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CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

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Primary Cutaneous Small/Medium CD4 T-Cell Lymphomas: A Heterogeneous Group of Tumors With Different Clinicopathologic Features and Outcome

Adriana Garcia-Herrera, Luis Colomo, Mireia Camo ´s, Joaquı´n ´s, ´n Carreras, Olga Balague, Antonio Martinez, Armando Lope´z-Guillermo, ´z-Guillermo, Teresa Estrach, and Elias Campo From the Hematopathology Section,

Department of Pathology, Department of Hematology, and Dermatology, Hospitall Clı´nic, Hospita ´nic, Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. Submitted January 10, 2008; accepted April 4, 2008; published online ahead of print at www.j www.jco.org co.org on June 9, 2008. Supported by the Spanish Comisio´ n

Purpose To deﬁne the clinical and pathologic characteristics of primary cutaneous small/medium CD4 T-cell lymphoma (PCSM-TCL) and identify parameters of prognostic signiﬁcance.

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Patients and Methods We have investigated 24 patients with primary cutaneous lymphomas composed of small/medium mature T-cells with a F1, CD3, CD4 and/or noncytotoxic, CD8– and CD30– phenotype. The proliferation index and CD8 inﬁltrating cells were quantiﬁed with an automated image analysis system. 

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Interministerial de Ciencia y Tecnologı´a ´a SAF05-5855 (E.C.), Instituto de Salud Carlos III, Fondo de Investigacio´ n Sanitaria (PI050458-TE and PI070409-ALG), Red Tema´tica de Investigacio´ n Cooperativa de Ca´ncer (RET 20 39), and Instituto Institu to de Salud Carlos III (whe (where re O.B. is a fellow). Authors’ disclosures of potential conﬂicts of intere interest st and author contribucontributions are found at the end of this article. Corresponding author: Elias Campo, MD, Hematopathology Section, Hospital Clı´nic, ´nic, Villarroel 170, 08036Barcelona, Spain; e-mail: [emailprotected] clinic.ub.es.

Results Sixteen patients presenting with solitary or localized plaques or small nodules (  3 cm) had an indolent course. Only three patients experienced repeated cutaneous relapses, and none of them died as a result of the disease after 1 to 168 months (median, 17 months) of follow-up. The tumors had a low pro prolif lifera eratio tion n (me (media dian n Ki-6 Ki-67, 7, 9%  5%) and an int intens ense e inﬁ inﬁltr ltrate ate of rea reacti ctive ve CD8 (median, 20%  11.7%). Five patients presenting with rapidly evolving large tumors or nodules ( 5 cm) had an aggressive disease and died with extracutaneous dissemination 18 to 36 months after diagnosis (median, 23 months). These tumors had a signiﬁcantly higher proliferation (median Ki-67, 22%  11.3%;P  .05) and lower number of inﬁltrating CD8 (median, 1%  3%; P  .05) than the previous group. A third group of three patients had a peculiar clinical presentation with multifocal relapsing lesions without extracutaneous dissemination after a long period of follow-up ranging from 41 to 92 months. Histologically, these cases had an intense inﬁltrate of eosinophils. 

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Conclusion PCSM-TC PCSM -TCL L is a het hetero erogen geneou eous s gro group up of tum tumors ors wit with h dif differ ferent entiat iated ed clin clinica icall and pat pathol hologi ogical cal characteristics with impact in the outcome of the patients.

0732-183X/08/2620-3364/$20.00 DOI: 10.1200/JCO.2008.16.1307

Primary cutan cutaneous eous lymphomas lymphomas encom encompass pass a heter heteroogeneou gen eouss gro group up of neo neopla plasms smswit with h cli clinic nical al and andbio biolog logic ic behavior that are different from secondary cutaneous involvemen invol vementt of syste systemic mic lymp lymphomas. homas.1 The rec recent ent WHO-E WH O-Euro uropea pean n Org Organi anisat sation ion for Res Resear earch ch and Treatm Tre atment ent of Can Cancer cer(EO (EORTC RTC)) cla classi ssiﬁca ﬁcatio tion n has cla clarriﬁed some relevant aspects and proposed a consensus framework for further studies of entities not yet well characterized.2 Among T-cell lymphomas, the category of unspec unspeciﬁed iﬁed prima primary ry cutan cutaneous eous perip peripheral heral T-cell lymphoma remains scarcely deﬁned. Tumors includ inc luded ed in thi thiss cla class ss rep repres resent ent a het hetero erogen geneou eouss gro group up

nantlyof nantly of mat mature ureCD CD30 30– lar large geT-c T-cell ells, s, and andthe thepro progno gno-sisisusuallypoor.Inaddition,threeprovisionalentities with particular clinicopathologic features have been recognized: primary cutaneous small/medium CD4 T-cell lymphoma (PCSM-TCL), primary cutaneous aggressive aggre ssiveepid epidermot ermotropic ropicCD8 CD8 cytot cytotoxic oxicT-cel T-celll lymphoma,, and phoma andcutan cutaneous eous / T-cel T-celll lymph lymphoma. oma.Patients Patients with wi th PC PCSMSM-TC TCL L usu usual ally ly pr prese esent nt wi with th sol solit itary ary plaques or tumors and have a favorable clinical evolution.3-5 Multifocal skin lesions may occur but always alwa ys wit withoutthe houtthe cli clinica nicall prog progress ression ionfrompatche frompatchess to plaques and tumors typical of mycosis fungoides (MF).. Hist (MF) Histolog ologica ically lly,, thes thesee neop neoplasm lasmss are arechar characte acterrized by a proliferation of small/medium-sized small/medium-sized lym-

of mat mature ureT-c T-cell ellneo neopla plasms smstha thatt do not ful fulﬁll ﬁllthe thedia diaggnostic criteria of the other, better-deﬁned subtypes. Thiss ter Thi term m is res restri tricte cted d to tum tumors ors com compos posed ed pre predom domii-

phocytes with pleomorphic morphology, as well as an admixture of reactive lymphocytes and histiocytes.3,4,6 The curr current ent cons consensu ensuss WHO WHO-EOR -EORTC TC

INTRODUCTION

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Primary Cutaneous Small/Medium CD4 T-Cell Lymphomas

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classiﬁc class iﬁcat ation ionhas has res restri trict cted ed thi thiss cat categ egory oryto to cas cases es wi with th a CD CD44 phenotype on the basis of observations suggesting that tumors with a CD8 phenotype may follow a more aggressive clinical behavior. 7-10 However, previous studies describing these tumors are based on small number numb er of pati patients ents,, not notalwa always ys wel welll char characte acterize rized, d, and andincl include udetum tumors ors – – CD8 or CD4 /CD8 that may correspond to other entities. Therefore,, the prec fore precise ise cli clinico nicopath patholog ologic ic feat feature uress of thes thesee neop neoplasm lasmss are not well character characterized. ized. In this study, we have examined a series of patients with PCSMTCL diagnosed according to the current WHO-EORTC criteria to

multifocal lesions that were mostly located on the extremities (n  11), the back (n  5), and head and neck (n  5). The median durati dur ation on of theskin theskinle lesio sions ns be befor foree dia diagno gnosiswas siswas 4 mon months(rang ths(range, e, 1 to 18 mo month nths). s). Tw Two o pa patie tients ntshad hadaa pre previo vious us his histo tory ry of can cancer cer.. Pat Patie ient nt 20 had been diagnosed with an acral lentiginous melanoma and a renal clear-cell carcinoma 11 years and 2 months earlier, respectively, and patient 24 had an invasive ductal carcinoma of the breast 5 years earlier. No evidence of these neoplasms was observed at the time of diagnosi diag nosiss of the cut cutaneo aneous us lym lymphom phoma. a. Theinit The initial ial trea treatme tment nt was topi topical calster steroidsin oidsin two twopati patients ents,, surg surgical ical

deﬁne their clinicopathologic features and determine the potential parame par ameter terss tha thatt ma mayy be use usefu full to pre predic dictt the their ir out outcom come. e.

resection alone in eight, local radiatio radiation n therapy in six, chemotherapy in ﬁve, and immunotherapy with interferon- in one; one elderly patient did not receive any speciﬁc treatment. Information on the initi ini tial al tr treat eatmen mentt wa wass not av avail ailab able le in one cas case. e. The me media dian n fol follo loww-up up of th thee ca case sess wa wass 24 mo mont nths hs (r (ran ange ge,, 1 to 16 1688 mo mont nths hs). ). Morphologically, all tumors were composed of a population of small/medium-sized atypical lymphocytes with less than 30% large cells and a variable background of reactive cells. All cases expressed F1 an and d CD CD3, 3, an and d we were re CD CD30 30–, CD8–, an and d CD CD56 56–. CD CD44 was pos posit itiv ivee in 21 tumors in which the staining was technically satisfactory, but partia par tiall lo loss ss was obs observ erved ed in ﬁve cas cases. es. Although all patients shared these histologic and phenotypic characteristics, they could be grouped in three different categories accordin acco rdingg to the cli clinic nical al pres presenta entation tion and out outcome come.. Thus Thus,, 16 pati patients ents hadsmal had smalll lesi lesions onsand andfol followe lowed d an indo indolentclinic lentclinical al cou course;ﬁve rse;ﬁve pati patients ents

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PATIENTS AND METHODS Case Selection Thirty-two Thirt y-two pati patients ents diagn diagnosed osed with a prima primary ry cutan cutaneous eous perip periphera herall T-cell lymphoma composed predominantly of small-/mediumsmall-/medium-sized sized cells were retrieved from the ﬁles of the Departments of Dermatology and Pathology at Hos Hospit pital al Clı´nic ´nic (Ba (Barce rcelon lona, a, Spa Spain)cover in)coveringthe ingthe per period1987 iod1987 to 20 2006 06.. In all cases, original tissue sections were reviewed. Additional immunohistochemical and molecular studies were performed from the parafﬁn blocks available. The tumors were reclassiﬁed according to the new WHO-EORTC classiﬁcat class iﬁcation ionof of cutan cutaneouslymphoma eouslymphomas. s.11 Eightcases wereexclude wereexcluded d for forfurth further er analysis. Two of them were reclassiﬁed as a tumoral MF, two as a primary cutaneous cutan eous CD30 lymp lymphopro hoprolifer liferative ative disor disorder, der,three three were F1 ne negat gative ive anda / phenotype could not be ruled out, and one was reclassiﬁed as an unspeciﬁed primary cutaneous peripheral T-cell lymphoma. All of the remaining patients were considered PCSM-TCL with no evidence of extracutaneous disea dis ease se at tim timee of dia diagno gnosis sis or pre presen sence ce of pri prior or or con concur curren rentt pat patche chess typ typica icall of MF. Clinical information, including medical history, clinical presentation, staging, therapy, and follow-up, was obtained from the medical records and from infor informatio mation n prov provided ided by the patie patients’ nts’ physi physicians cians.. Immunohistochemistry Immunophe Immun ophenotyp notyping ingwas wasperf performe ormed d in allcases with withaa pane panell of antib antibododies reactive in parafﬁn-embedded tissues (Appendix Table A1, online only) usingaa pero using peroxida xidase se or alka alkaline line phos phosphat phatase-l ase-label abeled ed dete detection ctionsyste system, m, stand standard ard antigen retrieval protocols, and an automated immunostainer (TechMate 500/500 500/ 500 Plus Plus,, DAKO DAKO,, Cope Copenhag nhagen, en, Denm Denmark) ark) as prev previousl iouslyy desc described ribed..12  ThenumberofKi-67andCD8 cell cellss werequantiﬁ werequantiﬁed ed in allsamplesusing an automated scanning microscope and image analysis system (Ariol 2.1, SL-50; Applied Imaging Corporation, Newcastle on Tyne, United Kingdom) as prev previousl iouslyy descr described. ibed.13 Molecular Studies In situ hybridization for Epstein-Barr virus (EBV) was examined using the EBV-encoded early nuclear RNAs (EBER-1 and EBER-2) as previously described.14-16 Polymerase chain reaction analysis ofTCRofTCR-and/orTCRand/or TCR- genes were performed using previously described protocols,17,18 and DNA extrac ext racted ted fro from m for formal malinin-ﬁxe ﬁxed d tis tissue suess usi using ng the QUI QUIamp amp DNA min minii kit (Qi (Qiaagen,, Cra gen Crawle wley, y, We West st Sus Sussex sex,, Uni United ted Kin Kingdo gdom; m; App Appen endix dix,, onl online ine onl only). y). Statistical Analysis Comparisons between different subgroups of patients were performed using the Fisher’s exact test for categoric variables (cross table) or the MannWhitney test for continuous variables. For statistical analysis the software packag pac kagee for soc social ial sci scienc ences es (SP (SPSS SS 13. 13.0; 0; SPS SPSSS Inc Inc,, Chi Chicag cago, o, IL) was use used. d.

RESULTS

Patients were 13 women and 11 men, with a median age of 58 years (rang (ra nge, e, 28 to 85 ye years ars). ). At pre presen sentat tation ion,, 17pati 17patient entss (70 (70%) %) hadsoli hadsolitar tary y plaques, nodules or tumors, three had localize localized d lesions, and four had www.jco.org

showed rapi showed rapidly dlyprog progress ressive ivelarg largee nodu nodules lesor or tum tumors orswit with h an agg aggress ressive ive clini cl inicalevol calevolut ution ion,, eve eventu ntual ally ly dyi dying ng as a re resul sultt of the thedis diseas ease; e; and andthr three ee patients pati entspres presente ented d with withmul multifo tifocal cal and rela relapsi psing ng skin skinlesi lesions, ons,but but wit with h no systemic dissemination dissemination or lymphom lymphoma-related a-related deaths. The clinical and path patholog ologic ic char characte acterist ristics icsof of thes thesee grou groups ps are desc describe ribed d sepa separate rately ly (Appendi (App endixx Tab Tables les A2A2-A7, A7, onli online ne only only). ). PCSM-TCL With Indolent Clinical Cours PCSM-TCL Course e These 16 patients were nine women and seven men with a median di an ag agee at di diag agno nosi siss of 55 ye year arss (r (ran ange ge,, 28 to 85 ye year ars; s; Ta Tabl blee 1) 1).. Mo Most st patients(14 pati ents(14 of 16)had soli solitarystable tarystableles lesionsthat ionsthat wer weree plaq plaques uesor or smal smalll nodule nod uless andtumo andtumors rs bet betwee ween n 1 and3 cm cmin in di diam amete eterr (Fi (Figg 1) 1).. Fou Fourt rteen een patients pati entswere weretrea treated tedwithlocal withlocal ther therapy apy (eig (eight ht exc excisio ision, n, ﬁve ﬁveradi radiothe otherrapy, and one topical steroids), one patient received no therapy, and treatme trea tment nt is unkn unknown ownin in anot another. her.A A com complet pletee rem remissi ission on was achi achieve eved d

in 12 of the 14 pat patien ients ts wi with th ass asses essab sable le res respon ponse se.. Th Three ree pat patie ients nts ex expe pe-rienced repeated cutaneous relapses with persistence of the disease at thee la th last st fo foll llow ow-u -up p in tw two o of th them em.. Al Alll of th thes esee pa pati tien ents ts we were re al aliv ivee af afte terr 1 to 16 1688 mo month nthss (me (media dian, n, 17 mo month nths) s) of fol follo low-u w-up. p. Histologically (Fig 1), the tumor cells were located within the dermi der miss wi with th fo focalexte calextensi nsion on int into o thesubc thesubcuti utiss in ni nine ne ca cases ses(5 (56% 6%). ). Th Thee lesions were predominantly nodular (75%), and three cases showed prominentband-lik prominent band-likee inﬁltrate inﬁltrates. s. Focal epiderm epidermotropism otropismwas was observed in ﬁve cases and inﬁltration of the follicu follicular lar epithelium in two. Three tumors tum ors had abu abunda ndant nt eos eosino inophi phils ls and ﬁv ﬁvee cas cases es sho showed wed a mo moder derate ate-prominent histiocytic inﬁltrate. Aggregates of plasma cells were observe ser ved d in fo four ur cas cases. es. Immunoh Imm unohist istoche ochemic micall ally, y, all case casess exam examine ined d expr expresse essed d CD5 (n  12 12). ). Mar Markedlossof kedlossof CD CD77 wasobse wasobserv rved edin in13of 13of 15case 15cases. s. Onl Onlyy tw two o casess show case showed edCD4loss CD4loss of expr expressi ession onin inaa prop proporti ortion onof of cel cells.Cytotox ls.Cytotoxic ic granules were seen only in one case (patient 16). The proliferative index of these tumors was low (median Ki-67, 9%; range, 1% to 20%). Most tumors had an intense inten se inﬁltration of CD8 T 

Garcia-Herrera et al

Table 1. 1. Comparison of Different Groups of Patients With PCSM-TCL Criterion Patient characteristics Male:female ratio, No. Age, years Median Range Cutaneous lesions, No. Solitary Localized Multifocal Bulky ( 5 cm) Initial therapy, No. Excision Local radiotherapy Multiagent chemotherapy Other None Not available Response to initial therapy, No. Complete remission Partial remission No response Progression Relapse, No. Skin only Systemic None Follow-up, months Median Range Status at last follow-up, No. No evidence of disease Alive with disease Died as a result of lymphoma Died as a result of other cause Tumoral immunophenotype CD4 Cases with CD4  50%, No. Total cases, No. % CD7 Cases with CD7 loss  50%, No. Total cases, No. 

% Proliferation index (Ki-67), % CD8 tumor-inﬁltrating lymphocytes, % TCRrearrangement rearrangement Cases with clonalTCR rearrangement, No. Total cases, No. %

PCSM-TCL With Indolent Clinical Course

PCSM-TCL With Aggressive Clinical Outcome

PCSM-TCL With Prominent Eosinophilia

All Patients

16 7:9

5 4:1

3 0:3

24 11:13

55 28-85

65 52-78

57 56-57

58 28-85

1 1 5

0 8 5

1 4

1 1 1 13 1 2

2 1

17 3 0

3 4 5

1 2

8 6 5 3 1 1

1 2

16 4 2 2

6 5 13

2 3 5 13 17 1-168

26 18-36

12 4

69 41-96

24 1-168

12 6 5 1

2 5†

2 14 14

2 4 50

1 3 33

5 21 24

13 15

5 5

2 3

20 23

87 9 20

100 22 1

67 5 10

90 10 14

11 12 92

1 2 50

3 3 100

15‡ 17 88

Abbreviation: PCSM-TCL, primary cutaneous small/medium CD4  T-cell lymphoma. Interferon- (n  1), topical steroids (n  2). †Three patients had proved (n  2) or suspected (n  1) CNS involvement. ‡Both TCR- and and TCR- (n  7); TCR- only only (n  4), TCR- only (n  4). 

cells varying from 9% to 47% (median, 20%; Fig 1). B cells were also relatively common, and in 11 cases tended to form nodular

12). These two cases have been included in a recent published study.19 The ISHfor the EBV was negative in both tu-

aggregates that, in four cases, had a small meshwork of follicular dendritic cells. In two tumors, the aggregates of plasma cells showed a monotypic light-chain restriction (patients 11 and

mors as well as in eight additional cases studied. Molecular TCR CR gene studies demonstrated demonstrated a clonal rearrangement rearrangement of the T in 11 (TCR-9; 9; TCR- 8) of the 12 cases with DNA available,

JOURNAL OF CLINICAL ONCOLOGY

Primary Cutaneous Small/Medium CD4 T-Cell Lymphomas

Fig 2. Primary Fig Primary cutane cutaneous ous small small/medi /medium um CD4 T-c T-cell ell lym lympho phoma ma wit with h an aggressive clinical outcome. (A, B) Clinical presentation with tumoral lesions. (C, D) Neoplastic small-/medium-sized cells inﬁltrating the dermis. The inset demonstrates neural invasion. The cells express CD3 and CD4 (E, F), but this group shows (G) few and isolated reactive CD8  lymphocytes and (H) high proliferation index (Ki-67). Image magniﬁcations were (C) 40 and (D to H) 400.

4,000 3,000 2,000 1,000 0 150

18 0

20 0

220

24 0

260

2 80

30 0

320

3 40

36 0

Fig 1. 1. Primary cutaneous small/medium CD4 T-cell lymphoma with indolent clinical course. (A) Gross appearance of a solitary plaque. (B, C) Diffuse dermal involvement by irregular small-/medium-sized cells. (D-F) The cells express CD3 and CD4, but CD7 is lost. (G) High numbers of reactive CD8  cells and (H) low proliferation index (Ki-67) are typical in this group. (I) Clonal rearrangement of TCR- gene. Image magniﬁcations were (B) 40 and (C to H) 400.

dissemination (median time to relapse, 14 months; range, 9 to 11 months), including two cases in the lymph nodes and three with suspected (patient 19) or documented (patients 20 and 21) CNS invol inv olvem vemen ent. t. Al Alll pat patien ients ts di died ed as a res resul ultt of thedise thediseasebetw asebetween18 een18 and

PCSM-TCL With an Aggre PCSM-TCL Aggressive ssive Clinical Outcome These The se pat patie ientswere ntswerefo four ur me men n andone wo womanwith manwithaa me media dian n ag agee of 65 years (range, 52 to 78 years; Table 1). All of them had rapidly growing and bulky tumors or nodules ( 5 cm in diameter; Fig 2). Twoof Two of thembecameulcera thembecameulcerated tedin inthe thefol followi lowing ng week weeks. s. Allpatient Allpatientss had ambulato ambu latory ry perf performa ormance nce stat status us (Eas (Eastern tern Coo Coopera perativ tivee Onco Oncolog logy y Group performance performance status of 0 to 1) and normal serum lactate dehydrogenas drog enasee lev levels. els. Four pati patients ents were trea treated ted wit with h mul multiag tiagent ent syst systemic emic chemotherapy regimens resulting from the rapid progression of the cutaneous lesions, whereas the remainder received local radiation

36 mo month nthss af after ter th thee ini initi tial al di diag agnos nosis is (me (medi dian an su survi rviva val, l, 23 mon months ths). ). Histologically (Fig 2), all of these tumors were composed of small/medium-sized atypical lymphocytes, growing with a nodular archit arc hitec ectur turee in th three reeca cases sesanda anda di diffu ffuse se pat patte tern rn in two two.. In allcases allcases,, th thee tumor involved the reticular dermis and in two extended into the subcutis. Focal epidermotropism was present in three cases. Two patients (20 and 21) who subsequently developed CNS involvement showed focal endoneural inﬁltration of small nerves by tumor cells (Fig2). One Onecaseshowed caseshowedaa gran granulom ulomatou atouss inﬂa inﬂamma mmation(patien tion(patientt 17) 17),, but no eosinophils or plasma cells were observed in any tumor. Two simultaneous biopsies in patient 20 showed a PCSM-TCL in a trunk lesion lesi on and a Lang Langerha erhans ns cell(LC) hist histiocy iocytosi tosiss (LCH (LCH)) wit with h high highnum num-ber of mitosis and atypical cells in the arm, without admixture of the different lesions in the respective biopsies. The lymphoma of this patient pati ent tran transfor sformed med int into o a larg large-ce e-cell ll lym lymphom phomaa 18 mont months hs afte afterr dia diagg-

therapy. Only two patients achieved complete remission, one had a partial remission, and two showed progressive disease. Two patients had cutaneous relapses, and all of them developed extracutaneous

nosis, maintaining CD3 andF1 but with loss of CD4 and acquired CD57 expression. Simultaneously, the patient had axillary lymph nodes nod es wi with th an LC sar sarco coma. ma.

including in patient 11 with a light-chain restriction in the plasma cells.

www.jco.org

Garcia-Herrera et al

Immunohi Immunohistochemi stochemically, cally, CD4 was expresse expressed d in four cases with partia par tiall lo loss ss in two two,, andwas te techn chnic ical ally ly uns unsati atisfa sfact ctory oryin in one one.. CD CD77 was decrea dec reasedor sedor lo lost st in al alll ca cases ses.. Pat Patie ient nt 21 sho showe wed d ab aberr errant ant co coexp expres ressio sion n of CD20 in the tumor cells. The proliferative index in this group of tumors was signiﬁcantly higher that in the previous one (median Ki-67, 22%; range, 15% to 43%; P  .05). CD8 tumor-inﬁltrating lymphocytes lymphocy tes were also signiﬁcantly lower than in the previous group (medi (me dian, an, 1% 1%;; ran range ge,, 0. 0.3% 3% to 7. 7.7% 7%;; P .0 .05; 5; Fi Figg 2) 2).. B ce cell llss we were re sc scar arce ce and disp disperse erse wit without hout form forming ing agg aggrega regates. tes. A clon clonal al TCR-and TCR- gen genee rear rearrang rangeme ement nt was obse observedin rvedin one of the two cases with available material (patient 20). The LC sarcoma of this patient showed a germ-line conﬁguration of the TCR gene.

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PCSM-TCL With Prominent Eosinophilia Threee pati Thre patients entshad had a pec peculia uliarr cli clinica nicall pres presenta entatio tion n with withrecu recurren rrentt multifocal skin plaques or nodules in the extremities and abdomen (Table (Ta ble 1). On Onee pat patie ient nt (22 (22)) had a lon longg his histo tory ry of rec recur urren rentt cu cutan taneou eouss lesions lesi ons that had been beeninte interpre rpreted ted as “rea “reacti ctive ve lym lymphoi phoid d and hist histiocy iocyte te hyperpl hype rplasia asia”” befo before re deﬁn deﬁniti itive ve dia diagnos gnosis is of cuta cutaneou neouss lym lymphom phoma. a. Persistent eosinophilia eosinophilia in the periphera peripherall blood was observed in this case. At last follow-up examination, two patients were alive with skin disease (follow-up, 72 and 96 months), and one died 41 months after diagnosi diag nosiss of lym lymphom phomaa resu resultin ltingg from frommeta metastat static ic brea breast st canc cancer. er. Mor Mor-phologi phol ogicall cally, y, thes thesee tum tumors ors show showed ed a derm dermal al inﬁl inﬁltrat tratee of atyp atypical ical small-/medium-si small-/m edium-sized zed lymphoc lymphocytes ytes admixed with numerous eosinophils (Fig 3). Partial loss of CD4 was observed in patient 23. The media med ian n pe perce rcenta ntage ge of Ki Ki-6 -677 po posit sitiv ivee ce cell llss wa wass 5% (ra (range nge,, 1% to 24 24%). %). The number of inﬁltrating CD8 lymphocytes was moderate (median, 10%; range, 9% to 13%) whereas many scattered or small clusterss of CD ter CD20 20 B cel cells ls we were re pr prese esent nt.. A TCR gen genee clon clonal al rear rearrang rangemen ementt wasdetect wasdete cted ed in thethre thethreee ca casesand sesand in theperi theperiphe phera rall bl blood(PB) ood(PB) of one (patient 22). This latter case showed 33% of T lymphocytes in the PB with wit h ano anomal malou ouss phe phenot notype ype (pa (part rtial ial los losss of CD CD77 and CD CD3). 3). 



DISCUSSION

300 200 100 0 150 160 170 180 190 20 200 0

210 21 0 22 220 0 23 230 0 24 240 0 25 250 0 26 260 0

Fig 3.Primary 3. Primary cutaneous small/medium CD4 T-cell lymphoma with prominent eosinophilia. (A) Clinical presentation with multiple violaceous plaques in the legs. (B, C) Band-like inﬁltrate with atypical small lymphocytes mixed with high number of eosinophils. (D,E) CD3 and CD4 expression. (F) CD7 is lost in this case. (G) Clonal rearrangement of TCR- gene. Image magniﬁcations were (B) 40 and (C gene. to F) 400.

small lesions ( 3 cm), had low prolifer proliferative ative activity (Ki67, 9  5.4) and an in inten tense se inﬁ inﬁltr ltrate ateof of re react activ ivee CD CD88 lym lymphoc phocyte ytess (CD (CD8, 8, 20%  11.7%) whereas neoplasms with an aggressive clinical course presented with rapidly evolving large tumors or nodules ( 5 cm), variabl4expr abl4 expressi ession on of CD4 CD4,, hig high h prol prolifer iferatio ation n (Ki6 (Ki67, 7, 22%  11. 11.3%), 3%), and 

In this study, we have examined a series of primary cutaneous T-cell lymphomas characterized by a proliferation of small/medium-sized 

–

lymphoid cells with a F1, CD3, CD4 and/or CD8 and CD30 phenot phe notyp ype. e. Mos Mostt of ou ourr pa patie tients nts had an ind indole olent nt cli clini nical cal co cours ursee wit with, h, only three patients developing cutaneous relapses and none of them progress prog ressed ed to syst systemicdiseas emicdisease. e. The These se ﬁndi ﬁndings ngsare areconc concorda ordant nt withthe previous descriptions of PCSM-TCL that recognized the relatively indolent behavior of these tumors, particularly particularly when the clinical presentatio sent ation n was loca localize lized d or soli solitary tary..1,3-5,7,20,21 Ho Howev wever, er, we al also so ide identi nti-ﬁed ﬁe d ﬁv ﬁvee pa pati tien ents ts (2 (21% 1%)) wi with th pr prog ogre ress ssiv ivee sk skin in di dise seas asee an and d extrac ext racut utane aneous ousdi disse ssemi minat natio ion n wh who o die died d of the thely lymp mphom homaa in le less ss th than an three years after diagnosi diagnosis. s. Occasional cases of small cell CD4 cutaneous T-cell lymphoma with aggressive behavior have been reported but the clinical and pathological characteristics that may distinguish thiss sub thi subsetof setof pat patie ients ntshav havee notbeen rec recog ogniz nized. ed.4 Alt Althoug hough h case casess wit with h rapid dissemination were histologically and phenotypically similar to thetum the tumors ors wit with h an indo indolentbehavi lentbehavior, or, we have haveobse observeddiffer rveddifference encess in

scarce sca rce nu numb mber er of ass associ ociat ated ed CD CD88 cel cells ls (CD (CD8, 8, 1%  3. 3.03 03%) %) (Fi (Figg 4) 4).. The high proliferation observed in the group with aggressive behavior is concordant with the rapid clinical presentation and the large lar ge si size ze of th thee le lesio sions. ns. Th Thee pro proli lifer ferati ative ve act activ ivit ityy has bee been n re recog cogni nized zed recently as an independent adverse prognostic parameter in peripheral T-c T-cell ell lym lymphom phoma, a, unsp unspeciﬁ eciﬁed, ed, but its prog prognost nostic ic valu valuee in cut cutaneaneous T-cell lymphoma is less known. 22-24 Our observations would indicate that proliferation is also an important outcome predictor in PCSM-TCL. The number of CD8 tumor-inﬁltrating lymphocytes was also signiﬁcantly lower in the subgroup of aggressive PCSMTCLthan in cas cases es wit with h an ind indole olent nt beh behavi avior. or. Thi Thiss ﬁnd ﬁndingis ingis sim simil ilar ar to the relationship between CD8 -inﬁltrating cells and progression in MF, where the loss of these cells have been associated with tumor tum or pro progre gressi ssion,less on,less res respon ponse se to the therap rapy, y, andshort andshorter er sur survi vivalof valof 25-29 the patients.

the clinical presentation and pathologic characteristics that may be useful to distinguish these two subsets of tumors. Thus, tumors with an indolent clinical behavior presented with stable not progressing

Three of the ﬁve patients who died as a result of the lymphoma developed develope d CNS invo involve lvement ment.. Thi Thiss comp complic licatio ation n has been doc docuu30-34 mented ment ed in pati patients ents with cut cutaneo aneous us lym lymphom phomas. as. Interestingly, Interest ingly, we

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Primary Cutaneous Small/Medium CD4 T-Cell Lymphomas

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small les small lesion ionss wit with h a hig high h inﬁ inﬁltr ltrate ate of CD8 and B-c B-cell ellss tha thatt are als also o a common ﬁnding in pseudo–T-cell lymphomas. However, our patients had a constellation of ﬁndings favoring the diagnosis of PCSM-TCL. Thus, none of our cases had a history of spontaneous regression of the lesions or previous medication, insect bite or systemic immunologic disorders that have been associated with pseudo–T-c pseud o–T-cell ell lymph lymphomas. omas.44 Hi Histo stolog logica ically lly,, the tum tumor or cel cells ls showedcommo sho wedcommon n epi epider dermot motrop ropism(six ism(six of 16 16), ), had fre freque quent nt los losss of T-cell T-c ell ant antige igens, ns, and and,, mol molecu ecular larly, ly, a clo clonal nal TCR rearr rearrangem angement ent was demons dem onstra trated ted in vir virtua tuallyall llyall cas cases es exa exami mined ned.. The These se ﬁnd ﬁnding ingss wou would ld suppor sup portt the ide ideaa of the these se les lesion ionss as ind indole olent nt lym lympho phomas mas.. How Howeve ever, r, to determine the boundaries between PCSM-TCL and cutaneous pseudo–T-cell lymphomas in some cases may be difﬁcult and debata deb atable ble,, and req requir uiree the com combin binati ation on of cli clinic nical, al, pat pathol hologi ogic, c, and 43,45-48 molecular criteria. From a practical point of view, it is importan por tantt to rec recogn ognizethat izethat pat patien ients ts wit with h theindol theindolentform entform of PCS PCSMMTCL have a good clinical evolution with only local therapy. In ou ourr stu study dy,, we id ident entiﬁ iﬁed ed thr three ee add addit ition ional al pat patie ients nts wi with th a pe pecu cu-liarcli liar clinica nicall and path patholog ologic ic pres presenta entatio tion n that dif differs fersfrom fromthe the prev previou iouss cases. Although these tumors had certain morphologic and phenotypic similarities with group 1, the patients had recurrent multifocal skin lesi lesions ons but no syst systemi emicc diss dissemi eminati nation on or lym lymphom phoma-re a-relat lated ed deaths. deat hs. Hist Histolog ologica ically, lly, the CD4 T cel cells ls wer weree ass associ ociate ated d wi with th a pro promminent ine nt eos eosino inophi phili licc in inﬁlt ﬁltrat ratee bu butt a lownumb lownumber er of CD CD88 or B ce cell lls. s. Th Thee TCR clonal rearra rea rrang ngem ement ent det detec ected tedin in the thethr three ee pa patie tients nts,, one oneof of th them em

A P< <

.05

) % ( 8 D 20 C

0 PCSM-TCL with indolent clinical course

PCSM-TCL with an aggressive clinical course

PCSM-TCL with prominent eosinophilia

Group B P< <

.05

) % ( 7 20 6 i K



6 12

PCSM-TCL with indolent clinical course

PCSM-TCL with an aggressive clinical outcome

PCSM-TCL with prominent eosinophilia

Group

also in the blood associated with eosinophilia, and the persistence of the le lesio sions ns sug sugges gestt tha thatt the theyy are a pe pecu culi liar ar fo form rm of pri prima mary ry cu cutan taneou eouss indolen indo lentt T-c T-cell ell lym lymphom phoma. a. In summary, our observations indicate that PCSM-TCL may present with different clinical and pathologic characteristics that are assoc ass ociat iated ed wi with th the bi biolo ologi gicc beh behav avior ior of the tu tumor mors. s. Pat Patie ients nts pr prese esent nt-ing wi with th sm small all le lesi sions ons,, lo low w pr proli olife ferat rativ ivee in index dex,, and an in inten tense se inﬁ inﬁltr ltraation of the tumor by reactive CD8 cells have an excell excellent ent prognosis withonly occ occasio asional nal cut cutaneo aneous us rela relapses pses,, wher whereas easpati patientswith entswith rapi rapidly dly growing grow ing lesi lesions, ons,high highprol prolife iferati rative ve tumo tumors rs ,and ,andlow low inﬁl inﬁltrat tratee of CD8 cells develop extracutaneous extracutaneous dissemination dissemination and have a poor prognosis.. Th sis These ese pat patie ients nts hav havee a bi biolo ologi gicc be behav havior ior tha thatt is mo more re rel relate ated d to the aggressi aggr essive ve prim primary ary cuta cutaneou neouss T-c T-cell ell lym lymphom phomas, as, unsp unspeci eciﬁed, ﬁed, desp despite ite the sm small all/m /med ediu ium m si size ze of the tu tumor mor cel cells ls.. 

Fig 4. Box plots representing representing percentage of (A) CD8 cel cells ls and (B) KiKi-67 67 expression in groups of primary cutaneous small/medium CD4  T-cell lymphoma (PCSM-TCL) quantiﬁed in all samples using an automated scanning microscope and image analysis system (Ariol 2.1, SL-50; Applied Imaging Corp, Newcastle on Tyne, United Kingdom). Boxes represent the quartiles, and circles show atypical values (1.5 to 3 the length of the box).



observed focal endoneural inﬁltration of small nerves in the initial cutaneo cutan eous us bi biops opsyy of two of the these se pa patie tients nts,, sug sugge gest sting ing th that at thi thiss ﬁnd ﬁnding ing may raise the suspicion of an aggressive behavior. The tumor cells of oneof one of thes thesee case casess (pat (patien ientt 21)coexpr 21)coexpresse essed d CD2 CD20. 0.Aber Aberrantexpres rantexpression sion of CD79a and CD20 has been described in a small number of PTCL, including one primary cutaneous T-cell lymphoma.35-37 Curiously, most of these cases were cytotoxic lymphomas expressing CD8 , wherea whe reass our ca case se ex expre presse ssed d CD CD44 and was neg negat ativ ivee fo forr cyt cytoto otoxi xicc gr grananules.. One ules Onepati patient ent(20 (20)) had hadaa sim simult ultaneo aneous us LC sarc sarcoma omawithcutaneo withcutaneous us and lym lymph-n ph-node ode invo involvem lvement. ent. LCH has been obse observed rved in asso associat ciation ion with other lymphoproliferative disorders including cutaneous lymphomas.38 Inte Interest restingl ingly, y, a clo clonal nalrela relatio tionshi nship p bet betweenLCH weenLCH and andT-c T-cell ell 39 lymphoblastic lymphoma has been documented. However, in our case, theTCRclonal rearrangement detected in the PCSM-TCL was not observed in the LC sarcoma, suggesting that they were two separate neop neoplasm lasms. s.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conﬂicts of interest.

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The differential diagnosis between the indolent PCSM-TCL and cutaneous pseudo–T-cell lymphomas may be difﬁcult since they share some overl overlappin appingg featu features. res.40-43 Mos Mostt of our pat patien ients ts had www.jco.org

AUTHOR CONTRIBUTIONS Conception and design:Adriana design:Adriana Garcia-Herrera, Luis Colomo, Antonio Martinez, Teresa Estrach, Elias Campo Financial support:Teresa support:Teresa Estrach, Elias Campo ´n Provision of study materials or patients:Mireia patients:Mireia Camos, Joaquı´n Carreras, Olga Balague, Armando Lope´z-Guillermo, ´z-Gui llermo, Teresa Estrach, Elias Campo Collection and assembly of data:Adriana data: Adriana Garcia-Herrera, Luis Colomo Data analysis and interpretation:Adriana interpretation:Adriana Garcia-Herrera, Luis Colomo, Joaquı´n ´n Carreras, Antonio Martinez, Armando Lope´z-Guillermo, ´z-Gui llermo, Teresa Estrach, Elias Campo © 2008 by America American n Society of Clinic Clinical al Oncolo Oncology gy 3369

Garcia-Herrera et al

writing:Adriana Garcia-Herrera, Luis Colomo, Mireia Manuscript writing:Adriana Camos, Joaquı´n ´n Carreras, Olga Balague, Antonio Martinez, Armando Lope´z-Guillermo, ´z-Gui llermo, Teresa Estrach, Elias Campo

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