(CANCER RESEARCH (SUPPL) 45, 4665s-4670s, September1985j

Peter Biberfeld,2Anna Porwft-Ksiazek, Blenda Bottiger, Linda ---------@--, and Gunnel Biberfeld

Departmentof Pathology, Karollnska Institute and Hospital (P. B., A. P-K.J,Departmentof Immunology,Nat/One!Bacteriology Laboratory (B. B., 0. B.), and Departmentoflnfectious Diseases,RoslagstullsHospital (L. MM.), Stockholm,Sweden

Abstract

Lymphnodebiopsiesfrom43 malehomosexualswithpersistentgeneralizedlymphadenopathyandfromtenacquiredimmunodeficiencysyndromepatients,all with serum antibodiestohumanT-celIleukemiavirusIII, were studiedwith regardtohistopathology,immunohistology,andT-cellsubsetsincellsuspensions.All acquiredimmunodeficiencysyndromebiopsiesexcaptonewithKaposi'ssarcomahadthesamehistopathologicalpatternof folliculardepletion,whereasthepersistentgeneralizedlymphadenopathy nodes showed a spectrum of changes characterizedas follicularhyperplasia,involutionwithfollicularfragmentation,or involutionwith follicularatrophy.Immunohistologyshowed a temporal and structural relation between follicularinvolution, disappearance of follicular dendritic reticulum cells,andfollicularinvasionby T-cells.Theseobservationssuggesteliminationof dendnticreticulumcells as part of a pathogenicmechanismin follicularinvolution.Angiogenesismeasuredbystainingof endothelialcells with antibodiesto FactorVIll wasincreasedin manybiopsiesin stagesof involutionanddepletion.Our observationsindicatethe occurrenceof markedchangesnotonlyinT-cellsbutalsointheB-cellcompartmentofpatientswith persistent generalized lymphadenopathy or acquired immunodeficiency syndrome. The possibility of staging lymphnodesof thesepatientsby combinedhistopathologyandimmunohistologyis indicated.This might improvethe evaluationofprognosisin thesepatients.A possibleimportanceof angiogenesisforthetumorigenesisof Kaposi'ssarcomaissuggested.

Introduction

SincefirstdescribedintheUnitedStatesAIDS3(1,2)hasbeenreportedto spreadin epidemicformamonghomosexualmeninmanycountries,includingSweden(3).

Mostcasesof AIDSshowprodromalsymptomslikePGL(4,5). However,the numberof homosexualmenwith PGLwhoprogressto thehighlylethalstageofAIDSvariesfromapproximately5 to20%dependingonobservationtimeandgeographicregion(6, 7).

Obviouslyit is importantto try to definein riskgroupstheearliestpossiblestageandrelatedfactorsthat mightbe associatedwithanirreversibleprogressionto manifestAIDS.

I Presented at the HTLV Symposium, December 6 and 7, 1984, Bethesda, MD.

SuppOrtedbytheSwedishCancerSociety,theCancerSocietyof Stockholm,andthe Swedish Medical ResearchCouncil.

2 To whom requests for reprints should be addressed, at Immunopathology

Laboratory,Departmentof Pathology,KarollnskaSjukhuset,5-10401Stockholm,Sweden.

S The abbreviations used are: AIDS, acquired Immunodeficiency syndrome; PGL,

persistentgeneralizedlymphadenopathy;FH, foScularhyperplasla;FF, folllcularfragmentation;FA,follicularatrophy;FD,folliculardepletion;DAC,dendriticratioulumcells.

Recently a retrovirus, called HTLV-Ill or lymphadenopathyvirus,hasbeenisolatedwithhighfrequencyfromAIDSas wellas fromPGL patients(8, 9). ThisvirusinfectsT-cellsof thehelper phenotype (9—11) which probably causes the observedreduction of this T-celI subset and eventually the developmentofimmunodeficiencyinthesepatients(12).TheratiobetweenTcellsof the helperphenotypefF4) and of the suppressor-cytotoxicphenotype(T8)isusuallydecreasedinthesepatientsasaresultof the reductionof T4 cells.However,a decreasedT4/T8ratiodue to increasednumbersof T8 cellscanalsooccuras aresultofotherviralinfectionscommoninthesesubjects(13).

Some histopathological studies have described florid, reactivehyperplasieand involutionof follicleswith effacementof nodalarchitecturein lymphnodesfrom patientswith PGLandAIDS,respectively(4, 14, 15).However,comparativelylittle is knownaboutthe relationshipof variousmorphologicalfindingsto alterationsin the occurrenceanddistributionof T- andB-cellsin thelymph nodes of patients with PGL and AIDS. More recentlymorphologicalchangesin somePGLlymphnodeswere relatedto the distributionof T-cellsand immunoglobulin-bearingcells(16,17).

Thepresentstudyisasystematicanalysisofthemorphologicalchanges in relation to immunohistochemical and immunologicalfindingsin lymphnodes of 43 Swedish homosexualmen withPGLand10 patientswithAIDS.

Materialsand Methods

PatientsandBiopsyMaterial.Lymphnodebiopsiesfromhomosexualmenwith PGL(43 cases)or with AIDS(10 cases),all seropositiveforHTLV-III(3).wereeachpartlyfixedandprocessedforconventionalhistopathoiogy, partly frozen and used for immunohistology,and parifyresuspendedfor cell surface lmmunotyping. Frozen sections were fixedbrieflylfl aCetO(@eandkTimunostainedby irdrect or triplelayerimmunoperoxidaseor immunoalkalinephosphatasetechniques(18).Quantifyingofimmunohistochemlcalstalningswasperformedusinga digitalImagequantifier (10130;Cortex COntrOllerS,Cambridge,UnitedKingdom).

Cell suspensionsfrom blood and lymph nodes were studied forreactivitywithvariousmonoclonalantibodies(seebelow)by immunofluorescence, and the number of positive cells were measured by flowcytofluorometry(SpectrumIll; Ortho).T4/T8ratios(seebelow)in bloodfrom 50 normal blood donors and in cell suspensionfrom 6 lymph nodeswithnormalhistopathologywerealsoevaluated.

Lymphocyte and Othar Cell Markers. The following monoclonalantibodIesto variouscellmarkers(phenotypes)wereusedIntheimmunofluorescenceandimmunoenzymestudies:OKT3/Leu4(pan-fl;OKT4/Leu3 (T helper/induced);OKT8/Leu2(I-suppressor/cytotoxic);OKT6(commonthymocyte);Leu7(lymphocytesubsetsandNKcells);andLeu8fr-cell subpopulations).The OKT and the Leu series of antibodies werepurchasedfrom Ortho (Raritan,NJ) and from BeCtOn-DicIcinSOnAB(Stockholm,Sweden),respectively.ThemonoclonalantibodesB1(panB)andB2(B-lymphocytesubset)werepurchasedfromCoulterElectron103(Luton,Wfted Kingdom).ThemonoclonalsDakO-8cell(pan-B)and

CANCERRESEARCHVOL 45 SEPTEMBER19854665s

Immunohistopathologyof LymphNodes in HLTV-lll InfectedHomosexualswithPersistentAdenopathyor AIDS1

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Alterations in lymph nodes ofpatlents with P01.orAIDSFHFollicular

involutionwithFDFF

FAIncreased

numberandsizeFragmentation of hyperplasticfollicles Coliapseof follicularstructuresNofolliclesIncreasein largefolliclecentercellsSerrated germinalcenterborders Decreasednumberof follicularcan AngulatingvascularproliferationStarry

skyFocal and/or diffuse lymphocyte Infiltra- ter cellsthroughout lymphnodeIncreaseinnumberof mitosestion AmorphousdepositsofperiodicDiffuse distribution of mainly lympho

Unevenmantis zonesIrregular mantiszones acid-Schiff-positivematerialincreasedangiogenesisbetweenfollicles Diffuselymphocyticinfiltrationin

folicularremnantsIncreasedangiogenesiscytes,

histiocyticcells,scantymastcells, few epitheliokicellsAt

progressionFOIIicUIar

pleomorphismIncreased fragmentationof germinalcan- EndOthellalproliferationFolbcularinfiltration by lymphocytestare

Increasedfollicularinfiltrationof lymphocytes

Irregularand/ordisappearingmantlezone

IMMUNOPATHOLOGYIN PGLANDAIDS

Dako-DRC1 (dendntic reticulum cells) and the rabbit antibody directedatFactorVIIIrelatedantigen(endothelialassociatedmarker)aswellasperoxidase and alkaline phosphatase conjugated antibodies to mouseimmunoglobulins were purchased from Dakopatts (Stockholm, Sweden).

Antibodies to HTLV-lll in patients' sara were demonstrated by a dotimmunobindingassay(19)andbyenzymelinkedimmunosorbentassay(kindlyperformedbyDr.Saxinger,NationalCancerInstitute,Bethesda,MD).

Results

HistopathologicalObservations.Themostmarkedandconsistent morphological changes involved germinal centers, follicular mantlezones,and angiogenesisof smallvessels.Withregard to the follicular changes four morphologicalpatternsprevailed,whichwereoperationallycharacterizedas FH,FF,FA,and FD. The major morphological changes characteristic of thesepatternsaresummarizedin Table1.

ImmunohistochemicalObservations.Characteristicimmunohistochemicalfindingswererelatedto thedifferentmorphological patterns describedabove. The follicularalterationswereparticulatlysalientafter staIningwith antibodiesto the DRC,B-cells(pan-B,-Bi , -B2),andT-cells(Leu2,-3, -4).

In biopsiesof caseswithfollicularhyperplasia,the folliclesusuallyappeareddenselystainedby B2 (Fig.1) andDRCantibodies,the latterantibodiesgivinga finelyreticularpattern(Fig.2).

However,inbiopsieswithmorphologicalpatternsof follicularfragmentation,a varying number of follicles usually showedirregular staining patterns for DRC and B2 (Figs. 3 and 4). Thisseemed to reflect varying degrees of destruction of dendriticreticulumcells,initiallyappearingaspatchesdevoidofDRCandB2 reactivity(Figs.4 and5). Whenparallelsectionsof biopsieswith the FFpatternwerestainedfor T-cellmarkers,bothT-cellsofhelperandsuppressorphenotypeswereusuallyfoundinareasdevoidof DRCreactivity(Figs.6 and7).A considerablenumberof theseinfiltratingT-cellsalsostainedforLeu8,buttherewaslessfrequentstainingforLeu7andnoneforOKT6.IncontrastinbiopsieswithfollicularhyperplasiapatternT-cellswithinfollides were much less frequent and usually diffusely dispersed(Fig. 8). Follicleswith an “exploded―appearanceafter DRCstainingwereassociatedwith increasedT-celIinfiltration(Fig.9).

Thefollicularatrophypatternappearedas a furtherprogressionof the follicularfragmentation,with extensivedestructionofdendriticreticulumcellsandgradualdissolutionoffollicularstructures(Fig.10).Stainingfor B-cellsshowedonlysmalldustersofB2@,IgM@,and IgD@cells,presumablyremnantsof marginalzonecells(Figs.11 and12). Diffuselyspreadplasmacellswereoftenratherfrequent.

Biopsiescharacterizedas folliculardepletionwere virtuallydevoidof DACbut stillshowednestsof lymphocytesstainedforBi and1gM.At thisstagethemajorityof lymphocyteswereTcells, mostly Leu2@and some Leu3@.

Angiogenesis.A gradualincreasein angiogenesisof smallvesselswas often seen in stages of follicular involutionanddepletion(Figs. 13 and 14). However,considerableindividualvariationwas observedin quantitativemeasurementsof FactorVIII immunostainedbiopsiesby data basedimageanalysis.Angiogenesisas shownby FactorVIIIstainingwas increasedinapproximatelyone-third(10 of 31) of the nodeswithfollicularinvolutionand depletion(FF, FA, and FD) as comparedto a fewcases(2 of 11)with follicularhyperplasia(Chart1).

Cell Suspension Studies. The relationshipbetweenT4/T8cell ratios in bloodand lymphnodesto morphologyand clinicalstageofPGLorAIDSisdocumentedinChart2. TheT4/T8ratioof thelymphnodeswasusuallyhighercomparedto thatof thebloodinthesameindividual.

Thiswas alsothe casefor suspensionsof normal-lookinglymphnodesand for blood from healthydonors. However,allexceptone of the lymphnoderatiosfromthe patientswerelowerthan the lowestvalue(=2.4) for the controlnodes(Chart2).

Comparisonof morphologicalstage with lymphnodeT4/T8ratiosshowedsignificantlylowerT-cellratiosin biopsiesdiagnosedasfolliculardepletion(FD,AIDS)(p < 0.01)comparedtothosewiththemorphologicalpatternsof FH,FF,andFA(Chart2). However,a considerableindividualvariationin ratioswasobservedamongthe PGLcasesin differentstagesof follicularinvolution.

Discussion

Ourstudiesconfirmpreviousfindingsof follicularhyperplasiaandinvolutioninlymphnodesofhomosexualmenwithPGLand

Table1

Statistics. For statistical analysis the Kruskal-WaIlistest was used.

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IMMUNOPATHOLOGYIN PGLANDAIDS

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MorphologyChart1. Measurementofangiogenesisbyquantificationofimmunohistochem

ical reactivity to Factor VIII (endothelialassociated antigen; see Fig. 14) in sectionsfromlymphnodeswithFH,FF,FA,andFD.

AIDS,respectively(4,5, 14, 15).Bycomparativehistologicalandimmunohistochemicalstudiesvariousconsistentpatternsoflymphnodechangeswerecharacterizedin moredetail.Theseobservationssuggestthat the definedpatternsprovisionallycalledFF and FA representa continuousprocessof follicularinvolutionpresumablyreflectinga progressionof immunodeficiencyeventuallyleadingtoa stageofFDandclinicallymanifestAIDS.We havethusfar notobservedclinicallymanifestAIDSassociatedwith FH, FF, or FA, contrary to the more variedmorphologyreportedfor AIDSlymphnodeswith Kaposi'ssarcoma (20). The more uniform lymph node histopathology of ourAIDScasesmaythusreflectthe so far lowincidence(one)ofKaposi's sarcoma in our material. The often marked increase inlymphnodeangiogenesiswithoutsignsof Kaposi'ssarcoma,characteristicof mostof ourAIDScasesandof manyof ourPGLbiopsies,isof interest.Theincidenceof Kaposi'ssarcomain AIDS may depend on geographical, ethnic, and/or epidemiological factors. Such factors could presumably be of importanceinthemalignanttransformationof an initiallyreactiveangiogenesis.However,the importanceof reactiveangiogenesisas apredisposingfactorforthedevelopmentof Kaposi'ssarcomainthesepatientshasyet to be proved.In consideringthe causeandnatureof the observedangiogenesis,it is of interestthatstimulatedlymphocyteshavebeenshowntoproduceangiogenicfactor(s)(21).

Ourimmunohistochemicalobservationsconcerningalterationsof follicularstructuresindicatea temporalandhistologicalrelationshipbetweentheoccurrenceof follicularinfiltratingT-cells,

FH FF FA FDMorphology

Chart2. T4/T8 cell ratios in blood (BL) (& A) and lymph nodes (LN) (0, •)inrelationto lymphnodemorphologycharacterizedasFH,FF,FA,or FDin 43homosexualmenwithPGL(&O)andin10caseswithAIDS(A,•).Bars,asithmeticmean.Inthebloodof 50healthyblooddonorsthemeanT4/T8cellratiowas1.75(range,0.6-4.42), and in 6 control lymph nodes it was 3.4 (range, 2.4-5.6).

thedisappearanceofdendriticreticulumcells,andthemorphologicalchangescharacterizedasfollicularfragmentation.Continuousdestructionof dendnticreticulumcellsand infiltrationoffolliclesby T-cellscorrespondedto a progressiveinvolutionoffollicularstructures.An increasednumber of T8 cells withinfollicles of homosexual men with PGL has also been noted byothers(16, 17, 20,22).Similarobservationsincludingdestructionof dendriticreticulumcellsduringgerminalcenterinvolutionhavealsorecentlybeenobservedin somecaseswith PGLby others(22).Themechanism(s)of thedestructionofdendriticreticulumcellsandthe type of a possibleeffectorcellcanat presentonlybespeculatedon.T-cellswithbothsuppressorandhelperphenotypeswereobservedwithinfolliclesundergoinginvolutionandcouldthusbe incriminatedin the destructionof DRC by cellmediatedcytotoxicreactionsor bythe releaseof lymphokines(factors).

AdestructionofDRC,inferredfromourimmunohistochemicalfindings,isalsocorroboratedbypreliminaryelectronmicroscopicobservationson suspendedlymphnodes,suggestinganin vivoinducedcytopathogeniceffectonsomeof thedendriticreticulumcells.4

NoobviousexplanationforthedestructionofDRCwasevidentfromourobservations.RecentlyArmstrongandHome(23)havereportedultrastructuralobservationsof retrovirus-Iikeparticles

4 Unpublished data.

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IMMUNOPATHOLOGYIN PGL AND AIDS

Korat,E.,Yankowftz,S.H.,Klein,M.J.,William,D.C.,Mlldvan,U.Longitudinalstudyof persistentgeneralizedtymphadenopathyinhomosexualmen:relationto acquiredEnmunodeflciencysyndrome.Lancet,1:1033-1038,1984.

8. Barré-Sinoussi,F.,Q@ermann,J.C.,Aey,F.,Nugeyre,M.T.,Chamaret,S.,Gruest,J., Daugnet,C.,Axler-Blin,F.,Vezinet-Brun,C.,Aouzloux,W.,Aozenbaum,W., Montagnier,L Isolationof a T-lymphOtrOpICretrovirusfromapatientat risk for acquiredimmunedeficiencysyndrome(AIDS).Science(Wash.DC),220:868—871, 1983.

9. Gallo,A.C.,Salahuddin,S. Z., Popovic,M.,Sheener,G. M.,Kaplan,M.,Haynes,B.F.,Palker,T.,Rodfield,A.,Oleske,J.,Safai,B.,White,G.,Poster,P., Markham,P. Frequentdetectionandisolationof cytopathicviruses(HTLVIII) from patientswith AIDS and at risk for AIDS. Science(Wash. DC), 224:500-502.1984.

10. Popovic,M., Samgadharan,M. G., Read, E., Gallo,A. C. Detection,isolationandcontinuousproductionof cytopathicretroviruses(HTLV-lll)frompatientswithAIDSandpro-AIDS.Science(Wash.DC),224:497-500,1984.

11. Klatzmann,D., Barré-Sinoussi,F., Nugeyre,M. T., Dauguet,C., Vdmer,E.,Grlsce5,C., Brun-Vezinet,F.,Aouzioux,C., Gluckman,J. C.,Coermann,J.C.,Montagnier,L Selectivetropismof lymphadenopathyassociatedvirus(LA@f)for helper-induceT lymphocytes.Science(Wash.DC),225: 59-62,1984.

12. Bowen,D. L, LaneH. C., Feud, A. S. Cellularimmunity.In: Ebbesen,Bigger,andMelbye(eds.),AIDS.pp.135-150.Copenhagen:EjnarMunksgaard,1984.

13. Camey,W. P., Aubin,A. H.. Hoffman,A. A., Hansen,W. P., Healey,K., Hirsch,M.S.Analysisof T lymphocytesubsetsincytomegalovimsmononucleosis.J.lmmunol., 126: 2114—2116,1981.

14. Guarda,L A., Butier,J. J., Mansell,P.,Harsh,P.M.,Reuben,J., New@,G.A.Lymphadenopathyinhomosexualmen.MorbidanatomywithclinicalandImmunologiccorrelations.Am.J. @Iin.Pathol.,79:559,1983.

15. loachlm,H. L, Lamer,C. W., Tapper,M. L The lyrnpholdlesionsassociatedwiththeacquiredimmunedeficiencysyndrome.Am.J. Surg.Pathol.,7:543,1983.

16.MangkOmkanOk-Mark,M.,Mark,A.S.,Doug,J.Immunoperoxidaseevaluatlonof lymphnodesfromacquiredimmunedeficiencypatients.Chin.Exp.Immunol,55: 581—586,1984.

17. Said,J. W., Shintaku,I. P., Teitelbaum,A., Coien,K., Sassoon,A. F. Dlstributionof T-cellphenotypicsubsetsandsurfaceEnmunoglobulln-bearinglymphocytesin lymphnodesfrommalehomosexualswithpersistentgeneralizedadenopathy:anEnmunohistochemicalandultrastructuralstudy.Hum.Pathol,15:785—790,1984.

18. Mason,D. V., Nalem,M., Abouiaziz,Z., Nash,J. A. G., Gatter, K. C., Stein,H. Immunohistologicalapplicationsof monoclonalantibodies. In: A. J.McMkhaelandJ. W.Fabre(eds.),MonocionalAntibodiesinclinicalMedicine,p. 583. New York:AcademicPress,1983.

19. Biberfeld,G., Bredberg-Râden,U., Bottiger,B., Biberfeld,P., Modeft-M@son,L, Sun, Y., Vaheri, A., Saxinger, C., Gallo, A. Antibodiesto human TlymphocyticvlrustypeIIIdemonstratedbyadot-Immunobindingassay.Scand.J. Immunol.,inpress,1984.

20. Modlin,A.L, Meyer,P.A.,Ammann.A.J.,Aea,T.H.,Hofman,F.M.,Vaccaro,S. A., Conant,M. k, Taylor,C. A. Altereddlsthbutionof B andT lymphocytesinlymphnodesfromhomosexualmenwithKaposi'ssarcoma.Lancet,2: 768—771.1983.

21. Sidky,V. A., Auerbach,A. LymphOcyte-IndUcedanglogenesis:a quantitativeandsensitiveassayof thegraftvs hostreaction.J. Exp.Med.,141:1084—1100,1975.

22. Janossy,G.,Pinching,A.J., Boflil,M.,Weber,J., McLaughlin,J. E.,Omstein,M., Ivory, K.. Harris, J. A. W., Favrot, M., MacDonald-Bums,D. C. Animmunohistologicalapproachto persistentlymphadenopathyanditsrelevanceto acquired @munedeficiencysyndrome,J. @Iin.Exp.Immunol,59:, 257—266,1985.

23. Armstrong,J. A., Home, A. Folliculardendriticcellsand virus-likeparticlesinAIDS-relatedlymphadenopathy.Lancet,2:370-372,1984.

24. Nossal,0. J.V.,Abbot,J.,Mitchell,J.,Lummus,Z.AntigensinImmunityxv.Litrastructuralfeaturesof antigencapturein pñmaryandsecondarylymphokifollicles.J. Exp.Med.,127:277—290,1968.

closelyassociatedto the surfaceof alteredDRCin lymphnodesectionsof AIDScases.However,evidencefor the direct productionof virusby the DRCwasnot observed.Accordingto ourfindings, the possibility should be considered that HLTV-IlI canbe locally releasedby intrafollicularT4 cells in areasof DRCdestruction.Consideringthe strong antigen-antibodybindingpropertyof DAC (24) trappingof virus as immunecomplexesmightalsooccur(23).

OurobservationsshowedconsistentlyhigherT4/T8 ratiosinthelymphnodesas comparedto the blood.Thiswasalsothecase in normalsubjects.Neverthelessvariationsin blood andlymphnoderatiosweredearlyconcordantandrelatedsignificantlywith the clinicalstageof the patientswhenPGLandAIDSwere comparedas well as with lymphnodemorphologywhenfolliculardepletionandotherstagesof follicularinvolutionwerecompared.

However,amongthe PGLcasesT4/T8 lymphnoderatios,although deatly below normal values, did not always correlatewiththe degreeof follicularinvolution.Thismightindicatethatdifferent etiopathological mechanisms for the decrease in T4/T8ratiosandthefollicularinvolutioncanoccur.Obviously,longitudinal studies with repeated biopsiesare needed for a moreconclusivedemonstrationofhow thevariouspatternsof follicularinvolutionmay progress or revert. Such studies would alsoelucidatethe prognosticimportanceof anglogenesisin caseswithPGLforthetumorigenesisof Kaposi'ssarcoma.

Acknowledgments

WethankMarieDan@ssonandMananneEkmanforexcellentassistance.

References

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2. Masur, H., Michelle,M. A., Greene,J. B., at a!. An outhreakof communityacquired Pneumocystis carini! pneumonia: initial manifestation of cellular Enmune dysfunction. N. EngI.J. Med., 305:1431-1438,1981.

3. Biberfeld,G.,Bottiger.B..Karisson,A.,SandstrOm,E.,Morteldt-Mánsson,L,Blomb@k, M., Nllsson, l.-M., Wlechel, B., Sadnger, C., Gallo, A. HTLV.41linfection in homosexuals and hemophiliacs in Sweden. Cancer Aes. (Suppi).,45: 4609s—4611s,1985.

4. Metroka,C. E., Cunningham-Rundles,S., Pollack,M. S., Sonnabend,J. A.,Davis, J. M., Gordon, B. Generalized lymphadenopathy in homosexual men.Ann. Intern. Med.. 99: 585, 1983.

5. Mildvan,U., Mathur, U. Persistent,generaIl@edlymphadenopathyamonghomosexualmales.Morbid.Mortal.WeeldyAep.,31:249-251,1982.

6. Abrams,D.I.,Lewis,B.J.,Volberding,P.A.Lymphadenopathy:endpointorprodrome—updateof a 24 month prospective study. Ann. NY Aced. Sd., inpress, 1984.

7. Mathur-Wagh,U., Enlow,A. W., Spigland,I., Winchester,A. J., Sacks,H. S.,

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1985;45:4665s-4670s. Cancer Res   Peter Biberfeld, Anna Porwit-Ksiazek, Blenda Böttiger, et al.   Homosexuals with Persistent Adenopathy or AIDSImmunohistopathology of Lymph Nodes in HLTV-III Infected

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