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2405

113 Cutaneous T-Cell Lymphoma and Cutaneous

B-Cell LymphomaThomas M. Habermann and Mark R. Pittelkow

S U M M A R Y O F K E Y P O I N T S

Incidence• The estimated annual incidence of

cutaneous T-cell lymphoma (CTCL) is0.4 in 100,000 cases.

• Cutaneous B-cell non-Hodgkin’slymphoma (NHL) representsapproximately 10% of all primary

cutaneous lymphomas.• The average age at presentation is 50

to 60 years, but CTCL has beenreported in children and adolescents.

Differential Diagnosis CTCL• The median lag time to diagnosis of

CTCL is approximately 6 years.• Premalignant disorders that may

potentially evolve into CTCL includeparapsoriasis, lymphomatoid papulosis,pre-Sézary syndrome, atypicaldermatitis, and dermal reticulosis.

• Histologic and clinical variants of CTCLconstitute 10% of the cases.

• CTCL must be further distinguishedfrom adult T-cell leukemia/lymphoma,Ki-1+ anaplastic large cell lymphoma,peripheral T-cell NHL, cutaneous B-celllymphomas, T-cell chronic lymphocytic

leukemia, leukemia cutis, cutaneouslymphoid hyperplasias, lymphomatoidcontact reactions, and insect bites.

Staging Evaluation CTCL• The initial evaluation of the patient

with CTCL should include completehistory, physical examination, andcomplete blood count (CBC) anddifferential to assess for the presenceof disease in peripheral blood;chemistry studies; and chestradiography.

• The physical examination shoulddetermine the percentage of bodysurface area involved.

• Skin biopsy specimens must beobtained for routine histologic studies,immunohistochemistry analysis, and T-cell receptor gene rearrangement orpolymerase chain reaction studies atthe time of the initial diagnosis.

Natural History CTCL• CTCL is an extranodal lymphoma,which may be indolent, as in mycosisfungoides, or aggressive, as in Sézarysyndrome.

• Localized limited-stage disease ispotentially curable. All otherpresentations are incurable.

Primary Therapy CTCL• Current initial therapies for CTCL are

tailored to extent, burden, and type ofdisease present and include use ofemollients or topical corticosteroids,topical chemotherapy (nitrogenmustard, BCNU, bexarotene),phototherapy, psoralen–ultraviolet A(PUVA) therapy, electron beamirradiation, photon irradiation,extracorporeal photochemotherapy,chemotherapy, peripheral blood stemcell transplantation, and allogeneictransplantation.

Selective Second- and Third-Line Therapies CTCL• Patients may respond to the same

therapeutic modality on more than one

occasion.• Multiple other palliative managementoptions are available as well.

INTRODUCTION

Primary cutaneous lymphomas represent the second most commonextranodal site for NHL.1 CTCL is a heterogeneous group of NHLsthat represent about 80% of all primary cutaneous lymphomas.These disorders of malignant lymphocytes have a proclivity for theskin and epidermis. The diagnosis of CTCL is based on clinico-pathologic criteria. This class of malignant lymphomas includes

mycosis fungoides with variants and Sézary syndrome. In addition tothese CTCLs, other malignant lymphoproliferative T-cell diseasesthat involve the skin include primary cutaneous CD30+ lymphopro-liferative disorders, peripheral T-cell lymphoma, adult T-cell leuke-mia/lymphoma, and others. CTCL forms a group of clinically diversedisorders that include cutaneous B-cell lymphomas (Table 113-1).Cutaneous lymphomas are distinguished on the basis of their clinical,histologic, immunologic, and molecular features. This chapter reviewsthe clinicopathologic features of and therapy for cutaneous lympho-mas including mycosis fungoides, Sézary syndrome, and cutaneousB-cell lymphoma, as well as their variants and related disorders.

EPIDEMIOLOGY

The estimated annual incidence of mycosis fungoides and Sézarysyndrome in the SEER (Surveillance, Epidemiology, and End Results)cancer registry was 1 per 100,000 population and in the well-definedpopulation of Rochester, Minnesota, is 0.9 per 100,000 residents.1,2 Epidemiologic data from the SEER program showed an increase inincidence of CTCL, from 0.2 case per 100,000 in 1973 to 0.4 case

per 100,000 in 1984, with no increase from 1983 to 1994.3,4

Theincidence of cutaneous lymphoma increases with age. Most reportedcases of CTCL are in adults. The average age at diagnosis is 50 to 60years,3 but cases have been reported in children and adolescents. 5 CTCL is more likely to develop in black populations.3 Mycosis fun-goides is the most common CTCL, representing 40% to 82% of newcases.6

Although environmental factors have been implicated in thepathogenesis of CTCL, two case-control studies have not supportedthe concept that industrial or related exposures cause the disease.7 Furthermore, no significant differences were documented in

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2406 Part III: Specific Malignancies

cutaneous allergy to plants, metals, and cosmetics or in reactions tomedications, foods, or insect bites between cases of mycosis fungoidesand controls, indicating that in most cases prolonged exposure tocontact allergens is not related to the development of CTCL.7 Inselected cases, however, patients with atopy, contact sensitivity,chronic dermatitis, or immunodeficiency may develop CTCL.8 Thevast majority of patients are human T-cell lymphotrophic virus type1 (HTLV-1)-negative. CTCL has been documented after B-cell lym-phomas, Hodgkin’s lymphoma, and renal transplantation.9–11 CTCLalso has been reported in the acquired immunodeficiency syn-drome.12

CLASSIFICATION

Previous classifications have not adequately characterized the cutane-ous lymphomas. The most recent lymphoma classification is the

World Health Organization (WHO) classification.13 The EuropeanOrganization for Research and Treatment of Cancer (EORTC) pro-posed a classification that divided patients into those with primaryT-cell or B-cell lymphomas.14 Significant differences, however, existbetween the two classification systems. The WHO-EORTC classifi-cation for cutaneous lymphomas was the result of consensus meetings(see Table 113-1).15 The relative frequency and survival data for 1905patients derived from Dutch and Austrian cutaneous lymphoma reg-

istries illustrate the clinical significance of the WHO-EORTC clas-sification (Table 113-2). This classification will lead to a moreuniform diagnosis of cutaneous lymphomas and also improves defini-tions of cutaneous lymphomas other than mycosis fungoides andSézary syndrome and provides definitions of cutaneous B-cell lym-phomas, allowing for a more reliable distinction between aggressiveand indolent types of cutaneous B-cell lymphoma.

Of the CTCLs, 50% are mycosis fungoides. The tumor-node-

metastasis (TNM) classification system is used in cutaneous lym-phoma (Table 113-3). A TNM classification system is used to stagepatients with mycosis fungoides and Sézary syndrome but is notappropriate for use with other primary cutaneous lymphomas (Table113-4). A consensus TNM classification system applicable for allprimary cutaneous lymphomas other than mycosis fungoides andSézary syndrome has been proposed.16

GENERAL CLINICAL MANIFESTATIONSOF MYCOSIS FUNGOIDESAND SÉZARY SYNDROME

The cutaneous clinical manifestations of cutaneous lymphoma arediverse, ranging from difficult-to-diagnose to indeterminate derma-titis-like lesions of skin to plaque- or tumor-stage CTCL. The mostcommon cutaneous lymphoma is mycosis fungoides. The second

most common cutaneous lymphoma is Sézary syndrome. Sézary syn-drome more characteristically arises without a previous history ofmycosis fungoides. If mycosis fungoides evolves into Sézary syn-drome, then the diagnosis should be erythrodermic mycosis fungoi-des. Atypical cutaneous lesions eventually are found to representCTCL. Patients may have a premalignant phase with eczematous ordermatitic skin lesions for several years, or even decades, before thediagnosis is established. The median time from appearance of of thepreceding skin eruption to diagnosis is approximately 6 years. Peri-odic skin examination and repeat skin biopsies as necessary are essen-tial in patients with suspicious cutaneous lesions. The spectrum ofpremalignant disorders includes various less common but distinctivelymphoid dermatoses, such as large-plaque parapsoriasis, poikilo-derma atrophicans vasculare, follicular mucinosis (alopecia muci-nosa), pityriasis lichenoides et varioliformis acuta (Mucha-Habermanndisease), and other atypical lymphocytic infiltrates of the skin. Gen-

erally, no specific clinical or pathologic markers have been identifiedthat clearly delineate those cases that will progress to CTCL.

The classic malignant phases of CTCL are manifested principallyin the skin and include patch-stage CTCL, plaque-stage CTCL,tumor-stage CTCL, and erythrodermic CTCL (Fig. 113-1). Extra-cutaneous involvement, nodal or extranodal, of CTCL develops withdisease progression.

The patch stage of mycosis fungoides (see Fig. 113-1A) is charac-terized by cutaneous erythematous macules and slightly infiltratedpatches of variable size, often located over the waist or on the trunk orproximal extremities. Pruritus may or may not be a feature. Individualskin lesions occasionally exhibit superficial scale, whereas indurationis minimal or absent. Pigmentation may be altered; depending on thenatural degree of pigment, hypopigmentation or hyperpigmentationmay be observed. The lesions may be present for months to yearsbefore the plaque stage of CTCL develops (see Fig. 113-1B).

Since the initial description of this disease by the French derma-tologist Alibert during the early 1800s, the discrete plaque stage andtumor stages of CTCL have been classically defined as mycosis fun-goides.17 The lesions of plaque- and tumor-stage CTCL are sharplydemarcated circular plaques that are infiltrated and elevated abovethe surrounding normal skin on the trunk and extremities. Theplaques are erythematous or occasionally violaceous and may exhibitcentral involution. Individual patches may overlap, producing a geo-graphic appearance. The lesions may be scaly or encrusted, occasion-ally exhibiting a papular quality (see Fig. 113-1B) They rarely become

Table 113-1 WHO-EORTC Classificationof Cutaneous Lymphomaswith Primary Cutaneous Manifestations

CUTANEOUS T-CELL AND NK-CELL LYMPHOMAS

Mycosis fungoides

Mycosis fungoides variants and subtypes

Folliculotropic mycosis fungoides

Pagetoid reticulosis

Granulomatous slack skin

Sézary syndrome

Adult T-cell leukemia/lymphoma

Primary cutaneous CD30+ lymphoproliferative disorders

Subcutaneous panniculitis-like T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Primary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma(provisional)

Cutaneous gamma/delta T-cell lymphoma (provisonal)

Primary cutaneous CD4+

small/medium-sized pleomorphic T-celllymphoma (provisional)

CUTANEOUS B-CELL LYMPHOMAS

Primary cutaneous marginal zone B-cell lymphoma

Primary cutaneous follicle center lymphoma

Primary cutaneous diffuse large B-cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lyphoma, other

Intravascular large B-cell lymphoma

PRECURSOR HEMATOLOGIC NEOPLASM

CD4+ /CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)

NK, natural killer; WHO-EORTC, World Health Organization–European Organization

for Research and Treatment of Cancer.

From Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous

lymphomas. Blood 2005;105:3768–3785.

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Cutaneous T-Cell Lymphoma and Cutaneous B-Cell Lymphoma • CHAPTER 113

vesicular or pustular or exhibit bolus features or a translucent granu-lomatous appearance. Patches evolve into larger plaques, with ovaland well-demarcated lesions with elevated borders. The plaques mayaffect the face, and the dermal thickening on the face may progressto give the classic leonine facies. Infiltration of the skin of the palmsand soles leads to hyperkeratosis and fissuring. More extensiveinvolvement of the scalp and other hair-bearing areas often is accom-panied by alopecia (see Fig. 113-1C). Pruritus may be significant andcan involve both lesional and nonlesional skin. Rarely, a solitaryplaque or nodule of mycosis fungoides has been observed in thecomplete absence of other skin findings.18

Tumor-stage lesions of CTCL have variable growth rates andtypically occur at sites of previous plaque-stage involvement. Progres-sion probably reflects local proliferation and evolution of moreaggressive clones of malignant cells. Multiple tumor-stage lesions ofCTCL arise de novo in the absence of patch-stage or plaque-stageCTCL but, when observed, have been reported as the d’emblée formof mycosis fungoides. The tumorous lesions may appear anywhereon the body but have a predilection for the body folds, includinggroin, antecubital fossa, neck, axilla, and inframammary areas. Thenodules and tumors typically are reddish brown or purplish and havea tendency to ulcerate (see Fig. 113-1D). Multiple lobulated and

coalescing lesions may develop on the face, resulting in leonine facies(see Fig. 113-1E). Tumor-stage CTCL is more clinically aggressivethan patch-stage CTCL, probably owing to the evolution of a laterstage of malignancy. Nodular lesions infrequently are pruritic andmore often are painful and tender, especially after ulceration hasoccurred. Ulcerative lesions frequently become colonized with bacte-ria and purulent. Histologically, the lesions may be similar to thosein plaque-stage disease, but they are denser and extend into the deepdermis and subcutaneous fat. Cellular composition may demonstratelymphoid polymorphism and inflammation, or the lesions may bemonomorphous, with almost exclusively less mature malignant T

cells and minimal or absent epidermatropism. At presentation,approximately 40% of patients have plaques on less than 10% of thebody surface area, 30% have extensive plaques, 15% exhibit a tumorphase, and 10% exhibit an erythroderma phase.

The classic erythrodermic form of CTCL, Sézary syndrome, is adistinctive CTCL entity that derives its name from the descriptivestudies and identification of unique blood cells by Sézary andBouvrain during the 1930s.19 Although this disease initially wasreported in the late 19th century, Sézary and Bouvrain associated themalignant reticulemic (leukemic) erythroderma with circulatinghyperchromatic mononuclear cells containing convoluted and/or

Table 113-2 Relative Frequency and Disease-Specific 5-Year Survival for 1905 Patients with PrimaryCutaneous Lymphomas Classified According to the WHO-EORTC Classification

WHO-EORTC Classification No. of Patients Frequency (%)*

Disease-Specific5-Year Survival(%)

CUTANEOUS T-CELL LYMPHOMA

Indolent clinical behavior

Mycosis fungoides 800 44 88

Folliculotropic mycosis fungoides 86 4 80

Pagetoid reticulosis 14 <1 100

Granulomatous slack skin 4 <1 100

Primary cutaneous anaplastic large cell lymphoma 146 8 95

Lymphomatoid papulosis 236 12 100

Subcutaneous panniculitis-like T-cell lymphoma 18 1 82

Primary cutaneous CD4+ small/medium pleotropic T-cell lymphoma† 39 2 75

Aggressive clinical behavior

Sézary syndrome 52 32 4

Primary cutaneous NK/T-cell lymphoma, nasal-type 7 <1 NR

Primary cutaneous aggressive CD8+

T-cell lymphoma†

14 <1 18 Primary cutaneous gamma/delta T-cell lymphoma† 13 <1 NR

Primary cutaneous peripheral T-cell lymphoma, unspecified‡ 47 2 16

CUTANEOUS B-CELL LYMPHOMA

Indolent clinical behavior

Primary cutaneous marginal zone B-cell lymphoma 127 7 99

Primary cutaneous follicle center lymphoma 207 11 95

Intermediate clinical behavior

Primary cutaneous diffuse large B-cell lymphoma, leg type 85 4 55

Primary cutaneous diffuse large B-cell lymphoma, other 4 <1 50

Primary cutaneous intravascular large B-cell lymphoma 6 <1 65

NR, not reached.

*Data for 1905 patients with primary cutaneous lymphoma registered with the Dutch and Austrian Cutaneous Lymphoma Group between 1986 and 2002.‡Primary cutaneous peripheral T-cell lymphoma, unspecified, excluding the three provisional entities indicated with a dagger (†).

From Willemze R, Jaffe E, Burg Gunter, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768–3785.

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cerebriform nuclei. These same cells infiltrate adenopathic lymphnodes. The cells subsequently were designated Sézary cells . The firstdescription in the English literature of Sézary syndrome was byTaswell and Winkelmann in 1961.20 The clinical presentation of thissyndrome includes exfoliative erythroderma, lymphadenopathy, andkeratoderma or thickening of the skin of the palms and soles, often

with development of cracks and fissures (palmoplantar hyperkerato-

sis; see Fig. 113-1F and G). Pruritus is a characteristic, often intensesymptom leading to excoriations, exudation, and crust formation.Nail dystrophy (onychodystrophy), ectropion (eversion, giving a“pulled-down” appearance) of the lower eyelids, and alopecia fre-quently are observed.

Sézary syndrome is defined by the presence of Sézary cells in theperipheral blood and the characteristic clinical and histologic featuresof the skin. Although mycosis fungoides may manifest with erythro-

derma and similar clinical findings, Sézary cells are not detected inthe peripheral blood by routine microscopic examination.Extracutaneous disease involving sites beyond the blood and

peripheral lymph nodes occurs in advanced CTCL. The reportedfrequency of extracutaneous involvement at autopsy ranges from54% to 100%.21,22 Loss of epidermotropism may play a role as thedisease disseminates.23 With disease progression, extracutaneousinvolvement becomes more common.22 Clinical evidence of extracu-taneous involvement of CTCL is classically manifested by peripherallymhadenopathy.22 Computed tomography (CT) demonstratesinvolvement of pelvic, abdominal, and axillary nodes that may notbe palpable. Less commonly, thoracic nodal disease is recognized withthis imaging technique. CT is not routinely used to stage earlyCTCL, because the yield is low. Positron emission tomography(PET) may be more sensitive than CT scanning.24 In a retrospectivereview of 251 lymph nodes in 200 patients, Vonderheid and col-

leagues reported lymph node involvement to be associated with apoor prognosis and the survival of patients with small cell type(median survival, 40 months) to be better than that for those withother types (median survival, 20 months).25 The Dutch CutaneousLymphoma Group reported that the presence of extracutaneousdisease, the type and extent of cutaneous involvement, the responseto initial therapy, and the presence of follicular mucinosis were asso-ciated with a higher rate of disease progression and mortality.26

Bone marrow involvement may develop during progression ofCTCL. At autopsy, the incidence is 27% to 47%.4,21 At initial staging,7% to 13% of patients have evidence of marrow involvement.27 Mostpatients with bone marrow involvement have concomitant nodal ororgan involvement and shortened survival.28 Liver involvement byCTCL is documented by nodular lymphoid infiltration of the portaltracts on liver biopsy and has been reported in 8% to 16% of patients

with CTCL.29,30 The presence of abnormal cells is not diagnostic of

liver involvement.29

Rarely, involvement of the central nervous systemby CTCL has been documented by imaging studies, on tissue biopsy,or at autopsy.

TISSUE DIAGNOSIS

The diagnosis of cutaneous lymphoma is established by tissue biopsy.Punch biopsy of involved skin, to obtain specimens 4 to 6 mm deep,is recommended for evaluation of patch-, plaque-, and tumor-stagelesions. In selected tumor-stage cases, elliptical excision biopsy maybe necessary. Several biopsies should be performed because multiplespecimens often are required to demonstrate diagnostic findings.Specimens for immunophenotyping and molecular genetic studiesshould be snap-frozen in liquid nitrogen and stored at −70° C. Cellsuspensions for flow cytometry and cytogenetic evaluation may beprepared from tissue.

The classic histologic findings diagnostic of CTCL consist ofabnormal lymphocyte morphology, a band-like superficial dermalinfiltrate, epidermotropism, and Pautrier’s microabscesses (Fig.113-2). Of note, significant variability exists in the expression of thesepathologic characteristics and the degree of individual abnormali-ties.31 In addition, significant intraobserver and interobserver vari-ability has been documented. In a study of 73 skin biopsy specimensfrom patients with mycosis fungoides reviewed on two separate occa-sions by three expert hematopathologists, an accurate diagnosis wasrendered on both readings approximately 50% of the time.32 Nosingle histopathologic criterion will establish the diagnosis. Lympho-

Table 113-3 Staging of Cutaneous T-CellLymphoma: Tumor-Node-MetastasisClassification

Classification Description/Definition

T: Skin

T0 Lesions clinically and/or pathologically suggestive

of CTCL

T1 Limited plaques, papules, or eczematous patchescovering <10% of skin surface

T2 Generalized plaques, papules, or erythematouspatches covering ≥10% of skin surface

T3 Tumors

T4 Generalized erythroderma

N: Lymph nodes

N0 No palpable adenopathy, lymph node pathologynegative for CTCL

N1 Palpable lymphadenopathy; lymph node pathologynegative for CTCL

N2 No palpable lymphadenopathy, lymph nodepathology positive for CTCL

N3 Palpable adenopathy, lymph node pathologypositive for CTCL

B: Peripheral blood

B0 Atypical circulating cells not present (<5%)

B1 Atypical circulating cells present (>5%)

M: Visceral organs

M0 No visceral organ involvement

M1 Visceral involvement (must have pathologicconfirmation, and organ involved should bespecified)

Table 113-4 Modified Tumor-Node-MetastasisStaging System for Classificationof Cutaneous T-Cell Lymphoma

Stage T N M

IA 1 0 0

IB 2 0 0IIA 1, 2 1 0

IIB 3 0, 1 0

III 4 0, 1 0

IVA 1–4 2, 3 0

IVB 1–4 0–3 1

B, peripheral blood; M, visceral organ; N, lymph node; T, skin.

From Bunn PA Jr, Lamberg SI: Report of the Committee on Staging and

Classification of Cutaneous T-Cell Lymphomas. Cancer Treat Rep 1979;63:725–728.

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A B

C D E

F G

Figure 113-1 • Cutaneous malignant phases and skin findings in cutaneous T-cell lymphoma. A, Patch stage. B, Plaque stage with scaling.C, Alopecia of scalp. D, Tumor stage. E, Leonine facies of tumor phase. F, Erythroderma of Sézary syndrome. G, Erythema, hyperkeratosis, andfissuring of soles in Sézary syndrome.

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cytes within the epidermis that are larger than those within the dermisis an important feature of epidermatropism.33 Pautrier’s microab-scesses are present in 4% to 37% of cases.34

On microscopic examination, the lymphocytes in CTCL (calledmycosis cells or Sézary cells) have variable but usually ample cyto-plasm. Nucleoli of the neoplastic cells are relatively large and hyper-chromatic. Mycosis cells can be isolated from various tissues by touchpreparation and microscopic examination. Sézary cells circulate in theblood and can be enriched in vitro by density centrifugation orimmunophenotypic characteristics. The prominent characteristics ofindividual nuclei of Sézary cells are their irregularity, with prominentindentations or convolutions that have a cerebriform appearance19 (Fig. 113-3). In 1968, Lutzner and Jordan further characterized theserpentine, or cerebriform, nuclei by electron microscopic examina-

tion35

(Fig. 113-4). Reactive lymphoid cells infiltrating the skin indermatitis, lichen planus, drug eruptions, psoriasis, and other derma-toses may have similar nuclear morphologic features on light micros-copy, but further examination reveals a normal nuclear diameter,nuclear-to-cytoplasm ratio, and nuclear contour index in these dis-orders. A review of 222 biopsy specimens from patients with mycosisfungoides or Sézary syndrome reported that CTCL produces thepatterns for diagnosing inflammatory disease, including superficialperivascular invasion and atypical lymphocytes in nearlyt half of thecases.36 The cells that mimic mycosis cells or Sézary cells representactivated T lymphocytes. Therefore, morphologic examination alone

A B

C

Figure 113-2 • Skin biopsy specimens of cutaneous T-cell lymphoma. A, Mononuclear cell infiltrate in perivascular area and bandlike distribution inepidermis with single cell exocytosis into epidermis of early mycosis fungoides.(Hematoxylin-eosin; original magnification, 40×.) B, Collections of lymphoidcells in the epidermis forming Pautrier’s microabcess, and dermal infiltrationof lymphocytes in plaque of mycosis fungoides. (Hematoxylin-eosin; originalmagnification, 40×.) C, Lichenoid dermatitis-like pattern with basal epidermalinfiltration by atypical lymphocytes (Hematoxylin-eosin; original magnifica-tion, 160×.)

Figure 113-3 • Peripheral blood smear demonstrating irregular Sézarynucleus with cerebriform appearance. (Wright’s stain.)

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lymph node involvement by clonal TCR gene rearrangement hasbeen associated with decreased survival.48 Clonal TCR gene rear-rangements are found in disorders that are not overtly malignant,however, including lymphomatoid papulosis, pityriasis lichenoides,and pagetoid reticulosis. T-cell clonality has been reported in 6% to24% of benign skin disorders characterized by a lymphoid infiltrate.49 Polymerase chain reaction (PCR) techniques to amplify specificgenetic rearrangements can increase the sensitivity 1000-fold.50 Thedetection of circulating clonal cells is not likely to be an indicator of

worse prognosis. These technical advances provide the capability toimprove monitoring of disease progression and response to treatment

and for earlier detection of minimal residual disease, quiescent disease,or relapse.

VARIANTS OF MYCOSIS FUNGOIDESAND SÉZARY SYNDROME AND CUTANEOUSB-CELL LYMPHOMA

A remarkable spectrum of variants of Sézary syndrome and mycosisfungoides and B-cell lymphoma have been recognized. These disor-ders are characterized by unique immunohistologic features andrequire disease-specific clinical and therapeutic interventions. Thecurrently recommended therapeutic interventions are summarized inTable 113-3.

Variants and Subtypes of Myosis Fungoides

Folliculotropic mycosis fungoides is a disorder of localized alopecia with mucin deposition in the hair follicle, with variable inflamma-tion, characterized clinically by multiple grouped follicular papules

with occasional formation of patches or nodules, with preferentialinvolvement of the head and neck area with severe pruritus 51 (Fig.113-7). On histopathologic examination, sparing of the epitheliumis seen, and most cases demonstrate mucinous degeneration of thefollicular epithelium.

Pagetoid reticulosis is characterized by solitary slow-growingplaques (Woringer-Kolopp type) or disseminated patches on thehands or feet that grow slowly and progress to disseminated skin

lesions (Ketron-Goodman type).52 The CD30 antigen often isexpressed. The solitary slow-growing lesion has a chronic course ofyears to decades.

Granulomatous slack skin is a disorder characterized by excessiveredundant folds of skin and plaques in the axilla and groin.53–55 Astriking granulomatous reaction and loss of dermal elastic tissueaccompany the lymphocytic infiltrate, and the disease may progressto disseminated T-cell lymphoma. Although in most cases the disease

has an indolent course, an association with Hodgkin’s lymphoma hasbeen reported in one third of affected patients, and an association with mycosis fungoides has been reported.54

Variants and Subtypes of Sezary Syndrome

The variants and subtypes of Sézary syndrome are multiple. Theyinclude adult T-cell leukemia/lymphoma; primary cutaneous CD30+ lymphoproliferative disorders (primary cutaneous anaplastic large celllymphoma, lymphomatoid papulosis, and borderline cases); subcuta-neous panniculitis-like T-cell lymphoma; extranodal natural killer(NK)/T-cell lymphoma of nasal type; primary cutaneous peripheralT-cell lymphoma, unspecified; and CD4+/CD56+ hematodermicneoplasm (blastic NKcell lymphoma).

Adult T-cell leukemia/lymphoma may manifest with skin lesionsbut few or absent circulating cells and is associated with the humanT-cell leukemia virus 1 (HTLV-1) with integrated HTLV-1 genes inall cases.55 A skin lesion smoldering variant has been reported.56 Patients may present with papules (22%) or plaques (19%).57

Primary cutaneous CD30+ lymphoproliferative disorders, whichinclude primary cutaneous anaplastic large cell lymphoma, lympho-matoid papulosis, and borderline cases, may account for up to 30%of cutaneous lymphomas.58 Histologic criteria alone do not separatethese disorders, and long-term follow-up establishes the diagnosis.59 Primary cutaneous anaplastic large-cell lymphoma expresses CD30in more than 75% of cells, and most express the cutaneous lympho-cyte antigen (CLA). Patients initially present with localized nodules,tumors, or papules. Up to 20% of patients have multifocal lesions,and 10% have disseminated disease. The survival is greater than 10years.59 Lymphomatoid papulosis is defined as a chronic, recurrent,erythematous, and self-healing papulonecrotic or papulonodular skindisease with histologic features suggestive of a (CD30+) malignantlymphoma 60 (Fig. 113-8). The lesions spontaneously resolve in 3 to12 weeks. The clinical course is unpredictable, with duration ofdisease activity ranging from a few months to 20 years. Hodgkin’slymphoma, cutaneous anaplastic large cell lymphoma, or mycosisfungoides may precede, be associated with, or follow lymphomatoidpapulosis.59 Morphologic patterns have been classified as types A, B,

A B

C PBJβ1 Jβ2 Tγ

Figure 113-6 • A, Immunogenotyping by Southern blot analysis for apatient with Sézary syndrome. Control (C), skin (S), and peripheral blood

(PB) specimens. A distinct band of clonal rearrangment is identified (arrow) using probes that recognize the T-cell beta chain genes (Jβ2). Only germlinebands are identified in the Jβ1 gene. B, Polymerase chain reaction (PCR)analysis of PB identified a distinct band of clonal rearrangement (arrow).

Figure 113-7 • Follicular mucinosis manifested as patches of alopecia.

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and C.60 Type A lesions resemble those of CD30+ anaplastic largecell lymphoma or Hodgkin’s lymphoma, and type B lesions arecomposed of small lymphoid cells. In one series of 118 patients with

lymphomatoid papulosis, progressive disease developed in only 4%;2% died of systemic disease.59

Subcutaneous panniculitis-like T-cell lymphoma characteristicallyinvolves the legs, with infiltrates of γ /β+, CD3+, CD8+, and CD4− cytotoxic protein–expressing lymphocytes that may rim fat cellsaccompanied by many macrophages; the epidermis and dermisremain uninvolved.15 Fevers, fatigue, weight loss, and the hemo-phagocytic syndrome may be clinical manifestations and are associ-ated with a rapid and progressive course.61 The nodules or plaquesmay be solitary or multiple (Fig. 113-9).

Other disorders to be considered in the differential diagnosisinclude extranodal NK/T-cell lymphoma, nasal type; primary cutane-ous peripheral T-cell lymphoma, unspecified; primary cutaneousaggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (provi-sional entity); cutaneous gamma/delta T-cell lymphoma (provisional

entity); primary cutaneous CD4+ small or medium-sized pleomor-phic T-cell lymphoma (provisional entity); primary cutaneousperipheral T-cell lymphoma, unspecified; and CD4+/CD56+ hema-todermic neoplasm (blastic NK-cell lymphoma).15 The managementof disorders other than mycosis fungoides and Sézary syndrome asrecommended by the WHO-EORTC is outlined in Table 113-5.

Cutaneous B-Cell Lymphomas

Primary cutaneous B-cell lymphoma may account for to 20% of cuta-neous lymphomas62 (Fig. 113-10). This group of disorders must bedistinguished from pseudolymphoma.63 The WHO-EORTC classifi-cation recognizes primary cutaneous marginal zone B-cell lymphoma(PCMZL); primary cutaneous follicle center lymphoma (PCFCL);primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT);and primary cutaneous large B-cell lymphoma, other (PCLBL–other).The reclassification resulted in reassignment to other categories for5.3% of the EORTC scheme cases and 36.3% of the WHO schemecases.64 The 5-year disease specific survival rates are 98% in PCMZL,95% in PCFCL, and 50% in PCLBCL-LT.64 In this classification,PCFCL is defined as a tumor of follicle center cells,composed pre-dominantly of large cleaved cells that do not express Bcl-2 and MUM-1, in contradistinction to PCLBCL-LT cells, which express Bcl-2 andMUM-1.65 PCFCL-LT has been associated with a poor prognosis.

The reported disease-specific 5-year survival rate was 50%, and theoverall survival (OS) rate was 37%.64

PCMZL is an indolent lymphoma composed of small B cells andis considered to be part of the spectrum of extranodal marginal zoneB-cell lymphomas, which commonly involve mucosal sites, calledmucosa-associated lymphoid tissue (MALT) lymphomas. This groupincludes cases previously designated as primary cutaneous immuno-cytoma and includes primary cutaneous myeloma (extramedullaryplasmacytoma of skin).66,67 These lesions occur most commonly infemales and most commonly develop on sun-exposed areas of theskin, especially on the arms. The lesions are violaceous papules,plaques, or nodules. Dissemination is rare.67 These lymphomas arenodular or diffuse, with sparing of the epidermis, and rarely trans-form into diffuse large B-cell lymphoma. The lesions are CD20+,CD79a +, Bcl-2+, CD5−, CD10−, and Bcl-6−, with clonally rearrangedimmunoglobulin heavy chain (IgH) genes. Localized lesions can be

treated with radiation therapy or surgical resection. Multifocal lesionscan be treated with oral chlorambucil, interferon-α (intralesional orsubcutaneous), or rituximab.68

PCFCLs are follicular, follicular and diffuse, or diffuse, with sparingof the epidermis; lesions typically appear on the head and torso.Patients present with solitary or grouped plaques and tumors. In aminority of cases, the initial presentation is with multifocal disease,

which has an unfavorable prognosis.69 The cells are CD20+, CD79a +,CD10+ in follicular cases, CD5−, and Bcl-2−, and genes are clonallyrearranged with no consistent cytogenetic abnormalities.15 In contrast

with systemic follicular lymphoma, these lesions do not demonstratethe t(14;18) translocation.70 The therapy of choice in patients withlocalized disease is radiation therapy, even in cases with a predomi-nance of large “cleaved” cells.71 Cutaneous relapses may be treated withradiation therapy. Anthracycline-based chemotherapy is recommendedin patients with extensive cutaneous disease and extracutaneous

disease.72

Systemic and intralesional rituximab is active in this disease.73

Recent studies report t(14;18) and Bcl-2 expression; expression of Bcl-2 by more than 50% of neoplastic cells in patients with a diffuse patternis associated with an unfavorable prognosis.74,75

PCLBCL-LT is PCLBCL characteristically manifesting with redor bluish-red skin lesions on the lower extremities, and uncommonlyseen in other sites, that often disseminate to extracutaneous sites andoccurs predominantly in females.64 The cells are CD20+, CD79a +,and Bcl-2+. Patients with a single lesion on one leg had a 5-yeardisease-free survival rate of 100%, versus 45% for patients withmultiple skin lesions on one leg and 36% for those with lesions on

Figure 113-8 • Lymphomatoid papulosis: Characteristic erythematouspapulonodules with crust and ulceration.

Figure 113-9 • Subcutaneous T-cell lymphoma.

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Table 113-5 Management of Disorders Other Than Mycosis Fungoides and Sézary Syndromeas Recommended by the WHO-EORTC

Disease Type Management Strategies

Folliculotropic mycosis fungoides Total body electron beam irradiation

PUVA combined with retinoids or interferon-α

Local radiation therapy

Pagetoid reticulosis Radiation therapy or surgical excision

Topical steroids or topical nitrogen mustard

Granulomatous slack skin Radiation therapy

Surgical excision

Adult T-cell leukemia/lymphoma In chronic and smoldering cases affecting skin only, skin-targetedtherapies

Primary cutaneous anaplastic large-cell lymphoma Solitary or localized: Radiation therapy or surgical excision

Extracutaneous or progressive disease Anthracycline-based chemotherapy

Lymphomatoid papulosis Observation

Methotrexate 5–20 mg/week

PUVA

Topical chemotherapy

Subcutaneous panniculitis-like T-cell lymphoma Systemic corticosteroidsAnthracyline chemotherapy and radiation therapy

Extranodal NK/T-cell lymphoma, nasal type Radiation therapy ± chemotherapy (stage I/II disease)

Chemotherapy for advanced disease

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma Anthracycline chemotherapy

Cutaneous gamma/delta T-cell lymphoma Systemic chemotherapy

Primary cutaneous CD4+ small or medium-sized pleomorphic T-cell lymphoma Radiation therapy or surgical excision

Cyclophosphamide

Interferon-α

Primary cutaneous peripheral T-cell lymphoma, unspecified Anthracycline chemotherapy

CD4+ /CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) Acute leukemia systemic therapy regimens

NK, natural killer; WHO-EORTC, World Health Organization–European Organization for Research and Treatment of Cancer.

Data from Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768–3785.

Figure 113-10 • Diffuse large B-cell lymphoma. A, Unicentric disease. B, Multicentric disseminated disease.

A B

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both legs.76 Systemic anthracycline-based chemotherapy is recom-mended.76 Rituximab is active in this disease in combination withsystemic chemotherapy.73

Primary cutaneous diffuse large B-cell lymphoma–other includesmorphologic variants of lymphoma, plasmablastic lymphomas,primary cutaneous T-cell or histiocyte-rich B-cell lymphomas, andintravascular large B-cell lymphoma. Intravascular large B-cell lym-phoma is characterized by an accumulation of malignant large B cells

within the blood vessels that affects the central nervous system, lungs,and skin.77 Patients characteristically present with disseminated diseasebut initially may exhibit only skin involvement, with violaceouspatches or plaques or telangiectasias of the legs or torso.78 Patientspresenting with only cutaneous disease enjoy better survival, with a3-year OS rate of 56%, versus 22% for the disseminated form.78

Anthracycline-based chemotherapy is associated with a 60% responserate and a 3-year OS rate greater than 30%.77 The R-CHOP regimen(rituximab, cyclophosphamide, doxorubicin, vincristine, and predni-sone) should be considered as an initial treatment approach. 77

STAGING AND PROGNOSIS OF MYCOSISFUNGOIDES AND SÉZARY SYNDROME

As with Hodgkin’s disease and NHL, the prognosis for CTCL andits variants is related to the stage of the disease. The significant prog-

nostic factors in CTCL are the extent and type of skin involvement.The Mycosis Fungoides Cooperative Group adopted a modifiedTNM classification in 1975, which was further modified by theStaging Committee at the International Workshop on Mycosis Fun-goides (see Tables 113-3 and 113-4).79 A modified TNM classifica-tion for primary cutaneous lymphomas other than mycosis fungoidesand Sézary syndrome has been proposed.80 The TNM classificationsystem is not routinely used in clinical practice.

The greater the percentage of involvement of skin surface area byCTCL, the worse the prognosis. Involvement of less than 10% of thebody surface area by CTCL—stage IA—portends a better prognosisthan that associated with stage IB, defined as greater than 10% skininvolvement. Patients with plaque-stage disease have a more favorableprognosis than that for patients with tumor-stage disease. In mycosisfungoides, 90% of patients with patch- or plaque-stage disease withless than 10% skin involvement survived 15 years or longer.81 Among

309 patients with mycosis fungoides, the 5-year disease-free survivalrate was 100% for those with limited cutaneous disease, 80% forthose with tumor-phase disease, and 40% for those with lymphnode–phase disease.82 Survival of patients with tumor-stage disease isreported to be better than that of patients with stage III or erythro-dermic disease.83 For patients with limited patch- or plaque-stagemycosis fungoides, life expectancy is similar to that for an age-, sex-,and race-matched control population. Unequivocal histologic involve-ment in the lymph nodes is predictive of survival, with a mediansurvival actuarial survival of 53 months with such involvement and137 months without.84 The prognosis in Sézary syndrome is poor,

with a median survival time of 2 to 4 years.85

The recommended approach to clinical evaluation for staging isoutlined in Box 113-1 and can serve as a general guide for clinicaltrials.79 Liver biopsies are not indicated in routine staging for patients

with CTCL. The role of CT scans is controversial. Routine CT scan-

ning does not improve detection of advanced disease but may beclinically useful in early plaque-stage disease.86 CT provides onlyanatomic information. Lymphadenopathy in CTCL may be relatedto underlying disease but also to dermatopathic lymphadenopathy.87 In a study at Stanford University, only 5 patients had enlarged lymphnodes on CT, whereas integrated PET and CT (PET/CT) revealedmetabolic activity in all 13 patients.88 The intensity of PET activitycorrelated with the histologic lymph node grade.

On initial diagnosis, approximately 42% of patients have plaquescovering less than 10% of the body surface (T1), 30% are character-ized by T2, 16% have tumors (T3), and 12% have erythroderma(T4).79,83

Bone marrow involvement is determined by the method of assess-ment. On morphologic analysis, Salhany and colleagues demon-strated aggregates of lymphocytes and cerebriform nuclei in 21.7%of cases and abnormal lymphoid aggregates in 31.6%.89 Infiltrativedisease was associated with peripheral blood involvement. The fre-quency of clonal T-cell involvement in the bone marrow has beenreported to be 75% and does not alter prognosis. 90

Other prognostic factors have been reported. The absence or pres-ence of greater than 5% of Sézary cells in total lymphocyte count anda CD4+/CD7− phenotype double the risk of death.91 Additionalprognostic factors include age of 60 years or older, elevated lactatedehydrogenase (LDH) level, and a low percentage of CD8+ cells inthe lymph node.92,93

HISTOLOGIC TRANSFORMATIONTransformation is defined as the presence of greater than 25% largecells and represents an evolution of the original clone. The risk oftransformation has been reported to be 12% to 23%, with thereported median times from diagnosis to transformation of 12 months

to 6.5 years and a median survival time of 19 to 22 months.

94,95

Age and extracutaneous involvement were associated with worseprognosis.95

SECOND CANCERSThe Finnish Cancer Registry and others have reported an increasedoverall risk of lung cancer, small cell lung cancer, Hodgkin’s lym-phoma, and NHL.96,97

CAUSE OF DEATHThe most common cause of death in CTCL is infection, the mostcommon organisms of which are Staphylococcus aureus , members ofthe family Enterobacteriaceae, and Pseudomonas aeruginosa .98, 99 Dis-seminated herpes and fungal infections may occur in patients withadvanced disease. Up to 47% of deaths are caused by cardiopulmo-nary disease and secondary malignancy.99, 100 Patients with cutaneous

tumors and erythroderma characteristically die of complications ofprogressive disease.

THERAPY

OverviewTherapeutically, CTCL is similar to low-grade NHL in that onlylimited stage disease is potentially curable, and both of these diseasesare remarkably responsive to many different therapeutic modalitiesdespite eventual relapse. Patients with either type of lymphoma mayrespond to the same therapeutic modality on more than one occasion,and they typically survive for years after the initial diagnosis. Advanced

Box 113-1. APPROACH TO CLINICALEVALUATION FOR STAGINGOF CUTANEOUS T-CELL LYMPHOMA

• Complete history and physical examination

• Whole-body mapping of skin lesions with or without photography

• Complete blood count, differential count, and platelet count; Sézary

cell count• Serum chemistries (liver and renal function tests; determination of

serum levels of calcium, phosphorus, creatinine, and uric acid)

• Chest radiography

• Skin biopsy for routine histology and possible immunophenotyping/

T-cell receptor gene rearrangement analysis

• Lymph node biopsy (palpable node from draining area; cervical

before axillary before inguinal)

• Evaluation of other organs if foregoing tests suggest involvement;

computed tomographic scan, liver biopsy, and bone marrow biopsy

only for patients with stage II, III, and IV disease

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disease is rarely curable, and both CTCL and indolent NHL maytransform into higher-grade lymphoproliferative disorders. In theabsence of a therapeutic approach that leads to long-term disease-freesurvival and cure, current therapies are tailored to the extent, burden,and type of disease present. The primary goals of treatment are tocontrol the cutaneous disease, to obtain symptomatic relief, and toachieve complete clinical remission.

Therapies available for the treatment of CTCL are wide ranging

and illustrate the distinctive presentation and disease course of thistype of lymphoproliferative disorder, as well as reflecting unique chal-lenges that face clinicians and therapists in treatment of CTCL and inclinical management of the patient. Therapies broadly include skin-directed biologic response modifiers, monoclonal antibodies, andcytotoxic therapy. Therapeutic options include topical treatments

with corticosteroids, chemotherapy with nitrogen mustard or carmus-tine (BCNU), ultraviolet B (UVB) phototherapy, photochemother-apy with psoralen plus ultraviolet A (PUVA), irradiation with electronbeam or photon therapy, systemic chemotherapy with either single ormultiple agents, combined-modality therapy (chemotherapy, electronbeam radiation therapy, and other combinations), extracorporealphotochemotherapy, interferons, monoclonal antibody therapy, reti-noids, purine analogs, cyclosporine, acyclovir, autologous peripheralblood stem cell transplantation, allogeneic bone marrow transplanta-tion, dentileukin difitox, and alemtuzumab (Table 113-6).

Factors other than disease stage that require consideration in themanagement of patients with CTCL include the general health andage of the patient, availability of various therapeutic options, and theextent and aggressiveness of the disease (see Table 113-6). In thecontext of therapeutic results and toxicities, it must be recognizedthat many of the published studies of CTCL are not prospectiverandomized trials with control groups. Because CTCL is an uncom-mon disease, multicenter cooperative clinical trials have been limited,and consensus is not well defined at this time. Table 113-7 detailsspecific treatment options for different stages of mycosis fungoidesand Sézary syndrome.

General Skin Care Measures

Nonspecific topical treatment of mycosis fungoides and Sézary syn-drome includes supportive therapies that miminize skin irritation,

provide lubrication and adequate hydration, and ameliorate inflam-matory reactions of the skin that accompany CTCL. After the diag-nosis of CTCL has been established with skin biopsy, low-potencyand mid-potency topical corticosteroid creams or ointments may beused to control the symptoms of pruritus and dermatitis.101 Topicalcorticosteroids should be avoided or discontinued for several weeksbefore skin biopsy because these agents suppress cutaneous inflam-matory responses and can potentially mask the histopathologic fea-tures of CTCL. Regular soaking baths and application of lubricatingcream to maintain skin hydration also are beneficial. Prompt treat-ment of infected areas of the skin and colonized or purulent ulcersminimizes the potential for more serious infections.99

Topical Therapies

Topical Chemotherapy

Topical corticosteroids are the mainstay of treatment for CTCL.Twice-daily application of topical class I steroids for 2 to 3 monthsis effective in mycosis fungoides plaque- and patch-stage disease,probably by inducing apoptosis. Skin atrophy and adrenal suppres-sion are potential complications. In a series of 79 patients, 63%achieved a complete remission and 31% a partial remission on follow-up evaluation at a median of 9 months.102

Mechlorethamine (nitrogen mustard), available as mechloretha-mine hydrochloride, was the first topical agent with demonstratedefficacy in CTCL.103 Since its initial clinical use during the late1940s at the Mayo Clinic, this alkylating drug has proved effective

Table 113-6 Therapeutic Options for CutaneousT-Cell Lymphoma

Topical medications

Corticosteroid

Mechlorethamine (nitrogen mustard)

Carmustine (BCNU)

Bexarotene gel

Imiquimod

UVB phototherapy

PUVA photochemotherapy

High-intensity UVAI phototherapy

Photodynamic therapy (PDT)-5-ALA

Radiotherapy with electron beam

Photon irradiation

Single-agent chemotherapy

Methotrexate

Pegylated liposomal doxorubicin

Temozolomide

Combination chemotherapy

CHOP

Combined-modality therapy

Extracorporeal phototherapy (ECP)

Cytokines

Interferons

Interleukin-2

Thymopetin

Monoclonal antibody therapy

Alemtuzumab (anti-CD52)

Anti-CD4

Retinoids

Isotretinoin Acitretin

Bexarotene

Purine nucleoside analogs

2′-Deoxycoformycin (pentostatin)

Fludarabine

2-Chlorodeoxyadenosine (cladribine)

Gemcitabine

Immunotoxins

IL-2 fusion toxin (denileukin diftitox)

Pseudomonas immunotoxin anti-Tac(Fv)-PE38 (LMB-2)

Histone deacetylase inhibitors

Vorinostat

Depsipeptide

Vaccination-immunotherapy

Bone marrow transplantation

Autologous

Allogeneic

Nonmyeloablative allogeneic

CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IL-2, interleukin-2;

PUVA, psoralen plus ultraviolet light A; UVB, ultraviolet (light) B.

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ethamine can be suspended in an oil-water base such as Aquaphor, which remains stable for longer than a month. Mechlorethamine isroutinely applied to the entire skin surface, except the eyelids, geni-talia, rectum, and intertriginous areas, where the potential for sig-nificant irritation limits its use. Application of the solution isperformed daily and increased to twice a day, or the concentrationcan be doubled. The initial treatment program lasts 6 to 12 months,and maintenance therapy 3 times per week is continued for 1 to 2

years or longer. The agent does not cause cytopenias or secondaryleukemias because it is not absorbed systemically. Its use as describedis an efficient and conservative outpatient program in patients withoutlarge tumors or systemic involvement.

Mechlorethamine had been evaluated in clinical trials. Vonder-heid and colleagues reported on 324 patients with CTCL, withcomplete remission rates of 80% in stage IA disease, 68% in stageIB, 61% in stage IIA, 49% in stage IIB, and 60% in stage III.104 Twenty percent of patients had a complete remission of 4 years ormore, and 11% had continuous complete remission. Other therapieshave been used in numerous patients, including local irradiation,electron beam radiation therapy, PUVA therapy, UVB phototherapy,and chemotherapy. None of the 34 patients who were in long-termcomplete response (CR) received electron beam radiation therapy orphototherapy, but 9 patients received chemotherapy, including intra-venous methotrexate and mechlorethamine. Therapy was discontin-

ued within 6 months of attainment of CR in 10 of 34 patients, whodid not experience a relapse after 8 years. The probability of achiev-ing a CR at 2 years was 75.8% for stage I, 44.6% for stage II, and48.6% for stage III in 117 patients for whom the only other treat-ment was radiation therapy, and the median time to CR was 11months.105 In 123 patients who received only ointment-based mech-lorethamine in Aquaphor or polyethylene gel, the CR rate was 51%in T1 disease; 26% in T2 disease; zero in T3; and 22% in T4.106,107 Of the patients who relapsed, 54% achieved a second CR.107 Thetreatment durations were variable, with Hoppe and associates recom-mending treatment for 1 to 2 years after achieving a response,106 Ramsay and coworkers, treatment for 6 months after clearing anda taper of 1.5 years,105 and Vonderheid and colleagues, only 6months of therapy.104 The major toxic effect of mechlorethamine isallergic toxic contact dermatitis, which occurs in 35% to 65% ofpatients.104–107 The incidence can be decreased to less than 10% with

use of mechlorethamine dissolved in ointment. Avoidance of skinexposure to sunlight is recommended. Other toxicities include dryskin, irritant dermatitis, hyperpigmentation, bullous reactions, urti-caria, Stevens-Johnson syndrome, and telangiectasias.106 An increasedrisk of second malignancies of squamous cell carcinoma and basal cellcarcinoma with use of this agent has been recognized, 104,106 althoughmost patients received multiple other therapies. In the series reportedby Hoppe and associates,106 secondary cutaneous malignancies devel-oped in only 1 of 14 patients who received mechlorethamine alone.No randomized trials with adequate patient numbers have comparedtopical therapy with other therapeutic modalities.

Carmustine applied at daily doses of 10 to 20 mg per day for 4to 8 weeks produced responses similar to those observed with mech-lorethamine.108 In contrast with the absence of such effects withmechlorethamine, bone marrow suppression occurred in 7.4% ofpatients. Chronic skin telangiectasias also may develop with use of

carmustine.Topical bexarotene 1%, applied twice daily, is the first syntheticretinoid approved by the U.S. Food and Drug Administration (FDA).The complete remission rates ranges from 21% to 23%, and themean overall response (OR) rate is 63%, with a median time toprogression of 149 days (range, 52 to 342 days).109,110 The responserate in a series of 94 patients was reported to be 45% with a doseschedule of 300 mg/m2 per day.110 Rash was reported in 56% of thepatients and pruritus in 18%. The most frequent side effects arehypertriglyceridemia, pancreatitis, hypercholesterolemia, hypothy-roidism, and headaches. Bexarotene induces apoptosis in CTCL.111

Table 113-7 Stage-Specific Optionsfor Management of CutaneousT-Cell Lymphoma

PATCH, LIMITED AND GENERALIZED PLAQUE

Primary therapy

Topical corticosteroids

PUVA photochemotherapy

UVB phototherapy

Bexarotene gel or capsule

Mechlorethamine (nitrogen mustard)

Electron beam

Secondary therapy

BCNU (carmustine)

Imiquimod

High-intensity UVAI phototherapy

TUMOROUS DISEASE

Primary therapy

CHOP

Denileukin diftitox

Bexarotene capsule

Secondary therapy

Radiation therapy



ERYTHRODERMA, SÉZARY SYNDROME

Primary therapy

Extracorporeal photophoresis (ECP)

Interferon-α

Bexarotene

Secondary therapy

Denileukin diftitox

Interleukin-2



EXTRACUTANEOUS DISEASE

Primary therapy

CHOP

Denileukin diftitox

Secondary therapy




CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; PUVA, psoralen

plus ultraviolet light A; UVAI, ultraviolet light A; UVB, ultraviolet light B.

in limiting the progression of disease and controlling symptoms ofcutaneous lesions in patients with CTCL. The agent undergoes rapiddegradation to an active ethylenimonium ion, which has high anti-mitotic activity and a half-life of less than 10 minutes. Mechloretha-mine may be prepared and applied in any of several different ways.It is soluble in water and typically is formulated at a concentrationof 10 to 20 mg/dL. Alternatively, an alcoholic extract of mechlor-

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Other topical agents that have been evaluated include cytarabine,dianhydrogalactitol, dacarbazine, guanazole, teniposide, hydroxy-urea, thiotepa, and methotrexate.112

Ultraviolet B Phototherapy and Ultraviolet APhotochemotherapy

UVB phototherapy has been used for years in the treatment of early

patch-stage CTCL and the premalignant dermatosis, large-plaqueparapsoriasis. The treatment is administered three times per week. Aretrospective study has supported the clinical observations that UVBphototherapy provides favorable responses including clinical remis-sion and lasting improvement in early patch-stage CTCL.113 UVBpenetrates only the epidermis and the superficial dermis, however,and has no effect on more indurated plaque-stage or extensive formsof CTCL. UVB phototherapy in patients with darkly pigmented skinis less effective because melanin absorbs the ultraviolet radiation.114 UVB phototherapy has a tendency to aggravate the erythrodermaand pruritus of Sézary syndrome and should be avoided for thisdisorder.

Treatment of CTCL with PUVA with 8-methoxypsoralen prepa-rations administered orally has been shown to be effective in thecontrol of early disease. 8-Methoxypsoralen is a member of a familyof photoactivated compounds that inhibit DNA synthesis through

formation of monofunctional or bifunctional adducts and crosslinksof nucleic acids, resulting in apoptotic cell death. PUVA has otherbiologic effects that may contribute to the responses in CTCL,including direct cytotoxic, anti-inflammatory, and immunomodula-tory reactions. A dose of 0.6 mg/kg of 8-methoxypsoralen is given 2hours before UVA treatment, or an encapsulated form (OxsoralenUltra or Uvadex) is ingested 1 hour before treatment. The maintoxicity is nausea and vomiting, which may be avoided by using 5-methoxypsoralen.115 This drug is contraindicated in liver disease.

The patient is exposed to UVA lamps, which emit long UV (A-band) radiation in the wavelength range of 320 to 400 nm. UV-protective eyeglasses are worn for 24 hours after treatment. Thistherapy usually is given three times per week for 3 to 6 months, fol-lowed by tapering. After an initial report by Gilchrest and colleagues,multiple trials of efficacy of PUVA in early-stage disease have beenreported.116,117 Roenigk and colleagues reported that at a mean follow-

up of 45 months, 82% of patients had complete clearing of plaquedisease, with 88% remaining in complete remission for a medianduration of 13 months.118 Clearing of lesions was observed in 51.9%of the patients with extensive plaque disease, with a mean durationof 11 months; no clearing occurred in patients with tumor-stage ornodal-stage disease. In erythrodermic CTCL, 46% of the patientsdemonstrated clearing of the disease, but 75% relapsed. In patientsfollowed for a mean of 44 months, no recurrences were noted in55.6% of patients with stage 1A disease and in 38.5% of patients

with stage IIB disease.119

PUVA has been combined with topical nitrogen mustard, reti-noids, aerosolized granulocytemacrophage colony stimulating factor(GM-CSF), and interferon alfa-2a.120–124 Retinoids have been reportedto decrease the number of PUVA treatments and the total UVAdose.123 The OR rate in 39 patients with mycosis fungoides was 90%(62% CR and 28% partial response [PR]), with a median response

duration of 28 months. Retrospective evaluation of data for 30patients who received low-dose interferon alfa-2a showed a CR in83% (25 of 30) after a median of 5 months of treatment, with amedian remission duration of 22 months.125

Contraindications to UV radiation therapy include systemic lupuserythematosus, skin cancer, porphyria, and genetic syndromes sec-ondary to DNA repair defects.115 Toxic reactions from PUVA therapyinclude nausea, vomiting, pruritus, erythema, xerosis, dry skin, blis-tering, and burns. Other, less common or potential side effectsinclude development of pigmented melanocytic macules of the skin,nail pigmentation, and cataract formation.125 Amyloid deposition hasbeen reported.126 UV light–blocking eyeglasses should be worn for

24 hours after psoralen is administered. Long-term toxic reactions ofgreater concern include squamous cell carcinoma of the skin orgenitalia, photoaging, and amyloid deposition in the skin.127

Electron Beam Radiation Therapy

Electron beam radiation therapy was first used for malignant cutane-ous lesions lesions in 1953 and has been advocated for treatment ofCTCL with both limited and extensive cutaneous involvement.128,129

Electrons are delivered to a depth of several millimeters to 1 cm. Ina series of 192 patients with CTCL treated at Stanford Universitybetween 1966 and 1987 to a total dose of more than 2000 cGy, thecomplete remission rate in limited plaque disease (T1) was 98%, witha freedom-from-relapse rate of 50%; in generalized plaque disease(T2), 71%, with a freedom-from-relapse rate of 20%; in tumor-stagedisease, 36%; and, in erythroderma, 64%.130 Most relapses occur

within 5 years. The 10-year survivor rate was 46%. Other studieshave reported an OS rate of 70%.131 The usual total dose is 3000 to3600 cGy delivered over 8 to 10 weeks of treatment. The toxic reac-tions include desquamative skin reactions on the feet and toes, ery-thema, blister formation, exfoliation, dryness, extensive alopecia witheventual recovery of hair growth, temporary nail loss, inability tosweat because of loss of sweat glands, hyperpigmentation, and telan-giectasias.128–130 The increased risk of squamous and basal cell carci-nomas is perhaps greatest in those patients who have received

multiple therapies including irradiation, topical nitrogen mustard,and PUVA.132 Most patients are given only a single course of treat-ment. One study evaluating retreatment for CTCL, however, reported6 CRs and 8 PRs in 15 patients.133 Adjuvant therapy with nitrogenmustard, PUVA, or extracorporeal photochemotherapy may be usedto decrease the risk of relapse.134

Systemic Therapies

Extracorporeal Photochemotherapy

Extracorporeal photochemotherapy (ECP), or photopheresis, is asystemic form of PUVA therapy that combines leukapheresis withphotochemotherapy and is efficacious in Sézary syndrome and eryth-rodermic mycosis fungoides. The biologic mechanisms of action thatmediate clinical responses to ECP in CTCL are not clearly defined.

Direct effects on DNA synthesis and membrane alterations inducedby psoralens and UVA may cause cytotoxicity with release of tumorantigens, resulting in a systemic antitumor response, but the immu-nomodulatory effects and possible induction of immune responses tothe malignant lymphoid cell population also may explain the clinicalresponses observed.135 The ECP process induces an anti-idiotypiccytotoxic T-cell response against circulating CTCL cells, which sub-sequently undergo apoptosis. Patients ingest 8-methoxypsoralen andthen undergo leukapheresis and cell separation. Cells of the mono-nuclear fraction are exposed to ultraviolet (UVA) radiation fromlamps housed ex vivo in the apheresis device followed by reinfusionof the treated cells. This results in DNA crosslinking, apoptosis, andcell death. The process usually is performed on two consecutive daysevery 4 weeks.

The initial experience by Edelson and colleagues reported that 27of 37 patients with therapy-resistant or -refractory CTCL exhibited

greater than 25% skin improvement.136

Long-term follow-up evalu-ation of patients with erythroderma revealed a median survival timeof 60.3 months and a median survival time from onset of treatmentof 47.9 months, with a CR rate of 21%.137 Clinical indications forfavorable ECP results include Sézary syndrome, widespread diseaseof less than 2 years’ duration, and CTCL cases in which the patient’sCD8+ count is near normal.135 Significant beneficial responses havenot been demonstrated in patients with patch- or plaque-stage ortumor-stage mycosis fungoides or with advanced CTCL, but thistreatment may prolong remission in patients who had previouslyreceived radiation therapy.138 After a minimum of six cycles of ECP,photopheresis is continued through clearing and for approximately 6

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additional months of treatment.136,138 A higher baseline lymphocytecount and higher absolute Sézary cell count were associated with adecrease in skin score and response after 6 months. 139 Toxicitiesinclude nausea, fever, occasional erythematous flares after reinfusion,and hypotension during apheresis. Septicemia has occurred and prob-ably is related to the immunocompromised state associated withCTCL. OR rates range from 54% to 75%, and 15% to 25% ofpatients achieve a CR.140 Other agents have been added to photo-

pheresis, including methotrexate, interferon, and immunomodula-tory therapy.141 ECP is not active in limited-stage mycosisfungoides.

Interferons

Interferon is the therapeutic agent of choice in advanced stages ofmycosis fungoides and Sézary syndrome and is the most effectiveagent in the treatment of advanced SS/mycosis fungoides alone or incombination with interferon alfa-2a (Roferon-A, Hoffman-LaRoche,Inc., Nutley, NJ) and interferon alfa-2b (Intron-A, Shering-PloughCorp., Kenilworth, NJ), which differ by only one amino acid, havesignificant activity in mycosis fungoides and Sézary syndrome. Ini-tially, high doses of drug were used.142 The OR rates up to 60% havebeen reported.143 In a randomized trial of intralesional interferonalfa-2b at a dose of 1 × 106 IU three times daily for 4 weeks resultedin CR in 10 of 12 patients who received the drug, compared with 1

of 12 patients whose lesions were treated with placebo.144

The sug-gested systemic dose of interferon is 1 to 3 × 106 IU administeredthree times weekly, increased to 9 to 12 × 106 IU daily or as tolerated,because no dose-response data have been published.145 A tachyphy-laxis develops subsequent to the initial fevers and chills. Leukopeniaoccurs in the first 3 months of therapy but usually is of no clinicalsignificance. Patients may experience chronic fatigue while receivingrecombinant interferon.

Systemic Chemotherapy

Chemotherapy, administered orally or parenterally in either a single-agent or a combination regimen, is used in patients with CTCL, inpatients with relapsed or refractory disease, and in patients whosetumor cells have undergone histologic transformation. Patients withextracutaneous or extranodal disease are candidates for systemic che-motherapy. Initial results of chemotherapy have been reviewed.146

The duration of response to single-agent therapy ranged from 3 to22 months. In a total of 331 patients with CTCL treated with com-bination chemotherapy, the OR rate was 81%, but the median dura-tion of response was less than 1 year.

Moderate doses of methotrexate (60 to 240 mg/m2) accompaniedby oral leucovorin calcium followed by maintenance oral methotrex-ate for 6 to 30 months resulted in a CR in 7 of 11 patients and a PRin 2 of 9 patients.147 A common intravenous regimen is the combina-tion of cyclophosphamide, vincristine, prednisone (CVP); doxorubi-cin (Adriamycin) may be added to CVP (CHOP), as well asmethotrexate and other agents.148 Seven of 10 patients receivingbleomycin, doxorubicin, methotrexate, and topical nitrogen mustardexhibited a CR, with a median duration of response of 19 months.149 Pegylated liposomal doxorubicin (Doxil) at a dose of 20 to 40 mg/m2 every 4 weeks resulted in a CR in 6 and a PR in 2 of 10 patients,

with a response duration of 15 months.150 A retrospective multicenter

study in 34 patients reported an 88% OR rate.151

Valid interpretation of the efficacy of chemotherapy in CTCL iscomplex. The current role of chemotherapy in the management ofCTCL compared with other therapies is difficult to determine. Inpublished studies, patients have received multiple and variable previ-ous treatments; the series have reported small numbers of patients;stage of disease was not reported; various stages of CTCL wereincluded; pathologic documentation of extra cutaneous disease often

was lacking; and studies often combined patients with Sézary syn-drome and those with mycosis fungoides. No clinical trial has dem-onstrated a survival benefit in patients receiving aggressive treatment.Therefore, more aggressive chemotherapy should be reserved for clin-

ical studies or should be used after topical regimens have failed orother therapies no longer provide benefit. This therapy is palliative.

Purine Nucleoside Analogs

The purine nucleoside analogs in CTCL have been evaluated inseveral clinical trials. The class of drugs includes 2′-deoxycoformycin,fludarabine, cladribine, and gemcitabine. Of 34 patients with CTCLtreated with single-agent pentostatin in five phase II studies, the CR

rate was 7%, with an OR rate of 40% and a median time to progres-sion of 1.3 to 8.3 months.152 The OR rate with fludarabine was 19%in 33 patients in a Southwestern Oncology Group trial.153 Fludara-bine followed by ECP produced an overall response rate of 63.2%versus 29.5% in patients treated with fludarabine monotherapy.154

Aproximately one third of patients respond to cladribine.155 Theseagents have been combined with other therapeutic approaches suchas interferon therapy. Neutropenia and thrombocytopenia are adverseeffects associated with use of these agents. In a recent study, gem-citabine at a dose of 1200 mg/m2 intravenously was given on days 1,8, and 15 of a 28-day schedule for a total of three courses in 30patients with mycosis fungoides; a CR rate of 10% and a PR rate of60% were reported, with a median duration of 15 months.156

Vitamin A Analogs

Retinoids are derivatives of vitamin A that have been reported to be

effective in CTCL. Isotretinoin (Accutane) and acitretin (Soriatane)have moderate activity. Of 25 patients with disease staged as T2 orhigher, 11 (44%) had a response to isotretinoin (13-cis -retinoic acid),

with a median duration of 8 months.157 As single agents, retinoidshave limited clinical use. Toxic effects include dry mucous mem-branes, skin fragility, arthralgias, myalgias, headache, fatigue, andincreased triglyceride levels. The results of multiple studies suggest aCR rate of 19% and an OR rate of 58%.

Bexarotene at a dose of 300 mg/m2 is a retinoid approved by theFDA for the treatment of refractory or relapsed CTCL that selectivelyactivates retinoid X receptors.158,159 In 94 patients, the OR rate was49%, with a CR rate of 4% and a median duration of response of10 months.158 Toxic effects include hyperlipidemia, hypothyroidism,and cytopenias. In patients with disease staged as IB or higher, oralbexarotene may be considered a first-line treatment alone or in com-bination with PUVA. Combining PUVA and bexarotene allows for

a decreased dose of both but does not increase the response rates.Other Oral Chemotherapy Agent Approaches

Chlorambucil in a dose of 0.1 to 0.2 mg/kg daily for 2 to 4 weeksfor 6 to 8 cycles results in a reported OR rate of 25% to 30%, witha median duration of response of 3 to 22 months.146

Etoposide in a dose of 50 mg/m2 daily for 21 days every 28 to 35days is active in chemotherapy-refractory disease.160 Temozolomide,an oral alkylating agent, in a dose of 150 to 200 mg/m2 for 5 daysevery 28 days also is active.

Monoclonal Antibodies

Murine monoclonal antibodies have been used as unaltered immu-noglobulin, conjugated to toxins, conjugated to radioisotopes, ormodified as chimeric antibodies. Initial trials included 90 Y-T101,90 Y–anti-CD25, and anti-Tac Pseudomonas exotoxin. Anti-CD52

monoclonal antibody, alemtuzumab (Campath-1H), produced a CRrate of 23% and an OR rate of 59% in patients with erythrodermaand 40% in those with plaque and skin tumors, with a median timeto treatment failure of 12 months.161 Alefecept (Aminvive, BiogenIdec) is a fully humanized recombinant protein that has been designedto modulate immune responses through interaction with the CD2receptor on T lymphocytes inhibiting LFA-3/CD2 interaction thatis FDA approved for psoriasis and is now in phase I trials for CTCL.The reduction in CD2+ cells results in a reduction in CD4+ andCD8+ T-lymphocyte counts. Toxic effects include urticaria, infec-tions, angioedema, and injection site reactions. Alemtuzumab is asso-ciated with significant myelosuppression, with associated viral, fungal,

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and bacterial infections, including reactivation of cytomegalovirusinfection, herpes zoster, and herpes simplex. Prophylactic antibioticsand antiviral and antifungal agents are required.

Interleukins and Recombinant Fusion Proteins

Bioactive recombinant interleukins and other cytokines have favor-able prospects in the treatment of CTCL. Recombinant interleukin-2 (IL-2) was administered in four patients, and all had a response,

with two CRs.162

Approximately half of the patients with mycosisfungoides or Sézary syndrome have IL-2 receptors (IL-2R alphachain, CD25). Denileukin diftitox (Ontak) is a genetically engi-neered fusion protein containing the portion of IL-2 that interacts

with IL-2 and a synthetic protein identical to diphtheria toxin. TheIL-2 portion of this drug binds with IL-2R on the mycosis fungoi-des/SS cells, the toxin is internalized, and apoptosis is induced. Deni-leukin diftitox administered at a dose of 9 or 18 µg daily for 5 daysevery 21 days is FDA approved. A randomized double-blind studyof 71 patients with CD25 expression in 20% of lymphocytes orgreater reported an OR rate of 30% (10% CR and 20% PR), witha median duration of response of 6.9 months (range, 2.7 to 46.1months).163 Toxic effects include flu-like symptoms, acute infusion-related events (episodes of hypotension, chest pain, and back pain),vascular leak syndrome, elevated liver function tests (61%), andhypoalbuminemia (79%). Bexarotene upregulates the expression of

the high-affinity IL-2R. The OR rate with denileukin diftitox withescalating doses of bexarotene was 57%.164

Histone Deacetylase Inhibitor

Vorinostat (Zolinza) is a histone deacetylase inhibitor that results inhistone acetylation and activation of gene expression and is FDAapproved. The recommended dose is 400 mg per day orally, withtreatment continuing until disease progression. In a phase II trial in33 patients who previously had received a median of five prior ther-apies, 8 patients achieved a PR, 7 of whom had Sézary syndrome. 165 The median time to response was 11.9 weeks. Fourteen of 31 evalu-able patients experienced relief of pruritus. Of 74 patients enrolledin a phase IIB trial,166 the OR rate was 29.7% in all patients andsimilar in those with disease staged as IIB or higher. The median timeto progression was 4.9 months in all patients and up to 9.8 monthsin responders with stage IIB or higher disease.

Common toxic effects include diarrhea, fatigue, nausea, dysgeusia,and anorexia. Less common toxicities include severe thrombocytope-nia, pulmonary embolism, and elevations in creatinine level. Prolon-gation of the prothrombin time in patients receiving concomitantcoumarin derivative anticoagulants may occur.

Other Therapies

Antithymocyte globulin, cyclosporine, and acyclovir have beenreported to induce transient responses.167–169

Stem Cell Transplantation

Studies of autologous peripheral blood stem cell transplantation andallogeneic transplantation strategies are ongoing. Five of six patients

who underwent autologous bone marrow transplantation responded,but three of these patients relapsed in less than 100 days.170 With use

of a T cell–depleted peripheral transplant strategy, seven of ninepatients relapsed at a median of 7 months (range 2 to 14 months),engraftment did not occur in one patient, and another patient died ofsepsis.171 In studies of allogeneic bone marrow transplantation, 3patients were alive and disease-free 15 months to 4 years.172,173 Alloge-neic transplantation produces more durable complete remissions, anoutcome attributed to an immune-mediated graft-versus-lymphomaeffect.174 Mortality is significant with this approach, however, and otherassociated toxicities including graft-versus-host disease create muchhigher risks for morbidity and early death. Nonmyeloablative (“mini”)allogeneic transplantation creates a graft-versus-lymphoma effect, with

less conditioning regimen–related toxicity. Engraftment occurred in 10of 11 patients, and after a median follow-up period of 2.9 years (range,3 months to 4.4 years), 7 of the patients were in remission and 4 hadchronic graft-versus-host disease necessitating treatment.175

Combined-Modality Therapy

In one study, results with the combination of electron beam radiationtherapy and local radiation therapy followed by combination chemo-

therapy suggested that survival and remission duration may beimproved.176 The median disease-free survival period was 12 months,and all patients with plaque-stage disease relapsed within 25months.177 Fifty nonrandomized patients received total-skin electronbeam radiation therapy followed by combination chemotherapy withdoxorubicin and cyclophosphamide.178 The CR rate was 88%, witha significant increase in the duration of response in early-stage CTCLbut not in advanced disease.

The first randomized clinical trial compared conservative sequen-tial topical therapy with total electron beam radiation therapy in 103patients.179 Patients with disease of all stages were eligible, and norestrictions were assigned on the basis of performance status. Thesequential topical regimen was initiated with topical nitrogen mustardand was changed to PUVA if progression of CTCL occurred ortoxicity developed from the topical nitrogen mustard. For continueddisease progression, the patient received total-skin electron beam

radiation therapy, followed by methotrexate administered orally. Ifextracutaneous disease developed, systemic chemotherapy was admin-istered. The combination regimen consisted of 3000 cGy total-skinelectron beam radiation therapy followed by cyclophosphamide,doxorubicin, etoposide, and vincristine administered intravenously.

After a median follow-up period of 75 months, the only significantdifference was in the CR rates for the two treatment groups: 38% inthe combined-modality group and 10% in the topical group. Nostatistical difference was observed in the disease-free survival rate orOS rate as a group or by stage for the two treatment groups. Toxic-ity was greater in the combined-modality group and included myelo-suppression, radiodermatitis, neuropathy, and congestive heartfailure. Less than 10% of patients in both groups remained diseasefree. Other regimens and approaches have been published.180,181

In another study, 124 patients with early stage I and II mycosisfungoides disease were randomized to receive PUVA or PUVA plus

interferon alfa-2a (Roferon-A) at a dose of 9 × 106

U three times per week.182 Fifty patients in the PUVA treatment group and 43 patientsin the interferon-PUVA treatment group were evaluable. On follow-up evaluation at a median of 101 weeks, median progression-freesurvival times were 53 weeks with PUVA and 113 weeks with inter-feron-PUVA (P = 0.0398). This combination therapy is the initialtreatment of choice for limited-stage disease.

CONCLUSIONS

Most cases, of CTCL cannot be cured. Early-stage (i.e., IA to IIA)mycosis fungoides should be treated with skin-targeted therapeuticinterventions to achieve a complete remission. Disease recurrence isfrequent, but long-term survival is not influenced by relapse status.Progress has been made in defining and classifying the cutaneouslymphomas, and in characterizing the relationship of mycosis fungoi-

des and Sézary syndrome and other premalignant conditions withCTCL and B-cell lymphomas. Recent advances in immunobiology,cell biology, and molecular biology have further identified and definedthe malignant lymphoid population involved in CTCL and the mech-anisms by which these cells may interact with skin and manifest theclinical features of CTCL.183 Treatment approaches are institutiondependent, although consensus guidelines are published for thiscomplex group of diseases.184 Continued advances in the understand-ing of the pathobiology of CTCL and the uncovering of potentialtargets will provide new therapeutic interventions that will improvethe outcomes with cutaneous T-cell and B-cell lymphomas.

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