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, 18 Journal of the Dermatology Nurses’ Association Copyright @ 2011 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. The pathology of MF and SS is characterized by neo- plastic 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 cyto- kines 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+ phe- notype, 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 abnormali- ties 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 VOLUME 3 | NUMBER 1 | JANUARY/FEBRUARY 2011 19 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 sur- face 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).