Cutaneous T-Cell Lymphoma

Abstract

INTRODUCTION Cutaneous T-cell lymphoma (CTCL) represents a category of complex and diverse disease states that involve the skin as the primary site of malignant T-lymphocyte proliferation and is a type of non-Hodgkin lymphoma. These malignant CD4+ T cells (lymphocytes) also can invade the lymphatic nodes, blood, and visceral organs. Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are the most common types of CTCL. These chronic diseases are rare and have considerable variation in cutaneous presentation, histologic appearance, degree of blood involvement, immunophenotypic profile, and prognosis. Historically, the French were pioneers in the discovery of CTCL. Approximately 200 years ago, Jean Louise Alibert published an article describing the appearance of tumors on the skin similar to that of a mushroom and coined the term mycosis fungoides (Alibert, 1806). In 1938, French physicians Sézary and Bouvrain published the discovery of an atypical T lymphocyte in the blood of a patient who had skin findings that were consistent with MF and who was erythrodermic at the same time. Further advances in cutaneous lymphomas continued in the 20th century with the discoveries of cutaneous B-cell, natural killer cell, and gamma delta-cell lymphomas, as well as variants of MF. In the mid-1970s, Edelson and Lutzner coined the term CTCL to unify all the diagnoses recognized as cancer that shared a common T-cell phenotype including MF and SS (Lutzner et al., 1975). The term CTCL should not be used interchangeably with MF and SS; rather, it should be used only to describe the complete spectrum of cutaneous lymphomas of T-cell origin. The World Health Organization and the European Organisation for Research and Treatment of Cancer met in 2003 and 2004 to organize and define the cutaneous lymphomas and to separate them from systemic lymphomas with similar histology (Willemze et al., 2005). Lymphomas are now classified as either T-cell or B-cell lymphoma with indolent, intermediate, or aggressive clinical behavior, allowing for more consistent diagnosis and treatment regimens (see Figure 4-1).FIGURE 4-1: World Health Organization/European Organisation for Research and Treatment of Cancer Classification. Note. Based on information from Willemze et al., 2005.EPIDEMIOLOGY MF and SS are rare diseases despite evidence that their prevalence is increasing. Utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Results data, Criscione and Weinstock (2007) reported that the incidence of CTCL tripled to 6.4 per million from 1973 to 2002 in the United States, with a 2.9-per-million increase per decade over the same period. This increased incidence may be a result of better medical awareness and screening methods. CTCL occurs 32% more often in blacks than in whites, and the ratio of male to female is 2:1 with an increase in incidence with age. CTCL in children is confirmed but uncommon. MF was found to be responsible for 72% of all CTCL cases, and SS represented 2.5% of all CTCLs. Overall, CTCL represents 3.9% of all non-Hodgkin lymphomas, with substantial geographic variation in incidence. An increased incidence is found in areas with high physician density, high family income, higher education, and high home property values. These findings may represent a difference in access to medical care and, thus, earlier or better diagnosis. Nurses should be alert to the potential for opportunities for patient/community education about CTCL. Given the evidence of an increasing incidence of CTCL, dermatology and oncology nurses must remain apprised of the latest literature on accurate detection and treatment of CTCL. PATHOPHYSIOLOGY The cause of MF and SS (as well as other CTCLs) is unknown. Infectious agents, including bacteria and viruses, have been proposed as possible triggers for CTCL (Hwang, Janik, Jaffe, & Wilson, 2008). Herne, Talpur, Breuer-McHam, Champlin, and Duvic (2003) associated cytomegalovirus infection with CTCL, and Chang, Liu, Chen, and Chow (1998) detected the Epstein-Barr virus in patients with T-cell lymphomas of the skin. Although these associations are intriguing, the data are not strong enough to conclude that a causal relation exists. However, the quest to find the etiology of MF and SS has led to a great increase in information available about the genetic and immune abnormalities found in MF and SS. Ultimately, understanding the pathophysiology of MF and SS may help in the development of novel therapies to treat these lymphoid malignancies (Hwang et al.). The pathology of MF and SS is characterized by neoplastic CD4+ T cells that preferentially home to migrate and expand in the skin. CD4+ T cells help to regulate the generation of T-cell-mediated responses, which are functionally mediated by another class of T cells that express the surface protein CD8+. Generally, the malignant T cells in MF and SS show signs of activation, releasing cytokines and other proteins that cause the skin cells (keratinocytes) to proliferate, leading to scaling and thickening of the epidermis characteristic of these diseases. These cytokines, including interleukin (IL)-4, may contribute to the mild-to-moderate immunosuppression that may be present in patients with MF and SS. Moreover, the release of cytokines may contribute to the pruritus that is present in many patients at all stages of MF and SS. In the patch and plaque stages of the disease, malignant T cells represent a relatively small proportion of total T cells in the skin because normal T cells, including those of the CD8+ phenotype, often are present as a "reaction" to the malignant T cells. When patients develop thick plaques and tumors, the majority of the T cells in these lesions are derived from the malignant clone (Girardi, Heald, & Wilson, 2004). Hwang et al. (2008) proposed that multiple abnormalities in the immune environment in the skin, including the antigen-presenting cells (also known as dendritic cells) that stimulate T cells, contribute to the clinical signs and symptoms of MF and SS. Malignant CD4+ MF and Sézary cells generally express the CD45RO surface protein marker, which identifies these cells as "memory" T cells that have previously been activated by antigen. This marker differentiates these cells from CD45RA+ T cells that are "naïve" and have not yet been stimulated to proliferate by antigen. Memory T cells have an enhanced ability to proliferate and to secrete cytokines, even in the presence of small amounts of antigen presented by antigen-presenting cells. Memory T cells are proficient at migrating from the blood to inflamed tissue, including skin, because they express specific chemotactic receptors known as chemokine receptors and adhesion molecules (Sallusto, Lenig, Forster, Lipp, & Lanzavecchia, 1999). Evidence exists that CD45RO+ tumor cells in patients with MF may escape immune recognition and destruction through expression of proteins that potentially induce apoptosis of antitumor, cytotoxic CD8+ T cells, which may otherwise control the malignant T cells (Ni, Hazarika, Zhang, Talpur, & Duvic, 2001). Alterations in specific cytokines and chemokines (small chemotactic proteins) have been proposed to contribute to clonal expansion and immunosuppression in MF and SS (Yamanaka et al., 2006b). IL-18 expression may play a role in the immunosuppression that is characteristic of late-stage CTCL (Yamanaka et al., 2006a). IL-15, which requires presentation by antigen-presenting cells, may contribute to T-cell proliferation (Dooms et al., 1998). IL-4 and IL-5, which skew the immune environment, can lead toward a humoral (antibody-mediated) Th2-type immune response (Vowels et al., 1994). Additionally, chemokines may play a role in attracting malignant T cells to the skin and enhancing their ability to survive by acting upon G-protein-coupled chemokine receptors found on the surface of T cells (Clark et al., 2006; Notohamiprodjo et al., 2005; Sokolowska-Wojdylo et al., 2005). Edelson (2001) hypothesized that the survival and proliferation of the neoplastic T cells in MF and SS were enhanced by antigen-presenting dendritic cells based on evidence that dendritic cells support the long-term culture of SS cells. Interestingly, skin dendritic cells known as Langerhans cells frequently localize in the epidermis adjacent to malignant T cells in MF, creating the so-called Pautrier abscess, an often-observed histologic sign of MF (see Figure 4-2).FIGURE 4-2: Histology Slide of Mycosis Fungoides. Note. Slide courtesy of Dr. Richard Lee, National Institutes of Health, National Cancer Institute, Laboratory of Pathology.Recent evidence suggests that MF, even in its early stages, may be a systemic disease. In normal individuals, the T-cell receptor varies tremendously among different T cells for these cells to bind hundreds of thousands of potential antigens. The normal T-cell repertoire in humans is diverse and large. Yawalkar et al. (2003) recently reported the loss of normal T-cell repertoire in all stages of MF and SS, a finding that may have a relationship to the origin of these diseases. The loss of normal T-cell repertoire is a phenomenon that has been observed after infection with certain viruses, including HIV-1. Hwang et al. (2008) have speculated that MF may arise from continued (chronic) reactivity of malignant T cells to normal skin antigens following initial infection with a yet-undefined virus. In summary, although the etiologies of MF and SS remain unknown, multiple abnormalities in cytokine expression, chemokine expression, and antigen presentation have been revealed. Together, these abnormalities may contribute to the immunosuppression seen in MF, particularly in the late stages, or in SS. Therapies that target these abnormalities are beginning to show positive benefits in the treatment of MF and SS. STAGING The most common staging system in use for CTCL was created in 1978 at a National Cancer Institute Workshop on CTCL (Lamberg & Bunn, 1979). Subsequently, the International Society for Cutaneous Lymphoma updated the criteria for blood involvement to distinguish among three subsets of erythrodermic CTCL (E-CTCL). The subsets include SS as leukemic phase E-CTCL, erythrodermic MF as secondary E-CTCL, and E-CTCL as not otherwise defined (Vonderheid et al., 2002). The leukemic criteria of SS are intended to differentiate these patients with a poorer prognosis from the other E-CTCL subsets. The leukemic criteria are further explained under SS in Patient Assessment. The MF staging system employs a multistep process. Because the malignant T cells can traffic among skin, lymph nodes, blood, and viscera, the staging system was designed to include each possible area of T-cell involvement. Each category or classification employs a label to identify the involved system so that skin = T, lymph = N, viscera or systemic metastasis = M, and blood = B. Then, each category is ranked according to the type or extent of T-cell involvement. For example, T2 = patch or plaque involving ≥ 10% of the body surface area, but the lymph nodes, viscera, and blood are not affected (see Table 4-1). The ability to correctly stage a patient is important for determining prognosis (Kim, Liu, Mraz-Gernhard, Varghese, & Hoppe, 2003). Patients diagnosed with early-stage MF have a good prognosis and typically die for reasons usually unrelated to MF. Patients with advanced-stage MF (IIB-IVB) and SS, however, are much more likely to die from their disease. Staging also serves as an effective treatment guide (Trautinger et al., 2006), which will be discussed later in this chapter.TABLE 4-1: Classification for Mycosis Fungoides and Sézary SyndromePATIENT ASSESSMENT In contrast to a host of other skin disorders both common and exotic, a diagnosis of CTCL may not be rendered until considerable time has passed or multiple investigations have taken place. Fortunately, the dermatology community has become increasingly aware of the subtle presentations of early-stage MF, thus lowering the threshold for pursuing a diagnostic workup. Patients suspected of having MF often describe a prolonged history of an indolent, pink or red, scaly, waxing and waning eruption that may be classified as eczematous dermatitis, psoriasis, or just dry skin. Because of the relatively nonspecific and mild skin signs leading to a presumptive diagnosis of eczema, a biopsy-which can provide histologic evidence for CTCL-may be delayed. Performing a skin biopsy in patients with recurrent, intractable dermatitis is critical. Symptoms of pruritus are common but do not always accompany the rash. When patients experience pruritus related to MF and SS, it ranges from mild to profoundly disruptive to both sleep and performance of daily activities. The skin findings associated with the early patch and plaque stages of MF can diminish following outdoor ultraviolet light exposure. Hence, patients will report decreased pruritus as well as an overall improvement in the appearance of the rash during summer months. In addition to sun exposure, the lesions of MF most often prove transiently responsive to topical corticosteroid therapy, thus explaining why skin biopsy often is delayed. In fact, skin biopsies performed early in the course of MF quite frequently yield nondiagnostic results (Hymes, 2005). Pathology reports may describe a psoriasiform dermatitis or spongiotic dermatitis with only a suspicion raised for a more significant disorder such as a CTCL. Repeat skin biopsies may be required over time to confirm a diagnosis of CTCL. Patches, plaques, tumors, and generalized erythroderma are the important descriptors for the cutaneous lesions of MF and SS. A patient who manifests more than one cutaneous feature is not unusual (Girardi et al., 2004). Disease staging and appropriate therapy largely are dependent on the accurate characterization of the observed skin findings. Patch-stage lesions (see Figure 4-3) present as erythematous to salmon-colored, flat to slightly raised, finely scaling lesions. Regression or atrophy within the patches can produce a crinkled or cigarette paper-like appearance referred to as poikiloderma. A predisposition for covered, unexposed areas, such as the bather's trunk distribution, including breasts, hips, thighs, and buttocks, is quite common. Pruritus may accompany patch-stage lesions.FIGURE 4-3: Patch Stage. Note. Photos courtesy of National Institutes of Health, National Cancer Institute, Dermatology Branch.Plaques (see Figure 4-4) are erythematous, elevated lesions that can present as a single discrete lesion, multiple lesions, or coalesced larger formations. Generally, far less scaling is associated with MF plaques compared to the plaques of psoriasis. These lesions also may demonstrate small telangiectasias and varying degrees of pigmentation. Plaques may be shaped in arcuate (part of a circle) or annular (ring-like) arrangements. A predilection for skin plane cleavage lines is quite typical.FIGURE 4-4: Plaque Stage. Note. Photos courtesy of National Institutes of Health, National Cancer Institute, Dermatology Branch.Cutaneous tumors (see Figure 4-5) are red-brown nodules (>1 cm in diameter) that elevate above the plane of the skin as dome-shaped or ulcerating lesions. In many patients, tumors may form in the absence of prior patch or plaque stage disease (referred to as de novo), so the stepwise progression of patch to plaque to tumor does not occur. In addition, certain variants of CTCL will present exclusively with tumors, and an accurate diagnosis only can be rendered with attentive patient history gathering and clinical data analysis (Willemze et al., 2005). In contrast to the earlier-stage lesions, tumors often develop on sun-exposed as well as covered areas. Ulcerating tumors may become secondarily infected and present considerable management challenges for patients. In tumors, a histologic feature known as "large-cell transformation" may carry a poorer prognosis (Girardi et al., 2004).FIGURE 4-5: Tumor Stage. Note. Photos courtesy of National Institutes of Health, National Cancer Institute, Dermatology Branch.Erythroderma (see Figure 4-6) refers to poorly defined, generalized (> 80% body surface area) erythema on the skin of patients with MF. Erythrodermic MF can arise spontaneously or following long-term progression of patch or plaque stage disease. Patients with erythroderma are far more likely to have concurrent blood involvement than those presenting with more limited skin involvement (Girardi et al., 2004). Patients presenting with erythroderma may report heat and cold intolerance, intense pruritus, and skin pain. In erythrodermic states, diffuse exfoliation, lichenification (pronounced skin lines), and atrophy of skin surfaces are observed.FIGURE 4-6: Erythroderma. Note. Photo courtesy of National Institutes of Health, National Cancer Institute, Dermatology Branch.SS (see Figure 4-7) refers to the leukemic variant of MF whereby patients experience the triad of erythroderma, generalized lymphadenopathy, and presence of Sézary cells (abnormal, hyperconvoluted lymphoid cells) in the peripheral blood (Foss, 2004). The generalized erythroderma observed in SS ranges from bright red to violaceous to salmon-colored with associated leathery textural skin changes. Additional clinical findings include temperature dysregulation, keratoderma (skin thickening) of the palms and soles, alopecia, nail-plate dystrophy, and ectropion of the lower eyelids.FIGURE 4-7: Sézary Syndrome Generalized Erythroderma With Keratoderma of the Hand and Feet. Note. Photos courtesy of National Institutes of Health, National Cancer Institute, Dermatology Branch.In SS, lymphomatous skin infiltrates are less dense because the malignant T cells traffic more readily to the peripheral blood and lymph nodes. Skin biopsies performed in this setting may be interpreted as MF or may simply reveal nonspecific histologic changes. Therefore, an evaluation of the blood to determine the presence or absence of an abnormal T-cell population has become increasingly important for establishing a diagnosis of SS. Recently, the International Society for Cutaneous Lymphoma proposed guidelines to quantify and define significant blood involvement with SS by measurements of molecular or flow-cytometric analysis (Vonderheid et al., 2002). These criteria include an absolute Sézary cell count of at least 1,000/mm3, a ratio of CD4+ T cells to CD8+ T cells of 10 or greater (e.g., a CD4:CD8 ratio of > 10:1), an increased number of circulating T cells with an aberrant expression of pan-T-cell markers, increased lymphocyte count with evidence of a T-cell clone in the blood (detected by Southern blot or polymerase chain reaction [PCR] analysis), and chromosomal abnormalities in the T-cell clone (Willemze et al., 2005). When the burden of skin disease becomes extensive (e.g., tumors, erythroderma), the opportunity for the malignant T cells to collect and involve the blood, lymph nodes, liver, spleen, lungs, and central nervous system is increased. The lymphadenopathy typically observed in MF and SS is restricted to the more skin-draining chains. Bone marrow involvement is quite rare (Hymes, 2005). In academic settings, dermatology and oncology disciplines often collaborate on the evaluation and treatment plan of patients with CTCL. Clinical evaluation of a suspected MF and SS diagnosis requires a history and physical examination and integration of data derived from skin biopsy, laboratory, and imaging studies. Patients are encouraged to describe the evolution of their skin lesions/rash, associated cutaneous symptoms, such as pruritus or discomfort, and responsiveness to prior therapies. Special attention should be paid to constitutional symptoms, such as fevers, chills, fatigue, weight changes, night sweats, and lymphadenopathy. Typically, patients with CTCL lack these systemic signs upon presentation. Physical examination should not only characterize and quantify the type and body surface area percentage of skin lesions but also should include a complete lymph node examination aimed at establishing the presence or absence of adenopathy in the correlating skin-draining nodes. Abdominal examination should be incorporated with palpation of the liver and spleen to determine possible enlargement. Comprehensive and convincing histopathologic findings aid in establishing the diagnosis and further classify the disease. Performance of light microscopy of formalin-fixed, hematoxylin-eosin-stained tissue sections is the initial step in the evaluation of a suspected skin lymphoma. The ideal specimen is derived from an excisional, incisional (punch), or shave biopsy that is then formalin fixed (Fung, Murphy, Hoss, & Grant-Kels, 2002). In most cases, superficial perivascular and band-like infiltrates consisting of lymphocytes and histiocytes are present within the papillary and reticular dermis with focal projections into the epidermis. Epidermotropism refers to the infiltration of the small to medium lymphocytes within the epidermis. Another highly specific but inconsistent feature is the intraepidermal collection of atypical lymphocytes called Pautrier microabscesses (Smoller, Santucci, Wood, & Whittaker, 2003). Immunophenotyping, which often can be performed on formalin-fixed tissue, can prove valuable. In MF, the neoplastic lymphocytes are positive for T-cell markers CD2, CD3, CD4, and CD5 and are characteristically CD7 negative. T-cell receptor gene rearrangement studies confirm clonality and are performed by either Southern blot or PCR methods. Both immunophenotyping and gene analysis studies performed on patients suspected of CTCL should be reviewed in the clinical context because false positives and negatives can occur. Laboratory studies recommended for patients with an MF or SS diagnosis include a complete blood count with manual differential, lactate dehydrogenase, HTLV-1 antibody assay, and flow cytometry of the peripheral blood. For staging patients with IB disease or greater, a computed tomography (CT) scan of the chest, abdomen, and pelvis should be performed. With greater availability, the positron-emission tomography scan combined with CT (PET-CT) has proven to be more sensitive for detection of lymphadenopathy in advanced disease. TREATMENT MODALITIES In keeping with the unique and often puzzling MF and SS presentations along with unpredictable course of disease, delineation of a treatment plan can present equal challenge. Planning care also includes the therapeutic aims of avoiding immunosuppression, augmenting antitumor immune response, reducing toxicities, and improving quality of life. Current therapies available to patients with a confirmed MF or SS diagnosis are intended to produce optimal clinical response rather than cure. Treatments for CTCL are broad in scope, and with this, patients may receive more than one therapy simultaneously. The aim is to reduce disease burden and postpone progression for as long as possible. In most clinical situations, treatment of CTCL is tailored to the stage and particular features of the disease, general health concerns, and lifestyle considerations. Patients with disease limited to the skin (stages I and II) often can achieve clinical response with one of the readily available skin-directed therapies. This approach to treatment is supported by the understanding that the malignant T cells spend the majority of their time in the skin because of the homing tendencies to antigens and are dependent on the skin for survival. Thus, therapies can be delivered efficiently to the target organ, namely the skin. In contrast, patients with recalcitrant skin disease or those with demonstrated involvement of peripheral blood, lymph nodes, or visceral organs require one or more systemic therapies. In later stages of the disease, more aggressive therapies become necessary as the malignant T cells' dependence on the skin diminishes, and the disease becomes clinically established at extracutaneous sites. Skin-Directed Therapies Topical Corticosteroids Topical corticosteroids are the cornerstone of treatment for myriad skin disorders, both acute and chronic in their origins. These agents are employed as first-line treatments of MF because of ease of administration and product accessibility. Topical corticosteroids possess multiple immunomodulatory and anti-inflammatory effects by downregulation of cytokine production and promotion of inflammatory mediators (Barnes & Karin, 1997). In the early stages of the disease, topical corticosteroid therapy has proven to be a mainstay for both induction and maintenance of clinical remissions. In a prospective study of 79 patients with patch-and-plaque stage disease, daily use of topical corticosteroids for three to six months resulted in a complete response in 63% and a partial remission in 31% for a total response rate of 94% (Zackheim, Kashani-Sabet, & Amin, 1998). Topical corticosteroids are packaged in a variety of vehicle systems including creams, ointments, lotions, foams, gels, and solutions. Clinicians may recommend alternating a stronger potency (class I) agent with a less potent (class III or IV) agent over time in an effort to diminish the side-effect profile as well as to provide opportunity for longer duration of treatment. Local side effects from topical corticosteroids include skin atrophy, striae, purpura, acneform eruptions, and telangiectasias. Hypothalamic pituitary axis suppression is a very rare consequence of prolonged topical corticosteroid application. Topical Chemotherapy: Nitrogen Mustard and Carmustine The alkylating agents nitrogen mustard (NM) (also known as mechlorethamine) and carmustine (also known as bichloronitrosourea or BCNU) are cytotoxic chemotherapeutic agents employed for topical management of CTCL. During the past four decades, they have been used widely for the treatment of the early stages (IA, IB, and IIA) of CTCL. In 1977, Vonderheid et al. reported induction of clinical remission in 68% of patients treated with topical NM daily over the course of several months. A subsequent smaller study demonstrated an 87% complete response rate with application of NM daily (Hamminga et al., 1982). Topical NM therapy requires thoughtful collaboration among the patient, clinician, and compounding pharmacist. A 10 mg formulation of NM is dissolved in the water, ointment, or gel base. Typically, patients apply a thin film at bedtime to all skin surfaces, excluding the eyelids, lips, and genital region. They should be advised to wash their hands with soap and water after the application process. Disposable gloves should be used if others assist with NM application. The most frequent complication associated with NM therapy is the development of an irritant reaction characterized by local erythema and itching. This reaction can be addressed with product dilution and subsequent desensitization. Drug cessation is warranted if a true allergic reaction with urticarial response occurs. Patients with CTCL who demonstrate clinical clearing of patch-and-plaque lesions for the duration of NM therapy for 6-12 months may taper the frequency of treatments over time to a less cumbersome schedule. Less frequently encountered toxicities of NM therapy include potential for myelosuppression, reduced spermatogenesis, and secondary nonmelanoma skin cancers (Hymes, 2005). Carmustine is available in powder and ointment forms. Local application site erythema can develop, although irritant and contact reactions occur less often. In current care practice, carmustine is rarely, if ever, selected as an alternative to NM. Topical Retinoid: Bexarotene Gel The synthetic retinoid agent bexarotene (Targretin®, Ligand Pharmaceuticals) selectively binds and activates retinoid X receptors (RXRs). These receptors function as transcription factors that regulate expression of genes that control cellular differentiation and proliferation. The precise mechanism of action for RXRs in the management of CTCL remains unclear. In a phase III clinical trial, Duvic, Hymes, et al. (2001) observed a 44% response rate in patients applying bexarotene gel to all lesions in early-stage refractory CTCL. Erythema, pruritus, and pain at the application site may occur in the initial weeks of therapy. For some patients, the solution to this problem may be titration of bexarotene with careful and conservative drug application ranging from every other day to two to four times daily over time. In clinical practice, the topical retinoid class of drugs is considered second-line therapy for patients who have demonstrated persistent disease after treatment with topical corticosteroids or other conservative skin-directed therapies. Phototherapy: Broadband Ultraviolet B (290-320 nm), Narrowband UVB (311 nm), and Psoralen With UVA (320-400 nm) Ultraviolet light therapy is one of the most widely used skin-directed therapies for early-stage CTCL. Radiation within the ultraviolet B (UVB) (290-320 nm) and UVA (320-400 nm) spectrums is prescribed for a host of T-cell-mediated skin diseases, including psoriasis, vitiligo, and cutaneous graft-versus-host disease. In early-stage MF, phototherapy is typically selected when skin involvement is diffuse and/or topical treatments have proven to be impractical. The benefits of UVA and UVB have been described for decades as the correlation between MF manifestations in covered areas of the body (e.g., bather's trunk, flanks, folds) and sparing in sun-exposed skin was observed. As mentioned previously, patients anecdotally share subjective reports of improvement in their skin during the summer months or following a tropical vacation. The mechanism of action for ultraviolet light therapy is broad with effects produced on surface membrane proteins and soluble mediators in addition to induction of apoptosis. In general, UVB reaches epidermal keratinocytes and Langerhans cells, and UVA penet