The Pathogenesis of Mycosis Fungoides

review article

The

new england journal

of

medicine

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medical progress

The Pathogenesis of Mycosis Fungoides

Michael Girardi, M.D., Peter W. Heald, M.D., and Lynn D. Wilson, M.D., M.P.H.

From the Departments of Dermatology(M.G., P.W.H., L.D.W.) and TherapeuticRadiology (L.D.W.), Yale University Schoolof Medicine, New Haven, Conn. Addressreprint requests to Dr. Wilson at the De-partment of Therapeutic Radiology, YaleUniversity School of Medicine, HRT 136,333 Cedar St., New Haven, CT 06520, or [email protected].

N Engl J Med 2004;350:1978-88.

Copyright © 2004 Massachusetts Medical Society.

utaneous t-cell lymphoma represents a complex array of dis

-orders with various manifestations, clinical courses, and therapeutic consider-ations. Mycosis fungoides — in which the skin is variably affected by flat patch-

es, thin plaques, or tumors — is the most common form of cutaneous T-cell lymphoma;consequently, more is understood about it from a basic immunologic and molecularperspective than is understood about the other variants. The related Sézary syndrome isa more aggressive form of cutaneous T-cell lymphoma in which the skin is diffusely af-fected and there is measurable involvement within the peripheral blood. In addition tomycosis fungoides and the Sézary syndrome, several other disease entities have beengrouped under the heading of cutaneous T-cell lymphoma, each of which has distinctclinical manifestations and natural histories but all of which are characterized by expan-sions of malignant T cells within the skin. In this review, we focus on recent discoveriesin the field of T-cell biology as they relate to the pathogenesis of mycosis fungoides andthe Sézary syndrome.

Advances in cellular and molecular biology have revealed many details about lym-phocytes, including the incredible diversity of their T-cell antigen receptors, the efficien-cy with which they navigate the endoreticular system, and their capacity for recruitmentto specific tissues.

1

The integration of these activities may result in the beneficial elim-ination of foreign microbial agents and the inhibition of tumor development and growth,or it may lead to the untoward effects seen in inflammatory and autoimmune diseases.The complexity of mycosis fungoides may best be appreciated as a cancer of T cells thatcontinue in many respects to function as T cells under normal physiologic conditions,but the behavior of which is dominated by their propensity to home to the skin, be ac-tivated and persist in an activated state, and achieve clonal dominance, thereby accumu-lating in the skin, lymph nodes, and peripheral blood. Knowledge of the unifying char-acteristics relating to disease behavior influences the evaluation and therapy of patientswith mycosis fungoides, and an understanding of the pathogenesis and treatment of my-cosis fungoides offers insights into fundamental mechanisms of T-cell signaling, ap-optosis, and immunosurveillance.

Mycosis fungoides is a relatively rare, extranodal, non-Hodgkin’s lymphoma with astable incidence of approximately 0.36 per 100,000 person-years.

2,3

Infectious agents,occupational exposures, and genetic mutations have been evaluated as etiologic factorsin relation to mycosis fungoides, but evidence of causation has not been readily forth-coming.

4

Whereas viruses have been identified as etiologic agents in at least two cutane-ous lymphomas (human T-cell lymphotropic virus–associated adult T-cell lymphoma–leukemia and Epstein–Barr virus–associated nasal natural-killer–T-cell lymphoma), nosuch relation has been confirmed for mycosis fungoides. Nevertheless, according to arecent intriguing report, 97 percent of patients with late-stage mycosis fungoides or theSézary syndrome are seropositive for cytomegalovirus, in contrast to healthy bone mar-row donors, whose seropositivity rate is 57 percent.

5

In addition, it is important to notethat a variety of T-cell lymphomas may involve the skin during their clinical evolution,

c

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and these entities often have quite remarkable clin-ical presentations, which may be very different fromthose of the more commonly encountered myco-sis fungoides. This diversity is recognized by thetwo primary classification systems in current use(Table 1).

Approximately 200 years after the first descriptionof lesions of cutaneous T-cell lymphoma as “myco-sis fungoides,” immunophenotyping studies re-vealed that mycosis fungoides was actually one ofmany cutaneous T-cell lymphomas, typically of theCD4 helper T-cell phenotype.

8

As shown in Figure 1,a patient with mycosis fungoides may present withone or more of many diverse cutaneous manifesta-tions.

9

The patch or plaque lesions of mycosis fun-goides have a predilection for non–sun-exposed ar-eas (e.g., the buttocks, medial thighs, and breasts),although any area of the skin may be affected. In-sidious in onset, it is not uncommon for the diseasein this form to go unrecognized for several years,most often misdiagnosed as chronic contact der-matitis, atopic dermatitis, or psoriasis. The lesionsmay become variably thickened, may coalesce toform larger plaques, or may undergo partial involu-tion, leaving residual annular plaques. Patches andplaques may show hypopigmentation or hyperpig-mentation, atrophy, and petechiae as well as a vari-ety of tropisms in which the malignant cells accu-mulate in specialized areas of the epidermis, such asfollicles or sweat glands.

The skin of patients with mycosis fungoides mayalso show more poorly defined areas of erythema,apparently arising spontaneously or after the pro-gression of patch-or-plaque disease (Table 2).

10

When the erythema reaches a point of predomi-nance (i.e., covering more than 80 percent of thebody-surface area, as in so-called erythrodermic my-cosis fungoides

11

), patients are far more likely tohave leukemic involvement than are patients withlimited body-surface involvement. Historically, theterm “Sézary syndrome” has been used to describepatients with mycosis fungoides who have erythro-derma and atypical circulating cells with highly con-voluted nuclei, but a more relevant distinction insuch patients would be based on an accurate assess-ment of the degree of peripheral-blood involvementby molecular or flow-cytometric analysis. Specificfeatures might include the expansion of a particularT-cell receptor V

b

family, increases in the ratio of

helper (CD4) to cytotoxic (CD8) T cells, or the pres-ence of a T-cell population showing loss of the CD26T-cell marker.

12-15

Recently, the International Socie-ty for Cutaneous Lymphomas

11

proposed criteria foridentification of the Sézary syndrome with leukemicblood involvement, as follows: an absolute count ofSézary cells (enlarged, atypical lymphocytes withconvoluted nuclei) of at least 1000 per cubic milli-meter; a ratio of CD4 T cells to CD8 T cells of 10 orhigher; an increase in circulating T cells with aber-rant expression of pan–T-cell markers, as assessedby flow cytometry; an increased lymphocyte countwith evidence of a T-cell clone in the blood, as as-sessed by Southern-blot or polymerase-chain-reaction (PCR) analysis; and a T-cell clone withchromosomal abnormalities (e.g., deletions ortranslocations).

Cutaneous tumors can arise in patients withpatch-or-plaque mycosis fungoides or can arise denovo. The tumors are characterized by an exagger-ated vertical growth phase, resulting in the develop-ment of protruding and often ulcerating lesions.Cellular morphologic features are used to definemycosis fungoides tumors further,

6,7

with “large-

clinical features

* The information is from Willemze et al.

6

and Sander et al.

7

Table 1. Classification of Cutaneous T-Cell Lymphomas.*

Type ofDisease

European Organizationfor Research and Treatment

of Cancer ClassificationWorld Health Organization

Classification

Indolent Mycosis fungoides Mycosis fungoides

Mycosis fungoides and follicular mucinosis

Mycosis fungoides–associ-ated follicular mucinosis

Pagetoid reticulosis Pagetoid reticulosis

Large-cell cutaneous T-cell lymphoma, CD30-positive

AnaplasticImmunoblasticPleomorphic

Primary cutaneous anaplastic large-cell lymphoma

Lymphomatoid papulosis Lymphomatoid papulosis

Aggressive Sézary syndrome Sézary syndrome

Large-cell cutaneous T-cell lymphoma, CD30-negative

ImmunoblasticPleomorphic

Peripheral T-cell lymphoma (not otherwise specified)

Provisional Granulomatous slack skin Granulomatous slack skin

Cutaneous T-cell lymphoma, pleo-morphic, small-to-medium size

Peripheral T-cell lymphoma (not otherwise specified)

Subcutaneous panniculitis-like T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma



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cell transformation” carrying a poor prognosis if itoccurs within two years after diagnosis.

16

Primarycutaneous CD30-positive anaplastic large-cell lym-phoma, which appears in the skin without any pre-ceding clinical or histologic evidence of mycosisfungoides, may manifest in the form of localized orbroadly distributed tumors.

17-19

The major histologic findings in patch-or-plaquemycosis fungoides represent several important fea-tures of the disease.

20,21

A lymphocytic infiltrate inthe superficial dermis, with individual lymphocytesmigrating among epidermal keratinocytes, definesthe so-called epidermotropism that characterizesthis lymphoma. The clustering of clonal T cellsaround Langerhans’ cells (forming what are calledPautrier’s microabscesses) is illustrative of the ap-parent dependence of the T cells on interactionswith these dendritic cells, particularly in the earlystages of the disease. The lymphocytes may show

varying degrees of atypia (pleomorphic, hyperchro-matic, and convoluted nuclei). In addition to rou-tine histologic examination, staining of skin-biopsyspecimens with a panel of lymphocyte markers isused to help define the malignant clone for subclas-sification.

18-21

Such distinctions can have importantprognostic implications. For example, mycosis fun-goides that is positive for T-cell receptor

g

/

d

is as-sociated with more aggressive disease than is thatwithout the receptor rearrangement.

22

Examinationof multiple biopsy specimens from various lesionsat various times will increase the likelihood that anaccurate diagnosis will be made, and PCR analysisof T-cell receptor genes to determine clonality mayalso be helpful. Nevertheless, combining informa-tion about clinical, pathologic, and molecular fea-tures is essential to making an accurate diagnosis ofmycosis fungoides, which may still be elusive de-spite recent diagnostic and technical advances.

Figure 1. Various Cutaneous Manifestations of Mycosis Fungoides.

Panel A shows patch-or-plaque mycosis fungoides affecting the lower trunk. The patches are thin, slightly scaly, erythematous lesions typically greater than 4 cm in diameter and distributed in sun-shielded areas such as those covered by a bathing suit or intertriginous regions. Plaques are thicker than patches. Panel B shows pagetoid reticulosis, a variant of mycosis fungoides that typically consists of a single patch or plaque located in an acral area. Panel C shows syringotropic mycosis fungoides, which is manifested as papules 1 to 3 mm in diameter distributed in the eccrine ducts, indicating the propensity of lymphoma cells to accumulate in these locations. Panel D shows follicular mycosis fun-goides, in which lesions characterized by alopecia develop. In a similar variant, there is mucin deposition in the follicles. Panel E shows hy-popigmented mycosis fungoides. This variant is more noticeable in persons with dark pigmentation and may be more common in childhood and adolescence than in adulthood. Hypopigmentation to full depigmentation occurs in patches. Panel F shows erythrodermic mycosis fun-goides. This variant may evolve from patch-or-plaque mycosis fungoides and eventually involve more than 80 percent of the body-surface area. It may also arise spontaneously, as in the Sézary syndrome. Panel G shows the Sézary syndrome. In its most florid form, the diffuse infiltration of the skin may produce the exaggerated facial lines, resulting in “leonine facies.” The Sézary syndrome is also associated with atypical lym-phocytes on the blood smear. Panel H shows a mycosis fungoides tumor. Such tumors define the T3 stage of disease and may arise at the site of plaques or appear on their own, without being preceded by a patch-or-plaque lesion. The vertical growth phase is accelerated, and tumors tend to appear more quickly than plaques. Tumors not characterized by epidermotropism or previous mycosis fungoides are sometimes called “non–mycosis fungoides cutaneous T-cell lymphoma.”

A B C D

E F G H



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The molecular interactions that facilitate the capac-ity of malignant cells in cutaneous T-cell lymphomato migrate and reside in the skin are fundamental tothe normal physiology of immunosurveillance.

23

T cells that have yet to encounter their appropriateantigens repeatedly pass from the blood to thelymph nodes to survey antigen-presenting cells forpeptides complementary to their T-cell receptors.Principally guiding this efficient navigation are cell-surface molecules such as L-selectin (CD62L) andCC chemokine receptor 7 (CCR7) on naive T cells,with corresponding expression of complementaryligands on lymph-node endothelial cells. Once an-tigens and other signals are delivered, the T cellsbecome activated and are induced to alter their cell-surface profiles. In skin-draining lymph nodes, con-ditions appear to favor the induction of expressionof molecules such as cutaneous lymphocyte antigenand CC chemokine receptor 4 (CCR4), which great-ly facilitate T cells’ eventual migration to the skin,thus defining “cutaneous T cells” (Table 3).

24-26

One of the skin’s primary responses to cellularinjury or stress is the release by keratinocytes of cy-tokines that drive the recruitment of leukocytes thatcharacterize the initiation and maintenance of cu-taneous inflammation. This primary cytokine re-sponse will up-regulate adhesion molecules on der-mal endothelial cells, as well as stimulate basalkeratinocytes to release chemokines that infuse thedermis, bind the extracellular matrix, and coat theluminal endothelium. Thus, the cell surface exposedto the intravascular compartment is ready to alertcirculating leukocytes that the local tissue warrantsattention. Passing T cells with complementary lig-ands will “tether and roll” along the sticky endo-thelium, principally guided by the binding of cuta-neous lymphocyte antigen to endothelial E-selectinin the skin, before firm adhesion and extravasationinto the dermis. These activities are enhanced byskin-associated chemokines such as CC chemokineligands 17 and 22 (CCL17 and CCL22, respectively),both of which are ligands for CCR4 on the skin-homing T cells (Fig. 2).

By surface analysis, the malignant clone in patch-or-plaque mycosis fungoides fits the skin-homing,cutaneous-lymphocyte-antigen–positive, CCR4-positive profile,

24,27-29

and CCL17 and CCL22 haveboth been shown to have high levels of expressionin skin lesions. The secretion of primary cytokines

and chemokines by keratinocytes is probably im-portant for the initiation or perpetuation of a skinlesion in mycosis fungoides.

29,30

Furthermore, thecells in this disorder may express integrin adhesionmolecules (e.g.,

a

E

b

7

) and chemokine receptors(e.g., CCR4 and CXC chemokine receptors 3 and 4)that can bind ligands on endothelial cells, keratino-cytes, and Langerhans’ cells, thus enhancing migra-tion into the epidermis.

31-34

Bagot et al.

35

demonstrated the marked affinityof malignant T cells to home to the epidermis in my-cosis fungoides, and clone-identifying antibodieswere used to identify cells in tissue sections with theuse of immunoperoxidase. The only cells reactingwith the clone-specific antibodies were in the epi-dermis, and most of the dermal cells did not ex-press the same surface markers as did the malignantclone. These findings suggested that the malignantclone is closer to the surface than are the nonmalig-nant components of the infiltrate.

35

Microdissec-

skin-homing capacity

of malignant cells

* The staging system was originally designed by the Committee on Staging and Classification of Cutaneous T-Cell Lymphomas and published by Bunn and

Lamberg

10

in 1979. TNM denotes tumor–node–metastasis.

Table 2. Classic TNM Staging of Mycosis Fungoides.*

Classification Definition

Stage

T1 Patches, plaques, or both involving <10% of body-surface area

T2 Patches, plaques, or both involving ≥10% of body-surface area

T3 One or more cutaneous tumors

T4 Erythroderma

N0 Lymph nodes clinically uninvolved

N1 Lymph nodes clinically enlarged but not histologically involved

N2 Lymph nodes clinically nonpalpable but histologically involved

N3 Lymph nodes clinically enlarged and histologically involved

M0 No visceral disease

M1 Visceral disease

B0 No circulating atypical cells (Sézary cells)

B1 Circulating atypical cells (Sézary cells)

Stage groups

IA T1N0M0

IB T2N0M0

IIA T1–2N1M0

IIB T3N0–1M0

IIIA T4N0M0

IIIB T4N1M0

IVA T1–4N2–3M0

IVB T1–4N0–3M1



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tion studies, in which single cells are laser-capturedfrom tissue sections and analyzed for T-cell–recep-tor

rearrangement status, have demonstrated thatvirtually all epidermal lymphocytes identified in le-sions of cutaneous T-cell lymphoma belong to themalignant clone, whereas they are present in rela-tively small numbers in the dermal infiltrate.

36,37

The skin-homing behavior of malignant cells inmycosis fungoides has several implications for themanagement of the disorder. The staging of thedisease at the time of diagnosis is based largely onthe degree of skin involvement.

10

Repeated retro-spective studies have confirmed the prognostic sig-nificance of the burden of the cutaneous tumor,since the rate of survival decreases with increasingstage,

38-40

increasing body-surface area affectedwithin a given stage,

41

and the detection of clonal-ity in the blood.

42

For limited patch-or-plaque my-cosis fungoides, the treatment of choice is often askin-directed therapy, which potentially can simul-taneously target both the malignant T cells and thestimulating Langerhans’ cells. External-beam radio-therapy in a localized field for limited disease andtotal-skin electron-beam therapy for more advancedstages have been shown to be associated with rela-tively high rates of response and disease control.Electron-beam therapy clearly has a direct effect onthe death of T cells and may effectively modulate thecutaneous milieu in a manner that is conducive toslowing the progression of mycosis fungoides.

43,44

Several other skin-based therapies, such as pso-ralen in combination with ultraviolet A light, nar-row-band ultraviolet B light, nitrogen mustard,

bis-chloronitrosourea, topical corticosteroids, andbexarotene gel, have been used with success.

45

Overtime, however, the malignant cells in mycosis fun-goides may lose their apparent dependence on theskin environment, alter their surface expression,and expand within the dermis, peripheral blood,and lymph nodes and thus evolve into a more life-threatening and more treatment-resistant form ofthe disease, characterized by erythroderma, skin tu-mors, leukemia, and lymph-node involvement andwarranting more aggressive management thanskin-directed therapy alone (Table 4).

46

In vitro systems that model the interactions un-derlying the skin-homing behavior of malignantcells in mycosis fungoides may prove useful in thedevelopment of pharmacologic agents that haveapplication not only in the treatment of cutaneousT-cell lymphoma, but in the treatment of other in-flammatory skin diseases as well. Flow chambersmay be used to study the effects of compounds onT-cell rolling, adhesion, and chemotaxis underphysiologic shear-stress conditions.

47,48

CutaneousT-cell lymphoma plus autologous dendritic-cellcoculture systems may be used to test variouspharmacologic agents for their capacity to disruptcellular interactions that play a critical role in fos-tering the development and perpetuation of myco-sis fungoides or other aberrant T-cell populations.

49

Hence, therapies with specific biologic targets maybe designed and then improved.

In addition to their tissue-homing capabilities, acti-vated T cells have the ability to switch on the produc-tion of signaling molecules and various cytokinesthat execute specific beneficial effector functions(e.g., elimination of infection) or, conversely, thatmediate inflammatory disease. Examination of theclonal cells in skin-biopsy specimens and peripher-al-blood samples from patients with leukemic in-volvement has shown that they commonly expressseveral activation markers, including CD45RO, pro-liferating-cell nuclear antigen, and the interleukin-2

a

receptor (CD25).

50,51

After stimulation of theinterleukin-2 receptor, activated T cells undergophosphorylation of several intracellular signalingproteins in the JAK-STAT family of molecules. Thereis evidence in mycosis fungoides that constitutiveactivation of such molecules contributes to the ma-lignant T cells’ apparent persistent state of activa-tion.

52-55

t-cell activation

* CLA denotes cutaneous lymphocyte antigen; CCR4 CC chemokine receptor 4; CCL17 and CCL22 CC chemokine ligands 17 and 22, respectively; CXCR3 CXC chemokine receptor 3; LFA-1 lymphocyte-function–associated antigen 1; and

ICAM-1 intercellular adhesion molecule 1.

Table 3. Cutaneous T Cells in Mycosis Fungoides and Cutaneous Inflammation.*

T-Cell Surface Molecule Ligand Cutaneous Cells Bearing Ligand

CLA E-selectin Endothelial cells

CCR4 CCL17 Basal keratinocytes, endothelial cells

CCR4 CCL22 Langerhans’ cells

CXCR3 Interferon gamma–inducible protein 10

Basal keratinocytes

Integrin

a

E

b

7

E-cadherin Keratinocytes, Langerhans’ cells

LFA-1 ICAM-1 Endothelial cells, Langerhans’ cells



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Figure 2. Mycosis Fungoides: A Cancer of Skin-Homing T Cells.

In cutaneous T-cell lymphoma, cells home to the skin by virtue of interactions with dermal capillary endothelial cells. Circulating lymphoma cells bearing cutaneous lymphocyte antigen (CLA) roll along endothelial cells expressing E-selec-tin. Chemokine receptors (e.g., CC chemokine receptor 4 [CCR4]) on the malignant T cells recognize chemokines (e.g., CC chemokine ligand 17 [CCL17]) that have emanated from the epidermis and bound to the luminal side of endothelial cells, greatly facilitating the binding of leukocyte-function–associated antigen type 1 on the lymphoma cells to intercellular adhesion molecule 1 on the endothelial cells and subsequent extravasation into the dermis. From there, the lymphoma cells often display an affinity for epidermal cells and cluster around Langerhans’ cells, forming Pautrier’s microabscess-es, which can be observed on histologic examination. This process is principally guided by the interactions of lympho-ma-cell integrin

a

E

b

7

, CCR4, and the CD4 T-cell receptor complex with E-cadherin, CCL22, and major-histocompatibility-complex class II (MHC-II) molecules, respectively. TCR denotes T-cell receptor.

T cell

T cell

Langerhans' cell

Dermis

Epidermis

Endothelial cellE-selectin

CCR4

CCR4

CCL22

MHC-II

TCR

CD4E-cadherin

�E�7

CLA

CCL17

Capillary

Extravasation

Epidermotropism

Pautrier'smicroabscess



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Hence, in addition to being a lymphoma, myco-sis fungoides may simultaneously be considered aninflammatory skin disease involving early stages ofclonal and reactive cells that have the capacity to pro-duce cytokines. For example, increased productionof cytokines such as interleukin-4 and interleukin-5in advancing stages of the disease has been implicat-ed in the eosinophilia and atopy-like symptoms thatoften affect patients, especially those with erythro-dermic disease.

56,57

Playing a role in this bias toward

type 2 helper T cytokines, as is evident in the expres-sion profile of peripheral-blood leukocytes frompatients with leukemic mycosis fungoides or theSézary syndrome, is hyperexpression of GATA-3, atranscription factor mediating type 2 helper T-celldifferentiation, and JunB, a regulator of interleu-kin-4 expression.

58

The activated cells in mycosis fungoides may alsohave significant regulatory effects on the host’s nor-mal T cells. For example, it has been shown that theactivated cells have the ability to produce interleu-kin-10 and transforming growth factor

b

, both ofwhich can profoundly inhibit cell-mediated immu-nity.

59,60

Furthermore, the cells can produce extraor-dinary amounts of soluble interleukin-2 receptor,which may competitively bind the interleukin-2 nec-essary for normal T-cell activation.

61

These phe-nomena may in part account for the increased riskof secondary cancer and infections in patients withmycosis fungoides.

62

Thus, although there is evi-dence of an antitumor immune response in mycosisfungoides, substantial hurdles may need to be over-come before immunotherapy will be effective in agiven patient.

Successful therapies in mycosis fungoides pref-erentially or selectively affect the malignant clone,as is true of most of the skin-directed therapies thatcapitalize on the skin-homing behavior of the ma-lignant cells. Likewise, the activated state of the cellsin mycosis fungoides also makes them a semiselec-tive target for biologic therapy (Table 4). One suchtherapeutic agent is denileukin diftitox, which wasoriginally designed to target activated T cells in cu-taneous inflammatory disease; it is a recombinantprotein consisting of a portion of diphtheria toxinconjugated to interleukin-2 and was recently ap-proved for treatment of mycosis fungoides.

63,64

After interleukin-2 receptor–mediated endocytosisinto activated T cells, the toxin is enzymaticallycleaved and then able to uncouple protein synthesiswithin the cell. This mechanism highlights the in-timate link between inflammatory skin disease andmycosis fungoides.

In several noncutaneous T-cell leukemias and lym-phomas, clear associations with specific mutationsand chromosomal abnormalities have been identi-fied in which direct effects on the expression of on-cogenes or inactivation of tumor-suppressor geneswould be expected to result in clonal expansion. Al-

clonal dominance of t cells

* Therapeutic decisions are largely guided by the status of the disease in the skin (i.e., the tumor [T] status in tumor–node–metastasis staging). Consider-ation is also given to whether a therapeutic course is intended for complete re-mission or palliation, since the disease tends to be indolent and chronic.

45

Consideration for the latter would include ease of administration, minimal in-terference with activities of daily living, and an absence of adverse effects. Pa-tients with T3 and T4 disease have clinical manifestations that are often more pronounced and require a more aggressive therapeutic approach than in those with T1 or T2 disease. Maintenance of a complete response may be accom-plished by continuing the therapy that established the remission, but on a less frequent basis. Local radiotherapy or total-skin electron-beam therapy, though they can be repeated, are typically followed by another form of therapy for maintenance. Additional combinations of the therapies listed in the table may be used to achieve remission or a palliative response. Generally, in patients who do not have a response to the listed therapies, those in whom nodal or visceral disease develops, and those who have transformation to a large-cell lymphoma, the disease is managed with more aggressive, systemic therapies (e.g., allogeneic transplantation). We list examples of commonly used thera-pies in the management of mycosis fungoides and the Sézary syndrome, but the list is not exhaustive and reflects the general approaches that we favor. Phototherapy refers to psoralen with ultraviolet A light, broad-band ultraviolet

B light, or narrow-band ultraviolet B light.

Table 4. Therapeutic Options in the Management of Mycosis Fungoides and the Sézary Syndrome.*

Limited Patch-or-Plaque

Disease (T1)

Widespread Patch-or-Plaque

Disease (T2) Tumors (T3)Erythroderma

(T4)

Topical cortico-steroids

Phototherapy Total-skin electron-beam therapy with or without local radio-therapy

Total-skin elec-tron-beam therapy plus extracorpore-al photo-chemotherapy

Phototherapy Nitrogen mustard Oral bexarotene Oral bexarotene

Bis-chloronitroso-urea ointment

Oral bexarotene Denileukin diftitox Chlorambucil

Bexarotene gel Methotrexate Local radiotherapy Denileukin diftitox

Nitrogen mustard Total-skin elec-tron-beam therapy

Radiotherapy plus nitrogen mus-tard

Extracorporeal photochemo-therapy

Local radiotherapy Interferon alfa-2b Radiotherapy plus phototherapy

Interferon alfa

Interferon alfa-2b Psoralen with ul-traviolet A light plus interferon alfa-2b



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though such molecular signatures have not been asreadily recognized in any form of cutaneous T-celllymphoma, several key observations have beenmade in mycosis fungoides and the Sézary syn-drome at the genetic level.

65

For example, mutationsin the cell-cycle regulator gene

p53

are associatedwith disease progression. Comparative genomic hy-bridization analysis, a tool for wide-scale survey forgenomic aberrations, has revealed several hot spotsof chromosomal rearrangement (e.g., deletions onchromosomes 1p, 17p, 10q, and 19 and gains on4q, 18, and 17q) in mycosis fungoides and theSézary syndrome and has thus helped to focus at-tention on genes critical to disease progression.

55

More recently, Scarisbrick and colleagues

66

notedthat some patients with mycosis fungoides have mi-crosatellite instability, a high propensity toward ge-netic instability that is highly characteristic of he-reditary nonpolyposis colorectal cancer, a familialcancer syndrome. Moreover, the microsatellite-instability phenotype was much more prevalentamong patients with advanced forms of mycosisfungoides, strongly suggesting that this phenome-non is a major contributor to the mutation of tu-mor-suppressor genes implicated in clonal expan-sion and disease progression.

The detection of clonal T-cell expansion in myco-sis fungoides has been exploited for diagnostic pur-poses. In very early stages of the disease, a clonallyexpanded population may be detected by PCR analy-sis of T-cell–receptor gene rearrangements.

67,68

Certain other well-defined skin diseases may be as-sociated with T-cell clonality; however, once thosediseases have been ruled out by physical examina-tion, the molecular identification of a clone can fa-cilitate diagnosis in cases in which clinical findingsand histologic features are consistent with, but notentirely typical of, mycosis fungoides. In addition,if detection of the same clone is evident in more thanone lesion or in a given patient over time, there is anincreased risk of disease progression.

69

AlthoughPCR can also detect the physiologic recirculation ofmalignant cells in the peripheral blood of patientswith varying tumor burdens, including limitedpatch-or-plaque disease, late-stage disease is char-acterized by dominance of the malignant clone anddiminution of the normal T-cell population. Oneobvious surrogate marker of the fading of nonma-lignant T cells is the reduction in the normal CD8lymphocyte population. As the disease progresses,there are decreased numbers of CD8 cells in skinlesions

70

and in the peripheral blood.

71,72

Recently, Yawalkar and colleagues have usedT-cell receptor

V

b

gene spectratyping to reveal thatthe status of the diversity of the T-cell repertoire,even in patients with early mycosis fungoides, ismore complex than simple clonal expansion.

73

Thiswas reflected in the disruption of normal Gaussiandistribution patterns of every third in-frame V

b

T-cell–receptor rearrangement length, with expan-sion within several V

b

families (some showing frankclonality) and diminution or complete absence ofother V

b

family lengths or even entire V

b

families.These findings clearly indicate not only that myco-sis fungoides is a disease of T-cell clonal expansionreflected in the peripheral blood, even in the absenceof leukemia, but also that there may be profoundabnormalities within the normal repertoire of pe-ripheral T cells that further contribute to the immu-nodeficient state of patients who have the disease.The persistence of the malignant clone and its dom-inance over other, nonmalignant T cells imply thatmycosis fungoides is characterized by a disorder inthe regulation of the normal population of T cells.It further justifies the use of therapies that minimizetoxicity to the normal lymphocytes.

After antigen-driven stimulation and expansionunder normal physiologic conditions, eliminationof the majority of the activated T cells is essential toprevent excessive cellular accumulation (as in leu-kemia and lymphoma) and overexuberant T-cell–mediated tissue damage (as in autoimmune andinflammatory disease states). One built-in checkon the system is activation-induced cellular death,whereby, after subsequent T-cell–receptor engage-ment of previously activated T cells, the apoptoticcascade is initiated and culminates in programmedcellular suicide. Engagement of cell-surface Fas(CD95) by Fas ligand, the external and most up-stream connection to apoptosis initiation, pro-vides an alternative pathway through which acti-vated T cells may be eliminated. In addition toreleasing cell-damaging molecules (e.g., perforinand granzymes), cytotoxic T lymphocytes, whichare the principal effectors in cell-mediated antitu-mor responses, may induce apoptosis by the ex-pression of FasL and the engagement of Fas on themalignant cells. Given the evidence that cytotoxicT lymphocytes mount an antitumor response in cu-taneous T-cell lymphoma, it may not be surprisingthat the cells in mycosis fungoides show a relativedecrease in Fas expression with advancing disease.A variety of Fas mutations and splice variants havebeen identified in the lesions of mycosis fungoides;



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the majority result in a nonfunctioning Fas pro-tein.

74,75

Thus, avoidance of Fas-mediated stimula-tion of apoptosis appears to be an important mech-anism by which the malignant cells in mycosisfungoides evade immune regulation, and it may con-tribute to these cells’ clonal emergence and domi-nance. Paradoxically, the malignant T cells may inturn express Fas ligand themselves to eliminate po-tential antitumor CD8 T cells.

76

The weakening immune system in mycosis fun-goides, in the setting of dominance by the malig-nant clone, is a foremost therapeutic consideration.In patients with erythroderma, photopheresis in-volves harvesting a small portion of the circulatingcells. The cells are selectively damaged and re-infused to stimulate a therapeutic response.

77

Pho-topheresis treatment in patients with leukemicmycosis fungoides or the Sézary syndrome simul-taneously renders malignant T cells apoptotic andinduces the differentiation of peripheral monocytesinto dendritic cells,

78

thereby providing the key cel-lular components of a tumor-cell vaccine. Thus, ithas been proposed that photopheresis may take ad-vantage of specific determinants on the malig-nant T cells, including T-cell–receptor peptides

79,80

and other tumor antigens,

81

to induce an antitu-mor immune response.

82

Immune-stimulating cy-tokine therapy with interferon alfa-2b is an effectiveform of monotherapy for mycosis fungoides

83

andmay have effects synergistic with those of photo-pheresis.

84

There is increasing recognition of the effects ofpharmacologic targeting of the retinoid-receptorcomplex in leukemia and lymphoma.

85,86

Retinoicacid receptors typically bind retinoid X receptors toform heterodimers capable of activating the pro-

moters of genes that regulate the expression of cell-surface receptors, structural proteins, and other keymediators of cellular function. Bexarotene, often re-ferred to as a “rexinoid” since it preferentially bindsretinoid X receptors (not retinoic acid receptor–like“retinoids”), directly affects the expanding popula-tion of malignant cells in mycosis fungoides by in-hibiting proliferation, inducing differentiation, andpromoting apoptosis.

87,88 When administered oral-ly, bexarotene has resulted in improvements at allstages of mycosis fungoides without compromis-ing immune status.89,90

A wide variety of T-cell lymphomas are unified bytheir propensity to home to the skin. The most com-mon of these, mycosis fungoides, is a non-Hodg-kin’s, peripheral T-cell lymphoma of the skin with awide spectrum of potential clinical manifestations.Recent advances in the understanding of the molec-ular and biologic behavior of T cells in this disorder— the propensity of the cells to home to the skin, tofunction in an activated state, and to achieve clonaldominance — have had a tremendous influence onthe development of treatments. With an expandingarmamentarium of biologic agents, phototherapeu-tic methods, and irradiation techniques, as well asgrowing recognition of the benefits of combinationregimens,84,91 caregivers are better equipped thanever to wage battle against mycosis fungoides. Thedeepening appreciation of the molecular mecha-nisms that underlie the behavior of mycosis fun-goides can be expected to improve therapy furtherand to affect the understanding and treatment ofother T-cell–mediated disorders.

conclusions

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The Pathogenesis of Mycosis Fungoides