primary and secondary iPBL were selected from an international database of 499 patients with a histopathological diagnosis of non-Hodgkin lymphoma and skeleton involvement, and clinical features, management and prognosis were analyzed. Twenty-six (5%) patients had an iPBL. Ten patients had small lymphocytic lymphoma, 10 had follicular lymphoma and six had lymphoplasmacytic lymphoma. Eleven patients had limited stage and 15 had advanced disease. The overall response rate was 73% (95% confidence interval [CI] ⴝ 57–89%). Median follow-up was 58 months, and the 5- and 10-year progression-free survival (PFS) rates were 37 ⴞ 10% and 25 ⴞ 12%, respectively. Nine patients are alive, with 5- and 10-year overall survival (OS) rates of 46 ⴞ 10% and 29 ⴞ 11%, respectively. Patients with small lymphocytic lymphoma showed significantly better outcome than patients with follicular lymphoma. Performance status and stage of disease were independently associated with OS. The prognosis of patients with primary bone lymphoplasmacytic or follicular lymphoma was less favorable.
Primary bone lymphoma (PBL) is a rare disease, accounting for ∼3% of all primary bone malignancies, less than 5% of extranodal lymphomas and 1–2% of all malignant lymphomas in adults [1–5]. Almost 90% of patients with PBL present with diffuse large B-cell lymphoma (DLBCL) histological subtype [6,7]. The available literature shows relatively favorable outcomes for patients with limited-stage DLBCL of the bone, and recommends treatment with anthracycline-based chemotherapy followed or not by radiotherapy, depending on risk [3,6,7–17]. Conversely, the available literature on the clinical features, management and prognosis of indolent lymphomas primarily involving the skeleton is anecdotal and fragmentary. Indolent lymphomas represent ⬍ 1% of reported cases of PBL, with usually one or two cases in each reported series, which are not reported separately. A recent systematic review of PBL stated that primary follicular, small lymphocytic, marginal zone and lymphoplasmacytic lymphomas of bone are extremely rare [18]. Thus, studies reporting the clinical features, management and prognosis of primary bone indolent lymphoma (iPBL) in an adequate number of cases are needed. Against this background, we analyzed the clinical features, management and prognosis of 26 patients with indolent bone lymphoma (considering both primary and secondary
Keywords: Indolent lymphoma, primary bone lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma, follicular lymphoma, osteolymphoma
*These authors contributed equally. Correspondence: Andrés J. M. Ferreri, MD, Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 – Milan, Italy. Tel: 0039-02-26437649. Fax: 0039-02-26437625. E-mail: [email protected] There is an accompanying commentary that discusses this paper. Please refer to the issue Table of Contents. Received 3 July 2013; revised 26 September 2013; accepted 3 October 2013
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Indolent bone lymphomas 1797 involvement) registered in a multicenter clinicopathological database of 499 cases of non-Hodgkin lymphoma and skeleton involvement, performed under the sponsorship of the International Extranodal Lymphoma Study group (IELSG).
Patients and methods
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Study population The members of the IELSG were invited to participate in a retrospective study focused on PBL (IELSG #14 study). A questionnaire requesting information about patient characteristics, clinical presentation, diagnosis, staging, treatment, objective response, site and date of relapse, second-line treatment, late effects and survival of patients with a histopathological diagnosis of non-Hodgkin lymphoma and skeleton involvement was sent to referring centers. To investigate clinical and therapeutic features of iPBL, only patients diagnosed and treated at the participating institutions between 1980 and 2000 and fulfilling the following criteria were considered: (1) age ⱖ 18 years; (2) histological diagnosis of indolent lymphoma (small lymphocytic lymphoma, follicular lymphoma or lymphoplasmacytic lymphoma); (3) disease involving at least one bone; (4) complete staging work-up with at least enhanced total-body computed tomography (CT) scan and bone marrow biopsy; (5) no evidence of human immunodeficiency virus type 1 (HIV-1) infection (negative serologic tests; absence of epidemiological risk, opportunistic infections or lymphopenia for patients diagnosed in the early 1980s) or other immunodeficiencies. Bone involvement was defined either by radiological procedures (radiography, CT scan, magnetic resonance imaging [MRI]) or histopathological examination of surgical biopsies. Whenever possible, histopathological specimens were reviewed by a local pathologist before data submission, but there was no central pathology review.
Statistical considerations The Fisher exact test for categorical variables was used to compare clinical characteristics and response rates of the therapeutic subgroups. Survival curves were generated by the Kaplan–Meier method. Overall survival (OS) was calculated from the date of pathologic diagnosis to death or to the last date of follow-up, while progression-free survival (PFS) was calculated from the first day of treatment to relapse, progression or death, or to the last date of follow-up. Impact on survival of clinical and treatment-related variables was evaluated by comparing the survival curves by means of the log-rank test. The independent prognostic value of variables was analyzed using the Cox proportional hazards model. All of the probability values were two-sided. Analyses were carried out using the Statistica 4.0 statistical package for Windows (1993; Statsoft Inc., Tulsa, OK).
Results Patient characteristics The database of the IELSG #14 study included 499 patients from 32 institutions in 14 countries (a list of participating centers with the number of registered patients/center is given
in the Supplementary Appendix to be found online at http:// informahealthcare.com/doi/abs/10.3109/10428194.2013. 853298). Twenty-six (5%) patients from that database had a histological diagnosis of indolent lymphoma, with a median age of 60 years (range 27–80) and a male:female ratio of 1.3 (Table I). Ten patients had small lymphocytic lymphoma, 10 had follicular lymphoma and six had lymphoplasmacytic lymphoma. Ten patients had stage I disease (single osseous lesion), one had stage II disease (single osseous lesion and regional lymphadenopathies) and 15 patients had stage IV disease (systemic disease plus at least a bone lesion). There was no significant difference in the distribution of histological types between the two stage subgroups, although there was a trend toward a higher prevalence of follicular lymphoma among patients with advanced stage. Pain was the most common presenting symptom so far, which was recorded in 10 (91%) patients with limited stage and in 13 (87%) with advanced disease. Pathological fracture was recorded in one patient per subgroup. Multifocal lesions were observed in 14 (93%) patients with advanced disease, in which the most common sites were pelvic bones (47%) and the spine (40%). The spine (27%) was the most common site of disease in patients with limited-stage iPBL.
Treatment Various treatment strategies were employed according to physician discretion (Table I). Radiation treatment alone was recorded in four patients; chemotherapy was indicated as exclusive treatment in eight patients, and followed by radiotherapy in 14. Cyclophosphamide, doxorubicin, Table I. Patients’ characteristics.
Median age; years (range) Males Histological type Small lymphocytic lymphoma Follicular lymphoma Lymphoplasmacytic lymphoma Clinical presentation Fever Swelling Weight loss Pain Tumefaction Fracture Sites of involvement Skull Column Pelvis Humerus Femur Upper limbs Lower limbs Lymph nodes Cerebrospinal fluid Extranodal sites Bone marrow Treatment Radiotherapy alone Chemotherapy ⫹ radiotherapy Chemotherapy alone *Patients with stage I or stage II lymphoma.
Limited disease* (n ⫽ 11)
Stage IV disease (n ⫽ 15)
63 (27–77) 5 (46%)
57 (40–80) 10 (67%)
5 (46%) 3 (27%) 3 (27%)
5 (33%) 7 (47%) 3 (20%)
1 (9%) 0 (0%) 0 (0%) 10 (91%) 2 (18%) 1 (9%)
3 (20%) 1 (7%) 1 (7%) 13 (87%) 5 (33%) 1 (7%)
2 (18%) 3 (27%) 2 (18%) 0 (0%) 2 (18%) 0 (0%) 2 (18%) 1 (9%) – – –
4 (27%) 6 (40%) 7 (47%) 2 (14%) 5 (33%) 1 (7%) 1 (7%) 4 (27%) 1 (7%) 5 (33%) 4 (27%)
4 (36%) 4 (36%) 3 (27%)
0 (0%) 10 (66%) 5 (33%)
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vincristine and prednisone (CHOP) or CHOP-like were the most commonly used regimens (n ⫽ 15). The median radiation dose was 35 Gy (range 25–45). Irradiated volume included the whole bone in 11 patients, and partial bone in seven. Management according to each histological type is reported in Table II.
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Response and survival Response to first-line treatment was complete in 12 patients (complete response rate [CRR] ⫽ 46%; 95% confidence interval [CI] ⫽ 28–64%) and partial in seven, with an overall response rate (ORR) of 73% (95% CI ⫽ 57–89%). At a median follow-up of 58 months (range 8–120), 16 patients experienced lymphoma treatment failure (progressive disease or relapse after initial response), with a 5- and 10-year PFS of 37 ⫾ 10% and 25 ⫾ 12%, respectively. Failures involved the primary site of disease in two patients, other bones in four, lymph nodes in two and distant organs in eight. All failed patients received salvage treatment, with a significant survival benefit (second remission longer than the first) in onethird of the patients. Nine patients are alive, with a 5- and 10-year OS of 46 ⫾ 10% and 29 ⫾ 11%, respectively. Eleven patients died of lymphoma and six died of unrelated causes (three with no evident disease [NED]). Outcome according to histological type is summarized in Table II. Among the 11 patients with limited-stage lymphoma, four patients received radiotherapy alone, three received chemotherapy alone and four patients received both therapies. All eight patients who received radiotherapy achieved a complete remission (CR), and only three of them experienced relapse, whereas only one of the three patients managed without radiotherapy achieved a CR, and all of them experienced relapse. The addition of chemotherapy was not associated with different OS in irradiated patients; at a median follow-up of 45 months, only one patient had died of lymphoma progression.
Subgroup analysis Univariate analyses are summarized in Table III. Patients with limited disease showed better PFS and OS. Patients with small lymphocytic lymphoma showed a significantly better PFS and OS than patients with follicular lymphoma. Regardless of lymphoma category, three of the four patients treated with radiotherapy alone were alive at a follow-up of 24–120 months (median 68⫹). A multivariate analysis Table II. Management and outcome per histological type. Lymphoma
Therapy (n)
Stage I CR – PR Failures
Patients alive (months)
SLL
RT (2) CHT (2) CHT ⫹ RT (6)
2 1 1
2–0 1–1 3–2
0 2 3
1 (120) 0 4 (31–72)
FL
RT (1) CHT (3) CHT ⫹ RT (6)
1 0 2
1–0 0–2 3–1
1 2 3
1 (96) 1 (8) 1 (58)
Lpc
RT (1) CHT (3) CHT ⫹ RT (2)
1 1 1
1–0 0–0 1–1
0 3 2
1 (29) 0 0
SLL, small lymphocytic lymphoma; FL, follicular lymphoma; Lpc, lymphoplasmacytic lymphoma; n, number of patients per subgroup; RT, radiotherapy; CHT, chemotherapy; CR, complete remission; PR, partial response.
Table III. Therapeutic outcome of analyzed subgroups. Subgroups Age ⱕ 60 years ⬎ 60 years ECOG PS 0–1 2–4 Stage I–II III–IV Surgical resection No Yes Radiotherapy No Yes Histological type SLL FL Lpc
n
5-year PFS
p-Value
5-year OS
p-Value
13 13
42 ⫾ 13% 52 ⫾ 13%
0.46
56 ⫾ 13% 53 ⫾ 13%
0.10
15 9
57 ⫾ 13% 30 ⫾ 14%
0.02
73 ⫾ 11% 36 ⫾ 15%
0.03†
11 15
64 ⫾ 13% 24 ⫾ 13%
0.07
78 ⫾ 11% 32 ⫾ 12%
0.01†
20 6
43 ⫾ 10% 53 ⫾ 16%
0.15
50 ⫾ 11% 67 ⫾ 16%
0.19
8 18
13 ⫾ 12% 55 ⫾ 13%
0.06
26 ⫾ 16% 64 ⫾ 11%
0.13
10 10 6
56 ⫾ 17% 25 ⫾ 15% 33 ⫾ 19%
0.05*
67 ⫾ 16% 23 ⫾ 14% 50 ⫾ 20%
0.02*
ECOG PS, Eastern Cooperative Oncology Group performance status; SLL, small lymphocytic lymphoma; FL, follicular lymphoma; Lpc, lymphoplasmacytic lymphoma; PFS, progression-free survival; OS, overall survival. *Comparison between patients with SLL and FL. †Independent association between these variables (performance status and stage) and OS was confirmed by multivariate analysis. Conversely, no independent association between other variables (age, histological type, surgical resection, use of radiotherapy) and OS was detected.
addressing variables independently associated with OS confirmed that performance status and stage of disease were independently associated with OS, while age, histological type, surgical resection and use of radiotherapy were not (see Table III footnote).
Discussion This is the one of the largest studies to specifically address the clinical features, management and prognosis of iPBL. Differences in prognosis were observed between different histological types, with better results reported in patients with small lymphocytic lymphoma, who frequently achieved long-term remission and rarely died of lymphoma. The prognosis of patients with limited-stage lymphoplasmacytic lymphoma or follicular lymphoma was less favorable, with a higher proportion of tumor dissemination, possibly reflecting limitations in staging sensitivity. Patients with advancedstage iPBL showed response and survival rates similar to those patients with the same stage and histological type, but without skeleton involvement. The major limitations of this study are the retrospective design, the absence of a standard contemporary, central pathology review and the treatment given in a pre-positron emission tomography (PET) and pre-rituximab era. The percentage of iPBL among patients with lymphoma and bone involvement (5%) and the representation of the three pathological subtypes may not be accurate, as the database may not represent all patients with lymphoma and bone involvement treated in the reporting institutions. This may suggest patient selection bias and may affect the ratio among treatment options. The retrospective nature of the study resulted in treatment heterogeneity and small subgroups that limited the power of the comparisons. The absence of a central pathology review poses a risk that misclassification has occurred, and may be associated with bias. However,
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Indolent bone lymphomas 1799 selected cases were reviewed at participating institutions, which are specialized centers with high levels of expertise in the management of lymphomas. PET unavailability may have resulted in under-staging. Hopefully, the present results may be further improved in patients treated in the rituximab era. Although the efficacy of rituximab is heterogeneous among the three considered lymphoma categories, all of these lymphomas are CD20-positive, and the addition of this antibody may result in better disease control. Only one other study has identified as many indolent cases [5], reporting that indolent lymphomas constituted 5% of patients with PBL, the same prevalence rate as observed in our database. In pathology reviews of PBL, indolent disease is not specifically described [18], but is simply included among a list of rare lymphoma subtypes that occur in bone. The list also includes T-cell and Hodgkin lymphomas. In the present series, we found approximately equal numbers of small lymphocytic lymphomas and follicular lymphomas. We also found approximately equal numbers of limited and advanced stages. No patients with Richter syndrome were identified, although a case is reported in the literature [19]. The clinical features of iPBL were similar to those of the remainder of the IELSG #14 series, most of which were DLBCL, including the proportion of patients with pain, swelling, B symptoms and fracture. The sites of involvement, the presence of polyostotic disease and the types of treatment offered to patients were also similar, with most patients receiving a combination of chemotherapy and radiotherapy. Prognostic factors were identified, including performance status and disease stage, but also we noted that patients with small lymphocytic lymphoma had a better prognosis than those with either follicular lymphoma or lymphoplasmacytic lymphoma, although small numbers make these conclusions uncertain. Considering all subtypes together, the response to treatment was similar to that of DLBCL, but the 5- and 10-year rates of PFS and OS were not as good, with distant sites dominating the failure pattern. Therefore, treatment of iPBL should continue to include combinations of chemotherapy and radiotherapy, but with the addition of more effective systemic agents, such as rituximab, the results can be expected to improve. Molecular studies of these uncommon cases are likely to determine whether the iPBL subtypes are separate entities that deserve further consideration and possibly different therapeutic approaches compared to their nodal counterparts. In conclusion, with all the limitations of a retrospective study, such as lack of standardization and central pathology review, a series treated before rituximab and the relatively small number of patients, this study suggests differences in prognosis between different iPBL categories, with better results reported in patients with small lymphocytic lymphoma. Response and survival rates in patients with
Supplementary material available online Supplementary Appendix.
advanced-stage iPBL seem to be similar to those reported for patients with the same stage and histological type, but without skeleton involvement. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Fletcher CD. The evolving classification of soft tissue tumours: an update based on the new WHO classification. Histopathology 2006;48:3–12. [2] Limb D, Dreghorn C, Murphy JK, et al. Primary lymphoma of bone. Int Orthop 1994;18:180–183. [3] Ramadan KM, Shenkier T, Sehn LH, et al. A clinicopathological retrospective study of 131 patients with primary bone lymphoma: a population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann Oncol 2007;18:129–135. [4] Maruyama D, Watanabe T, Beppu Y, et al. Primary bone lymphoma: a new and detailed characterization of 28 patients in a single-institution study. Jpn J Clin Oncol 2007;37:216–223. [5] Jawad MU, Schneiderbauer MM, Min ES, et al. Primary lymphoma of bone in adult patients. Cancer 2010;116:871–879. [6] Heyning FH, Hogendoorn PC, Kramer MH, et al. Primary nonHodgkin’s lymphoma of bone: a clinicopathological investigation of 60 cases. Leukemia 1999;13:2094–2098. [7] Jones D, Kraus MD, Dorfman DM. Lymphoma presenting as a solitary bone lesion. Am J Clin Pathol 1999;111:171–178. [8] Hsieh PP, Tseng HH, Chang ST, et al. Primary non-Hodgkin’s lymphoma of bone: a rare disorder with high frequency of T-cell phenotype in southern Taiwan. Leuk Lymphoma 2006;47:65–70. [9] Lee HY, Kim SJ, Kim K, et al. Bone involvement in patients with stage IV diffuse large B-cell lymphoma: does it have a prognostic value? Leuk Lymphoma 2012;53:173–175. [10] Pettit CK, Zukerberg LR, Gray MH, et al. Primary lymphoma of bone. A B-cell neoplasm with a high frequency of multilobated cells. Am J Surg Pathol 1990;14:329–334. [11] Christie DR, Barton MB, Bryant G, et al. Osteolymphoma (primary bone lymphoma): an Australian review of 70 cases. Australasian Radiation Oncology Lymphoma Group (AROLG). Aust NZ J Med 1999;29:214–219. [12] Beal K, Allen L, Yahalom J. Primary bone lymphoma: treatment results and prognostic factors with long-term follow-up of 82 patients. Cancer 2006;106:2652–2656. [13] Durr HR, Muller PE, Hiller E, et al. Malignant lymphoma of bone. Arch Orthop Trauma Surg 2002;122:10–16. [14] Horsman JM, Thomas J, Hough R, et al. Primary bone lymphoma: a retrospective analysis. Int J Oncol 2006;28:1571–1575. [15] Brousse C, Baumelou E, Morel P. Primary lymphoma of bone: a prospective study of 28 cases. Joint Bone Spine 2000;67:446–451. [16] Achemlal L, Mikdame M, Nouijai A , et al. Dramatical improvement of chemoresistant bone lymphoma with rituximab. Clin Rheumatol 2006;25:394–395. [17] Cai L, Stauder MC, Zhang YJ, et al. Early-stage primary bone lymphoma: a retrospective, multicenter rare cancer network (RCN) study. Int J Radiat Oncol Biol Phys 2012;83:284–291. [18] Bhagavathi S, Micale MA , Les K, et al. Primary bone diffuse large B-cell lymphoma: clinicopathologic study of 21 cases and review of literature. Am J Surg Pathol 2009;33:1463–1469. [19] Hensel M, Buss EC, Tiemann M, et al. Secondary follicular lymphoma of the bone, transformed into large cell lymphoma, in a patient with chronic lymphocytic leukaemia: an uncommon manifestation of Richter’s syndrome. Eur J Haematol 2004;72:217–221.
ORIGINAL ARTICLE: CLINICAL
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The clinical features, management and prognosis of primary and secondary indolent lymphoma of the bone: a retrospective study of the International Extranodal Lymphoma Study Group (IELSG #14 study) Silvia Govi1*, David Christie2*, Silvia Mappa1, Emerenziana Marturano1, Marta Bruno-Ventre1, Carlo Messina1, Elías A. Gracia Medina3, David Porter4, John Radford5, Dae Seog Heo6, Yeon Park7, Barbara Pro8, Jayasingham Jayamohan9, Nick Pavlakis10, Emanuele Zucca11, Mary Gospodarowicz12 & Andrés J. M. Ferreri1; for the International Extranodal Lymphoma Study Group (IELSG) 1Unit of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy, 2Premion
and Bond University, Tugun, Australia, 3Servicio de Oncología Médica, Instituto Nacional de Oncología y Radiobiología, La Habana, Cuba, 4Auckland Hospital, Auckland, New Zealand, 5Christie Hospital, Manchester, United Kingdom, 6Seoul National University Hospital, Seoul, Korea, 7Korea Cancer Center Hospital, Seoul, Korea, 8M. D. Anderson Cancer Center, Houston, TX, USA, 9Westmead Hospital, Sydney, Australia, 10Royal North Shore Hospital, Sydney, Australia, 11Oncology Institute of Southern Switzerland, Bellinzona, Switzerland and 12Department of Radiation Oncology, Princess Margaret Hospital, Ontario Cancer Institute, Toronto, Canada
Introduction
Abstract Indolent lymphomas primarily involving the skeleton (iPBL) represent ⬍ 1% of all primary bone lymphomas. The management and prognosis have not been previously described. Patients with primary and secondary iPBL were selected from an international database of 499 patients with a histopathological diagnosis of non-Hodgkin lymphoma and skeleton involvement, and clinical features, management and prognosis were analyzed. Twenty-six (5%) patients had an iPBL. Ten patients had small lymphocytic lymphoma, 10 had follicular lymphoma and six had lymphoplasmacytic lymphoma. Eleven patients had limited stage and 15 had advanced disease. The overall response rate was 73% (95% confidence interval [CI] ⴝ 57–89%). Median follow-up was 58 months, and the 5- and 10-year progression-free survival (PFS) rates were 37 ⴞ 10% and 25 ⴞ 12%, respectively. Nine patients are alive, with 5- and 10-year overall survival (OS) rates of 46 ⴞ 10% and 29 ⴞ 11%, respectively. Patients with small lymphocytic lymphoma showed significantly better outcome than patients with follicular lymphoma. Performance status and stage of disease were independently associated with OS. The prognosis of patients with primary bone lymphoplasmacytic or follicular lymphoma was less favorable.
Primary bone lymphoma (PBL) is a rare disease, accounting for ∼3% of all primary bone malignancies, less than 5% of extranodal lymphomas and 1–2% of all malignant lymphomas in adults [1–5]. Almost 90% of patients with PBL present with diffuse large B-cell lymphoma (DLBCL) histological subtype [6,7]. The available literature shows relatively favorable outcomes for patients with limited-stage DLBCL of the bone, and recommends treatment with anthracycline-based chemotherapy followed or not by radiotherapy, depending on risk [3,6,7–17]. Conversely, the available literature on the clinical features, management and prognosis of indolent lymphomas primarily involving the skeleton is anecdotal and fragmentary. Indolent lymphomas represent ⬍ 1% of reported cases of PBL, with usually one or two cases in each reported series, which are not reported separately. A recent systematic review of PBL stated that primary follicular, small lymphocytic, marginal zone and lymphoplasmacytic lymphomas of bone are extremely rare [18]. Thus, studies reporting the clinical features, management and prognosis of primary bone indolent lymphoma (iPBL) in an adequate number of cases are needed. Against this background, we analyzed the clinical features, management and prognosis of 26 patients with indolent bone lymphoma (considering both primary and secondary
Keywords: Indolent lymphoma, primary bone lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma, follicular lymphoma, osteolymphoma
*These authors contributed equally. Correspondence: Andrés J. M. Ferreri, MD, Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 – Milan, Italy. Tel: 0039-02-26437649. Fax: 0039-02-26437625. E-mail: [email protected] There is an accompanying commentary that discusses this paper. Please refer to the issue Table of Contents. Received 3 July 2013; revised 26 September 2013; accepted 3 October 2013
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Indolent bone lymphomas 1797 involvement) registered in a multicenter clinicopathological database of 499 cases of non-Hodgkin lymphoma and skeleton involvement, performed under the sponsorship of the International Extranodal Lymphoma Study group (IELSG).
Patients and methods
Leuk Lymphoma 2014.55:1796-1799. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/05/14. For personal use only.
Study population The members of the IELSG were invited to participate in a retrospective study focused on PBL (IELSG #14 study). A questionnaire requesting information about patient characteristics, clinical presentation, diagnosis, staging, treatment, objective response, site and date of relapse, second-line treatment, late effects and survival of patients with a histopathological diagnosis of non-Hodgkin lymphoma and skeleton involvement was sent to referring centers. To investigate clinical and therapeutic features of iPBL, only patients diagnosed and treated at the participating institutions between 1980 and 2000 and fulfilling the following criteria were considered: (1) age ⱖ 18 years; (2) histological diagnosis of indolent lymphoma (small lymphocytic lymphoma, follicular lymphoma or lymphoplasmacytic lymphoma); (3) disease involving at least one bone; (4) complete staging work-up with at least enhanced total-body computed tomography (CT) scan and bone marrow biopsy; (5) no evidence of human immunodeficiency virus type 1 (HIV-1) infection (negative serologic tests; absence of epidemiological risk, opportunistic infections or lymphopenia for patients diagnosed in the early 1980s) or other immunodeficiencies. Bone involvement was defined either by radiological procedures (radiography, CT scan, magnetic resonance imaging [MRI]) or histopathological examination of surgical biopsies. Whenever possible, histopathological specimens were reviewed by a local pathologist before data submission, but there was no central pathology review.
Statistical considerations The Fisher exact test for categorical variables was used to compare clinical characteristics and response rates of the therapeutic subgroups. Survival curves were generated by the Kaplan–Meier method. Overall survival (OS) was calculated from the date of pathologic diagnosis to death or to the last date of follow-up, while progression-free survival (PFS) was calculated from the first day of treatment to relapse, progression or death, or to the last date of follow-up. Impact on survival of clinical and treatment-related variables was evaluated by comparing the survival curves by means of the log-rank test. The independent prognostic value of variables was analyzed using the Cox proportional hazards model. All of the probability values were two-sided. Analyses were carried out using the Statistica 4.0 statistical package for Windows (1993; Statsoft Inc., Tulsa, OK).
Results Patient characteristics The database of the IELSG #14 study included 499 patients from 32 institutions in 14 countries (a list of participating centers with the number of registered patients/center is given
in the Supplementary Appendix to be found online at http:// informahealthcare.com/doi/abs/10.3109/10428194.2013. 853298). Twenty-six (5%) patients from that database had a histological diagnosis of indolent lymphoma, with a median age of 60 years (range 27–80) and a male:female ratio of 1.3 (Table I). Ten patients had small lymphocytic lymphoma, 10 had follicular lymphoma and six had lymphoplasmacytic lymphoma. Ten patients had stage I disease (single osseous lesion), one had stage II disease (single osseous lesion and regional lymphadenopathies) and 15 patients had stage IV disease (systemic disease plus at least a bone lesion). There was no significant difference in the distribution of histological types between the two stage subgroups, although there was a trend toward a higher prevalence of follicular lymphoma among patients with advanced stage. Pain was the most common presenting symptom so far, which was recorded in 10 (91%) patients with limited stage and in 13 (87%) with advanced disease. Pathological fracture was recorded in one patient per subgroup. Multifocal lesions were observed in 14 (93%) patients with advanced disease, in which the most common sites were pelvic bones (47%) and the spine (40%). The spine (27%) was the most common site of disease in patients with limited-stage iPBL.
Treatment Various treatment strategies were employed according to physician discretion (Table I). Radiation treatment alone was recorded in four patients; chemotherapy was indicated as exclusive treatment in eight patients, and followed by radiotherapy in 14. Cyclophosphamide, doxorubicin, Table I. Patients’ characteristics.
Median age; years (range) Males Histological type Small lymphocytic lymphoma Follicular lymphoma Lymphoplasmacytic lymphoma Clinical presentation Fever Swelling Weight loss Pain Tumefaction Fracture Sites of involvement Skull Column Pelvis Humerus Femur Upper limbs Lower limbs Lymph nodes Cerebrospinal fluid Extranodal sites Bone marrow Treatment Radiotherapy alone Chemotherapy ⫹ radiotherapy Chemotherapy alone *Patients with stage I or stage II lymphoma.
Limited disease* (n ⫽ 11)
Stage IV disease (n ⫽ 15)
63 (27–77) 5 (46%)
57 (40–80) 10 (67%)
5 (46%) 3 (27%) 3 (27%)
5 (33%) 7 (47%) 3 (20%)
1 (9%) 0 (0%) 0 (0%) 10 (91%) 2 (18%) 1 (9%)
3 (20%) 1 (7%) 1 (7%) 13 (87%) 5 (33%) 1 (7%)
2 (18%) 3 (27%) 2 (18%) 0 (0%) 2 (18%) 0 (0%) 2 (18%) 1 (9%) – – –
4 (27%) 6 (40%) 7 (47%) 2 (14%) 5 (33%) 1 (7%) 1 (7%) 4 (27%) 1 (7%) 5 (33%) 4 (27%)
4 (36%) 4 (36%) 3 (27%)
0 (0%) 10 (66%) 5 (33%)
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vincristine and prednisone (CHOP) or CHOP-like were the most commonly used regimens (n ⫽ 15). The median radiation dose was 35 Gy (range 25–45). Irradiated volume included the whole bone in 11 patients, and partial bone in seven. Management according to each histological type is reported in Table II.
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Response and survival Response to first-line treatment was complete in 12 patients (complete response rate [CRR] ⫽ 46%; 95% confidence interval [CI] ⫽ 28–64%) and partial in seven, with an overall response rate (ORR) of 73% (95% CI ⫽ 57–89%). At a median follow-up of 58 months (range 8–120), 16 patients experienced lymphoma treatment failure (progressive disease or relapse after initial response), with a 5- and 10-year PFS of 37 ⫾ 10% and 25 ⫾ 12%, respectively. Failures involved the primary site of disease in two patients, other bones in four, lymph nodes in two and distant organs in eight. All failed patients received salvage treatment, with a significant survival benefit (second remission longer than the first) in onethird of the patients. Nine patients are alive, with a 5- and 10-year OS of 46 ⫾ 10% and 29 ⫾ 11%, respectively. Eleven patients died of lymphoma and six died of unrelated causes (three with no evident disease [NED]). Outcome according to histological type is summarized in Table II. Among the 11 patients with limited-stage lymphoma, four patients received radiotherapy alone, three received chemotherapy alone and four patients received both therapies. All eight patients who received radiotherapy achieved a complete remission (CR), and only three of them experienced relapse, whereas only one of the three patients managed without radiotherapy achieved a CR, and all of them experienced relapse. The addition of chemotherapy was not associated with different OS in irradiated patients; at a median follow-up of 45 months, only one patient had died of lymphoma progression.
Subgroup analysis Univariate analyses are summarized in Table III. Patients with limited disease showed better PFS and OS. Patients with small lymphocytic lymphoma showed a significantly better PFS and OS than patients with follicular lymphoma. Regardless of lymphoma category, three of the four patients treated with radiotherapy alone were alive at a follow-up of 24–120 months (median 68⫹). A multivariate analysis Table II. Management and outcome per histological type. Lymphoma
Therapy (n)
Stage I CR – PR Failures
Patients alive (months)
SLL
RT (2) CHT (2) CHT ⫹ RT (6)
2 1 1
2–0 1–1 3–2
0 2 3
1 (120) 0 4 (31–72)
FL
RT (1) CHT (3) CHT ⫹ RT (6)
1 0 2
1–0 0–2 3–1
1 2 3
1 (96) 1 (8) 1 (58)
Lpc
RT (1) CHT (3) CHT ⫹ RT (2)
1 1 1
1–0 0–0 1–1
0 3 2
1 (29) 0 0
SLL, small lymphocytic lymphoma; FL, follicular lymphoma; Lpc, lymphoplasmacytic lymphoma; n, number of patients per subgroup; RT, radiotherapy; CHT, chemotherapy; CR, complete remission; PR, partial response.
Table III. Therapeutic outcome of analyzed subgroups. Subgroups Age ⱕ 60 years ⬎ 60 years ECOG PS 0–1 2–4 Stage I–II III–IV Surgical resection No Yes Radiotherapy No Yes Histological type SLL FL Lpc
n
5-year PFS
p-Value
5-year OS
p-Value
13 13
42 ⫾ 13% 52 ⫾ 13%
0.46
56 ⫾ 13% 53 ⫾ 13%
0.10
15 9
57 ⫾ 13% 30 ⫾ 14%
0.02
73 ⫾ 11% 36 ⫾ 15%
0.03†
11 15
64 ⫾ 13% 24 ⫾ 13%
0.07
78 ⫾ 11% 32 ⫾ 12%
0.01†
20 6
43 ⫾ 10% 53 ⫾ 16%
0.15
50 ⫾ 11% 67 ⫾ 16%
0.19
8 18
13 ⫾ 12% 55 ⫾ 13%
0.06
26 ⫾ 16% 64 ⫾ 11%
0.13
10 10 6
56 ⫾ 17% 25 ⫾ 15% 33 ⫾ 19%
0.05*
67 ⫾ 16% 23 ⫾ 14% 50 ⫾ 20%
0.02*
ECOG PS, Eastern Cooperative Oncology Group performance status; SLL, small lymphocytic lymphoma; FL, follicular lymphoma; Lpc, lymphoplasmacytic lymphoma; PFS, progression-free survival; OS, overall survival. *Comparison between patients with SLL and FL. †Independent association between these variables (performance status and stage) and OS was confirmed by multivariate analysis. Conversely, no independent association between other variables (age, histological type, surgical resection, use of radiotherapy) and OS was detected.
addressing variables independently associated with OS confirmed that performance status and stage of disease were independently associated with OS, while age, histological type, surgical resection and use of radiotherapy were not (see Table III footnote).
Discussion This is the one of the largest studies to specifically address the clinical features, management and prognosis of iPBL. Differences in prognosis were observed between different histological types, with better results reported in patients with small lymphocytic lymphoma, who frequently achieved long-term remission and rarely died of lymphoma. The prognosis of patients with limited-stage lymphoplasmacytic lymphoma or follicular lymphoma was less favorable, with a higher proportion of tumor dissemination, possibly reflecting limitations in staging sensitivity. Patients with advancedstage iPBL showed response and survival rates similar to those patients with the same stage and histological type, but without skeleton involvement. The major limitations of this study are the retrospective design, the absence of a standard contemporary, central pathology review and the treatment given in a pre-positron emission tomography (PET) and pre-rituximab era. The percentage of iPBL among patients with lymphoma and bone involvement (5%) and the representation of the three pathological subtypes may not be accurate, as the database may not represent all patients with lymphoma and bone involvement treated in the reporting institutions. This may suggest patient selection bias and may affect the ratio among treatment options. The retrospective nature of the study resulted in treatment heterogeneity and small subgroups that limited the power of the comparisons. The absence of a central pathology review poses a risk that misclassification has occurred, and may be associated with bias. However,
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Indolent bone lymphomas 1799 selected cases were reviewed at participating institutions, which are specialized centers with high levels of expertise in the management of lymphomas. PET unavailability may have resulted in under-staging. Hopefully, the present results may be further improved in patients treated in the rituximab era. Although the efficacy of rituximab is heterogeneous among the three considered lymphoma categories, all of these lymphomas are CD20-positive, and the addition of this antibody may result in better disease control. Only one other study has identified as many indolent cases [5], reporting that indolent lymphomas constituted 5% of patients with PBL, the same prevalence rate as observed in our database. In pathology reviews of PBL, indolent disease is not specifically described [18], but is simply included among a list of rare lymphoma subtypes that occur in bone. The list also includes T-cell and Hodgkin lymphomas. In the present series, we found approximately equal numbers of small lymphocytic lymphomas and follicular lymphomas. We also found approximately equal numbers of limited and advanced stages. No patients with Richter syndrome were identified, although a case is reported in the literature [19]. The clinical features of iPBL were similar to those of the remainder of the IELSG #14 series, most of which were DLBCL, including the proportion of patients with pain, swelling, B symptoms and fracture. The sites of involvement, the presence of polyostotic disease and the types of treatment offered to patients were also similar, with most patients receiving a combination of chemotherapy and radiotherapy. Prognostic factors were identified, including performance status and disease stage, but also we noted that patients with small lymphocytic lymphoma had a better prognosis than those with either follicular lymphoma or lymphoplasmacytic lymphoma, although small numbers make these conclusions uncertain. Considering all subtypes together, the response to treatment was similar to that of DLBCL, but the 5- and 10-year rates of PFS and OS were not as good, with distant sites dominating the failure pattern. Therefore, treatment of iPBL should continue to include combinations of chemotherapy and radiotherapy, but with the addition of more effective systemic agents, such as rituximab, the results can be expected to improve. Molecular studies of these uncommon cases are likely to determine whether the iPBL subtypes are separate entities that deserve further consideration and possibly different therapeutic approaches compared to their nodal counterparts. In conclusion, with all the limitations of a retrospective study, such as lack of standardization and central pathology review, a series treated before rituximab and the relatively small number of patients, this study suggests differences in prognosis between different iPBL categories, with better results reported in patients with small lymphocytic lymphoma. Response and survival rates in patients with
Supplementary material available online Supplementary Appendix.
advanced-stage iPBL seem to be similar to those reported for patients with the same stage and histological type, but without skeleton involvement. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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