Cutaneous T-Cell Lymphoma: Mycosis Fungoides/Se´Zary Syndrome: Part 1

FEATURE ARTICLE Cutaneous T-Cell Lymphoma: Mycosis Fungoides/Se´zary Syndrome: Part 1

Susan Booher, MS, RN, Sue Ann McCann, MSN, RN, DNC, Marianne C. Tawa, RN, MSN, ANP

INTRODUCTION (Lutzner et al., 1975). The term CTCL should not be used Cutaneous T-cell lymphoma (CTCL) represents a category interchangeably with MF and SS; rather, it should be used of complex and diverse disease states that involve the skin only to describe the complete spectrum of cutaneous lym- as the primary site of malignant T-lymphocyte proliferation phomas of T-cell origin. and is a type of non-Hodgkin lymphoma. These malignant The World Health Organization and the European CD4+ T cells (lymphocytes) also can invade the lymphatic Organisation for Research and Treatment of Cancer met nodes, blood, and visceral organs. Mycosis fungoides (MF) in 2003 and 2004 to organize and define the cutaneous and its leukemic variant, Se´zary syndrome (SS), are the lymphomas and to separate them from systemic lymphomas most common types of CTCL. These chronic diseases are with similar histology (Willemze et al., 2005). Lymphomas rare and have considerable variation in cutaneous presen- are now classified as either T-cell or B-cell lymphoma with tation, histologic appearance, degree of blood involvement, indolent, intermediate, or aggressive clinical behavior, al- immunophenotypic profile, and prognosis. lowing for more consistent diagnosis and treatment regi- Historically, the French were pioneers in the discovery of mens (see Figure 4-1). CTCL. Approximately 200 years ago, Jean Louise Alibert published an article describing the appearance of tumors on EPIDEMIOLOGY the skin similar to that of a mushroom and coined the term MF and SS are rare diseases despite evidence that their mycosis fungoides (Alibert, 1806). In 1938, French phy- prevalence is increasing. Utilizing the National Cancer sicians Se´zary and Bouvrain published the discovery of an Institute_s Surveillance, Epidemiology, and End Results atypical T lymphocyte in the blood of a patient who had data, Criscione and Weinstock (2007) reported that the skin findings that were consistent with MF and who was incidence of CTCL tripled to 6.4 per million from 1973 to erythrodermic at the same time. Further advances in cuta- 2002 in the United States, with a 2.9-per-million increase neous lymphomas continued in the 20th century with the per decade over the same period. This increased incidence discoveries of cutaneous B-cell, natural killer cell, and may be a result of better medical awareness and screening gamma delta-cell lymphomas, as well as variants of MF. methods. CTCL occurs 32% more often in blacks than In the mid-1970s, Edelson and Lutzner coined the term in whites, and the ratio of male to female is 2:1 with CTCL to unify all the diagnoses recognized as cancer that an increase in incidence with age. CTCL in children is shared a common T-cell phenotype including MF and SS confirmed but uncommon. MF was found to be respon- sible for 72% of all CTCL cases, and SS represented 2.5% of all CTCLs. Overall, CTCL represents 3.9% of all non- Reprinted with permission by the Oncology Nursing Society from Site Hodgkin lymphomas, with substantial geographic varia- Specific Cancer Series: Skin Cancer. Muehlbauer, P & McGowan, C(Eds).Chap4:pp81Y93. Copyright 2009, Oncology Nursing tion in incidence. An increased incidence is found in areas Society. Part 2 will appear in the March/April issue of the Journal of with high physician density, high family income, higher the Dermatology Nurses’ Association. education, and high home property values. These findings DOI: 10.1097/JDN.0b013e31820a3e82 may represent a difference in access to medical care and,

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. 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-cellYmediated responses, which are func- tionally 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 Breaction[ 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 FIGURE 4-1. World Health Organization/European Organi- symptoms of MF and SS. sation for Research and Treatment of Cancer Classifica- Malignant CD4+ MF and Se´zary cells generally ex- tion. Note. Based on information from Willemze et al., 2005. press the CD45RO surface protein marker, which identi- fies these cells as Bmemory[ T cells that have previously been activated by antigen. This marker differentiates these thus, earlier or better diagnosis. Nurses should be alert cells from CD45RA+ T cells that are BnaBve[ and have to the potential for opportunities for patient/community not yet been stimulated to proliferate by antigen. Memory education about CTCL. Given the evidence of an in- T cells have an enhanced ability to proliferate and to creasing incidence of CTCL, dermatology and oncology secrete cytokines, even in the presence of small amounts nurses must remain apprised of the latest literature on of antigen presented by antigen-presenting cells. Memory accurate detection and treatment of CTCL. T cells are proficient at migrating from the blood to in- flamed tissue, including skin, because they express specific chemotactic receptors known as chemokine receptors PATHOPHYSIOLOGY and adhesion molecules (Sallusto, Lenig, Forster, Lipp, The cause of MF and SS (as well as other CTCLs) is un- & Lanzavecchia, 1999). Evidence exists that CD45RO+ known. Infectious agents, including bacteria and viruses, tumor cells in patients with MF may escape immune re- have been proposed as possible triggers for CTCL cognition and destruction through expression of pro- (Hwang, Janik, Jaffe, & Wilson, 2008). Herne, Talpur, teins that potentially induce apoptosis of antitumor, Breuer-McHam, Champlin, and Duvic (2003) associated cytotoxic CD8+ T cells, which may otherwise control the cytomegalovirus infection with CTCL, and Chang, Liu, malignant T cells (Ni, Hazarika, Zhang, Talpur, & Duvic, Chen, and Chow (1998) detected the Epstein-Barr virus 2001). in patients with T-cell lymphomas of the skin. Although Alterations in specific cytokines and chemokines (small these associations are intriguing, the data are not strong chemotactic proteins) have been proposed to contribute enough to conclude that a causal relation exists. How- to clonal expansion and immunosuppression in MF and ever, the quest to find the etiology of MF and SS has led SS (Yamanaka et al., 2006b). IL-18 expression may play to a great increase in information available about the a role in the immunosuppression that is characteristic of genetic and immune abnormalities found in MF and SS. late-stage CTCL (Yamanaka et al., 2006a). IL-15, which Ultimately, understanding the pathophysiology of MF requires presentation by antigen-presenting cells, may con- and SS may help in the development of novel therapies to tribute to T-cell proliferation (Dooms et al., 1998). IL-4 treat these lymphoid malignancies (Hwang et al.). and IL-5, which skew the immune environment, can lead

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. toward a humoral (antibody-mediated) Th2-type immune contribute to the immunosuppression seen in MF, particu- response (Vowels et al., 1994). Additionally, chemokines larly in the late stages, or in SS. Therapies that target these may play a role in attracting malignant T cells to the abnormalities are beginning to show positive benefits in skin and enhancing their ability to survive by acting upon the treatment of MF and SS. G-proteinYcoupled chemokine receptors found on the surface of T cells (Clark et al., 2006; Notohamiprodjo et al., STAGING 2005; Sokolowska-Wojdylo et al., 2005). The most common staging system in use for CTCL was Edelson (2001) hypothesized that the survival and created in 1978 at a National Cancer Institute Workshop proliferation of the neoplastic T cells in MF and SS were on CTCL (Lamberg & Bunn, 1979). Subsequently, the enhanced by antigen-presenting dendritic cells based on International Society for Cutaneous Lymphoma updated evidence that dendritic cells support the long-term cul- the criteria for blood involvement to distinguish among ture of SS cells. Interestingly, skin dendritic cells known three subsets of erythrodermic CTCL (E-CTCL). The as Langerhans cells frequently localize in the epidermis subsets include SS as leukemic phase E-CTCL, erythro- adjacent to malignant T cells in MF, creating the so- dermic MF as secondary E-CTCL, and E-CTCL as not called Pautrier abscess, an often-observed histologic sign otherwise defined (Vonderheid et al., 2002). The leuke- of MF (see Figure 4-2). mic criteria of SS are intended to differentiate these pa- Recent evidence suggests that MF, even in its early tients with a poorer prognosis from the other E-CTCL stages, may be a systemic disease. In normal individuals, the subsets. The leukemic criteria are further explained T-cell receptor varies tremendously among different T cells under SS in Patient Assessment. for these cells to bind hundreds of thousands of potential The MF staging system employs a multistep process. antigens. The normal T-cell repertoire in humans is diverse Because the malignant T cells can traffic among skin, lymph and large. Yawalkar et al. (2003) recently reported the nodes, blood, and viscera, the staging system was designed loss of normal T-cell repertoire in all stages of MF and to include each possible area of T-cell involvement. Each SS, a finding that may have a relationship to the origin of category or classification employs a label to identify the these diseases. The loss of normal T-cell repertoire is a phe- involved system so that skin = T, lymph = N, viscera or nomenon that has been observed after infection with cer- systemic metastasis = M, and blood = B. Then, each cate- tain viruses, including HIV-1. Hwang et al. (2008) have gory is ranked according to the type or extent of T-cell speculated that MF may arise from continued (chronic) involvement. For example, T2 = patch or plaque involv- reactivity of malignant T cells to normal skin antigens ing Q 10% of the body surface area, but the lymph following initial infection with a yet-undefined virus. nodes, viscera, and blood are not affected (see Table 4-1). In summary, although the etiologies of MF and SS re- The ability to correctly stage a patient is important main unknown, multiple abnormalities in cytokine ex- for determining prognosis (Kim, Liu, Mraz-Gernhard, pression, chemokine expression, and antigen presentation Varghese, & Hoppe, 2003). Patients diagnosed with have been revealed. Together, these abnormalities may early-stage MF have a good prognosis and typically die for reasons usually unrelated to MF. Patients with advanced-stage MF (IIBYIVB) 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.

PATIENT 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 pursu- ing 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 FIGURE 4-2. Histology Slide of Mycosis Fungoides. Note. signs leading to a presumptive diagnosis of eczema, a Slide courtesy of Dr. Richard Lee, National Institutes of biopsyVwhich can provide histologic evidence for Health, National Cancer Institute, Laboratory of Pathology. CTCLVmay be delayed. Performing a skin biopsy in

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. TABLE 4-1. Classification for Mycosis Fungoides and Se´zary Syndrome

Stage Skin Lymph Nodes Viscera Blood Mycosis Fungoides (MF) IA Patch/plaque G 10% Not enlarged (N0) Negative M0 Y body surface area affected (T1) IB Patch/plaque Q 10% Not enlarged (N0) Negative M0 Y body surface area affected (T2) IIA Patch/plaque any Biopsy negative, lymph Negative M0 Y amount of body nodes enlarged (N1) surface area (T1Y2) IIB Tumors (T3) Biopsy negative, Negative M0 Y whether lymph nodes enlarged or not (N0Y1) III Erythroderma (T4) Biopsy negative, Negative M0 Y whether lymph nodes enlarged or not (N0Y1) IVA Any above skin Biopsy positive, lymph Negative M0 Y presentation (T1Y4) nodes not enlarged (N2) or enlarged (N3) IVB Any above skin Lymph node may or Biopsy positive Y presentation (T1Y4) may not be affected (M1) (N0Y3) Se´ zary Syndrome Erythrodermic MF Erythroderma (T4) Biopsy negative Negative M0 Abnormal circulating and erythrodermic whether lymph nodes TcellsG 5% (B0); cutaneous T-cell enlarged or not (N0Y1) abnormal T cells Q 5% (B1) lymphoma (E-CTCL): Not otherwise specified (III) Leukemic phase: Erythroderma (T4) Biopsy negative Negative M0 Se´ zary cell count Q 1,000; E-CTCL (IVA) whether lymph nodes CD4/CD8 ratio Q 10 by enlarged or not (N0Y1) flow cytometry; aberrant expression of normal T-cell markers; increased T-cell clones and abnormal chromosome in T-cell clone (B2)

Note. Based on information from Lamberg & Bunn, 1979; Vonderheid et al., 2002.

patients with recurrent, intractable dermatitis is critical. transiently responsive to topical corticosteroid therapy, Symptoms of pruritus are common but do not always thus explaining why skin biopsy often is delayed. In fact, accompany the rash. When patients experience pruritus skin biopsies performed early in the course of MF quite related to MF and SS, it ranges from mild to profoundly frequently yield nondiagnostic results (Hymes, 2005). Pa- disruptive to both sleep and performance of daily activities. thology reports may describe a psoriasiform dermatitis The skin findings associated with the early patch and or spongiotic dermatitis with only a suspicion raised for plaque stages of MF can diminish following outdoor a more significant disorder such as a CTCL. Repeat skin ultraviolet light exposure. Hence, patients will report de- biopsies may be required over time to confirm a diagno- creased pruritus as well as an overall improvement in the sis of CTCL. appearance of the rash during summer months. In addi- Patches, plaques, tumors, and generalized erythro- tion to sun exposure, the lesions of MF most often prove derma are the important descriptors for the cutaneous

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. 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 paperYlike 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 4-4. Plaque 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 predilec- tion for skin plane cleavage lines is quite typical. Cutaneous tumors (see Figure 4-5) are red-brown no- dules (91 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 FIGURE 4-3. Patch Stage. Note. Photos courtesy of National sun-exposed as well as covered areas. Ulcerating tumors Institutes of Health, National Cancer Institute, Dermatology may become secondarily infected and present consider- Branch. able management challenges for patients. In tumors, a

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. FIGURE 4-5. Tumor Stage. Note. Photos courtesy of National Institutes of Health, National Cancer Institute, Dermatology Branch. histologic feature known as Blarge-cell transformation[ may carry a poorer prognosis (Girardi et al., 2004). Erythroderma (see Figure 4-6) refers to poorly defined, generalized (9 80% body surface area) erythema on the skin of patients with MF. Erythrodermic MF can arise

FIGURE 4-7. Se´ zary Syndrome Generalized Erythroderma FIGURE 4-6. Erythroderma. Note. Photo courtesy of Nation- With Keratoderma of the Hand and Feet. Note. Photos al Institutes of Health, National Cancer Institute, Dermatol- courtesy of National Institutes of Health, National Cancer ogy Branch. Institute, Dermatology Branch.

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. spontaneously or following long-term progression of patch attention should be paid to constitutional symptoms, such or plaque stage disease. Patients with erythroderma are as fevers, chills, fatigue, weight changes, night sweats, and far more likely to have concurrent blood involvement lymphadenopathy. Typically, patients with CTCL lack than those presenting with more limited skin involvement these systemic signs upon presentation. Physical exami- (Girardi et al., 2004). Patients presenting with erythro- nation should not only characterize and quantify the type derma may report heat and cold intolerance, intense and body surface area percentage of skin lesions but also pruritus, and skin pain. In erythrodermic states, diffuse should include a complete lymph node examination exfoliation, lichenification (pronounced skin lines), and aimed at establishing the presence or absence of adenop- atrophy of skin surfaces are observed. athy in the correlating skin-draining nodes. Abdominal SS (see Figure 4-7) refers to the leukemic variant of MF examination should be incorporated with palpation of the whereby patients experience the triad of erythroderma, liver and spleen to determine possible enlargement. generalized lymphadenopathy, and presence of Se´zary Comprehensive and convincing histopathologic findings cells (abnormal, hyperconvoluted lymphoid cells) in the aidinestablishingthediagnosis and further classify the peripheral blood (Foss, 2004). The generalized erythro- disease. Performance of light microscopy of formalin-fixed, derma observed in SS ranges from bright red to hematoxylinYeosin-stained tissue sections is the initial step violaceous to salmon-colored with associated leathery in the evaluation of a suspected skin lymphoma. The ideal textural skin changes. Additional clinical findings include specimen is derived from an excisional, incisional (punch), temperature dysregulation, keratoderma (skin thickening) or shave biopsy that is then formalin fixed (Fung, Murphy, of the palms and soles, alopecia, nail-plate dystrophy, and Hoss,&Grant-Kels,2002).Inmostcases,superficial ectropion of the lower eyelids. perivascular and band-like infiltrates consisting of lym- In SS, lymphomatous skin infiltrates are less dense be- phocytes and histiocytes are present within the papillary cause the malignant T cells traffic more readily to the periph- and reticular dermis with focal projections into the eral blood and lymph nodes. Skin biopsies performed in this epidermis. setting may be interpreted as MF or may simply reveal Epidermotropism refers to the infiltration of the small nonspecific histologic changes. Therefore, an evaluation of to medium lymphocytes within the epidermis. Another the blood to determine the presence or absence of an ab- highly specific but inconsistent feature is the intraepi- normal T-cell population has become increasingly important dermal collection of atypical lymphocytes called Pautrier for establishing a diagnosis of SS. Recently, the International microabscesses (Smoller, Santucci, Wood, & Whittaker, Society for Cutaneous Lymphoma proposed guidelines to 2003). Immunophenotyping, which often can be per- quantify and define significant blood involvement with SS by formed on formalin-fixed tissue, can prove valuable. In measurements of molecular or flow-cytometric analysis MF, the neoplastic lymphocytes are positive for T-cell (Vonderheid et al., 2002). These criteria include an absolute markersCD2,CD3,CD4,andCD5andarecharacteris- Se´zary cell count of at least 1,000/mm3, a ratio of CD4+ tically CD7 negative. T-cell receptor gene rearrangement T cells to CD8+ T cells of 10 or greater (e.g., a CD4:CD8 studies confirm clonality and are performed by either ratio of 9 10:1), an increased number of circulating T cells Southern blot or PCR methods. Both immunophenotyp- with an aberrant expression of panYT-cell markers, ing and gene analysis studies performed on patients increased lymphocyte count with evidence of a T-cell clone suspected of CTCL should be reviewed in the clinical in the blood (detected by Southern blot or polymerase context because false positives and negatives can occur. chain reaction [PCR] analysis), and chromosomal abnor- Laboratory studies recommended for patients with an malities in the T-cell clone (Willemze et al., 2005). MF or SS diagnosis include a complete blood count with When the burden of skin disease becomes extensive manual differential, lactate dehydrogenase, HTLV-1 anti- (e.g., tumors, erythroderma), the opportunity for the ma- body assay, and flow cytometry of the peripheral blood. lignant T cells to collect and involve the blood, lymph For staging patients with IB disease or greater, a computed nodes, liver, spleen, lungs, and central nervous system is tomography (CT) scan of the chest, abdomen, and pel- increased. The lymphadenopathy typically observed in vis should be performed. With greater availability, the MF and SS is restricted to the more skin-draining chains. positron-emission tomography scan combined with CT Bone marrow involvement is quite rare (Hymes, 2005). (PET-CT) has proven to be more sensitive for detection of In academic settings, dermatology and oncology dis- lymphadenopathy in advanced disease. ciplines often collaborate on the evaluation and treatment plan of patients with CTCL. Clinical evaluation of a sus- TREATMENT MODALITIES pected MF and SS diagnosis requires a history and phy- In keeping with the unique and often puzzling MF and SS sical examination and integration of data derived from presentations along with unpredictable course of disease, skin biopsy, laboratory, and imaging studies. Patients are delineation of a treatment plan can present equal chal- encouraged to describe the evolution of their skin lesions/ lenge. Planning care also includes the therapeutic aims of rash, associated cutaneous symptoms, such as pruritus or avoiding immunosuppression, augmenting antitumor im- discomfort, and responsiveness to prior therapies. Special mune response, reducing toxicities, and improving quality

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. of life. Current therapies available to patients with a Topical Chemotherapy: Nitrogen Mustard confirmed MF or SS diagnosis are intended to produce and Carmustine optimal clinical response rather than cure. Treatments The alkylating agents nitrogen mustard (NM) (also known for CTCL are broad in scope, and with this, patients may as mechlorethamine) and carmustine (also known as receive more than one therapy simultaneously. The aim is bichloronitrosourea or BCNU) are cytotoxic chemothera- to reduce disease burden and postpone progression for as peutic agents employed for topical management of CTCL. long as possible. During the past four decades, they have been used widely for In most clinical situations, treatment of CTCL is the treatment of the early stages (IA, IB, and IIA) of CTCL. tailored to the stage and particular features of the disease, In 1977, Vonderheid et al. reported induction of clinical general health concerns, and lifestyle considerations. remission in 68% of patients treatedwithtopicalNMdaily Patients with disease limited to the skin (stages I and II) over the course of several months. A subsequent smaller often can achieve clinical response with one of the readily study demonstrated an 87% complete response rate with available skin-directed therapies. This approach to treat- application of NM daily (Hamminga et al., 1982). ment is supported by the understanding that the malignant Topical NM therapy requires thoughtful collaboration T cells spend the majority of their time in the skin because among the patient, clinician, and compounding pharma- of the homing tendencies to antigens and are dependent on cist. A 10 mg formulation of NM is dissolved in the water, the skin for survival. Thus, therapies can be delivered effi- ointment, or gel base. Typically, patients apply a thin film ciently to the target organ, namely the skin. In contrast, at bedtime to all skin surfaces, excluding the eyelids, lips, patients with recalcitrant skin disease or those with demon- and genital region. They should be advised to wash their strated involvement of peripheral blood, lymph nodes, or hands with soap and water after the application process. visceral organs require one or more systemic therapies. In Disposable gloves should be used if others assist with NM later stages of the disease, more aggressive therapies become application. necessary as the malignant T cells_ dependence on the skin The most frequent complication associated with NM diminishes, and the disease becomes clinically established therapy is the development of an irritant reaction char- at extracutaneous sites. acterized by local erythema and itching. This reaction can be addressed with product dilution and subsequent de- sensitization. Drug cessation is warranted if a true allergic Skin-Directed Therapies reaction with urticarial response occurs. Patients with Topical Corticosteroids CTCL who demonstrate clinical clearing of patch-and- Topical corticosteroids are the cornerstone of treatment for plaque lesions for the duration of NM therapy for 6Y12 myriad skin disorders, both acute and chronic in their months may taper the frequency of treatments over time origins. These agents are employed as first-line treatments to a less cumbersome schedule. Less frequently encoun- of MF because of ease of administration and product tered toxicities of NM therapy include potential for mye- accessibility. Topical corticosteroids possess multiple im- losuppression, reduced spermatogenesis, and secondary munomodulatory and anti-inflammatory effects by down- nonmelanoma skin cancers (Hymes, 2005). regulation of cytokine production and promotion of Carmustine is available in powder and ointment forms. inflammatory mediators (Barnes & Karin, 1997). In the Local application site erythema can develop, although early stages of the disease, topical corticosteroid therapy irritant and contact reactions occur less often. In current has proven to be a mainstay for both induction and care practice, carmustine is rarely, if ever, selected as an maintenance of clinical remissions. In a prospective study alternative to NM. of 79 patients with patch-and-plaque stage disease, daily use of topical corticosteroids for three to six months Topical Retinoid: Bexarotene Gel resulted in a complete response in 63% and a partial re- The synthetic retinoid agent bexarotene (TargretinA,Ligand mission in 31% for a total response rate of 94% (Zackheim, Pharmaceuticals) selectively binds and activates retinoid X Kashani-Sabet, & Amin, 1998). Topical corticosteroids receptors (RXRs). These receptors function as transcription are packaged in a variety of vehicle systems including factors that regulate expression of genes that control creams, ointments, lotions, foams, gels, and solutions. cellular differentiation and proliferation. The precise mech- Clinicians may recommend alternating a stronger potency anism of action for RXRs in the management of CTCL (class I) agent with a less potent (class III or IV) agent remains unclear. In a phase III clinical trial, Duvic, Hymes, over time in an effort to diminish the side-effect profile as et al. (2001) observed a 44% response rate in patients well as to provide opportunity for longer duration of applying bexarotene gel to all lesions in early-stage refrac- treatment. Local side effects from topical corticosteroids tory CTCL. Erythema, pruritus, and pain at the applica- include skin atrophy, striae, purpura, acneform eruption site may occur in the initial weeks of therapy. For tions, and telangiectasias. Hypothalamic pituitary axis some patients, the solution to this problem may be titra- suppression is a very rare consequence of prolonged tion of bexarotene with careful and conservative drug topical corticosteroid application. application ranging from every other day to two to four

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. times daily over time. In clinical practice, the topical re- ments are delivered three days per week initially until a tinoid class of drugs is considered second-line therapy for maximalresponseisachieved.Overtime,patientswillre- patients who have demonstrated persistent disease after duce the frequency of treatments to a less cumbersome treatment with topical corticosteroids or other conserva- maintenance schedule. Toxicities of PUVA include burn- tive skin-directed therapies. ing, nausea related to psoralen administration, and increased risk of melanoma and nonmelanoma skin cancer. Phototherapy: Broadband Ultraviolet B (290Y320 nm), Patients are expected to wear UVA eye protection up to Narrowband UVB (311 nm), and Psoralen With 24 hours following treatment because of the small but UVA (320Y400 nm) theoretical risk of cataract formation. Ultraviolet light therapy is one of the most widely used skin- directed therapies for early-stage CTCL. Radiation within Radiation the ultraviolet B (UVB) (290Y320nm)andUVA(320Y400 Radiation therapy shares a long history in the management nm) spectrums is prescribed for a host of T-cellYmediated of lymphomas, with CTCL as the first variant to be treated skin diseases, including psoriasis, vitiligo, and cutaneous dating back to 1902. Photons initially were employed, but graft-versus-host disease. In early-stage MF, phototherapy is by the 1940s Trump and colleagues replaced photon- typically selected when skin involvement is diffuse and/or based radiation with radiation from accelerated electrons topical treatments have proven to be impractical. The in an effort to more effectively deliver treatment to a wide benefits of UVA and UVB have been described for decades field, such as the skin surface, while ensuring patient as the correlation between MF manifestations in covered safety (Jones, Hoppe, & Glatstein, 1995). Over the past areas of the body (e.g., bather_s trunk, flanks, folds) and 50 years, total skin electron beam therapy (TSEBT) has sparing in sun-exposed skin was observed. As mentioned undergone multiple modifications with the goal of previously, patients anecdotally share subjective reports of delivering a sufficient dose to the target tissue volume improvement in their skin during the summer months or while minimizing radiation damage to normal skin. The following a tropical vacation. The mechanism of action for premise for electron therapy in CTCL is to produce direct ultraviolet light therapy is broad with effects produced on toxicity to tumor cells within the target volume. Candi- surface membrane proteins and soluble mediators in dates for TSEBT are those patients who have extensive addition to induction of apoptosis. In general, UVB reaches skin involvement of their MF lesions or have exhausted epidermal keratinocytes and Langerhans cells, and UVA other conventional skin-directed therapies such as topical penetrates deeper into the dermis reaching dermal fibro- agents and phototherapy. The target volume or depth of blasts, infiltrating inflammatory cells and dendritic cells penetration for electrons is quite minimal, approximately (Krutmann & Morita, 1999). only 5 mm; therefore, radiation effects are produced only Both broad- and narrowband UVB therapies are car- as deep as the dermal skin layer. Typically a total dose of ried out in dermatology practices equipped with specially 36 Gy is administered over a 9Y10-weekperiod(Voss& calibrated Blight boxes.[ UVB therapy does not require Kim-Sing, 1998). Some naturally shielded body areas, administration of an oral sensitizing agent to produce be- such as the perineum, flexural folds, and palms and soles, neficial effects in the skin. It is a reasonable choice for may require additional boost treatments for a short therapy when the lesions are thin and do not involve the duration following the standard TSEBT course. Patients hair follicle (folliculotropic MF). Patients are exposed to receiving TSEBT assume six standing positions during the the UVB spectrum in a graduated fashion at increased course of therapy. Contact lenses, goggles, and shields for doses with treatments taking place two to three days per the finger- and toenail plates are placed prior to radiation week. The goal of therapy is a clinical response with an exposure to ensure protection to these important struc- eventual taper to a more manageable schedule of one day tures. Patients are assessed at weekly intervals for findings per week. One of the major hindrances to phototherapy is of erythema, edema, bullae, or secondary infection. In the time requirement for patient visits, which may disrupt some instances, treatment schedules may be interrupted work or home life. In addition, access to a treatment cen- ter may be geographically challenging for patients who reside in rural or remote areas. Redness and burning can be problematic in certain fair-complexioned individuals; therefore, patients should be assessed prior to each treatment. Psoralen and UVA (PUVA) phototherapy involves the combination of the photosensitizing agent 8- methoxypsoralen with UVA light. UVA radiation has a longer wavelength than UVB and can penetrate window glass and likewise can penetrate the larger and thicker 1 lesions of MF. Patients ingest the psoralen 1 /2Y2 hours before exposure to an escalating dose of UVA light. Treat- FIGURE 4-8. Skin-Directed Therapies.

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. FIGURE 4-9. Therakos Photopheresis. Note. Figure courtesy of Therakos, Inc. Used with permission. for short recovery periods. The side-effect profile for More than 20 years of experience with ECP as a TSEBT includes pruritus, dry skin, fissuring, telangiecta- monotherapy demonstrates that the best responders sias, fatigue, temperature dysregulation, sun sensitivity, usually include immunocompetent patients with erythro- radiation dermatitis, skin infections, brittle nails, alopecia, dermic CTCL and early stages of SS. For immunodeficient and secondary malignancies. Patients are instructed patients and more advanced stages of SS, combination throughout the course of TSEBT and for a period of time therapy of ECP plus total skin electron beam (especially thereafter to keep the skin well hydrated with emollients for widespread plaques or tumors), interferons, and such as AquaphorA or EucerinA (Beiersdorf, Inc.), to apply retinoids, among others, provide adjuvant boosts to de- UVA/UVB-blocking sunscreens, to wear sunglasses, and bulking tumors, inducing apoptosis, and immune system to consider photo-protective garments for outdoor expo- stimulation (Girardi, Knobler, & Edleson, 2003). In the sures (Reavely & Wilson, 2004) (see Figure 4-8). first clinical trial to establish efficacy in CTCL, 27 of 37 patients with refractory disease (73%) responded with improved skin scores (Edelson et al., 1987). Since Systemic Therapies that initial report, multiple studies have reported efficacy Extracorporeal Photopheresis data for ECP as single or combination therapy in 438 Extracorporeal photopheresis (ECP) is a unique immune- patients with all stages of MF or SS. A compiled modulating therapy involving the pheresis of 5%Y10% of summary of these studies by Zic (2003) demonstrates the patient_s white blood cells (WBCs) and subsequent an overall response rate of 55.7% (n = 244) and a exposure to a prescribed dose of UVA light in combina- complete response rate of 17.6%. Response definitions tion with the injectable light-sensitizing agent methoxsa- varied, but the minimum response criteria, where len. ECP may be conceptualized simply as PUVA applied defined, was 9 25% clearing of skin lesions. to the blood rather than the skin. Once the WBC fraction ECP most often is performed on two consecutive days is exposed to UVA light, this treated blood product is every month in an outpatient hospital/clinic setting at returned to the patient via peripheral or central venous specialized treatment centers or within therapeutic apher- access (see Figure 4-9). The mechanism of action is esis units (see Figure 4-9). Accelerated therapy, adminis- thought to involve an immunologic response cascade tered every two weeks, may be appropriate for patients initiated by cellular apoptosis (Foss, 2006). with SS or erythrodermic CTCL. Each ECP treatment

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. averages three hours and requires adequate peripheral togens and cannot be used in women who may become venous access or, as a last resort because of greatly in- pregnant. creased risk of infection, the placement of a central Interferons venous access device (Parker & Bradley, 2006). As A Interferons (IFNs), including IFN alfa-2b (Intron A , described for PUVA, ultraviolet light eye and skin pro- A Schering Corporation) and IFN gamma-1b (Actimmune , tection are required for 24 hours after each procedure. InterMune, Inc.), represent a class of naturally occurring Side effects of ECP are uncommon, mild, and transient glycoproteins produced in response to immune system trig- but may include those risks associated with any veni- gers. IFNs contribute to important immune regulatory func- puncture procedure, hypotension primarily in anemic or tions, including stimulation of antiviral and antitumor low-weight patients, exacerbation of existing congestive responses (Hymes, 2005). IFNs are employed as a systemic heart failure secondary to positive fluid balance following therapy in the management of immediate stages II-B, III, the procedure, and anemia associated with accelerated and IV CTCL. In recent years, the genes for alpha, beta, and treatment schedules. More directly related to the reinfu- gamma IFN were cloned, paving the way for commercially sion of photoactivated white blood cells, low-grade fever, available recombinant forms. IFN alfa has been studied in increased erythema, or pruritus may occur transiently MF and SS for more than 20 years. IFN gamma also is used post-procedure (Therakos, Inc., 2006). in recalcitrant MF and SS but only after patients fail IFN alfa therapy or experience significant side effects. Retinoids IFN is delivered by subcutaneous injection three times Vitamin A analogs known as retinoids are prescribed in per week at dosages ranging from three to six million MF and SS as single agent or in combination with other units. In certain situations, the frequency of injections skin-directed or systemic therapies. Similar to natural may be reduced to once weekly (Parker & Bradley, 2006). vitamin A hormone, systemic retinoid agents bind to The side-effect profile associated with IFN therapy can be retinoid receptors in the cell and modify gene expression. quite burdensome. Flu-like symptoms, including fevers, Retinoid-A receptors (RARs) promote cellular differenti- chills, fatigue, and myalgia, frequently are time limited ation and proliferation, and RXRs induce apoptosis or and can be alleviated proactively with increased fluid in- cell death. The nonselective RAR agonist agents isotreti- A take and administration of acetaminophen one hour noin (Accutane , Roche Pharmaceuticals) and acitretin A prior to injection. Additionally, evening-hour adminis- (Soriatane , Stiefel Laboratories) are better known for tration of IFN therapy may diminish the experience of their utility in the management of the more common skin side effects, as patients sleep through the more bother- disorders nodulocystic acne and psoriasis, respectively. some ones. The more challenging and more significant However, these same agents when prescribed in MF alone side effects of IFN include depression, anxiety, sleep dis- or in combination with PUVA, interferons, or ECP have turbances, gastrointestinal distress, hair loss, weight loss, demonstrated significant response rates (Kim et al., increased infection risk, and elevated blood pressure. 2005). RAR retinoid agents Accutane and Soriatane Coincident with therapy, laboratory studies, including generally are well tolerated with some patients experi- liver enzymes and complete blood count, are assessed at encing side effects, such as headache, arthralgia, myalgia, regular intervals. dry skin and lips, and sun sensitivity. Patients should be monitored for hyperlipidemia, hepatic enzyme elevation, Denileukin Diftitox and leukopenia. Denileukin diftitox (DAB IL-2, OntakA, Ligand Pharma- Bexarotene (Targretin) is a synthetic RXR compound ceuticals) is a novel targeted therapy approved for refrac- that has gained interest and use since its U.S. Food and tory CTCL. Created with recombinant technology, this Drug Administration (FDA) approval in 1999. Targretin protein represents a fusion of a portion of the diphtheria in its granular, oral formulation is recommended as toxin with IL-2 cytokine. Malignant T-cell clones express monotherapy or can be used in combination with other IL-2 receptor in most CTCL patients. DAB IL-2 binds to treatments in patients with MF and SS. RXR agonists act the IL-2 receptor on the lymphoma cell and is internalized in a more selective manner than RARs by inhibiting cell with the receptor. Diphtheria toxin is released, protein growth, modulating differentiation, and inducing apopto- synthesis is interrupted, and cell death (apoptosis) ensues. sis in the malignant T-cell population. Targretin produces DAB IL-2 binds to the IL-2 receptor CD25+ that is iden- fewer subjective complaints than the RAR agents iso- tified by routine clinical immunopathology studies (Hymes, tretinoin and acitretin. The significant risk of hypertrigly- 2005). DAB IL-2 is delivered by IV infusion, typically five ceridemia (79%) and central hypothyroidism (53%) consecutive days in a 21-day cycle. The side-effect profile can create an additional layer of pharmacologic com- includes flu-like symptoms, fever, hypersensitivity reac- plexity (Duvic, Martin, et al., 2001). Most patients are tions, infusion-related hypotension, hypoalbuminemia, placed on HMG-CoA reductase inhibitors (statins) to and the more serious capillary leak syndrome. Premedi- correct the lipid excess and require supplemental thy- cating with steroids, antihistamines, and acetaminophen roid hormone. Both RAR and RXR retinoids are tera- dramatically can reduce the incidence of adverse events.

28 Journal of the Dermatology Nurses’ Association

Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. and availability of donor stem cells (Molina et al., 2005). Autologous transplantation has lower morbidity and mortality rates but is associated with a higher incidence of relapse (Knobler, 2004). Allogeneic transplantation is associated with more toxicity with the use of conventional chemotherapy conditioning regimens but shows lower incidence of relapse (Dearden). Allogeneic transplantation effectiveness may result from the ability to diminish patients_ malignant cells and reconstitute their immune system. However, therapy can be complicated FIGURE 4-10. Systemic Therapies. by the effects of chemo-immunoregulation or the chemo- antitumor interaction. The longer remission rates may be from the graft-versus-lymphoma effect, which is an Vorinostat immune-mediated response in which the engrafted donor Vorinostat (ZolinzaA, Merck & Co.) belongs to the new cells attack the patient_s malignant cells (lymphoma), but class of antineoplastic agents known as histone deacytylase evidence is inconclusive (Molina et al.). HSCT for treat- (HDAC) inhibitors. Approved by the FDA in October ment of CTCL is limited, but under the right circum- 2006, the oral HDAC vorinostat is indicated for the treat- stances, it may be the most effective solution to an ment of patients with CTCL with persistent or recurrent dis- aggressive, life-threatening MF or SS. ease following two systemic therapies. Vorinostat inhibits the enzymatic activity of HDAC 1, HDAC 2, HDAC 3, and HDAC 6. In some cancer cells, HDACs are overex- Investigational and Future Trends pressed or an aberrant recruitmentofHDACstooncogenic Treatment regimens for CTCL are continuously changing transcription factors occurs. This may lead to the eventual as new therapies emerge to replace or supplement those repression of gene transcription. In vitro, HDAC inhibitors which have been limited in use by their toxicities, lack of such as vorinostat cause the accumulation of acetylated disease response, or failure to affect survival. New trends histones and subsequently induce cell cycle arrest and in CTCL research currently target modulating disease- apoptosis in the transformed cells. In an open-label, single- specific pathways of the immune system to reduce tumor arm, multicenter study, the overall objective response rate burden and enhance the host response. was 29.7% with a median time to response of 55 days Vaccine Therapy: One vaccine therapy approach (Merck & Co., 2006). Commonly experienced side effects utilizes the clonotypic TCR peptide as a source to deliver with vorinostat include gastrointestinal disturbances, antigenic information and stimulate antitumor CD8+ weight loss, fatigue, chills, headache, taste alterations, in- T cells (Winter et al., 2003). Enhanced dendritic cells creased blood creatinine, and swelling of the lower ex- with autologous monocytes injected into a patient_saf- tremities. The more serious adverse events reported in fected lymph nodes have shown promising results (Maier clinical trials were pulmonary embolism and deep vein et al., 2003). Maier et al. suggested that this type of thrombosis, dose-related thrombocytopenia, anemia, hy- vaccine therapy may prove to be more effective when used perglycemia, dehydration, and QTc prolongation noted with a lower tumor burden, prior to the development of on electrocardiogram. Prior to initiation of therapy, at immune dysregulation. Also, some beneficial effect has two-week intervals for the first two months and period- been shown when synthetic peptides are employed in ically thereafter, hematology and chemistry labs as well as vaccine therapy to stimulate cytotoxic CD8+ T cells electrocardiograms are monitored. Patients are encour- (Tumenjargal et al., 2003). Although vaccine therapy for aged to hydrate with two liters of fluid daily. Dose re- CTCL is just beginning to be explored, it does show po- ductions may be necessary if patients prove intolerant to tential as an effective treatment for MF and SS. therapy (Merck & Co.) (see Figure 4-10). Cytokine Therapy: The antitumor properties of the cytokine IL-12 relate to its ability to stimulate prolifera- Bone Marrow Transplantation tion of antigen-presenting cells and phagocytic cells, as Autologous and allogeneic hemopoietic stem cell trans- well as to augment cytolytic T-cell and NK cell functions plantation (HSCT) is reserved for advanced-staged, that are necessary to induce IFN gamma production by refractory CTCL. HSCT use for CTCL has declined since activated T cells (Hwang et al., 2008). IL-12, given as a 2000, as new, more effective therapies have become subcutaneous injection or intralesionally, resulted in a sig- available (Dearden, 2007). Optimal timing for HSCT in nificant (56%) clearing of skin lesions in patients with CTCL is unknown, and multiple factors influence the MF without major toxicities (Rook et al., 1999). IL-12 decision to transplant for MF or SS. Considerations combined with IL-2 resulted in a synergistic effect with include patient age, presence of other disease(s), perfor- improved antitumor response and increased production of mance status, response to previous systemic therapies, IL-12 (Zaki et al., 2002). IL-2 given alone had a very

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Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. minor response in advanced MF and SS (Querfeld et al., To summarize, treatment modalities are varied and 2007). complex, and disease staging is a critical factor in deciding which treatment to institute. Treatment can range from Investigational Histone Deacetylase Inhibitors topical steroids to investigational therapies depending on Romidepsin, previously called depsipeptide, is an HDAC the extent of skin involvement and the presence of inhibitor that currently is under investigation in phase II systemic disease. A holistic view of the patient should be trials for CTCL. Romidepsin functions in the same man- considered when choosing a treatment regimen, including ner as vorinostat, inducing cell growth arrest, cell differ- financial, social, and emotional concerns. The lack of entiation, and apoptosis; however, its chemical structure effective long-term treatment remains a major problem is bicyclical and more potent (Piekarz et al., 2004). Clini- for patients with MF and SS, with no curative therapy cal responses seen in patients with SS include decreased known to date. h numbers of circulating Se´zary cells, decreased incidence of erythroderma, and decreased pruritus (Piekarz et al., REFERENCES 2001). In a phase II international multicenter romidepsin Alibert, J. L. (1806). Description des maladies de la peau observe´es a`l_Hoˆpital study, promising clinical responses are being seen in pa- Saint-Louis et exposition des meilleurs me´thodes suivies pour leur traite- tients with SS and stages IBYIVA MF. Seventeen percent ment.Paris:Barroisl_a>ne´etfils. of patients achieved either a complete or partial response; Barnes, P. J., & Karin, M. (1997). Nuclear factor-kappa B: A pivotal transcription factor in chronic inflammatory diseases. New England 30% maintained stable disease (Whittaker et al., 2006). Journal of Medicine, 336(15), 1066Y1071. Cardiac toxicity has been a concern and is closely moni- Chang, Y. T., Liu, H. N., Chen, C. L., & Chow, K. C. (1998). Detection of Epstein-Barr virus and HTLV-I in T-cell lymphomas of skin in Taiwan. tored in the romidepsin studies. This HDAC inhibitor is American Journal of Dermatopathology, 20(3), 250Y254. notassociatedwithmyocardialdamageorimpairedcar- Clark, R. A., Chong, B. F., Mirchandani, N., Yamanaka, K., Murphy, G. F., diac function but does cause transient prolongation of the Dowgiert, R. K., et al. (2006). A novel method for the isolation of skin resident T cells from normal and diseased human skin. Journal of QTc interval despite electrolyte replacement. The safety Investigative Dermatology, 126(5), 1059Y1070. profile for romidepsin remains under investigation (Piekarz Criscione, V. D., & Weinstock, M. A. (2007). Incidence of cutaneous T-cell lymphoma in the United States, 1973Y2002. Archives of Dermatology, et al., 2006). Other toxicities associated with romidepsin 143(7), 854Y859. include nausea, fatigue, and myelosuppression. Dearden, C. (2007). Is there a role for hemopoietic stem-cell transplanta- Toll-Like Receptors: Toll-like receptors (TLRs) are tion in CTCL? Oncology, 21(2 Suppl. 1), 1Y6. immune modulators that comprise a family of molecules Demierre, M. F., Gan, S., Jones, J., & Miller, D. R. (2006). Significant impact of cutaneous T-cell lymphoma on patients_ quality of life: Results of a that act as alarms for the immune system. TLR9 is ex- 2005 National Cutaneous Lymphoma Foundation Survey. Cancer, pressed by human B cells and dendritic cells. When 107(10), 2504Y2511. Demierre, M. F., Kim, Y. H., & Zackheim, H. S. (2003). Prognosis, clinical stimulated, increasing dendritic cells are thought to enhance outcomes, and quality-of-life issues in cutaneous T-cell lymphoma. 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Editor’s Note: Many thanks to the Oncology Nursing Society (ONS) for allowing us to reprint, in 2 parts, this chapter from the book, Site-Specific Cancer Series: Skin Cancer, published by ONS. To order, call the Oncology Nursing Society toll-free at 866-257-4ONS or visit ONS online at www.ons.org. ONS Member Price: $40, Nonmember price: $60. Part 2 will appear in the March/April issue of the Journal of the Dermatology Nurses’ Association.

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