Dupilumab therapy in atopic dermatitis when cutaneous lymphoma is suspected: Consensus recommendations from the EORTC Cutaneous Lymphoma Tumour Group.

An unusual case of cytotoxic peripheral T-cell lymphoma

Lethal anaplastic large-cell lymphoma occurring in a patient treated with dupilumab

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Comment on “Diagnostic testing of eczematous dermatitis with incomplete response to dupilumab”

Cutaneous T-Cell Lymphoma

A case of secondary syphilis masquerading as cutaneous lymphoma

Cutaneous pseudolymphomatous drug eruption secondary to supplemental flaxseed oil

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. involvement is quite rare (Hymes, 2005). In dermatology and oncology often on the evaluation and treatment of patients with CTCL. evaluation of a suspected MF and SS diagnosis requires a history and and of data derived from skin and Patients are to describe the of their skin associated cutaneous such as pruritus or and to prior should be to such as and patients with CTCL these systemic signs upon should not only and quantify the type and body surface area of skin lesions but also should include a complete lymph at establishing the presence or absence of in the skin-draining nodes. should be with of the and to determine possible and findings in establishing the diagnosis and further the disease. of light of is the initial in the evaluation of a suspected skin lymphoma. The is derived from an or biopsy that is & 2002). In most cases, and infiltrates of and are present within the and with the refers to the of the small to within the specific but feature is the of atypical Pautrier & 2003). which often can be performed on tissue, can prove In MF, the neoplastic are positive for T-cell and and are T-cell receptor confirm and are performed by either Southern blot or methods. and analysis performed on patients suspected of CTCL should be in the clinical because and can occur. Laboratory for patients with an MF or SS diagnosis include a complete blood count with and of the peripheral For staging patients with disease or a of the and should be With greater the with has to be more for detection of lymphadenopathy in disease. In with the and often MF and SS presentations with course of disease, of a treatment can present care also the of immune and of therapies available to patients with a confirmed MF or SS diagnosis are intended to produce clinical response than for CTCL are in and with patients may more than one therapy The is to disease burden and progression for as as In most clinical treatment of CTCL is to the stage and of the disease, and Patients with disease limited to the skin and often can clinical response with one of the readily available This to treatment is by the understanding that the malignant T cells the majority of their time in the skin because of the to antigens and are dependent on the skin for therapies can be to the target the skin. In patients with skin disease or those with involvement of peripheral blood, lymph nodes, or visceral one or more systemic In later stages of the disease, more aggressive therapies become as the malignant T on the skin and the disease becomes at Therapies are the of treatment for skin both and chronic in their These are as of MF because of of and multiple and by of cytokine and of & In the early stages of the disease, topical corticosteroid therapy has to be a for both and of clinical In a of patients with stage disease, daily use of topical for three to in a complete response in and a in for a total response of & 1998). are in a of including and may a with a less or over time in an to diminish the as well as to provide opportunity for of from topical include skin and is a rare of prolonged topical corticosteroid and The (also known as and (also known as or are cytotoxic for topical management of CTCL. the they have been used for the treatment of the early stages and of CTCL. In et al. reported of clinical in of patients with topical daily over the course of months. A an complete response with of daily et al., therapy requires among the and A 10 of is in the or patients a at to all skin the and should be to their with and after the process. should be used with The most associated with therapy is the development of an reaction characterized by erythema and This reaction can be with and is a reaction with response Patients with CTCL who demonstrate clinical of lesions for the of therapy for may the of over time to a less frequently of therapy include potential for and secondary skin (Hymes, 2005). is available in and site erythema can although and less In care is as an to The and receptors These receptors as that regulate expression of that control and The of for in the management of CTCL In a phase clinical Duvic, et al. (2001) observed a response in patients to all lesions in early-stage CTCL. pruritus, and at the site may in the initial of For patients, the to this may be of with and from other to to daily over time. In clinical the topical class of is therapy for patients who have disease after treatment with topical or other and With light therapy is one of the most used therapies for early-stage CTCL. within the ultraviolet and is for a host of T-cell-mediated skin including psoriasis, and cutaneous disease. In early-stage MF, is typically skin involvement is diffuse topical have to be The benefits of and have been for as the MF in covered areas of the body (e.g., bather's and in sun-exposed skin was patients reports of improvement in their skin during the summer or following a The of for ultraviolet light therapy is with on surface proteins and in addition to of In and Langerhans cells, and

Dupilumab as a therapy option for treatment refractory mogamulizumab-associated rash

Primary cutaneous lymphomas (PCLs) are a group of extranodal non-Hodgkin lymphomas characterized by early accumulation of mononuclear cells, most of them lymphocytes, on skin, with no evidence of extracutaneous disease at diagnosis. T-cell and natural killer (NK) cell lymphomas (CTCL/NK) with an absolute predominance of mycosis fungoides (MF) represent approximately 44% of all PCLs. The etiology and the exact steps in the pathogenesis of CTCL are not understood. It is more reasonable to assume that these diseases represent the endpoint of several different processes. Genetic, environmental, and infectious factors should all be considered in the etiology of CTCL. The current classification for PCLs was proposed in 2005 by the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). WHO-EORTC Classification for primary cutaneous T- and NK-cell lymphomas is MF and subtypes of MF (folliculotropic MF, pagetoid reticulosis, granulomatous cutis laxa); Sezary syndrome; adult T-cell leukemia/lymphoma; primary cutaneous CD30+ lymphoproliferative diseases (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis); subcutaneous panniculitis-like T-cell lymphoma; extranodal NK/T-cell lymphoma, nasal type; and primary cutaneous peripheral T-cell lymphoma, unspecified (primary aggressive epidermotropic CD8+ cutaneous T-cell lymphoma, provisional entity; cutaneous γδ T-cell lymphoma, provisional entity; and cutaneous lymphoma of small and medium pleomorphic CD4+ T-cell, provisional entity).

Induction of remission in a patient with end-stage cutaneous T-cell lymphoma by concurrent use of radiation therapy, gentian violet, and mogamulizumab

Clinical outcomes in a cohort of patients with cutaneous T-cell lymphoma and COVID-19

Análisis comparativo de la expresión de moléculas de adhesión celular en linfomas cutáneos (micosis fungoide/síndrome de Sézary) y dermatosis inflamatorias mediadas por células T

Comparative Analysis of the Expression of Cell Adhesion Molecules in Cutaneous T-Cell Lymphomas (Mycosis Fungoides/Sézary Syndrome) and Inflammatory Skin Diseases

120 - Cutaneous T-Cell Lymphoma