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Hodgkin's disease

Author: Doctor Jos Snchez de Toledo1

Creation Date:March 2003Update: October 2004

Scientific Editor: Professor Rafael Fernandez-Delgado

1Pediatric Oncology Unit, Hospital Vall d'Hebron, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.

[email protected]

AbstractKeywordsDisease name and synonymsDisease historyFrequencyDefinition and PathologyDifferential diagnosisClinical presentationDiagnostic methodsManagement includingtreatmentTreatment of relapsesEtiologyReferencesAbstract

Hodgkin disease (HD) is a malignant tumor characterized by pleomorphic lymphocytic and histiocyticinfiltrate with multinucleated Reed-Sternberg cells. Childhood cancers represent only 2% of neoplasmsaffecting the general population and HD accounts for 5.5% of all pediatric cancers. The primary nodal siteof HD is situated above the diaphragm in two-thirds of patients. The usual clinical presentation consists ofpainless cervical or supraclavicular adenopathy. Splenomegaly and hepatomegaly often indicateadvanced disease. Systemic symptoms are typical of B symptoms, including fever, weight loss, and nightsweats. Epstein-Barr Virus is likely to be pathologic agent in a HD subgroup, although it is not anecessary factor for the development of HD or supraclavicular adenopathy. Currently, almost all childrenreceive combined chemotherapy with low dose irradiation (1500 - 2000 cGy) solely in the initially involvedarea. Overall survival is more than 90%. New therapeutic strategies targeting molecular mechanisms inHD are currently emerging. Children with HD should be referred to multidisciplinary teams in pediatriconcology units with experience in treating pediatric cancers.

KeywordsHodgkin's disease; combined treatment; late effects; second tumors

Disease name and synonyms

Hodgkin's disease (HD)

Hodgkin's Lymphoma

Disease his toryIn 1832, Thomas Hodgkin provided the anatomicdescription of the disease (1). Sternberg, in 1898and Reed (2), in 1902, identified themultinucleated giant cell, a pathognomic findingof the disease, known as Reed-Sternberg cell

(RS). Subsequently, throughout the 20thcentury, advances in the diagnosis andtherapeutic fields contributed significantly to themanagement and prognosis of this disease.

FrequencyAlthough childhood cancers account for only 2%of neoplasms affecting the general population,they represent the second cause of childhoodmortality in industrialized countries, in spite ofremarkable advances achieved in survival rates.

Snchez de Toledo J. Hodgkins disease. Orphanet Encyclopedia. October 2004.

http://www.orpha.net/data/patho/GB/uk-Hodgk.pdf 1
mailto:[email protected]://www.orpha.net/mailto:[email protected]


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According to data from the National PediatricCancer Registry, the annual incidence ofpediatric cancers in Spain is 132 new cases permillion children aged between 0-15 years. HDconstitutes 5.5% of all pediatric cancers (3,4).

Definition and PathologyHD is a malignant tumor characterized bypleomorphic lymphocytic and histiocytic infiltratewith multinucleated Reed-Sternberg cells. Reed-Sternberg cell is a monoclonal and aneuploidcell and can form tumors inimmunocompromised animals. Of all the cellspresent in HD affected tissues, only 2% are RScells, the remaining cells include lymphocytes,macrophages, granulocytes and eosinophils.Recent studies indicate that RS cells are clonesof B origin, which are located in the lymphoidgerminal centres. These cells secrete powerful

cytokines, which are responsible for B symptomsof the disease, while promoting growth andhelping to avoid immunologic vigilance. A RScell produces at least 12 cytokines, includinginterleukin-1, interleukin-6 and tumor necrosisfactor, and any of which could be responsible forHD systemic symptoms (5,6,7). The malignantRS cells are known to constitutively express highlevels of activated nuclear factor kappaB (NFkB),which plays an important role in their survival (8).This aberrant activation of NFkB has been linkedto genetic defects in the NFkB inhibitors genes(9), to Epstein-Barr viral infection, and to

stimulation by cytokines. HD is divided into fourcategories: lymphocytic predominance, mixedcellularity, lymphocythic depletion and nodularsclerosis. About two thirds of pediatric patientspresent with nodular sclerosis subtype atdiagnosis. Patients with lymphocyticpredominant subtype generally have localizeddisease and are asymptomatic. Nowadays, withmultiagent chemotherapy regimens, histologicsubtypes have no influence on the diseaseoutcome.

Differential diagnosis

HD must be differentiated from other causes oflymphadenopathy. The differential diagnosis ofadenophaty may include inflammatory causessuch as atypical mycobacterial infections, cat-scratch disease and infectious mononucleosis aswell as other primary or metastatic tumors. Non-Hodgkins Lymphoma should be included indifferential diagnosis because it may presentwith signs and symptoms similar to those of HD.

Clinical presentationThe primary nodal site of HD is situated abovethe diaphragm in two-thirds of patients. The

usual clinical presentation consists of painlesscervical or supraclavicular adenopathy. If HDarises within the chest (mediastinalinvolvement), there may be no symptoms or

signs until compression of the airway causesrespiratory distress. Splenomegaly andhepatomegaly often indicate advanced disease.The systemic symptoms of fever, weight loss of10% and night sweats are well known as Bsymptoms (10).

Diagnostic methodsClinical examination is important for thedetection of peripheral node involvement. Thechest radiological evaluation by conventionalradiology and CT scan must be performed. CTscan localised on neck should be performed incervical node enlargement. CT scan and MRIboth provide useful information aboutinfradiaphragmatic disease. Gallium scan is auseful diagnostic method in Hodgkins disease.Positron emission tomography is a newdiagnostic method that is currently under

investigation. Bone marrow involvement atdiagnosis is not usual. Finally, excisional lymphnode biopsy is a better biopsy approach forhistological diagnosis.

Management including treatmentCurrently, more than 90% of children diagnosedwith HD benefit from complete remission andprolonged disease-free survival. For years, thetreatment of HD children has been based on thesame therapeutic concept as that applied toadults, i.e. laparotomy for staging and possiblesplenectomy, which causes high morbidity, and

treatment with standard doses of radiotherapy(3600 - 4000 cGy) applied as mantle field (neck,chest and axilla) or standard inverted-Y field(abdominal para-aortic and spleen field). Thistype of radiation therapy caused cosmeticanomalies and unacceptable skeletalabnormalities in children, as well ascardiomyopathy and risk of second tumors,especially thyroid and breasts neoplasias.Multiagent chemotherapy regimens, whichappeared in 1964 (MOPP) and 1974 (ABVD)provided a combined therapy directed towardsmaintaining an elevated rate of survival and a

decrease in morbidity in children. Donaldson'sstudy in Stanford was one of the first todemonstrate that combined modality treatmentwith MOPP and low irradiation doses in theaffected field was highly efficacious and wasassociated with a decreased incidence of lateeffects (11). Combined modality therapy coupledwith progressive advances in new diagnosticmethods (CT scan, MR, and Gallium scan) helpsto avoid surgical staging and splenectomy. Atpresent, almost all children receive combinedchemotherapy with low dose irradiation (1500 -2000 cGy) solely in the initially involved area.

Several studies are now exploring the possibilityof avoiding radiotherapy treatment on the basisof the response to chemotherapy regimens.Novel anticancer treatments are being designed


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to target specific molecular pathways that arecritical for cancer cell growth and survival inlymphoma such as HD (12).The proteasome inhibitor PS-341 has beenrecently shown to modulate tumor cellproliferation and survival by inhibiting NFkB and

modulating critical cellular regulatory proteins.The in vitro activity of PS-341 against HD-derived cell lines suggests that PS-341 mayhave a therapeutic value for the treatment of HD(13).The leukocyte activation marker CD30, which ishighly expressed on the RS cells is a target formonoclonal antibody (mAb)-based therapies ofHodgkins disease. Anti-CD30 antibodies havebeen recently evaluated in phase I studies inpatients with relapsed HD or anaplastic large celllymphoma. These studies demonstrated thatanti-CD30 antibody is a promising treatment

strategy (14, 15).

Treatment of relapsesRelapse is a serious issue. Patients relapsingafter radiotherapy alone can be salvaged withchemotheraphy or combined-modality therapy.For these patients, high doses of chemotherapyfollowed by hematopoietic stem celltransplantation (HSTC) has been investigatedwith encouraging results when the procedure iscarried out in the second complete remission(16). The same approach is performed inrefractory HD.

Late effects

The quality of life during and after treatment is amost important issue. Survivors of HD presentan elevated risk of conduct disorders (17).Delayed effects of HD treatment in survivors aresterility caused by testicular toxicity of alkylatingagents. Cryopreservation of semen has so farreceived scant attention (18). Sperm storage iscomplicated by the fact that many HD patientshave low sperm counts at presentation.It is recommended that patients over 10 years ofage undergo sexual development evaluation to

assess the cryopreservation of semen. Recently,new experimental approaches have beendeveloped to combat male infertility. One ofthem is an intracytoplasmatic injection of spermcell into the ovocyte. By means of this techniqueeffective fecundation can be achieved even withlow quality sperm. The cryopreservation oftesticular or ovarian tissue are techniquescurrently under development.Prevention from developing cardiomyopathy isbased on the use of combined chemotherapyschedules, which enables administration of lowerdoses of radiotherapy in the mediastinum, or

even complete avoidance of radiotherapy.Cardiomyopathy could also be prevented withthe development of chemotherapy regimens

using no anthracycline or lower accumulativedoses of anthracycline.Second tumors such as acute myeloid leukemia(AML) or non-Hodgkin Lymphoma areassociated with the use of alkylating agents. Themedian time for development of myelodysplasia

and leukemia is approximately 4 years. Solidtumors such as sarcomas or breast carcinomasare associated with radiation therapy. The risk ofepithelial neoplasia such as breast cancer ismaintained until more than 25 years aftertreatment. Breast cancer (19) is the second solidneoplasia most frequently found in radiated girls.The risk is related to age (older than 10 years) atthe time of radiation and to the radiation doseadministered. It seems therefore reasonable forwomen who have had mantle-type radiotherapyto undergo an early breast examination.Chemotherapy regimens are being studied to

limit the use of alkylating agents andanthracycline in order to lower the risks ofsecond neoplasias, loss of fertility andcardiomyopathy. While developing futuretreatments for HD, efficacy and potentialassociated risks must be taken into account.Curative treatment associated with minimalmorbidity and an highest quality of life should beachieved.Children with cancer should be referred tomultidisciplinary team in pediatric oncology unitswith experience in treating pediatric cancers.

EtiologyEpstein-Barr virus (EBV) has been implicated inthe etiology of HD. Indirect evidence, based onepidemiologic data relating to bimodaldistribution patterns, suggests that delayedexposure to a common infection is anetiopathologic mechanism in HD. Serologic data,such as elevated levels of specific antibodies inHD patients, or the risk of HD followingmononucleosis infection support also thishypothesis. It has not been determined whetherthe serologic data reflect the pathogenic role ofthe virus or, on the contrary, the consequence of

an immune defect following the reactivation ofthe infection by Epstein-Barr virus (20,21,22).The presence in the tumor tissue of EBV DNAand of RNA virus in RS cells has subsequentlyprovided direct evidence for the association ofHD and EBV. In cases of positive EBV, theinfection of RS cells occurs prior to clonalexpansion and it seems that the virus isnecessary for the maintenance and progressionof the disease. A higher incidence of associationHD/ EBV is found in underdeveloped countries inmales, in pediatric patients under 10 years ofage as well as in mixed cellularity type. EBV is

probably a pathologic agent in a HD subgroup,although it is not a necessary factor for thedevelopment of HD. Other studies suggestgenetic susceptibility to HD and risk factors such




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as exposure to pesticides or tonsillectomy,confirming the hypothesis of multiple etiology(23). However, the different epidemiologicalstudies supporting the existence of multiple riskfactors require a profound methodologicalvalidation of their results.

References1. Hodgkin T: On some morbid appearances ofthe absorbent glands and spleen. Med ChirTrans 1832;17:68-114.2. Reed DM: On the patholoical changes inHodgkins disease, with special reference to itsrelation to tuberculosis. Johns Hopkins HospRep 1902; 10:133-196.3. Peris R, Muoz A, Melchor I, Alvarez AM,Perez S, Gonzalez MC et al.Supervivencia delcncer infantil en Espaa.Casos diagnosticadosen el periodo 1980-1988.Datos del Registro

Nacional de Tumores Infantiles. Oncologa1997;20:421-428.4. Peris-Bonet R, Sanchez de Toledo J,Gonzalez C, Cruz O, Contra T, Navajas A et al.Childhood cancer survival in five autonomousregions of Spain:data from the Nationalchildhood cancer registry of the Spanish Societyof Paediatric Oncology. Eur J Cancer2001;37supplement2:S77-S126.5. Bruninger A, Hansmann ML, Strckler JG,Dummer R, Burg G, Rajewsky, Kppers R,Identification of common Germinal Center B-cellprecursors in two patients with both Hodgkin's

disease and non-hodgkins lymphoma. NewEngl J Med 1999;340:1239-1247. , 6. SchwartzRS.Hodgkin's disease.Time for a change.N EnglJ Med 1997;337:494-496.7. Manis JP. Precursors of Hodgkin's diseaseand B-cell lymphoma. New Engl J Med1999;340:1280-1282.8. Hinz M, Loser P, Mathas S, Krappmann D,Dorken B, Scheidereit C. Constitutive NF-kappaB maintains high expression of acharacteristic gene network, including CD40,CD86, and a set of antiapoptotic genes inHodgkin/Reed-Sternberg cells. Blood.

2001;97:2798-2807.9. Emmerich F, Theurich S, Hummel M, HaeffkerA, Vry MS, Dohner K, Bommert K, Stein H,Dorken B. Inactivating I kappa B epsilonmutations in Hodgkin/Reed-Sternberg cells. JPathol. 2003;201:413-420.10. Hudson M, Donaldson SS. Hodgkin'sdisease. In Pizzo PA,Poplack DG,eds. Principlesand practice of pediatric oncology.4ded.Philadelphia:JB Lippincott,2002,637-660.11. Hunger SP, Link MP, Donaldson SS.ABVD/MOPP and low-dose involved-fieldradiotherapy in pediatric Hodgkin's disease:the

Stanford experience. J Clin Oncol 1994;12:2160-2166.

12. Pro B, Younes A. New molecular targets fortreatment of lymphoma.Curr Oncol Rep.2004;6:360-368.13. Zheng B, Georgakis GV, Li Y, Bharti A,McConkey D, Aggarwal BB, Younes A. Inductionof cell cycle arrest and apoptosis by the

proteasome inhibitor PS-341 in Hodgkin diseasecell lines is independent of inhibitor of nuclearfactor-kappaB mutations or activation of theCD30, CD40, and RANK receptors. Clin CancerRes. 2004;10:3207-3215.14. Bartlett NL, Bernstein SH, Leonard JP:Antitumor activity and pharmacokinetics of sixweekly doses of SGN-30 (anti-CD30 monoclonalantibody) in patients with refractory or recurrentCD30 hematologic malignancies [abstract].Blood 2003, 102:2390.15. Ansell SM, Byrd JC, Horwitz SB: Phase I/IIstudy of a fully human anti-CD30 monoclonal

antibody (MDX-060) in Hodgkin's disease (HD)and anaplastic large cell lymphoma (ALCL)[abstract]. Blood 2003, 102:632.16. Jones RJ, Piantadosi S, Mann RB, et al;High-dose cytotoxic therapy and bone marrowtransplantation for relapsed Hodgkin's disease. JClin Oncol 1990; 8;527-537.17. Wasserman AL, Thompson EI, Wilmas JA etal: The psychological of survivors ofchildhood/adolescent Hodgkins disease. Am JDis Child 1987;141:626-631.18. Muller J, Sonksen J, Sommer P,Schmiegelow M, Petersen PM, Heilman C,

Schmiegelow K. Cryopreservation of semenfrom pubertal boys with cancer Med PedatrOncol 2000;34:191-194.19. Bhatia S, Robison LL,Oberlin O, GreenbergM, Bunin G, Fossati-Bellani F, Meadows AT.Breast cancer and other second neoplasms afterchildhood hodgkin's disease. New Engl J Med1996;334:745-751.20. Cohen JI. Epstein-Barr virus infection; NEngl J Med;2000:343:481-492.21. Goldman JM, Aisenberg AC: Incidence ofantibody to Epstein-Barr virus, herpes simplexand cytomegalovirus in Hodgkin's disease.

Cancer 1970;26:327-331.22. Weiss LM, Movahed LA, Warnke RA, SklarJ: Detection of Epstein-Barr viral genomes inRedd-Sternberg cells of Hodgkin's disease. NEngl J Med 1989; 320:502-506.23. MacMahon B. Epidemiology of Hodgkin'sdisease. Cancer Res 1966;26:1189-1201.



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