lymphoma of the bone is a rare malignancy , first suggested by oberling in 1928 and further described by parker and jackson in a series on  reticulum cell sarcoma of bone .
   primary bone lymphoma , as originally defined by ostrowski , is a lymphoma of bone without disease present elsewhere for at least 6 months after initial diagnosis , account for less than 1% of all malignant lymphomas and occur at a median age of 46 years .
the characteristics of bone lymphoma have been further defined by a number of case series : the most common locations of bone lymphoma are variously reported as the spine , the ischium , and long bones , particularly the femur ; the most common presenting symptom is pain associated with swelling ; the most common histology is diffuse large b - cell lymphoma , and the phenotype may be germinal center- or activated b cell - like .  
the current treatment of primary bone lymphoma appears to typically be a combination of chemotherapy and radiotherapy .  
we encountered two male patients , both age 19 , whose chief complaint was knee pain and each had a biopsy of the proximal tibia that was diagnostic of a b - cell lymphoma . in both cases ,
one patient had bilateral proximal tibia involvement by diffuse large b cell lymphoma , not otherwise specified .
the other had unilateral tibia involvement by a low grade b cell lymphoma ( not further classifiable ) that was treated with local radiation and recurred 17 months later in the contralateral tibia . both patients bone x - rays showed a sclerotic pattern .
these cases prompted us to review all lymphomas with an initial diagnosis of lymphoma in bone at one institution , to identify all patients with tibial lymphoma at two additional institutions , and to examine the association of age and relative incidence of lower limb bone lymphoma within a national cancer database .
correlation of the clinical and pathology records of the university of rochester medical center from 2003 - 2011 identified all lymphomas in patient s whose initial diagnosis was based on a bone biopsy ( excluding iliac crest ) directed at a radiographic lesion .
the demographics , symptoms at presentation , radiologic findings , clinical stage , treatment , and follow - up were identified for the subset of bone lymphoma specimens for which the site was tibia in the pathology report ( table1 )
. the demographics and clinical stage were also obtained for the subset of bone lymphoma specimens for which the site was femur .
reproducibility of findings was assessed by searching the pathology records of two other institutions for lymphomas diagnosed in the tibia ; the latter searches were preformed without age restriction and without the stipulation that the specimen represent the patient s initial diagnosis .
the surveillance , epidemiology , and end results ( seer ) program of the national cancer institute is a population - based national cancer database comprised of data on incident cancer cases contributed from registries across the united states .
seer began collecting data from 9 registries in 1973 ; currently seer includes data captured on incident cases from 17 participating registries , a catchment area representing approximately 28% of the us population .   in order to limit the influence of variability in referral and diagnosis patterns , data from the 2000 - 2009 seer dataset
was used for this analysis ; this dataset was comprised of incident cancer cases captured in 17 seer site registries .
inclusion in the analysis dataset was limited to patients with a lymphoma diagnosis ( icdo3 codes 9590 , 9591 , 9650 , 9663 , 9670 , 9671 , 9673 , 9675 , 9680 , 9684 , 9687 , 9690 , 9691 , 9695 , 9698 , 9699 , 9702 , 9714 , 9727 , 9728 , 9729 , 9920 , and 9930 ; n=129,097 ) , and bone as their primary site of disease ( only included if site was c40.0 , c40.1,c40.2 , c40.3 , c40.8 , c40.9 , c41.0 , c41.1 , c41.2 , c41.3 , c41.4 , c41.8 , c41.9;n=1,315 ) .
patients diagnosed with plasma cell tumors ( icdo3 9730 - 9739 ) were excluded from this analysis ( n=923 ) .
our final analysis dataset included 808 lymphomas with bone involvement diagnosed from 2000 - 2009 .
histology was grouped by icdo3 codes into malignant lymphomas not otherwise specified or diffuse , hodgkin lymphomas , non - hodgkin lymphoma - mature t- and nk - cell lymphomas , non - hodgkin lymphoma -precursor cell lymphoblastic lymphoma , myeloid leukemias , and non - hodgkin lymphoma -mature b - cell lymphomas , which was further categorized into diffuse large b cell lymphoma , not otherwise specified and other .
involvement of the tibia , specifically , is not captured with the icdo3 site codes ; therefore , patients with primary involvement of the long bones of the lower limb and associated joints ( c40.2 ) were designated as the lower extremity cases and were compared to other bone lymphoma patients with involvement of all other sites . from this point forward , patients with lymphoma involvement of any long bones of the lower limb and associated joints will be referred to as  lower extremity cases .
descriptive analyses included presentation of case characteristics by frequency and percents , stratified by age , site of bone involvement ( lower extremity versus other bone sites ) and gender .
differences in age and stage of lymphoma at diagnosis by site of bone involvement were analyzed using chi - squared tests .
overall survival was defined as time from diagnosis to date of death from any cause ; patients who were still alive at the end of follow - up were censored as of december 31 , 2009 .
we compared overall survival between cases with lower extremity involvement and cases with lymphoma involvement of other bone sites using the log - rank test .
analyses were implemented using sas software system ( sas institute , cary , nc ; version 9.3 ) .
49 cases of non - hodgkin lymphoma with biopsy - proven initial presentation in bone were identified at the index institution ; these had a median age at presentation of 42 years ( data not shown ) .
these patients were significantly younger ( median age of 21.5 years ; p<0.001 ) . in all of these 10 cases ,
review of the clinical data indicated that knee pain or swelling was the primary symptom .
none of these specimens included any other involved sites although subsequent imaging suggested the involvement of other bone sites and lymph nodes in several patients ( table 1 ) ; 6 fulfilled criteria for  primary bone lymphoma  .
the remaining 4 cases showed predominant involvement of the tibia and clinically were thought most likely to represent primary tibial lymphoma .
eleven patients had initial presentation of lymphoma in the femur and these patients were strikingly older than those who presented with tibial disease ( median age of 74 ; p<0.001 ) .
similar searches of bone lymphomas ( without restrictions with regard to patient age or initial site of presention ) at 2 other institutions identified 10 additional tibial non - hodgkin lymphoma cases ; the median age was 24.5 years .
together , the 20 cases of tibial lymphoma had an age range of 13  85 , median age of 22.5 years and a male : female ratio of 3:1 ( table 1 ) . with the exception of a 56 year old patient , the available radiographs for all patients at the index institution showed sclerotic changes ( figure 1 ) .
no radiographic features or case histories were particularly suggestive of antecedent osgood - schlatter disease .
all tumors were b - cell lymphomas ; all but two had diffuse large b - cell lymphoma histology and were positive for cd20 and/or cd79a .
one patient ( table 1 , patient 1 ) showed a low - grade histology composed of monomorphic small lymphocytes ; this material was the subject of extensive extramural consultation which corroborated the diagnosis .
one patient with atypically widespread disease had precursor b cell lymphoblastic leukemia / lymphoma ( 3 in table 1 ) .
of the 17 cases where stage was available , 10 cases were limited to the tibia ( stage ie ) .
bilateral tibia involvement was identified in 4 of the 10 index institution cases . for cases where therapy was known ,
most were treated with combined modalities of chemotherapy and radiation . of the 9 cases at the index institution with follow - up ( average 56.4 months ) , one recurred in the contralateral tibia ,
one died of his lymphoma ( 56 years old at presentation ) , and 7 had no recurrence of disease .
the seer database ( 2000 to 2009 ) includes 808 cases of lymphoma with bone presentation .
because the seer database does not specify bone site beyond lower extremity , we used this subgroup as a surrogate for the proximal tibia .
the most common histology for the lymphomas with bone involvement was diffuse large b cell lymphoma , not otherwise specified , regardless of site of involvement .
no difference was apparent in the median ages for presentation in the lower extremity ( 187 cases , median age 57 ) versus all other bone sites ( 621 cases , median age 63 ) . in younger patients , a significantly larger fraction of bone lymphoma present in the lower extremity bones compared to other bones ( 38% for 40 vs 19% for > 40 years , p<0.0001 ) ( table 2 ) .
this difference is most striking for males aged 10 - 30 years ( figures 2a and 2b ) . over all , half ( 53.3% ) of bone lymphomas , regardless of age were limited stage disease ( stage i / ie ) .
a significantly greater fraction of lower extremity bone lymphomas were low stage compared to other sites regardless of age ( table 3 ) .
young patients with lower extremity bone presentation of non - hodgkin lymphoma had a superior overall survival compared to young patients with other bone sites at presentation ( figure 3 ) . as expected , survival was worse in patients over 40 years ( figure 3b ) in comparison to patients 40 ( figure 3a ) .
more striking is the differential effect of site of bone involvement when stratified by age .
five - year overall survival in patients 40 with lower extremity presentation was 97% versus 82% in non - lower extremity presentation ( figure 3a ) .
the difference in overall survival by site of bone involvement among patients 40 is highly significant ( p=0.0086 ) .
after controlling for stage , the effect of lower extremity presentation on overall survival remains statistically significant ( p=0.0485 ) . among patients
> 40 ( figure 3b ) , two - year overall survival among those with lower extremity involvement was 73% versus 68% in non - lower extremity bone involvement and five - year overall survival was 68% versus 57% , ( log - rank p=0.15 ) .
because the curves repeatedly cross and do not separate until 12 months , site may have no real effect on survival in those > 40 .
our data reveal a syndromic pattern of presentation of lymphoma that occurs specifically in the proximal tibia of young people (  40 years old ) presenting with knee pain and/or swelling , is frequently bilateral , and shows sclerotic changes on imaging .
epidemiologic data indicate that lymphoma of lower extremity bones has excellent prognosis compared to bone non - hodgkin lymphoma presenting in young patients at other sites .
furthermore , in our patients the lymphoma was often highly restricted to the proximal tibia and showed a profound tropism for this site : of 10 patients at the index institution , 6 patients had lymphoma solely in the proximal tibia as the only bone site and 4 patients demonstrated bilateral proximal tibial involvement with relative sparing of other bone sites .
our institutional data show a striking bias toward tibial rather than femoral presentation in young patients ( 25 versus 74 years median age of presentation ) . strikingly , the youngest patient ( 18 years old ) with femoral presentation of lymphoma at this institution had disease characterized by the surgeon as  knee and distal femur  , suggesting a similarity to the presentations seen in the proximal tibia .
although the seer database does not include localization specifically to the proximal tibia , the data on the lower extremity corroborates and extend our institutional findings .
most importantly , cases of lower extremity lymphoma in young patients had significantly better overall survival in comparison to lymphomas of non - lower extremity bone sites in young patients .
although lower extremity presentation tended to be associated with a lower stage , low stage did not fully account for the improved overall survival ; site of bone involvement remained statistically significant after adjustment for stage in the multivariate cox proportional hazards model .
a sclerotic radiographic pattern was identified in all 7 cases at the index institution in patients  40 for whom imaging was available .
overall , 9/11 patients with available radiologic information had either purely sclerotic or mixed sclerotic lesion , and only 2 had a purely lytic lesion .
this finding is in contrast with the typical lytic appearance of non - hodgkin lymphomas of the bone which is either permeative or moth - eaten , with bone destruction as a significant feature .
a predominately sclerotic image , while more often seen in classical hodgkin lymphoma of the bone , is described in just 2% of bone non - hodgkin lymphoma .
therefore , radiographic sclerosis may be a diagnostic clue for non - hodgkin lymphoma presenting in the proximal tibia .
while a range of common studies was attempted ( e.g. immunohistochemical studies for cd10 , mum1 , bcl-2 , bcl-6 , ebv - lmp , and ki-67 , as well as in - situ hybridization for eber ) , no shared histologic , immunophenotypic , or genetic features that further characterized these b cell tumors were identified .
the specimens were in general small and crushed , and the decalcification performed on most hindered any pcr - based analyses .
bone lymphomas are often difficult to diagnose and classify and the osteoblastic / sclerotic nature of these tumors makes them particularly prone to crush artifact and limited sample size . in fact , several of the patients required repeat procedures to obtain sufficient material for the final diagnosis .
this syndromic pattern of presentation of lymphoma may have escaped notice in prior studies of  primary bone lymphoma  because many of our patients ( for example patients 2 - 5 ) would have been excluded from those series since there was lymph node involvement at the time of presentation .
furthermore , the patient ages straddled the cut - off between adult and pediatric series ; our two index cases were both seen in adult clinics and were not enrolled on pediatric trials .
still , the seer data show that the highest incidence of lower extremity bone lymphomas for males is in the second decade ( see figure 2 ) .
our review of the literature identified 9 publications describing 7 case series of pediatric bone lymphomas ( the two largest series are each reported in two parts , with a publication describing a follow - up time point or the clinical and histologic data described separately ) . these series document that pediatric primary bone lymphoma commonly presents in the lower limb . while the femur may be a more common site of lymphoma than the tibia
, it is unclear if the femoral presentation is associated with the same syndromic pattern of presentation involving a complaint of knee pain with sclerosis on bone x - ray .
regardless , one of these series of pediatric primary bone lymphomas showed a striking similarity to the series we describe here ; zhao et al describe a series of 10 pediatric patients with 
, all male , four with tibial presentation , one of which was bilateral . the bilateral presentation in the proximal tibias with sparing of other sites has also been described by others .
for example , two recent case reports both show striking images of bilateral proximal tibial lymphoma , although both in older males .
several non - hodgkin lymphoma subtypes with site - specific biology , prognostic and treatment characteristics , and even distinctive molecular features have been described and incorporated into the world health organization s classification of lymphoid tumors .
the site - specific pathogenesis of a subset of these is thought to be dependent on chronic , local inflammation , the most common of which are the various forms of mucosal associated lymphoid tissue ( malt ) lymphoma .
, the prototypical form of which occurs in males in the seventh decade and specifically in the pleural cavity ; it has also been described associated with inflammation around metal implants in the femur . a small case series of bone lymphomas putatively associated with trauma has been reported .
our reviews of the patients medical records did not suggest any obvious etiologies for the cases of proximal tibial non - hodgkin lymphoma , but one possible explanation relates to the increased athletic activities of this age group that might result in repetitive , microtrauma and subsequent inflammation of the proximal tibia .
while evidence of ebv infection is typically found in cases of  diffuse large b cell lymphoma associated with chronic inflammation 
, we were unable to detect ebv in any of the tumors from patients < 40 years old in this series . in sum
, we describe a strong association between proximal tibial lymphoma ( often bilateral ) , young age , sclerotic lesions on x - ray and excellent prognosis , associations that are reinforced by analyses of the seer database .
due to the uncommon nature of these tumors , an increased awareness of the possibility of this unusual lymphoma in young patients is essential , since ample diagnostic material is required for diagnostic studies , including immunohistochemical and molecular studies , and prognosis may vary significantly by site of involvement .
in addition , this syndromic pattern of presentation suggests intriguing hypotheses regarding the relationship between microtrauma and the development of lymphoma .
 the presentation of two 19 year old males with stage i non - hodgkin lymphoma in the proximal tibia prompted an extensive review of institutional and national databases to assess if there is any statistical evidence that these reflected a previously overlooked syndromic pattern of presentation . 
 the institutional records of a single institution were reviewed for presentation of non - hodgkin lymphoma in bone . 
 the records of two additional institutions were reviewed for all reports of non - hodgkin lymphoma in the tibia . 
 analysis was performed on data from seer ( surveillance , epidemiology , and end results ) dichotomized to bone presentation in the lower extremity versus other bones . 
 institutional databases included 20 patients with tibial presentation of lymphoma with a median age of 22.5 years ( versus 42 for all bone lymphomas ; p<0.001 ) . 
 18/20 were diffuse large b cell lymphoma , and all patients  40 achieved remission and apparent cure . 
 distinctive and unusual features were a tendency for bilateral involvement of the tibia and sclerotic changes on x - ray . 
 seer data included 808 cases of bone lymphoma ; the fraction of cases presenting in the lower extremity vs other bone sites is higher at ages  40 years ( 38% vs 19% ; p < 0.0001 ) . 
 presentation in the lower extremity , as compared to other bone sites , confers 97% overall survival in patients  40 ( vs. 82% ; p = 0.01 ) . 
 this survival effect was independent of stage . 
 in contrast , no significant difference in overall survival was identified for lower extremity versus non - lower extremity site for age > 40 . 
 these data show a previously undescribed syndromic pattern of disease presentation : bone lymphoma in young patients is likely to present in the lower extremity , specifically the proximal tibia , has atypical sclerotic features on x - ray , is often bilateral , and has an excellent prognosis compared to bone lymphomas at other sites matched for stage and age . 
Introduction
Materials and Methods
Results
Discussion