Review of the Treatment of Mycosis Fungoides and Sézary

Original Article

436

copy Journal of the National Comprehensive Cancer Network Volume 6 Number 4 April 2008

From aMemorial Sloan-Kettering Cancer Center New York New York bDuke University Durham North Carolina cM DAnderson Cancer Center Houston Texas dOhio State UniversityColumbus Ohio and eStanford University Stanford CaliforniaSubmitted December 23 2007 accepted for publication February 13 2008Dr Horwitz serves as a consultant for and receives honoraria fromMerck amp Co Inc THERAKOS Inc and Eisai Pharmaceuticals Drs Olsen Duvic Porcu and Kim have no financial interestarrangement or affiliation with the manufacturers of any productsdiscussed in the article or their competitorsCorrespondence Steven M Horwitz MD Memorial Sloan-KetteringCancer Center 1275 York Avenue New York NY 10021 E-mail horwitzsmskccorg

Review of the Treatment of Mycosis Fungoidesand Seacutezary Syndrome A Stage-Based Approach

Steven M Horwitz MDa Elise A Olsen MDb Madeleine Duvic MDc Pierliugi Porcu MDd and Youn H Kim MDe

New York New York Durham North Carolina Houston Texas Columbus Ohio and Stanford California

tients results in a much higher overall prevalence In2007 the NCCN created its first guidelines on MFSSThere are not sufficient randomized studies to recom-mend a preferred treatment strategy for MFSS nor do uni-versally accepted standard treatments exist Thechronicity of the disease results in many patients beingtreated with multiple therapies in their lifetime includ-ing skin-directed therapies such as ultraviolet light top-icals and radiation an increasing armamentarium ofsystemic agents ranging from retinoids to other biologicsto chemotherapy and an emerging role for allogeneicstem cell transplantation Thus the algorithms of theseguidelines are complex This article overviews the ap-proach to diagnosis and discusses the critical importanceof stage-based prognosis and its logical sequelae stage-based therapy It does not provide a detailed review ofthe data behind all therapies or choices of therapies pre-sented in the guidelines

Clinical Features and DiagnosisPatients with MFSS present with patch plaque tumoror erythrodermic involvement on their skin23 (Figure 1)The most classic presentation involves poikilodermatous(epidermal atrophy often with telangiectasia pigmentalteration) patches in the ldquobathing trunkrdquo distributionHowever many clinical and histologic variants or subtypeshave atypical or unique clinical presentations such ashypopigmentedvitiliginous MF Woringer-Kolopp dis-ease (pagetoid reticulosis) folliculocentric (+ follicularmucinosis) MF granulomatous MF pigmented purpuriceruption-like MF interstitial MF and papular MF2

Patients often present with more than 1 type of skin in-volvement (eg patches and plaques or patches plaquesand tumor lesions) This polymorphic skin involvementis important to acknowledge when determining the

Key Words Mycosis fungoides Seacutezary syndrome cutaneous T-cell lymphoma

AbstractThe NCCN Clinical Practice Guidelines in Oncology Non-HodgkinrsquosDisease were recently revised to include recommendations for treat-ing mycosis fungoides and Seacutezary syndrome These uncommon lym-phomas require a specialized evaluation and use a unique TNMBstaging system Unlike the other forms of non-Hodgkinrsquos lymphomasstage overwhelmingly determines prognosis and defines radically dif-ferent treatment approaches For patients with early-stage diseaseinitial treatment with skin-directed therapies is preferred and manypatients never require systemic therapy For patients with refrac-tory or advanced-stage disease biologic therapies are often the firstchoices whereas chemotherapies are reserved for later in the dis-ease course Many milder therapies may be repeated several timesin the disease course and maintenance and tapering strategies arecommon This article also discusses the emerging role of allogeneicstem cell transplantation (JNCCN 20086436ndash442)

Mycosis fungoides (MF) and its leukemic variant Seacutezarysyndrome (SS) are the most common forms of cutaneousT-cell lymphoma (CTCL) The annual incidence ofCTCL (more broadly defined than MFSS) is reportedlyincreasing and currently estimated at 96 cases per 1 mil-lion person-years1 The long-term survival of most pa-

JN064_Jrnl_60403Hrwtzqxd 42108 1007 PM Page 436

Original Article 437

Treatment of Mycosis Fungoides and Seacutezary Syndrome


optimal treatment strategy For example patients whohave primary patchplaque disease with limited skintumors are often managed with treatment options usedfor the patchplaque disease combined with localradiation therapy to the tumor lesions Patients mayundergo changes in their primary type of skin involve-ment (eg present with tumor disease but have mostlypatchesplaques after treatment [or visa-versa]) orprogress to extracutaneous involvement thus the man-agement strategy should be modified accordingly

SS is a leukemic form of CTCL in which patientshave significant blood involvement with Seacutezary cellsand diffuse skin erythema (erythroderma) Lym-phadenopathy is a frequent finding in patients withSS and can range from reactive dermatopathicchanges to frank lymphoma on histopathologic ex-amination Additional clinical findings commonlyseen in SS include keratoderma nail dystrophyalopecia ectropion and skin edema (especially inthe legs) These patients often experience intractableitching (pruritus) which can be the most significantlife-altering symptom and therefore treatments thatcan successfully reduce pruritus even without meas-urable objective response may still be a valuable option

MF is suspected in patients who present withyears of refractory or recurrent skin eruption with

a poikilodermatous or polymorphic skin involve-ment in typical distribution SS should be suspectedin patients with unexplained erythroderma associ-ated with atypical lymphocytes in their blood In MFor SS clinicians must rule out drug reactions thatcan mimic the clinical or histologic appearance(lymphomatoid drug eruptions) As specified in theNCCN guidelines on non-Hodgkinrsquos lymphomas(NHL in this issue to view the most recent versionplease visit wwwnccnorg) some diagnostic evalu-ations are considered essential and some useful un-der certain circumstances45 The key element ofdiagnosis is the skin biopsy reviewed by a der-matopathologist However skin biopsies of patientswith erythrodermic skin involvement often do nothave well-established diagnostic features thus as-sessment of other sites of potential involvementsuch as blood or lymph nodes may help confirmthe clinical diagnosis In MF and SS it is importantto know when to obtain ancillary immunohisto-chemical or molecular studies (because of false-pos-itive and -negative cases) and to learn how tointerpret and incorporate the information for opti-mal clinical pathologic diagnosis6 Ancillary testsshould be performed when routine histology is notdiagnostic but a high clinical suspicion of MF or SSexists

Figure 1 Representative photographs of presenting skin lesions in patients with mycosis fungoides All lesions are categorized as patch plaque tumoror erythroderma The type of skin lesions present are important in determining stage and planning therapy


438 Original Article

Horwitz et al


Staging and PrognosisAfter the diagnosis is established appropriate stagingworkup should be obtained before treatment optionsare considered Accurate staging is important becausetherapeutic strategies in MF are primarily based onthe clinical stage of the disease Most staging studiesdescribed in the NCCN guidelines are essential in-cluding comprehensive skin examination peripheralblood evaluation for Seacutezary cells and appropriate im-aging studies45 The bone marrow biopsy nonessentialevaluation which can be considered in patients be-lieved to have marrow involvement including thosewith SS The staging workup recommended by NCCNinstitutions is consistent with the guidelines in theconsensus document of the revised staging in MFSSproposed by the International Society for CutaneousLymphomas (ISCL) and the Cutaneous LymphomaTask Force of the EORTC5 In the revised staging sys-tem (Tables 1 and 2 ) blood involvement (B classifi-cation) is incorporated into the overall clinical stagebecause cumulative prognostic data show that SS levelof blood tumor burden (B2) is associated with compro-mised survival equivalent to frank nodal lymphoma378

Several large studies have shown that the most significant prognostic factors in MF includetype and extent of skin involvement (T classifica-tion) and presence or absence of extracutaneous disease (NMB classifications) which determine overall clinical stage (Figures 2 and 3)39ndash11 Patientswith limited patch andor plaque disease (stage IA)have a very favorable long-term outcome life expectancy is not altered compared with matchedcontrol population involvement Patients with disease limited to generalized patch andor plaqueinvolvement (stage IBIIA) have a median sur-vival of 11 to 12 years with fewer than 20 expe-riencing progression to a worse TNMB stage Patientsdiagnosed with tumor disease (T3) or erythroderma(T4) have a worse overall outcome with mediansurvivals of 4 to 5 years The actual survivals ofpatients with T3T4 disease also depend on other prognostic variables such as large-cell trans-formation or blood involvement These patients are also at a greater risk for developing extracu-taneous disease Those who either present with or develop extracutaneous disease have the

Table 1 Revised Components and Definitions of TNM Staging for Mycosis FungoidesSeacutezary SyndromeT (Skin) N (Nodes)

T1 Limited patchplaque(lt 10 of total skin surface)

T2 Generalized patchplaque(ge 10 of total skin surface)

T3 Tumors

T4 Generalized erythroderma

M (Viscera) B (Blood)

M0 No visceral involvement B0 No significant blood involvement

M1 Visceral involvement B1dagger Low blood tumor burden

B2Dagger High blood tumor burden

bull CD4CD8 ratio ge 10 (setting of an expanded CD4) or CD4+CD7- cells ge 40 or CD4+CD26- ge 30 of lymphocytes or otheraberrant expression of pan T-cell markers

N0 No clinically abnormal LNs

N1 Clinically abnormal LNs histopathology Dutch grade 1 or NCI LN0-2 (clone +)

N2 Clinically abnormal LNs histopathology Dutch grade 2 or NCI LN3 (clone +)

N3 Clinically abnormal LNs histopathology Dutch grade 3-4 or NCI LN4 (clone +)

Nx Clinically abnormal LNs no histopathology info

Seacutezary cells le 5 lymphsdaggerSeacutezary cells gt 5 lymphs but lt 1000 mm3 by morphology lack of other B2 parametersDaggerSeacutezary syndrome ge 1 of following parameters morphology positive relevant clone and Seacutezary cells ge 1000 mm3 relevantclone+ or Immunophenotypic abnormalities (flow cytometry)Abbreviations LN lymph node NCI National Cancer Institute This research was originally published in Blood Olsen E Vonderheid E Pimpinelli N et al Revisions to the staging and classificationof mycosis fungoides and Seacutezary syndrome a proposal of the International Society for Cutaneous Lymphomas (ISCL) and theCutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Blood 20071101713ndash1722 copythe American Society of Hematology


worst outcome with median survivals of 15 to 3years35

In addition to the unfavorable prognostic associ-ation of blood involvement the proposed revisedstaging system5 recognizes additional prognostic factorsincluding histologic subtypes that have been associ-ated with a worse outcome namely folliculocentric

and transformed MF (gt 25 large cells + CD30+)12ndash14

These additional prognostic variables should be con-sidered when deciding appropriate management asshown in the NCCN guidelines

Treatment Selection FactorsChoosing appropriate treatment is based primarily onmajor prognostic factors TMNB classification andoverall clinical stage4 However other prognostic vari-ables such as folliculocentric involvement or large celltransformation should also be considered Additionalfactors in treatment selection include acuity or sever-ity of associated symptoms (eg pruritus tumor ulcer-ation) data on efficacy (response rate) time to andduration of treatment response comorbidities and dataon treatment-related toxicities and accessibility orcostndashbenefit features of treatments

Patients with stage I (patchplaque) disease whoconstitute two thirds of the newly diagnosed withexcellent prognosis require only skin-directed therapyoptions as primary treatment and many will never re-quire systemic therapy For these patients who haveadditional poor prognostic factors (eg folliculocen-tric MF large-cell transformation B1 blood involve-ment) treatment may be intensified with thecombination of skin-directed therapies or skin-directed plus systemic therapy4 Patients with stage IIB(tumor) disease may require total skin electron beam

Figure 2 Actuarial overall survival of 525 patients with mycosis fungoidesSeacutezary syndromeaccording to TNM stage at diagnosis (stages IAndashIV) Clinical stage and T score which arethe primary determinants of stage are the most important factors in determining prognosisChoice of therapy is heavily determined by stage From Kim YH Liu HL Mraz-Gernhard S et al Long-term outcome of 525 patients withmycosis fungoides and Seacutezary syndrome clinical prognostic risk factors for disease progres-sion Arch Dermatol 2003139857ndash866 Copyright copy 2003 American Medical AssociationAll Rights reserved

Table 2 Revised TNM Staging for Mycosis FungoidesSeacutezary Syndrome

Clinical Stages TNM Classification

IA T1 N0 M0 B0-1

IB T2 N0 M0 B0-1

IIA T1-2 N1-2 M0 B0-1

IIB T3 N0-2 M0 B0-1

IIIA T4 N0-2 M0 B0

IIIB T4 N0-2 M0 B1

IVA T1-4 N0-3 M0 B0-2

IVB T1-4 N0-3 M1 B0-2

This research was originally published in Blood Olsen EVonderheid E Pimpinelli N et al Revisions to the staging andclassification of mycosis fungoides and Seacutezary syndrome aproposal of the International Society for CutaneousLymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research andTreatment of Cancer (EORTC) Blood 20071101713ndash1722copyThe American Society of Hematology




therapy a combination of skin-directedplus systemic therapy or systemic ther-apy alone depending on symptomseverity and other prognostic factorsBecause those with erythrodermic skin(T4 stage III) can be sensitive to mostskin-directed therapies other than top-ical steroids these should be used withcaution A systemic therapy option isindicated for patients who have anyblood involvement

Patients with SS (T4B2 stage IVA)require intensive systemic therapybecause of associated poor prognosisSingle or a combination of biologictreatment with agents denileukin difti-tox histone deacetylase inhibitor ormethotrexate may be considered as aprimary treatment option Because thesepatients may have severe intractable



Horwitz et al


pruritus supportive anti-itch treatments such as anti-histamines gabapentin or mirtazapine may be helpfulAggressive topical steroid treatment (+ occlusivewraps or suits) can often significantly improve symp-toms Secondary skin infections are common becauseof frequent scratching and compromised skin Patientsmay benefit from long-term oral antibiotics and peri-odic cultures to rule out methicillin-resistantStaphylococcus aureus or other atypical microbes if symp-toms are not controlled

Chemotherapy regimens are most appropriate inpatients with bulky lymph node or visceral disease or assalvage therapy when other options have failed Singleagents are often attempted before combination regi-mens After tumor reduction with combinationchemotherapy maintenance with biologic therapy (egbexarotene interferon) may be considered to optimizeresponse duration

Several management concepts unique in MFSSmust be emphasized Patients who experience com-plete response with a primary therapy may undergo thesame treatment if they experience disease relapse pa-tients who respond well to an initial primary therapytend to respond well again to the same therapyUnmaintained remissions in MFSS are uncommonparticularly in patients requiring systemic therapy Inpatients experiencing clinical response maintenance

ical steroids are commonly used as initial therapyHowever if one primary treatment fails other optionsin the primary therapy list should be tried includingtopical nitrogen mustard topical retinoids and pho-totherapy Local radiation therapy may be used in pa-tients with unilesional presentation or those withrecalcitrant or aggressive local disease Narrow-bandUVB (nbUVB) can be highly effective for patientswith patch or thin plaque disease Psoralen plus UVA(PUVA) may be more effective in patients with thickerplaques although it has a greater long-term phototox-icity and risk for secondary UV-associated skin cancerthan nbUVB Total skin electron beam therapy con-sidered the most intensive skin-directed therapy is re-served for patients with extensive generalized diseaseand severe skin symptoms Although the reliabilityof clinical response is greater with more intensiveskin-directed treatments no data show that moreaggressive therapies are associated with improvedprogression-free or overall survival

Combinations of skin-directed therapies (eitheralone or in combination with systemic therapy) are in-dicated when monotherapy fails with severe skinsymptoms or in the presence of other unfavorableprognostic factors In patients with advanced clinicalstage (ge IIB) most skin-directed therapies are used ascombination strategy or adjuvant support After

andor tapering schedules should beincorporated to optimize response du-ration balancing long-term toxicityand cost issues No studies show thatone particular therapy can positivelyimpact survival in MFSS Thus as ageneral guideline less-toxic therapiessuch as skin-directed therapies or bi-ologics usually yield longer diseasecontrol and less risk to the patientthan more active agents such aschemotherapy which cannot bemaintained because of cumulative sideeffects

Skin-Directed TherapyA list of the most commonly used skin-directed therapies are included in theNCCN guidelines (in this issue toview the most recent version pleasevisit wwwnccnorg)4 If patients havelimited patchplaque (T1) disease top-

Figure 3 Disease-specific survival of 525 patients with mycosis fungoidesSeacutezary syndromeaccording to TNM stage Patients with early-stage disease have excellent disease-specific survivalwith most dying of causes other then mycosis fungoidesSeacutezary syndrome Patients with advanced-stage disease usually die of their lymphoma From Kim YH Liu HL Mraz-GernhardS et al Long-term outcome of 525 patients with mycosis fungoides and Sezary syndromeclinical prognostic risk factors for disease progression Arch Dermatol 2003139857ndash866Copyright copy 2003 American Medical Association All Rights reserved


maximal response maintenance or taper regimen can beinitiated tailored for the patient and specific therapy

Systemic Therapy Category AWhen managing patients with MFSS initial systemictherapies are most commonly mild immunomodulatingagents (biologics) broadly defined as category A Thesetherapies have a slow time to response and generallyprovide partial response rates no greater than 5015ndash17

Their prime advantages are little to no immunosup-pression and lack of cumulative toxicity allowing themto be used to maintain remissions for long periods un-like combination chemotherapies These systemictherapies are most commonly used when skin-directedtherapies do not provide adequate control in patientswith stage IB or IIA disease or as primary therapy (of-ten in combination with skin-directed therapy or otherbiologics) for those with more advanced disease (stageIIBndashIV) No comparative studies guide initial choiceof systemic therapy and many patients are managedwith a combination approach1819 For example patientswho start on bexarotene may frequently have inter-feron added if the response is suboptimal or vice versaExtracorporeal photopheresis is most commonly usedfor patients with SS and frequently in combinationwith interferon or bexarotene or both20ndash22 Choice ofinitial therapy involves factors such as side effectprofile route of administration accessibility and costMost patients will undergo multiple category A thera-pies in sequence or combination before proceeding tomore traditional cytotoxic chemotherapy

Systemic Therapy Category BMany chemotherapeutics show good activity in pa-tients with MFSS Compared with biologics theyhave the advantage of shorter times to response andhigher response rates2324 However frequent immuno-suppression and subsequent toxicity and cumulativetoxicities that prevent a maintenance strategy have rel-egated combination chemotherapy to use only in pa-tients with the most advanced stage or refractorydisease Several single agents such as liposomal doxo-rubicin and gemcitabine2526 have recently been usedas common initial chemotherapeutic choices Theseagents along with older chemotherapies such as chlo-rambucil can be used in low enough doses to minimizethe risks for myelosuppression and can often be con-

tinued for extended periods Patients often move fromone single agent to another before proceeding to com-bination chemotherapies or referral for transplantation

Systemic Therapy OtherAlemtuzumab recently showed activity particularlyin patients with SS The first reports described signif-icant infectious toxicity which appeared to limit itsuse27 More recent reports including those using lowerdoses suggest that alemtuzumab can be used safelyalthough the authors generally reserve this drug forpatients with advanced SS who have experienced pro-gression after biologic therapies2829 Emerging data onallogeneic hematopoietic stem cell transplant(HSCT) particularly using nonmyeloablative condi-tioning suggest the existence of a graftndashversusndashT-celllymphoma effect30 Allogeneic HSCT may be consid-ered for patients with advanced disease (ge stage IIB)whose disease fails to respond to all primary therapyoptions or who do not experience durable responseswith any primary or salvage therapies Long-term re-mission and potential curative outcomes have beenshown in selected patients30 The timing of the allo-geneic HSCT remains controversial because somepatients whose disease progresses rapidly to severely recalcitrant disease become ineligible However earlyexposure of patients to this high-risk procedure is notadvisable Finally all patients whose disease fails torespond to primary treatment options should be con-sidered for clinical trials

ConclusionsPatients with MFSS are increasingly managed byoncologists and therefore how approaches for theselymphomas differ from those of other NHLs is impor-tant to understand Unlike other NHLs which usethe Ann Arbor staging system MFSS uses a TNMstaging that is critical to understand because prog-nosis varies widely according to stage Accordinglytreatment is also staged-based and many patientswith early-stage disease experience lifelong controlwith skin-directed therapies and never require sys-temic therapy Compared with other NHLs unmain-tained remissions are uncommon and milder biologictherapies often in combination are frequently usedchronically These agents are often different thanthose used for other NHLs and several are unique to






Horwitz et al


MFSS Conventional chemotherapies are reservedfor patients whose disease is more advanced andrefractory

References 1 Criscione VD Weinstock MA Incidence of cutaneous T-cell lym-

phoma in the United States 1973ndash2002 Arch Dermatol 2007143854ndash859

2 Willemze R Jaffe ES Burg G et al WHO-EORTC classification forcutaneous lymphomas Blood 20051053768ndash3785

3 Kim YH Liu HL Mraz-Gernhard S et al Long-term outcome of525 patients with mycosis fungoides and Sezary syndrome clinicalprognostic risk factors for disease progression Arch Dermatol2003139857ndash866

4 Zelenetz AD Advani RH Byrd JC et al NCCN Clinical PracticeGuidelines in Oncology Non-Hodgkinrsquos Lymphomas v 12008 Lastaccessed 14 February 2008

5 Olsen E Vonderheid E Pimpinelli N et al Revisions to the stagingand classification of mycosis fungoides and Seacutezary syndrome a pro-posal of the International Society for Cutaneous Lymphomas (ISCL)and the cutaneous lymphoma task force of the European Organizationof Research and Treatment of Cancer (EORTC) Blood 20071101713ndash1722

6 Pimpinelli N Olsen EA Santucci M et al Defining early mycosisfungoides J Am Acad Dermatol 2005531053ndash1063

7 Vonderheid E Bernengo MG The Sezary syndrome hematologic cri-teria Hematol Oncol Clin N Amer 2003171367ndash1389

8 Vonderheid EC Bernengo MG Burg C et al Update on erythro-dermic cutaneous T-cell lymphoma report of the international so-ciety for cutaneous lymphomas J Am Acad Dermatol 20024695ndash106

9 Zackheim HS Amin S Kashani-Sabet M McMillan A Prognosisin cutaneous T-cell lymphoma by skin stage long-term survival in489 patients J Am Acad Dermatol 199940418ndash425

10 van Doorn R Van Haselen CW van Voorst Vader PC et al Mycosisfungoides disease evolution and prognosis of 309 Dutch patientsArch Dermatol 2000136504ndash510

11 Diamandidou E Colome M Fayad L et al Prognostic factor analy-sis in mycosis fungoidesSeacutezary syndrome J Am Acad Dermatol199940914ndash924

12 Vergier B de Muret A Beylot-Barry M et al Transformation of my-cosis fungoides clinicopathological and prognostic features of 45cases French Study Group of Cutaneious Lymphomas Blood2000952212ndash2218

13 van Doorn R Scheffer E Willemze R Follicular mycosis fungoidesa distinct disease entity with or without associated follicular muci-nosis a clinicopathologic and follow-up study of 51 patients ArchDermatol 2002138191ndash198

14 Diamandidou E Colome-Grimmer M Fayad L et al Transformationof mycosis fungoidesSeacutezary syndrome clinical characteristics andprognosis Blood 1998921150ndash1159

15 Olsen EA Kim YH Kuzel TM et al Phase IIb multicenter trial ofvorinostat in patients with persistent progressive or treatment

refractory cutaneous T-cell lymphoma J Clin Oncol 2007253109ndash3115

16 Olsen E Duvic M Frankel A et al Pivotal phase III trial of twodose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma J Clin Oncol 200119376ndash388

17 Duvic M Hymes K Heald P et al Bexarotene is effective and safefor treatment of refractory advanced-stage cutaneous T-cell lym-phoma multinational phase II-III trial results J Clin Oncol 2001192456ndash2471

18 Straus DJ Duvic M Kuzel T et al Results of a phase II trial of oralbexarotene (Targretin) combined with interferon alfa-2b (Intron-A)for patients with cutaneous T-cell lymphoma Cancer 20071091799ndash1803

19 McGinnis KS Junkins-Hopkins JM Crawford G et al Low-doseoral bexarotene in combination with low-dose interferon alfa in thetreatment of cutaneous T-cell lymphoma clinical synergism and possible immunologic mechanisms J Am Acad Dermatol 200450375ndash379

20 Vonderheid EC Bigler RD Greenberg AS et al Extracorporeal pho-topheresis and recombinant interferon alfa 2b in Seacutezary syndromeUse of dual marker labeling to monitor therapeutic response Am JClin Oncol 199417255ndash263

21 McGinnis KS Ubriani R Newton S et al The addition of interferongamma to oral bexarotene therapy with photopheresis for Seacutezarysyndrome Arch Dermatol 20051411176ndash1178

22 Gottlieb SL Wolfe JT Fox FE et al Treatment of cutaneous T-celllymphoma with extracorporeal photopheresis monotherapy and incombination with recombinant interferon alfa a 10-year experienceat a single institution J Am Acad Dermatol 199635946ndash957

23 Kaye FJ Bunn PA Jr Steinberg SM et al A randomized trial com-paring combination electron-beam radiation and chemotherapy withtopical therapy in the initial treatment of mycosis fungoides N EnglJ Med 19893211784ndash1790

24 Bunn PA Jr Fischmann AB Schechter GP et al Combined modalitytherapy with electron-beam irradiation and systemic chemotherapy forcutaneous T-cell lymphomas Cancer Treat Rep 197963713ndash717

25 Wollina U Dummer R Brockmeyer NH et al Multicenter study ofpegylated liposomal doxorubicin in patients with cutaneous T-celllymphoma Cancer 200398993ndash1001

26 Duvic M Talpur R Wen S et al Phase II evaluation of gemcitabinemonotherapy for cutaneous T-cell lymphoma Clin LymphomaMyeloma 2006751ndash58

27 Lundin J Hagberg H Repp R et al Phase 2 study of alemtuzumab(anti-CD52 monoclonal antibody) in patients with advanced myco-sis fungoidesSeacutezary syndrome Blood 20031014267ndash4272

28 Bernengo MG Quaglino P Comessatti A et al Low-dose intermit-tent alemtuzumab in the treatment of Seacutezary syndrome clinical andimmunologic findings in 14 patients Haematologica 200792784ndash794

29 Querfeld C Rosen ST Guitart J et al Alemtuzumab (Campath-1H)in patients with erythrodermic cutaneous t-cell lymphoma (E-CTCL)the Northwestern University experience [abstract] Blood 2006108Abstract 2732

30 Molina A Zain J Arber DA et al Durable clinical cytogeneticand molecular remissions after allogeneic hematopoietic cell trans-plantation for refractory Sezary syndrome and mycosis fungoides J Clin Oncol 2005236163ndash6171





optimal treatment strategy For example patients whohave primary patchplaque disease with limited skintumors are often managed with treatment options usedfor the patchplaque disease combined with localradiation therapy to the tumor lesions Patients mayundergo changes in their primary type of skin involve-ment (eg present with tumor disease but have mostlypatchesplaques after treatment [or visa-versa]) orprogress to extracutaneous involvement thus the man-agement strategy should be modified accordingly

SS is a leukemic form of CTCL in which patientshave significant blood involvement with Seacutezary cellsand diffuse skin erythema (erythroderma) Lym-phadenopathy is a frequent finding in patients withSS and can range from reactive dermatopathicchanges to frank lymphoma on histopathologic ex-amination Additional clinical findings commonlyseen in SS include keratoderma nail dystrophyalopecia ectropion and skin edema (especially inthe legs) These patients often experience intractableitching (pruritus) which can be the most significantlife-altering symptom and therefore treatments thatcan successfully reduce pruritus even without meas-urable objective response may still be a valuable option

MF is suspected in patients who present withyears of refractory or recurrent skin eruption with

a poikilodermatous or polymorphic skin involve-ment in typical distribution SS should be suspectedin patients with unexplained erythroderma associ-ated with atypical lymphocytes in their blood In MFor SS clinicians must rule out drug reactions thatcan mimic the clinical or histologic appearance(lymphomatoid drug eruptions) As specified in theNCCN guidelines on non-Hodgkinrsquos lymphomas(NHL in this issue to view the most recent versionplease visit wwwnccnorg) some diagnostic evalu-ations are considered essential and some useful un-der certain circumstances45 The key element ofdiagnosis is the skin biopsy reviewed by a der-matopathologist However skin biopsies of patientswith erythrodermic skin involvement often do nothave well-established diagnostic features thus as-sessment of other sites of potential involvementsuch as blood or lymph nodes may help confirmthe clinical diagnosis In MF and SS it is importantto know when to obtain ancillary immunohisto-chemical or molecular studies (because of false-pos-itive and -negative cases) and to learn how tointerpret and incorporate the information for opti-mal clinical pathologic diagnosis6 Ancillary testsshould be performed when routine histology is notdiagnostic but a high clinical suspicion of MF or SSexists

Figure 1 Representative photographs of presenting skin lesions in patients with mycosis fungoides All lesions are categorized as patch plaque tumoror erythroderma The type of skin lesions present are important in determining stage and planning therapy



Horwitz et al







T3 Tumors























IA T1 N0 M0 B0-1

IB T2 N0 M0 B0-1

IIA T1-2 N1-2 M0 B0-1

IIB T3 N0-2 M0 B0-1

IIIA T4 N0-2 M0 B0

IIIB T4 N0-2 M0 B1

IVA T1-4 N0-3 M0 B0-2

IVB T1-4 N0-3 M1 B0-2









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Horwitz et al





































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T3 Tumors























IA T1 N0 M0 B0-1

IB T2 N0 M0 B0-1

IIA T1-2 N1-2 M0 B0-1

IIB T3 N0-2 M0 B0-1

IIIA T4 N0-2 M0 B0

IIIB T4 N0-2 M0 B1

IVA T1-4 N0-3 M0 B0-2

IVB T1-4 N0-3 M1 B0-2









Horwitz et al























Horwitz et al













































IA T1 N0 M0 B0-1

IB T2 N0 M0 B0-1

IIA T1-2 N1-2 M0 B0-1

IIB T3 N0-2 M0 B0-1

IIIA T4 N0-2 M0 B0

IIIB T4 N0-2 M0 B1

IVA T1-4 N0-3 M0 B0-2

IVB T1-4 N0-3 M1 B0-2









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Documents

Review of the Treatment of Mycosis Fungoides and Sézary