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Tumour Review

Primary and secondary bone lymphomas

Carlo Messina a,1, David Christie b,1, Emanuele Zucca c,1, Mary Gospodarowicz d,1, Andrés J.M. Ferreri a,1,⇑a Unit of Lymphoid Malignancies, Department of Onco-Haematology, San Raffaele Scientific Institute, Milan, Italyb Genesiscare and Bond University, Inland Dr., Tugun, QLD, Australiac Oncology Institute of Southern Switzerland, Bellinzona, Switzerlandd Department of Radiation Oncology, Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada

a r t i c l e i n f o

Article history:Received 15 December 2014Received in revised form 20 January 2015Accepted 1 February 2015

Keywords:Primary bone lymphomaOsteolymphomaExtranodal lymphomaDiffuse large B-cell lymphomaPolyostotic lymphoma

a b s t r a c t

Recent studies have contributed to the enhancement of clinical and molecular knowledge on bone lym-phomas, a group of rare malignancies with particular characteristics. Nevertheless, several questionsremain unanswered and the level of evidence supporting some diagnostic and therapeutic decisionsremains low. Currently, three different forms of bone lymphomas can be distinguished: the primary bonelymphoma, consisting of a single bone lesion with or without regional lymphadenopathies; the polyos-totic lymphoma, consisting of multifocal disease exclusively involving the skeleton; and the disseminatedlymphoma with secondary infiltration of the skeleton. The first two forms exhibit a good prognosis,requiring treatments similar to those commonly used for nodal lymphomas of the same category, butseveral issues regarding the role of surgery and local control of the disease, the sequence of treatment,radiation volumes and doses, management of pathological fractures and prevention of late sequelaedeserve particular attention. Due to its rarity, prospective trials exclusively focused on bone lymphomasappear unrealistic, thus, critical revision of our own experience and analyses of large cumulative series aswell as molecular studies on archival cases remain valid alternatives to improve our knowledge on thisobscure lymphoproliferative malignancy.

The present review is based on the analysis of the largest available database of bone lymphomas estab-lished under the sponsorship of the International Extranodal Lymphoma Study Group (IELSG) as well ason the critical revision of related literature. We provide recommendations for diagnosis, staging, treat-ment, and response assessment of these patients in everyday practice as well as for the managementof special conditions like pathological fractures, indolent forms and central nervous system prophylaxis.

� 2015 Elsevier Ltd. All rights reserved.

Introduction

Every lymphoma category can involve the skeleton, as an exclu-sive lesion or as a part of a disseminated disease. Although skeletalinvolvement is relatively common in non-Hodgkin lymphomas, theavailable literature on diagnostic and therapeutic management ofprimary bone lymphomas, that is lymphomas exclusively involvingthe skeleton, is sparse and fragmentary, mostly reported beforeworldwide use of rituximab and positron emission tomography(PET). The level of evidence supporting therapeutic decisions inprimary bone lymphomas is very low as no prospective trials havebeen published. The relevant literature is almost exclusively

constituted by small, retrospective series often furnishing conclu-sions on unreliable subgroup analyses, and with important inter-pretation biases due to stage migration and use of obsoletehistopathological classifications. An additional bias regards theuse of radiotherapy as exclusive treatment in unfit patients,whereas recent advances in supportive care have extended thenumber of patients treated with curative intent. As a consequenceof these methodological caveats and the impossibility of conduct-ing large prospective trials, several therapeutic questions remainopen: the role of surgery and radiotherapy, the best radiation vol-umes and doses, the most effective chemoimmunotherapy combi-nation, and prognostic factors, among others. In this complicatedcontext, large, retrospective studies of cumulative, unselected ser-ies remain a valid tool to improve our knowledge on primary bonelymphomas.

This review is based on the analysis of the largest availabledatabase of bone lymphomas, established under the sponsorshipof the International Extranodal Lymphoma Study Group (IELSG),

http://dx.doi.org/10.1016/j.ctrv.2015.02.0010305-7372/� 2015 Elsevier Ltd. All rights reserved.

⇑ Corresponding author at: Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, San Raffaele ScientificInstitute, Via Olgettina 60, 20132 Milan, Italy. Tel.: +39 02 26437649; fax: +39 0226437625.

E-mail address: andres.ferreri@hsr.it (A.J.M. Ferreri).1 International Extranodal Lymphoma Study Group.

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as well as on the critical analysis of related literature. It providesrecommendations for the diagnosis, staging, treatment, andresponse assessment of these patients, and addresses themanagement of special conditions like pathological fractures, indo-lent bone lymphomas and CNS dissemination risk in everydaypractice.

Definition, incidence and epidemiology

Criteria used to define and classify primary bone lymphomaschanged several times in the last decades. While there is generalagreement that cases with a solitary lesion arising in a bone shouldbe considered as a primary bone lymphomas, there is no consen-sus over the best categorization of cases with multifocal osseousdisease or cases with concomitant soft tissue, visceral and/orlymph nodal infiltration [1–5]. In the previous version of theWorld Health Organization (WHO) classification of tumours of softtissue and bone, primary bone lymphoma was defined by (1) a sin-gle skeletal tumour without regional lymph node involvement, orby (2) multiple bone lesions without visceral or lymph nodeinvolvement [6,7]. Conversely, the last versions of the WHO Clas-sification does not provide definition criteria for these disorders[8]. The opinion of the authors is that only cases with a clear boneorigin should be considered as primary bone lymphomas, that is,primary bone lymphomas should include cases with a single bonylesion, with or without involvement of regional lymph nodes aswell as cases with multiple bony lesions, but without lymph nodalor visceral disease. The latter subgroup is usually called ‘‘multifo-cal osseous lymphoma’’ or ‘‘polyostotic lymphoma’’, and repre-sents an entity with particular clinical and prognosticcharacteristics [9]. Disseminated lymphomas with concomitantinvolvement of the skeleton should be defined as ‘‘secondary bonelymphoma’’. In these cases, bone involvement counts as a systemicextra-nodal site and the disease should be considered to be stageIV [10]. A lymphoma that has arisen in soft tissues, lymph nodesor other organs and infiltrates an adjacent bone secondarily shouldnot be considered to be a primary bone lymphomas. However, thisis a common issue in many types of extranodal lymphomas and,similarly, in bone lymphomas the differences are not so clear cutin practice and it may be very difficult to separate these two situ-ations. Special difficulties arise in specific anatomical locations; forinstance, it is difficult to distinguish lymphomas primarily arisingin nasal-paranasal bones from lymphomas arising in the mucosalsurfaces of paranasal sinuses. Similarly, it is often difficult to dis-tinguish the primary site of disease in lymphomas of the spine(i.e., bone or nearby soft tissues) [7]. In many cases, a subjectivejudgement will be required about whether a case should be cate-gorised as primary bone lymphomas or lymphoma secondarilyaffecting the bone.

The exact incidence of primary bone lymphomas is difficult todefine, but it seems to account for about 5% of extranodal lympho-mas, <1% of all non-Hodgkin lymphomas (NHL), and 3–7% of allmalignant bone tumours [2,6,11]. Most reports suggest a slightmale prevalence (male/female ratio: 1.5), with a median age atdiagnosis ranging between 45 and 60 years old, and a wide range(15–99 years); paediatric cases have been also reported [12–14].No racial or geographic predominance has been demonstrated.

Primary bone lymphomas have been reported in associationwith some specific conditions including HIV infection [15,16], sar-coidosis [17], Gaucher disease [18,19], hereditary exostoses [20],Paget’s disease [21], osteomyelitis [4], and following some specifictreatments including hip replacements [22,23], renal transplants[24], and cladribine therapy [25]. However, none of these putativeassociations are consistent enough to suggest a true relationship orpredisposition towards the development of primary bonelymphomas.

Clinical presentation

Table 1 summarizes the main patient characteristics at presen-tation reported in the largest available series of bone lymphomas[9,26]. Although the tumour itself can affect fitness, particularlyif it occurs in weight-bearing bones, most patients have ECOG per-formance status of 0–1. Pain is the most common presenting symp-tom (80–95%), tumour mass is present in 30–40% of cases andpathological fracture in 15–20%, with a mean duration of the per-iod between symptoms and diagnosis of 8 months [11]. Mostpatients have an early-stage disease at presentation [27]. Everybone is a potential site for lymphoma development, but the femuris the most commonly affected [4]. Lymphomatous lesions occurmost often in the diaphysis, whereas metaphysis and epiphysisinvolvement often reflects progressive disease [28]. Small bonesof the hands and feet are rarely involved. Spinal cord compressionis the first presenting complication in 16% of cases [29]. Pelvicbones seem to be more commonly involved in Japanese studies,but these series were mostly constituted by patients with dissem-inated lymphoma [30]. Osteolysis and hypercalcemia are observedin 5–15%, of patients, mostly related to progressive disease. Symp-toms related to hypercalcemia, such as constipation, lethargy andsomnolence are uncommon.

Radiographic findings

Radiographic findings of primary bone lymphomas are usuallynon-specific, with important limitations to distinguish lymphomasfrom other primary bone tumours like Ewing’s sarcoma, osteogenicsarcoma and chondrosarcoma. On plain films, lesions are mostlylytic, but half of the patients have also osteoblastic lesions, andboth patterns can coexist, even in the same bone [28]. The bonecortex shows a mixture of permeative, moth-eaten or destructivepatterns. The periosteum often shows reactive changes, and fea-tures usually occurring in osteosarcoma, like onionskin layering,breach of the periosteum or sunburst appearance, can be occasion-ally recorded in primary bone lymphomas.

Table 1Patient’s characteristics at presentation in the IELSG-14 series.

Limited stage DLBCL(n = 161)

MB-DLBCL(n = 37)

Stage IV DLBCL(n = 63)

Males 51% 59% 40%Median age; years (range) 55 (18–99) 53 (17–75) 62 (28–83)

Clinical presentation (%)ECOG-PS > 1 15% 38% 62%High LDH serum level 34% 30% 65%B symptoms 9% 24% 30%Pain 82% 92% 90%Swelling 40% 45% 34%Bulky disease 23% 15% 32%Fracture 15% 25% 29%

Sites of involvement (%)Skull 15% 32% 19%Spinal cord 17% 65% 51%Pelvis 17% 32% 33%Humerus 7% 13% 17%Forearm 7% 16% 8%Femur 20% 38% 24%Forefoot 13% 19% 14%Lymph nodes – – 28%Cerebrospinal fluid – 3% 1%Bone marrow – – 35%Other 4% – –

DLBCL = diffuse large B-cell lymphoma; MB-DLBCL = multifocal bone diffuse largeB-cell lymphoma; ECOG PS: Eastern Cooperative Oncology Group PerformanceStatus; LDH lactate dehydrogenase.

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The standard contrast-enhanced computed tomography (CT)scan is the primary modality for staging, restaging, and follow-upof lymphoma patients. CT demonstrates the boundaries of anyextraosseous extension as well as indicating cortical breakthroughby the tumour [31], and may detect osteolysis, osteosclerosis andfragments of bone sequestra [32]. Magnetic Resonance Imaging(MRI) reveals the extent of disease in more detail, particularly byidentifying cortical changes such as linear channels of corticaldestruction, as well as intratumoural fibrosis, replacement of tra-becular bone and bone marrow by tumour [33,34]. Abnormal sig-nal intensity areas are visible on both T1 and T2 weightedimages with minimal contrast enhancement, hypointense in T1-weighted and hyperintense in T2-weighted [35]. Accordingly toits relatively high cellularity [35], primary bone lymphomas exhi-bit restricted diffusion with low apparent diffusion co-efficiencyvalue on diffusion-weighted imaging [36]. An increased post-treat-ment apparent diffusion co-efficiency value correlates with highertumour necrosis [37] and is usually consistent with decreased18fluorodeoxyglycose (18FDG) uptake on 18FDG-PET scan [38], sug-gesting tumour response (see below).

Functional imaging

Bone lesions usually result in increased uptake on99technecium scanning, while functional imaging (18FDG-PET)also reveals associated soft tissue involvement. 18FDG-PET displaya higher specificity and sensitivity than conventional bone scin-tigraphy in identifying lymphomatous infiltration of skeleton[39]. 18FDG-PET-computed tomography scan (PET-CT) is a hybridimaging technique that simultaneously provides functional andanatomical information, with a higher sensitivity and specificitythan standard CT scan in lymphoma patients [40–44]. In stagingof extranodal lymphomas, sensitivity, specificity and accuracy ofPET-CT are 97%, 100% and 98% compared to 87%, 85% and 84%of CT [44]; diagnostic sensitivity is not correlated to lymphomacategory [45]. Disagreements between PET-CT and CT usuallyregard spleen involvement or extranodal lesions, like bonemarrow, bone, thyroid, and prostate [45]. In fact, diagnostic sen-sitivity of CT in lymphoma patients with bone lesions is 17%, andaddition of this procedure to PET/CT does not further improvediagnostic sensitivity [46]. Conversely, the addition of18FDG-PET to CT scan results in upstaging in 42% of lymphomapatients, with a low rate of false positive scans [46]. Although itis supported only by small, retrospective studies, PET-CT is rec-ommended by the recent Lugano Classification as a standard toolfor initial evaluation, staging and response assessment ofFDG-avid lymphomas, whereas CT plays a central role in non-avidlymphoma categories [47].

Diagnosis

A clinic-radiological suspicion of bone lymphoma must be con-firmed by histopathological examination (morphological exam,immunohistochemistry and molecular analyses) of a diagnosticsample obtained by surgical procedure. This is mandatory to con-firm lymphomatous nature and to define histotype since currentknowledge and available radiologic tools do not allow a distinc-tion among the different lymphoma categories involving the skel-eton. Excision biopsy should be avoided; biopsies should belimited in size to reduce the risk of pathological fracture. Somebony sites such as the skull base can be particularly difficult tobiopsy [48], with the risk of false negative results and delayeddiagnosis [49]. In cases with stage-IIE disease, lymphadenectomyis advisable because it is associated with a lower risk of

orthopaedic sequelae and facilitates pathologist’s diagnostic per-formance. Interestingly, a role of serum soluble interleukin-2receptor (sIL-2R) levels to achieve a non-surgical diagnosis ofprimary bone lymphomas was recently suggested [50,51]; nor-malized serum sIL-2R levels seems to be consistent with a thera-peutic response in primary bone lymphomas [52]. These findingsneed for further investigation and confirmation in well-designedstudies.

Pathology, morphology and immunophenotype

Histopathological diagnosis and categorization of primary bonelymphomas can be difficult due to some frequent problems likecrush artefacts in biopsy specimens [53], the presence of reticulumor hyalinised fibrosis, inflammation and some specific diagnostictraps, including sarcoma-like spindle cells and carcinoma-like clus-tering [6].

Diffuse large B-cell lymphoma (DLBCL) is the most common his-tological subtype of lymphoma, either primarily or secondarilyinfiltrating the skeleton. It accounts for 70–80% of all bone lympho-mas [1,5,29,30,54], with rare to anecdotal occurrences of follicular,marginal zone, lymphoplasmacytic, anaplastic large cell, NK/T-cell,Burkitt, and Hodgkin lymphomas [55,56]. Morphologically, tumourcells are large sized and consistent with follicle centre or centrob-lastic cell type, often with nuclear cleavage [4,57,58]; large mul-tilobated cells are reported in around half the cases. Evidence ofgerminal centre (GC) derivation has been noted in at least 50% ofcases [59]. Tumour cells are immunoreactive for B-cell markers:CD45, CD20, CD21, CD45, CD79a [53,60,61]; immunoreactivityfor CD75 and CD10 is variable [62]. T-cell markers are usually neg-ative, but small CD3+ cells are often present. BCL-2 and BCL-6immunoreactivity has been reported in 35% and 69% of cases,respectively [62]. Monotypic IgG, IgH and HLA-DR have been noted[61].

Available data on primary bone T-cell lymphomas are sparse;primary bone T-cell lymphomas do not exhibit distinctive featuresthan extra-osseous T-cell lymphomas. Most reported cases of pri-mary bone T-cell lymphomas are anaplastic large-cell lymphoma(CD3�/+; CD43+/�; CD30+), often associated witht(2;5)(p23;q35) and ALK-1 expression [62–64].

Cytogenetic and molecular abnormalities

Cytogenetic and molecular studies of primary bone lymphomasare limited and usually relate to DLBCL. A monoclonal patternassessed by PCR is detected in 54% of cases, IgH gene rearrange-ment in 72% [60] and BCL-2 translocation in 5% of cases [62]. Dis-crepancy between high BCL2 protein expression (55–70%) and lowprevalence of BCL2/IgH rearrangements (4%) [65] indicates thatother mechanisms (e.g., gene amplification) may be responsiblefor the BCL2 protein over-expression in primary bone DLBCL. Stud-ies using fluorescence in situ hybridization has shown BCL2 and c-MYC translocations respectively in 28% and 9% of primary boneDLBCL; none of these cases showed BCL6, PAX5, ALK, and CCND1rearrangements [66]. These features seem to provide specific char-acteristics to primary bone DLBCL in comparison with otherextranodal B-cell lymphomas. Most primary bone lymphomas are‘‘de novo’’ DLBCL with a follicle-centre origin, which is suggestedby frequent MUM1 positivity and less common BCL-6 mutations[67–69]. To date, there are no published studies evaluating geneexpression profiles in primary bone DLBCL.

Increased expressions of osteoclast-activating factors, such asMIP-1alpha, MIP-1beta and RANKL, in primary bone DLBCL suggesta potential causative role in osteolysis and hypercalcemia [33,70].

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Staging

Diagnostic tests and procedures in the initial work-up ofpatients with primary bone lymphomas are listed in Table 2. Stageof disease is defined according to the Ann Arbor staging system[71]. However, this staging system has some important limitationswhen attempting to analyze different stage subgroups and to com-pare reported studies. Based on their different prognosis and out-come (Fig. 1), the IELSG staging system has been proposed(Table 3), where bone lymphomas are classified into four differentstages: stage IE = single bony lesion; IIE = single bony lesion plusregional lymphadenopathy; IVE = polyostotic lymphoma; andIV = conventional stage-IV lymphoma with skeleton involvement.Most patients with bone DLBCL present with unifocal disease,

but improvement in sensitivity and specificity of radiologic andfunctional procedures led to increasing detection of multifocal dis-ease. This suggests that multifocal disease, both within a singlebone (monostotic disease) and in different bones (polyostotic dis-ease), was underestimated in the past decades. Direct soft tissueinfiltration is detected in about 20% of patients, but this is superflu-ous to staging, therapeutic and prognostic considerations (seeTable 4).

Prognosis

The survival of patients with primary bone DLBCL is signifi-cantly related to disease stage, with the 5-year overall survival(OS) varying from 82% for patients with stage-IE disease to 38%for patients with disseminated DLBCL and skeleton involvement(Fig. 1). In early-stage disease, relapses occur equally within andoutside the primary sites of disease, with local and systemicrelapse rate of 10% and 17%, respectively [72]. In polyostotic lym-phomas, most relapses exclusively involve the skeleton, withinvolvement of secondary sites in 21% of recurrences; the exclusiveinvolvement of bones both at presentation and at relapse seem to

Table 2Staging procedures in patients with bone lymphoma.

Test/procedureDemographics and medical history*

Physical examinationBlood tests#

Chest X-rayContrasted CT scan of the neck, chest, abdomen, and pelvisMRI of bony lesions18FDG-PETBone marrow biopsy

In case of suspicion of involvement of particular organsCerebrospinal fluid (CSF) examination§

Gadolinium-enhanced brain MRI§

Gastrointestinal tract endoscopyBlood smears

* This includes family history, exposure to a toxic agent, prior malignancies,analysis of comorbidities.

# This includes full blood count, alkaline phosphatase, lactate dehydrogenase,erythrocyte sedimentation rate, C-reactive protein, beta-2 microglobulin and pro-tein electrophoresis.§ In patients with high risk of CNS dissemination (see ‘‘CNS prophylaxis’’).

Stage IE Stage IIE Stage IVE Stage IV

0 12 24 36 48 60 72 84 96 108

Months

0,0

0,2

0,4

0,6

0,8

1,0

Prob

abilit

y O

S

Fig. 1. Overall survival curves of bone DLBCL according to stage of disease. Stage IE: single bone lesions without regional lymphadenopathies; stage IIE: single bone lesionsplus regional lymphadenopathies; stage IVE: polyostotic DLBCL (multifocal lymphoma involving exclusively the skeleton); stage IV: advanced-stage DLBCL with secondaryinvolvement of the skeleton. Only patients managed with primary anthracycline-based chemotherapy followed or not by radiotherapy were considered. Similar results wereobtained when the whole unselected subgroups were considered.

Table 3IELSG staging system for DLBCL of the bone.

IELSGstage

Lymphoma extension Ann Arborstage

IE Single bony lesion IEIIE Single bony lesion with involvement of regional

lymph nodesIIE

IVE Multifocal disease in a single bone or lesions inmultiple bones in a disease exclusively limited to theskeleton (without lymph nodal or visceral disease) –called also ‘‘multifocal osteolymphoma’’ or‘‘polyostotic lymphoma’’

IV

IV Disseminated lymphoma with at least one bonylesion

IV

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suggest a homing mechanism in polyostotic lymphoma [73,74],but molecular and biological explanations for this behaviourremain unknown. In these patients, half of the deaths are due tolymphoma [9].

Overall, prior to the IELSG-14 study [9,26,55,75], no consistentprognostic factors were noted. Several unconfirmed prognostica-tors have been recorded in undersized, retrospective studies withevident selection biases [1,3,5,29,59,76–79]. Conventional Interna-tional Prognostic Index (IPI) plays a prognostic role in patients withadvanced-stage DLBCL with skeleton involvement but not in poly-ostotic lymphoma and primary bone lymphomas [9,80]. This isdue to the fact that stage and number of extranodal sites have novariability in primary bone lymphomas. Importantly, the IELSG-14 study has revealed that age, performance status and serumLDH levels, the three remaining IPI variables, are independentlyassociated with OS in every subgroup of bone lymphomas.

The prognostic significance of the phenotypic and genetic char-acteristics of primary bone DLBCL has been studied in a few series.In fact, the germinal centre (GC) phenotype and related molecularfeatures (CD10 expression, BCL-6 mutations, translocations involv-ing 3q27) are associated with favourable outcome in primary boneDLBCL [30,62,65,81], whereas non-GC signature and related fea-tures (immunoblastic variant, MUM1 expression) are unfavourablepredictors in DLBCL of the bone [82,83]. Prognosis is poorer in pri-mary bone T-cell lymphomas than in primary bone B-cell lympho-mas [30,84], in CD56-positive ALCL in particular [85].

Treatment of different clinical forms

Stage IE-IIE DLBCL of the bone (or primary bone DLBCL)

Different strategies like chemotherapy, immunotherapy, sur-gery and radiotherapy have been used to treat primary bone DLBCL,a separate entity usually displaying favourable clinical features andgood prognosis. The role of surgery in primary bone lymphomas islimited to sampling for histopathological diagnosis, stabilizationand internal fixation of affected bone and resolution of pathologicalfracture (see below). The use of surgery instead of radiotherapy hasbeen suggested in patients with extensive destruction of weight-bearing bones in order to reduce the risk of pathological fractures[86]. Excision of weight-bearing bones and amputation are nolonger used to control local disease since they may result inseverely impaired outcomes due to post-surgical complications,chemotherapy delay and long-term sequelae [87].

Two large cumulative studies of the Rare Cancer Network andthe IELSG suggest anthracycline-based chemotherapy followed,when indicated, by involved-field radiotherapy as first-line treat-ment for patients with primary bone DLBCL [26,72]. With thisstrategy, the overall response rate (ORR) is over 90% and the 5-yearOS is 84%. In line with other pre-rituximab studies (Table 5), theIELSG study demonstrates that chemo-radiotherapy produces sig-nificantly better results than the inverse sequence. CHOP (cyclo-phosphamide, doxorubicin, vincristine, prednisone) is the first-choice regimen in primary bone DLBCL; discrepancies mostlyregard radiotherapy [88]. Variations in chemotherapy, like substi-tution of doxorubicin with mitoxanthrone or liposomal doxorubi-

cin to reduce cardiotoxicity and the use of infusional, third-generation or 14-day regimens, should follow the same criteriaused in nodal DLBCL.

A survival benefit of the addition of the anti-CD20 monoclonalantibody rituximab to CHOP in primary bone DLBCL has not beendemonstrated. Although a recent retrospective study suggests nosurvival benefit with the addition of rituximab in localized extran-odal lymphomas [92], this antibody has essentially changed thenatural behaviour of DLBCL, and, with a few exceptions, is anunavoidable part of first-line treatment for this lymphoma, bothin nodal and extranodal forms. Moreover, a positive effect of ritux-imab in a low-risk malignancy like primary bone DLBCL is also sug-gested by favourable results reported in patients with low-riskDLBCL enrolled in the MINT trial [93]. In a recent, small series of pri-mary bone DLBCL [89], R-CHOP was associated with a completeremission (CR) rate of 95%, and an 8-year OS of 95%. A few retro-spective studies suggest a benefit with the addition of rituximab,with a 3-year PFS of 80–90% after R-CHOP and 50–60% after CHOP[29,90,91].

The survival benefit of the irradiation of affected bones afterprimary chemotherapy and the potential for complications are amatter of debate in patients with primary bone DLBCL. Prospectivestudies focused on this therapeutic issue in patients with primarybone DLBCL do not exist, thus, debate is mostly based on indirectevidence from large trials in nodal DLBCL. Before rituximab, afew randomized trials suggested that the addition of radiotherapyis superfluous in DLBCL patients who achieve a CR after primarychemotherapy [94,95]. In the rituximab era, the addition of consol-idation radiotherapy significantly improved outcome in a large ret-rospective series of 469 DLBCL patients treated with R-CHOPcombination [96]. Consolidative irradiation of bulky residualmasses after R-CHOP14 has been associated with an improved out-come in a prospective series of 166 elderly patients with DLBCL[80]. However, these studies included all stages of disease, bothnodal and extranodal DLBCL, and, sometimes, the irradiation vol-ume was not prospectively defined nor described, resulting inimportant interpretation biases. Regarding primary bone DLBCL,a retrospective study of 161 patients treated with CHOP or deriva-tives suggests that the addition of consolidative post-chemother-apy radiotherapy does not further improve outcome, with bothchemo-radiotherapy and chemotherapy alone producing a 5-yearPFS of 74% and 67%, respectively [26]. However, selection biasesrelated to the small size of analyzed subgroups and the manage-ment of primary bone DLBCL with more favorable features withchemotherapy alone cannot be excluded. It is clear that the useof intensive immunochemotherapy without consolidation radio-therapy requires formal testing and validation in a randomizedtrial before it can be used as an alternative treatment for early-stage DLBCL. In particular, the role of PET-driven consolidativeradiotherapy remains an appealing open question in the manage-ment of limited-stage DLBCL.

The choice of radiation volume in primary bone lymphomaspatients should result from an accurate risk–benefit analysis. Thisshould consider the risk of exposure of sensitive organs, such aslung, brain, bowel or kidney, among others, and of late bone effects.Although most radiotherapy experts favor whole-bone irradiation,with a dose of 38–40 Gy [88], evidence supporting irradiation ofthe whole bone and/or regional lymph nodes is limited. In line withprevious series [72], the IELSG-14 study has showed a 5-year PFS of76% and 64% respectively for primary bone DLBCL patients man-aged with CHOP followed by irradiation of the whole bone or ofa part of the affected bone (partial-bone irradiation) [26]. However,the clinical relevance of the irradiation of a whole long bone (a.e.,femur, humerus) or a whole flat bone (a.e., vertebra) is very differ-ent. In cases where the irradiation of the whole bone appears risky,a smaller volume that maintains wide margins (3–5 cm) around

Table 4More frequent pathological fractures sites at presentation.

Site of pathological fracture Frequency at presentation (%)

Lower limb 49Spine 38Upper limbs 27Pelvis 17Skull 8

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pre-chemotherapy tumour borders within the affected bone isadvisable. Margins around the soft tissue or extra-osseous borderscan be further restricted to 1–2 cm around post-chemotherapy vol-umes as the distinction between normal and abnormal tissue is notso problematic, and some individualisation of dose and volumewill always be required.

Radiation dose depends on the size of the irradiated volume, theanatomical area and response to primary chemotherapy. Data sug-gesting better results with a dose >40 Gy are outdated [97]. In theIELSG-14 study, no significant survival difference between 47patients irradiated with a dose 636 Gy and 58 patients irradiatedwith >36 Gy have been shown, with a 5-year PFS of 72% and 75%,respectively [26]. This is in line with a large randomized trial thathas demonstrated that, compared with previous standard doses of40–45 Gy, a radiation dose of 30 Gy is not associated with loss ofefficacy in aggressive lymphomas, with no significant differencesin in-field relapse rate, PFS and OS [98].

Polyostotic lymphoma

Polyostotic lymphoma is characterized by exclusive multifocalinvolvement of the skeleton, without affecting lymph nodes orother organs. Although patients with polyostotic DLBCL andpatients with disseminated DLBCL and skeletal involvement dis-play similar clinical presentation [9], prognosis is significantly bet-ter in patients with polyostotic DLBCL, with an ORR of 92% and 65%(p = 0.002), a 5-year PFS of 57% and 35% (p = 0.01) and 5-year OS of75% and 37% (p = 0.008), respectively [9]. These differences areindependent from the IPI score and other variables, and suggestthat polyostotic lymphoma may be a different entity, that deservesto be investigated from biological and molecular points of view. Anintriguing finding is that the use of post-chemotherapy radiother-apy in patients with polyostotic DLBCL has been associated with asignificantly better outcome, with a 5-year OS of 83% for patientsmanaged with chemoradiotherapy and 55% for patients managedwith chemotherapy alone [9]. Accordingly, patients with polyos-totic DLBCL should be treated with the same strategy used for dis-seminated nodal DLBCL, considering consolidation radiotherapy inpatients with lesions located in adjacent bones that can be irradi-ated with acceptable side effects.

Advanced-stage DLBCL with skeletal involvement

Secondary bone involvement by systemic lymphoma is morecommon than primary bone lymphomas [53,99,100]. Bone involve-ment is frequently observed in cases of DLBCL with high tumourburdens and disseminated disease, mostly occurring in patientswith an intermediate-high IPI. The prognostic value of boneinvolvement in DLBCL remains controversial [77,80,101,102];related articles include heterogeneous series managed with variedstrategies, and the prognostic value of skeleton infiltration mayhas changed after rituximab wide use [80]. In the pre-rituximabera, patients with stage-IV DLBCL and skeletal involvement man-aged with anthracycline-based chemotherapy, followed or not bybone irradiation, achieved a 65% ORR and a 5-year PFS of 34% [9].In the rituximab era, R-CHOP treatment, with or without radiother-apy, is associated with a 65% CR rate, and a 5-year PFS of 54%[101,103]. Nevertheless, the clinical benefit of the addition of ritux-imab to CHOP chemotherapy in patients with stage-IV DLBCL andskeletal involvement remains matter of debate. A retrospectiveanalysis of 292 DLBCL patients with skeletal involvement registeredin nine consecutive prospective trials did not demonstrate anadvantage with the addition of rituximab [80]. However, one-fifthof patients had primary bone lymphoma and not disseminated dis-ease, and 80% of analyzed patients had been treated without ritux-imab, which may result in unbalanced comparisons and low-level

evidence. Thus, chemoimmunotherapy of bone DLBCL should bethe same routinely used for nodal DLBCL, that is a combination ofCHOP or CHOP-like regimen plus rituximab.

The clinical benefit of irradiation of involved bone in patientswith disseminated DLBCL is an important open question. A benefi-cial effect of this strategy was suggested by a recent retrospectivestudy of the German High-Grade Non-Hodgkin lymphoma StudyGroup [80]. The analysis of the effect of radiotherapy was restrictedto patients with disease responsive to anthracycline-based chemo-therapy ± rituximab, with a significantly and independently betteroutcome among patients who received radiotherapy to sites ofskeletal involvement. Contrasting results in smaller series shouldbe considered with caution because it is possible that patients withmore aggressive disease were more likely to receive irradiation[29]. The discretionary nature of the indications for bone irradia-tion and heterogeneity of bone involvement (bulky or not, singleor multiple) preclude firm conclusions concerning the usefulnessof radiotherapy in patients with advanced-stage DLBCL and skele-ton involvement. Importantly, a recent study suggested a benefitfor the rational use of PET-guided radiotherapy in patients withadvanced DLBCL and residual abnormalities at CT scan after R-CHOP [104]. In fact, 18FDG-PET is an important tool to define ther-apeutic response (see ‘‘Response to treatment’’), and, in that study[104], irradiation of PET-positive residual disease resulted in sur-vival figures similar to those reported for patients with negativepost-R-CHOP PET. This strategy may avoid superfluous radiationexposure of PET negative patients. However, 18FDG-PET exhibitssome technical and interpretative limitations (see below), andwhether this procedure can identify those primary bone lym-phoma patients who can be spared from radiotherapy remains tobe shown in appropriately designed studies.

Indolent bone lymphomas

Indolent primary bone lymphomas represents up to 8% of allbone lymphomas (Table 6), and these anecdotal cases are not spe-cifically described in histopathological series [105,106]. The largestseries of indolent bone lymphomas was recently reported by theIELSG [55]. Out of an international series of 499 patients with adiagnosis of NHL and skeleton involvement, 26 (5%) patients hadan indolent bone lymphomas; ten of them had a small lymphocyticlymphoma, 10 had a follicular lymphoma and 6 had a lymphoplas-macytic lymphoma. Eleven patients had limited stage and 15 hadadvanced disease. No patients with Richter’s syndrome were iden-tified [107]. With all the limitations of a pre-PET retrospectivestudy, a significantly better outcome in patients with small lym-phocytic lymphoma has been recorded; these patients frequentlyachieved long-term remission and rarely died of lymphoma. Theprognosis of patients with limited-stage lymphoplasmacytic lym-phoma or follicular lymphoma was less favourable, with a higherproportion of tumour dissemination, possibly reflecting limitationsin staging sensitivity. Patients with primary indolent bone lympho-mas in the IELSG series had been managed with varied first-linetreatments, obtaining an ORR of 73%, and a 5-year PFS and OS of37% and 46%, respectively. Performance status and stage of diseasewere independently associated with OS. All patients with limited-stage indolent bone lymphomas managed with radiotherapyachieved a CR, and 63% of them remained relapse-free; conversely,only 33% of patients managed without radiotherapy achieved a CR,and all of them experienced relapse [55]. The addition of chemo-therapy was not associated with improved OS in irradiated patientswith limited-stage indolent bone lymphomas. Patients withadvanced-stage indolent bone lymphomas showed response andsurvival rates similar to those reported in patients with the samestage and histological type but without skeleton involvement.Accordingly, patients with localized indolent bone lymphomas

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assessed with complete staging procedures are candidate for radio-therapy alone [55,108], while patients with advanced-stage indo-lent bone lymphomas should be managed like other patients withdisseminated indolent lymphomas.

Uncommon aggressive bone lymphomas

Some anecdotal cases of aggressive lymphomas other thanDLBCL primarily arising in the bones have been anecdotallyreported (Table 6) [82,109]; lymphoblastic and Burkitt lymphoma,among B-cell categories, and anaplastic large cell lymphoma andperipheral T-cell lymphoma not otherwise specified, among T-cell

categories, being the most common forms [84]. Skeletal involve-ment does not seem to play a prognostic role in these patients. Cur-rently, there is no evidence suggesting that these patients shouldbe treated differently to patients with the same lymphoma cate-gory and stage of disease but without skeletal involvement.

Special therapeutic issues

Response to treatment

Conventional radiologic and functional procedures exhibit lim-itations in the assessment of response to treatment in primary

Table 5Largest available series of bone lymphomas.

Reference No. ofpatients

Medianage

Years ofenrollment

Most commonprimary site

Aggressivetype (%)

StageI–II (%)

CT(%)

RT(%)

CT + RT(%)

Rituximab(%)

ORR(%)

DFS OS (years)

Ostrowski[6]

261 45 1907–1982 Femur (21%) 77 68 6 63 22 0 NA NR 53% (10 – uni)35% (10 – mul)

Heyning[81]

60 48 1943–1996 Femur (24%) 92 62 NR 8 58 0 56 46% (5) 61% (5)

Dosoretz[57]

30 58 1950–1978 Femur (30%) 93 100 0 76 12 0 NR 40% (5) 63% (5)

De Camargo[125]

24 38 1955–1999 Spine (25%) 83 NA 37 8 43 0 NR NR 70% (5)

Ueda [126] 34 56 1961–1988 Pelvis (29%) 53 44 26 10 41 0 NR NR 75% (5 – st I) 50%(5 – st II)

Beal [1] 82 48 1963–2003 Femur (27%) 80 81 30 14 56 6 NR 81% (5) 88% (5)Marshall

[127]28 52 1962–1997 Femur (18%) 100 100 0 32 68 0 100 48% (10) 53% (10)

Rathmell[5]

27 53 1967–1988 NR 85 100 0 56 33 0 NR 39% (10) 40% (10)

Dubey[128]

45 52 1967–1992 Femur (20%) 98 100 9 11 80 0 NR 63% (10) 60% (10)

Fidias [129] 37 41 1970–1995 Appendix (75%) 100 100 0 0 100 0 100 73% (10) 87% (10)Fairbanks

[3]63 63 1970–1989 Long bone

(57%)93 100 3 79 16 0 NR 90% (5 – CT + RT)

57% (5 – RT)NR

Horsman[27]

37 55 1970–2003 Pelvis (24%) 73 100 16 41 38 0 57 NR 50% (10)

Bacci [82] 26 NR 1972–1982 Fenur (23%) 80 100 0 0 100 0 100 88% (13) 88% (13)Baar [116] 17 36 1975–1992 Femur (29%) 100 88 30 6 64 0 94 77% (3) 77% (3)Christie

[124]70 60 1973–1999 Spine (29%) 65 80 0 44 56 0 83 NR 59% (5)

Stein [130] 19 54 1979–2000 NR 95 58 42 0 58 0 95 90% (6 – st I–II)87% (6 – st IV)

NR

Messina [9] 37 53 1980–2005 Spine (65%) 100 0 35 0 65 0 92 56% (5) 74% (5)Govi [55] 26 60 1980–2005 Pelvis (47%) 0 42 30 15 55 0 73 25% (10) 29% (10)Bruno

Ventre[26]

161 55 1980–2005 Femur (20%) 100 100 8 14 78 0 91 68% (5) 75% (5)

Zinzani [59] 52 58 1982–1998 Femur (27%) 85 79 16 21 63 0 90 84% (8 – CR pts) 68% (9)Gianelli

[62]28 51 1982–1999 Femur (24%) 93 100 20 3 74 0 NA 75% (4) 78% (4)

Barbieri[76]

77 42 1983–2001 Extremities(51%)

97 100 0 13 87 0 95 76% (15) 88% (15)

Ramadan[29]

131 63 1983–2005 Spine (29%) 79 46 44 8 48 21 NR 40% (10) 41% (10)

Lewis [131] 28 45 1984–1994 Femur (39%) 89 71 36 14 50 0 NA 46% (6) 60% (6)Ford [86] 22 50 1985–2003 Long bone

(50%)91 77 18 0 82 0 NR 85% (10) 74% (10)

Bayrakci[87]

20 48 1986–1997 Femur (24%) NR 70 35 0 65 0 65 NR 78% (st I) 16%(st IV)

Cai [72] 116 51 1987–2008 Spine (28%) 86 100 13 12 75 3 91 62% (4) 72% (10)Catlett [90] 30 49 1989–2005 Long bone

(57%)90 70 16 10 71 40 NR NR 73% (5)

de Leval[65] 20 44 1990–2000 Femur (35%) 100 90 15 15 65 0 NA NR 74% (5)Kim [132] 33 40 1992–2010 Pelvis (39%) 100 39 48 0 52 39 88 NR 75% (4)Maruyama

[30]28 47 1995–2004 Pelvis (41%) 68 32 50 0 50 0 89 77% (3) 84% (3)

Pellegrini[89]

21 34 1999–2009 Long bone(38%)

100 10 48 0 52 100 95 100% (8 – CR pts) 95% (8)

Alencar[91] 53 52 2000–2007 Femur (24%) 90 77 12 21 62 37 92 83% (4) 100% (4)Christie

[133]31 55 2000–2007 Femur (26%) 97 68 0 0 100 19 96 64% (5) 90% (5)

Nasiri [134] 28 41 2001–2009 Femur (25%) 100 78 30 3 66 0 NR 62% (2) NR

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bone lymphomas patients; architectural osseous distortion canremain unchanged for many years in X-rays and CT scans, andresidual uptake can persist in bone scintigraphy and 18FDG-PET(Fig. 2). Bone remodelling and artefacts due to stabilizing hardwarecomplicate the assessment of local disease control; in particular,artefacts caused by intramedullary titanium rods interfere withinterpretation of changes and limit the usefulness of post-treat-ment MRI and CT scans. These persisting changes prevent the des-ignation of CR using international criteria [99]. In this case, the

designation of response is usually made upon resolution of anysymptoms, particularly pain, signs such as swelling, resolution ofsoft tissue infiltration at CT, MRI and/or PET, evidence of bone heal-ing on X-ray, and absence of signs of progressive disease. Replace-ment of intraosseous tumour and adjacent bone marrow with fattymarrow and sclerosis in follow-up MRI scans can help to confirmCR. 18FDG-PET is more useful than bone scanning in the assess-ment of response to treatment [110,111], and may be used to driveconsolidative radiotherapy [104]. However, although 18FDG-PET

Table 6Pathological classification with relative frequencies in the largest series of PBL.

Histology Zinzani [59] Beal [1] Ramadan [29] Alencar [91] Cai [72]Diffuse large B-cell 44 (84%) 66 (80%) 103 (79%) 44 (83%) 91 (78%)Diffuse mixed – 4 (5%) – – –Follicular 2 (4%) 3 (4%) 7 (5%) 3 (5.7%) 7 (6%)Peripheral T-cell – – 2 (1.5%) 2 (3.8%) –Extra-nodal marginal zone – – 4 (3%) 1 (1.9%) –Mantle cell – – 1 (1%) 1 (1.9%) –Small lymphocytic 2 (4%) 3 (4%) 2 (1.5%) 1 (1.9%) –Transformed MALT – – – 1 (1.9%) –Burkitt’s/Burkitt like 2 (4%) 1 (1%) 2 (1.5%) – –Anaplastic large T-cell 2 (4%) – 4 (3%) – 6 (5%)Lymphoma NOS – 2 (2%) – – –Plasmocitoid – 1 (1%) – – –Immunoblastic – 1 (1%) – – –Lymphoblastic – 1 (1%) 2 (1.5%) – –Unclassifiable low grade – – 1 (1%) – –Other – – – – 12 (11%)

Fig. 2. CT scan (left column) and PET (right column) features in a patient with a stage-IE DLBCL of the left femur. CT scan (A) and PET (B) performed at diagnosis show evidentosseous abnormalities and increased FDG uptake (arrows), respectively. CT scan (C) and PET (D) performed immediately after treatment conclusion show persistence ofosseous abnormalities and reduced FDG uptake (arrows), respectively. CT scan (E) and PET (F) performed at one year of follow-up show respectively persistence of evidentosseous abnormalities (arrow), which may be interpreted as residual disease (false positive), and remission of FDG uptake (arrow).

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has a high sensitivity for the detection of osseous disease [39], itspredictive value is limited in primary bone lymphomas due tofalse-positive findings related to post-chemotherapy bone remod-eling, inflammation, marrow hyperplasia and bone necrosis andfalse negatives related to the resolution of the equipment, the tech-nique used and the variability of FDG avidity among lymphomacategories [43,112–114]. As a logical consequence of these limita-tions, response rates in primary bone lymphomas trials should beconsidered with caution. In routine practice, the current plan inthe absence of definitive evidence of local or distant failure is tocontinue surveillance with CT scans [115], whereas the role ofthe PET scans as a follow-up procedure remains to be defined [99].

Management of pathological fractures

Pathological fractures occur in 10–15% of patients with DLBCLof the bone, with the humerus being the most frequently affectedbone (66%) [10,29,91]. The analysis of the IELSG-14 study hasclearly showed that the presence of pathological fracture at pre-sentation is associated with independently worse outcome inpatients with primary bone DLBCL, with a 5-year OS of 54% forpatients with pathological fracture and 68% for patients withoutthis complication [75]. Unfortunately, this study was not able toidentify pre- and post-treatment variables predicting the occur-rence of a pathological fracture (i.e., lysis of the cortex, tumour size,soft tissue infiltration).

The goals of initial surgical stabilization of the pathological frac-ture are usually to preventing further bone destruction and dis-placement, to enable weight-bearing, to assist pain relief orhealing and to obtain a better quality of life. While these are allimportant goals, there is no evidence of an improved cancer-related outcome with initial surgical stabilization of the patholog-ical fracture, with a 5-year OS of 45% and 54%, respectively foroperated and not operated patients [75]. These data suggest thatany initial surgical stabilization should be kept to a minimum,and used to improve patient’s quality of life and prevent bone dis-integration only if chemotherapy delays can be avoided.

A pathological fracture or a high risk of fracture may lead thetreating physician to start the treatment program with radiother-apy. Importantly, irradiation of a fractured bone before chemother-apy does not improve disease control or survival, when comparedto the chemo-radiotherapy sequence [75]. These results should betaken into account with caution since a selection bias related to ini-tial irradiation of patients with more destructive lesions, and, thus,with more aggressive lymphoma, cannot be excluded. Neverthe-less, patients with pathological fracture should be managed likenodal DLBCL, including anthracycline-based chemotherapy fol-lowed by consolidation radiotherapy to the fractured bone with30–40 Gy [75,76,116]. Radiation volumes and doses should followthe above-discussed recommendations for primary bone DLBCLpatients.

CNS prophylaxis

CNS dissemination is an early and fatal event reported in �5% ofDLBCL [117,118]. The risk of CNS recurrence associated with skel-etal involvement is a matter of debate, with rates of 4% and 0.6%,respectively for DLBCL patients with and without skeletal involve-ment [80,119]. In the IELSG-14 study, CNS involvement, usuallymeningeal lymphomatosis, occurred in 2.5% of patients with pri-mary bone DLBCL [26], 5% of patients with polyostotic DLBCL[9,120] and 2% of patients with stage-IV DLBCL and skeletonlesions [9,75]. Probably, these rates would be even lower in the rit-uximab era, since CNS dissemination has been reduced in DLBCLpatients treated with this antibody [121]. Importantly, the smallnumber of events hampers the identification of reliable predictors

of CNS recurrence in primary bone lymphomas studies, but avail-able evidence suggests that CNS prophylaxis is superfluous in pri-mary bone DLBCL. Noteworthy, an accurate CSF assessment, brainMRI and personalized prophylaxis are advised in patients with dis-seminated DLBCL and involvement of bones close to the CNS (skulland/or spine). CNS recurrence occurs in 7% of these patients, espe-cially in patients with other high-risk features [9,75].

Late iatrogenic sequelae

Chronic pain, limb dysfunction and late pathological fracture arethe most common iatrogenic sequelae in patients with bone lym-phoma. The involvement of the femur, pelvis and the spine is morecommonly associated with chronic symptoms, and a second patho-logical fracture after anti-lymphoma treatment has been recordedin 10% of patients with secondary bone DLBCL [75]. Such fracturescan occur in the absence of local recurrence and can lead to persist-ing non-union with subsequent disability, mostly in bones of thelower limb. Contributing factors may include architectural distur-bance due to previous tumour, pathological fracture before treat-ment and the existence of other medical conditions such as post-surgical osteomyelitis, Paget’s disease and osteoporosis, particu-larly among elderly women. Both radiotherapy and chemotherapyhave been implicated as incurring a higher risk of subsequent path-ological fracture; in particular, this risk has been attributed to corti-costeroids and large radiation fields, fractions and doses [122,123].These and other risk factors, such as involvement of weight-bearingbones, local recurrence at the fracture site and the size of the biopsydefect should be accurately considered. Orthopaedic fixation of frac-tures, limitation of the use of corticosteroids, reduction of radiationdoses to <5000 cGy and fraction sizes, limiting the size of the biopsyat diagnosis and relapse, early local disease control with adequatechemo-radiotherapy, and monitoring of patients for signs of subse-quent pain or disability have been recommended to prevent thisdisabling complication [124]. Amputations have been reported inthe absence of local failure as a way of dealing with painful non-healing fractures. However, such drastic measures are likely to beavoidable if the preventive measures described herein are adopted.Osteonecrosis, osteomyelitis and second cancers are important lateeffects of radiation therapy and chemotherapy for bone lymphomas.With modern radiotherapy techniques, post-treatment malignan-cies are usually limited to incidental skin cancers, rare cases of sar-comas and other solid tumours [91]. Avascular bone necrosisoutside the irradiated area has been described most probably dueto high-dose prednisolone [86].

Bone health preventative measures, as used in many other skel-etal malignancies, should also be discussed with primary bonelymphomas patients; accurate monitoring of bone density andappropriate use of calcium and vitamin D are recommended[108]. There are no guidelines on the role of bisphosphonates inthis setting but prophylactic oral therapy should be addressedearly, especially, in the case of risk factors for the developmentof osteoporosis, pathological fracture and other related complica-tions [108].

Conflict of Interest

The authors declared no conflict of interest.

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