practical evaluation and management of cutaneous lymphomathose for cd23 and αβ t-cell receptor...

325

From the Department of Dermatology, University of ConnecticutHealth Center.

Reprint requests: Maxwell A. Fung, MD, Department ofDermatology, University of Connecticut Health Center, 263Farmington Ave, Suite 300, Farmington, CT 06030.

Copyright © 2002 by the American Academy of Dermatology, Inc.0190-9622/2002/$35.00 + 0 16/2/121355doi:10.1067/mjd.2002.121355

P erhaps more often than with any other skindisease, establishing or excluding a de novodiagnosis of cutaneous lymphoma is compli-cated or difficult, or both. A comprehensive, multi-disciplinary evaluation is often facilitated by referralto a tertiary care center.1

Scientifically, although our tools for evaluatinglymphoid infiltrates have never been more sophisti-cated, numerous, or available, none is perfect, andno single attribute mandates a specific diagnosiswithout incorporating all available clinical, patholog-ic, immunohistochemical, and cytogenetic findings.Even after all available data have been obtained,definitive, specific, and prognostically or therapeuti-cally relevant diagnoses may remain elusive. Reasonsfor uncertainty may include the inability to excludeconcomitant or impending systemic lymphoma,inability to definitively distinguish low-grade lym-phomas from reactive infiltrates, and/or lack of expe-rience because of the rarity of some lymphomas.

Underlying and complicating these issues is theconstantly expanding knowledge in the field and thevarying and conflicting opinions about how to inter-pret new data, which result in constantly evolvingclassification systems. Eponyms, acronyms, andabbreviations abound, and terms employed by dif-ferent classification systems are similar but slightlydifferent, adding to the confusion. In an effort tominimize confusion, a glossary defining commonlyused terms is included in the Appendix.

This article reviews the evaluation and manage-ment of cutaneous lymphoid infiltrates, focusing oncutaneous lymphoma.

HISTORY AND PHYSICAL EXAMINATIONWith the exception of early mycosis fungoides

(MF), most cutaneous lymphomas and pseudolym-phomas manifest as smooth, tumid, erythematous orviolaceous papules, nodules, or plaques and are thusrelatively nonspecific in appearance like other der-mal or subcutaneous infiltrates. However, solitary orgrouped lesions, particularly above the waist, oftenindicate primary cutaneous lymphoma or pseudo-lymphoma. In contrast, widespread lesions oftenindicate preexisting or concomitant systemic lym-phoma (secondary cutaneous lymphoma). Somelymphoproliferative disorders have distinctive clini-cal features. For example, adult T-cell leukemia/lym-

CONTINUING MEDICAL EDUCATION

Practical evaluation and management ofcutaneous lymphoma

Maxwell A. Fung, MD, Michael J. Murphy, MD, Diane M. Hoss, MD, and Jane M. Grant-Kels, MDFarmington, Connecticut

Accurate evaluation of patients with suspected or known cutaneous lymphoma requires the integration ofmany sources and types of information, including clinical evaluation, microscopic analysis of tissue,immunophenotyping, gene rearrangement studies, clinical staging, and longitudinal observation.Diagnoses should be based on knowledge of specific lymphoma types as described in modern classificationsystems. Management of patients with cutaneous lymphoma requires collaboration among dermatologists,dermatopathologists, hematopathologists, and medical, surgical and radiation oncologists. (J Am AcadDermatol 2002;46:325-57.)

Learning objective: At the conclusion of this learning activity, participants should better understand howto evaluate and manage patients for suspected or established lymphoma of the skin. Components includethe clinical history and physical examination, optimal biopsy and tissue handling, interpretation ofpathology and adjunctive test results, clinicopathologic correlation, and therapy. Participants should alsounderstand the basis for establishing a specific diagnosis of cutaneous lymphoma based on currentclassification and staging.

in large numbers, have characteristic tendencies inrelation to appearance, location, or age at onset andare detailed later in this article (Table I).Lymphoproliferative disorders associated withimmunosuppression such as AIDS or the posttrans-plantation setting also represent a unique butdiverse subset.

THE INITIAL BIOPSYFor the evaluation of cutaneous lymphoma or

pseudolymphoma characterized by dermal papules,nodules, or plaques, the ideal specimen is from anexcisional or incisional biopsy and includes subcutisand is part formalin-fixed and, if possible, partfresh/frozen. (Specimens must be handled gentlysince lymphoid infiltrates are particularly susceptibleto crush artifact.) Gene rearrangement analysis(GRA) and an ever-increasing number of immuno-phenotypic studies can be performed on formalin-fixed tissue, but there remain important markersthat are best studied in fresh-frozen tissue, such asthose for CD23 and αβ T-cell receptor (TCR) or γδTCR expression. In practice, an initial biopsy speci-men will confirm the lymphoid nature of a lesion,and the patient may need a second biopsy, some orall of which may be preserved frozen.

Having stated that, distinguishing early MF frominflammatory disorders is the most common lym-phoma setting encountered by dermatologists, andan alternative sampling technique is acceptable.Since the diagnostic features in early MF are superfi-cial, often focal, often subtle, and thus often nondi-agnostic, obtaining a long, approximately 1 cm (butnot necessarily wide) shave biopsy specimen, sec-tioned longitudinally, often makes histologic analysiseasier and may improve diagnostic precision, whichwould avoid repeat biopsy. The tissue can be placedflat onto a piece of paper to prevent curling duringformalin fixation. Obtaining fresh-frozen tissue forearly MF remains the routine at some academic med-ical centers but is generally not a necessary compo-nent of the initial biopsy.

LIGHT MICROSCOPYMicroscopic assessment of formalin-fixed, hema-

toxylin-eosin–stained tissue sections is a requisitefirst step in the evaluation of suspected cutaneouslymphoproliferative disorders. Based on the growthpattern and cytologic features, most neoplasms canbe classified as lymphoid or nonlymphoid andbenign or malignant. However, distinguishing nodu-lar T- or B-cell pseudolymphoma from lymphomascontaining small or medium-sized cells, such as mar-ginal zone lymphoma (MZL), is often not possiblewithout further studies.

phoma (ATL) should be suspected in patients fromcharacteristic geographic locations who present withrapidly progressive skin lesions and systemic symp-toms, including hypercalcemia. The skin lesions inpatch- or plaque-stage MF frequently present withdiagnostic clinical morphology and distribution.Chronically recurring, randomly scattered papulesthat spontaneously involute and histologicallyresemble MF, large T-cell lymphoma, or Hodgkin’sdisease (HD) are diagnostic of lymphomatoid papu-losis (LyP). In fact, most lymphomas, when studied

326 Fung et al J AM ACAD DERMATOLMARCH 2002

Abbreviations used:

AILD: angioimmunoblastic lymphadenopathy with dysproteinemia

ALL: acute lymphoblastic leukemiaATL: adult T-cell leukemia/lymphomaBCL: B-cell lymphomaB-LBL: B-lymphoblastic lymphomaCBCL: cutaneous B-cell lymphomaCLL: chronic lymphocytic leukemiaCTCL: cutaneous T-cell lymphomaEBV: Epstein-Barr virusEMA: epithelial membrane antigenEORTC: European Organization for Research and

Treatment of CancerFCCL: follicle center cell lymphomaFCL: follicle center lymphomaFDA: Food and Drug AdministrationFL: follicular lymphomaGRA: gene rearrangement analysisHD: Hodgkin’s diseaseHTLV-I: human T-lymphotropic virus type 1IFN: interferonIL: interleukinLBCL: large B-cell lymphomaLBL: lymphoblastic lymphomaLL: Lennert’s lymphomaLyP: lymphomatoid papulosisMALT: mucosa-associated lymphoid tissueMCL: mantle cell lymphomaMF: mycosis fungoidesMZL: marginal zone lymphomaNK: natural killer (cell)PCR: polymerase chain reactionPTL: pleomorphic T-cell lymphomaREAL: Revised European-American Lymphoma

(classification)SLL: small lymphocytic lymphomaSPTL: subcutaneous panniculitis–like T-cell

lymphomaSS: Sézary syndromeTCR: T-cell receptorT-LBL: T-lymphoblastic lymphomaTSEB: total skin electron beam (therapy)WHO: World Health Organization

Patch- or plaque-stage lesions of MF are usuallydiagnosed on the basis of light microscopic featuresand clinical correlation. Histologic criteria for the diag-nosis of MF are especially important because, unlikemost lymphomas, attempts to strengthen a diagnosisof early MF using immunohistochemistry are fre-quently inconclusive. In addition, very early MF resem-bles inflammatory dermatoses. Thus pathologists, der-matologists, and dermatopathologists are at risk forovercalling or undercalling this diagnosis or else can-not render a diagnosis with confidence. In fact, studiesdocument interobserver and intraobserver variabilityin the diagnosis of early MF even among experts.2-6

IMMUNOPHENOTYPINGAll suspected cutaneous lymphomas should be

evaluated by immunohistochemical studies, com-monly referred to as “B and T cell markers” (Tables IIand III). Immunohistochemical studies are essential

for distinguishing B, T, natural killer (NK), and non-lymphoid cells, identifying subsets of these cellsbased on their immunophenotype (eg, CD3+/CD4+ Thelper cells [TH] or CD3+/CD8+ T cytotoxic/suppres-sor [TC] cells), and inferring clonality among B cellsthat manufacture immunoglobulin as evidenced by κor λ light-chain restriction. Most reactive, polyclonalinfiltrates express a κ/λ ratio of approximately 2:1.Ratios greater than 5-10:1 (κ restriction) or less than0.5-1:1 (λ restriction) indicate clonality. Flow cytome-try studies using fluorescence-activated cell sorteranalysis accomplish essentially the same task,although without benefit of correlating the micro-scopic findings with the immunophenotype. Flowcytometric analysis may provide more objective,quantitative immunophenotyping, but skin speci-mens are often smaller and not as purely lymphoid astissue obtained from lymph nodes or bone marrowand are often not amenable to analysis by flow cytom-

Fung et al 327J AM ACAD DERMATOLVOLUME 46, NUMBER 3

Table I. Clinical features of cutaneous lymphomas

SpontaneousMorphology regression? Typical distribution Other features

MF Patches, P, N, E Occasionally Patches: bathing trunk Many clinical variantsSS E Generalized Keratoderma, lymphadenopathyLarge T-cell P, N, ulcer Occasionally Trunk or extremity Primary: adults; secondary:

lymphoma children, adultsAngiocentric N, ulcer, hydroa-like Extremities Found in Asia, Central/South

lymphoma America more often than in North America or Europe;hemophagocytosis

SPTL P, N Extremities Indolent or aggressive with hemophagocytosis

ATL P, N Random HOTSAILD P, N, maculopapular, Occasionally Maculopapular: trunk; B symptoms, adenopathy

purpura acral petechiaePTL P, N Random AdultsLL P, N Random AdultsLyP N, ulcer/papulonecrotic Always Random —MZL P, N Primary: extremity —FL P, N Primary: head/neck —LBCL P, N Random; leg —CLL P, N, leonine facies, vesi- — Random; sites of old —

culobullous HSV/VZV lesionsPlasmacytoma P, N — Random Secondary: bone pain,

paraproteins, amyloidosis,renal failure

MCL P, N, vegetating surface — Random —LBL N — Random Children or adultsHD P, N — Extremity distal to involved B symptoms

lymph nodeIntravascular Purpura, patches, P — Trunk, extremity Neurologic symptoms

lymphoma

E, Erythroderma; HOTS, hypercalcemia, osteolytic bone lesions, T-cell leukemia, splenomegaly; HSV/VZV, herpes simplex virus/varicella zostervirus; N, papules/nodules; P, plaques; for all other abbreviations, see abbreviations box at beginning of article.

rearranged in a manner characteristic for each singlelymphocyte (ie, immunoglobulin genes in B cellsand TCR genes in T cells).7 Because clonal prolifera-tion originating from a single lymphocyte is a con-stant feature of malignancy, populations of neoplas-tic lymphocytes contain the same “signature” gene

etry. Fluorescence-activated cell sorter analysis ofperipheral blood samples is effective.

GENE REARRANGEMENT ANALYSISAs lymphocytes differentiate into B and T cells

from undifferentiated thymocytes, certain genes are


Table II. Immunogenetic features in T- and NK-cell lymphomas

CD2 CD3 CD4 CD5 CD7 CD8 CD30 CD45RO CD56

MF Patch + + + > – + +/– – > + – + –Plaque + + + > – + +/– – > + – + –Tumor +/– +/– + > – +/– – > + – > + – > + +/– –Erythrodermic + + + > – + – > + – > + – + –Follicular mucinosis + + + > – + + – > + – + –Pagetoid reticulosis + +/– + +/– +/– +/– +/– –Granulomatous slack skin + + – > + – – –

SS + + + +/– – – + –Large T-cell CD30– +/– +/– + +/– – – –

lymphomaCD30+ +/– +/– + > – +/– – +

LyP Types A, C +/– + + > – +/– – + –Type B + + – – –

Angiocentric + +/– +/– +/– +/– +/– +/–lymphoma

SPTL + +/– +/– +/– +/– – > +ATL + + + > – + – – > + –AILD + + –PTL +/– + > – + > – + > – – – > + – > + – > +T-LBL + > – + +/– +/– + +/– + –

CLL +/– + + > – +/– + – > + –

+, Positive; –, negative; ALK, anaplastic lymphoma kinase; TdT, terminal deoxynucleotidyl transferase; for all other abbreviations see the abbre-viations box at beginning of article.

Table III. Immunogenetic features in CBCL and HD

CD5 CD10 CD19 CD20 CD21 CD23 CD30 CD43 CD79a

MZL – – > + + + > – – > + +/– +Immunocytoma – – + + > – – +/–FL/FCCL – – + + – > + – +LBCL – > + – > + + + – +CLL/SLL + (f ), +/–(p) – + + + + +Plasmacytoma – – +/– +/– +/–MCL + – + + + – +B-LBL – + + – > + +HD Lymphocyte- + + +/– +

predominantNodular sclerosing – – + –Mixed cellularity – > + – > + + – > +Lymphocyte- – – + –

depletedIntravascular lymphoma + + +

f, Frozen tissue; p, paraffin-embedded, formalin-fixed tissue; for all other abbreviations, see abbreviations box at beginning of article.

rearrangement, whereas most populations of reac-tive lymphocytes contain a mixture of generearrangements. This difference can be detectedusing GRA of DNA extracted from a tissue specimen.NK cells are not antigen-specific and do not undergoa known characteristic gene rearrangement.

The Southern blot technique requires DNAextracted from fresh-frozen tissue and has a sensitiv-ity range of 1% to 5%, meaning that a clonal popula-tion comprising as little as 1% to 5% of the cells inthe specimen can be identified. This level of sensi-tivity is usually sufficient for analysis of peripheralblood, lymph nodes, and dense lymphoid infiltratesin other tissues including skin. The technique canalso be used to identify integration of viral genomes,such as HTLV-I in the neoplastic lymphocytes of ATL.Drawbacks of the Southern blot technique includethe requirement for fresh tissue and the inability toreliably detect gene rearrangements in sparse infil-trates below the sensitivity of the technique.

The techniques of polymerase chain reaction(PCR) employ nucleotide primers to locate and ampli-fy specific DNA segments from tissue and have a sen-sitivity range of 0.001% to 1%, up to 1000 times moresensitive than Southern blot. A second advantage ofPCR is the ability to utilize DNA extracted fromunstained sections of archived, formalin-fixed tissue.Fresh-frozen tissue also works but is not necessarilybetter. PCR-based methods have become the stand-ard for evaluating cutaneous lymphoid infiltrates.8

As with immunophenotyping, results of GRA byeither method should always be interpreted in theclinical context. False-negative and false-positiveresults may occur depending on several factorsincluding sample size, sample characteristics, sam-pling error, and other technical factors or limitations.For example, PCR-GRA requires the use of multipleprimers that recognize critical segments of therearranged TCR β- or γ-chain genes or the rearrangedheavy and light chains of immunoglobulin genes.Unfortunately, even the most comprehensive sets ofavailable primers are not complete and thus cannotdetect all possible rearrangements. Furthermore,rearranged genes may be deleted or undergo somaticmutation (resulting in suboptimal primer binding).Despite the fact that most T cells and T-cell lym-phomas express TCR α/β, TCR γ-chain genes containfewer variable (V) and junctional (J) gene segmentsand are rearranged earlier (and more frequently) in T-cell lymphomas than TCR β genes. Therefore GRA forrearranged TCR γ-chain genes is currently the sim-plest and best single study. PCR-GRA can be used tomonitor the response of CTCL to therapy and detectminimal residual disease. Clinical responses are cor-related with the presence or absence of the malignantclone in the skin or blood. Like immunohistochem-istry, protocols for PCR are variable and optimized inthe laboratories that perform them.

Critically important is the recognition thatalthough clonality is a hallmark of malignancy, not allclonal proliferations are malignant. Examples of clin-


Lesional GRA Other

+/–+++ Sézary cell count +/–++++ Sézary cell count ++

+ ALK +/–, t(2;5)+ > – CD15–/EMA–

+ > –+ (T-cell), – (NK-cell) EBV+ if CD56+

+/–+ HTLV-I, CD25+ blood++ > –+/– TdT+; CD4+CD8+ or CD4–CD8–;

usually B cell in skin + Usually B cell

cIg sIg Lesional GRA Other

+/– +/– + Trisomy 3+ +/– +– + +

+/– +/– +– > + + + Trisomy 12, bcl-1+

+ – + CD45–, EMA+/–

– + + bcl-1+

+/– – +/– TdT+

– – – CD15–

– > + CD15+

– CD15+

– CD15+

+ +

have not been formally established, but a baselinework-up should include complete physical examina-tion with attention to lymphadenopathy and hepato-splenomegaly, and, with the possible exception ofearly (stage I) MF, peripheral blood analysis (com-plete blood cell count with manual differential, Sézarycell count, flow cytometry, and/or GRA), and comput-ed tomographic scanning of the chest, abdomen, andpelvis. Bone marrow involvement in MF is uncom-mon except in advanced disease. However, patientswith CTCL expressing a cytotoxic phenotype (CD8,TIA-1, granzyme), TCR γδ, all NK, and all B-cell lym-phomas should be considered for bone marrow biop-sy. The potential role of sentinel lymph nodectomy incutaneous large B-cell lymphomas (LBCLs) confinedto the extremities has been reported.13 In all forms ofcutaneous lymphoma, even after complete remissionhas been achieved, indefinite follow-up is indicated.

The TNMB (tumor, node, metastasis, blood) clas-sification system (Table IV) defines the clinical stagein CTCL (Table V). Since chronic patches andplaques of CTCL are generally assumed to representprimary CTCL, namely MF, patients are often classi-fied as having T1 (stage Ia), T2 (stage Ib), T3(tumors, stage IIb) or T4 (erythroderma, stage III)disease. The determination of whether lesions rep-resent patches or plaques should include both clini-cal and histopathologic criteria.

In cutaneous B-cell lymphoma (CBCL), involve-ment is considered either primary cutaneous or sec-ondary to spread from an extracutaneous site suchas a lymph node– or mucosa-associated lymphoidtissue (MALT). The term secondary cutaneous lym-phoma is less commonly used to designate transfor-mation of low-grade cutaneous lymphoma into high-grade lymphoma but, to avoid confusion, has notbeen encouraged.14

CLASSIFICATIONModern lymphoma classifications attempt to rec-

ognize discrete clinicopathologic entities based onboth clinical features and identification of the neo-plastic cell type based on resemblance to its postu-

ically benign diseases that sometimes demonstrateclonal TCR gene rearrangement include LyP, lichenplanus, pityriasis lichenoides, pigmented purpura,and lichen sclerosus.9 The term clonal dermatitishas been suggested for histologically benign der-matoses that demonstrate clonal bands. These der-matoses may be the precursors of CTCL or mayalready be CTCL, without diagnostic histologic find-ings.10 This raises the important issue of the balancebetween the sensitivity and specificity of PCR assaysin the differential diagnosis of benign cutaneous lym-phoid infiltrates and cutaneous lymphoma. The esti-mated maximal T-cell clonal density in “true” inflam-matory lesions such as allergic contact dermatitis is0.1%.11 Therefore the optimal diagnostically relevantsensitivity may be less than the maximal sensitivity ofPCR-based assays, in the range of 0.1% to 1.0%.

STAGINGWith respect to cutaneous lymphoma, it is critical

to recognize whether the lymphoma is a primary cuta-neous lymphoma or has arisen in association with anodal or extranodal systemic lymphoma (secondarycutaneous). The prognosis is invariably worse in sec-ondary compared with primary cutaneous lymphoma,irrespective of the histologic diagnosis. The earlystages of MF are generally assumed to be primarycutaneous. The European Organization for Researchand Treatment of Cancer (EORTC) has proposed aworking definition requiring a negative systemic eval-uation at baseline and at 6 months before establishinga diagnosis of primary cutaneous lymphoma.12

Explicit guidelines for the evaluation and longitudinalmanagement of patients with cutaneous lymphoma


Table IV. TNMB classification system for CTCL155,245

T T0 Nondiagnostic (eg,“parapsoriasis”)T1 Limited patch/plaque (

lated physiologic counterpart. Other designationssuch as angiocentric, subcutaneous panniculitis-like,or intravascular lymphoma are defined by theirgrowth pattern and may have variable immuno-genetic features. These may require further reclassi-fication in the future.

Several lymphoma classifications have been pro-posed, and more revisions are on the way. Earlierefforts such as the Kiel, Rappaport, and Lukes andCollins classifications were based on morphologicfeatures of systemic lymphomas and did not accountfor clinical features, immunophenotypic and cytoge-netic characteristics, or particular aspects of cuta-neous lymphomas. The 1994 Revised European-American Lymphoma (REAL) classification of theInternational Lymphoma Study Group was the firstto incorporate clinical, histologic, immunopheno-typic, and molecular genetic information.15 Themost recent classification of the World HealthOrganization (WHO) follows the same principles andis the most current and comprehensive classifica-

tion.16 Developing in parallel, however, was theincreasing recognition that primary cutaneous lym-phomas invariably carry a better prognosis com-pared with systemic lymphomas that are otherwisehistologically and immunophenotypically identical.This concept is highlighted in the 1997 PrimaryCutaneous Lymphoma classification of the EORTC,12

which does not address lymphomas that presentwith secondary cutaneous lesions and was not basedon an international consensus group, but representsthe most comprehensive classification devoted tocutaneous lymphoma. The following discussionincludes most cutaneous lymphomas, primary orsecondary, included in the EORTC, REAL, and/orWHO classifications.17

CUTANEOUS T-CELL LYMPHOMAS:CHARACTERISTICSMycosis fungoides (Fig 1)

MF is classified as an indolent lymphoma by theEORTC. The postulated normal counterpart is the


Fig 1. MF. A-C, Patches and plaques of MF. D, Follicular mucinosis in patient with MF. E, Hypopigmented variant of gen-eralized patch-stage (T2) MF. F, Tumors of MF arising in association with patches and plaques. G, Ulcerative plaques.H, Epidermotropism is characteristic in patches, plaques, and erythroderma. I, Pautrier’s microabscesses. This patient waserythrodermic.

A B C

D E F

G H I

ly scattered at all levels of the epidermis, and usuallyassociated with spongiosis),34 necrotic kera-tinocytes, vacuolar alteration,35 psoriasiform epider-mal hyperplasia, papillary dermal fibrosis, dermaleosinophils and plasma cells, orthokeratosis, focalparakeratosis, and atrophy/effacement of rete ridgeswith dermal melanophages typical of poikiloderma-tous MF. Skin biopsy specimens may prove nondiag-nostic, and longitudinal observation and repeatbiopsy may be required to establish a definitive diag-nosis. Rather than relying on any single criterion, thehistologic diagnosis depends on integrating a con-stellation of parameters.36 Plaques of MF, in contrast,are usually diagnostic, exhibiting all of the findings ofpatches, and more, including (1) deeper and denserdermal infiltrates, producing a lichenoid pattern atscanning magnification, often with perivascular ordiffuse infiltrates in the reticular dermis; (2) cytolog-ically atypical intraepidermal lymphocytes; (3) easilyfound Pautrier’s microabscesses; and (4) moreprominent psoriasiform hyperplasia and papillarydermal fibrosis. Follicular mucinosis may be seen,characterized by folliculotropism and often numer-ous eosinophils and plasma cells. In the granuloma-tous variant, nodular, palisaded, or interstitial granu-lomatous infiltrates may obscure the neoplasticnature of MF. Except for the presence of overlyingepidermotropism, the lesions may resemble those ofLennert’s (lymphoepithelioid) lymphoma (LL), a sys-temic T-cell lymphoma that involves skin in only 10%of cases.

Other notable histologic features that may beseen in MF include spongiotic vesiculation, dermalmucin, predominantly dermal infiltrates (usuallyassociated with concurrent therapy), adnexotropic(eccrine gland and hair follicle) infiltrates,37

syringolymphoid hyperplasia, verrucous hyper-keratosis, pustules, subepidermal or intraepidermalbullae, angiocentricity, acanthosis nigricans–like epi-dermal hyperplasia, or superimposed lichen simplexchronicus.28 Atypical changes reminiscent of thoseassociated with systemic chemotherapy, includingatypical keratinocytes, vacuolar interface dermatitis,plump atypical endothelial cells, and atypical fibro-blasts have been reported in patients being treatedwith topical nitrogen mustard.38 Tumors containnodular or diffuse proliferations of small, medium-sized, and sometimes large atypical lymphocytes.Large lymphocytes in small nodules or comprisingmore than 25% of the total infiltrate indicates trans-formation, characteristically a sign of poor progno-sis. Transformation is a common feature in tumors ofMF.39 Epidermotropism is frequently diminished, sothe differential diagnosis may initially include CBCL.Erythrodermic MF may be histologically indistin-

recirculating epidermotropic CD4+ T cell. The prog-nosis for patch-stage or limited plaques, whichincludes most cases, is similar to that for normal age-matched control subjects.18-20 In contrast, 5-year sur-vival for tumor and erythrodermic stages decreasesto approximately 40%.21 Like most other lym-phomas, the cause is unknown; however, HTLV-Imay play a role in some cases.22 This theory is con-troversial.23 Patients with industrial occupationshave been reported to have a relatively higher risk ofacquiring MF as well as decreased survival,24

although modifiable risk factors were not identifiedin the largest case control study to date.25

Classically, MF is typified by the gradual progres-sion from patches (flat, scaly, various shades of red,variably pruritic) and plaques (indurated, oftenannular with central clearing), mostly on photopro-tected sites, to tumors. However, most patients withpatches or plaques never have disease progressionto tumor or erythrodermic stages, in contrast toAlibert’s original description of the disease in 1846.Erythroderma may intervene at any time, and its dis-tinction from Sézary syndrome (SS) depends on thefindings in peripheral blood and other clinical fea-tures (see the section on SS). In fact, MF may pre-sent at any stage and unusual clinical and histopatho-logic variants often coexist with typical patches orplaques. Clinical variants include pagetoid reticulo-sis, follicular mucinosis with or without alopecia(alopecia mucinosis), hypopigmented MF, and gran-ulomatous slack skin. Rarely, pityriasis lichenoides–like,26 verrucous, purpuric,27 pustular, or bullouslesions have been described.28 Leukoderma (depig-mentation) is uncommonly associated with erythro-derma.29 The common denominator among all vari-ants is the presence of diagnostic histologic findings.

Microscopically, patch-stage MF exhibits a sparsepapillary dermal lymphocytic infiltrate with epider-motropism, in which small to medium-sized lym-phocytes aggregate usually within the lower half ofthe epidermis near the basal layer. Compared withspongiotic (eczematous) dermatitis, associatedspongiosis is usually absent or disproportionatelyminimal. Hyperchromatic, convoluted, or cerebri-form nuclei may not be apparent, though there maybe conspicuous halos caused by retraction artifactsurrounding intraepidermal lymphocytes, and thoselymphocytes may have slightly larger nuclei, on aver-age, than those in the dermis. Atypical lymphocytes,either in collections (Pautrier’s microabscesses) orsingly within the epidermis, are probably the mostspecific finding in early MF but are infrequently pres-ent in the earliest patches.30-33 Variable findingsinclude presence of exocytosis (defined here as thepresence of lymphocytes in the epidermis, random-


guishable from patch-stage MF. Unfortunately, thecritical features are often even more subtle, so non-diagnostic biopsies are more common.40 Pagetoidreticulosis exhibits prominent epidermotropismwith clustered medium-sized and large atypical lym-phocytes with hyperchromatic cerebriform nuclei,clear pericellular halos, and abundant vacuolatedcytoplasm in pagetoid array within an acanthotic epi-dermis. The pendulous lesions in granulomatousslack skin show a marked expansion of the reticulardermis containing small atypical lymphocytes andcharacteristic multinucleated histiocytes that oftencontain numerous nuclei, often in a wreath-likearray, and some with lymphophagocytosis. There iselastophagocytosis and a marked decrease in dermalelastic tissue. Early lesions are similar to classicpatch-stage MF. MF cells variably express T-cell mark-ers (CD2, CD3, CD5, CD7, Leu-8, CD45RO), the hall-mark being the T helper/inducer subset marker,CD4. Rare cases are CD4–/CD8+ (cytotoxic/suppres-sor subset) and may correlate with a more aggressiveclinical phenotype.41-43 The T cells in many cases ofpagetoid reticulosis express a cytotoxic/suppressorphenotype, suggesting that at least some examplesmay represent a distinct subset of CTCL.44-48

Deletion of CD7 (Leu-9) or Leu-8 is present inapproximately 50% to 75% of cases, usually tumors,but these deletions are also present in more than40% of nonlymphoma controls.49 However, CD7deletion becomes more specific for MF if a lowerpercentage of positive cells is used as the cutoff.50-52

CD25 (interleukin 2 [IL-2] receptor) is expressed ina minority of cases. Rarely, intraepidermal lympho-cytes may express CD30.53 Clonal rearrangement ofTCR genes can be demonstrated in lesional tissue inmost cases, including pagetoid reticulosis, follicularmucinosis, and granulomatous slack skin, and atleast 50% of patch-stage lesions by PCR-based meth-ods.54 Mutations of the p16INK4a tumor suppressorgene have been detected in MF.55 Flow cytometrymay detect aneuploidy in a minority of early cases.56

Although more common in adults, the occur-rence of MF in children is well documented.57-61

Children and adults younger than 35 years tend topresent with early-stage disease, with no apparentdifference in prognosis.60

Sézary syndromeSS is classified by the EORTC as an aggressive lym-

phoma. Some consider SS to be a variant within thespectrum of MF, but the estimated 5-year survivalrate in SS is 11%.12 The historical SS triad includeserythroderma, lymphadenopathy, and cerebriformlymphocytes (Sézary cells) in the peripheral blood,lymph nodes, and skin. Today, peripheral blood and

lesional immunophenotyping and gene rearrange-ment studies supplement and, in some institutions,replace the more variable and subjective Sézary cellcount. Thus, in the appropriate clinical context, evi-dence supporting a diagnosis of SS includes Sézarycells comprising more than 5% to 20% of circulatinglymphocytes or more than 1000/mm3, an expandedpopulation of CD4+/CD7– circulating lymphocytesby flow cytometry,62 an elevated CD4/CD8 ratio,63 ora clonal TCR gene rearrangement. As in MF, the pos-tulated normal counterpart is the recirculating epi-dermotropic CD4+ T cell. Pruritus, erythroderma,keratoderma, alopecia, lymphadenopathy, andsplenomegaly characterize SS. Patients with SS mayalso have patches, plaques, and tumors, which areclinically and histologically indistinguishable fromthose in MF. Histologicaly, SS is indistinguishablefrom patch-stage and erythrodermic MF, althoughthe histologic features are often extremely subtle. SSmay also be associated with lymphopenia that maycorrelate with an increased incidence of secondarymalignancy including squamous cell carcinoma ofthe skin or oral mucosa, or HD.64,65

Large T-cell lymphoma, CD30+/CD30–

Termed anaplastic large-cell lymphoma in theREAL classification, EORTC dropped the “anaplastic”from these histologically distinctive lymphomasbecause not every such tumor histologically exhibitsanaplastic cells.66 Other designations include large-cell anaplastic lymphoma and regressing atypical his-tiocytosis.67 The postulated normal counterpart is aCD30+ (or CD30–) extrafollicular blast. CD30+ largeT-cell lymphoma may be the most common form ofnon-MF primary CTCL,68 although in one recentseries, pleomorphic T-cell lymphoma (PTL) slightlyoutnumbered anaplastic large-cell lymphoma.69

CD30– lymphomas with similar histologic featuresappear to have an entirely different natural history.Thus a critical distinction is whether the large cellslabel with CD30 (Ki-1), since primary cutaneousCD30+ large-cell lymphomas are relatively indolentneoplasms with estimated 5-year survival of up to90%, whereas otherwise indistinguishable primarycutaneous CD30– lymphomas are aggressive neo-plasms, with an abysmal 15% 5-year survival in thesame registry.12 One report suggests that promptinduction of clinical remission may not affect thisprognosis.70 Primary cutaneous examples usuallyappear as a solitary or localized nodule (Fig 2), oftenulcerating, usually on the extremity71 or trunk of anadult. Up to 25% of these patients may experiencecomplete or partial spontaneous regression. The dif-ferential diagnosis may include pyoderma gangreno-sum.72 Primary cutaneous CD30+ lesions occur in


and cutaneous lymphocyte antigen is positive in pri-mary cutaneous examples. Clonal TCR generearrangements are present. Benign, self-limitederuptions containing predominantly large CD30+

large atypical cells have also been described in asso-ciation with chemotherapy for non–T-cell hema-tolymphoid malignancies. These eruptions haveexhibited a superficial perivascular pattern of infil-trate, but clinical correlation and follow-up areessential.80

Lymphomatoid papulosisLyP is included in most discussions of CTCL

because of its associations with and histologicresemblance to lymphoma, and it is positioned atthe benign end of a spectrum of CD30+ lymphopro-liferative disorders with CD30+ large T-cell lym-phoma.81 It is classified as an indolent form of CTCLby EORTC and survival approximates 100%. Rarecases that have been diagnosed histologically as pri-mary cutaneous HD, pseudo-HD, or lymphomatoidpityriasis lichenoides could be classified as LyP.82,83

“Rhythmic paradoxical eruptions” are also unitedunder this heading.84 Clinically, LyP is characterizedby randomly scattered, occasionally pruritic papulesand nodules, often crusted or necrotic, in variousstages of evolution, which spontaneously regressusually within 1 to 2 months, leaving scars and dys-pigmentation. The condition runs a chronic courselasting months to decades, mostly frequently involv-ing the trunk, buttock, and extremities. In approxi-mately 25% of cases diagnosed in referral centers,LyP is associated with MF/SS.69 Most cases of MF pre-cede the diagnosis of LyP, but associations may alsooccur concurrently or subsequently.85 CD30+ largeT-cell lymphoma, HD, and other lymphomas havealso been associated with LyP.86 LyP may occur at anyage but most commonly arises in the fourth or fifthdecade of life.71,86 Three histologic subtypes areunited under the clinical phenotype of LyP. Type Alesions exhibit a dense wedge-shaped mixed inflam-matory infiltrate with neutrophils, eosinophils, histio-cytes, small lymphocytes, frequent mitotic figures,and clustered or scattered large atypical cells resem-bling the anaplastic cells of large T-cell lymphoma orReed-Sternberg cells. Eosinophilic histiocytosis mayrepresent a variant of type A LyP.87 Occasionally,there is associated vasculitis with atypical mononu-clear cells in venules or increased dermal mucindeposition. Overlying atypical epithelial prolifera-tions have been reported as pseudocarcinomatoushyperplasia88 or keratoacanthoma.89 Early and wan-ing type A lesions may have few large atypical cells.90

The differential diagnosis may include pityriasislichenoides or an arthropod bite reaction. Type B

adults but are rare in children,73 whereas systemicCD30+ lymphomas occur bimodally in children andadults. Expression of anaplastic lymphoma kinase isassociated with a t(2;5) translocation and is a favor-able prognostic factor in systemic CD30+ large T-celllymphomas that may involve the skin. Anaplasticlymphoma kinase expression is rare in LyP and pri-mary cutaneous large T- or NK cell lymphoma.74-76 Inlarge T-cell lymphomas (CD30+ or CD30–), there isusually a diffuse, nonepidermotropic, sheetlike pat-tern of growth, often with overlying ulceration, epi-dermal hyperplasia, and neutrophilic infiltrates.Many of the large cells possess anaplastic nuclear fea-tures, consisting of large, irregularly and variablyshaped hyperchromatic or vesicular nuclei with oneor more prominent eosinophilic nucleoli (reminis-cent of those seen in the Reed-Sternberg cell of HD)and abundant slightly basophilic cytoplasm.Anaplastic cells often have kidney-shaped, horse-shoe-shaped, U-shaped, or embryo-shaped nucleiand may be multinucleate (termed “donut cells”when in wreath-like array). Anaplastic cells are usual-ly larger than immunoblasts or centroblasts, whichthemselves are classified as large and are typicallypresent. Overall, large cells comprise at least 30% ofthe cellular infiltrate with at least 75% of large cellsreactive for CD30+ in a membranous and paranu-clear pattern. There is sometimes an admixture ofsmall lymphocytes, histiocytes, neutrophils, andeosinophils, creating a resemblance to LyP. RareCD30/CD56 coexpression has been reported andmay correlate with aggressive biologic behavior.77,78

However, expression of a TIA-1+/granzyme B+ cyto-toxic phenotype is relatively common and does notappear to correlate with aggressive behavior.79 Incontrast to systemic lymphomas, CD15 and epithe-lial membrane antigen (EMA) are usually negative


Fig 2. A 53-year-old man with primary cutaneous CD30+

large (anaplastic) T-cell lymphoma on the lower back.

lesions exhibit a bandlike or nodular monomor-phous infiltrate containing small and medium-sizedlymphocytes with cerebriform nuclei and epider-motropism resembling a plaque of MF. Large CD30+

cells are not present, and eosinophils and neu-trophils are rare. The differential diagnosis mayinclude patch- or plaque-stage MF. Some lesionsshow a mixture of type A and type B patterns or dif-ferent patterns in concurrent lesions. A follicular pat-tern has also been described. Type C lesions containlarge clusters or aggregates of large atypical CD30+

cells with few admixed inflammatory cells, similar tolarge T-cell lymphoma. In fact, the atypical cells intype A and type C lesions are immunophenotypical-ly identical to those in CD30+ large T-cell lymphoma.Clonal TCR gene rearrangement is detected inapproximately 60% of cases.

Angiocentric lymphomaClassified in the REAL classification as nasal-type

extranodal NK/T-cell lymphoma, angiocentric lym-phoma is a systemic lymphoma with frequent skinmanifestations related to its angiodestructive nature.Many cases previously classified as lymphomatoidgranulomatosis, lethal midline granuloma, or angio-centric immunoproliferative lesion could be includ-ed here, although currently the term lymphomatoidgranulomatosis should be reserved for B-cell lym-phomas involving primarily the lung but sometimesother sites, including skin. The prognosis varies fromindolent to aggressive, correlating with the propor-tion of large cells making up the infiltrate, which inturn may directly correlate with expression of an NKphenotype and clonal integration with Epstein-Barrvirus (EBV). The overal 5-year survival is less than50%.91 The physiologic counterpart is unknown,presumably a peripheral NK or T-cell subset.

Angiocentric lymphoma is uncommon in the UnitedStates and Europe and more common in Asia. Casesresembling hydroa vacciniforme in children havebeen reported in Mexico and Bolivia.92 Clinically,angiocentric lymphoma presents as dermal or sub-cutaneous papules or nodules that may ulcerate (Fig3). Lesions are usually widespread and frequentlyinvolve the lower extremities. Pulmonary, neurolog-ic, hemophagocytic, and other systemic symptomsmay precede or follow the cutaneous presentation.In hydroa-like angiocentric lymphoma, there arepapulovesicles and necrotic scars on the face andextremities.92

Microscopically, angiocentric lymphoma exhibitsneoplastic lymphocytes within and around the wallsof small and medium-sized vessels of the dermis andsubcutis associated with zonal tissue necrosis andevidence of vascular damage, namely fibrin deposits,thrombosis, and fibrosis in and around vessel wallswith occasional extension into the subcutis.93 Thenumber of neoplastic lymphocytes may be small,mimicking a reactive infiltrate, particularly whencytologic atypia is minimal. Infiltrates may bemonomorphous or variably composed of small,medium-sized, and large lymphocytes with round orirregularly shaped borders and pale cytoplasm.Cerebriform nuclei are uncommon, although thepresence of epidermotropism is variable. Ultra-structurally, cells with NK features contain cytoplas-mic granules. These may be appreciated on Wrightor Giemsa preparations. Eosinophils, plasma cells,and histiocytes are variably present. Angiocentriclymphomas display a spectrum of immunopheno-types, ranging from a T-cell phenotype with variableexpression of CD2, CD3, CD4, CD5, CD7, or CD8 onone hand, to an NK (CD2+/CD3ε+/CD56+) pheno-type with variable expression of other NK markers,


Fig 3. Angiocentric lymphoma. A, Crusted, ulcerated plaques. B, Atypical lymphocytes disruptvessel walls.

A B

infiltrates. Often a characteristic rimming of neoplas-tic cells around individual adipocytes can beobserved. The neoplastic cells resemble those seen inPTLs or node-based peripheral T-cell lymphomas withsmaller cells displaying hyperchromatic, irregularnuclei and inconspicuous nucleoli, and occasionallarge anaplastic cells in varying proportions. In somecases, the neoplastic T cells resemble histiocytes, andsome authorities believe that some cases of malignanthistiocytosis represent SPTL.100 In addition, whensmall lymphocytes predominate in SPTL lesions, theneoplastic nature of the lesion may be missed alto-gether, and the differential diagnosis includes reactiveprocesses such as lupus profundus. There is a variablehistiocytic component and occasionally eryth-rophagocytosis and/or lymphophagocytosis, resultingin “bean-bag cells,” correlating with the hemophago-cytic syndrome clinically. Nuclear debris, fat necrosis,and granulomatous inflammation are variable find-ings. Neoplastic lymphocytes are usually CD4+ orCD8+ and may lack CD5 or CD7. CD30 expression isvariable.99 Some cases express CD56, multiple-drugresistance phenotype, and/or contain EBV genome.101

Clonal TCR gene rearrangements are present. A sub-set expressing γ/δ TCR may have a poorer progno-sis.102,103

Adult T-cell leukemia/lymphomaATL is induced by infection with human T-cell lym-

photropic virus type 1 (HTLV-I), which is endemic tosouthern Japan, Southeast Asia, the Caribbean, LatinAmerica, equatorial Africa and is more common inrecreational intravenous drug users. Only a fraction ofinfected persons will develop ATL. (HTLV-I is alsoimplicated in tropical spastic paraparesis and infectivedermatitis.) ATL is a systemic lymphoma with a medi-an survival of less than 1 year. The postulated normalcounterpart is a peripheral CD4+ T cell in variousstages of transformation. Typically, there is an acuteonset to ATL with leukocytosis, lymphadenopathy,and a characteristic clinical presentation bearing theacronym HOTS (hypercalcemia, osteolytic bonelesions, T-cell leukemia, splenomegaly). Plaques andnodules resemble those of MF, but patches are rare.Chronic (milder symptoms, slightly longer survival)and “smoldering” (peripheral lymphocytosis only)forms have also been described. The transition to theacute form is termed “crisis.”104 Serum anti-HTLV-Iantibodies have been negative in otherwise classiccases.105 Southern blot technique detects clonal inte-gration of HTLV-I genome within lesional or circulat-ing neoplastic cells.

Papular lesions in ATL contain dense, lichenoidinfiltrates of medium-sized lymphocytes with convo-luted nuclei. Epidermotropism and periadnexal and

CD16 or CD57. Cases with an intermediate pheno-type are termed “NK-like” or “T-NK-like” and mayrepresent a distinct entity with a propensity for bonemarrow involvement.94 Angiocentric NK lymphomacells usually contain clonally integrated EBV,95

detectable by immunohistochemistry or in situhybridization. Angiocentric T-cell lymphomas mayalso contain EBV. Variable CD30 labeling has beenreported in some cases, including those with NKphenotype.78,79,92,96 TCR gene rearrangement stud-ies are germline (negative) in NK phenotypes butclonal in T and T-NK cases.

Subcutaneous panniculitis–like T-cell lym-phoma

Subcutaneous panniculitis–like T-cell lymphoma(SPTL) occurs worldwide and may overlap clinicallyand histologically with angiocentric lymphoma.96a

SPTL may evolve from cases initially classified ascytophagic histiocytic panniculitis97,98 and presum-ably represents at least some cases that have beenpreviously classified as Weber-Christian disease andfatal panniculitis. The prognosis is poor despiteaggressive chemotherapy, with a median survival ofless than 3 years.68 However, a subset of patients fol-low a chronic, indolent course. The physiologic coun-terpart is an unknown peripheral T- or NK-cell subset.SPTL presents with subcutaneous nodules andplaques on the legs and less commonly on the trunk,often in young adults (Fig 4).68,99 Weight loss, fever,and fatigue frequently herald the onset of a rapidlyprogressive hemophagocytic syndrome, the majorcause of death in these persons. Dissemination oflymphoma to extracutaneous sites of hemophagocy-tosis is uncommon.99,100 Microscopically, there areseptal and lobular infiltrates in the panniculus withzonal tissue necrosis and sometimes angiocentric


Fig 4. SPTL. (Courtesy of George J. Murakawa, MD, PhD,Detroit, Mich.)

perivascular extension are variable features. Nodulesalso contain larger lymphocytes with vesicular nucleiresembling histiocytes, the anaplastic cells in large-cell lymphomas, or Reed-Sternberg cells. Theperipheral blood contains multilobated (rather thancerebriform) lymphocytes with a classic “cloverleaf ”or “flower” appearance. ATL cells are usuallyCD3+/CD4+/CD7–. CD8 expression is rare. CD25 (IL-2 receptor) is expressed on the circulating cells.Clonal TCR gene rearrangements are present.

Angioimmunoblastic T-cell lymphomaAlso known as angioimmunoblastic lymphadenop-

athy with dysproteinemia (AILD), angioimmunoblas-tic T-cell lymphoma is a rare, moderately aggressivesystemic lymphoma previously regarded as reactive inlight of its occasional spontaneous remission and/orapparent response to corticosteroid therapy. In fact,some authorities continue to distinguish AILD as areactive condition. However, most cases eventuallyevolve into lymphoma, with 3-year survival reportedat approximately 50%.106,107 The physiologic counter-part is a peripheral T cell of unknown subset in vari-ous stages of transformation. The disorder usuallypresents in the sixth or seventh decade of life withfever, generalized lymphadenopathy (sometimesmassive), weight loss, hepatosplenomegaly, dyspro-teinemia, and skin lesions in about 40% of cases, usu-ally a pruritic morbilliform or maculopapular rash,urticarial lesions, plaques and nodules, or acralpetechiae. Some cases are associated with drug use,including penicillin, griseofulvin, phenytoin, sulfon-amides, aspirin, and halothane.106 The histologic fea-tures in the lymph nodes are distinctive. The nodularskin lesions are similarly composed, with dense der-mal and subcutaneous infiltrates of large immuno-blastic lymphocytes admixed with plasma cells andeosinophils.108 The histologic features of the macu-lopapular eruptions are usually nonspecific, withperivascular lymphocytic infiltrates with occasionalatypical lymphocytes. Lymphocytic91 and leukocyto-clastic107 vasculitis has been reported. Vascular hyper-plasia may be appreciated. Identical clonal TCR generearrangements can be identified in maculopapular orinfiltrated skin lesions and affected lymph nodes ofpatients with AILD.107 EBV has been detected withinaffected lymph nodes and, less commonly, cutaneouslesions of some cases, but EBV is not clearly patho-genic.107,109-111

Pleomorphic T-cell lymphomaTermed “pleomorphic small/medium-sized CTCL”

by EORTC, PTL accounts for fewer than 3% of prima-ry CTCL cases and is associated with an intermediate5-year survival of 62%.12 In one recent series, PTL

comprised 3% of all primary cutaneous lymphomas.69

Patients with pleomorphic small cell–type lymphomahave a better prognosis. The physiologic counterpartis an unspecified peripheral T-cell subset. Typically,PTL presents in adults as asymptomatic, solitary orlocalized but usually widespread, red-purple noduleswhose size ranges from 5 mm to 15 cm without patch-es. Lymphadenopathy is variable and is usually reac-tive histologically.112 Histologically, PTL exhibits denseand nodular, diffuse, perivascular, or periadnexal infil-trates in the papillary dermis, reticular dermis, and/orsubcutis. Infiltrates of PTL contain a pleomorphicpopulation of small and medium-sized lymphocyteswith irregular, hyperchromatic nuclei (without cere-briform configuration), occasional mitotic figures,and scant cytoplasm. Large lymphocytes may be pre-sent but comprise less than 30% of the infiltrate.Epidermotropism, angiocentricity, eosinophils, neu-trophils, plasma cells, and granulomatous features arevariable findings.68,112 Most cases are CD3+/CD4+/CD5+/CD7–. CD2 expression is variable, and CD8 isusually negative. CD4+/CD56+ lymphomas with simi-lar histologic features but negative for other T-cellmarkers appear to have a poorer prognosis.94 ClonalTCR gene rearrangements are present.

Lennert’s lymphomaAlso known as lymphoepithelioid lymphoma, LL

is a rare systemic CD4+ T-cell lymphoma not desig-nated in current classifications, except within theheading of unspecified peripheral T-cell lym-phoma.113 LL usually presents in adults with lymphnode involvement and is classified as low-grade untiltransformation to large-cell lymphoma intervenes.Cutaneous lesions may be papules, plaques, or nod-ules (but not patches as in MF) and occur in fewerthan 10% of cases.114 Skin lesions in LL do not alwaysrepresent lymphoma cutis because nonspecificinflammatory reactions and palisaded granuloma-tous infiltrates have also been reported.115 Reactiveepithelioid histiocytes accompany smaller CD4+ MF-like T cells, although the histologic diagnosis isbased primarily on the characteristic epithelioid his-tiocytes surrounding the neoplastic T cells. Thus dis-tinction from granulomatous MF depends on clinicalfeatures. One series reported several cases with acytotoxic T-cell phenotype.116 TCR β-chain genes areclonally rearranged.117

CUTANEOUS B-CELL LYMPHOMAS:CHARACTERISTICSMarginal zone lymphoma

Although universal consensus classification isabsent regarding its terminology, MZL appears to bethe most commonly applied. Alternative nomencla-


cases the marginal zone cells may not be easily iden-tified and their quantity may vary between cutaneouslesions from the same person.121 Reactive lymphoidfollicles, eosinophils, T cells, and histiocytes oftenaccompany the neoplastic cells. Amyloid depositsmay occur.119 In primary cutaneous MZL, light-chainrestricted plasmacytoid lymphocytes and plasmacells tend to be aggregated around the peripheriesof nodular infiltrates.119 In cases containing plasma-cytic differentiation, eosinophilic intranuclear(Dutcher body) or intracytoplasmic (Russell body)inclusions of immunoglobulin may be seen. Dutcherbodies may be a somewhat specific but not sensitivefeature of MZL (Fig 5, B),122,123 whereas Russell bod-ies are seen in other disorders with plasmacytic infil-trates, including Rosai-Dorfman disease (sinus histi-ocytosis with massive lymphadenopathy) andrhinoscleroma. Lymphoepithelial lesions, a charac-teristic feature of MZL in MALT, are sometimes seenin cutaneous infiltrates and resemble the epider-motropism characteristic of CTCL. MZL label withmonotypic cytoplasmic immunoglobulin (cIg),CD19, and CD79α. CD20 is negative on plasma cellsand some plasmacytoid cells. There is variable aber-rant expression of CD11c and the T-cell markerCD43. Cytoplasmic light-chain restriction is apparentin formalin-fixed tissue by immunoperoxidase (or insitu hybridization for light-chain mRNA) in the pre-ponderance of cases with plasmacytoid or plasma-cytic differentiation. Cases that have more homoge-neous populations of centrocyte-like cells label vari-ably for surface/cell membrane immunoglobulin(sIg) and/or cIg. Bcl-2 expression unassociated witht(14;18) translocation has been reported.124 Clonalrearrangement of immunoglobulin genes is present.Trisomy 3 and t(11;18) have been reported in extra-nodal cases.

ture associated with MZL includes marginal zonelymphoma of MALT type, MALToma or SALToma(skin-associated lymphoid tissue), primary cuta-neous immunocytoma, and monocytoid B-cell lym-phoma (reserved for primary nodal lymphoma).MZL may represent the most common form of pri-mary CBCL and is classified by EORTC as an indolentprocess with 5-year survival of 100% for primarycutaneous lesions, unless transformation to large-cell lymphoma intervenes.118 Secondary cutaneousMZL, representing spread from a nodal or extranodalprimary site, is also usually indolent, although incur-able, and transformation to large-cell lymphoma mayoccur. The postulated normal counterpart is a nodalor extranodal (MALT or SALT, depending on the pri-mary site) marginal zone B cell with capacity for plas-macytic differentiation and tissue-specific homing.Primary cutaneous MZL presents with solitary ormultiple asymptomatic dermal nodules or plaques(Fig 5, A), usually on an extremity.119 MZL involvingorbital and periorbital soft tissue has been associatedwith solid facial edema.120 Widespread lesions sug-gest secondary spread to the skin. Individual cases ofsystemic MZL/immunocytoma have been associatedwith epidermolysis bullosa acquisita, Sjögren’s syn-drome, idiopathic thrombocytopenic purpura,119

and anetoderma.120a Microscopically, there is anodular, diffuse, or periadnexal infiltrate that is vari-ably heterogeneous in composition, containing“centrocyte-like cells,” which exhibit small but lessindented nuclei and slightly more abundant pale orclear cytoplasm than centrocytes or the centrocyticcells of follicular lymphoma (FL). Some degree ofplasmacytoid and plasmacytic differentiation is usu-ally present, as are occasional larger cells with a largevesicular nucleus and a large, centrally situatednucleolus resembling immunoblasts. In fact, in some


Fig 5. MZL. A, Plaques on the upper back of a 74-year-old woman. B, Intranuclear inclusion ofimmunoglobulin (Dutcher body) in MZL.

A B

Follicular lymphomaRenamed in the WHO classification, FL is an indo-

lent CBCL that may be primary or secondary in skin.Equivalent terms include follicle center lymphoma(FCL) in the REAL classification and follicle centercell lymphoma (FCCL), although consensus is absentregarding criteria for distinguishing primary cuta-neous FCCL, as defined in the EORTC classification,from primary cutaneous MZL. Thus some observersbelieve that cases classified as primary cutaneousFCCL might be more accurately classified as MZL. Inprimary cutaneous FCCL, the 5-year survival is97%.12 Secondary cutaneous FL represents advanceddisease with a poorer prognosis. The postulated nor-mal counterparts are centrocytes and/or centroblastsof the reactive follicle center in lymph nodes.Human herpesvirus-8 DNA sequences have beendetected in some FL and MZL cases but may repre-sent epiphenomena.125 The skin lesions resemblethose of MZL except they are usually located on thehead and neck region or upper trunk rather than theextremities. The lesions may be surrounded byannular erythema and usually increase gradually insize over time. Dissemination of primary cutaneouslesions is uncommon but has been reported.126

Microscopically, FL exhibits a nodular or diffuse pat-tern composed of varying proportions of small andlarge cells sometimes associated with reactive orneoplastic lymphoid follicles (Fig 6). CutaneousFCCL often lacks a follicular growth pattern.12 (Theconverse is also true: other types of B-cell lymphomamay exhibit a follicular pattern of growth.) Small cen-trocytes predominate in low-grade FL. Intermediate-and high-grade FLs have progressively higherpercentages of large cells, although the risk of dis-semination in high-grade primary cutaneous exam-ples does not appear to be greater as is the case withnodal FL. Cells are reactive with pan-B cell markers

and monotypic sIg. Expression of CD10 or bcl-2 isnegative in FCCL as defined in the EORTC classifica-tion, in contrast to traditional criteria for nodal FL. Incontradistinction to some cases of MZL, FLs are cIg,CD11c, and CD43 negative. Clonal rearrangement ofimmunoglobulin genes is present.

(Diffuse) large B-cell lymphomaLBCLs are high-grade lymphomas histologically, but

histologic grade does not appear to correlate withprognosis in primary cutaneous disease. LBCL is also a“lumper’s” diagnosis, since immunoblastic lymphomahas been united with high-grade FL under this head-ing, at least until a clinically relevant basis for furthersubclassification can be established.127 Primary cuta-neous lesions of LBCL that arise on the head and neckare indistinguishable from high-grade FL and may bemanaged with equal success. The EORTC recognizes adistinctive subset arising on the leg associated with an“intermediate” prognosis and a 5-year survival of58%.12,128 Reticulohistiocytoma of the dorsum (ofCrosti) describes plaques of LBCL arising on the back.Nodal LBCL is an aggressive, high-grade systemic lym-phoma that may secondarily involve skin. The postu-lated normal counterpart is a proliferating B cell,which may be of peripheral (ie, immunoblast) or ofgerminal center (ie, centroblast) origin. Clinically,LBCL presents as red or purple papules, nodules, orplaques. Solitary or localized lesions are typical of pri-mary cutaneous LBCL, whereas widespread lesionssuggest primary nodal disease.91 Histopathologically,LBCL exhibits a diffuse monomorphous dermal and/orsubcutaneous proliferation of large atypical lympho-cytes resembling immunoblasts or centroblasts (Fig7). Rarely, epidermotropism has been described.129

The cells have large vesicular nuclei with prominentnucleoli and abundant indistinct or basophilic cyto-plasm. Immunophenotypically identical cells exhibit-


Fig 6. Neoplastic lymphoid follicles in FL. Fig 7. Cutaneous LBCL.

thematous papules, plaques, nodules, tumors, dif-fuse infiltrates, or leonine facies. Bullae and vesiclesmay overlie plaques. Occasionally lesions will be con-fined to an area of previous herpes zoster or herpessimplex infection.132 Three histologic patterns maybe encountered: superficial and deep perivascularinfiltrates (Fig 8), bandlike or interstitial infiltratesresembling other forms of leukemia cutis, and nodu-lar and diffuse infiltrates. All 3 patterns spare the epi-dermis. CLL cells are small lymphocytes with roundnuclei, dense chromatin aggregated against thenuclear membrane, small nucleoli, and scant cyto-plasm. Diffuse infiltrates may contain zones of cellswith paler nuclei, termed “proliferation centers” or“pseudofollicles.” Plasmacytoid differentiation orDutcher bodies may be noted. A predominant T-cellinfiltrate may rarely occur in B-CLL.133 B-CLL cellslabel with monotypic sIgM, CD19, CD20, and CD79α.Labeling for CD23 and aberrant reactivity of someantibodies againt the T-cell markers CD5 and CD43are particularly useful for this diagnosis.132 PCRdetects clonal rearrangement in immunoglobulingenes and sometimes the bcl-1 gene, resulting froma t(11;14) translocation. The presence of trisomy 12,significant CD38 expression, and absence ofimmunoglobulin V region somatic mutation maycorrelate with poor prognosis.134,135 T-CLL/SLLexpresses CD7 and other T-cell–associated antigensand is negative for CD25.15

Plasmacytoma/myelomaPlasmacytoma may represent an isolated bone

marrow or extramedullary (including skin) lym-phoma but more often arises secondary to systemicdisease (multiple myeloma) in about 2% of suchcases.91 Primary cutaneous and other extramedullarylesions have a lower rate of progression to multiple

ing spindled, twisted, or elongated nuclei and scantcytoplasm may predominate in some foci.130 Othercases exhibit a majority of large cleaved centrocyticcells.127 Typically, immunoblasts exhibit a larger, morecentrally located nucleolus, and more basophilic cyto-plasm compared with a centroblast, though distin-guishing their neoplastic counterparts is more diffi-cult. Plasmacytoid differentiation, anaplastic cytology,and folded/indented nuclei may be observed.Ulceration, epithelial necrosis, and numerous mitoticfigures are usually present. Variable features includepseudocarcinomatous epithelial hyperplasia and infil-tration of the epidermis. The cells usually expressCD19, CD20, CD79α, and variably monotypic sIg orcIg. Bcl-2 is strongly expressed in LBCL of the leg andin about 30% of nodal LBCL15 (although not associat-ed with the t(14;18) translocation). Clonal rearrange-ment of immunoglobulin genes is present.

Chronic lymphocytic leukemiaA significant peripheral lymphocytosis is requisite

for the diagnosis of chronic lymphocytic leukemia(CLL) versus small lymphocytic lymphoma (SLL),and associated skin lesions are nearly always sec-ondary to CLL or primary nodal SLL that has dissem-inated to skin. The postulated normal counterparthas been regarded as a recirculating CD5+/CD23+ Bcell resembling the cells comprising primary (naive)lymphoid follicles, although in some cases the cellsdifferentiate toward memory B cells,131 exhibitingsomatic mutations of the variable regions of theimmunoglobulin gene. CLL is incurable but remainsindolent until transformation to large-cell lymphomaintervenes (Richter’s syndrome). T-CLL is rare but isgenerally more aggressive than B-CLL. CLL arises inolder adults and is often asymptomatic. Cutaneousmanifestations include localized or generalized ery-


Fig 8. CLL. A, Sparse cutaneous perivascular infiltrates. B, Infiltrates of small, round,monomorphous lymphocytes in the subcutis.

A B

myeloma, probably because of early detection. Thusisolated cutaneous lesions are potentially curable (5-year survival >90%),68 whereas myeloma is general-ly fatal. The postulated normal counterpart is theplasma cell. Cutaneous plasmacytomas usually pre-sent as violaceous papules, nodules, or plaques.Manifestations of systemic involvement include bonepain, fractures, renal failure, amyloid deposits, mono-clonal immunoglobulin or light chain in urine andperipheral blood, and plasma cell leukemia.Myeloma may also potentially arise in associationwith other acute or chronic skin diseases, includingchronic pruritus, chronic urticaria, Sweet’s syn-drome, pyoderma gangrenosum, leukocytoclasticvasculitis, erythema elevatum diutinum, subcornealpustular dermatosis (Sneddon-Wilkinson disease),POEMS (polyneuropathy, organomegaly, endocri-nopathy, M protein, skin lesions) syndrome, scle-romyxedema, necrobiotic xanthogranuloma, andplane xanthomas. Myeloma may arise after solidorgan transplantation.136 Unlike other types of lym-phoma in which focal plasmacytic differentiationmay be observed, plasmacytomas have dense nodu-lar or interstitial monomorphous infiltrates of plas-ma cells and no recognizable areas with other typesof lymphocytes (Fig 9). Mitotic figures are common.The neoplastic cells may resemble the classicMarschalko-type plasma cell or immunoblastic oranaplastic large cells (plasmablasts). The proportionof large cells and the degree of nuclear atypia maycorrelate directly with a poorer prognosis.Eosinophilic intranuclear (Dutcher body) or intracy-toplasmic (Russell body) inclusions of immunoglob-ulin, as seen in MZL, are uncommon. Plasmacytomasexpress monotypic cIgG, cIgA, κ or λ light chain, orrarely cIgD or cIgE. sIg is negative. CD79α is variablyexpressed and CD19 and CD20 are negative. EMA,CD43, and CD30 are also variably expressed. Clonal

rearrangement or deletion of Ig heavy (IgH) andlight chain (IgL) genes is demonstrable.

Mantle cell lymphomaCutaneous lesions of mantle cell lymphoma (MCL)

are rare and represent secondary cutaneous lesionsuntil proved otherwise. Primary cutaneous lesionsapparently do occur, may be underrecognized, andmay not be as indolent as MZL. Nodal MCL is classifiedas “moderately aggressive” and incurable in the REALclassification with a median survival of 3 to 5 years.15

The postulated normal counterpart is the CD5+/CD23– follicle mantle zone cell of reactive lymphnode follicles. Clinical descriptions are rare, butdome-shaped red-purple plaques or nodules withsmooth or “vegetating” surfaces have been describedon the conjunctiva, head, trunk, and extremi-ties.137,138 MCL may display patchy rather than diffuseand “top-heavy” infiltrates of small to medium-sizedlymphocytes that resemble the cells of CLL/SLL orMZL with round or irregular nuclei, inconspicuousnucleoli, dense or slightly dispersed nuclear chro-matin, and scant pale cytoplasm. The “mantle-zone”growth pattern is expansion of the mantle zone areasurrounding and seemingly compressing the centerof a reactive lymphoid follicle. Because this growthpattern is not alway present, the designation “mantlecell lymphoma” is preferable to “mantle zone lym-phoma.”15,139 Large lymphocytes are rare, except inthe blastoid variant. MCL cells are generally CD5+/CD23–/sIgM+/sIgD+/CD43+. A t(11;14) translocationis present in most cases of nodal MCL resulting inapposition of the IgH and bcl-1 loci, resulting in over-expression of cyclin D1.

B-lymphoblastic lymphomaCutaneous lesions of B-lymphoblastic lymphoma

(B-LBL) are rare and should be considered sec-


Fig 9. Cutaneous plasmacytoma. Fig 10. Lymphoblastic lymphoma.

Intravascular lymphomaPreviously known as “malignant angioendothe-

liomatosis,” intravascular lymphoma was considered avascular proliferation. This form of CBCL generally hasa poor prognosis, but primary cutaneous cases maydemonstrate a more favorable clinical course. The esti-mated 5-year survival published by EORTC is 50%.12

The skin is commonly involved, usually with smoothhemorrhagic, indurated patches and plaques on thetrunk or extremities, particularly the lower legs whereit resembles panniculitis that may eventuate in ulcera-tion (Fig 11). The central nervous system is also com-monly involved with fever and dementia; there alsoare visual, speech, or sensory abnormalities. Masslesions and lymphadenopathy are often absent.91 Onecase was diagnosed by sampling a cutaneous cherryangioma.143 Intravascular lymphoma cells are cytolog-ically atypical often with large vesicular nuclei, multi-ple nucleoli, irregular nuclear contours, and visiblecytoplasm, like the cells that make up LBCL. In fact,one case of LBCL of the leg relapsed as intravascularlymphoma.17 The cells are situated within the lumensof venules, capillaries, and arterioles of the dermis andsubcutis, associated with fibrin; however, slight inter-stitial extension of cells occurs in only 20% of cases.12

Cells label with CD19, CD20, CD22, CD79α, and sIg.T-cell immunophenotypes occur less commonly.Immunoglobulin genes are clonally rearranged.

Hodgkin’s diseaseHD is unique among nodal lymphomas for its (1)

lack of lineage-specific markers, (2) characteristic cell(Reed-Sternberg) and other unique histologic fea-tures, (3) and the tendency to spread locally. HD israre in skin, usually presenting in the setting ofadvanced nodal or visceral disease as an indicator of

ondary cutaneous lesions until proved otherwise.Significant peripheral lymphoblastosis (>25%) indi-cates a diagnosis of acute lymphoblastic leukemia(ALL) in most, but not all, cases. B-LBL accounts foronly 10% of all LBLs (the remainder are T-LBL) butrepresents the majority of cutaneous lesions.Currently there does not appear to be a significantclinical or pathologic difference between LBL of T-or B-cell lineage, although B-ALL has a better prog-nosis than T-ALL, and accurate discriminationbetween lymphoma and leukemia cannot always beachieved. LBL is a clinically aggressive, histologicallyhigh-grade lymphoma with a median survival of 12months. Prognosis is more favorable in those withisolated cutaneous involvement. LBL usually pre-sents in children and adults as solitary or multipleerythematous or purpuric papules and nodules onthe head and neck (Fig 10).91,140,141 Histologically,LBL presents as a nodular or diffuse proliferation ofsmall to medium-sized cells with round or convolut-ed nuclei, thin but well-defined nuclear membranes,fine chromatin, inconspicuous nucleoli, and scantbasophilic cytoplasm. Tingible body-type macro-phages are sometimes interspersed, resulting in a“starry sky” pattern. T-LBL and B-LBL are indistin-guishable without immunophenotyping. LBL cellsexpress terminal deoxynucleotidyl transferase. B-LBL will also label with CD10, CD19, CD20, CD79α,and often cIg. T-LBL expresses cCD3, CD7, CD45ROand variably CD4, CD5, and CD8. CD4 and CD8 areoften both positive (“double positive”) or both neg-ative. The NK marker, CD56, is rarely expressed.142

Gene rearrangement studies are clonal, but TCRrearrangements are occasionally seen in B-LBL, andimmunoglobulin rearrangements may be seen inT-LBL.


Fig 11. Intravascular lymphoma. A, Chronic leg ulcer. B, This patient’s biopsy specimenrevealed large atypical B cells within blood vessels. (A, Courtesy of George J. Murakawa, MD,PhD, Detroit, Mich.)

A B

poor prognosis. Single-cell gene rearrangement stud-ies suggest that HD typically represents a form ofBCL,144,145 but the postulated normal counterpart(s)is (are) unknown, possibly a follicle center cell withdefective immunoglobulin production. TCR generearrangements occur less commonly.146 CutaneousHD usually presents as papules, plaques, or noduleswithin an upper or lower extremity distal to involvedlymph nodes.147-149 Generalized pruritus or prurigonodularis may be associated.150-152 The 4 general his-tologic types are lymphocyte-predominant, nodularsclerosing, mixed cellularity, and lymphocyte-deplet-ed. Cutaneous HD is usually a nodular or diffuse infil-trate sparing the epidermis and exhibiting the histo-logic features of nodal disease. Reed-Sternberg cellsare large binucleate cells with vesicular nuclei, promi-nent eosinophilic nucleoli (“owl eyes appearance”),and clumped chromatin (Fig 12). Similar mononucle-ate cells are termed Hodgkin’s cells. These cells areoutnumbered by a reactive inflammatory infiltrate ofsmall lymphocytes, eosinophils, neutrophils, and plas-ma cells, depending on the variant. Lymphocyte-predominant HD rarely involves the skin. Nodularsclerosing HD contains lacunar (“popcorn”) cells,which contain multilobated nuclei with surroundingretraction artifact. Lymphocyte-depleted HD demon-strates necrosis and more monomorphous infiltratesof Reed-Sternberg and Hodgkin’s cells.15,91 The hall-mark is expression of CD30 and CD15 by Reed-Sternberg cells. The differential diagnosis includesCD30+ large T-cell lymphoma (containing Reed-Sternberg–like cells) and LyP. However, cutaneousinvolvement by HD is generally indicative of systemicdisease, and LyP and primary cutaneous large T-celllymphomas are usually CD15–. As previously men-tioned, cases diagnosed as primary cutaneous HD maybe indistinguishable from LyP.82

THERAPY: CUTANEOUS T-CELLLYMPHOMA

For practical purposes, therapy for CTCL is cur-rently dependent on the clinical stage rather than onthe specific subtype, although the vast majority ofdata relates to treatment of patients diagnosed witheither MF or SS. The tumor, node, metastasis, blood(TNMB) system is used to determine overall clinicalstages, I through IV (see Tables I and IV). Althoughsome patients with localized primary cutaneous lym-phoma may have been cured, therapy for CTCL isoriented toward achieving and maintaining clinicalremission and, in advanced cases, palliation.Controlled trials associating a survival benefit withany particular therapy do not yet exist. Additionalperspectives regarding management and therapyhave been published.21,153-155

Established successful practice patterns havebeen developed at the major referral institutions forCTCL, although their individual preferences andmethods vary. In the absence of controlled trials,assumptions exist that (1) available therapies reducemorbidity and possibly mortality in CTCL, (2) clini-cally visible disease should be actively treated, and(3) patients in remission should be followed upindefinitely. Whether maintenance therapy forpatients in complete remission is advantageous isequivocal, although such maintenance therapy isroutine at some centers.

There is general agreement regarding the thera-pies available (Table VI), but with few exceptionsimpressions about relative efficacy are based on non-randomized, uncontrolled outcomes. Many of themost commonly utilized therapies are not specifical-ly indicated for CTCL by the Food and DrugAdministration (FDA). In the single most influentialrandomized trial to date, investigators found thataggressive treatment (combination chemotherapyand total skin electron beam therapy [TSEB]) doesnot offer a survival benefit in early-stage CTCL whencompared with topical therapy.156

Topical therapyTopical therapy is appropriate for limited (T1) or

generalized (T2) patches and plaques of MF. Topicalchemotherapy with either nitrogen mustard or car-mustine (BCNU) is the most popular specific first-line therapy for early MF. These agents are also usedas adjuvant therapy after the achievement of com-plete remission with the use of TSEB.157

Nitrogen mustard (mechlorethamine hydrochlo-ride) solution or ointment may be the most widelyused topical agent in CTCL, with an 88% totalresponse rate (51% complete response) in stageT1.158 Use of nitrogen mustard has been limited by a


Fig 12. HD. Large lymphocytes with prominent nucleoliscattered among smaller reactive lymphocytes.

are available from several pharmacists, includingCrown Drugs (Philadelphia, Pa) or the Yale MedicalCenter Pharmacy (New Haven, Conn). As an addition-al reference, Zackheim’s recent review168 of topicalchemotherapy is suggested.

Corticosteroids have been used for early MF at leastsince the 1960s.169-171 Recently their efficacy wasreported in a large series, with total response rates of94% (complete response, 63%) in T1 disease, which iscomparable to the results seen with topical chemother-apy.172 The complete response rate decreased to 25%in T2 disease. One patient with T1 disease who wasrefractory to multiple alternative modalities achievedcomplete remission with corticosteroids. Most patientswere treated with clobetasol propionate emollientcream. Data comparing corticosteroids and long-termfollow-up are not yet available. Other corticosteroidshave reportedly been used for MF, including fluoci-nolone acetonide under occlusion,169 triamcinolone,

frequency of allergic contact dermatitis ranging from30% to 80%,159 although the ointment preparationappears to be associated with a lower incidence ofthis complication.160 Rare complications of nitrogenmustard therapy include localized bullous reac-tions,161 urticarial, anaphylactoid,162 and Stevens-Johnson–type reactions.163 BCNU ointment or solu-tion appears to have comparable efficacy when com-pared with nitrogen mustard with a 98% totalresponse rate (86% complete response) in stageT1.164 In comparison with nitrogen mustard, there isa lower frequency of contact dermatitis,165 but BCNUoften leaves persistent telangiectasia at treatedsites.166 In addition, mild leukopenia has been associ-ated in 3% to 5% of patients treated with BCNU solu-tion or ointment.153 In either case, a 2- to 6-monthtrial of daily application of solution (either lesional ortotal body surface) or a 6- to 12-month trial is sug-gested.153 Both should be kept refrigerated166,167 and


Table VI. Therapy for CTCL

Use(disease Photo- Photochemo-

Modality stage) Topical therapy therapy Radiation Oral IL SQ IM IV

Corticosteroids T1-2 X X XNitrogen mustard T1-2 XCarmustine (BCNU) T1-2 XUVB T1-2 XPUVA T1-2 X XPhotopheresis T2-4 X XMethotrexate T2-4 X X X XBexarotene, gel T1-2 XBexarotene, oral T1-4 XAcitretin T1-4 XIFN-α T1-4 X X XIFN-γ T1-4 X ? X XElectron beam therapy: localized T1-3 XElectron beam therapy: total skin T2-4 XOrthovoltage radiation: localized T1-3 XDenileukin diftitox T2-4 XOther single agent or combination T2-4 X

chemotherapy

bid, Twice daily; IL, intralesional; IM, intramuscular; IV, intravenous; qd, once daily; SQ, subcutaneous.aRetail price, Yale Medical Center Pharmacy, New Haven, Conn (July 2001).bDepartment of Dermatology, University of Connecticut (July 2001).cDoes not include cost of psoralen.dPhotopheresis unit, Department of Dermatology, Yale University, New Haven, Conn (July 2001).eAverage wholesale price, University of Connecticut Health Center, Farmington (August 2000).fAssume 10% body surface area involvement (approximately 3 g/application).gAssume 3 treatments per week.hAssume 2 treatments per month.iAssume dose of 20 mg by mouth per week.jAssume dose of 300 mg/m2 with a body surface area of 1.0 m2.kAssume dose of 25 mg/d.lAssume dose of 3 × 106 U, 3 times per week.mAssume dose of 18 µg/kg per day for 5 days per month, body weight of 70 kg.

fluocinonide, diflorasone diacetate, halobetasol propi-onate, and betamethasone valerate.172 Advantages ofcorticosteroids compared with topical chemotherapyinclude ease of application, superior product stability,reduced carcinogenicity, increased familiarity with useand side effects, and possibly reduced cost andincreased compliance.

Bexarotene 1% retinoid gel (Targretin) wasrecently approved by the FDA, with an overallresponse rate of 44% to 63% (complete response,8%-21%) in patients with refractory stage Ia-IIaCTCL.173,174 The predominant side effect is mild tomoderate local irritation or rash.

With all topical therapy, the complete responserate drops to below 50% in T2 disease.172

PhototherapyEach of the methods outlined in this section gen-

erally has a superior complete response rate when

compared with topical modalities in stage T2 MF,although broad-band ultraviolet B (UVB) photother-apy is largely ineffective for infiltrated plaques.175

Traditional broad-band UVB phototherapy (280-320 nm) has been associated with an 83% total andcomplete response rate in T1 disease.175 Morerecently, narrow-band UVB (TL-01, 311 nm)176,177

and UVA1 (340-400 nm) phototherapy have beenused for early MF178 as well as more advancedstages179 with good short-term responses in a limit-ed number of patients.

Oral photochemotherapy (PUVA) is a well-estab-lished modality for early MF, with the largest seriesreporting total response rates of 95% (completeresponse in 79% of T1 cases, 59% of T2 cases).Duration of remission averaged 3.6 years with main-tenance PUVA at least once per month.180 One pos-sible advantage of PUVA is that complete remissionappears to occur faster compared with topical thera-py. There is usually a negligible response, or a short-lived or partial response, in T3 and T4 disease.

Extracorporeal photochemotherapy (photo-pheresis) is FDA-approved for refractory CTCL.181 Itinvolves extracorporeal photoactivation of 8-methoxypsoralen-enriched leukocytes from thepatient’s peripheral blood. The irradiated cells arethen returned to the patient. A typical regimen is 2consecutive days per month. Overall, total and com-plete response rates have been reported at 50% and25%, respectively, with clinical responses within thefirst 6 to 8 months associated with greater long-termsurvival.182 Some investigators consider absence of aperipheral clone to be a contraindication to use ofthis modality.183 Photopheresis may be most effec-tive when used before immunosuppressivechemotherapy, since a competent immune systemmay be required for optimal response.185 Reportsare inconsistent regarding the survival benefit ofphotopheresis, particularly in SS, compared withother modalities183,184; hence the need for a ran-domized, multicenter trial has been emphasized.186

However, investigators continue to explore methodsfor optimizing the photopheresis protocol.185

Radiation therapyRadiotherapy is useful for definitive treatment of

a variety of primary CTCL types, including MFtumors, pagetoid reticulosis, large T-cell lymphoma,or PTL. For cutaneous lesions associated with sys-temic disease, radiotherapy may play a palliative role.Megavoltage photon irradiation may be used in com-bination with chemotherapy or other regimens forpatients with nodal involvement.

TSEB therapy may be the single most reliablemethod for inducing complete clinical remission in


Monthly costCost (US $)/Quantity example (US $)

48/45 g (clobetasol propionate ointment)a 192f (bid)42/60 g 10 mg/dL ointmenta 63f qd42/60 g ointmenta 63f qd480/12 sessionsb 480g

600/12 sessionsb,c 600g

3900/1 sessiond 7800h

98/#30 (2.5 mg)a 104i

1100/60 g gela 3300f bid550/#30 (75 mg)a 2200j

413/#30 (25 mg)a 413k

35/3 × 106 U (RoferonA)e 420l

$992/300 µge 20,832m

other modalities. Recombinant (Roferon-A) IFN-α2a is the most frequently reported single systemictherapeutic agent and is effective as intralesional,subcutaneous, or intramuscular therapy. In a ran-domized, blinded, placebo-controlled trial, intrale-sional IFN-α2b (Intron A) proved to be superior tobetamethasone dipropionate ointment.191 Morethan 26 publications detailing experience withinterferons in more than 300 patients have beenreported with an average complete remission rateof about 25% and overall response rate of up to80%. The single best predictor of response is clini-cal stage at the start of therapy, with the best resultsfor T1 or T2 disease.192 In one study, length ofremission averaged 7.5 months, with the majority ofpatients experiencing relapse.193 SubcutaneousIFN-α2a, 3 × 106 U, 3 times a week or daily for a 6-to 9-month trial, is suggested. Injection near moreadvanced lesions is advised. Consideration shouldbe given to combination therapy with PUVA or pho-topheresis (see “Combination chemotherapy”).Although most experience has been reported withsubcutaneous IFN-α2a, the efficacy of IFN-α2a,recombinant and natural (Wellferon, Cilferon) IFN-α2b, and IFN-γ may be comparable and has notbeen subjected to a comparative trial. IFN-γ maybenefit patients who are no longer responsive toIFN-α.193 IFN-γ has also been employed in the treat-ment of granulomatous slack skin.194 There is someevidence that alternating use of natural and recom-binant IFN-α2b may improve or prolong efficacybecause of the development of anti-IFN-α antibod-ies.195 Common adverse effects of interferonsinclude flu-like symptoms, depression, depressedblood cell counts, and elevated transaminase levels.As in the treatment of other disorders, bullous reac-tions have been reported.196

Oral bexarotene (Targretin) is a retinoid that wasrecently approved by the FDA for all stages of refrac-tory CTCL. In stage IA-IIA (early) disease, the overallresponse rate was 48% with a complete response rateof 12% using varying doses.197 In stage IIB-IVB dis-ease, the overall response rate was 49% with a com-plete response rate of 7%.198 A 3- to 5-month trial ofbexarotene, 300 mg/m2, is suggested. Common sideeffects include hypothyroidism and hyperlipidemia.Isotretinoin (Accutane) or acitretin (Soriatane) maybe useful either as monotherapy199 or in combinationwith calcitriol (for PTL)201 or PUVA.202

Intravenous denileukin diftitox (Ontak) is a fusiontoxin, DAB389IL-2, that is approved by the FDA forrefractory CTCL in patients whose neoplastic cellsexpress CD25 (IL-2 receptor). Fresh-frozen tissue orperipheral blood analysis is recommended to deter-mine CD25 status. In 35 patients with refractory

generalized patches, plaques, and tumors of MF, withcomplete response rates of up to 98% for limitedplaques and 36% for tumors in the largest reportedseries.187 The majority of patients have a relapse with-in 5 years.187,188 TSEB has been recommended asfirst-line therapy for MF-associated follicular muci-nosis.12 Some consider TSEB too toxic for first-linetherapy in erythrodermic MF and SS,187 but TSEB maybe effective in erythroderma, particularly when com-bined with photopheresis.189 Availability of TSEB isgenerally limited to regional referral centers, althoughelectron beam therapy for localized lesions is morewidely available. Many patients will tolerate a secondcourse of TSEB, but remissions tend to be the mostsustained after the first course.189 A typical regimenconsists of a cumulative exposure of 36 Gy (1.5-2.0Gy/d) divided over a 10-week course. Common sideeffects include alopecia (reversible with exposure

CTCL stages IA-IVB, the overall response rate was37%, with a complete response rate of 14%.202 Atreatment cycle consists of daily infusions, 18 µg/kgper day for 5 days, and may be repeated every 3weeks. Most patients respond within 2 to 6 cycles,although responses in patients with stage IV CTCLhave not been documented. Common side effectsinclude flu-like symptoms, nausea, vomiting, andhypotension that may be associated with a vascularleak syndrome characterized by peripheral edemaand hypoalbuminemia.

Methotrexate is available by oral, subcutaneous,intramuscular, and intravenous routes and isapproved by the FDA for treatment of advancedMF. More data exist for methotrexat

practical evaluation and management of cutaneous lymphomathose for cd23 and αβ t-cell receptor...

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