nowadays it is obvious that the disease can be divided into two groups by its pathogenesis and clinical features : the nodular lymphocyte predominant ( nlp ) and the classic subtypes . due to the development of diagnostics and the prognosis - based risk - adopted treatment strategies ,
the exact etiology of the disease is still unknown , however , is not uniform since genetic features , viral infections , and other factors such as different lifestyle habits can contribute to the development of the disease .
the so - called  two - disease hypothesis  , which proposes that the hl seen in the younger group is infectious in nature whereas that in the older persons has causes similar to other types of lymphomas .
the incidence of hl shows differences worldwide , it is more frequent in developed countries , most common in north america , and less frequent in asia .
data from mid-1990s reported an increasing prevalence among young adults in developing countries and stagnant incidence in western countries . in the usa from 1974 to 1996 ,
the incidence of the disease was stagnant among white females , only decreased among white males ; meanwhile , a definite increase of incidence can be found among black females . until 1985 an increase after dropping can be found among black males .
as compared to the incidence of hl in the european union in 2002 ( males : 2.5/100000 , females : 1.9/100000 ) , in hungary the disease is less frequent among males while is minimally more frequent among females ( males : 2.1/100000 , females : 2.1/100000 ) . among the twenty - five countries of the european union ( data not known in romania and bulgaria ) , hungary
is ranked the sixth place in the incidence of the disease among females and the twenty - second place among males . in 2002 worldwide , the hl was the most frequent among males in yemen , the less frequent in egypt , and , additionally , less frequent than the average in hungary .
pattern 1 , seen in developing countries and in patients of low socioeconomic status , shows an early childhood peak and a second peak around the age of fifty , with tumors predominantly of classical mixed cellularity ( cmc ) and classical lymphocyte depletion ( cld ) subtypes with ebv positivity .
pattern 3 , seen in developed countries and in patients of high socioeconomic status , shows a bimodal age group pattern with a peak incidence among young adults with tumors mainly of classical nodular sclerosis ( cns ) subtype with ebv negativity .
pattern 2 , seen in countries with transitional economies , has an early childhood peak and a second ( female ) decade peak with equal frequencies of the cmc and cns subtypes [ 1 , 2 ] . considering the socioeconomic changes in hungary
, the authors regarded them as worthwhile to investigate , whether the pathological or clinical nature and the treat worth of hl have changed in the past decades .
the clinical data of 439 hl patients treated at the university of debrecen , medical and health science center , institute for internal medicine , 3rd department of medicine from 01/01/1980 until the 12/31/2008 were processed in a division of calendar periods of approximately ten years ( first period : 19801989 , second period : 19901999 , third period : 20002008 ) .  
identification of histological subtypes was done according to rye 's classification , recently according to real / who classification .
clinical staging was done according to the ann arbor classification   and later with its cotswold 's modification .
the prognosis of the patients was given according to the eortc recommendation   in early stage . in case of advanced - stage patients
in advanced - stage disease , we considered the prognosis to be favourable , when the ips value was 03 , and unfavourable if it was at least 4 .
the therapy of the patients occurred due to the current therapeutic protocols ( radiotherapy , chemotherapy , or combined radio- and chemotherapy ) .
primary polychemotherapy was dominantly cv(o)pp ( cyclophosphamide , vinblastine ( vincristine ) , procarbazine , prednisone ) until 1991 , then copp / abv ( cyclophosphamide , vincristine , procarbazine , prednisone / adriamycin , bleomycin , vinblastine ) from 1991 , recently abvd ( adriamycin , bleomycin , vinblastine , dacarbazine ) from 1999 .
salvage protocols were mainly beacopp ( bleomycin , etoposide , adriamycin , cyclophosphamide , vincristine , procarbazine , prednisone ) , dhap ( dexamethasone , cytarabin , cisplatin ) , and cep ( ccnu , etoposide , chlorambucil , prednisone ) . the irradiation consisted of extended - field , mantle - field , converse y , ( sub)total nodal- or involved - field radiotherapy  initially with telecobalt machine , then from 2000 with linear accelerator .
high - dose treatment and autolog hematopoietic stem cell transplantation were also accessible for treating relapsed or primary resistant patients from the 1990s .  
survival data were analysed using the kaplan - meier method by spss15 computer software . for the statistical analyses
a total of 439 hl patients were treated primarily during the investigated period of 29 years .
male- to female - ratio decreased to 1.05 recently , instead of male predominance until now .
the mean and median age was decreasing ( table 1 ) . investigating the age of the patients ,
the age group pattern of the first period is unimodal , with one incidence peak between 30 and 39 years of age .
the first incidence peak of this pattern can be found between 20 and 29 ( like nowadays ) , the second peak between 40 and 49 in the second period , and between 50 and 59 in the third period ( figure 1 ) . the number of hl patients with classic mixed cellularity histological subtype was decreasing after a temporary increase ( 43.7% , 58.23% , 42.6% , p = 0.0098 ( it is only significant in the second period ) ) .
the classic nodular sclerosis subtype shows a increasing tendency ( 25% , 27.32% , 34.78% , p = 0.1734 ) .
classical lymphocyte predominant subtype ( clp ) was decreasing ( 17.1% , 7.57% , 5.21% , p = 0.0038 ) .
the number of classical lymphocyte depletion ( cld ) subtype was decreasing significantly also ( 14.2% , 6.19% , 6.06% , p = 0.0181 ) , nodular lymphocyte predominant ( nlp ) histological subtype can be seen only in the past decade , when the real / who classification was used ( figure 2 ) .
we found that the first incidence peak of the age group pattern is created predominantly by cns ; meanwhile , the second incidence peak is created by cmc histological subtype ( figures 3(a ) and 3(b ) ) .
investigating the histological subtypes according to the sexual distribution , we found that cmc subtype is predominant among males in every period , its ratio is much lower among females , and in the third period cns subtype became predominant . among males the cmc subtype , meanwhile among females the cns subtype , is the most common in the third period .
the incidence of clp and cld subtypes decreased ; cld shows a slight increase in the third period again .
furthermore , nlp subtypes have been diagnosed in the last periods with an incidence of 6.08% ( figure 4 ) . comparing the early- ( first - second ) and advanced- ( third - fourth ) stage disease
, we found an increased ratio of early - stage disease , and the difference was statistically significant .
the increase comes on one hand from the significant growth of the number of second stage patients ( 25.8% , 26.35% , 49.56% , p < 0.0001 ) and on the other hand from the significant reduction of the number of third stage patients ( 53.4% , 50.67% , 20% , p < 0.0001 ) .
nowadays half of the patients is diagnosed in the second stage of the disease ( figure 5 ) . from the first symptom ( lymphadenomegaly and/or complain ) until the diagnosis of the disease lasted an average 6.2 months in the first period . in the second period
we found that 45.59% of the early - stage patients and 28.26% of the advanced - stage patients were concerned to be in the unfavourable prognostic group .
the 5-year overall survival was 59.7% , 77.4% , and recently 90.5% ( p < 0.001 ) , and the 10-year overall survival data were also progressing : 44.1% , 70.6% and 90.5% ( prognosed survival ) in the last decade ( figure 6 ) . during the investigated period ,
more than 60% of them were diagnosed in the first period ; they died predominantly of hodgkin 's lymphoma .
the mortality coming from the basic disease was decreasing after this time ( in the second period the basic disease mortality reduced into half ) , the remaining patients died of infection , second tumor , cardiopulmonary failure , and other factors ( e.g. , accidents ) in nearly the same ratio . comparing to the others , in the last period the mortality became minimal with still the predominance of the basic disease ( figure 7 ) .
the incidence of hl was the greatest in north america ( male : 3.2/100000 , female : 2.4/100000 ) , the smallest in east asia ( male : 0.3/100000 , female : 0.1/100000 ) , in central and eastern europe ? ? ? both males and females : 2.3/100000 in 2002 .
data of hungary from 2000 to 2003 reports an average incidence of 2.02/100000 among males and 1.59/100000 among females , but estimating hungarian data , the fact must be considered that probably not every case was reported . hence , the incidence of the disease can be considered average , both on the whole and due to sexual distribution .
our current trial is not representative ; hence , estimating incidence is not possible . in hungary 9 trials dealed with data of hl patients ( table 2 ) .
the duration of these trials differs significantly from each other ( 1 year   to 22 years [ 13 , 19 ] ) ; furthermore , these trials show great variability due to geographic differences ( data from whole hungary [ 14 , 20 ] to investigate patients from only one county [ 13 , 15 ] ) .
hence , exacting comparison and drawing conclusions is not possible , and attention can be attracted to further comprehensive trials .
investigating sexual distribution generally male predominance was found ; three trials found slight female predominance [ 12 , 14 , 15 ] .
this ratio came from the female predominance in the cns subtype in kelnyi et al . estimating the results of ivnyi et al .
is hard , because among the diagnosed 86 patients only 66 patients ' data were processed during their investigated period .
the mean age is around 40 in every trial ( 35.841.7 years ) and shows a persistent slight decrease . the most common histological subtype  except for one trial
presented countrywise data , whereas cns was found to be the most common subtype during the investigated period of 4 years ( between 2000 and 2003 ) .
both uni- and bimodal age group patterns were found ; the incidence peak in young adults around twenties was present everywhere .
b symptoms were present unequivocally , more than half of the patients in every trial .
the majority of the patients were diagnosed in the advanced stage , but it is hope worthy that both a trial in the current decade ( 20002003 countrywise data ) and our investigation 's last period reports the diagnosis in early stage . between 1960 and 1997 in scandinavian countries , in india , and in north america , the increase of the incidence of hl was found among teenagers and young adults .
this increase was found rather among females and was primarily linked to the cns subtype . in elderly
rather a decreasing tendency was found , which was explained by the development of diagnostical methods . a trial between 1984 and 1993 in the united kingdom found the decrease of the incidence in both sexes , in every age groups , except for males between 1 and 24 .
investigating seven european countries no changes was found in the incidence between 1985 and 1992 . in our current study , the authors found the decrease of the number of patients , although the last period was one year shorter .
the male / female ratio decreased as well , currently the number of male and female patients is almost equal .
although the reason of this phenomenon is unknown , but shows similarity to the mentioned international data above . whereas we found a unimodal age group pattern in the first two periods , nowadays a bimodal age group pattern can be seen , with an incidence peak in young adults ( 2029 years ) and another in elderly ( 5059 years ) , likewise to developed countries
the fact that not all patients  especially the elderly  were treated in oncohematological centers can play a role in the explanation of the previously observed unimodal age group pattern .
hence , reporting the disease to the hungarian hodgkin 's disease work group did not occur every time .
we found the significant decrease of the cmc subtype and the increase of the cns subtype ( not significantly ) . in the last period the incidence peak of young adults
is created by the cns subtype ; meanwhile , the other incidence peak among elderly is created by the cmc subtype . due to the introduction of the who 's histological classification since 2000 , the number of patients with clp subtype decreased and with the new subtype , the nlp increased .
the number of patients in the advanced stage decreased significantly , parallel with the significant increase of early - stage patients . nowadays every second patient is diagnosed in stage two in the last decades the number of patients in stage three was decreasing continuously ; accordingly , the number of stage two and early - stage patients were increasing continuously .
this tendency suits with international authors ' observation [ 24 , 25 ] . beyond the developing diagnostic methods ( immunohistochemical examinations ,
developing imaging methods , like using pet / ct routinely ) , the patients ' awareness ( thanks to media , internet ) and the highly educated workers in basic medical attendance can also play a role in the backstage of this phenomenon . hence , the patients are treated earlier . since , the patients are diagnosed in earlier stages , their chance to survive and their quality of life are continuously progressing , because of the lower dose and less toxic treatment at their case .
accordingly , the overall survive progressed . according to international data , the 10-year overall survival of hl patients is 7585% [ 20 , 26 ] , which are similar to our results .
5-year overall survival progressed , because of better treatment based on prognostic factors and better supportation .
the decrease of mortality  especially the mortality because of the basic disease  can be explained by developing treating methods as well .
the mortality because of the basic disease fall to the half between the first and the second periods and fall to the third between second and third periods . due to the more toxic polichemotherapy and extended - field , greater - dose irradiation used in the previous periods ,
only further follow can decide , whether how much can new treatment methods reduce these factors of mortality . investigating hl patients in the same geographical localisation in different periods gives an opportunity to observe the effects of different factors ( e.g. , viral infection , socioeconomic changes ) on the characteristics of the disease . based on our results
, it can be established that the clinical pathological features of hodgkin lymphoma are changing in hungary .
we found the pattern to be characteristic to the developed countries out of the three epidemiologic patterns .
the population is infected ( e.g. , ebv ) fewer times . beside the changes of these immunological features ,
these facts and comprehensive ( countrywise or different geographical locations ) epidemiological trials can help in questing for the reasons , the treatment , and the survival of the disease .
 
 introduction . 
 hodgkin lymphoma shows a well - known geographic pattern , but temporal changes have been found recently as well . 
 patients and methods . 
 439 hodgkin lymphoma patients ' clinicopathological and treatment data were processed in calendar periods of approximately ten years . 
 the patients were treated at our department from 1980 until the end of 2008 . 
 results . the first period ( 198089 ) 
 contained 177 patients , the second ( 199099 ) 147 , and the third ( 200008 ) 115 hodgkin lymphoma patients . 
 the mean age of the patients was 40.1 , 35.9 , and 36.8 years in order . 
 the male / female ratio : 1.42 , 1.45 , 1.05 in order . 
 contrary - wise a unimodal age group pattern could have been seen with an incidence peak between 30 and 39 in the past decades . 
 the incidence of classical mixed cellularity histological subtype is decreasing ( 43.7% , 58.23% , 42.6% , p = 0.0098 ( it is only significant in the second period ) ) ; classical nodular sclerosis shows an increasing tendency ( 25% , 27.32% , 34.78% , p = 0.1734 ) . 
 the first incidence peak is predominantly created by classical nodular sclerosis , meanwhile the second peak by classical mixed cellularity . 
 the number of early - stage patients ( 59.12% ) is beyond the advanced stage ( 40% ) in the last decade . 
 meanwhile , the number of second - stage patients was increasing ( 25.8% , 26.35% , 49.56%  p < 0.0001 ) and of patients in third stage was decreasing ( 53.4 % , 50.67% , 20%  p < 0.0001 ) . 
 the 5- and 10-year overall survival data were progressing : 59.7 % , 77.4 % , and 90.5 % and 44.1 % , 70.6 % and 90.5 % ( expected survival ) in the last decade . 
 conclusions . 
 changes can be explained by the altered nature of hodgkin lymphoma , the changes in socioeconomic status and the development of diagnostic and therapy methods . 
1. Introduction
2. Patients and Methods
3. Results
4. Conclusion