The Pathogenesis of Mycosis Fungoides
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《新英格兰医药杂志》
Cutaneous T-cell lymphoma represents a complex array of disorders with various manifestations, clinical courses, and therapeutic considerations. Mycosis fungoides — in which the skin is variably affected by flat patches, 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 molecular perspective than is understood about the other variants. The related Sézary syndrome is a more aggressive form of cutaneous T-cell lymphoma in which the skin is diffusely affected and there is measurable involvement within the peripheral blood. In addition to mycosis fungoides and the Sézary syndrome, several other disease entities have been grouped under the heading of cutaneous T-cell lymphoma, each of which has distinct clinical manifestations and natural histories but all of which are characterized by expansions of malignant T cells within the skin. In this review, we focus on recent discoveries in the field of T-cell biology as they relate to the pathogenesis of mycosis fungoides and the Sézary syndrome.
Advances in cellular and molecular biology have revealed many details about lymphocytes, including the incredible diversity of their T-cell antigen receptors, the efficiency with which they navigate the endoreticular system, and their capacity for recruitment to specific tissues.1 The integration of these activities may result in the beneficial elimination 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 that continue 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 activated and persist in an activated state, and achieve clonal dominance, thereby accumulating in the skin, lymph nodes, and peripheral blood. Knowledge of the unifying characteristics relating to disease behavior influences the evaluation and therapy of patients with mycosis fungoides, and an understanding of the pathogenesis and treatment of mycosis fungoides offers insights into fundamental mechanisms of T-cell signaling, apoptosis, and immunosurveillance.
Mycosis fungoides is a relatively rare, extranodal, non-Hodgkin's lymphoma with a stable incidence of approximately 0.36 per 100,000 person-years.2,3 Infectious agents, occupational exposures, and genetic mutations have been evaluated as etiologic factors in relation to mycosis fungoides, but evidence of causation has not been readily forthcoming.4 Whereas viruses have been identified as etiologic agents in at least two cutaneous lymphomas (human T-cell lymphotropic virus–associated adult T-cell lymphoma–leukemia and Epstein–Barr virus–associated nasal natural-killer–T-cell lymphoma), no such relation has been confirmed for mycosis fungoides. Nevertheless, according to a recent intriguing report, 97 percent of patients with late-stage mycosis fungoides or the Sézary syndrome are seropositive for cytomegalovirus, in contrast to healthy bone marrow donors, whose seropositivity rate is 57 percent.5 In addition, it is important to note that a variety of T-cell lymphomas may involve the skin during their clinical evolution, and these entities often have quite remarkable clinical presentations, which may be very different from those of the more commonly encountered mycosis fungoides. This diversity is recognized by the two primary classification systems in current use (Table 1).
Table 1. Classification of Cutaneous T-Cell Lymphomas.
Clinical Features
Approximately 200 years after the first description of lesions of cutaneous T-cell lymphoma as "mycosis fungoides," immunophenotyping studies revealed that mycosis fungoides was actually one of many cutaneous T-cell lymphomas, typically of the CD4 helper T-cell phenotype.8 As shown in Figure 1, a patient with mycosis fungoides may present with one or more of many diverse cutaneous manifestations.9 The patch or plaque lesions of mycosis fungoides have a predilection for non–sun-exposed areas (e.g., the buttocks, medial thighs, and breasts), although any area of the skin may be affected. Insidious in onset, it is not uncommon for the disease in this form to go unrecognized for several years, most often misdiagnosed as chronic contact dermatitis, atopic dermatitis, or psoriasis. The lesions may become variably thickened, may coalesce to form larger plaques, or may undergo partial involution, leaving residual annular plaques. Patches and plaques may show hypopigmentation or hyperpigmentation, atrophy, and petechiae as well as a variety of tropisms in which the malignant cells accumulate in specialized areas of the epidermis, such as follicles or sweat glands.
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 fungoides, in which lesions characterized by alopecia develop. In a similar variant, there is mucin deposition in the follicles. Panel E shows hypopigmented 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 fungoides. 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 lymphocytes 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."
The skin of patients with mycosis fungoides may also show more poorly defined areas of erythema, apparently arising spontaneously or after the progression of patch-or-plaque disease (Table 2).10 When the erythema reaches a point of predominance (i.e., covering more than 80 percent of the body-surface area, as in so-called erythrodermic mycosis fungoides11), patients are far more likely to have leukemic involvement than are patients with limited body-surface involvement. Historically, the term "Sézary syndrome" has been used to describe patients with mycosis fungoides who have erythroderma and atypical circulating cells with highly convoluted nuclei, but a more relevant distinction in such patients would be based on an accurate assessment of the degree of peripheral-blood involvement by molecular or flow-cytometric analysis. Specific features might include the expansion of a particular T-cell receptor V family, increases in the ratio of helper (CD4) to cytotoxic (CD8) T cells, or the presence of a T-cell population showing loss of the CD26 T-cell marker.12,13,14,15 Recently, the International Society for Cutaneous Lymphomas11 proposed criteria for identification of the Sézary syndrome with leukemic blood involvement, as follows: an absolute count of Sézary cells (enlarged, atypical lymphocytes with convoluted nuclei) of at least 1000 per cubic millimeter; a ratio of CD4 T cells to CD8 T cells of 10 or higher; an increase in circulating T cells with aberrant expression of pan–T-cell markers, as assessed by flow cytometry; an increased lymphocyte count with evidence of a T-cell clone in the blood, as assessed by Southern-blot or polymerase-chain-reaction (PCR) analysis; and a T-cell clone with chromosomal abnormalities (e.g., deletions or translocations).
Table 2. Classic TNM Staging of Mycosis Fungoides.
Cutaneous tumors can arise in patients with patch-or-plaque mycosis fungoides or can arise de novo. The tumors are characterized by an exaggerated vertical growth phase, resulting in the development of protruding and often ulcerating lesions. Cellular morphologic features are used to define mycosis fungoides tumors further,6,7 with "large-cell transformation" carrying a poor prognosis if it occurs within two years after diagnosis.16 Primary cutaneous CD30-positive anaplastic large-cell lymphoma, which appears in the skin without any preceding clinical or histologic evidence of mycosis fungoides, may manifest in the form of localized or broadly distributed tumors.17,18,19
The major histologic findings in patch-or-plaque mycosis fungoides represent several important features of the disease.20,21 A lymphocytic infiltrate in the superficial dermis, with individual lymphocytes migrating among epidermal keratinocytes, defines the so-called epidermotropism that characterizes this lymphoma. The clustering of clonal T cells around Langerhans' cells (forming what are called Pautrier's microabscesses) is illustrative of the apparent dependence of the T cells on interactions with these dendritic cells, particularly in the early stages of the disease. The lymphocytes may show varying degrees of atypia (pleomorphic, hyperchromatic, and convoluted nuclei). In addition to routine histologic examination, staining of skin-biopsy specimens with a panel of lymphocyte markers is used to help define the malignant clone for subclassification.18,19,20,21 Such distinctions can have important prognostic implications. For example, mycosis fungoides that is positive for T-cell receptor / is associated with more aggressive disease than is that without the receptor rearrangement.22 Examination of multiple biopsy specimens from various lesions at various times will increase the likelihood that an accurate diagnosis will be made, and PCR analysis of T-cell receptor genes to determine clonality may also be helpful. Nevertheless, combining information about clinical, pathologic, and molecular features is essential to making an accurate diagnosis of mycosis fungoides, which may still be elusive despite recent diagnostic and technical advances.
Skin-Homing Capacity of Malignant Cells
The molecular interactions that facilitate the capacity of malignant cells in cutaneous T-cell lymphoma to migrate and reside in the skin are fundamental to the normal physiology of immunosurveillance.23 T cells that have yet to encounter their appropriate antigens repeatedly pass from the blood to the lymph nodes to survey antigen-presenting cells for peptides complementary to their T-cell receptors. Principally guiding this efficient navigation are cell-surface molecules such as L-selectin (CD62L) and CC chemokine receptor 7 (CCR7) on naive T cells, with corresponding expression of complementary ligands on lymph-node endothelial cells. Once antigens and other signals are delivered, the T cells become activated and are induced to alter their cell-surface profiles. In skin-draining lymph nodes, conditions appear to favor the induction of expression of molecules such as cutaneous lymphocyte antigen and CC chemokine receptor 4 (CCR4), which greatly facilitate T cells' eventual migration to the skin, thus defining "cutaneous T cells" (Table 3).24,25,26
Table 3. Cutaneous T Cells in Mycosis Fungoides and Cutaneous Inflammation.
One of the skin's primary responses to cellular injury or stress is the release by keratinocytes of cytokines that drive the recruitment of leukocytes that characterize the initiation and maintenance of cutaneous inflammation. This primary cytokine response will up-regulate adhesion molecules on dermal endothelial cells, as well as stimulate basal keratinocytes to release chemokines that infuse the dermis, bind the extracellular matrix, and coat the luminal endothelium. Thus, the cell surface exposed to the intravascular compartment is ready to alert circulating leukocytes that the local tissue warrants attention. Passing T cells with complementary ligands will "tether and roll" along the sticky endothelium, principally guided by the binding of cutaneous lymphocyte antigen to endothelial E-selectin in the skin, before firm adhesion and extravasation into the dermis. These activities are enhanced by skin-associated chemokines such as CC chemokine ligands 17 and 22 (CCL17 and CCL22, respectively), both of which are ligands for CCR4 on the skin-homing T cells (Figure 2).
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-selectin. Chemokine receptors (e.g., CC chemokine receptor 4 ) on the malignant T cells recognize chemokines (e.g., CC chemokine ligand 17 ) 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 microabscesses, which can be observed on histologic examination. This process is principally guided by the interactions of lymphoma-cell integrin E7, 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.
By surface analysis, the malignant clone in patch-or-plaque mycosis fungoides fits the skin-homing, cutaneous-lymphocyte-antigen–positive, CCR4-positive profile,24,27,28,29 and CCL17 and CCL22 have both been shown to have high levels of expression in skin lesions. The secretion of primary cytokines and chemokines by keratinocytes is probably important for the initiation or perpetuation of a skin lesion in mycosis fungoides.29,30 Furthermore, the cells in this disorder may express integrin adhesion molecules (e.g., E7) and chemokine receptors (e.g., CCR4 and CXC chemokine receptors 3 and 4) that can bind ligands on endothelial cells, keratinocytes, and Langerhans' cells, thus enhancing migration into the epidermis.31,32,33,34
Bagot et al.35 demonstrated the marked affinity of malignant T cells to home to the epidermis in mycosis fungoides, and clone-identifying antibodies were used to identify cells in tissue sections with the use of immunoperoxidase. The only cells reacting with the clone-specific antibodies were in the epidermis, and most of the dermal cells did not express the same surface markers as did the malignant clone. These findings suggested that the malignant clone is closer to the surface than are the nonmalignant components of the infiltrate.35 Microdissection studies, in which single cells are laser-captured from tissue sections and analyzed for T-cell–receptor rearrangement status, have demonstrated that virtually all epidermal lymphocytes identified in lesions of cutaneous T-cell lymphoma belong to the malignant clone, whereas they are present in relatively small numbers in the dermal infiltrate.36,37
The skin-homing behavior of malignant cells in mycosis fungoides has several implications for the management of the disorder. The staging of the disease at the time of diagnosis is based largely on the degree of skin involvement.10 Repeated retrospective studies have confirmed the prognostic significance of the burden of the cutaneous tumor, since the rate of survival decreases with increasing stage,38,39,40 increasing body-surface area affected within a given stage,41 and the detection of clonality in the blood.42 For limited patch-or-plaque mycosis fungoides, the treatment of choice is often a skin-directed therapy, which potentially can simultaneously target both the malignant T cells and the stimulating Langerhans' cells. External-beam radiotherapy in a localized field for limited disease and total-skin electron-beam therapy for more advanced stages have been shown to be associated with relatively high rates of response and disease control. Electron-beam therapy clearly has a direct effect on the death of T cells and may effectively modulate the cutaneous milieu in a manner that is conducive to slowing the progression of mycosis fungoides.43,44
Several other skin-based therapies, such as psoralen in combination with ultraviolet A light, narrow-band ultraviolet B light, nitrogen mustard, bis-chloronitrosourea, topical corticosteroids, and bexarotene gel, have been used with success.45 Over time, however, the malignant cells in mycosis fungoides may lose their apparent dependence on the skin 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 of the disease, characterized by erythroderma, skin tumors, leukemia, and lymph-node involvement and warranting more aggressive management than skin-directed therapy alone (Table 4).46
Table 4. Therapeutic Options in the Management of Mycosis Fungoides and the Sézary Syndrome.
In vitro systems that model the interactions underlying the skin-homing behavior of malignant cells in mycosis fungoides may prove useful in the development of pharmacologic agents that have application not only in the treatment of cutaneous T-cell lymphoma, but in the treatment of other inflammatory skin diseases as well. Flow chambers may be used to study the effects of compounds on T-cell rolling, adhesion, and chemotaxis under physiologic shear-stress conditions.47,48 Cutaneous T-cell lymphoma plus autologous dendritic-cell coculture systems may be used to test various pharmacologic agents for their capacity to disrupt cellular interactions that play a critical role in fostering the development and perpetuation of mycosis fungoides or other aberrant T-cell populations.49 Hence, therapies with specific biologic targets may be designed and then improved.
T-Cell Activation
In addition to their tissue-homing capabilities, activated T cells have the ability to switch on the production of signaling molecules and various cytokines that execute specific beneficial effector functions (e.g., elimination of infection) or, conversely, that mediate inflammatory disease. Examination of the clonal cells in skin-biopsy specimens and peripheral-blood samples from patients with leukemic involvement has shown that they commonly express several activation markers, including CD45RO, proliferating-cell nuclear antigen, and the interleukin-2 receptor (CD25).50,51 After stimulation of the interleukin-2 receptor, activated T cells undergo phosphorylation of several intracellular signaling proteins in the JAK-STAT family of molecules. There is evidence in mycosis fungoides that constitutive activation of such molecules contributes to the malignant T cells' apparent persistent state of activation.52,53,54,55
Hence, in addition to being a lymphoma, mycosis fungoides may simultaneously be considered an inflammatory skin disease involving early stages of clonal and reactive cells that have the capacity to produce cytokines. For example, increased production of cytokines such as interleukin-4 and interleukin-5 in advancing stages of the disease has been implicated in the eosinophilia and atopy-like symptoms that often affect patients, especially those with erythrodermic disease.56,57 Playing a role in this bias toward type 2 helper T cytokines, as is evident in the expression profile of peripheral-blood leukocytes from patients with leukemic mycosis fungoides or the Sézary syndrome, is hyperexpression of GATA-3, a transcription factor mediating type 2 helper T-cell differentiation, and JunB, a regulator of interleukin-4 expression.58
The activated cells in mycosis fungoides may also have significant regulatory effects on the host's normal T cells. For example, it has been shown that the activated cells have the ability to produce interleukin-10 and transforming growth factor , both of which can profoundly inhibit cell-mediated immunity.59,60 Furthermore, the cells can produce extraordinary amounts of soluble interleukin-2 receptor, which may competitively bind the interleukin-2 necessary for normal T-cell activation.61 These phenomena may in part account for the increased risk of secondary cancer and infections in patients with mycosis fungoides.62 Thus, although there is evidence of an antitumor immune response in mycosis fungoides, substantial hurdles may need to be overcome before immunotherapy will be effective in a given patient.
Successful therapies in mycosis fungoides preferentially or selectively affect the malignant clone, as is true of most of the skin-directed therapies that capitalize on the skin-homing behavior of the malignant cells. Likewise, the activated state of the cells in mycosis fungoides also makes them a semiselective target for biologic therapy (Table 4). One such therapeutic agent is denileukin diftitox, which was originally designed to target activated T cells in cutaneous inflammatory disease; it is a recombinant protein consisting of a portion of diphtheria toxin conjugated to interleukin-2 and was recently approved for treatment of mycosis fungoides.63,64 After interleukin-2 receptor–mediated endocytosis into activated T cells, the toxin is enzymatically cleaved and then able to uncouple protein synthesis within the cell. This mechanism highlights the intimate link between inflammatory skin disease and mycosis fungoides.
Clonal Dominance of T Cells
In several noncutaneous T-cell leukemias and lymphomas, clear associations with specific mutations and chromosomal abnormalities have been identified in which direct effects on the expression of oncogenes or inactivation of tumor-suppressor genes would be expected to result in clonal expansion. Although such molecular signatures have not been as readily recognized in any form of cutaneous T-cell lymphoma, several key observations have been made in mycosis fungoides and the Sézary syndrome at the genetic level.65 For example, mutations in the cell-cycle regulator gene p53 are associated with disease progression. Comparative genomic hybridization analysis, a tool for wide-scale survey for genomic aberrations, has revealed several hot spots of chromosomal rearrangement (e.g., deletions on chromosomes 1p, 17p, 10q, and 19 and gains on 4q, 18, and 17q) in mycosis fungoides and the Sézary syndrome and has thus helped to focus attention on genes critical to disease progression.55 More recently, Scarisbrick and colleagues66 noted that some patients with mycosis fungoides have microsatellite instability, a high propensity toward genetic instability that is highly characteristic of hereditary nonpolyposis colorectal cancer, a familial cancer syndrome. Moreover, the microsatellite-instability phenotype was much more prevalent among patients with advanced forms of mycosis fungoides, strongly suggesting that this phenomenon is a major contributor to the mutation of tumor-suppressor genes implicated in clonal expansion and disease progression.
The detection of clonal T-cell expansion in mycosis fungoides has been exploited for diagnostic purposes. In very early stages of the disease, a clonally expanded population may be detected by PCR analysis of T-cell–receptor gene rearrangements.67,68 Certain other well-defined skin diseases may be associated with T-cell clonality; however, once those diseases have been ruled out by physical examination, the molecular identification of a clone can facilitate diagnosis in cases in which clinical findings and histologic features are consistent with, but not entirely typical of, mycosis fungoides. In addition, if detection of the same clone is evident in more than one lesion or in a given patient over time, there is an increased risk of disease progression.69 Although PCR can also detect the physiologic recirculation of malignant cells in the peripheral blood of patients with varying tumor burdens, including limited patch-or-plaque disease, late-stage disease is characterized by dominance of the malignant clone and diminution of the normal T-cell population. One obvious surrogate marker of the fading of nonmalignant T cells is the reduction in the normal CD8 lymphocyte population. As the disease progresses, there are decreased numbers of CD8 cells in skin lesions70 and in the peripheral blood.71,72
Recently, Yawalkar and colleagues have used T-cell receptor V gene spectratyping to reveal that the status of the diversity of the T-cell repertoire, even in patients with early mycosis fungoides, is more complex than simple clonal expansion.73 This was reflected in the disruption of normal Gaussian distribution patterns of every third in-frame V T-cell–receptor rearrangement length, with expansion within several V families (some showing frank clonality) and diminution or complete absence of other V family lengths or even entire V families. These findings clearly indicate not only that mycosis fungoides is a disease of T-cell clonal expansion reflected in the peripheral blood, even in the absence of leukemia, but also that there may be profound abnormalities within the normal repertoire of peripheral T cells that further contribute to the immunodeficient state of patients who have the disease. The persistence of the malignant clone and its dominance over other, nonmalignant T cells imply that mycosis fungoides is characterized by a disorder in the regulation of the normal population of T cells. It further justifies the use of therapies that minimize toxicity to the normal lymphocytes.
After antigen-driven stimulation and expansion under normal physiologic conditions, elimination of the majority of the activated T cells is essential to prevent excessive cellular accumulation (as in leukemia and lymphoma) and overexuberant T-cell–mediated tissue damage (as in autoimmune and inflammatory disease states). One built-in check on the system is activation-induced cellular death, whereby, after subsequent T-cell–receptor engagement of previously activated T cells, the apoptotic cascade is initiated and culminates in programmed cellular suicide. Engagement of cell-surface Fas (CD95) by Fas ligand, the external and most upstream connection to apoptosis initiation, provides an alternative pathway through which activated T cells may be eliminated. In addition to releasing cell-damaging molecules (e.g., perforin and granzymes), cytotoxic T lymphocytes, which are the principal effectors in cell-mediated antitumor responses, may induce apoptosis by the expression of FasL and the engagement of Fas on the malignant cells. Given the evidence that cytotoxic T lymphocytes mount an antitumor response in cutaneous T-cell lymphoma, it may not be surprising that the cells in mycosis fungoides show a relative decrease in Fas expression with advancing disease. A variety of Fas mutations and splice variants have been identified in the lesions of mycosis fungoides; the majority result in a nonfunctioning Fas protein.74,75 Thus, avoidance of Fas-mediated stimulation of apoptosis appears to be an important mechanism by which the malignant cells in mycosis fungoides evade immune regulation, and it may contribute to these cells' clonal emergence and dominance. Paradoxically, the malignant T cells may in turn express Fas ligand themselves to eliminate potential antitumor CD8 T cells.76
The weakening immune system in mycosis fungoides, in the setting of dominance by the malignant clone, is a foremost therapeutic consideration. In patients with erythroderma, photopheresis involves harvesting a small portion of the circulating cells. The cells are selectively damaged and reinfused to stimulate a therapeutic response.77 Photopheresis treatment in patients with leukemic mycosis fungoides or the Sézary syndrome simultaneously renders malignant T cells apoptotic and induces the differentiation of peripheral monocytes into dendritic cells,78 thereby providing the key cellular components of a tumor-cell vaccine. Thus, it has been proposed that photopheresis may take advantage of specific determinants on the malignant T cells, including T-cell–receptor peptides79,80 and other tumor antigens,81 to induce an antitumor immune response.82 Immune-stimulating cytokine therapy with interferon alfa-2b is an effective form of monotherapy for mycosis fungoides83 and may have effects synergistic with those of photopheresis.84
There is increasing recognition of the effects of pharmacologic targeting of the retinoid-receptor complex in leukemia and lymphoma.85,86 Retinoic acid receptors typically bind retinoid X receptors to form heterodimers capable of activating the promoters of genes that regulate the expression of cell-surface receptors, structural proteins, and other key mediators of cellular function. Bexarotene, often referred to as a "rexinoid" since it preferentially binds retinoid X receptors (not retinoic acid receptor–like "retinoids"), directly affects the expanding population of malignant cells in mycosis fungoides by inhibiting proliferation, inducing differentiation, and promoting apoptosis.87,88 When administered orally, bexarotene has resulted in improvements at all stages of mycosis fungoides without compromising immune status.89,90
Conclusions
A wide variety of T-cell lymphomas are unified by their propensity to home to the skin. The most common of these, mycosis fungoides, is a non-Hodgkin's, peripheral T-cell lymphoma of the skin with a wide spectrum of potential clinical manifestations. Recent advances in the understanding of the molecular and biologic behavior of T cells in this disorder — the propensity of the cells to home to the skin, to function in an activated state, and to achieve clonal dominance — have had a tremendous influence on the development of treatments. With an expanding armamentarium of biologic agents, phototherapeutic methods, and irradiation techniques, as well as growing recognition of the benefits of combination regimens,84,91 caregivers are better equipped than ever to wage battle against mycosis fungoides. The deepening appreciation of the molecular mechanisms that underlie the behavior of mycosis fungoides can be expected to improve therapy further and to affect the understanding and treatment of other T-cell–mediated disorders.
Source Information
From the Departments of Dermatology (M.G., P.W.H., L.D.W.) and Therapeutic Radiology (L.D.W.), Yale University School of Medicine, New Haven, Conn.
Address reprint requests to Dr. Wilson at the Department of Therapeutic Radiology, Yale University School of Medicine, HRT 136, 333 Cedar St., New Haven, CT 06520, or at lynn.wilson@yale.edu.
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Schechner JS, Edelson RL, McNiff JM, Heald PW, Pober JS. Integrins alpha4beta7 and alphaEbeta7 are expressed on epidermotropic T cells in cutaneous T cell lymphoma and spongiotic dermatitis. Lab Invest 1999;79:601-607.
Lu D, Duvic M, Medeiros LJ, Luthra R, Dorfman DM, Jones D. The T-cell chemokine receptor CXCR3 is expressed highly in low-grade mycosis fungoides. Am J Clin Pathol 2001;115:413-421.
Kallinich T, Muche JM, Qin S, Sterry W, Audring H, Kroczek RA. Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides. J Invest Dermatol 2003;121:1045-1052.
Bagot M, Wechsler J, Lescs MC, Revuz J, Farcet JP, Gaulard P. Intraepidermal localization of the clone in cutaneous T-cell lymphoma. J Am Acad Dermatol 1992;27:589-593.
Gellrich S, Lukowsky A, Schilling T, et al. Microanatomical compartments of clonal and reactive T cells in mycosis fungoides: molecular demonstration by single cell polymerase chain reaction of T cell receptor gene rearrangements. J Invest Dermatol 2000;115:620-624.
Yazdi AS, Medeiros LJ, Puchta U, Thaller E, Flaig MJ, Sander CA. Improved detection of clonality in cutaneous T-cell lymphomas using laser capture microdissection. J Cutan Pathol 2003;30:486-491.
Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 1999;40:418-425.
Demierre MF, Kim YH, Zackheim HS. Prognosis, clinical outcomes and quality of life issues in cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 2003;17:1485-1507.
Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003;139:857-866.
Quiros P, Kacinski BM, Wilson LD. Extent of skin involvement as a prognostic indicator of disease free and overall survival in patients with T3 cutaneous T-cell lymphoma treated with total skin electron beam radiation therapy. Cancer 1996;77:1912-1917.
Fraser-Andrews EA, Russell-Jones R, Woolford AJ, Wolstencroft RA, Dean AJ, Whittaker SJ. Diagnostic and prognostic importance of T-cell receptor gene analysis in patients with Sezary syndrome. Cancer 2001;92:1745-1752.
Jones GW, Hoppe RT, Glatstein E. Electron treatment for cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 1995;9:1057-1076.
Jones GW, Kacinski BM, Wilson LD, et al. Total skin electron radiation in the management of mycosis fungoides: consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol 2002;47:364-370.
Smith BD, Wilson LD. Management of mycosis fungoides. 2. Treatment. Oncology (Huntingt) 2003;17:1419-1428.
Heald P. Clinical trials and efficacy assessment in the therapy of cutaneous T cell lymphoma. Ann N Y Acad Sci 2001;941:155-165.
Kieffer JD, Fuhlbrigge RC, Armerding D, et al. Neutrophils, monocytes, and dendritic cells express the same specialized form of PSGL-1 as do skin-homing memory T cells: cutaneous lymphocyte antigen. Biochem Biophys Res Commun 2001;285:577-587.
Hwang ST, Fitzhugh DJ. Aberrant expression of adhesion molecules by Sézary cells: functional consequences under physiologic shear stress conditions. J Invest Dermatol 2001;116:466-470.
Berger CL, Hanlon D, Kanada D, et al. The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells. Blood 2002;99:2929-2939.
Neish C, Charlry M, Jegasothy B, Tharp M, Deng JS. Proliferation cell nuclear antigen and soluble interleukin 2 receptor levels in cutaneous T cell lymphoma: correlation with advanced clinical diseases. J Dermatol Sci 1994;8:11-17.
Nagatani T, Matsuzaki T, Iemoto G, et al. Comparative study of cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma: clinical, histopathologic, and immunohistochemical analyses. Cancer 1990;66:2380-2386.
Nielsen M, Nissen MH, Gerwien J, et al. Spontaneous interleukin-5 production in cutaneous T-cell lymphoma lines is mediated by constitutively activated Stat3. Blood 2002;99:973-977.
Eriksen KW, Kaltoft K, Mikkelsen G, et al. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia 2001;15:787-793.
Brender C, Nielsen M, Kaltoft K, et al. STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. Blood 2001;97:1056-1062.
Mao X, Lillington D, Scarisbrick JJ, et al. Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides. Br J Dermatol 2002;147:464-475.
Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol 1992;99:90-94.
Papadavid E, Economidou J, Psarra A, et al. The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sezary syndrome. Br J Dermatol 2003;148:709-718.
Kari L, Loboda A, Nebozhyn M, et al. Classification and prediction of survival in patients with the leukemic phase of cutaneous T cell lymphoma. J Exp Med 2003;197:1477-1488.
Saed G, Fivenson DP, Naidu Y, Nickoloff BJ. Mycosis fungoides exhibits a Th1-type cell-mediated cytokine profile whereas Sezary syndrome expresses a Th2-type profile. J Invest Dermatol 1994;103:29-33.
Bagot M, Nikolova M, Schirm-Chabanette F, Wechsler J, Boumsell L, Bensussan A. Crosstalk between tumor T lymphocytes and reactive T lymphocytes in cutaneous T cell lymphomas. Ann N Y Acad Sci 2001;941:31-38.
Vonderheid EC, Zhang Q, Lessin SR, et al. Use of serum soluble interleukin-2 receptor levels to monitor the progression of cutaneous T-cell lymphoma. J Am Acad Dermatol 1998;38:207-220.
Kantor AF, Curtis RE, Vonderheid EC, van Scott EJ, Fraumeni JF Jr. Risk of second malignancy after cutaneous T-cell lymphoma. Cancer 1989;63:1612-1615.
Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1995;1:442-447.
Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 2001;19:376-388.
Whittaker S. Molecular genetics of cutaneous lymphomas. Ann N Y Acad Sci 2001;941:39-45.
Scarisbrick JJ, Mitchell TJ, Calonje E, Orchard G, Russell-Jones R, Whittaker SJ. Microsatellite instability is associated with hypermethylation of the hMLH1 gene and reduced gene expression in mycosis fungoides. J Invest Dermatol 2003;121:894-901.
Wood GS, Tung RM, Haeffner AC, et al. Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/Sézary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol 1994;103:34-41.
Benhattar J, Delacretaz F, Martin P, Chaubert P, Costa J. Improved polymerase chain reaction detection of clonal T-cell lymphoid neoplasms. Diagn Mol Pathol 1995;4:108-112.
Vega F, Luthra R, Medeiros LJ, et al. Clonal heterogeneity in mycosis fungoides and its relationship to clinical course. Blood 2002;100:3369-3373.
Hoppe RT, Medeiros LJ, Warnke RA, Wood GS. CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Am Acad Dermatol 1995;32:448-453.
Heald P, Yan SL, Edelson R. Profound deficiency in normal circulating T cells in erythrodermic cutaneous T-cell lymphoma. Arch Dermatol 1994;130:198-203.
Lu D, Patel KA, Duvic M, Jones D. Clinical and pathological spectrum of CD8-positive cutaneous T-cell lymphomas. J Cutan Pathol 2002;29:465-472.
Yawalkar N, Ferenczi K, Jones DA, et al. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 2003;102:4059-4066.
Dereure O, Levi E, Vonderheid EC, Kadin ME. Infrequent Fas mutations but no Bax or p53 mutations in early mycosis fungoides: a possible mechanism for the accumulation of malignant T lymphocytes in the skin. J Invest Dermatol 2002;118:949-956.
van Doorn R, Dijkman R, Vermeer MH, Starink TM, Willemze R, Tensen CP. A novel splice variant of the Fas gene in patients with cutaneous T-cell lymphoma. Cancer Res 2002;62:5389-5392.
Ni X, Hazarika P, Zhang C, Talpur R, Duvic M. Fas ligand expression by neoplastic T lymphocytes mediates elimination of CD8+ cytotoxic T lymphocytes in mycosis fungoides: a potential mechanism of tumor immune escape? Clin Cancer Res 2001;7:2682-2692.
Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med 1987;316:297-303.
Berger CL, Xu AL, Hanlon D, et al. Induction of human tumor-loaded dendritic cells. Int J Cancer 2001;91:438-447.
Berger CL, Longley J, Hanlon D, Girardi M, Edelson R. The clonotypic T cell receptor is a source of tumor-associated antigens in cutaneous T cell lymphoma. Ann N Y Acad Sci 2001;941:106-122.
Winter D, Fiebiger E, Meraner P, et al. Definition of TCR epitopes for CTL-mediated attack of cutaneous T cell lymphoma. J Immunol 2003;171:2714-2724.
Usener D, Schadendorf D, Koch J, Dubel S, Eichmuller S. cTAGE: a cutaneous T cell lymphoma associated antigen family with tumor-specific splicing. J Invest Dermatol 2003;121:198-206.
Girardi M, Berger C, Hanlon D, Edelson RL. Efficient tumor antigen loading of dendritic antigen presenting cells by transimmunization. Technol Cancer Res Treat 2002;1:65-69.
Olsen EA, Bunn PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 1995;9:1089-1107.
Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 2002;138:1054-1060.
Sanz MA, Martín G, Díaz-Mediavilla J. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1998;338:393-393.
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Zhang C, Hazarika P, Ni X, Weidner DA, Duvic M. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res 2002;8:1234-1240.
Cheng SX, Kupper T. A new rexinoid for cutaneous t-cell lymphoma. Arch Dermatol 2001;137:649-652.
Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 2001;137:581-593.
Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 2001;19:2456-2471.
Duvic M, Apisarnthanarax N, Cohen DS, Smith TL, Ha CS, Kurzrock R. Analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 2003;49:35-49.(Michael Girardi, M.D., Pe)
Advances in cellular and molecular biology have revealed many details about lymphocytes, including the incredible diversity of their T-cell antigen receptors, the efficiency with which they navigate the endoreticular system, and their capacity for recruitment to specific tissues.1 The integration of these activities may result in the beneficial elimination 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 that continue 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 activated and persist in an activated state, and achieve clonal dominance, thereby accumulating in the skin, lymph nodes, and peripheral blood. Knowledge of the unifying characteristics relating to disease behavior influences the evaluation and therapy of patients with mycosis fungoides, and an understanding of the pathogenesis and treatment of mycosis fungoides offers insights into fundamental mechanisms of T-cell signaling, apoptosis, and immunosurveillance.
Mycosis fungoides is a relatively rare, extranodal, non-Hodgkin's lymphoma with a stable incidence of approximately 0.36 per 100,000 person-years.2,3 Infectious agents, occupational exposures, and genetic mutations have been evaluated as etiologic factors in relation to mycosis fungoides, but evidence of causation has not been readily forthcoming.4 Whereas viruses have been identified as etiologic agents in at least two cutaneous lymphomas (human T-cell lymphotropic virus–associated adult T-cell lymphoma–leukemia and Epstein–Barr virus–associated nasal natural-killer–T-cell lymphoma), no such relation has been confirmed for mycosis fungoides. Nevertheless, according to a recent intriguing report, 97 percent of patients with late-stage mycosis fungoides or the Sézary syndrome are seropositive for cytomegalovirus, in contrast to healthy bone marrow donors, whose seropositivity rate is 57 percent.5 In addition, it is important to note that a variety of T-cell lymphomas may involve the skin during their clinical evolution, and these entities often have quite remarkable clinical presentations, which may be very different from those of the more commonly encountered mycosis fungoides. This diversity is recognized by the two primary classification systems in current use (Table 1).
Table 1. Classification of Cutaneous T-Cell Lymphomas.
Clinical Features
Approximately 200 years after the first description of lesions of cutaneous T-cell lymphoma as "mycosis fungoides," immunophenotyping studies revealed that mycosis fungoides was actually one of many cutaneous T-cell lymphomas, typically of the CD4 helper T-cell phenotype.8 As shown in Figure 1, a patient with mycosis fungoides may present with one or more of many diverse cutaneous manifestations.9 The patch or plaque lesions of mycosis fungoides have a predilection for non–sun-exposed areas (e.g., the buttocks, medial thighs, and breasts), although any area of the skin may be affected. Insidious in onset, it is not uncommon for the disease in this form to go unrecognized for several years, most often misdiagnosed as chronic contact dermatitis, atopic dermatitis, or psoriasis. The lesions may become variably thickened, may coalesce to form larger plaques, or may undergo partial involution, leaving residual annular plaques. Patches and plaques may show hypopigmentation or hyperpigmentation, atrophy, and petechiae as well as a variety of tropisms in which the malignant cells accumulate in specialized areas of the epidermis, such as follicles or sweat glands.
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 fungoides, in which lesions characterized by alopecia develop. In a similar variant, there is mucin deposition in the follicles. Panel E shows hypopigmented 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 fungoides. 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 lymphocytes 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."
The skin of patients with mycosis fungoides may also show more poorly defined areas of erythema, apparently arising spontaneously or after the progression of patch-or-plaque disease (Table 2).10 When the erythema reaches a point of predominance (i.e., covering more than 80 percent of the body-surface area, as in so-called erythrodermic mycosis fungoides11), patients are far more likely to have leukemic involvement than are patients with limited body-surface involvement. Historically, the term "Sézary syndrome" has been used to describe patients with mycosis fungoides who have erythroderma and atypical circulating cells with highly convoluted nuclei, but a more relevant distinction in such patients would be based on an accurate assessment of the degree of peripheral-blood involvement by molecular or flow-cytometric analysis. Specific features might include the expansion of a particular T-cell receptor V family, increases in the ratio of helper (CD4) to cytotoxic (CD8) T cells, or the presence of a T-cell population showing loss of the CD26 T-cell marker.12,13,14,15 Recently, the International Society for Cutaneous Lymphomas11 proposed criteria for identification of the Sézary syndrome with leukemic blood involvement, as follows: an absolute count of Sézary cells (enlarged, atypical lymphocytes with convoluted nuclei) of at least 1000 per cubic millimeter; a ratio of CD4 T cells to CD8 T cells of 10 or higher; an increase in circulating T cells with aberrant expression of pan–T-cell markers, as assessed by flow cytometry; an increased lymphocyte count with evidence of a T-cell clone in the blood, as assessed by Southern-blot or polymerase-chain-reaction (PCR) analysis; and a T-cell clone with chromosomal abnormalities (e.g., deletions or translocations).
Table 2. Classic TNM Staging of Mycosis Fungoides.
Cutaneous tumors can arise in patients with patch-or-plaque mycosis fungoides or can arise de novo. The tumors are characterized by an exaggerated vertical growth phase, resulting in the development of protruding and often ulcerating lesions. Cellular morphologic features are used to define mycosis fungoides tumors further,6,7 with "large-cell transformation" carrying a poor prognosis if it occurs within two years after diagnosis.16 Primary cutaneous CD30-positive anaplastic large-cell lymphoma, which appears in the skin without any preceding clinical or histologic evidence of mycosis fungoides, may manifest in the form of localized or broadly distributed tumors.17,18,19
The major histologic findings in patch-or-plaque mycosis fungoides represent several important features of the disease.20,21 A lymphocytic infiltrate in the superficial dermis, with individual lymphocytes migrating among epidermal keratinocytes, defines the so-called epidermotropism that characterizes this lymphoma. The clustering of clonal T cells around Langerhans' cells (forming what are called Pautrier's microabscesses) is illustrative of the apparent dependence of the T cells on interactions with these dendritic cells, particularly in the early stages of the disease. The lymphocytes may show varying degrees of atypia (pleomorphic, hyperchromatic, and convoluted nuclei). In addition to routine histologic examination, staining of skin-biopsy specimens with a panel of lymphocyte markers is used to help define the malignant clone for subclassification.18,19,20,21 Such distinctions can have important prognostic implications. For example, mycosis fungoides that is positive for T-cell receptor / is associated with more aggressive disease than is that without the receptor rearrangement.22 Examination of multiple biopsy specimens from various lesions at various times will increase the likelihood that an accurate diagnosis will be made, and PCR analysis of T-cell receptor genes to determine clonality may also be helpful. Nevertheless, combining information about clinical, pathologic, and molecular features is essential to making an accurate diagnosis of mycosis fungoides, which may still be elusive despite recent diagnostic and technical advances.
Skin-Homing Capacity of Malignant Cells
The molecular interactions that facilitate the capacity of malignant cells in cutaneous T-cell lymphoma to migrate and reside in the skin are fundamental to the normal physiology of immunosurveillance.23 T cells that have yet to encounter their appropriate antigens repeatedly pass from the blood to the lymph nodes to survey antigen-presenting cells for peptides complementary to their T-cell receptors. Principally guiding this efficient navigation are cell-surface molecules such as L-selectin (CD62L) and CC chemokine receptor 7 (CCR7) on naive T cells, with corresponding expression of complementary ligands on lymph-node endothelial cells. Once antigens and other signals are delivered, the T cells become activated and are induced to alter their cell-surface profiles. In skin-draining lymph nodes, conditions appear to favor the induction of expression of molecules such as cutaneous lymphocyte antigen and CC chemokine receptor 4 (CCR4), which greatly facilitate T cells' eventual migration to the skin, thus defining "cutaneous T cells" (Table 3).24,25,26
Table 3. Cutaneous T Cells in Mycosis Fungoides and Cutaneous Inflammation.
One of the skin's primary responses to cellular injury or stress is the release by keratinocytes of cytokines that drive the recruitment of leukocytes that characterize the initiation and maintenance of cutaneous inflammation. This primary cytokine response will up-regulate adhesion molecules on dermal endothelial cells, as well as stimulate basal keratinocytes to release chemokines that infuse the dermis, bind the extracellular matrix, and coat the luminal endothelium. Thus, the cell surface exposed to the intravascular compartment is ready to alert circulating leukocytes that the local tissue warrants attention. Passing T cells with complementary ligands will "tether and roll" along the sticky endothelium, principally guided by the binding of cutaneous lymphocyte antigen to endothelial E-selectin in the skin, before firm adhesion and extravasation into the dermis. These activities are enhanced by skin-associated chemokines such as CC chemokine ligands 17 and 22 (CCL17 and CCL22, respectively), both of which are ligands for CCR4 on the skin-homing T cells (Figure 2).
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-selectin. Chemokine receptors (e.g., CC chemokine receptor 4 ) on the malignant T cells recognize chemokines (e.g., CC chemokine ligand 17 ) 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 microabscesses, which can be observed on histologic examination. This process is principally guided by the interactions of lymphoma-cell integrin E7, 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.
By surface analysis, the malignant clone in patch-or-plaque mycosis fungoides fits the skin-homing, cutaneous-lymphocyte-antigen–positive, CCR4-positive profile,24,27,28,29 and CCL17 and CCL22 have both been shown to have high levels of expression in skin lesions. The secretion of primary cytokines and chemokines by keratinocytes is probably important for the initiation or perpetuation of a skin lesion in mycosis fungoides.29,30 Furthermore, the cells in this disorder may express integrin adhesion molecules (e.g., E7) and chemokine receptors (e.g., CCR4 and CXC chemokine receptors 3 and 4) that can bind ligands on endothelial cells, keratinocytes, and Langerhans' cells, thus enhancing migration into the epidermis.31,32,33,34
Bagot et al.35 demonstrated the marked affinity of malignant T cells to home to the epidermis in mycosis fungoides, and clone-identifying antibodies were used to identify cells in tissue sections with the use of immunoperoxidase. The only cells reacting with the clone-specific antibodies were in the epidermis, and most of the dermal cells did not express the same surface markers as did the malignant clone. These findings suggested that the malignant clone is closer to the surface than are the nonmalignant components of the infiltrate.35 Microdissection studies, in which single cells are laser-captured from tissue sections and analyzed for T-cell–receptor rearrangement status, have demonstrated that virtually all epidermal lymphocytes identified in lesions of cutaneous T-cell lymphoma belong to the malignant clone, whereas they are present in relatively small numbers in the dermal infiltrate.36,37
The skin-homing behavior of malignant cells in mycosis fungoides has several implications for the management of the disorder. The staging of the disease at the time of diagnosis is based largely on the degree of skin involvement.10 Repeated retrospective studies have confirmed the prognostic significance of the burden of the cutaneous tumor, since the rate of survival decreases with increasing stage,38,39,40 increasing body-surface area affected within a given stage,41 and the detection of clonality in the blood.42 For limited patch-or-plaque mycosis fungoides, the treatment of choice is often a skin-directed therapy, which potentially can simultaneously target both the malignant T cells and the stimulating Langerhans' cells. External-beam radiotherapy in a localized field for limited disease and total-skin electron-beam therapy for more advanced stages have been shown to be associated with relatively high rates of response and disease control. Electron-beam therapy clearly has a direct effect on the death of T cells and may effectively modulate the cutaneous milieu in a manner that is conducive to slowing the progression of mycosis fungoides.43,44
Several other skin-based therapies, such as psoralen in combination with ultraviolet A light, narrow-band ultraviolet B light, nitrogen mustard, bis-chloronitrosourea, topical corticosteroids, and bexarotene gel, have been used with success.45 Over time, however, the malignant cells in mycosis fungoides may lose their apparent dependence on the skin 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 of the disease, characterized by erythroderma, skin tumors, leukemia, and lymph-node involvement and warranting more aggressive management than skin-directed therapy alone (Table 4).46
Table 4. Therapeutic Options in the Management of Mycosis Fungoides and the Sézary Syndrome.
In vitro systems that model the interactions underlying the skin-homing behavior of malignant cells in mycosis fungoides may prove useful in the development of pharmacologic agents that have application not only in the treatment of cutaneous T-cell lymphoma, but in the treatment of other inflammatory skin diseases as well. Flow chambers may be used to study the effects of compounds on T-cell rolling, adhesion, and chemotaxis under physiologic shear-stress conditions.47,48 Cutaneous T-cell lymphoma plus autologous dendritic-cell coculture systems may be used to test various pharmacologic agents for their capacity to disrupt cellular interactions that play a critical role in fostering the development and perpetuation of mycosis fungoides or other aberrant T-cell populations.49 Hence, therapies with specific biologic targets may be designed and then improved.
T-Cell Activation
In addition to their tissue-homing capabilities, activated T cells have the ability to switch on the production of signaling molecules and various cytokines that execute specific beneficial effector functions (e.g., elimination of infection) or, conversely, that mediate inflammatory disease. Examination of the clonal cells in skin-biopsy specimens and peripheral-blood samples from patients with leukemic involvement has shown that they commonly express several activation markers, including CD45RO, proliferating-cell nuclear antigen, and the interleukin-2 receptor (CD25).50,51 After stimulation of the interleukin-2 receptor, activated T cells undergo phosphorylation of several intracellular signaling proteins in the JAK-STAT family of molecules. There is evidence in mycosis fungoides that constitutive activation of such molecules contributes to the malignant T cells' apparent persistent state of activation.52,53,54,55
Hence, in addition to being a lymphoma, mycosis fungoides may simultaneously be considered an inflammatory skin disease involving early stages of clonal and reactive cells that have the capacity to produce cytokines. For example, increased production of cytokines such as interleukin-4 and interleukin-5 in advancing stages of the disease has been implicated in the eosinophilia and atopy-like symptoms that often affect patients, especially those with erythrodermic disease.56,57 Playing a role in this bias toward type 2 helper T cytokines, as is evident in the expression profile of peripheral-blood leukocytes from patients with leukemic mycosis fungoides or the Sézary syndrome, is hyperexpression of GATA-3, a transcription factor mediating type 2 helper T-cell differentiation, and JunB, a regulator of interleukin-4 expression.58
The activated cells in mycosis fungoides may also have significant regulatory effects on the host's normal T cells. For example, it has been shown that the activated cells have the ability to produce interleukin-10 and transforming growth factor , both of which can profoundly inhibit cell-mediated immunity.59,60 Furthermore, the cells can produce extraordinary amounts of soluble interleukin-2 receptor, which may competitively bind the interleukin-2 necessary for normal T-cell activation.61 These phenomena may in part account for the increased risk of secondary cancer and infections in patients with mycosis fungoides.62 Thus, although there is evidence of an antitumor immune response in mycosis fungoides, substantial hurdles may need to be overcome before immunotherapy will be effective in a given patient.
Successful therapies in mycosis fungoides preferentially or selectively affect the malignant clone, as is true of most of the skin-directed therapies that capitalize on the skin-homing behavior of the malignant cells. Likewise, the activated state of the cells in mycosis fungoides also makes them a semiselective target for biologic therapy (Table 4). One such therapeutic agent is denileukin diftitox, which was originally designed to target activated T cells in cutaneous inflammatory disease; it is a recombinant protein consisting of a portion of diphtheria toxin conjugated to interleukin-2 and was recently approved for treatment of mycosis fungoides.63,64 After interleukin-2 receptor–mediated endocytosis into activated T cells, the toxin is enzymatically cleaved and then able to uncouple protein synthesis within the cell. This mechanism highlights the intimate link between inflammatory skin disease and mycosis fungoides.
Clonal Dominance of T Cells
In several noncutaneous T-cell leukemias and lymphomas, clear associations with specific mutations and chromosomal abnormalities have been identified in which direct effects on the expression of oncogenes or inactivation of tumor-suppressor genes would be expected to result in clonal expansion. Although such molecular signatures have not been as readily recognized in any form of cutaneous T-cell lymphoma, several key observations have been made in mycosis fungoides and the Sézary syndrome at the genetic level.65 For example, mutations in the cell-cycle regulator gene p53 are associated with disease progression. Comparative genomic hybridization analysis, a tool for wide-scale survey for genomic aberrations, has revealed several hot spots of chromosomal rearrangement (e.g., deletions on chromosomes 1p, 17p, 10q, and 19 and gains on 4q, 18, and 17q) in mycosis fungoides and the Sézary syndrome and has thus helped to focus attention on genes critical to disease progression.55 More recently, Scarisbrick and colleagues66 noted that some patients with mycosis fungoides have microsatellite instability, a high propensity toward genetic instability that is highly characteristic of hereditary nonpolyposis colorectal cancer, a familial cancer syndrome. Moreover, the microsatellite-instability phenotype was much more prevalent among patients with advanced forms of mycosis fungoides, strongly suggesting that this phenomenon is a major contributor to the mutation of tumor-suppressor genes implicated in clonal expansion and disease progression.
The detection of clonal T-cell expansion in mycosis fungoides has been exploited for diagnostic purposes. In very early stages of the disease, a clonally expanded population may be detected by PCR analysis of T-cell–receptor gene rearrangements.67,68 Certain other well-defined skin diseases may be associated with T-cell clonality; however, once those diseases have been ruled out by physical examination, the molecular identification of a clone can facilitate diagnosis in cases in which clinical findings and histologic features are consistent with, but not entirely typical of, mycosis fungoides. In addition, if detection of the same clone is evident in more than one lesion or in a given patient over time, there is an increased risk of disease progression.69 Although PCR can also detect the physiologic recirculation of malignant cells in the peripheral blood of patients with varying tumor burdens, including limited patch-or-plaque disease, late-stage disease is characterized by dominance of the malignant clone and diminution of the normal T-cell population. One obvious surrogate marker of the fading of nonmalignant T cells is the reduction in the normal CD8 lymphocyte population. As the disease progresses, there are decreased numbers of CD8 cells in skin lesions70 and in the peripheral blood.71,72
Recently, Yawalkar and colleagues have used T-cell receptor V gene spectratyping to reveal that the status of the diversity of the T-cell repertoire, even in patients with early mycosis fungoides, is more complex than simple clonal expansion.73 This was reflected in the disruption of normal Gaussian distribution patterns of every third in-frame V T-cell–receptor rearrangement length, with expansion within several V families (some showing frank clonality) and diminution or complete absence of other V family lengths or even entire V families. These findings clearly indicate not only that mycosis fungoides is a disease of T-cell clonal expansion reflected in the peripheral blood, even in the absence of leukemia, but also that there may be profound abnormalities within the normal repertoire of peripheral T cells that further contribute to the immunodeficient state of patients who have the disease. The persistence of the malignant clone and its dominance over other, nonmalignant T cells imply that mycosis fungoides is characterized by a disorder in the regulation of the normal population of T cells. It further justifies the use of therapies that minimize toxicity to the normal lymphocytes.
After antigen-driven stimulation and expansion under normal physiologic conditions, elimination of the majority of the activated T cells is essential to prevent excessive cellular accumulation (as in leukemia and lymphoma) and overexuberant T-cell–mediated tissue damage (as in autoimmune and inflammatory disease states). One built-in check on the system is activation-induced cellular death, whereby, after subsequent T-cell–receptor engagement of previously activated T cells, the apoptotic cascade is initiated and culminates in programmed cellular suicide. Engagement of cell-surface Fas (CD95) by Fas ligand, the external and most upstream connection to apoptosis initiation, provides an alternative pathway through which activated T cells may be eliminated. In addition to releasing cell-damaging molecules (e.g., perforin and granzymes), cytotoxic T lymphocytes, which are the principal effectors in cell-mediated antitumor responses, may induce apoptosis by the expression of FasL and the engagement of Fas on the malignant cells. Given the evidence that cytotoxic T lymphocytes mount an antitumor response in cutaneous T-cell lymphoma, it may not be surprising that the cells in mycosis fungoides show a relative decrease in Fas expression with advancing disease. A variety of Fas mutations and splice variants have been identified in the lesions of mycosis fungoides; the majority result in a nonfunctioning Fas protein.74,75 Thus, avoidance of Fas-mediated stimulation of apoptosis appears to be an important mechanism by which the malignant cells in mycosis fungoides evade immune regulation, and it may contribute to these cells' clonal emergence and dominance. Paradoxically, the malignant T cells may in turn express Fas ligand themselves to eliminate potential antitumor CD8 T cells.76
The weakening immune system in mycosis fungoides, in the setting of dominance by the malignant clone, is a foremost therapeutic consideration. In patients with erythroderma, photopheresis involves harvesting a small portion of the circulating cells. The cells are selectively damaged and reinfused to stimulate a therapeutic response.77 Photopheresis treatment in patients with leukemic mycosis fungoides or the Sézary syndrome simultaneously renders malignant T cells apoptotic and induces the differentiation of peripheral monocytes into dendritic cells,78 thereby providing the key cellular components of a tumor-cell vaccine. Thus, it has been proposed that photopheresis may take advantage of specific determinants on the malignant T cells, including T-cell–receptor peptides79,80 and other tumor antigens,81 to induce an antitumor immune response.82 Immune-stimulating cytokine therapy with interferon alfa-2b is an effective form of monotherapy for mycosis fungoides83 and may have effects synergistic with those of photopheresis.84
There is increasing recognition of the effects of pharmacologic targeting of the retinoid-receptor complex in leukemia and lymphoma.85,86 Retinoic acid receptors typically bind retinoid X receptors to form heterodimers capable of activating the promoters of genes that regulate the expression of cell-surface receptors, structural proteins, and other key mediators of cellular function. Bexarotene, often referred to as a "rexinoid" since it preferentially binds retinoid X receptors (not retinoic acid receptor–like "retinoids"), directly affects the expanding population of malignant cells in mycosis fungoides by inhibiting proliferation, inducing differentiation, and promoting apoptosis.87,88 When administered orally, bexarotene has resulted in improvements at all stages of mycosis fungoides without compromising immune status.89,90
Conclusions
A wide variety of T-cell lymphomas are unified by their propensity to home to the skin. The most common of these, mycosis fungoides, is a non-Hodgkin's, peripheral T-cell lymphoma of the skin with a wide spectrum of potential clinical manifestations. Recent advances in the understanding of the molecular and biologic behavior of T cells in this disorder — the propensity of the cells to home to the skin, to function in an activated state, and to achieve clonal dominance — have had a tremendous influence on the development of treatments. With an expanding armamentarium of biologic agents, phototherapeutic methods, and irradiation techniques, as well as growing recognition of the benefits of combination regimens,84,91 caregivers are better equipped than ever to wage battle against mycosis fungoides. The deepening appreciation of the molecular mechanisms that underlie the behavior of mycosis fungoides can be expected to improve therapy further and to affect the understanding and treatment of other T-cell–mediated disorders.
Source Information
From the Departments of Dermatology (M.G., P.W.H., L.D.W.) and Therapeutic Radiology (L.D.W.), Yale University School of Medicine, New Haven, Conn.
Address reprint requests to Dr. Wilson at the Department of Therapeutic Radiology, Yale University School of Medicine, HRT 136, 333 Cedar St., New Haven, CT 06520, or at lynn.wilson@yale.edu.
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