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uring the year 2005, there were hundreds of publica-tions related to the topic of cutaneous T-cell lymphomas

CTCLs). I have selected some of the most relevant articles onhe subject, from pathomechanisms, to molecular mecha-isms to clinical presentation and skin directed-therapeuticpproach. Our goal is to present the practicing dermatolo-ists with some of the new trends in the field of cutaneousymphomas.

lassification ofutaneous Lymphomas

t is well known that skin lymphomas have unique clinicalorphological, molecular, and even prognostic features that

re not shared with their nodal counterparts. In the last fewears, the World Health Organization and European Organi-ation for Research and Treatment of Cancer presented newroposals for classifying cutaneous lymphomas, with diver-ent views on the same entities. This difference in opinionrobably reflects the fact that one organization is mostly in-uenced by hematopathologists, whereas the Europeanroup is primarily composed of clinical dermatologists. In005, there were 2 publications regarding the newly pro-osed classification, which is a major advancement in ouromenclature of these lesions and represents a communionf the two groups.1,2 As a result of this work, we can expect aore uniform diagnostic approach to cutaneous lymphomas,

s well as a common framework among oncologists, pathol-gists, and dermatologists. Ultimately, this consensus willrovide a base for a more reasonable and consistent thera-eutic approach to our CTCL patients.Lymphomas are divided in 3 groups: T-cell and NK lym-

homas, B-cell lymphomas, and a new category of tumors ofendritic cell origin labeled as “hematodermic neoplasms.”hese lesions have a highly aggressive behavior and are char-cterized by hemorrhagic cutaneous nodules composed ofononuclear cells with expression of CD4 and CD56 but

acking lymphoid markers. In my opinion, this terminologys confusing. On the basis of their origin from plasmacytoid

orthwestern University, Chicago, IL.ddress reprint requests to Joan Guitart, MD, Department of Dermatology,

Northwestern University Medical School, 645 N. Michigan Avenue,

SSuite 520, Chicago, IL 60091. E-mail: j-guitart@northwestern.edu

085-5629/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.sder.2006.05.002

endritic cells, the term “dendritic cell sarcoma” may be pref-rable. A new designation also exists for large cell B-cell lym-homas of “leg type.” These tumors appear to have a moreggressive behavior than other primary cutaneous B-cell lym-homas of follicular center cell origin. The immunopheno-ype of these cases is similar to the activated B-cell like lym-homas of nodal origin with expression of MUM-1, bcl2, andRF4. Gamma-delta T-cell lymphomas also are classified in aeparate category. Although morphologically many of theseases present with a clinicopathological picture resemblinganniculitis, the term subcutaneous panniculitis-like T-cell

ymphoma is reserved for those cases that express the alpha-eta T-cell receptor heterodimer. This is certainly not the lastord on classification of cutaneous lymphomas, but rather aork in progress. It is encouraging to see that finally we areoving in the right direction.Another area in which experts are trying to reach consen-

us is regarding minimal criteria for the diagnosis of mycosisungoides (MF). The International Society for Cutaneousymphomas, representing a worldwide group of dermatolo-ists with interest in cutaneous lymphomas, has come upith a proposal that includes clinical criteria (poikiloderma-

ous features, lesions on sun protected skin, etc.), histomor-hological criteria, presence of a T-cell clone, and abnormal

mmunophenotype.3 Patients with more than 4 points fulfillhe required minimal criteria for the diagnosis of MF. Thisool provides a guideline to incorporate patients into clinicaltudies or lymphoma databases in a more uniform method.

rigin and Evolution of CTCLsften, it takes several years before the diagnosis of MF is

learly established. During the period preceding the diagno-is of CTCL, some patients suffer from a variety of distinctkin conditions of ambiguous origin. With the refinement inhe methods of T-cell clonal detection in skin biopsies, weave established that many of these preceding entities areharacterized by a T-cell clone. A number of cutaneous con-itions are characterized by the presence of an idiopathic-cell clone with the propensity for malignant transforma-

ion. Gniadecki and coworkers4 have reported a series ofatients with idiopathic erythroderma and a persistent T-celllone, but without hematological criteria for the diagnosis of

ézary syndrome. Although none of their patients evolve into

87

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TCL, similar cases have been reported in the past as pre-ézary syndrome with eventual evolution to the leukemicariant of CTCL. In my opinion, pre-Sézary should be in-luded included as a cutaneous lymphoid dyscrasia. Thisroup of skin conditions, including among others, parapso-iasis, follicular mucinosis, and pytiriasis lichenoides, areharacterized by persistent and recalcitrant skin lesions with-ut a known triggering event, minimal lymphoid atypia, T-ell clonality, and potential for progression into CTCL. Aroup from Finland also has corroborated that a subset ofatients with small plaque and large plaque parapsoriasis canrogress into having MF. Of interest, the tendency for pro-ression was not diminished by treating the condition withhototherapy. However, the course was fairly indolent in allatients.5

Gniadecki6 also has proposed that the origin of cutaneousymphomas, like other lymphoproliferative conditions, maye associated to the presence of a neoplastic stem cell. There

s some evidence supporting this theory. For instance, bonearrow biopsies obtained years before reaching the diagno-

is of lymphomatoid papulosis have shown occult and mor-hologically silent T-cell clones with the same molecular fin-erprint seen in the eventual lymphoproliferative lesions thatppeared years later. The multicentricity and often compositeature of many CTCL cases, along with the lack of curebserved after systemic chemotherapy also support this the-ry. Vonderheid and Matsui7 replied to this stem cell hypoth-sis by adding that a putative stem cell may be located in thekin rather than the bone marrow. The debate on this hotopic is likely to continue.

Recent studies have further characterized the CTCL cell ofrigin. We had previously identified a number of moleculeshat play a role in skin-homing such as CLA or LFA-1, now aew chemokine receptor CCR4 has been demonstrated byow cytometry in several patients with Sézary syndrome.8

he ligand for CCR4 in the skin antigen presenting cells isARC. Carol Berger and the group from Yale9 recently sug-ested that CTCL may be a malignancy of T regulatory cells.regulatory cells, a small subset of peripheral lymphocytes,

ownregulate activated T cells in response to autoantigens,nfectious agents, and other antigens to maintain homeostasisf the immune system. The profound depletion of the T-cellepertoire and the immunesuppressive complications ob-erved in patients with advanced CTCL support this newroposal. Furthermore, a recent report published in the Jour-al of Investigative Dermatology confirmed the increased ex-ression of CTLA-4 in CTCL cells. CTLA-4 is a costimulatoryolecule of T cells important in the interface of antigen pre-

enting cells and T cells and it is known to be highly ex-ressed in T regulatory cells.10

We also have learned that MF cells in vitro require signal-ng or a microenvironment, which is uniquely provided byntigen presenting cells. In vivo, using microscopy skin ex-mination, one also observes the close proximity of MF cellso Langerhans cells and dermal dendrocytes. However, de-ails about the antigenic stimuli driving this interaction areot known. A group from France has proposed that antigens

elated to Epstein Barr virus (EBV) may be driving this ab- C

ormal interaction. They identified EBV at the molecular androtein level in a few Langerhans cells from MF lesions.11

ther members of the herpesviridae family, like human her-esvirus 8, also have been reported in patients with MF andarapsoriasis.12 A superantigen effect associated to Staphylo-occus aureus has been proposed, based on the increased us-ge of V beta families associated with staphylococcus in MFells as well as nonclonal T cells in MF lesions.13,14 But know-ng that EBV is a common and highly prevalent virus and thattaphylococcus is commonly detected in the skin of MF pa-ients, we have to question these infectious agents as an epi-henomenon linked to the immunesuppressive nature of thisisease.Researchers are looking into new markers to predict out-

ome in patients with CTCL. In general, parameters such asNM staging, serum lactose dehydrogenase levels, large cell

ransformation, and Sézary cell count have shown good cor-elation with prognosis and tumor burden. Researchers at theniversity of Pennsylvania have reported that changes in thebnormal T-cell population on peripheral blood as measuredy flow cytometry appears to be a reliable marker for thelinical course of Sézary syndrome. This allows for detectionf important changes in the disease status preceding clinicalhanges by weeks. They also confirmed deletion of CD26 asn important marker for Sézary cells.15 Other recent publica-ions have emphasized the total CD8 count as an importantrognostic marker with a poor prognosis associated with arop of peripheral CD8 cells.16 The group from Zurich iden-ified neopterin, a protein secreted by macrophages, B cells,nd endothelial cells, as a marker that correlates with CTCLumor burden and T cell activation. However, the measure-ent of neopterin has limited utility without diagnostic orrognostic value.17 The search for markers reflecting tumorurden is probably not too relevant in CTCL because clinicalnd hematological assessments can provide a fairly good as-essment in most of the cases. Occasionally, we have ob-erved patients with advanced Sézary syndrome presentingith sudden “improvement” of the erythrodermic symptomsith a decrease in Sézary counts but with associated fatigue

nd constitutional symptoms. The complete blood counthowed pancytopenia, which resulted from blastic transfor-ation and marrow replacement by tumor cells. Hence, this

alse impression of clinical improvement may herald a poorutcome. This rare scenario is one of the few real indicationsor bone marrow biopsy in patients with CTCL, which tendso be negative even in most advanced stage IV patients.18

ew Clinical Presentationsnd Variants of CTCL

he group from Gratz has reported patients with a new vari-nt of MF characterized by a predominantly papular presen-ation. This variant could be easily confused with type Bymphomatoid papulosis, but the lesions remain stable with-ut the spontaneous resolution seen in lymphomatoid papu-osis.19 Furthermore, the atypical T cells failed to express

D30. I have some reservations about this diagnosis. For

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What’s new in cutaneous T cell lymphomas 89

nstance, CD30 is not a very reliable marker for early lesionsf lymphomatoid papulosis, which are dominated by small-o-intermediate atypical T cells that often lack CD30 expres-ion. Another possibility to consider in some of these cases ishe follicular variant or syringotropic CTCL, which also tendo present with a punctuate or papular pattern. As a matter ofact, one of the illustrations in their article showed a patternuggestive of follicular-based papules.

Extensive vitiligo has been reported in numerous patientsith Sézary syndrome. Most of these patients develop this

ondition after or during therapy with interferon. We nownow that development of autoimmune conditions, includ-

ng vitiligo, is a side effect of immune-manipulation withnterferon. A group from France demonstrated that the tu-

or infiltrating CD8 T cells in CTCL may have HLA-re-tricted cytotoxicity targeting MART-1 from skin melano-ytes.20 There are other hypopigmented variants of MFharacterized by CD8 phenotype and juxtabasal presenta-ion. In these rare cases of juvenile hypopigmented MF, per-aps the cytotoxic effect of the tumor cells is directly relatedo the hypochromic presentation.

Recent reports highlighted other uncommon presentationf CTCL and lymphomatoid papulosis involving the midfacend oral mucosal with features clinically resembling cellulitisr erysipelas.21,22 This rare presentation tends to be diagnos-ically and therapeutically challenging.

kin-Directed Therapy for MFkin-directed therapy remains the cornerstone treatment forhe early stages of MF. Topical steroids may alleviate theisease in early patch lesions, especially if a potent prepara-ion is applied rubbing the skin more than once daily. Even-ually topical steroids tend to fail in controlling the diseaseut can remain an alternative for combination therapy. Top-

cal mechlorethamine has proved to be a safe and effectivelternative therapy. Unfortunately, last year, the price ofechlorethamine in the United States increased by close to

ne thousand percent. The steep price, along with the lack ofpproval from the Food and Drug Administration (FDA) forhis topical preparation, pose a problem for the patients andhe prescribing physicians. The Cutaneous Lymphomaoundation has presently undertaken an initiative to obtainDA approval for the topical use of nitrogen mustard inTCL. De Quatrebarbes and coworkers,23 using an aqueousreparation, showed that the application of mechloreth-mine twice weekly and only to the skin lesions is as effectives a daily application to the entire integuement. Furthermore,he same group found that applying betamethasone 10 min-tes after the application of nitrogen mustard greatly de-reased the incidence of contact dermatitis. Nevertheless, theintment preparation of mechlorethamine commonly usedn the United States still has a lower incidence of contactermatitis than any protocol used with the aqueous prepara-ions. Patients with extensive skin involvement (T2) also mayave occult disease, which often is exposed only after theotal body application of mechlorethamine. Consequently,

ome of these patients with extensive skin involvement will c

ontinue to benefit from total body application. Immune-odifiers like topical Imiquamod have proved efficacious in

mall open nonblinded studies.24 Another problem withhese studies is that patients often received other treatmentodalities like phototherapy. On the basis of our experience

nd corroborated by few case reports, topical Imiquamodends to benefit patients who develop a significant contactermatitis often with blister formation.Narrow-band UVB is becoming standard of care for pa-

ients with patch skin lesions (T1 and T2) and but is lessffective for patients with thicker plaque lesions. Recent lit-rature has corroborated the benefits of this treatment mo-ality with response rates similar to PUVA therapy.25-27 How-ver, patients relapse unless a maintenance schedule isontinued to consolidate the response. We also found thatnce the therapy sessions are space more than 10 to 14 dayspart, patients often suffer burning even when lower energyevels are administered. Conversely, PUVA therapy can beapered to monthly sessions or even less frequently withoutignificant side effects assuming dose adjustment. The com-inations of PUVA with interferon or bexarotene also areffective treatment option for patients with extensive patchnd plaque disease (stage IB and IIA). A group from Italyecently reported their experience with PUVA and interferonwice or three times weekly, reporting a complete responseate of 84%.28 An interestingly observation in this study ishat patients with a greater CD8 count, as previously noted,ad a lower relapse rate.Last year, our group reported the long-term follow-up of

atients who had achieved complete remission with PUVAonotherapy for a mean duration of close to 10 years.29 We

ound that patients who achieve a complete response, if theyre maintained on intermittent PUVA session for a few years,ave an approximately 50% chance of prolonged remission,hich could arguably qualify as a cure. We also found thatatients with limited disease (T1) had a higher relapse ratehan patients with more extensive disease (T2). This obser-ation correlated with the fact that T2 patients received aigher average cumulative Joules than T1 patients. In con-lusion, we may be undertreating patients with limited dis-ase who responded rapidly and there is a need to consolidatehe response before tapering the frequency of treatments to aaintenance schedule. A multicenter, dose-randomized

tudy of low-dose bexarotene combined with PUVA is nearompletion in the United States. Initial results show a re-ponse rate of 87% with a complete response of 53% requir-ng a cumulative dose of 173 J at the time of remission.mong the patients treated at our phototherapy center, aomplete response was achieved with less cumulative Joules133J) than our previous institutional experience with PUVAonotherapy in similar patient population (157J). The pho-

ocarcinogenic effect of rexinoids has not been demonstrated,ut if proven it may turn out to be another important benefitf this combination therapy. In conclusion, we have reviewednumber of recent publications that enhance our under-

tanding of CTCL and bring new suggestions about how topproach skin directed therapy in patients suffering from this

hallenging disease.

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eferences1. Burg G, Kempf W, Cozzio A, et al: WHO/EORTC classification of

cutaneous lymphomas 2005: histological and molecular aspects. J Cu-tan Pathol 32:647-674, 2005

2. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification forcutaneous lymphomas. Blood 105:3768-3785, 2005

3. Pimpinelli N, Olsen EA, Santucci M, et al: International Society forCutaneous Lymphoma. Defining early mycosis fungoides. J Am AcadDermatol 53:1053-1063, 2005

4. Gniadecki R, Lukowsky A: Monoclonal T-cell dyscrasia of undeter-mined significance associated with recalcitrant erythroderma. ArchDermatol 141:361-367, 2005

5. Vakeva L, Sarna S, Vaalasti A, et al: A retrospective study of the prob-ability of the evolution of parapsoriasis en plaques into mycosis fun-goides. Acta Derm Venereol 85:318-323, 2005

6. Gniadecki R: Neoplastic stem cells in cutaneous lymphomas: evidenceand clinical implications. Arch Dermatol 140:1156-1160, 2004

7. Vonderheid EC, Matsui W: Do neoplastic stem cells underlie the patho-genesis of cutaneous lymphomas? Arch Dermatol 141:641-642, 2005

8. Sokolowska-Wojdylo M, Wenzel J, Gaffal E, et al: Circulating clonalCLA(�) and CD4(�) T cells in Sezary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymphnode-homing chemokine receptor CCR7. Br J Dermatol 152:258-264,2005

9. Berger CL, Tigelaar R, Cohen J, et al: Cutaneous T-cell lymphoma:malignant proliferation of T-regulatory cells. Blood 105:1640-1647,2005

0. Wong HK, Wilson AJ, Gibson HM, et al: Increased expression of ctla-4in malignant T-cells from patients with mycosis fungoides—cutaneousT cell lymphoma. J Invest Dermatol 126:212-219, 2006

1. Knol AC, Guilloux Y, Quereux G, et al: CD8(�) T lymphocytes reactiveagainst Epstein-Barr virus antigens in skin lesions of a patient withSezary syndrome. J Am Acad Dermatol 53:897-900, 2005

2. Trento E, Castilletti C, Ferraro C, et al: Human herpesvirus 8 infectionin patients with cutaneous lymphoproliferative diseases. Arch Derma-tol 141:1235-1242, 2005

3. Vonderheid EC, Bigler RD, Hou JS. On the possible relationship be-tween staphylococcal superantigens and increased Vbeta5.1 usage incutaneous T-cell lymphoma. Br J Dermatol 152:825-826, 2005

4. Vonderheid EC, Boselli CM, Conroy M, et al: Evidence for restrictedVbeta usage in the leukemic phase of cutaneous T cell lymphoma.J Invest Dermatol 124:651-661, 2005

5. Introcaso CE, Hess SD, Kamoun M, et al: Association of change in

clinical status and change in the percentage of the CD4�CD26- lym-

phocyte population in patients with Sezary syndrome. J Am AcadDermatol 53:428-434, 2005

6. Abeni D, Frontani M, Sampogna F, et al: Circulating CD8� lympho-cytes, white blood cells, and survival in patients with mycosis fun-goides. Br J Dermatol 153:324-330, 2005

7. Hassel JC, Meier R, Joller-Jemelka H, et al: Serological immunomarkersin cutaneous T cell lymphoma. Dermatology 209:296-300, 2004

8. Beylot-Barry M, Parrens M, Delaunay M, et al: Is bone marrow biopsynecessary in patients with mycosis fungoides and Sezary syndrome? Ahistological and molecular study at diagnosis and during follow-up. Br JDermatol 152:1378-1379, 2005

9. Kodama K, Fink-Puches R, Massone C, et al: Papular mycosis fun-goides: a new clinical variant of early mycosis fungoides. J Am AcadDermatol 52:694-698, 2005

0. Knol AC, Quereux G, Marques-Briand S, et al: Pathogenetic mecha-nisms of vitiligo in a patient with Sezary syndrome. Br J Dermatol153:1207-1212, 2005

1. Brill TJ, Ludwig RJ, Wolter M, et al: Complicated mycosis fungoidesmimicking facial erysipelas. Br J Dermatol 152:1381-1383, 2005

2. Pujol RM, Muret MP, Bergua P, et al: Oral involvement in lymphoma-toid papulosis. Report of two cases and review of the literature Derma-tology 210:53-57, 2005

3. deq Uatrebarbes J, Esteve E, Bagot M, et al: Treatment of early-stagemycosis fungoides with twice-weekly applications of mechlorethamineand topical corticosteroids: a prospective study. Arch Dermatol 141:1117-1120, 2005

4. Deeths MJ, Chapman JT, Dellavalle RP, et al: Treatment of patch andplaque stage mycosis fungoides with imiquimod 5% cream. J Am AcadDermatol 52:275-280, 2005

5. Kural Y, Onsun N, Aygin S, et al: Efficacy of narrowband UVB photo-therapy in early stage of mycosis fungoides. J Eur Acad Dermatol Ve-nereol 20:103-104, 2006

6. Boztepe G, Sahin S, Ayhan M, et al: Narrowband ultraviolet B photo-therapy to clear and maintain clearance in patients with mycosis fun-goides. J Am Acad Dermatol 53:242-246, 2005

7. Ghodsi SZ, Hallaji Z, Balighi K, et al: Narrow-band UVB in the treat-ment of early stage mycosis fungoides: report of 16 patients. Clin ExpDermatol 30:376-378, 2005

8. Rupoli S, Goteri G, Pulini S, et al: Marche Regional Multicentric StudyGroup of Cutaneous Lymphomas. Long-term experience with low-dose interferon-alpha and PUVA in the management of early mycosisfungoides. Eur J Haematol 75:136-145, 2005

9. Querfeld C, Rosen ST, Kuzel TM, et al: Long-term follow-up of patientswith early-stage cutaneous T-cell lymphoma who achieved completeremission with psoralen plus UV-A monotherapy. Arch Dermatol 141:

305-311, 2005