CTCLs are a heterogeneous group of extranodal lymphomas and were the subject of a new joint classification system in 2005 by the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) (Table 41.1) [2]. MF/SS is relatively uncommon and comprises approximately 3.9 % of all NHLs [3]. The incidence of CTCL has increased since 1973 with an annual age-adjusted incidence of 6.4–9.6 cases per million people in the United States [4]. The cause of the vast majority of MF/SS cases are unknown, despite numerous environmental and infectious etiologies having been investigated as potential sources of chronic antigenic stimulation. These include human T-cell lymphotrophic virus (HTLV), cytomegalovirus (CMV), Borrelia burgdorferi, human herpes virus-8 (HHV-8), Staphylococcus aureus, Chlamydia species, and chemical exposures such as aromatic or halogenated hydrocarbons [5, 6].

MF classically presents as scaly oval or annular patches/plaques (T1-2 tumor designation) on sun-protected areassuch as the trunk, buttocks, axillae, groin, and proximal extremities, (“bathing trunk” distribution) with or without pruritus (Fig. 41.1a–c). Typically, it has indolent behavior and in early disease when host immunity is intact and lesions may wax and wane spontaneously. Because of this, early disease may take years before definitive diagnosis is made and skin biopsies may demonstrate non-specific dermatitis. Lesions may also less commonly affect sun exposed areas such as the face and can also result in localized hair loss (as seen in the follicular variant). They may also progress to thicker, more infiltrated plaques (Fig. 41.1c), ulcerated tumors (T3 disease) (Fig. 41.1d), or coalesce into a confluent erythema >80 % body surface area (“erythroderma” or T4 disease) (Fig. 41.1d). In these cases, the disease can cause more symptoms and behave more aggressively.

In addition to the classic presentation, MF has myriad other clinical morphologies and histological variants (classic Alibert-Bazin subtype, erythrodermic/Sezary Syndrome, unilesional, hypopigmented, pagetoid reticulosis, follicular/follicular mucinosis, syringotropic, granulomatous/slack skin, bullous/vesicular, palmoplantar, pigmented purpuric dermatosis-like, interstitial, icthyosiform, hyperkeratotic/verrucous, vegetating/papillomatous) [7] and has been referred to as one of the great clinical imitators, similar to cutaneous syphilis and sarcoidosis. Subtypes may be characterized by more indolent behavior (hypopigmented MF) or by more aggressive behavior (follicular, granulomatous), depending on their clinical course. Follicular MF, even with limited lesions, can be recalcitrant to therapy given the depth of the malignant infiltrate.

SS typically has a more aggressive course than MF from its onset, and typically presents as de novo erythroderma with leukemic peripheral blood involvement by the atypical, hyperconvoluted, cerebriform, malignant T-cells known as Sézary cells (also previously referred to as Lutzner cells or cellules monstrueuses). This is in contrast to patients who have MF that evolves into erythroderma over time (erythrodermic MF). Originally, SS was described with the clinical triad of erythroderma, lymphadenopathy, and palmoplantar keratoderma (Fig. 41.1e). SS patients may also have severe pruritus, active scaling/desquamation, prominent conjunctival eversion of the eyelids (referred to as ectropion), diffuse alopecia, chills, low grade fevers, night sweats, or fatigue.

MF/SS patients, particularly erythrodermic patients, are heavily colonized by skin bacteria and are susceptible to recurrent infections with correct Staphylococcus aureus, which often are methicillin-resistant (MRSA). Patients with ulcerated tumors are also at high risk for bacterial sepsis and in general, infections have previously been the leading cause of mortality in MF/SS patients [8].

MF/SS patients may also present with other concomitant skin conditions, such as the chronic, recurrent primary cutaneous CD30+ lymphoproliferative disorders (LPDs) such as lymphomatoid papulosis (LyP) or CD30+ primary cutaneous anaplastic large cell lymphoma (ALCL) [9]. Patients with MF/SS may also be at higher risk for having secondary malignancies, such as other skin cancers (nonmelanoma and melanoma) and secondary lymphomas [10]. Young patients with MF/SS diagnosed before 30 years of age may experience an increased risk of secondary malignancies, particularly melanoma and lymphoma, but, despite this risk, have a favorable prognosis [11].

Early diagnosis of MF can be elusive, as the clinical and histopathology of early MF lesions can mimic benign dermatoses, such as eczematous dermatitis, allergic contact dermatitis, psoriasis and parapsoriasis. Traditionally, the diagnosis is made when a patient presents with typical lesions and skin biopsy reveals atypical lymphocytes (with large, hyperchromatic and hyperconvoluted nuclei) within the epidermis, in the absence of epidermal spongiosis, and often associated with epidermal dendritic cells (DCs) to form the pathognomonic “Pautrier’s microabcesses.” Currently there are sophisticated laboratory tools to aid in diagnosis, which include tissue immunohistochemistry and flow cytometry (which can demonstrate CD3 expression, CD4 > CD8 expression of greater than 4:1, as well as characteristic T-cell lineage antigen loss of CD5, CD7, CD26, and less often CD3). Molecular detection of clonal T-cell receptor (TCR) gene rearrangements (β and γ chains) in the skin or other tissue (such as the blood or lymph node) can also further strengthen the diagnosis [12]. These days, the standard evaluation of early MF often involves assessment of multiple criteria (clinical, histopathological and molecular) [13]. However, it must be noted that T-cell clonality can also be detected in benign and autoimmune inflammatory dermatoses and should not be automatically equated with neoplasia [14, 15]. Diagnosis ultimately rests on accurate clinicopathologic correlation with adjunctive molecular studies, if appropriate.

In SS, leukemic blood involvement was traditionally measured by the Sézary prep, visual examination of a peripheral blood buffy coat smear for the atypical Sézary cells (Sézary count >5 % total lymphocytes was considered significant). However, this method was laborious and was subject to considerable inter-observer variability. More sensitive and specific tools to measure peripheral blood involvement include anti-TCR Vβ-specific monoclonal antibodies, or T-cell surface marker antibodies (CD3, CD4, CD7, CD8, CD26) using fluorescence-activated cell-sorting (FACS) analysis/flow cytometry.

The identification of a clonal malignant TCR Vβ population aids in the diagnosis and allows for monitoring of the disease course in SS patients. However, as SS cells express molecules also present on normal activated CD4 T cells, diagnosis based on the phenotype of circulating malignant cells can be difficult [6]. SS patients without an identifiable circulating clone pose a particular diagnostic and therapeutic monitoring challenge, as loss of CD26 is suggestive but not definitive of the malignant population [16].

To that end, much work has been performed recently to identify additional diagnostic markers for SS. Wysocka and colleagues identified CD164 as a novel early detection marker for SS in patients with low-to-high tumor burden, demonstrating a statistically significant correlation between CD164 acquisition and loss of CD26 expression [17]. The studies further showed that while CD164 is present on CD4 T cells of SS patients with a wide range of tumor burdens, it is absent on CD4 T cells of healthy controls and patients with atopic dermatitis. Additionally, morphological examination of purified CD4 + CD164+ T cells demonstrates the morphology of malignant Sézary cells. Lastly, CD4 + CD164+ T cells were noted to disappear in SS patients who experienced clinical remission as a result of treatment, underscoring the potential for CD164 to serve as a marker for malignant cells in SS.

Other markers recently reported useful in flow cytometric analysis include vimentin, CD158k [18], T-plastin (PLS3) [19], Twist [20], and NKp46 [21]. Michel and colleagues demonstrated that combination of CD158k, PLS3, and Twist gene expression profiling by quantitative PCR can be used for an efficient molecular diagnosis of SS [22]. The authors showed that CD4⁺ T cells from SS patients expressed significant PLS3, Twist, CD158k, and NKp46 mRNA levels and that analysis of expression of these four markers accurately classified 100 % patients in the study.

In SS, molecular testing for T-cell receptor gene rearrangements can often detect the identical clonal T-cell population in the blood and the skin. In general, matching T-cell monoclonality detectable in several different skin lesions or tissues (skin, nodes, blood) in a patient over time is suggestive of CTCL [23].

Since 1979, a tumor-node-metastasis-blood (TNMB) classification and staging system has been used for MF/SS and TNMB stage has proven to be an important prognostic measure (Tables 41.2 and 41.3) [24]. In 2007, modifications were proposed by the International Society for Cutaneous Lymphomas (ISCL) regarding further stratification of blood involvement parameters to reflect the newer and more sensitive assays [25, 26]. The current B classification proposed by the ISCL includes B0 (no clinically significant blood involvement), B1 (clinically significant “minimal” blood involvement with Sézary cells <1.0 K/ul) and B2 (leukemic blood involvement detectable either as (a) Sézary cells >1.0 K/ul; (b) CD4/CD8 ratio >10 and CD4 + CD7- population >40 % or CD4 + CD26- population >30 %, (c) lymphocytosis with molecular genetic evidence of a clonal T-cell population; or (d) chromosomally abnormal T-cell clone). The updated blood involvement parameters may affect staging and prognosis of patients. Currently, the ISCL proposes that in patients with erythroderma (T4 skin classification), the B2 classification be considered the equivalent to nodal involvement (hence T4N0-1M0B2 would be upgraded from Stage III to Stage IVA1). A retrospective study by Vonderheid et al. demonstrated that using modified B criteria improved prognostication in erythrodermic patients [26]. Several large studies have since validated the 2007 ISCL staging classification for prognosis and risk stratification [27–29]. National Comprehensive Cancer Network Clinical Practice Guidelines for MF/SS have been available since 2008 and include recommendations for diagnostic and staging work up as well as current established treatments and treatment algorithms, and are updated yearly [30].

Once patients have an established diagnosis of MF/SS, a typical staging workup includes complete skin and physical examination, bloodwork including complete blood count with differential, comprehensive metabolic panel, lactate dehydrogenase, and either peripheral blood flow cytometry or Sézary cell prep (flow optional in T1a, limited patch disease with no high risk clinical or histologic characteristics). Computed tomography (CT) or positron emission tomography scanning (PET) is appropriate for patients with systemic symptoms, clinically palpable lymphadenopathy (>1.5 cm), or more advanced T classification (T1b follicular MF, extensive T2a/b, T3/tumors or T4/erythrodermic disease, patients with B symptoms). These tests are useful to assess nodal or visceral involvement by MF/SS. The role of staging bone marrow biopsy remains controversial [31]. In the United States, bone marrow biopsy is typically reserved only for patients with advanced disease with some evidence of other hematological abnormalities (i.e.: other cytopenias).

Overall survival in MF/SS is highly dependent on initial disease stage. Several studies have demonstrated that early stage disease (i.e.: skin disease only, limited to <10 % body surface area) if treated has overall median survival comparable to healthy control populations. However, with more advanced disease, overall survival also decreases with Stage IV disease having a 27 % 5-year survival and Sézary Syndrome patients having a 30 % 5-year survival [32]. In retrospective studies, the risk of disease progression ranged from 10 % (Stage IA) to 25 % (Stages IB or higher) over a 30 year period [33, 34]. While a 2003 study by Kim and colleagues [32] reported an overall survival (OS) of only 2.5 years in patients with SS, a study by Agar and colleagues [27] in 2010 reported a 3.1 year OS, and a study by Talpur and colleagues [28] from 2012 showed an OS of 4.64. As the major cause of death in patients with SS is line sepsis, which is often caused by Staphylococcus aureus, Talpur et al. report that Staphylococcus was prospectively cultured and was aggressively treated and prevented with antibiotics and skin care [35]. The authors thus postulate that the improved survival may have resulted in part from early treatment of coexisting infections, as well as earlier diagnosis of disease and advent of new therapies.

Various clinical prognostic factors have been demonstrated including patient age, initial stage, T classification, visceral disease, elevated LDH, eosinophilia, presence of Sézary cells, and B0b blood classification [27]. Important histological factors that indicate poor prognosis include “large cell transformation” (LCT, presence of >25 % large atypical T-cells in the infiltrate seen in the skin or lymph node or blood, may be either CD30+ or CD30-, with CD30- transformation having worse prognosis than CD30+) [36], folliculotropic or granulomatous infiltrate; in contrast, the presence of CD8+ tumor infiltrating cytotoxic lymphocytes (TILs) in the infiltrate has been demonstrated to be a favorable prognostic marker.

Recently, a new cutaneous lymphoma international prognostic index (CLIPi) for early and late stage CTCL has been developed and validated to aid with patient risk stratification [37]. Based on the proposed index, significant adverse prognostic factors at diagnosis included male gender, age >60, presence of plaques, folliculotropic disease, and stage N1 for early stage disease, and male gender, age >60, stages B1/B2, N2/3 and visceral involvement for late stage disease. Using these variables 3 distinct groups are designated for early and late stage patients: 0–1 (low risk), 2 (intermediate risk), and 3–5 factors (high risk). Using this prognostic index a 10 year OS for each group may be obtained (in the early stage model was 90.3 % (low), 76.2 % (intermediate) and 48.9 % (high) and 53.2 % (low), 19.8 % (intermediate) and 15.0 % (high) for the late stage model).

CLIPi thus supplements the current NCI Staging System and is a useful tool for individual prognostication and for making comparisons between different groups of patients in clinical trials.

Perhaps the most potentially powerful prognostic tool currently being developed in MF/SS is cDNA microarray analysis. Previously, MF/SS patients were shown to have a distinct gene expression profile that was distinguishable from other benign inflammatory dermatoses [38]. In addition, such profiles could also identify high risk patients with <6 month survival. The panel of genes identified included upregulated GATA3 (involved in Th2 differentiation), downregulated STAT4 (involved in Th1 differentiation), and CD26 (dipeptidylpeptidase IV, which regulates T-cell entry into the epidermis, see section “Chemokines”). Recently, several studies have confirmed that a similar panel of genes has been shown to be capable of molecularly diagnosing MF/SS patients [39, 40].

Treatment of MF/SS can be divided into 2 major categories: skin directed therapies (SDTs) and systemic therapies. As listed in Table 41.4, there are numerous options. Therapeutic approaches can vary widely from center to center, and the availability of many newer therapies varies among countries. It is useful to divide the discussion of therapies in regard to early stage vs. late stage disease (Table 41.5).