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Aggressive Epidermotropic Cutaneous CD8+ Lymphoma Citation for published version: Robson, A, Assaf, C, Bagot, M, Burg, G, Calonje, J, Castillo, C, Cerroni, L, Chimenti, N, Dechelotte, P, Franck, F, Geerts, M, Gellrich, S, Goodlad, J, Kempf, W, Knobler, R, Massone, C, Meijer, C, Ortiz, P, Petrella, T, Pimpelli, N, Roewert, J, Russell-Jones, R, Santucci, M, Steinhoff, M, Sterry, W, Wechsler, J, Whittaker, S, Willemze, R & Berti, E 2014, 'Aggressive Epidermotropic Cutaneous CD8+ Lymphoma: A cutaneous lymphoma with distinct clinical and pathological features Report of an EORTC Cutaneous Lymphoma Task Force Workshop', Histopathology. https://doi.org/10.1111/his.12371

Digital Object Identifier (DOI): 10.1111/his.12371

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Download date: 01. Oct. 2021 Accepted Article (20). S. (1),Berti (18), Willemze J. R. (19),Wechsler (2), E. Sterry Whittaker (2), Steinhoff W. M Roewer T. (16), N. PetrellaJ (15), Pimpelli (14), a: 02071886382 [email protected] Fax: Email: 0044(0) Telephone: United Kingdom 783 LondonSE1 7EH Westminster Bridge Road 4814446 St Thomas'Hospital of DermatologyInstitute John’s St. University of L’Aquila, Rome, (8)Departmentof Rome, of Pathol L’Aquila, University Lille,CHRU, (6)Department of DermatologyMedical Universityof Graz, (7)of Dept. , of (4)Dept.of (3) Dept.Universite, Paris, (1)St John’s Institute of London,Dermatology, (2) ofDept. Dermatology Charité-University , Berlin, type Article Article :Original Accepted Date : 12-Jan-2014 Revised Date :06-Nov-2013 Received Date :21-Aug-2013 This article This protectedis by Allcopyright. rights reserved. an 'Accepted Article', doi: 10.1111/his.12371 lead to differences betweenversionthis and the Versionof Record. Please cite this article as throughthebeen typesetting,copyediting, pagination and process proofreading which may This article hasbeen accepted for publicationand undergone fullpeer review but has not 2 Dept.Dermatopathology Address: Correspondingauthor: Dr Robson Alistair Un Leiden Dermatology of Dept. (19) de-Marne, Universityof Florence, Florence, (18) Departmentof Dermatology, Universityof Florence Medical FlSchool, of Division (16) Dijon, Hospital, University Dijon’s of Pathology of Dept. (15) Madrid, Complutense, Center Medical University VU Pathology of Dept. (13) Vienna, of University Dermatology of Dept. (12) Edinburgh, Hospital, General Western Pathology of Dept. (11) (2), JR Goodlad(11),(2), (4), WR Kempf Knobler S.Gellrich (9), (8), MGeerts (8), FFranck (7),P. Dechelotte Chimenti N L. (6), Cerroni (5), Authors: Keywords: Running Title: Report of an EORTC Cutaneous Lymphoma Task WorkshopForce features cutaneous lymphoma distinct with clinical andpathological Aggressive EpidermotropicCutaneous CD8+Lymphoma: A

A. Robson(1), C. Assaf (2), M. Bagot (3), M. Bagot (2), Assaf C. Robson(1), A. . lymphoma, CD8 antigen, ,diagnosis, prognosis AggressiveCD8+ Epidermotropic Lymphoma nd Floor, BlockC,South Wing Title Page Page Title iversity, (20) Dept. of Dermatology, Milan. of (20)Dept. Milan. iversity, Dermatology, Dermatology & of University Zurich, (5) Pathology Henri-Mondor hospital, University Paris-Val- Henri-Mondor Pathology Amsterdam, Hospital(14) Universitario, Universidad ogy, Clermont-Ferrand, Clermont-Ferrand, ogy, of(9) Dept.Gent, Dermatology (12), C. Massone, C. orence, (17) Division of Anatomy, (17) Pathological Division orence, t (2), R. Russell-Jones (1), M. Santucci (17), Santucci M. (1), Russell-Jones t R. (2), G G (1), C (4),JE.Calonje Burg Castillo Meijer (13),POrtiz Accepted Article features cutaneous lymphoma distinct with clinical andpathological Aggressive EpidermotropicCutaneous CD8+Lymphoma: A classifications. thatlymphoma warrants inclusion as a distinct entity in future revisions of lymphoma Conclusions documented in the CD4+ formsdiseases. ofthose papulosisfungoides, lymphomatoid and Woringer poor,prognosiswith is a median survival12Examples of months. ofCD8+mycosis butlymph nodes mucosae and centralnervoussystem involvement arenotThe uncommon. found in 7/18 with similarverya phenotype inthe remainder.. The tumours seldom involve CD45RA+ CD45RO- CD2-phenotype, CD5-CD56- haemorrhagic, andhave striking pagetoid patientstypically present with widespread conformed to the diagnosis of aggressive ep patient outcomewerediscussed & recorded. Eighteen caseshad distinct features and often withphotographs, sections,histological immunohistochemicalresults, andtreatment MethodsResults & nosologicalstatuswith respect toother cutaneous CD8+ lymphomas. detailinputativeandthe ofthis neoplasm convened its describe to features evaluate statusprovisional in the classificaWHO Aims This article This protectedis by Allcopyright. rights reserved. includedaggressive epidermotropic CD8+lymphom Background (20). (18) Wechsler J. (2), (2), Sterry W. Steinhoff J N.Pimpelli (16), (2), Roewert (15), Petrella (11),GoodladKempf W (4),R(12), Knobler C. F(8), P. Dechelotte (7), N Chimenti (6), Cerroni L. (5), (1), CCastillo JE. Calonje Burg (4), (3),G Bagot M. (2), Assaf C. Robson(1), A. Report of an EORTC Cutaneous Lymphoma Task Workshop.Force

: Aggressive : epidermotropic cutaneous CD8+ lymphoma is currently afforded Dermatology of Leiden University, (20) Milan. Dept. Dermatology, Departmenthospital, ofPathology Henri-Mondor of PathologicalFlorence, (17)Division School,Florence, University Anatomy, (18) of Florence, Dijon’s University Hospital,Dijon, (16) Divisionof Dermatology, UniversityFlorence of of Medical Pathology of Dept. (15) Madrid, Complutense, Universidad Universitario, Hospital (14) Amsterdam, Dept (13) Vienna, of University Dermatology of Dept. of Gent,Dermatology (11) of Dept. Patholog Rome,of (8) L’Aquila, University Dermatology, ofZurich, Lille, CHRU, Department (5) Medical of (7)Dept.(6) University of ofGraz, Dermatology Universite, ofParis, Berlin, Pathology (3)Dept. (1)St John’s Institute of London,Dermatology, (2) Dept. of Dermatology Charité-University Medicine, . : Aggressive : Epidermotropic Cutaneous CD8+ Lymphomais a distinct : The: recent WHO-EORTC consensus classificationon lymphomascutaneous :Sixty-one CD8+ caseswere analysed atthe workshop; details,clinical tionlymphomas. of Anwas EORTC Workshop epidermotropism histologically. ACD8+ plaques andoften ulcerated tumours, and Abstract idermotropic cutaneousidermotropic CD8+ Thelymphoma. , S. Whittaker (1), R. Willemze (19), E. Berti Berti (19), E. (1), Willemze R. S. Whittaker , (1),M.Santucci R. (17), Russell-Jones M . of Pathology VU University Medical ofCenter . University VU Pathology (4) Dept. of University(4) Dept.& Dermatology Venereology Massone, C.Meijer (13), POrtiz (14),T. Departmentof Pathology, Clermont-Ferrand, (9) Franck (8), MFranck (9),S. Geerts (2), Gellrich JR University Paris-Val-de-Marne, (19) Dept. of (19)Dept. Paris-Val-de-Marne, University -Kolopp presented thetypicalfeatures well y (12) General Dept. Hospital, Western Edinburgh, aoriginally described (as by Berti et al) with1 or more cytotoxic markers was Accepted Article distinctbothfrom classical and CD8+ ofcases mycosis Thisfungoides. justifies its inclusion hasCD8+lymphoma a characteristic presentation,clinical pathologyand prognosis, andis differ theusualfrom offorms CD4+thedi Conclusion: diseases. pagetoid reticulosisand not did differfromusual theCD4+ >50%fraction in the 13 of the 18 cases so investigated. CD8+ mycosis fungoides, phenotypethis in just 1 parameter; none labelledCD56, with thereand was proliferative a CD2- CD5- CD45RA+ CD45RO-phenotype in7 cases,withmany more varying cases from group,fungoides31 remain with alive or wit mycosis fungoides. The this survivalmedian group of 12 is(cf months CD8+mycosis historyof patches andplaques,or poikiloderma often haemorrhagic, orin some 2-3Noulceratedexamples, tumours. large patienthad a and, more specifically,the potential status cutaneous CD8+ lymphoma were assembled fr lymphoma. A meetingof the EORTC was convenedinLondon, inwhich cases ofprimary unequivocal status as a clinico-pathological entity distinctfrom other forms ofcutaneous fide categories,it has been concluded that moreare data required before granting each lymphoma. Although there is presumptive evidence to inclusionsupport the ofthese as bona small/medium pleomorphiclymphoma T-cell & primarycutaneous aggressive CD8+T-cell categoryprovisional beenretained has twofor there While littleremains with respectcontroversy to mycosis fungoides, Sezary diseases, constituting <10% ofcutaneous lym syndrome and primary cutaneous CD30+ lym arising at other sites. prognosis of many primary cutaneous lymphom lymphomas¹. This documentacknowledges the co publication ofthe WHO lymphoma classificationits with distinct section of cutaneous There has been consensus in the classification of cutaneous lymphoma culminating inthe Introduction classification. as adiscrete sub-categoryof cutaneouslymphoma in revisionsfuture ofthe consensus epidermotropic CD8+ lymphoma presented with and1 LyP borderline – anaplastic large cell lymphoma. Patientswith aggressivecutaneous ofcases CD8+ papulosis,lymphomatoid2 of solitarypagetoid reticulosis (Woringer-Kolopp) cutaneous epidermotropic CD8+lymphoma, 34examplesof CD8+ mycosis fungoides, 6 Results: cutaneous T-cell lymphoma. assessthe clinicopathological features of theCD8 variants ofthe more common forms of nosological status of aggressive cutaneous epidermotropic CD8+ lymphoma, and formally Cutaneous Task Lymphoma (EORTC),Force convened specifically in London, to assess the collected for a workshop theof European Organisation for Research andTreatment ofCancer Methods: this lymphoma & whether it warrants recognition as a discrete clinico-pathological entity. under the “provisional” category. This reflects the publishedpaucity of data with respectto This article This protectedis by Allcopyright. rights reserved. Of 71 cases,61 were included inthe study. These comprised18 cases of aggressive This study This collected 71 casesof CD8+ cutaneousThe lymphoma. caseswere Mycosis fungoides andlymphomatoid papulosis witha CD8+ do phenotype not of primary cutaneous aggressive CD8+ T-cell T-cell CD8+ aggressive cutaneous primary of seases. cutaneous Aggressive epidermotropic hout disease; p <0.002). Thetumourcells had a phoproliferations, thephoproliferations, remaining groupof phomas, problematic. more are In particular, a om many centres across Europe, discussed putative entities, viz.Primary cutaneous CD4+ othercharacteristic feature suggestive of as when comparedto their counterparts widespread ulcerated mpletely differentmpletely behaviour clinical and

plaques and tumours, Accepted Article Statistical Analysis Statistical defined as no individual authordissented. discussion in a lecture theatre and around amultiheadedmicroscope. A consensus was The casesreviewed were and classified by attendingpathologists and dermatologists in 1. used Antibodies Table for immunophenotyping. cells was defined as positive, <10% negative, 10-75% +/-. andby immunohistochemistryfor the antibodies listed in Table 1. Expression by>75%of available material, 5 All biopsy specimens were routinely processe Pathology Studies activelyexcluded this as disease formed the basis ofaseparateworkshop. cases were submitted for consideration. Furthermore, subcutaneous T-cell lymphoma was publications, is widely acknowledged as a particular variant of T-cell lymphoma, and no Juvenile CD8+hypopigmented mycosis fungoidesbeen has the subject ofseveral other organs, , length of andoutcome.follow-up recorded: sex, age at diagnosis,of site manifestation, clinical presentation, involvementof ofthemembers EORTC TaskCutaneous Lymphoma Force. The data following were A totalof 71examplesof CD8+ lymphomaweresubmitted for inclusioninstudy the bythe Cases andMethods Material classification. the inclusionof this aslymphoma aseparate categoryrevisionsof infuture the consensus haslymphoma distinct clinical, pathological lymphoma as a disease entity considered. The thefindingsconference of indicate this This article This protectedis by Allcopyright. rights reserved. rejectedwere & took nopart further inthe study. CD8+ATLL. Seven further cases had insufficie isolated sundryformed albeit well-recognis classification, e.g. unusualan double CD4+ /CD8+ lymphomaarisingHIV+ inan patient) or cutaneous T-cell lymphomaNOS (primary according to EORTCthe –WHO consensus from therejected study.were These as follows:three werecases eitherdeemed unclassifiable descriptions primary of cutaneous aggressive lymphoma. CD8+T-cell Ten werecases reticulosis. Eighteen cases were distinct fromthese groups andmatched the previous -papulosis cutaneous anaplasticcell largeoverlap lymphoma and2 casespagetoid of werefungoides; there6 of cases CD8+papulosis, lymphomatoid 1 ofCD8+lymphomatoid groups defined. were Themajority ofcases Basedon the collected histologicalclinical, ofDefinition Groups Results was set at in 0.05 significance all level forcut-off statistical analyses. death lymphoma-related or latest known follow- timewas calculatedSurvival theoffrom date diagnosis confirmed until the histologically μ m tissue sections were cut and stained with haematoxylin and eosin, eosin, and haematoxylin with stained and cut were sections m tissue ed diseases -HTLV-1+ CD8+lymphoma and and immunohistochemical datathree principal (34) becould classifi and immunophenotypicand features supporting thus d and paraffin. inembedded According to nt details supplied inclusion;allfor these up usingSAS 9.2 statistical package. The ed as CD8+ed asmycosis Accepted Article radiotherapy, methotrexate,radiotherapy, miltefosine, cy medianof 47 months. Treatmentsincluded;PUVA, UVB,topical steroids, nitrogenmustard, 1g); all but two patients are still havingalive, re mycosis fungoides survival time mirrored the more common CD4 form of the disease (Fig. and revealed a low proliferativ tested allexpressed CD2,whilst of16 tested11 labelledwithCD5. Ki-67 was assessed in 19 single case expressed CD56. In 23 cases of CD8+ MF so tested 18 were CD45RO+. Of 15 CD4 antibody. The majorityof caseslabelled withone orboth ofgranzyme B and TIA-1.A Bydefinition a majority oftumour cellsexpressedCD8 (Fig 1f); all failed to react withthe distinguishto the groupfrom commonplace CD4+ MF. infiltrate varied in accord with patch, plaque or tumour stage of disease. No features appeared nuclear contourscerebriform were each seen varying to degreesin group.thisThe dermal variable 1e), microabscesses, Pautrier(Fig. documented in, classical Thus, MF. epidermotropism, taggingalongthe basal epidermallayer in acaseof (H&E mycosis fungoides x200). 1e. Fig. Tagging lymphocytesperinuc of with 1d.Fig. A plaque of CD8+ mycosis fungoides on the lower limb. indistinguishable from classical CD4+disease. patients of examples Three bc. & 1a, Figs. CD8+ a phenotype with Table2 Cases ofMycosis fungoides,Lymphomatoid papulosis and Pagetoid Reticulosis (Figs 1a-c&1d). Thedisease distribution of did not differclassical from CD4+ MF. was the presentationofpatches clinical pl and age of 49.6 years (males 53, females 46.3 year group This constitutedof majority the submitted cases, 20 males andfemales 14with a mean CD8 phenotype (MF) with fungoides Mycosis This article This protectedis by Allcopyright. rights reserved. cellsakin CD30- those to seen typicalofB.Onetype MF, in LyP additional was case smaller In C. the comprised caseinfiltrate type a single of cells typifying sheets anaplastic atypicallarge mononuclear CD30+ cells, was seenin4 withcases, a further havingcase therapeuticstandard regimens, which includedsimple up,follow PUVA methotrexate.& LyP. Allpatientsbenignclassical a followed havingclinical course, treated been with hadlesionsa haemorrhagic appearance, butotherwise didnotdiffer appreciably from characteristically waxed waned,inand mannertypical the of LyP 2). (Table two In cases the 6patientsThese presented withgroups ofulcerating papules nodules,and which Papulosis. Lymphomatoid CD8+epidermotropic lymphoma 1g.Survival Fig. curves ofpatients CD8+with mycosis fungoides& aggressive bexarotene, TSEB & CHOP. Similarly, following a variety of accepted treatment regimens commonly used in in used commonly regimens treatment accepted of variety a following Similarly, The cases presentedhistomorphology the Histologically, Histologically, wedge-shapeda with infiltratemixed a of population cells, including e (10-<50%)infraction all. clophosphamide, gemcitabi dermal infiltrate of pleomorphic cells having with patches of CD8+ mycosis fungoides, fungoides, mycosis CD8+ of patches with aques typicalof classical mycosis fungoides s) (Table 2). A crucial feature of this group ceived a variety of standard aafter lear halos alonglearbasal the halos epidermallayer, usually associated with, and well-

ne, alpha-interferon, Accepted Article plaques (same patient as “a”:(samedeeply patient d) plaques plaques on the chest and trunk & limbs of these patients: c) ulcerated tumours & widespread ulceratedplaques and tumours, a) often haemorrhagic;b) haemorrhagic 2a-g.Figs. Presentations ofaggressive 3aTable Primary Cutaneous Aggressi 1g).0.002) (Fig significantly differedSurvival the from group,MF withmedian a of survival 12months (p< evolution from aevolution fromindolent period. more prodromal patient One had ahistoryof rheumatic 2h).(Fig. No patienta gave long history ofscaly patches orpoikiloderma tosuggest an patientslimited a number oftumours, particular Clinical follicular involvementnot was a in(Figs. plaquesdisease 2a-g); early the or foci. Infiltrated manifest tumours haemorrhagic in 2 cases. Ulcerated crusted and nodular lesions were most common, often with theincluding trunk, arms legs, and and face. Mucosal (oral) disease was notedatpresentation displayed lesions that had many similar features. Lesions were located in multiple sites from usualdiffered MF, lacking the patches andplaques that define that disease, but 54.5 years(males 51.6, 59.4; females 27-87). range The presentationclinical notonly Table3a. These patientsin weremainly adult intheincludedprevious groups. The clinical details ofthis groupofpatients summarised are In18 cases therewas consensus thatthelymphoma differed substantially casesfrom aggressivePrimary cutaneous epiderm and steroids (Table 2). Neither patient has progressive disease, with each responding to local directed therapy, UVB was marked pagetoid epidermotropism of medium-sized atypical mononuclear T-cells. ofpagetoidreticulosis, the solitaryvariant of form MF. Histologically, a recognised there solitaryTwo patients presented with hyperkeratotic patcheserythematous characteristic of pagetoidreticulosis(Woringer-Kolopp) Solitary thewith epidermispattern. a infiltrate pagetoid reticulosis recently describedlymphomatoid papulosis type inwhichD, CD8+ the lesional cells Theadmixed inflammatory cells. patient remain Histologically therewas a densepopulationof CD30+ CD8+T-cellswith relatively few classified and asoverlap, LyP/ALCL pres This article This protectedis by Allcopyright. rights reserved. in negative patientsthe 10 investigated; HTLV-1 was status HIV nodes. lymph mediastina and heart spleen, lungs, liver, of involvement examinations: in one, no evidence of visceral whorecorded, then subsequentlyrelapsed anddied.Two patientsunderwent autopsy WhilePUVA. a patients few enjoyed a partia 13 patients underwent or chemotherapy with or immunotherapy, withoutradiotherapy or medianwith a survivalof 12months. A variety revealinvolvement bydisease. In 13 cases the patients rapidlysuccumbed theto disease, allin to marrow patients Bone investigations be tofailed primary the lesions cutaneous. inlymph nodes only one instance at presentation, foundto be reactive onbiopsy, confirming patients, including chest X-rays, abdominal, chest and total body CT scans, revealed enlarged fever and clinicaladiagnosis ofvasculitiswasmade. initially Staging procedures, in 17

ve EpidermotropicCD8+ Lymphoma epidermotropic CD8+ included lymphoma epidermotropic otropic CD8+ T-cell lymphoma lymphoma T-cell CD8+ otropic feature feature commentedupon in anycase. Intwo ented as a solitary nodule, which regressed. ulcerated tumour: e)Disseminated ulcerated disease was found; the other had widespread l response, only 1had a responsecomplete with 11 males&7 and afemales, mean of age ly theon to led face, patient the presenting of therapies had been usedinthese patients; s well.of None the casesto conformed the status was assessed in 4 and was negative. 4 was in and assessed was status

Accepted Article hyperchromatic roundedhyperchromatic nuclei frequently with atypical cells in thevast majority of cases.The majority ofcells in most caseshad enlarged the epidermis 5.inThe dermal infiltrate consisted butquite ofmedium-sized monotonous Ischaemic necrosis withinthe dermispronounced was in2 cases andischaemic necrosis of (Figs.6a-d), observed in 11biopsies, sometimes accompanied byangiodestruction. wascells found inbiopsiesof the clinicalAngiocentricity tumours. was a common finding infocally a single case(Figs. 5a &b).A diffuse dense and dermal of population pleomorphic which these were clearly visualised but syringotropism proper was not convincing, present and epidermal infiltrate; malignant cells permeated between eccrine glands in 5 cases of 8 in diseasewasandof follicles absent, was follicular in all overshadowed cases the byinterstitial similarwith a patternof single cellinfiltratio was notedFolliculotropism in 8 cases of 11 in which follicles were well seen (Figs. 4a &b), individual atypical cells ofpagetoid that to seenakin forms reticulosis. diffuse in solitaryand by peppered liberally simply was the epidermis observation; an never was - – “tagging” layer cases, and then a minority feature; similarly,li were conspicuously lacking despite the number epidermis albeit most concentrated in the lower portion (Fig 3a-d). Pautrier microabscesses toconforming apagetoid reticulosispatterni.e. single atypical cells liberallyreplacingthe epidermotropism. The epidermotropism was a conspicuous observation in 15 cases, plaqueshyperkeratotic typically revealedhyperkeratosis and/or acanthosis, strikingand Thus,ulcerationhistology. was beingcommon, observed in 14patients. Erythematous the in reflected was this and lesions, clinical of variety a from taken been had Biopsies neoplasm. cell dendritic lymphomaextranodal NK/T-cell clinically mimickingandblastic plasmacytoid 2h. Fig. Aggressive CD8+ epidermotropic a solitary lymphoma; mass, periorbital necrotic plaques: g) Ulcerated tumours on the head and trunk. haemorrhagic plaques. This patient had no visceral diseaseat autopsy;f) haemorrhagic This article This protectedis by Allcopyright. rights reserved. sized, andwhilst markedlynever atypical, large orblastic (H&E, ax200, bx400). 7Fig. Tumour cellsof aggressive epidermotropic CD8+ lymphoma were mostlymedium x100,(d) (H&E, x200, x40, x200 respectively). vasculitis/angiodestruction with (d), sometimes ofangiocentricity finding common the Ischaemic 6a-d.Figs. changes, epid including syringotropism proper only found infocally one case (b) (H&E x 200). Figs. 5a& b. Permeationof sweat glands oftenwas seen (a)but convincing diseasex was (H&E, notconspicuous clinically 200). clinicalalthoughfollicular common, was folliculotropism & 4a Histological b. Figs. biopsiesvast majority of (H&E, x200) aggressive CD8+epidermotropic lymphoma, microabscesseswithout Pautrier in the A 3a-d. pagetoidreticulosispattern Figs. seen inany case. notweregrade” inMF that “high characterise cells transformation pleomorphic/anaplastic anycase,although perinuclearhalos wereoften seen.Nodular collections oflarge highly nuclear contour,the ofcerebriform hallmark MF, of epidermotropsim characteristic was of n, albeit oftenflorid, but mucinousdegeneration ningatypical of alongcells the basal epidermal a coarse pattern (Fig.7).Thechromatin ermal (a) and dermal (b) necrosis reflected reflected (b)necrosis dermal (a) and ermal of malignant cells, only being noted in two was notwas thepresent in of majority cellsin

Accepted Article possibility oflymphomatoid papulosispossibility type litt However, (8). of 5 patients 1 fatality only ofseries CD8+ epidermotropic lymphomas spontaneous foundand regression in 80%with cells cannotbeassumed toimpart prognosa poor CD8+lymphoma(3,4), benigna clinical course and/or that CD8 expression byneoplastic typical ofmycosis fungoides (2).Other authors presentedwithinfiltratedThe former plaques andthe nodules, latter had chronic patches outcome. Agnarsson et aldivided CD8+lym Discussion. proliferative fractiona high with b) CD8 of expression diffuse a) lymphoma: 8a-d. in Immunocytochemistry Figs cu cases* Lymphoma 3b Cutaof Primary Table Immunophenotype AllCD56. tumours were with negative in-situ hybridisation EBER.for cells in caseeach expressedorone both ofgranzymeTIA-1 or B;none expressedCD30 or proliferative fraction with Ki-67 was found in all but 2 cases investigated. The neoplastic cases investigated for Beta-F1 expression, 8 cells that labelled with antibody to CD45RO, and in these few cells were positive. Of 10 expressed CD45RA (14 cases, Figs. 8a-d). Conversely, only 3 of 17 presented a population of characteristic traits emergedwithin thisgroup. Most (14) cases lacked CD2 CD5,and/or and ofThe results immunophenotyping these cases arepresentedin Table 3b. Several wereotherrimming, sundry unremarkable observations. A variable interstitial component, andoccasiona This article This protectedis by Allcopyright. rights reserved. wanting. acceptedprovisionally aggressive epidermotropic of lymphoma cytotoxic Berti hasbeen cells. Nevertheless, formalevaluation ofthese variants and comparisons with the differ simply and disorders of these features histological appraisal; thus, these diseases display a cytotoxic phenotype. Insuch cases successfuldiagnosisrests on careful clinical and 16, 50). Itis accepted that MF,LyP anaplastic and large cellmay,lymphoma exceptionally, been ofisolateda number that to reports attest this 11,12, distinctive 13,(10, entity 14, 15, mycosismore common clinically fungoides and the from differed cases latter These (9). of disease CD8+ form epidermotropic aggressive anaplastic large lymphoma,cell mycosis andfungoides cases of hithertounreporteda di cytotoxic lymphoproliferative andclinicopathological details.In 1999,et Berti status nosological assess definitively to attempts undermined has data of a paucity which in clinicalfeatures pathologicaland morphologies. Thereremain a groupof rarer malignancies thelymphoproliferation, mostcommon neoplasms, T-cell lymphoid well-established have delineating disease entities. Mycosis fungoides, lymphomatoid papulosis and CD30 patholof clinical, collective importance The literatureof reports “CD8+ lymphomas” suggestmarkedly apatient variable Recent classifications of primary cutaneouslymphomas have emphasised the sorders,variably characterised lymphomatoid as papulosis, Ki-67was charac ogical immunophenotypicand parameters in taneous aggressive epidermotropic CD8+ presentthe “usual” clinical and histological s D(31; & seebelow)E not considered. inthe cytotoxic phenotype ofthe neoplastic were positive in the tumour cells.high A phomas into progressive indolentgroups.and le clinicalwasand description provided, the CD45RA and c) loss of CD5 expression.: d) emphasise, eitherthe aggressiveof nature alreported a 17series of patients with lsubcutaneous adipocyte extension, without neous AggressiveCD8+ Epidermotropic histopathologically. Sincethere thenhistopathologically. have is (5,is 6,7,49, 61). Hagiwara et al studied a teristic (x100). Accepted Article Similar observations obtain Similar with respectto CD8+ papulosisvariant lymphomatoid reticulosis (Woringer-Kolopp). Interestingly, the presence of haemorrhagic lesions was cutaneous anaplastic(LyP), large cell lymphoma (ALCL)the and solitary formofpagetoid arepoikiloderma, ofcritical importance for accurate diagnosis. plaques,& other or hallmarks ofMF e.g. follicular mucinosis, hypopigmentation or (25) and MFCD56+disease (51). Thus, careful typical otherwise of variant CD8- CD4- the to regard with made been has assertion same The in andof itself, cannotbetaken toimply a poorprognosis. (18, 6, 19), 20, 21, 22, 23, 24). furthermore, they arein agreement withprev usual CD4+ form of disease, differing only in the single immunphenotypic anomaly; TheMF. findings herein convincingly indicate CD8+ tobe MF indistinguishable the from the studygroup followed relativelya protracted, higher fraction was observedseries inthis 5 - of23 labelledwithCD45RA. Most patients in formalprevious studies, <9% ofMF cases displaythisimmunopositivity for marker (17);a malignant cells. This with contrasts CD45RO-“native” but CD45RA+ T-cells. In the limited neoplasmreflected of T-cells, memory in usual the immunoexpression ofCD45RO bythe whenloss, observed, did not conform to apartic were largely unextraordinary; a single case was CD56+, and the observation of T-cell antigen of a CD8 immunophenotype onbiopsy material. otherimmunocytochemicalThe findings commonplaceCD4 disease. Indeed, the first an Thus, nothing in thepresentation and clinical submitted,Of thecaseshadthe classic clinical34 of mycosis phenotype fungoides (MF). lymphoma. lymphoma, Woringer-Kolopp and the provisional entity aggressive epidermotropic cytotoxic paper, Inthis the histologicalclinical, andimmunphenotypic characteristics offorms papulosis,largemycosis encompass anaplasticproliferations lymphomatoid fungoides, cell of CD8+ cutaneous lymphoproliferative diseasebeen have collectedand analysed.These This article This protectedis by Allcopyright. rights reserved. patient. striking histologicalepidermotropism typiare are CD8+ (33, 53). The clinical observations of accounted2 for submitted.cases Approximately halfof reported casesof pagetoidreticulosis toindicatenodules associated LyPof any form, nordidthey express CD30. epidermotropic lymphoma group had a clinical hi furthe was ofthistype; series in this LyP to clinicaldetails and the presence or absence of CD30+ atypical cells.None of the casesof aggressive epidermotropic CD8+ lymphoma; dis angiocentrichistology (62).T CD8+phenotype. Similarly, LyPtypeE commonlya has CD8+ phenotype, displaysand an LyP, but of distinctive in theforms of pattern and pagetoid reticulosis epidermotropism typepapulosis D is a relatively distinct recently CD4 disease, including the favourable prognosis (28, 27, 29, 30, 52). Lymphomatoid to attestsimilarityreports the ofthe CD8+ fo typical LyP, and the reportsof previous exampl histologically. Allpatients remain alive andwell in accord withthe benign prognosis of classical LyP. The observationofclinical haemorrhage was reflected inevidence ofthis containing markedly atypicalCD30+ T-cells completedan almostidentical picture to upon commented severalinA cases. wedge-shaped characteristic infiltrate ulcerated skin, of The clinical appearance oftheof solitaryformreticulosis, pagetoid Woringer-Kolopp, hus, thedifferential ofdiagnosis these forms of LyPinclude rmore, nopatient inthe aggressive CD8+ ious authorsious who contend that CD8 expression, rm of primary cutaneous ALCLto the classical appraisal distinguished these patientsdistinguished these from appraisal cal, andthe disease did notprogress ineither d only unusual characteristic was the finding es of CD8 LyP (26, 27). Previous literature solitary scaly erythematous acral plaques, the ular pattern.MFis believed to representa form of LyP (31), ofLyP clinicallyform toother (31), identical clinicalassessment for characteristicpatches tinction betweenthese tworequires attention benign, course in accord with classical CD4 story of waxing and waning papules or

Accepted Article is, perhaps, more complex (6, 18, 19). CD8+lymphoma e.g. in hypopigmented tocomparison juvenile MF, emphasisesituationthe tested Nevertheless, lymphoma variability (35). theprognosis betweendifferent of of forms ofevolution disease. Theyexpression found of molecule this in allfour ofCD8+cases sites, may act to down-regulate the host na ofexpression HLA-G, a non-clas The basis for this aggressive behaviour remains speculative. Urosevic et al postulate that the hasThis been noted previously (11,12,13). 17 soinvestigated, a feature uncommon intumourunlessMF transformation has supervened. of 13 in antigen) Ki-67 (to MIB-1 with labelling cells malignant of >75%, often 50%, least continual antigen stimulation. (54). A high markedly fractionproliferative reflected was in at the switch betweenCD45RA and RO isnotirreversible, particularly in the absenceof ofwhichmajority are CD4+), without an adve CD45RO+therefore CD45RA-,thelatter be can seenin a smallof minority cases (thevast Althoughmycosis(2). fungoides neoplastic cells inMF are typically memory and T-cells, CD8+epidermotropiclymphoma, as opposed to butlikelythat this isto reflectwereprognosis, such cases in that series genuine aggressive Agnarrson was tosuggestthe first that loss ofCD2 expression correlatespoor witha thereforerelationship a between theexpressions oftheseimmuno-markers be may expected. memory (CD45RO+) T-cells there is up-regulation of the adhesion molecule, CD2, and beingpattern observed in7 cases. Inthephysiological transition naïve from (CD45RA+)to CD ofsuggestionCD2- CD5- a a is There presented with widespread, often haemorrhagicplaques andtumours. extensive Theremaining 18 casesof CD8+ lymphomadidnot toconform mycosis fungoides, histologicallyOf and clinically, 18 the 16 immunophenotypically. cases, patients initially lymphomatoid papulosis pagetoidreticulosis.or Nevertheless, they weredistinctive This article This protectedis by Allcopyright. rights reserved. although in the majority ofcases the tumour cells of section ofoneof these tumours was also negative for T-cell receptor CD56- phenotype, which is not thattypically seen in as theantigen maysimply fail to be expressed. In bothcases themalignant cellshad a CD8+ alsowerenegative beta-F1, for does this notprove thatthemalignant T-cells wereof negative for the beta ofchain the T-cell receptor. Although two of the cases in this series the of vast (37);in moreover,majority by the instances malignant will cells be definition, prognosis. Cutaneous verypicture similar to primary cutaneous The latter neoplastic theare cellinaggressive the circulating T-cells express the diagnosis,differential including cutaneous nodules andtumours notthe is usual clinicalpresentationof but MF, invites differenta to the commonplace CD4+ disease (24). demonstrate that clinicallytypical CD8+ MF follows natural a courseof progressionidentical These cases knownare distinct and from accepted of forms cutaneous lymphoma. fungoides. However, the cases ofCD8+MF in this series, and others,convincingly is these tum that interpretation One proffered Immunohistochemically, all hadcases a CD8+ - CD4 - EBVCD56 – phenotype. Furthermore, thehistoryFurthermore, relativelywidespread short haemorrhagic of ulcerated γδ lymphoma, however,has CD4- aCD8- CD56+ immunophenotype αβ chain inthe receptor T-cell withof < 5% the sical HLA class Ib molecule restricted to immunoprivileged CD8+ lymphoma, and hassimilarly a dismal 45RO- CD45RA+ phenotype, this collective tural anti-tumour response resulting rapidtural response in anti-tumour γδ ours represent an aggressive ofmycosisform lymphoma Ketron-Goodman and disease. Most rse prognosis in thestudied (17).Indeed,few the “chronic form” ofCD8+ lymphoma viz. γδ lymphoma, which may present a clinical γδ γδ lymphomas are CD8-, a small lymphomas. Furthermore, a frozen δ . Nevertheless, γδ subtype. subtype. γδ type, Accepted Article physiological populati This article This protectedis by Allcopyright. rights reserved. lymphoma can not always be excluded; nevertheless, most examples of somethat ofprimarycases CD8+ cutaneous lymphoma are arare formof series, and often havea poorprognosis (43,44, with present ulcerated plaques multiple tumour and suggestsimmunhistochemistry distinct phenotypes. the neoplastic cytology is more monotonous than is usual in MF. Finally, considerable epidermotropism, thereis a pagetoid reticulosispatternof epidermotropism and lymphoma. Conversely, unlike MF, therefew are no microabscessesor Pautrier despite seen inany ofthese cases egCD30 expression in lymphomatoid papulosis & anaplastic ofrecognisable forms CD8+present lymphoma T-cell histological diagnostic notfeatures CD8+T-cell lymphoma. However, the ofanalysis largethis series indicates thatother the distinction between aggressiveCD8+ epidermotropiclymphoma other and offorms authors (14, 56) & attributed to a CD8+ lymphoma, or worsening prognosis in this lymphoma, has been postulated by several ofInte CD15 has expression (42). reportedbeen demonstrate viralintegration into neoplastic cells. Finally, asingle casewith anomalous At least one case haslinked been toHTLV-1 the relationshiptheto ofthelymphomahistorylong original lesions dating 10 years previously ha precededby a lengthy period (39,prodromal 40) ourin series. CD56+, notseenin anyof ourcases, andimmunolabelling beta-F1 excludes for those tested angiocentricity, together with a CD8+ CD45RA+ phenotype, Ki-67 > or CD8+ 75%; togetherCD56(-) phenotype, a CD45RA+ either with angiocentricity, histologically, finding the of apagetoid plaques/tumours, often ulcerated/haemorrhagic,mucosal involvementis not rare; support manyof the suggested criteria; for diag diagnostic criteria for aggressive epidermotr in tumours the other patient. plaques onthe trunk, and there wassubsequentdevelopment rapid ofmultiple plaques and haslymphoma been (46).reported previously In single case ofaggressive CD8+epidermotropic lymphoma mimicking extranodal NK/T-cell the absenceof EBV expression is anexceptional event,ifseen all,inat NK/T-cell disease.A dendritic cellneoplasm. Bothare readily excluded by the immunophenotype; in particular, appearance thatresembled NK/T-cell extranodal lymphoma andblastic plasmacytoid lymphoma). CD8+ CD4- (43, 59, 60) (therefore representi CD8- phenotype (43, 44, 45, 57, 58) (and may, therefore, represent ofreports disseminated pagetoid reticulosis cutaneous reticulosispagetoid with disseminated have Patients withPatients disseminated the formreticulosis ofpagetoid disease)(Ketron-Goodman Previousreports bysomeof have the (1,9) authors indicated thedifficulties inmaking A few case reports do suggest that in rare cases, this aggressive lymphoma can be Recently, a report ofaRecently, report two cases andof the review literatureNofal byal, et proposed patientsThe two thatpresentedhadan lesions facial with limited more tumorous γδ lymphoma; minority may a represent rare on of CD4-CD8+ augmentation of Th1 immunity. augmentation ofTh1 reticulosis pattern of epidermotropism, and γδ T-cells is known to exist (38, 55). The possibility either aggressive epidermotropicCD8+ or opic CD8+cutaneousOur lymphoma(47). data detailvariable phenotypes,including a CD4- d not been presented ordiscussed; moreover, ng aggressive epidermotropic CD8+cutaneous infection, (41)althoughinfection, the authors’ did not nosis, we emphasise the acute presentation of 45). It is likely that many patients diagnosed restingly, the possibility oftherapyinducing possibility the restingly, one patient there weremore widespread , although inIto, etalthough althe histology the of s at various sites, similar patients into similar our sites, at various s of psoriasisof in Weenig et alis uncertain. examples of aggressive MF. Previous

γδ lymphomas), and γδ γδ lymphoma are lymphoma cutaneous Accepted Article

Dr David Loras, Clinical Epidemiology Unit, Hospital Universitario, Madrid, statisticalfor analysis. Acknowledgments in the future to try & improve patients withsurvival for this disease. very poor prognosis, a multicentre inlymphoma futurerevisionsof the WHO lymphoma classification.Finally, in view ofthe presentation, histopathology and immunphenotype, and should be classified as a specific current evidence, aggressive epidermotropic should Cutaneous lymphomas be considered, interms ofdiagnosis management,and rather thanany of these parameters in isolation. on thecollective bases of clinicalappearance, pathological findings immunophenotypeand documented a similarpattern. Proposeddiagnosticare criteria listed in table 4. finding, focal or complete loss ofofone CD2 or CD5is also previous common; have reports betaF1+, and expression ofoneorofmore TIA-1 orgranzyme B.Whilst not constanta This article This protectedis by Allcopyright. rights reserved.

8. 7. 6. 5. 4. 3. 1. 10. 9. 2.

CD8+T-cell lymphoma: indolentto from transformation aggressive phase in Kasuya A, Hirakawa S, Y. Prim Tokura patients. unspecifiedtype with cytotoxic phenotype:clinicopathological of analysis 27 Hagiwara M,Takata K, Shimoyama Y etal.Primary cutaneous T-cell lymphoma of cutaneous T-cell lymphoma. Khamaysi Z,Ben_Arieh Y, Epelbaum R et CD8+Pleomorphical. small/medium size with non-aggressive clinical behaviour. Dummer R, Kamarashev J, Kempf W et al.Junctional CD8+ cutaneous lymphomas cutaneous T-cell lymphomas. LuD, Patel KA, Duvic M et al. Clinical andpathological spectrumof CD8-positive 17: 287 – 291. cutaneous T-cellwith lymphomainvolvement. tongue Lesher DavisMJ, JL, LS Quatermanal: CD8-positive Rapidly progressive et Dermatology cutaneous lymphomawith T-cell primary multi-organ involvement. Ghislanzoni A, Gianelli Marzano M, U etal: FatalCD8+ cytotoxic epidermotropic lymphomas. Willemze, R,Jaffe ES,Burg G,et al. WHO– EORTC classification for cutaneous

epidermotropic cytotoxic T celllymphomas. Berti E, Tomasini D, Vermeer M et al: Primary cutaneous CD8-positive subtypes.chronic (CD8)suppressor/cytotoxic phenotype:identification ofrapidly progressive and AgnarssonBA, Vonderheid EC, Kadin ME et al. Cutaneous T-cell lymphoma with Cancer Sci Blood .2005; 211:.2005; 281-285. JAcad Am Dermatol 2005;105 (10):3768-85. . 2009; 100(1): 33-41. clinical trial using aggressive therapy might be considered Am J Dermatopathol. J Cutan Pathol CD8+ lymphomahas arecognisable clinical .1990; 22:569-577. ary cutaneous aggressive epidermotropic It theviewis of the workshop panelon that, Arch Dermatol. Am J Pathol Am J .2002; 29:.2002; 465-472. 2006; 28:434-437. AmDermatopathol. J 2002; 138:199-203, . 1999; 155: 483 – 492. 1995; Accepted Article

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previously unrecognised variant. KnappCF, Mathew R, MessinaJL et al. CD CD8+CD56+ immunophenotype: a case report and literature review. T, MonobeKuwabaraShiomi Y, C et Poikilodermatousal. mycosisfungoideswith a Nov.2012; 27doi:10.1111/cup.12067 ainvolvement: case report. Ishida M, Mochizuki Y, Saito Y et al. CD8+ mycosis fungoides with esophageal 26(4):450-457. fungoides. Frequent expression ofa CD8+ T-cell phenotype. Cerroni LE, L,Shabrawi-Caelen et LJ Medeiros al. Hypopigmented mycosis 1199 –1204. immunohistochemical and genotypicanalysis of six cases. Whittam LR, Calonje, E, Orchard G et a Cutan Pathol fungoides: clinical, histological andim MT,NovelliFierro M, P Savoia et al. CD45RA+ immunophenotype inmycosis Clin Pathol aggressive CD8+epidermotropic cytotoxicT-cell inyoung lymphoma a woman. J,Csomar Bognar A, Bednedek S, et al. Rare provisional entity:primary cutaneous Dermatol lymphoma with peripheral blood and central nervous system involvement. CE,Introcaso Kim EJ, Gardner J et al CD8+ T-cell lymphoma. Gormley RH, Hess SD, AnandD et al.. Primary cutaneous aggressive epidermotropic aggressive CD8+T-cellepidermotropic lymphoma. KikuchiA, Y,Kashii Gunji Y et alSix-year-old primarycutaneousgirl with casea reportofa rareand aggressi Geddes A, Savin J, White SJ al.et Primary cutaneousCD8-positive T-cell lymphoma: 2011; Sep; 38(7): 472-4, 476. Eur J Dermatol CD8+T-cell lymphoma; oftwo report cases Szepesi A, Csomor J, RajnaiH,et al. Primary cutaneous aggressive epidermotropic (10):5. association with CCR7-positive with association conversion. CCR7-positive Am Acad Dermatol.Am Acad variantanunusual ofcutaneous T-celllymphoma with a CD8+frequent phenotype. Pavlovsky L, Mimouni D, Amitay-Laish I et al. Hyperpigmented mycosis fungoides: . 2008;144(8): 1027-1029. . 2008;61:770-772. . 2001; 28: 356-362. . 2012;Sep-Oct; 22(5):690-691. 2012; Jul;67(1):69-75. J Am Acad Dermatol Oncol Lett Am J Dermatopathol. ve disease with oral presentation. . CD8+ epidermotropic cytotoxicT-cell . 2013;Jan;5(1):73-75. munophenotypical in22features patients. l: Juvenileonsetmycosis fungoides: an 4/CD8 dual-positive mycosis fungoides: a Dermatol Online J with no of systemicevidence disease. . 2010; 62”300-7.

Pediatrics Int. 2012; May; 34(3) e37-9. BrDermatol J Am J Surg Pathol SurgAm J . 2012; Oct 15;18 2011; 393-396. Dent Update J Cutan Pathol . 2000; 143: Arch Arch . 2002; . J J J . Accepted Article

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immunophenotype. immunophenotype. Wain EM, Orchard GE, MayouS et al 1796-1798. lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2. UrosevicM, KamarashevBurg J, G et al. Primary cutaneousCD8+ and CD56+ T-cell T-cell lymphoma. T-cell CD45RA and CD25 on CD4-positive periphe JakobNeuberK, T, Altenhoff J et al. Stage-dependent expressionof CD7, CD45RO, Pathol disease): anmolecular immunophenotypic, clinicopathologicaland study. Haghighi B,SmollerBR,LeBoit PEet Am AcadJ Dermatol cutaneousprimary CD30+ in lymphoproliferative disorder patienta sarcoidosis. with CD8+/CD4- etProgressiveMA, epidermotropic Vittorio C al. Wasik JM, Gelfand Description of 9 cases. primary cutaneous aggressive epidermotr GuliaSaggini A, A,Argenyi Z al. et A of variant lymphomatoid papulosis simulating

Jul-Aug;21(4):609-610. Jul-Aug;21(4):609-610. presentinglymphoma as multiple scrotalnodules and plaques. Xu H,QianJ, JWei et CD8-positive al. primary cutaneous anaplastic large cell PCALCL. cell lymphoma (PCALCL): case report and review of this unusual variant of Plaza JA,Ortega P, Lynott J et al. CD-8positive primarycutaneous anaplasticlarge T- celllarge lymphoma with fair prognosis.a Ichihashi T, Metal M, Masaki Fukunaga 2013; Feb;40(2):236-47. disorders with CD8 expression: a clinicopathologic studyof 21cases. Plaza JA, Feldman AL, Magro C. Cutaneous CD30-positive lymphoproliferative CD56+ immunophenotype. S,Flann Orchard G, Wain EM et al.Three cases oflymphomatoid papulosiswith a Am Acad DermatolAm Acad cutaneous T-cell lymphoma; animmunohistochemical variantof mycosis fungoides. Hodak E, David M, Maron L et al. CD4/CD8 double negative epidermotropic Dermatol CD8+cytotoxic variantof mycosis fungoides: a case series ofseven patients. of course and characteristics Clinical al. et A Katsambas E, Papadavid VA, Nikolaou

. 2000; May;13(5):502-10. . 2009;Oct; 161(4):826-30. Am J DermatopatholAm J Acta DermVenereol . 2006;. 55:276-284. J Am AcadJ Dermatol . 2004;Aug;51(2):304-8. Am JSurg Pathol. J AmJ Dermatol Acad . 2010; Jul;32(5):489-91. . Mycosiswith. fungoides a CD56+ (Stockh). 1996;76: 34-36. al. Pagetoidal. reticulosis (Woringer-Kolopp . 2005;53: 158-163. opic CD8+ cytotoxic T-cell lymphoma. . CD8-positive primary cutaneous primary anaplastic CD8-positive . 2010;Aug;34(8):1168-75. ActaVenereol Derm ral bloodT-lymphocytesin cutaneous . 2006;55:903-906. EurDermatol J . 2002;82(4): 312-4. Blood. J CutanPathol Mod 2004; 103: 2004; Br J Br J . 2011; J . Accepted Article

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13. new variant simulating aggressivelymphomas. JAm Surg Pathol. 2013Jan;37 (1):1- Kempf W, Kazakov DV, SchärerLet al. Angioinvasive papulosis: lymphomatoid a lymphomas. AmPathol. J 2001;158(5): 1593-1597 molecules andkiller cellreceptors in inhibitory CD8+and CD56+ cutaneous Kamarashev J, BurgG, Mingari MC et al Goodman) (In French). Cotton H,A, Janin GrossS et Lymal. Typ Ketron-Goodman (In German). H,Bacharach-Buhles Luther M,Schultz-Ehrenburg Uat PagetoidRetikuloseal. vom 23. presenting as disseminated pagetoid reticulosis. A,BertiCerri E, Cavicchini S etal. Primary cutaneousgamma/delta T-cell lymphoma Surg Pathol lymphomas share common histologic features Jones D,VegaF, Sarris et AH al. CD4-CD8- ‘double negative’ cutaneous T-cell 53(6): 1093 – 1095. bexarotene therapy ina patient with Sezary syndrome. AltmeyerKreuter A, P. onsetRapid of expression of T BucyPR, Chen CLH, Cooper MN. Tissuelocalisation andCD8accessory molecule Nature Bell EB, Sparshott SM. Interconversion of hypersensitivity reaction. Crowson AN, Magro CM. Woringer-Kolopp disease. A lymphomatoid 1992. rearrangement and electron microscopic studies. reportlymphoma; oftwo withimmunophenotyping,cases T-cell receptorgene Kikuchi A,Sakuraoka K,Kurihara S etal.CD8+ cutaneous anaplasticlarge cell immunophenotype. immunophenotype. Wain OrchardM, GE, Mayou S et al. mycosiswith fungoides a CD56+ Dermatol cytotoxic T-cell lymphoma clinically simulating gangrenosum. pyoderma Wang Y,Li T, Tu P et al. Primary cu . 1990;348: 163. . 2009;Oct;34(7):e261-2. . 2002; 26 225-231. (2): γδ cells inhumans. J Am AcadJ Dermatol Ann Pathol Am JDermatopathol . 1991;11: 117-21. J Immunol Hautarzt. taneous aggressive CD8+epidermotropic phome purement epidermotrope typephome (Ketron CD8+ aggressiveT-cell lymphoma during . 2005;53(1): 158-63. . Differential expressionof cytotoxic CD45R subsetsof CD4 T cells invivo. and an aggressive andanclinicalcourse. 1989; 40:530-5. . 1989; 142:3045– 3049. . 1994;16(5):542-8. J Invest Dermatol Br J DermatolBr J J AmJ Acad Dermatol . 1992;. 126:404-408, . 1991;96(5): 718- Clin Exp . 2005; Am J Accepted Article 1/15; 1/15; BetaF1 1/30; trypsin Granzyme Mouse, 1/200; citrate TIA-1 B IgG1 EDTA; citrate CD56 Mouse, Mouse, 8A3 1/50; 1/50 CD45RA Mouse, ThermoScientific IgG1 IgG2A 11F1 Mouse, 1/200 citrate CD45RO Novocastra IgG1 2G9A10F5 Mouse, EDTA; IgG1 Beckman CD7 1B6 EDTA;1/50 dilution EDTA; 4KB5 IgG2A UCHL-1 1/20 BioGenex Mouse, Novocastra CD8 Coulter DakoCytomation pre-diluted Rabbit, CD5 IgG2b EDTA; Mouse, CD4 Source monoclonal LP15 EDTA; pre-diluted Rabbit, SP57 CD3 IgG1 Novocastra Clone EDTA; pre-diluted Ventana Rabbit, CD2 4C7 polyclonal Species & type SP35 1/40 Novocastra Mouse Conditions monoclonal Antibody specificity Ventana 2GV6 IgG1 immunophenotyping. for used 1.Antibodies Table AB75 Ventana Novocastra This article This protectedis by Allcopyright. rights reserved. MF months 56 MF months 31 female MF months erythematous 26 male MF months 74 papules female MF months 10 Chemo scaly 42 MF months A+W 19 patches papules male MF months Diagnosis 12 Time period* PUVA male hips/arms erythematosus Topical A+D male papules Age/sex 36 lesions phenotype aon CD8+ with Reticulosis Pagetoid and papulosis Lymphomatoid fungoides, Mycosis of 2 Cases Table buttock A+D DXT limbs 22 Clinical A+W 1/5; MIB-1 72 DXT featu citrate A+W Mouse, 68 purpuraIgG1 MIB-1 DakoCytomation legs NK A+D 22 54 male patches buttocks 35 years Chemo A+D 48 res Therapy Outcome

Accepted Article 69 MF months 39 male MF months 44 female MF months generalised patches 51 MF months 49 patches axillae/groins PUVA male MF months 120 PUVA 51 male MF months A+D patches 43 A+W 40male male MF months A+D generalised retinoids PUVA, 30 11 on female MF months atropic 47 patches 50 –plaques/nodules eczematous lesions patches female MF months PUVA erythematous back 89 patch psoriasioform patches/pla buttock/hip female MF months 60male local atrophic A+D A+W PUVA 30 scaly erythematous hyperkerat male MF PUVA DXT, months buttock 55 female 120 steroids patches DXT A+D male MF months patches 58 female PUVA A+D psoriasioform A+W 360 MF buttocks 60 A+W poikilodermatous 42 tumour sacral poikiloderma, patches Erythrodermic months MF atropic 30 UVB NR 40 scaly MF months 39 female A+D A+D 52 male MF months 72 lesions PUVA, male MF months erythrodermic, 23 16 poikiloderma, Chemo HIV+ female petechial Chemotherapy A+D plaques 132 Died Chemo/DXT patches of DXT A+D A+D disease 180 120 7 patches arms/legs PUVA A+W 43 This article This protectedis by Allcopyright. rights reserved. LyP months 38 LyP months 51 male MF months male 50 ulceronecrotic MF months 55 ulceronecrotic male MF months lesions 46 female MF months generalised lesions patches/plaques 56 arm/hip female MF months psoriasioform - A+W 62 Many patches arm/leg PUVA, female MF months patch local 10 52 patches,plaque male MF therapies months DXT 46 on steroids female MF months A+D arms Widespread A+D poikiloderma 65 A+W 72 male MF 72 months thigh PUVA DXT 82 34 patches PUVA topicalmale MF months A+D A+D scaly male A+D 24 36 patches patches 36 scalp PUVA A+W and 36 A+D erosions, plaques 72 Steroids plaques, A+D nodules 49 DXT A+D 36 tclsos Chemot otic lesions us UA hm ido ies 132 disease of Died Chemo PUVA, ques eayUkon NA Unknown herapy Accepted Article 7 53 male nodules arm/face/chest N** PUVA/DXT Died of disease Died PUVA/DXT other Died of disease Died PUVA/IFN N** Chemo PUVA, N N arm/face/chest nodules A+ D epidermotropic Aggressive of disease Died Chemotherapy - papules/nodules patches/plaques Chemotherapy plaques/nodules male 53 disseminated female 80 NA 7 female 58 causes N N*** 6 3/12 ulcerated tumours trunk/extremities 12 lesions 5 ulcerated widespread weeks 6 84 4 27 months 32 male 12 3 NK/ months male 43 22 2 female Aggressive months 7 1 male Aggressive months plaques/nodules epidermotropic Time Aggressive months Case ND disseminated epidermotropic Aggressive Age/sex DXT period* Aggressive epidermotropic Died Diagnosis ulcerated epidermotropic epidermotropic of tumours Clinical disease features N Chemotherapy Died Staging Therapy of disease Outcome 18 74 male ulcerated nodules leg/trunk N IFN, Chemo Died of disease Died Died of disease Died of Chemo disease IFN, Chemotherapy DXT article This protectedis by Allcopyright. rights reserved. N N Died of disease N leg/trunk nodules Died ulcerated of disease Chemotherapy ulcerating tumours legs Died of disease male 74 IFN ulcerating tumour Chemotherapy elbow LN+ 12 67 male 18 generalised ulcerated nodules/tumours 6 17 months 66 Died of 72 disease male Chemotherapy/DXT 16 months 39 10 27 male N N 15 Aggressive months 7 Aggressive 14 female ulcerated months patches,plaques, nodules 43 N** epidermotropic 13 Aggressive months haemorrhagic55 tumour 28 orbit epidermotropic 12 ulcerating Aggressive months papulunecrotic tumours59 face/trunk 24 33 male Aggressive epidermotropic 11 female months 87 female 31 10 tumour epidermotropic 10 Aggressive male months 70 female 11 epidermotropic 9 necrotic Aggressive male months 36 erosive ear epidermotropic 8 Aggressive months 27 palaques/nodules tumour epidermotropic Aggressive months plaques N N** DXT epidermotropic Aggressive months N PUVA, HN2 elbow Died N epidermotropic Aggressive DXT Died epidermotropic A+W Aggressive Chemo, of epidermotropic of epidermotropic BXT disease disease Died of disease CD8+Lymphoma Epidermotropic Aggressive Cutaneous Table 3aPrimary A&D =alive with disease; A&W =alive and well; NK –known;not NA = not applicable. Woringer-Kolopp months 46 Woringer-Kolopp months 61 female solitary LyP months male 29 LyP months erythematous 43 solitary female LyPrelapsing 17 plaque DXT male LyP/ALCL months gluteal 72 papules/nodules A+W Ly female months exudative ulcerated 24 lesion 30 female 2 Excision nodules nodule female self-healing UVB papulonecrotic A+W face,chest + Steroids A+W papulonodular 24 lesions 72 papule NK lesions Excision NA buttock - A+W A+W Excision 120 30 A+W 24 **systemic *** -developedonly cutaneousdisease disease -autopsy revealed N – LNnegative, +lymphnode enlargement – – BXT –boneDXT radiotherapy,IFN chemotherapy, interferon transplantation marrow – NA not applicableknown not notdone NK ND *From diagnosis listedto outcome.

Accepted Article +++= >75% ++ = 50-75% + =25-50% MIB-1: +++ ND + EBER. for hybridisation situ None la *AllCD4-. CD8+, caseswere - - ND ND 18 17 - ND ND 16 - + + - + ND - ND 15 +++ +++ + - + + - 14 ND** + + - ND 13 12 +++ + + ND +/- ND 11 - ND ++ + ++ - + - 10 +** + + + +/- +++ - + - - +++ +- + - 9 + ND ND +++ + 8 - + ND ND -** 7 ++ +++ 6 + + + - + - +- - 5 + 4 +- - ND +/- + +- ND - 3 +++ 2 ND 1 - +/- MIB-1 - +/- + + Beta-F1 + Case CD CD45RA 2 CD45RO CD7 CD5 A Cutaneous Primary of Table 3bImmunophenotype This article This protectedis by Allcopyright. rights reserved. Ki-67> 50% At least 1 of or CD5(-) CD2(-), CD56(-) CD8+ Monomorphic atypia +/- apoptotic keratinocytes pattern reticulosis Pagetoid BetaF1(+)mucinosis orpoikiloderma evidence No history of patches, tumours Plaques and of Clinical CD8+ features Table 4criteri diagnostic Proposed CD45RA(+) Histology Immunohistochemistry All cases demonstrated T-cell clonality by analysis of T-cell receptor. ** Immunohistochemicallynegative forreceptor T-cell or TCR No immunosuppression disease cutaneous Staging confirms only EBER(-) +/- + - ND ND +++ +++ + ND ND - + +/- +/- = between 10-75% cells positive positive cells 10-75% between = +/- - =less than 10% cells positive + =at least 75% cells positive T-cell antigens: a for the diagnosis of Primary Cutaneous Aggressive Epidermotropic Epidermotropic Primary Aggressive Cutaneous of a for the diagnosis belled with or CD56 antibodies toLMP, and all were negative with in- ggressive Epidermotropic CD8+ Lymphoma cases* cases* Lymphoma CD8+ Epidermotropic ggressive δ on frozensection. δ (-)