Linfoma t Pequño Mediano

Primary Cutaneous Small/Medium CD4� T-CellLymphomas: A Heterogeneous Group of Tumors WithDifferent Clinicopathologic Features and OutcomeAdriana Garcia-Herrera, Luis Colomo, Mireia Camos, Joaquın Carreras, Olga Balague, Antonio Martinez,Armando Lopez-Guillermo, Teresa Estrach, and Elias Campo

From the Hematopathology Section,Department of Pathology, Departmentof Hematology, and Dermatology,Hospital Clınic, Institut d’InvestigacionsBiomediques August Pi i Sunyer,University of Barcelona, Barcelona,Spain.

Submitted January 10, 2008; acceptedApril 4, 2008; published online ahead ofprint at www.jco.org on June 9, 2008.

Supported by the Spanish ComisionInterministerial de Ciencia y TecnologıaSAF05-5855 (E.C.), Instituto de SaludCarlos III, Fondo de Investigacion Sani-taria (PI050458-TE and PI070409-ALG),Red Tematica de Investigacion Coop-erativa de Cancer (RET 20 39), andInstituto de Salud Carlos III (where O.B.is a fellow).

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Corresponding author: Elias Campo,MD, Hematopathology Section, Hospi-tal Clınic, Villarroel 170, 08036-Barcelona, Spain; e-mail: [email protected].

© 2008 by American Society of ClinicalOncology

0732-183X/08/2620-3364/$20.00

DOI: 10.1200/JCO.2008.16.1307

A B S T R A C T

PurposeTo define the clinical and pathologic characteristics of primary cutaneous small/medium CD4�

T-cell lymphoma (PCSM-TCL) and identify parameters of prognostic significance.

Patients and MethodsWe have investigated 24 patients with primary cutaneous lymphomas composed of small/mediummature T-cells with a �F1, CD3, CD4� and/or noncytotoxic, CD8– and CD30– phenotype. Theproliferation index and CD8� infiltrating cells were quantified with an automated image analy-sis system.

ResultsSixteen patients presenting with solitary or localized plaques or small nodules (� 3 cm) had anindolent course. Only three patients experienced repeated cutaneous relapses, and none of themdied as a result of the disease after 1 to 168 months (median, 17 months) of follow-up. The tumorshad a low proliferation (median Ki-67, 9% � 5%) and an intense infiltrate of reactive 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 monthsafter diagnosis (median, 23 months). These tumors had a significantly higher proliferation (medianKi-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 withmultifocal relapsing lesions without extracutaneous dissemination after a long period of follow-upranging from 41 to 92 months. Histologically, these cases had an intense infiltrate of eosinophils.

ConclusionPCSM-TCL is a heterogeneous group of tumors with differentiated clinical and pathologicalcharacteristics with impact in the outcome of the patients.

J Clin Oncol 26:3364-3371. © 2008 by American Society of Clinical Oncology

INTRODUCTION

Primary cutaneous lymphomas encompass a hetero-geneous group of neoplasms with clinical and biologicbehavior that are different from secondary cutaneousinvolvement of systemic lymphomas.1 The recentWHO-European Organisation for Research andTreatment of Cancer (EORTC) classification has clar-ified some relevant aspects and proposed a consensusframework for further studies of entities not yet wellcharacterized.2 Among T-cell lymphomas, the cate-gory of unspecified primary cutaneous peripheralT-cell lymphoma remains scarcely defined. Tumorsincluded in this class represent a heterogeneous groupof mature T-cell neoplasms that do not fulfill the diag-nostic criteria of the other, better-defined subtypes.This term is restricted to tumors composed predomi-

nantly of mature CD30– large T-cells, and the progno-sis isusuallypoor.Inaddition,threeprovisionalentitieswith particular clinicopathologic features have beenrecognized: primary cutaneous small/medium CD4�

T-cell lymphoma (PCSM-TCL), primary cutaneousaggressive epidermotropic CD8� cytotoxic T-cell lym-phoma, and cutaneous �/� T-cell lymphoma. Patientswith PCSM-TCL usually present with solitaryplaques or tumors and have a favorable clinicalevolution.3-5 Multifocal skin lesions may occur butalways without the clinical progression from patchesto plaques and tumors typical of mycosis fungoides(MF). Histologically, these neoplasms are character-ized by a proliferation of small/medium-sized lym-phocytes with pleomorphic morphology, as well asan admixture of reactive lymphocytes and histio-cytes.3,4,6 The current consensus WHO-EORTC

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VOLUME 26 � NUMBER 20 � JULY 10 2008

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classification has restricted this category to cases with a CD4� pheno-type on the basis of observations suggesting that tumors with a CD8phenotype may follow a more aggressive clinical behavior.7-10 How-ever, previous studies describing these tumors are based on smallnumber of patients, not always well characterized, and include tumorsCD8� or CD4–/CD8– that may correspond to other entities. There-fore, the precise clinicopathologic features of these neoplasms are notwell characterized.

In this study, we have examined a series of patients with PCSM-TCL diagnosed according to the current WHO-EORTC criteria todefine their clinicopathologic features and determine the potentialparameters that may be useful to predict their outcome.

PATIENTS AND METHODS

Case Selection

Thirty-two patients diagnosed with a primary cutaneous peripheralT-cell lymphoma composed predominantly of small-/medium-sized cellswere retrieved from the files of the Departments of Dermatology and Pathol-ogy at Hospital Clınic (Barcelona, Spain) covering the period 1987 to 2006. Inall cases, original tissue sections were reviewed. Additional immunohisto-chemical and molecular studies were performed from the paraffin blocksavailable. The tumors were reclassified according to the new WHO-EORTCclassification of cutaneous lymphomas.11 Eight cases were excluded for furtheranalysis. Two of them were reclassified as a tumoral MF, two as a primarycutaneous CD30 lymphoproliferative disorder, three were �F1 negative and a�/� phenotype could not be ruled out, and one was reclassified as an unspec-ified primary cutaneous peripheral T-cell lymphoma. All of the remainingpatients were considered PCSM-TCL with no evidence of extracutaneousdisease at time of diagnosis or presence of prior or concurrent patches typicalof MF. Clinical information, including medical history, clinical presentation,staging, therapy, and follow-up, was obtained from the medical records andfrom information provided by the patients’ physicians.

Immunohistochemistry

Immunophenotyping was performed in all cases with a panel of antibod-ies reactive in paraffin-embedded tissues (Appendix Table A1, online only)using a peroxidase or alkaline phosphatase-labeled detection system, standardantigen retrieval protocols, and an automated immunostainer (TechMate500/500 Plus, DAKO, Copenhagen, Denmark) as previously described.12

The number of Ki-67 and CD8� cells were quantified in all samples usingan automated scanning microscope and image analysis system (Ariol 2.1,SL-50; Applied Imaging Corporation, Newcastle on Tyne, United Kingdom)as previously described.13

Molecular Studies

In situ hybridization for Epstein-Barr virus (EBV) was examined usingthe EBV-encoded early nuclear RNAs (EBER-1 and EBER-2) as previouslydescribed.14-16 Polymerase chain reaction analysis of TCR-� and/or TCR-�genes were performed using previously described protocols,17,18 and DNAextracted from formalin-fixed tissues using the QUIamp DNA mini kit (Qia-gen, Crawley, West Sussex, United Kingdom; Appendix, online only).

Statistical Analysis

Comparisons between different subgroups of patients were performedusing the Fisher’s exact test for categoric variables (cross table) or the Mann-Whitney test for continuous variables. For statistical analysis the softwarepackage for social sciences (SPSS 13.0; SPSS Inc, Chicago, IL) was used.

RESULTS

Patients were 13 women and 11 men, with a median age of 58 years(range, 28 to 85 years). At presentation, 17 patients (70%) had solitaryplaques, nodules or tumors, three had localized lesions, and four had

multifocal lesions that were mostly located on the extremities (n �11), the back (n � 5), and head and neck (n � 5). The medianduration of the skin lesions before diagnosis was 4 months (range, 1 to18 months). Two patients had a previous history of cancer. Patient 20had been diagnosed with an acral lentiginous melanoma and a renalclear-cell carcinoma 11 years and 2 months earlier, respectively, andpatient 24 had an invasive ductal carcinoma of the breast 5 yearsearlier. No evidence of these neoplasms was observed at the time ofdiagnosis of the cutaneous lymphoma.

The initial treatment was topical steroids in two patients, surgicalresection alone in eight, local radiation therapy in six, chemotherapyin five, and immunotherapy with interferon-� in one; one elderlypatient did not receive any specific treatment. Information on theinitial treatment was not available in one case. The median follow-upof the cases was 24 months (range, 1 to 168 months).

Morphologically, all tumors were composed of a population ofsmall/medium-sized atypical lymphocytes with less than 30% largecells and a variable background of reactive cells. All cases expressed�F1 and CD3, and were CD30–, CD8–, and CD56–. CD4 was positivein 21 tumors in which the staining was technically satisfactory, butpartial loss was observed in five cases.

Although all patients shared these histologic and phenotypiccharacteristics, they could be grouped in three different categoriesaccording to the clinical presentation and outcome. Thus, 16 patientshad small lesions and followed an indolent clinical course; five patientsshowed rapidly progressive large nodules or tumors with an aggressiveclinical evolution, eventually dying as a result of the disease; and threepatients presented with multifocal and relapsing skin lesions, but withno systemic dissemination or lymphoma-related deaths. The clinicaland pathologic characteristics of these groups are described separately(Appendix Tables A2-A7, online only).

PCSM-TCL With Indolent Clinical Course

These 16 patients were nine women and seven men with a me-dian age at diagnosis of 55 years (range, 28 to 85 years; Table 1). Mostpatients (14 of 16) had solitary stable lesions that were plaques or smallnodules and tumors between 1 and 3 cm in diameter (Fig 1). Fourteenpatients were treated with local therapy (eight excision, five radiother-apy, and one topical steroids), one patient received no therapy, andtreatment is unknown in another. A complete remission was achievedin 12 of the 14 patients with assessable response. Three patients expe-rienced repeated cutaneous relapses with persistence of the disease atthe last follow-up in two of them. All of these patients were alive after1 to 168 months (median, 17 months) of follow-up.

Histologically (Fig 1), the tumor cells were located within thedermis with focal extension into the subcutis in nine cases (56%). Thelesions were predominantly nodular (75%), and three cases showedprominent band-like infiltrates. Focal epidermotropism was observedin five cases and infiltration of the follicular epithelium in two. Threetumors had abundant eosinophils and five cases showed a moderate-prominent histiocytic infiltrate. Aggregates of plasma cells were ob-served in four cases.

Immunohistochemically, all cases examined expressed CD5(n � 12). Marked loss of CD7 was observed in 13 of 15 cases. Only twocases showed CD4 loss of expression in a proportion of cells. Cytotoxicgranules were seen only in one case (patient 16). The prolifera-tive index of these tumors was low (median Ki-67, 9%; range,1% to 20%). Most tumors had an intense infiltration of CD8� T

Primary Cutaneous Small/Medium CD4� T-Cell Lymphomas

www.jco.org © 2008 by American Society of Clinical Oncology 3365Information downloaded from jco.ascopubs.org and provided by at ASCO on April 28, 2015 from 158.232.242.13

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cells varying from 9% to 47% (median, 20%; Fig 1). B cells werealso relatively common, and in 11 cases tended to form nodularaggregates that, in four cases, had a small meshwork of folliculardendritic cells. In two tumors, the aggregates of plasma cellsshowed a monotypic light-chain restriction (patients 11 and

12). These two cases have been included in a recent pub-lished study.19 The ISH for the EBV was negative in both tu-mors as well as in eight additional cases studied. Molecularstudies demonstrated a clonal rearrangement of the TCR genein 11 (TCR-� 9; TCR-� 8) of the 12 cases with DNA available,

Table 1. Comparison of Different Groups of Patients With PCSM-TCL

CriterionPCSM-TCL With Indolent

Clinical CoursePCSM-TCL With Aggressive

Clinical OutcomePCSM-TCL With Prominent

Eosinophilia All Patients

Patient characteristics 16 5 3 24Male:female ratio, No. 7:9 4:1 0:3 11:13Age, years

Median 55 65 57 58Range 28-85 52-78 56-57 28-85

Cutaneous lesions, No.Solitary 14 3 17Localized 2 1 3Multifocal 1 3 4Bulky (� 5 cm) 0 5 0 5

Initial therapy, No.Excision 8 8Local radiotherapy 5 1 6Multiagent chemotherapy 4 1 5Other� 1 2 3None 1 1Not available 1 1

Response to initial therapy, No.Complete remission 13 2 1 16Partial remission 1 1 2 4No response 2 2Progression 2 2

Relapse, No.Skin only 3 3 6Systemic 5 5None 13 13

Follow-up, monthsMedian 17 26 69 24Range 1-168 18-36 41-96 1-168

Status at last follow-up, No.No evidence of disease 12 12Alive with disease 4 2 6Died as a result of lymphoma 5† 5Died as a result of other cause 1 1

Tumoral immunophenotypeCD4

Cases with CD4 � 50%, No. 2 2 1 5Total cases, No. 14 4 3 21% 14 50 33 24

CD7Cases with CD7 loss � 50%, No. 13 5 2 20Total cases, No. 15 5 3 23% 87 100 67 90

Proliferation index (Ki-67), % 9 22 5 10CD8� tumor-infiltrating lymphocytes, % 20 1 10 14TCR rearrangement

Cases with clonal TCR rearrangement, No. 11 1 3 15‡Total cases, No. 12 2 3 17% 92 50 100 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 TCR-� (n � 7); TCR-� only (n � 4), TCR-� only (n � 4).

Garcia-Herrera et al

3366 © 2008 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY


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

PCSM-TCL With an Aggressive Clinical Outcome

These patients were four men and one woman with a median ageof 65 years (range, 52 to 78 years; Table 1). All of them had rapidlygrowing and bulky tumors or nodules (� 5 cm in diameter; Fig 2).Two of them became ulcerated in the following weeks. All patients hadambulatory performance status (Eastern Cooperative OncologyGroup performance status of 0 to 1) and normal serum lactate dehy-drogenase levels. Four patients were treated with multiagent systemicchemotherapy regimens resulting from the rapid progression of thecutaneous lesions, whereas the remainder received local radiationtherapy. Only two patients achieved complete remission, one had apartial remission, and two showed progressive disease. Two patientshad cutaneous relapses, and all of them developed extracutaneous

dissemination (median time to relapse, 14 months; range, 9 to 11months), including two cases in the lymph nodes and three withsuspected (patient 19) or documented (patients 20 and 21) CNSinvolvement. All patients died as a result of the disease between 18 and36 months after the initial diagnosis (median survival, 23 months).

Histologically (Fig 2), all of these tumors were composed ofsmall/medium-sized atypical lymphocytes, growing with a nodulararchitecture in three cases and a diffuse pattern in two. In all cases, thetumor involved the reticular dermis and in two extended into thesubcutis. Focal epidermotropism was present in three cases. Twopatients (20 and 21) who subsequently developed CNS involvementshowed focal endoneural infiltration of small nerves by tumor cells(Fig 2). One case showed a granulomatous inflammation (patient 17),but no eosinophils or plasma cells were observed in any tumor. Twosimultaneous biopsies in patient 20 showed a PCSM-TCL in a trunklesion and a Langerhans cell (LC) histiocytosis (LCH) with high num-ber of mitosis and atypical cells in the arm, without admixture of thedifferent lesions in the respective biopsies. The lymphoma of thispatient transformed into a large-cell lymphoma 18 months after diag-nosis, maintaining CD3 and �F1 but with loss of CD4 and acquiredCD57 expression. Simultaneously, the patient had axillary lymphnodes with an LC sarcoma.

A B

C D

E

G

F

H

I

1,0000

3,0002,000

4,000

150 180 200 220 240 260 280 300 320 340 360

Fig 1. Primary cutaneous small/medium CD4� T-cell lymphoma with indolentclinical course. (A) Gross appearance of a solitary plaque. (B, C) Diffuse dermalinvolvement by irregular small-/medium-sized cells. (D-F) The cells express CD3and CD4, but CD7 is lost. (G) High numbers of reactive CD8� cells and (H) lowproliferation index (Ki-67) are typical in this group. (I) Clonal rearrangement ofTCR-� gene. Image magnifications were (B) �40 and (C to H) �400.

A B

C D

E

G

F

H

Fig 2. Primary cutaneous small/medium CD4� T-cell lymphoma with anaggressive clinical outcome. (A, B) Clinical presentation with tumoral lesions. (C,D) Neoplastic small-/medium-sized cells infiltrating the dermis. The inset dem-onstrates neural invasion. The cells express CD3 and CD4 (E, F), but this groupshows (G) few and isolated reactive CD8� lymphocytes and (H) high proliferationindex (Ki-67). Image magnifications were (C) �40 and (D to H) �400.




Immunohistochemically, CD4 was expressed in four cases withpartial loss in two, and was technically unsatisfactory in one. CD7 wasdecreased or lost in all cases. Patient 21 showed aberrant coexpressionof CD20 in the tumor cells. The proliferative index in this group oftumors was significantly higher that in the previous one (medianKi-67, 22%; range, 15% to 43%; P � .05). CD8� tumor-infiltratinglymphocytes were also significantly lower than in the previous group(median, 1%; range, 0.3% to 7.7%; P � .05; Fig 2). B cells were scarceand disperse without forming aggregates.

A clonal TCR-� and TCR-� gene rearrangement was observed inone of the two cases with available material (patient 20). The LCsarcoma of this patient showed a germ-line configuration of theTCR gene.

PCSM-TCL With Prominent Eosinophilia

Three patients had a peculiar clinical presentation with recurrentmultifocal skin plaques or nodules in the extremities and abdomen(Table 1). One patient (22) had a long history of recurrent cutaneouslesions that had been interpreted as “reactive lymphoid and histiocytehyperplasia” before definitive diagnosis of cutaneous lymphoma. Per-sistent eosinophilia in the peripheral blood was observed in this case.At last follow-up examination, two patients were alive with skin dis-ease (follow-up, 72 and 96 months), and one died 41 months afterdiagnosis of lymphoma resulting from metastatic breast cancer. Mor-phologically, these tumors showed a dermal infiltrate of atypicalsmall-/medium-sized lymphocytes admixed with numerous eosino-phils (Fig 3). Partial loss of CD4 was observed in patient 23. Themedian percentage of Ki-67 positive cells was 5% (range, 1% to 24%).The number of infiltrating CD8� lymphocytes was moderate (me-dian, 10%; range, 9% to 13%) whereas many scattered or small clus-ters of CD20� B cells were present. A TCR gene clonal rearrangementwas detected in the three cases and in the peripheral blood (PB) of one(patient 22). This latter case showed 33% of T lymphocytes in the PBwith anomalous phenotype (partial loss of CD7 and CD3).

DISCUSSION

In this study, we have examined a series of primary cutaneous T-celllymphomas characterized by a proliferation of small/medium-sizedlymphoid cells with a �F1, CD3, CD4� and/or CD8– and CD30–

phenotype. Most of our patients had an indolent clinical course with,only three patients developing cutaneous relapses and none of themprogressed to systemic disease. These findings are concordant with theprevious descriptions of PCSM-TCL that recognized the relativelyindolent behavior of these tumors, particularly when the clinical pre-sentation was localized or solitary.1,3-5,7,20,21 However, we also identi-fied five patients (21%) with progressive skin disease andextracutaneous dissemination who died of the lymphoma in less thanthree years after diagnosis. Occasional cases of small cell CD4� cuta-neous T-cell lymphoma with aggressive behavior have been reportedbut the clinical and pathological characteristics that may distinguishthis subset of patients have not been recognized.4 Although cases withrapid dissemination were histologically and phenotypically similar tothe tumors with an indolent behavior, we have observed differences inthe clinical presentation and pathologic characteristics that may beuseful to distinguish these two subsets of tumors. Thus, tumors withan indolent clinical behavior presented with stable not progressing

small lesions (� 3 cm), had low proliferative activity (Ki67, 9 � 5.4)and an intense infiltrate of reactive CD8� lymphocytes (CD8, 20% �11.7%) whereas neoplasms with an aggressive clinical course pre-sented with rapidly evolving large tumors or nodules (� 5 cm), vari-abl4 expression of CD4, high proliferation (Ki67, 22% � 11.3%), andscarce number of associated CD8 cells (CD8, 1% � 3.03%) (Fig 4).

The high proliferation observed in the group with aggressivebehavior is concordant with the rapid clinical presentation and thelarge size of the lesions. The proliferative activity has been recognizedrecently as an independent adverse prognostic parameter in periph-eral T-cell lymphoma, unspecified, but its prognostic value in cutane-ous T-cell lymphoma is less known.22-24 Our observations wouldindicate that proliferation is also an important outcome predictor inPCSM-TCL. The number of CD8� tumor-infiltrating lymphocyteswas also significantly lower in the subgroup of aggressive PCSM-TCL than in cases with an indolent behavior. This finding is similarto the relationship between CD8�-infiltrating cells and progres-sion in MF, where the loss of these cells have been associated withtumor progression, less response to therapy, and shorter survival ofthe patients.25-29

Three of the five patients who died as a result of the lymphomadeveloped CNS involvement. This complication has been docu-mented in patients with cutaneous lymphomas.30-34 Interestingly, we

A B

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G

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0

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150 160 170 180 190 200 210 220 230 240 250 260

Fig 3. Primary cutaneous small/medium CD4� T-cell lymphoma with prominenteosinophilia. (A) Clinical presentation with multiple violaceous plaques in the legs.(B, C) Band-like infiltrate with atypical small lymphocytes mixed with high numberof 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 (Cto F) �400.




observed focal endoneural infiltration of small nerves in the initialcutaneous biopsy of two of these patients, suggesting that this findingmay raise the suspicion of an aggressive behavior. The tumor cells ofone of these cases (patient 21) coexpressed CD20. Aberrant expressionof 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�,whereas our case expressed CD4 and was negative for cytotoxic gran-ules. One patient (20) had a simultaneous LC sarcoma with cutaneousand lymph-node involvement. LCH has been observed in associationwith other lymphoproliferative disorders including cutaneous lym-phomas.38 Interestingly, a clonal relationship between LCH and T-celllymphoblastic lymphoma has been documented.39 However, in ourcase, the TCR clonal rearrangement detected in the PCSM-TCL wasnot observed in the LC sarcoma, suggesting that they were two sepa-rate neoplasms.

The differential diagnosis between the indolent PCSM-TCLand cutaneous pseudo–T-cell lymphomas may be difficult sincethey share some overlapping features.40-43 Most of our patients had

small lesions with a high infiltrate of CD8� and B-cells that are alsoa common finding in pseudo–T-cell lymphomas. However, ourpatients had a constellation of findings favoring the diagnosis ofPCSM-TCL. Thus, none of our cases had a history of spontaneousregression of the lesions or previous medication, insect bite orsystemic immunologic disorders that have been associated withpseudo–T-cell lymphomas.44 Histologically, the tumor cellsshowed common epidermotropism (six of 16), had frequent loss ofT-cell antigens, and, molecularly, a clonal TCR rearrangement wasdemonstrated in virtually all cases examined. These findings wouldsupport the idea of these lesions as indolent lymphomas. However,to determine the boundaries between PCSM-TCL and cutaneouspseudo–T-cell lymphomas in some cases may be difficult anddebatable, and require the combination of clinical, pathologic, andmolecular criteria.43,45-48 From a practical point of view, it is im-portant to recognize that patients with the indolent form of PCSM-TCL have a good clinical evolution with only local therapy.

In our study, we identified three additional patients with a pecu-liar clinical and pathologic presentation that differs from the previouscases. Although these tumors had certain morphologic and pheno-typic similarities with group 1, the patients had recurrent multifocalskin lesions but no systemic dissemination or lymphoma-relateddeaths. Histologically, the CD4� T cells were associated with a prom-inent eosinophilic infiltrate but a low number of CD8� or B cells. Theclonal TCR rearrangement detected in the three patients, one of themalso in the blood associated with eosinophilia, and the persistence ofthe lesions suggest that they are a peculiar form of primary cutaneousindolent T-cell lymphoma.

In summary, our observations indicate that PCSM-TCL maypresent with different clinical and pathologic characteristics that areassociated with the biologic behavior of the tumors. Patients present-ing with small lesions, low proliferative index, and an intense infiltra-tion of the tumor by reactive CD8� cells have an excellent prognosiswith only occasional cutaneous relapses, whereas patients with rapidlygrowing lesions, high proliferative tumors ,and low infiltrate of CD8�

cells develop extracutaneous dissemination and have a poor progno-sis. These patients have a biologic behavior that is more related to theaggressive primary cutaneous T-cell lymphomas, unspecified, despitethe small/medium size of the tumor cells.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Adriana Garcia-Herrera, Luis Colomo, AntonioMartinez, Teresa Estrach, Elias CampoFinancial support: Teresa Estrach, Elias CampoProvision of study materials or patients: Mireia Camos, JoaquınCarreras, Olga Balague, Armando Lopez-Guillermo, Teresa Estrach,Elias CampoCollection and assembly of data: Adriana Garcia-Herrera, Luis ColomoData analysis and interpretation: Adriana Garcia-Herrera, LuisColomo, Joaquın Carreras, Antonio Martinez, ArmandoLopez-Guillermo, Teresa Estrach, Elias Campo

AP < .05

P < .05

CD8

(%)

Group

0PCSM-TCL with

indolentclinical course

PCSM-TCL withan aggressiveclinical course

PCSM-TCL withprominent

eosinophilia

B

Ki67

(%)

Group

40

20

40

20

0PCSM-TCL with

indolentclinical course

PCSM-TCL withan aggressive

clinical outcome

PCSM-TCL withprominent

eosinophilia

O612

O2

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




Manuscript writing: Adriana Garcia-Herrera, Luis Colomo, MireiaCamos, Joaquın Carreras, Olga Balague, Antonio Martinez, ArmandoLopez-Guillermo, Teresa Estrach, Elias Campo

Final approval of manuscript: Adriana Garcia-Herrera, Luis Colomo,Mireia Camos, Joaquın Carreras, Olga Balague, Antonio Martinez,Armando Lopez-Guillermo, Teresa Estrach, Elias Campo

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