Mycosis Fungoides

Mycosis Fungoides

CHAPTER 79 Mycosis Fungoides   Grace L. Smith, Lynn D. Wilson, and Bouthaina S. Dabaja INCIDENCE The age-adjusted incidence of mycosis fungoides ...

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Mycosis Fungoides



Grace L. Smith, Lynn D. Wilson, and Bouthaina S. Dabaja

INCIDENCE The age-adjusted incidence of mycosis fungoides (MF) is approximately 6.4 cases per million. Three thousand cases per year are diagnosed in the United States, representing 72% of cutaneous T-cell lymphomas (CTCLs).

BIOLOGIC CHARACTERISTICS

MF is a chronic malignant disease of the skin involving skinhoming CD4+ T cells. The classical immunophenotype is CD2+ CD3+ CD4+ CD5+ CD45RO+ CLA+ (cutaneous lymphoid antigen) CD8− CD30−. Early disease is characterized by patches and plaques affecting the skin, with or without nodal or blood involvement. Advanced disease is characterized by cutaneous tumors, erythroderma, or lost epidermotropism and visceral involvement.

STAGING EVALUATION

TNMB staging is based on the percentage of cutaneous involvement, nature of the lesions, nodal, visceral, and blood involvement. History taking and a physical examination are needed to stage the disease. Skin biopsy with immunophenotyping and polymerase chain reaction (PCR) are performed to determine the T-cell receptor gene rearrangement. A complete blood count with manual differential, serum chemistries, liver function tests, and lactate dehydrogenase (LDH) should be performed. For stages IB to IV disease, peripheral blood flow cytometry, and peripheral blood T-cell receptor gene rearrangement should be assessed. A chest radiograph should be obtained for all patients. Computed tomography (CT) scanning should be done and positron emission tomography (PET)-CT considered for stages IB to IV disease. Suspicious lymph nodes require excisional or core biopsy.

achieving an optimally durable response but minimizing toxicity. Therapeutic options include irradiation, corticosteroids, psoralen plus ultraviolet A (PUVA), narrow band ultraviolet B, mechlorethamine, carmustine, and topical bexarotene. Total skin electron beam therapy (TSEBT) monotherapy produces a 10-year relapse-free survival rate of approximately 50% for IA disease. TSEBT provides rapid and effective palliation, with complete response rates of 95% for T1, 90% for T2, 60% for T3, and 75% for T4 disease. Total dose for TSEBT varies widely, with a growing emphasis on lower doses and repeat courses of TSEBT. TSEBT is also often followed by adjuvant maintenance therapy. However, skin-directed therapies are not anticipated to be curative over long-term follow-up, with the natural history of disease expected to be chronic and relapsing. For progressive or refractory disease, systemic therapies include interferon-α, retinoids, bexarotene, extracorporeal photochemotherapy, denileukin diftitox, vorinostat, nucleoside analogs, and cytotoxic chemotherapy. Biological response modifiers are being currently evaluated.

LOCALLY ADVANCED DISEASE

TSEBT is effective therapy for achieving durable control for most cutaneous lesions. Other skin-directed therapies are also applied for patients with locally advanced disease. Traditional multiagent systemic chemotherapy does not enhance survival times but may produce palliation. Allogeneic bone marrow transplant is a promising approach for young patients with a good performance status and is considered a curative option.

PALLIATION

PRIMARY THERAPY

For early-stage disease, therapy is focused on sequential skindirected therapies, to simultaneously balance the objectives of

Most patients require long-term therapy to relieve cutaneous symptoms. All of the skin-directed therapies produce substantial palliation. Additionally, novel biologic agents such as bexarotene, denileukin diftitox, and vorinostat (or other emerging histone deacetylase inhibitors [HDACs]) have efficacy in disease refractory to standard treatments.

MF is a low-grade, non-Hodgkin’s lymphoma caused by skin-homing CD4+ T cells that form cutaneous patches, plaques, and tumors.1,2 MF was initially described in 1806 when Alibert described a patient with cutaneous tumors that he attributed to yaws. Although initially termed pian fungoides, he later changed the name to mycosis fungoides.3 In 1938, Sézary and Bouvrain described a leukemic variant called the Sézary Syndrome (SS),4 and Lutzner and Jordan elucidated the ultrastructure of the Sézary cell in 1968.5 The term cutaneous T-cell lymphoma was introduced by Edelson in 1975 and encompasses a variety of cutaneous lymphoproliferative disorders including MF/SS, adult T-cell leukemia/lymphoma, primary cutaneous CD30+ anaplastic lymphoma, lymphomatoid papulosis, pagetoid reticulosis, and others.6 In clinical practice, the terms MF and CTCL are often used interchangeably; however, such usage is

incorrect.7 MF constitutes the majority of all CTCLs and the clinical history and therapy for each subtype of CTCL are different.2 MF is a challenging disorder from all perspectives. Despite improving molecular techniques, diagnosis early in the course of disease is often difficult because of the nonspecific nature of skin lesions and the numerous benign dermatoses that may mimic MF. Once a diagnosis of MF has been correctly established, the optimal initial treatment strategy often remains unclear, given heterogeneity of clinical presentations and limited data from controlled studies. Although radiotherapy is the most effective single agent in the treatment of MF,8 TSEBT is not readily available at many centers. This chapter provides a summary of the clinically relevant aspects of MF and describes the role and techniques of radiotherapy in patient management.

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ETIOLOGY AND EPIDEMIOLOGY MF primarily affects adults older than the age of 40, with incidence rates peaking in the seventh decade. The incidence of CTCL has consistently increased from 1974 through 2002, reaching a current yearly incidence rate of 9.6 cases per million (with approximately 6.4 cases per million represented by MF).9 Risk factors for development of CTCL include black race and male gender. Both characteristics are associated with higher T stage at presentation10 and a poor prognosis.11 Markers of high socioeconomic status, such as residence in areas with high home values, high level of educational attainment, and high physician density are associated with an increased incidence CTCL; it is unclear whether these factors are causative or simply increase the likelihood of diagnosis.9 Etiologic agents for the development of MF remain highly speculative.12 Although numerous exposures including pesticides, radiation, industrial solvents, tobacco, and alcohol have been investigated, no consistent causative factors have been identified.13 High rates of seropositivity for both cytomegalovirus14 and human T-cell lymphotrophic virus type I15,16 have been reported, but these studies await further corroboration before a causal relationship can be inferred.17-19 The observation that MF is more common in blacks and tends to present in sun-shielded areas (i.e. “bathing suit” distribution) suggests that sun exposure may protect against the development of MF. Sun exposure may mediate its protective effect by exerting a cytotoxic effect on either the malignant CD4+ T-cell of MF or the epidermal antigen-presenting dendritic cell, also known as the Langerhans cell. This cell pre­ sents antigens to the malignant CD4+ T cells of MF and may stimulate their growth. The histologic evidence for this interaction is Pautrier’s microabscess, an intraepidermal collection of malignant CD4+ T cells clustered around an antigen presenting dendritic cell. This finding is considered pathognomonic for MF and suggests that MF may be an antigendriven malignancy, though a specific antigen has yet to be identified.20

TABLE 79-1  Criteria

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Proposed Algorithm for Diagnosis of Early Mycosis Fungoides Score

CLINICAL 2 points for basic + two additional criteria   Basic 1 point for basic + one    Persistent or progressive patches additional criterion or thin plaques   Additional 1.  Nonsun-exposed location 2. Size/shape variation 3. Poikiloderma* HISTOPATHOLOGIC 2 points for basic + two additional criteria   Basic 1 point for basic + one    Superficial lymphoid infiltrate additional criterion   Additional 1. Epidermotropism without spongiosis 2. Lymphoid atypia† MOLECULAR BIOLOGIC 1 point for clonality   Basic    Clonal T-cell receptor gene rearrangement IMMUNOPATHOLOGIC 1 point for one or more criteria 1. <50% CD2+, CD3+, or CD5+ T cells 2. <10% CD7+ T cells 3. Epidermal/dermal discordance of CD2, CD3, CD5, or CD7‡ Four or more points satisfy criteria for a diagnosis of early MF. Adapted from Pimpinelli N, Olsen EA, Santucci M, et al: Defining early mycosis fungoides. J Am Acad Dermatol 53:1053–1063, 2005. *Poikiloderma is defined as the combination of skin atrophy, telangiectasia, and mottled pigmentation. †Lymphoid atypia is defined as cells with enlarged, hyperchromatic nuclei, and irregular or cerebriform nuclear contours. ‡T-cell antigen deficiency confined to the epidermis.

PREVENTION AND EARLY DETECTION

BIOLOGIC CHARACTERISTICS AND MOLECULAR BIOLOGY A malignant clone in patch-plaque MF bears the immunophenotype of activated, skin-homing CD4+ helper T cells.20 When a naïve T-cell identifies its cognate antigen in a skin-draining lymph node, activation occurs, and the T cells begins to

express cutaneous lymphocyte antigen (CLA) and CC chemokine receptor 4 (CCR4). As these activated T cells pass through the capillaries of inflamed skin, CLA and CCR4 bind to their respective ligands on the dermal capillaries, resulting in extravasation of the activated T cells into the dermal connective tissue. Once outside the circulation, activated T cells migrate to the epidermis and interact with antigen-presenting dendritic (Langerhans) cells (Figure 79-1). Clinically, progression of MF is associated with loss of epidermotropism and increasing tumor burden. Molecular studies have shown that progression of MF is associated with p53 mutation,31 numerous chromosomal rearrangements,32 and microsatellite instability.33 In addition, the malignant cells in MF develop mechanisms to escape destruction by the host immune system. For example, although benign activated T cells are eliminated by fas/fas-ligand mediated apoptosis, the malignant T cells of MF evade fas-mediated apoptosis via fas downregulation, mutation, or alternative splicing.34 As a malignancy of the immune system, MF results in substantial alteration of host immunity with consequent increased risk of infection35 and possibly second malignancy.36 For example, in patients with Sézary syndrome, the absolute number of normal circulating T cells often drops dramatically, reaching levels typically only seen in acquired immunodeficiency syndrome.37 In addition, malignant CD4+ T cells produce large amounts of interleukin-10 and transforming growth factor-β, resulting in further suppression of cell-mediated

DISEASE SITES

No agents have been identified that will prevent the development of MF. However, early diagnosis is critical because local therapy directed against uni- or oligolesional MF is highly curative.21-23 The most typical presentation of early disease— an erythematous patch with scale arising in a sun-shielded area—may be confused with a number of benign dermatoses including atopic dermatitis, psoriasis, and tinea corporis.24 At this early stage, most of the lymphocytes noted on histopathology represent reactive inflammatory cells rather than the malignant clone.25 As a result, the histopathology of early MF mimics numerous benign inflammatory conditions,25,26 and a rapid and correct histologic diagnosis is not always possible. In this setting, molecular studies such as PCR for the T-cell receptor will identify a clonal T-cell population in 50% to 80% of patients who ultimately develop overt histologic evidence of MF.27,28 To improve diagnostic accuracy of early MF, the International Society for Cutaneous Lymphoma proposed a points-based algorithm for early diagnosis (Table 79-1).29,30

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T cell

αEβ7

Pautrier’s microabscess

CD4 CCR4 TCR

CCL22 E-cadherin MHC-II

Langerhans’ cell

Epidermis Endothelial cell E-selectin

Epidermotropism

CCL17

Dermis

Extravasation CLA

CCR4

T cell Capillary Figure 79-1  Molecular pathology of mycosis fungoides. Activated skin-homing T cells extravasate through the dermal capillaries because of interactions of cutaneous lymphocyte antigen (CLA) and chemokine receptor 4 (CCR4) with their respective ligands on the dermal capillaries, E-selectin and chemokine ligand 17 (CCL17). T cells then migrate to the epidermis and interact with antigen presenting dendritic cells.

immunity.38,39 The malignant cells of MF also produce large amounts of soluble interleukin-2 receptor that can inacti­ vate interleukin-2,40 a cytokine needed to promote normal T-cell activation. Finally, the malignant cells of Sézary syndrome can elaborate large amounts of interleukin-4 and interleukin-5, producing a syndrome characterized by atopy and eosinophilia.39

PATHOLOGY AND PATHWAYS OF SPREAD The diagnosis of MF remains challenging, even for the experienced clinician and dermatopathologist, as a result of both the absence of a diagnostic gold standard and the number of benign inflammatory dermatoses that may mimic MF, particularly in its early stages. Currently, diagnosis relies on integrating clinical presentation with histopathologic, immunophenotypic, and genotypic data. The current World Health Organization–European Organization for the Research and Treatment of Cancer (WHO–EORTC) pathologic classification scheme for cutaneous T-cell lymphoma is presented in Table 79-2.41

Histopathology The most striking finding of early MF is profound epidermo­ tropism, characterized by lymphocytes clustered along the basement membrane of the epidermis (Figure 79-2, A, B).42 Microdissection studies have shown that virtually all of the lymphocytes in the epidermis belong to the malignant clone, whereas most dermal lymphocytes are reactive.43,44 Several microscopic findings help to discriminate early MF from benign inflammatory mimics. For example, an EORTC

study reported that identification of epidermal lymphocytes with extremely convoluted, medium-large (7-9 µm) nuclei enabled correct diagnosis of MF with 100% sensitivity and 92% specificity (see Figure 79-2, B).26 In contrast, a study from Stanford University found that intraepidermal atypical lymphocytes surrounded by a clear halo (an artifact of fixation) were the most robust indicator of MF in a multivariate model.45 Another finding, Pautrier’s microabscess, is considered pathognomonic but is seen in less than 20% of early lesions (see Figure 79-2, D).45 A proposed grading system has attempted to improve diagnostic accuracy.25,46 As MF progresses from patch to plaque stage, the lymphoid infiltrate increases in density and begins to invade the deeper reticular dermis (see Figure 79-2, C). Furthermore, as a result of the increased burden of neoplastic cells, findings such as Pautrier’s microabscesses (see Figure 79-2, D), haloed lymphocytes, and convoluted nuclei are more readily identified, resulting in improved diagnostic accuracy. Tumor formation results from vertical growth of the lymphoid infiltrate, and may be associated with complete loss of epidermotropism and sparing of the upper papillary dermis (see Figure 79-2, E). Erythrodermic MF often resembles patch-stage MF, although epidermotropism may be more subtle and neoplastic cells may be quite sparse.47

Immunophenotyping of Skin Lesions Assessment of T-cell marker expression within the lymphoid infiltrate provides additional information that helps to establish a diagnosis of MF. The hallmark of MF is expression of CD4, the marker of mature helper T cells. A typical immunophenotype for MF is CD2+ (pan T cells), CD3+ (pan T cells),



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TABLE 79-2 

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WHO–EORTC Classification for Cutaneous T-Cell Lymphomas

Histologic Findings Mycosis fungoides Variants of mycosis fungoides   Folliculotropic mycosis fungoides   Pagetoid reticulosis   Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30+ Lymphoproliferative disorders   Primary cutaneous anaplastic large cell lymphoma   Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma (α/β type) Extranodal NK/T-cell lymphoma, unspecified Primary cutaneous peripheral T-cell lymphoma, unspecified   Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)   Cutaneous γ/δ T-cell lymphoma (provisional)   Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

Frequency

5-year Disease-Specific Survival

44%

88%

Clinical Behavior

4% <1% <1% 3% —

80% 100% 100% 24% —

Indolent Indolent Indolent Aggressive —

8% 12% 1% <1% 2% <1%

95% 100% 82% — 16% 18%

Indolent Indolent Indolent Aggressive Aggressive Aggressive

<1% 2%

— 75%

Indolent

Indolent

Data from Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768–3785, 2005. NK, Natural killer; WHO–EORTC, World Health Organization–European Organization for the Research and Treatment of Cancer.

CD4+ (helper T cells), CD5+ (pan T cells), CD45RO+ (memory T-cell), CLA+ (cutaneous lymphoid antigen), CD8− (cytotoxic T-cell), CD30− (activated T-cell).48 Although many benign dermatoses express a similar immunophenotype, two markers, CD7 and Leu-8, are often underexpressed in MF and may be helpful in distinguishing between MF and benign mimics. Finally, rare cases of apparently classic MF that are CD4-, but CD3+ and CD8+ have been reported.49

T-Cell Receptor Gene Rearrangement

CLINICAL MANIFESTATIONS According to the EORTC classification of cutaneous lymphomas, the term mycosis fungoides should be reserved for those CD4+ cutaneous lymphomas that are “characterized by the subsequent evolution of patches to more infiltrated plaques and eventually tumors.”2 Over time, MF may spread to involve lymph nodes, blood, bone marrow, and visceral organs. Symptoms may vary by degree of involvement, but weight loss, night sweats, and fever are uncommon unless infection is present.

Clonal T-cell receptor gene rearrangements are frequently identified in MF skin lesions and may help to differentiate between early MF patches and benign mimics. Clinical data indicate that PCR will identify a dominant clonal T-cell receptor-γ rearrangement in 63% to 90% of skin biopsies that show definite histologic evidence of MF.50,51 Furthermore, PCR identifies a clonal T-cell population in 50% to 80% of histologically borderline biopsies obtained from patients who subsequently develop classic MF.27,28 In contrast, T-cell clonality occurs in only 6% to 24% of benign dermatoses that contain a lymphoid infiltrate.50,51 These observations suggest that identification of a clonal T-cell population should always be considered in light of the clinical and histologic context and may help to confirm a diagnosis of MF when already suspected on these grounds.

Premycotic Phase

Transformation to Large Cell Histology

Plaque Phase

Transformation to a large cell variant occurs in up to 39% of patients initially diagnosed with MF, and the likelihood of transformation is directly correlated with higher stage.52 Histologic diagnosis of transformation requires large cells (≥4 times the size of a small lymphocyte) comprising >25% of the lymphoid infiltrate or forming microscopic nodules.53 Transformation is associated with expression of CD30 in 30% of cases and expression of CD20 in 45% of cases. Transformed MF is typically aggressive, with clinical behavior similar to high-grade lymphoma, and must be treated as such, particularly with the goal of allogeneic transplantation when possible.

If untreated, some patches will progress to form more generalized, deeply infiltrative, scaling plaques that often have welldemarcated, palpable borders and may exhibit central clearance and arcuate morphology (see Figure 79-3, B). Associated findings include hyperkeratosis of the palms and soles and fissures.

Early MF typically begins with mildly erythematous, slightly scaling, annular or arcuate macules that classically involve sun-shielded areas (Figure 79-3, A). These lesions may wax and wane for years before histologic findings show definitive evidence of MF.

Patch Phase In this stage, patches lose their predilection for sun-shielded areas and may become eczematous, hypopigmented, or hyperpigmented. The trunk, pelvis, and proximal extremities are most commonly involved. Histologic features consistent with MF may now be discernible.

More than 80% of tumors emerge in the setting of established patch-plaque MF (see Figure 79-3, C). The most common sites

DISEASE SITES

Tumor Phase

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B

C

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D

F

Figure 79-2  Classic histopathologic findings in mycosis fungoides (MF) and Sézary syndrome. A, Advanced patch-stage lesion of MF exhibiting abundant lymphocytes within the basal layer of the epidermis, associated with an underlying band-like lymphocytic infiltrate and papillary dermal fibrosis. B, Advanced patch-stage lesion of MF exhibiting enlarged, convoluted lymphocytes within the epidermis. The lymphocyte cell size approximates the width of keratinocyte nuclei. C, Plaque-stage MF shows, in addition, involvement of the reticular dermis. D, Pautrier’s microabscesses are well-defined aggregates of lymphocytes within the epidermis, which are strongly indicative of MF. E, In tumor stage MF, the dermis is distended by the lymphocytic infiltrate. Epidermotropic capacity is often lost. F, Sézary cells, such as the cell at the right, are enlarged circulating lymphocytes that exhibit cerebriform nuclear convolutions. (Photos and legend courtesy of Earl Glusac, MD). Reprinted with permission from Figure 2 in Smith BD, Wilson LD: Management of mycosis fungoides. Part 1. Diagnosis, staging, and prognosis. Oncology (Williston Park) 17:1281–1288, 2003.



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A

B

C

D

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Figure 79-3  Spectrum of cutaneous lesions observed in mycosis fungoides. A, Patch stage. B, Plaque stage. C, Tumor stage. D, Erythrodermic stage. Adapted and reprinted with permission from Figures 1-4 in Dabaja BS: Mycosis fungoides, presentation, diagnosis, and treatment strategy. In Thomas CR, Jr, editor: Radiation medicine rounds: Hematologic malignancies, New York, 2012, Demos Medical Publishing.

of tumor involvement include the face, digits, and perineum. Tumors frequently ulcerate and are prone to infection.

Tumeur d’Emblée The term tumeur d’emblée refers to the rare patient who pre­ sents with tumors that arise in the absence of antecedent skin lesions; some cases may be more appropriately classified as CD30− cutaneous large T-cell lymphoma rather than MF.54 The clinical course may be more aggressive than patients with classic MF.

Erythroderma Erythroderma is defined as greater than 80% body surface involvement with confluent patches or plaques. It is associated with intense pruritus, hyperkeratosis of the palms and soles, skin atrophy, and lichenification (see Figure 79-3, D). Erythroderma may arise de novo or from progression of patch and plaque MF.

Lymph Nodes

Internal Organs Visceral involvement is typically seen only in patients with advanced cutaneous disease, nodal disease, and blood involvement. The most common sites include the lungs, central nervous system, oral cavity, and oropharynx,55,57 although MF

Proposed Hematologic Criteria for Diagnosis of Sézary Syndrome

Absolute Sézary cell count ≥1000 cells/µL. CD4/CD8 ratio ≥10 due to an increase in CD3+1 or CD4+1 cells by flow cytometry. Aberrant expression of pan-T-cell markers (CD2, CD3, CD4, CD5) by flow cytometry. Deficient CD7 expression on T cells (or expanded CD4+,1 CD7− cells ≥40%) is a tentative criterion. Increased lymphocyte count with T-cell clone in blood identified by Southern blot or polymerase chain reaction. A chromosomally abnormal T-cell clone. Adapted from Vonderheid EC, Bernengo MG, Burg G, et al: Update on erythrodermic cutaneous T-cell lymphoma. Report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 46:95–106, 2002.

has been observed in other sites such as the breast, thyroid, and pancreas. Visceral involvement is often subclinical and does not routinely precipitate death. Bone marrow involvement at initial staging has been reported in 6% to 28% of patients and is also associated with advanced skin and nodal disease.58,59

Sézary Syndrome Sézary syndrome (SS) is defined as erythroderma plus evidence of malignant circulating T cells that satisfy any of the five criteria listed in Table 79-3.60 For the purposes of these criteria, the Sézary cell is defined as “any atypical lymphocyte with [a] moderately to highly infolded or grooved nucleus”60 (see Figure 79-2, F). Clinical findings may include edema and tumorous involvement of the face leading to leonine facies, severe fissures of the palms and soles, intense pruritus, and cutaneous pain. Currently, no consensus has emerged

DISEASE SITES

Lymph node involvement is present in 15% of newly diagnosed patients and is associated with advanced cutaneous disease.55 Nodes are typically non-tender, mobile, and measure from 1 cm to 4 cm, though typically a size threshold of 1.5 cm is considered clinically abnormal, and biopsy is recommended to evaluate nodes that reach this threshold.56 Bulky adenopathy is uncommon.

TABLE 79-3 

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regarding the pathologic link between MF and SS. However, some clinical observations help to elucidate the relationship between these two disorders. SS often arises de novo without antecedent MF. MF may also evolve to an erythrodermic stage with concomitant hematologic findings that satisfy a diagnosis of SS.

VARIANTS OF MYCOSIS FUNGOIDES The progression from subtle patches to indurated plaques, cutaneous tumors, and erythroderma represents classical, so called “Alibert-Bazin” MF. According to the EORTC classification, variants such as bullous and hyper- or hypopigmented MF manifest similar clinical behavior and should not be considered separately from classical MF.2 Several variants sharing some clinical and pathologic features with MF have been described.

Folliculotropic Mycosis Fungoides This entity presents with follicular papules, comedolike lesions, milialike lesions, patches, and plaques, all of which may produce alopecia.1,41 Although it typically involves the head and neck, any skin site may be affected.2 Pathologically, atypical lymphocytes invade follicles and may deposit acid mucopolysaccharides in the pilosebaceous units. Folliculotropic MF, often presenting with thick plaques, tends to be refractory to topical treatments such as PUVA and nitrogen mustard, and risk of relapse after treatment with TSEBT appears to be higher when compared to patients with classical MF.61 Five-year disease-specific survival is approximately 80%41 but only 41% by 15 years.62

Pagetoid Reticulosis and Woringer–Kolopp Disease Pagetoid reticulosis, also known as Woringer–Kolopp disease, typically presents as slow-growing, hyperkeratotic or psoriasiform, localized patch or plaque involving a distal extremity. Pathologically, an abundant epidermotropic infiltrate composed of atypical large lymphocytes is noted, along with pagetoid spread of individual lymphocytes interspersed among keratinocytes. Benign-appearing small lymphocytes are found in the upper dermis.1 The prognosis for localized pagetoid reticulosis is excellent with either surgery or radiotherapy, and disease-related deaths have not been reported.2,41 Ketron– Goodman type is a disseminated, more aggressive cutaneous lymphoproliferative disorder that histologically resembles localized pagetoid reticulosis.

Granulomatous Slack Skin This rare variant presents with lax skin in the axillae, neck, breasts, and inguinal regions. Histological features include epithelioid or giant cell dermal granulomas and associated destruction of elastin fibers.2 Notably, Hodgkin lymphoma has been associated with granulomatous slack skin in roughly one third of reported cases.63 Because of its rarity, optimal treatment has not been established.

RELATED CUTANEOUS T-CELL LYMPHOPROLIFERATIVE DISORDERS In addition to MF and its variants, several other distinct cutaneous T-cell lymphoproliferative disorders have been described. Their clinical and pathologic features and optimal therapy is briefly reviewed here.

Primary Cutaneous Anaplastic Large Cell Lymphoma/CD30+ Large Cell CTCL This entity typically presents as a red or flesh-colored nodule or tumor that frequently ulcerates. Histopathology shows sheets of CD30+ large lymphocytes without epidermotropism. In contrast to systemic CD30+ anaplastic large cell lymphoma, overexpression of anaplastic lymphoma kinase (ALK) is not found in primary cutaneous CD30+ large cell lymphoma. Patients with localized disease are typically treated with radiotherapy alone, and prognosis is excellent with a 5-year disease-specific survival of approximately 90% to 95%.2,64,65 Treatment using anti-CD30 monoclonal antibody may be considered, but is typically not an upfront strategy.

Lymphomatoid Papulosis Lymphomatoid papulosis (LyP) presents with grouped erythematous or violaceous papules or nodules at different stages of development. Lesions typically resolve spontaneously within 2 to 8 weeks, but scarring is common.66 Three different histologic subtypes have been described, with types A and C consisting of malignant CD30+ T cells, often with an extensive inflammatory infiltrate, and type B simulating classical plaquestage MF. For type C lesions, discrimination between LyP and CD30+ large cell lymphoma may be difficult on histologic grounds, and assessment of the clinical context may be required to ensure the proper diagnosis.2 Although cytologically malignant, it should be emphasized that LyP is clinically benign with a 5-year survival of 100%.2,41,64 Thus, neither aggressive chemotherapy nor radiotherapy is indicated.67 Treatment options include PUVA or low-dose methotrexate, but neither is considered curative. In the long term, at least 15% to 20% of patients with LyP will develop a second malignancy, most commonly MF, CD30+ large cell lymphoma, or Hodgkin’s disease.67,68 In patients undergoing TSEBT for MF, a history of LyP is associated with an increased risk of relapse.61

Adult T-Cell Lymphoma/Leukemia Adult T-cell Lymphoma/Leukemia (ATLL) develops in 2% to 4% of individuals infected with human T-cell lymphotrophic virus type I (HTLV-I), a retrovirus endemic in southern Japan and the Caribbean.1,66,69,70 Skin findings are present in up to 60% of patients with ATLL and strongly resemble those of MF, including plaques, tumors, and erythroderma. The characteristic immunophenotype is CD2+ CD3+ CD4+ CD5+ CD7− CD8− and the malignant cells strongly express the high affinity interleukin-2 receptor (CD25, CD122, and CD132). Clinical features vary from an acute form presenting with B symptoms, hypercalcemia, metabolic bone disease, hepatosplenomegaly, generalized adenopathy, and leukemic infiltration to a smoldering or chronic form presenting with skin infiltration and little or no systemic involvement. Although patients often respond to conventional chemotherapy, long-term survival is rare. Other agents include denileukin diftitox71 and interferon-α in combination with zidovudine.72 In appropriately selected candidates, allogeneic stem-cell transplantation may be considered, though evaluation of efficacy in this scenario is ongoing.73

Subcutaneous Panniculitis-Like T-cell Lymphoma (α/β type) In prior years, subcutaneous panniculitis-like T-cell lymphoma was thought to run two markedly different clinical courses—an indolent course and an aggressive course. Recently, molecular studies have indicated that the indolent form of subcutaneous panniculitis-like T-cell lymphoma is



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caused by CD8+ T cells that express the α/β T-cell receptor. This entity typically presents with subcutaneous nodules or plaques involving the legs or trunk and has a 5-year diseasespecific survival of approximately 82%.41 In contrast, the more aggressive form of subcutaneous panniculitis-like T-cell lymphoma is caused by CD8− T cells that express the γ/δ T-cell receptor, and is now classified as cutaneous γ/δ T-cell lymphoma in the updated WHO–EORTC system.41 This entity is often fatal and complicated by hemophagocytic syndrome. Treatment for the α/β type is often observation while treatment for the γ/γ type includes combination chemotherapy and possibly cyclosporine.1,2

PROGNOSIS AND STAGING

SKIN T1 T2 T3 T4

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TNMB Classification for Mycosis Fungoides/Sézary Syndrome, Based on the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) Revision

Limited patches, papules, or plaques covering <10% of the skin surface Patches, papules, or plaques covering ≥10% of the skin surface One or more tumors (≥1 cm) Confluence of erythema covering ≥80% body surface area

NODE N0

No clinically abnormal peripheral lymph nodes; biopsy not required N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2   N1a Clone negative   N1b Clone positive N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3   N2a Clone negative   N2b Clone positive N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3-4 or NCI LN4; clone positive or negative Nx Clinically abnormal peripheral lymph nodes; no histologic confirmation VISCERAL M0 No visceral organ involvement M1 Visceral involvement (must have pathology confirmation and organ involved should be specified) BLOOD B0 Absence of atypical circulating cells: ≤5% of peripheral blood lymphocytes are atypical (Sézary) cells||   B0a Clone negative   B0b Clone positive B1 Atypical circulating cells, low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria of B2   B1a Clone negative   B1b Clone positive B2 Atypical circulating cells, high blood tumor burden: ≥1000/µL Sézary cells|| with positive clone Adapted from Abeloff MD, Armitage JO, Niederhuber JE, et al: Abeloff’s Clinical Oncology, ed 5, T107-4, 2014.

Data from Stanford showed that patients with limited patches and plaques (stage IA, T1 N0 M0) experience 10-year survival similar to a matched control population. In contrast, median survival for patients with extensive patches and plaques (T2), tumors (T3), and erythroderma (T4), was 11, 3.2, and 4.6 years, respectively.81 Patients with either pathologically documented lymph node involvement or visceral involvement experienced a median survival of roughly one year.55 Another multiinstitutional study showed that survival is also related to the pattern and extent of lymph node involvement, but the prognostic strength of nodal status is debated.82

DISEASE SITES

Early (skin involvement characterized by patches and plaques, regardless of nodal or blood involvement) versus advanced (involvement with tumor, high-grade nodal, or visceral organ) stage is the primary predictor of prognosis. Treatment strategy should be planned accordingly.56 Skin is systematically assessed and scored using the modified Severity Weighted Assessment Tool (mSWAT), which not only quantifies the percent body surface area (BSA) involved with patch, plaque, or tumor, but further weights the total score by the type of lesion (patch = 1, plaque = 2, tumor = 4).74,75 Various staging systems exist and have evolved over time. Previously, the American Joint Committee on Cancer (AJCC) staging system for MF identified extent and character of skin lesions, extracutaneous disease, and leukemic transformation.76 Shortcomings of this system included difficulty in assigning T stage for patients on the border between T1 and T2; failure to discriminate between the prognosis of patients with extensive patches as compared to extensive plaques; similarity in prognosis between patients with tumors and erythroderma; the questionable prognostic relevance of enlarged, pathologically uninvolved lymph nodes; and the rarity of the N2 descriptor because biopsies of nonpalpable lymph nodes are seldom performed.77,78 To address these shortcomings, the EORTC, in conjunction with the International Society for Cutaneous Lymphoma (ISCL), proposed a revised TNMB staging system (Tables 79-4 and 79-5) addressing both MF and SS and incorporating greater detail on skin and nodal involvement and also considering clonal and tumor burden in the blood.79 Detailed definitions and descriptions of the extent and character of skin as well as nodal and visceral disease are provided to provide more systematic classification. In addition to quantification of body surface involvement, pigmentation, scale, crusting, and poikiloderma are additional important features of skin classification. On histology, folliculotropism, large-cell transformation, CD30+ or CD30−, and ulceration are notable. T-cell clonality requires PCR or Southern blot analysis of the T-cell receptor gene.79 The TNMB system has been increasingly adapted into treatment algorithms and provides a systematic approach to prospectively compare longitudinal changes in tumor burden, and hence the clinical effectiveness, of various therapies.56,75,80 Furthermore, it provides a rational stratification of patients into “early” versus “advanced” stages, an initial categorization that drives therapeutic decision making. T stage continues to be a strong predictor of outcome. Data from a cohort of 468 patients with newly diagnosed MF evaluated at Stanford University are presented in Table 79-6.55 More than 60% of patients presented with patches or plaques without nodal or visceral disease. Such patients rarely developed disseminated disease, even at 20 years of follow up. In contrast, 50% to 60% of patients presenting with tumors or erythroderma will develop extracutaneous disease.

TABLE 79-4 

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TABLE 79-7 

Staging Classification for Mycosis Fungoides T1 N0 M0, any B T2 N0 M0, any B T1-2 N1-2 M0, any B T3 N0-2 M0, any B T4 N0-2 M0 B0 T4 N0-2 M0 B1 T1-4 N0-2 M0 B2 T1-4 N3 M0 B0-2 T1-4 N0-3 M1 B0-2

Adapted from Abeloff MD, Armitage JO, Niederhuber JE, et al: Abeloff’s Clinical Oncology, ed 5, T107-4, 2014.

TABLE 79-6 

T1 T2 T3 T4

Initial Stage and Natural History of 468 Patients with Mycosis Fungoides Evaluated at Stanford University at the Time of Initial Diagnosis

T Stage at Initial Presentation (%)

Percentage with Nodal or Visceral Involvement on Initial Diagnosis as Function of T Category

Percentage Developing Nodal or Visceral Involvement Over 20 Years as Function of T Category

28 36 20 16

0 2 13 25

0 10 36 41

Data from de Coninck EC, Kim YH, Varghese A, et al: Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides. J Clin Oncol 19:779–784, 2001.

For example, partial or complete effacement of nodal architecture by malignant lymphocytes conferred a median survival to 2.3 years. In contrast, lymph nodes with aggregates of atypical lymphocytes but preserved nodal architecture resulted in a median survival of 6 years and lymph nodes with only dermatopathic changes or few atypical lymphocytes resulted in a median survival of 9 years. Other factors that may herald a poor prognosis include age ≥60,83 elevated LDH,83 elevated soluble interleukin-2 receptor levels,40 a low percentage of CD8+ tumor infiltrating lymphocytes,84 extent of skin involvement in those with T3 disease,85 T-cell clonality within the cutaneous infiltrate detected by PCR,86,87 an identical T-cell clone in the skin and peripheral blood,88 and T-cell clonality in dermatopathic lymph nodes.89 For those patients with transformation to a large-cell variant of MF, median survival ranges from 19 months to 36 months.53,90 Factors predictive of poor survival after transformation include short interval between diagnosis of MF and transformation (< 2 years), and the presence of stages IIB to IV disease.53

PATIENT EVALUATION All patients should have a thorough history performed by the evaluating dermatologists, radiation oncologists, and any other consultants (Table 79-7). Careful attention should be given to the duration, change in appearance, and distribution of the eruption according to the patient. Inquiry related to a

Recommended Workup for Patients with Suspected Mycosis Fungoides

HISTORY AND PHYSICAL EXAMINATION WITH ATTENTION TO SKIN, LYMPH NODES, LIVER, AND SPLEEN Skin Biopsy with Attention to • Histologic findings • Epidermal lymphocytes with medium to large, extremely convoluted nuclei • Haloed epidermal lymphocytes • Pautrier’s microabscesses • Immunophenotype • Classically: CD2+ CD3+ CD4+ CD5+ CD45RO+ CD8− CD30− • Rarely, CD4− CD3+ CD8+ • PCR for T-cell receptor gene rearrangement Biopsy of Enlarged Lymph Nodes with Attention to • Histologic findings, both number of atypical lymphocytes and disruption of nodal architecture • In dermatopathic nodes, consider PCR for T-cell clonality and immunophenotyping to rule out occult involvement Evaluation of Blood • CBC with manual differential, liver function tests, and serum chemistries for all patients • In those with suspected stages IIB to IV disease • LDH, soluble interleukin-2 receptor • Flow cytometry for CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD45RO • PCR for T-cell receptor gene rearrangement Imaging • Posteroanterior and lateral chest radiograph for stage IA • CT of (neck), chest, abdomen, and pelvis for suspected stages IB to IV • Consider PET/CT scanning for patients with suspected stages IB to IV CBC, Complete blood count; CT, computed tomography; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; PET, positron emission tomography.

history of pruritus, pain, exfoliation, fissures, bullae, and perineal discomfort should be made. Previous diagnostic considerations, procedures, and therapies should be recorded in detail to establish temporal relationships. The clinical interview, along with the examination, are the two most important aspects of the workup because they can help exclude other diagnoses and establish whether the narrative and findings are consistent with a diagnosis of MF.

Physical Examination All patients should undergo a complete physical examination with special attention to the skin surface, lymph nodes, and abdomen for organomegaly. Specific notations should be made of the number, location, character, and distribution of cutaneous lesions and the presence of ulceration. The percentage of cutaneous involvement should also be quantified. Body surface area (BSA) along with a weighted severity score provides a systematic approach to assessing skin involvement.75 Other non-MF cutaneous findings such as previous excision sites, pigmented lesions, or any findings consistent with other skin malignancy should be noted. Adenopathy should be carefully documented with respect to location, size (particularly ≥1.5 cm), consistency, mobility, and discomfort on palpation. Photographs of the skin for baseline documentation should be considered.



Diagnostic Testing Pathology A biopsy of the most indurated area of involved skin should be performed for hematoxylin and eosin evaluation. Material for immunophenotyping (including at least CD2, CD3, CD4, CD5, CD7, CD8, and a B-cell marker such as CD20 or consideration of CD30) and T-cell receptor gene rearrangement should be obtained. Excisional biopsy of adenopathy is recommended and tissue should be submitted for the same pathologic studies. Needle aspiration of nodes is not recommended. Routine bone marrow examination is generally not required but may be considered in patients with blood or other visceral involvement. Bone marrow involvement at initial staging has been reported in 6% to 28% of patients and is associated with advanced skin and nodal disease.58,59 However, it is unclear that marrow involvement is an independent predictor of outcome.59,83 Furthermore, although a clonal T-cell population within the marrow is identified in 75% of patients with identical skin and peripheral blood T-cell clones, this finding does not appear to alter prognosis.58

Hematology and Chemistry A complete blood count including differential and smear in addition to serum chemistries (to include renal and hepatic function) and LDH should be obtained before initiation of therapy. For patients with stages IIB to IV disease, serum levels of soluble interleukin-2 receptor and LDH reflect overall tumor burden and could be used to assess response to therapy, although this measure is not an established standard for follow-up. A thorough examination of the peripheral blood for evidence of malignant T cells is indicated for those with stages IIB to IV MF, and may be considered for those with stages IA to IIA. Peripheral blood flow cytometry should be performed to assess expression of CD2, CD3, CD4, CD5, CD7, CD8, CD20, and CD45RO. Findings suggestive of blood involvement include an elevated CD4/CD8 ratio (normal range 0.5 to 3.5), or an expanded population of CD4+CD7−, CD4+CD26− or CD45RO+ lymphocytes.60 If initially abnormal, findings on peripheral blood flow cytometry should be followed to assess response to therapy. If flow cytometry is unremarkable, peripheral blood PCR for T-cell receptor gene rearrangement should be considered. PCR reveals a clonal T-cell population identical to that found in the cutaneous infiltrate in 40% of patients with erythroderma and 14% of patients with patches, plaques, or tumors.50

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transformation, excisional biopsy should be strongly considered for selected abnormal lymph nodes, which are radiographically identified.

PRIMARY THERAPY Because MF is a disease of cutaneous (i.e., skin-homing) lymphocytes, therapy is quite distinct from that of nodal lymphomas. A treatment algorithm for early versus advanced MF is presented in Table 79-8.93 Multiple treatment options are listed, which reflects the increasing variety of available therapies, heterogeneity in institutional treatment preferences, and the paucity of randomized trials directly comparing different treatment modalities. In general, however, the treatment approach to early disease involves selecting sequential skin-directed therapies, each based on the expectation to provide the greatest duration of response with the least toxicity, including radiation therapy as an option. Once the disease trajectory proves to be increasingly relapsing or refractory, repeat radiation therapy, systemic, or combined therapies as the second line may be considered. However, allogeneic stem-cell transplant has evolved as a promising therapy for long-term durable control or even cure. Transplant is appropriate for patients who have

TABLE 79-8 

Treatment Recommendations, Early and Advanced Mycosis Fungoides/Sézary Syndrome

Initial Treatment

Early (IA, IB, IIA)

Topical corticosteroids PUVA UVB Topical HN2 Local radiotherapy TSEBT

Advanced (IIB)

Interferon-α TSEBT PUVA

Advanced (III to IV)

Interferon-α PUVA PUVA + Interferon-α TSEBT

Treatment for Relapsed or Refractory Disease Retinoids, rexinoids Interferon-α Low-dose MTX HDACi Denileukin difitox Localized, superficial radiotherapy TSEBT Evaluate for allogeneic stem cell transplant with refractory disease Retinoids, rexinoids Interferon-α alone PUVA + interferon-α HDACi Denileukin difitox Novel agents Chemotherapy Evaluate for allogeneic stem-cell transplant with refractory disease Rexinoids HDACi Denileukin difitox Alemtuzamab or other monoclonal antibody Novel agents Chemotherapy TSEBT Evaluate for allogeneic stem cell transplant with refractory disease

BCNU, Bischlorethylnitrosourea; HDACi, histone deacetylase inhibitors, HN2, mechlorethamine; MTX, methotrexate; PUVA, psoralen plus ultraviolet A; TSEBT, total skin electron beam therapy; UVB, ultraviolet B.

DISEASE SITES

Stage

Diagnostic Imaging A minimum of chest radiography should be completed for stage IA disease. CT of the chest, abdomen, and pelvis (and neck as clinically indicated) should be considered for patients with higher stage disease, particularly patients with tumors, erythroderma, or nodal involvement.91 The role of fluorodeoxyglucose-positron emission tomography (FDGPET) is being refined but may be beneficial for staging patients with advanced skin disease; for example, Stanford University investigators reported that CT alone identified pathologic adenopathy by size criteria in only 5 of 13 patients, whereas the addition of PET identified hypermetabolic adenopathy in 13 of 13 patients. The standardized uptake value (SUV) of the FDG correlated with the extent of nodal involvement, with the highest SUVs noted in patients with complete nodal effacement and large cell transformation.92 Therefore, PET-CT may be considered for patients with ≥T2 disease, palpable adenopathy, abnormal laboratory studies, or patients with large cell transformed or folliculotropic MF.80 To confirm nodal involvement and document the presence or absence of

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failed multiple primary therapies and demonstrate a progressive course with decreasing durability of response, or who have undergone large cell transformation. Notably, however, this treatment strategy is being used selectively in appropriately selected candidate (in general, younger patients with good performance status).94-96 The available treatments for advanced disease are similar to early disease, but systemic therapy should be considered sooner in the disease trajectory given the systemic involvement of disease. At the same time, cutaneous lesions and symptoms remain problematic, and therefore maintaining a skin-directed regimen is also important, and therefore the treatment approach requires multimodality considerations. Novel agents may be considered as second-line therapy particularly for this group with a poorer prognosis compared with patients presenting with early-stage disease, and stemcell transplant should also be explored as a possible treatment option in this group. For patients with disease limited to the skin, topical therapy alone produces high rates of remission and even cure. Topical therapies include corticosteroids, mechlorethamine (nitrogen mustard), carmustine (BCNU), bexarotene gel (rexinoids), PUVA, ultraviolet B (UVB), and either localized or total skin electron radiotherapy. For patients with localized unilesional MF, topical therapies alone produce long-term disease-free survival rates in excess of 85%.21-23 For those with more than one patch or plaque but with less than 10% body surface area involvement (T1 N0 and T1 N1), topical therapies alone produce long-term disease-free survival rates ranging from 30% to 50%. For patients with more extensive patches or plaques, topical therapies may produce remission, but long-term cure is unlikely. Such patients should receive intensive topical therapy to induce a complete remission followed by less intensive adjuvant topical therapy to sustain a remission.97,98 Those with tumors or erythroderma experience severe cutaneous symptoms and are at high risk for extracutaneous dissemination. Of all the topical therapies, TSEBT is associated with the highest rates of complete response for this patient subgroup.98-100 Therefore, it is recommended that TSEBT be administered to induce cutaneous remission and that adjuvant systemic or topical therapy be administered to sustain remission. Systemic therapies include interferon, retinoids, oral bexarotene, denileukin diftitox, vorinostat or other histone deacetylase inhibitors, and extracorporeal photochemotherapy (photopheresis). Cytotoxic chemotherapies considered for this group include liposomal doxorubicin, gemcitabine, and low-dose methotrexate. In the following section, we first discuss all nonradiation topical therapies and then discuss the various systemic therapies. Finally, we discuss the clinical data for radiation and qualitatively compare this to clinical data for various topical and systemic therapies.

Skin-Directed Therapy Topical Corticosteroids High potency topical or intralesional glucocorticoids are an important component in the treatment of MF because of their ability to alleviate cutaneous symptoms and induce lesion regression. Typically, corticosteroids are applied to active lesions only, as widespread application can induce reversible depression of serum cortisol in 10% to 15% of patients.101 Persistent application can lead to skin atrophy.

Mechlorethamine Topical mechlorethamine hydrochloride (HN2), also known as nitrogen mustard, is an alkylating agent with proven activity

in the treatment of MF patches and plaques. Mechlorethamine is typically applied daily and continued for at least 6 months after complete response.77 Cutaneous intolerance, manifested by erythema and pruritus, occurs in roughly 50% of patients treated with aqueous HN2102 but is reduced to less than 10% in patients treated with HN2 dissolved in ointment such as Aquaphor.77 Other cutaneous side effects of HN2 may include xerosis, hyperpigmentation, and rarely, bullous reactions, urticaria, and Stevens–Johnson syndrome.102 Bone marrow suppression is not observed because of minimal systemic absorption. The carcinogenicity of HN2 remains debated, as one series reported no increased risk of secondary skin cancers in patients treated with HN2 monotherapy,77 whereas another series reported an eightfold increase in the risk of nonmelanoma skin cancers attributable to HN2 monotherapy.103 HN2 may also potentiate the carcinogenicity of other topical therapies such as total skin radiation or PUVA.104

Carmustine Topical carmustine (BCNU) is another alkylating agent with activity in MF. Because of systemic absorption that may produce bone marrow suppression, the drug should be applied to no more than 10% of the body surface area, duration of treatment should be limited to 4 months, and complete blood counts should be monitored. Cutaneous hypersensitivity is uncommon (7% in one series) but chronic skin telangiectasis and hyperpigmentation may occur.105

Topical Rexinoids Bexarotene belongs to a new class of agents called rexinoids that bind to the retinoid X receptor, resulting in transcription of various genes that control cellular differentiation and proliferation.106 Topical bexarotene gel was recently approved after Phase I and II trials demonstrated a 44% to 54% response rate in refractory cutaneous MF.107,108 Most patients will develop an irritant dermatitis and thus require close observation and dose titration. Because of its irritant effects, bexarotene gel is not indicated for patients with more than 15% body surface area involvement. As with systemic retinoids, bexarotene in both its topical and systemic forms should be avoided in pregnant women as a result of possible teratogenicity.

PUVA and Ultraviolet B Ultraviolet light used in the treatment of MF includes UVB (wavelength 320 nm to 290 nm), narrow-band UVB (wavelength 311 nm), or psoralen plus UVA (PUVA, wavelength 400 nm to 320 nm). Because UVB has limited penetration, its efficacy is limited to thin patches. PUVA penetrates more deeply and will effectively treat some plaque lesions. PUVA requires ingestion of a photochemotherapeutic agent, 8-methoxypsoralen, before UVA exposure. UVA activates 8-methoxypsoralen, resulting in DNA cross-linking and apoptotic cell death.109 Both PUVA and UVB are initially administered 2 to 3 days a week as the light dose is gradually increased. Once a complete response has been achieved, treatment frequency may be gradually reduced to once every 2 to 4 weeks. Ultraviolet treatments may be continued on a maintenance basis for several years, provided the patient remains in complete response with treatment administered once every 4 to 8 weeks. Acute side effects of PUVA and UVB include skin erythema that may be painful, hyperpigmentation, xerosis, pruritus, and blistering. Eye goggles are used to decrease the risk of cataract formation. One side effect unique to PUVA is nausea and vomiting after ingestion of 8-methoxypsoralen (8-MOP). This



may be avoided by substituting 8-MOP for either a topical “psoralen bath” or 5-methoxypsoralen, a nonemetogenic analog that is currently available in Europe.110 Long-term toxicity includes photoaging and increased risk of melanoma and nonmelanoma skin cancers.111,112

Systemic Therapy Interferon Interferon-α-2a (IFN-α) is an effective agent, particularly for patch and plaque disease, likely as a result of a direct antitumor effect or immunomodulation.113 IFN-α has been used alone113,114 or in combination with retinoids, PUVA,115-117 and extracorporeal photopheresis.118 A recent prospective trial showed a benefit from combining IFN-α with PUVA as compared to IFN-α plus a retinoid, but it is not clear that combination therapy is clearly superior to single-agent therapy.119 Toxicity may include flulike symptoms, psychiatric disturbances including depression and confusion, elevated transaminases, leukopenia, thrombocytopenia, proteinuria, and myelopathy.116,117 Despite these side effects, in a recent Phase II trial of IFN-α and PUVA, only 8% of patients withdrew as a result of toxicity.117

Retinoids Oral retinoids such as isotretinoin and acitretin influence cellular differentiation and may be particularly beneficial in the treatment of folliculotropic MF. Retinoids can be safely combined with other therapies such as PUVA,120 IFN-α, and TSEBT.121 Side effects include photosensitivity, xerosis, myalgias, arthralgias, headaches, impaired night vision, corneal opacities, teratogenicity, elevated transaminases, hyperlipidemia, and pancreatitis.81

Rexinoids

Denileukin Diftitox Denileukin diftitox is a recombinant fusion protein that contains portions of interleukin-2 and diphtheria toxin and has proven activity in refractory MF, stages IB to IVA.74 It selectively targets T cells that express the high affinity interleukin-2 receptor (a complex of CD25, CD122, and CD132), resulting in endocytosis of diphtheria toxin, inhibition of protein synthesis, and cell death. In the pivotal Phase III clinical trial leading to its approval, only patients with neoplastic T cells expressing

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the high affinity interleukin-2 receptor received denileukin diftitox, and it is currently controversial whether or not patients without significant expression of the high affinity interleukin-2 receptor benefit from denileukin diftitox.124 Recently published results reported 44% overall response rate, including 10% complete response and 34% partial response. This compared with 16% in the placebo group. Median time to progression exceeded 2 years in the treated group. In the randomized trial, the response rate was higher in the 18 µg/ kg group versus the 9 µg/kg group.125 Denileukin diftitox is typically administered by a 30-minute venous infusion given on 5 consecutive days and repeated every 3 weeks for up to eight cycles. Toxicities commonly encountered in the Phase III clinical trial of denileukin diftitox included acute hypersensitivity reactions including dyspnea, back pain, hypotension, and chest pain occurred in 60% of patients. Furthermore, a vascular leak syndrome characterized by hypotension, hypoalbuminemia, and edema was encountered in 25% of patients. Other toxicities may include constitutional symptoms, thrombotic events, infections, transaminase elevations, renal impairment, and lymphopenia. In total, 21% of the patients in this trial withdrew because of adverse events.74 Subsequent investigations have suggested that pretreatment with corticosteroids substantially reduces the risk of acute toxicity.126

Histone Deacetylase Inhibitors Vorinostat is a histone deacetylase inhibitor (HDAC) approved for use in patients with MF who have progressive, persistent, or recurrent disease following treatment with at least two prior systemic therapies. HDAC inhibitors increase accumulation of acetylated histones, resulting in decreased availability of nuclear DNA to bind to transcription factors. The decrease in transcription lowers intracellular protein levels, ultimately producing cell cycle arrest and apoptosis. In preclinical studies of MF cell lines, vorinostat has been shown to induce apoptosis and downregulate stat6.127 Phase II clinical studies have reported clinical response rates of 25% to 30% in pretreated patients, with a modest median response duration of 15 weeks to 26 weeks.128,129 Common toxicities include diarrhea, nausea, fatigue, and anorexia. Romidepsin is another approved HDAC inhibitor for relapsed/refractory CTCL. Initial single-arm studies suggest that the duration of response in treated patients is potentially even more sustained, with several patients who achieved response lasting longer than 3 years.130,131 Other potential novel HDAC inhibitors include belinostat and panobinostat.132

Other Novel Agents Studies are planned or ongoing to evaluate the role of monoclonal antibodies, purine nucleoside phosphorylase inhibitors, proteasome inhibitors, immunomodulatory drugs, synthetic oligodeoxynucleotides, fusion toxins, protein kinase C inhibitors, Toll-like receptor agonists, and antifolate agents. However, though feasibility testing for these agents is ongoing, the efficacy and role of these agents are not yet established.

Extracorporeal Photochemotherapy Extracorporeal photochemotherapy (EP), also known as photopheresis, is a novel immune therapy that has shown activity in the treatment of erythrodermic MF.109,133 Peripheral blood leukocytes are harvested by leukapheresis, mixed with 8-methoxypsoralen, exposed to 2 Joules/cm2 of ultraviolet A, and then reinfused into the patient. This results in DNA crosslinking and gradual apoptotic death of the circulating MF cells that were exposed to psoralen + UVA. For unclear reasons, monocytes are resistant to the apoptotic effects of EP, but, instead are stimulated to become immature antigen presenting

DISEASE SITES

Oral bexarotene has been approved by the Food and Drug Administration for use in all stages of treatment refractory MF.122,123 Preliminary data suggest that bexarotene can be combined safely with other therapies including PUVA, extracorporeal photopheresis, IFN-α, and HN2. Hypertriglyceridemia, the most common adverse event, occurs in 80% of treated patients and may result in reversible pancreatitis if triglyceride levels exceed 800 mg/dL.106 Therefore, atorvastatin or fenofibrate should be initiated if triglyceride levels exceed 350 mg/dL. Gemfibrozil increases serum bexarotene concentrations, resulting in a paradoxical elevation of triglycerides, and should therefore be avoided.106 Another side effect, central hypothyroidism, affects roughly 75% of patients but responds well to levothyroxine and resolves when treatment is discontinued.106 Patients taking bexarotene therefore require monitoring of estimated free thyroxine, as levels of thyroid-stimulating hormone (TSH) will always be low. Other side effects include self-limited headaches, mild neutropenia, mild transaminase elevations, skin peeling, and pruritus. In the Phases II to III trial of oral bexarotene for advanced, refractory cutaneous T-cell lymphoma, only 10% of patients receiving the optimal dose withdrew as a result of an adverse event.122

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dendritic cells because of the physical process of leukapheresis. Therefore, once treated leukocytes are reinfused into bloodstream, activated dendritic cells may phagocytose remnants of the apoptotic MF cells, present their antigens on major histocompatibility class I, and stimulate expansion of antitumor CD8+ T cells.134 EP is typically administered on 2 consecutive days every 4 weeks, although the frequency may be increased in patients with extensive disease.135 For patients who achieve a complete response, therapy should be maintained for roughly 6 months and then gradually tapered. In general, EP is well tolerated, although hypotension, arrhythmias, and heart failure may occur because of fluid shifts. Patients with a history of cardiac disease therefore require close monitoring.133 EP has been safely combined with IFN-α and TSEBT.118,136,137

Chemotherapy Systemic chemotherapy is typically reserved for refractory cutaneous disease, visceral disease, or large-cell transformation. Chemotherapy is not typically used in the initial management of patients with MF because a randomized Phase III trial comparing concurrent TSEBT and systemic chemotherapy to sequential topical therapy failed to show an improvement in disease-free or overall survival.138 For advanced, relapsed/ refractory disease, the durability of response may be limited. For patients who may benefit from chemotherapy, two main strategies exist. The first relies on oral agents such as methotrexate,139 etoposide, or chlorambucil. This strategy avoids the need for central venous lines, which are associated with a high risk of infection because of frequent bacteremia caused by open skin lesions. The second strategy relies on intravenously administered chemotherapy. One exciting new prospect is pegylated liposomal doxorubicin, an agent that tends to remain intravascular but will extravasate into the inflamed lesional skin of MF. A pilot study conducted on 34 patients with CTCL reported complete response in 15 patients, partial response in 15 patients, and six severe adverse events.140 Another notable agent is the nucleoside analog gemcitabine, which has been shown to induce complete response rates of approximately 10% and overall response rates of 70% without an increased risk of infection.141 Attention has also focused on purine analogs such as fludarabine, 2′-deoxycoformycin, and 2-chlorodeoxyadenosine. However, clinical trials of these agents have produced response rates ranging from only 28% to 51% and have documented substantial toxicity, including myelosuppression, infection, and pulmonary dysfunction.142-145 Other agents with activity in MF include the lipophilic antifolate trimetrexate146; 5-fluorouracil; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)147; etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH); cisplatin; etoposide; bleomycin; vinblastine141; and though early results are limited, temozolamide.148

High-Dose Chemotherapy with Autologous or Allogeneic Bone Marrow Transplant Increasing experience has been reported using high-dose chemotherapy with either autologous or allogeneic transplant in the treatment of advanced or refractory MF. Autologous stemcell rescue has resulted in several complete responses; however, relapses within 1 year are the rule rather than the exception.149-151 In contrast, myeloablative or nonmyeloablative conditioning regimens with allogeneic transplant may result in prolonged disease-free survival. One series of three patients treated with cytoreductive chemotherapy and total body irradiation (TBI) found that two of the three patients remained diseasefree at 4.5 years and 15 months after transplant. The third patient recurred after allogeneic transplant but developed a second complete response on withdrawal of prophylactic

cyclosporine, suggesting a graft-versus-tumor effect.152,153 In another series, six of eight patients with heavily pretreated, refractory MF who underwent allogeneic transplant with either TBI or non-TBI preparative regimens were alive without evidence of lymphoma at a median of 56 months posttransplant, but two deaths secondary to toxicity were reported.154 Nonmyeloablative transplants have also been reported, with one series reporting clearance of clonal T cells and durable complete remissions in three out of three patients, although one died from infectious complications.155 More recent series report significant improvements in overall survival and progression-free survival, particularly in patients who received matched related transplantation. Another recent experience reported 68% overall response rate and 58% complete response rate using debulking with total skin electron beam and reduced conditioning regimen. Bacterial sepsis was a major complication reported in this series.96 Overall, cumulative evidence supports the important role of graft-versus-lymphoma effect in producing durable remissions, lasting even up to several years in some cases.94,95,156 Collectively, these experiences strongly support the use of allogeneic transplant for younger patients with treatmentrefractory, advanced MF.

Radiotherapy Radiation is the most effective single modality in the treatment of MF8 and plays an important role in the treatment of localized or disseminated cutaneous disease and in the palliation of skin and nodal and visceral metastases.

Dose In general, a dose response has been reported both for radiation of single MF lesions and for TSEBT, and given that evidence, doses >30 Gy have served as the historical standard.99 More recently, however, lower doses for TSEBT, as low as 12 Gy, have been considered. The clinical decision for an individual patient on planned dose for a single course of therapy concomitantly considers two issues: first, the minimum dose that produces a clinical response for a single patient may be somewhat idiosyncratic; and secondly, patients are expected to require repeat skin-directed therapies including repeat courses of radiation, with chronic relapses over time. In an earlier study of 110 lesions from 14 patients with at least of 1 year follow-up, Cotter et al reported an infield recurrence rate of 42% for those treated to a total dose ≤10 Gy, 32% for 10.01 Gy to 20 Gy, 21% for 20.01 Gy to 30 Gy, and 0% for >30 Gy.157 In a study of 30 lesions from patients with stage IA MF treated with localized radiotherapy, Wilson et al reported local failure in 20% (4 of 20 patients) treated with ≤20 Gy, compared with 0% (0 of 10 patients) treated with >20 Gy.22 Kim et al treated different lesions from the same patient with various total doses and fraction sizes, finding that division of the total dose into two fractions separated by 1 or 7 days did not alter local control.158 This suggests that the malignant cells of MF have minimal ability to execute sublethal damage repair and provides justification for using low daily fraction sizes to minimize normal tissue toxicity without sacrificing local control. Collectively, these experiences initially suggested that a durable response required total doses of 20 Gy to 30 Gy. To spare normal tissue toxicity and to ensure that patients can receive TSEBT in the future, fraction sizes of 1.2 Gy to 2.0 Gy are generally recommended. Historically, the Stanford University experience with 176 patients undergoing TSEBT from 1958 to 1975 revealed that complete response rates increased with total dose: 18% for 8 Gy to 9.9 Gy, 55% for 10 Gy to 19.9 Gy, 66% for 20 Gy to 24.9 Gy, 75% for 25 Gy to 29.9 Gy, and 94% for 30 Gy to



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36 Gy.159 Similarly, patients treated with higher doses experienced improved overall survival, regardless of T stage. The experience at Hamilton Regional Cancer Center between 1977 and 1992 further supported the importance of high-dose TSEBT. From 1977 to 1980, 25 consecutive patients received 30 Gy TSEBT. From 1980 to 1992, 121 consecutive patients received 35 Gy TSEBT.160 Treatment with high-dose TSEBT was an independent predictor of response, with a complete response rate of 64% for the 30-Gy group and 85% for the 36-Gy group. The EORTC previously recommended that TSEBT deliver a total dose of 31 Gy to 36 Gy to the skin surface to produce a dose of 26 Gy at a depth of 4 mm in truncal skin along the central axis.161 Such doses were classically delivered over an 8-week treatment period, though a recent alternative schedule of 30 Gy in 20 fractions delivered over 5 weeks was reported with comparable response rates.162 Updated data continue to note an overall response rate of 100% to TSEBT with 60% complete response rate. In patients receiving a second course of TSEBT, 100% overall response rate was also seen, with a median duration of response of 6 months. However, in a separate retrospective analysis of patients with T2 to T4 tumors, analysis stratified by TSEBT dose still noted excellent response rates in patients treated to 10 Gy to <20 Gy of 98% compared with 20 Gy to <30 Gy of 97%.163 Given this newer evidence, the clinical potential of lower-dose TSEBT is being revisited.164 Currently, National Comprehensive Cancer Network (NCCN) guidelines recommend treatment doses of 12 Gy to 36 Gy,80 and our institutional experience suggests even lower doses, on the order of 8 Gy to 10 Gy can produce durable response for some patients.90

Clinical Results: Limited Superficial Radiotherapy Approximately 5% of patients with stage IA disease present with a single skin lesion, or with two or three lesions in close proximity, such that all clinically apparent disease can be encompassed by either one field or several abutting fields.22 Radiotherapy is the treatment of choice in this situation because results from three institutions have reported longterm disease-free survival in excess of 85%.22,23,165 Wilson et al published a series of 21 patients with minimal stage IA disease managed with local, superficial radiotherapy.22 Ten were treated with 100 Kv to 280 Kv and 11 with 4 MeV to 12 MeV electrons with appropriate bolus. The median dose was 20 Gy, and 17 of 21 received ≥20 Gy. With a median follow up of 36 months, the rate of complete clinical remission was 97% and the long-term disease-free survival was 91% among patients

TABLE 79-9 

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receiving ≥20 Gy. Similarly, Micaily et al reported an 86% 10-year disease-free survival in 18 patients with unilesional MF treated with localized radiotherapy to a median dose of 30.6 Gy.23 In summary, radiotherapy for unilesional stage IA disease is an excellent first-line therapy given minor acute and chronic toxicities and excellent long-term results. Because few patients with two to four lesions have been reported in the literature, optimal treatment for this subgroup remains unclear. Although some advocate limited superficial radiotherapy, others advocate a strategy such as TSEBT or PUVA to treat all skin surfaces.

Clinical Results: Total Skin Electron Beam Therapy Limited Patches or Plaques: T1 N0 M0 (IA) and T1 N1 M0 (IIA) Initial treatment options for patients with patches or plaques involving less than 10% body surface area include topical corticosteroids, mechlorethamine, topical carmustine, phototherapy, bexarotene gel, and TSEBT. Currently, no randomized data exist to support selection of a radiation-based strategy over another topical strategy for this patient population. Although single-institution experiences suggest that patients managed with TSEBT may experience superior complete response rates and relapse-free survival, there is little strong evidence to suggest that this will translate into improved overall survival. For example, patients with T1 disease treated with modern TSEBT experience a complete response rate of at least 90%99,166 (Table 79-9), compared with a complete response rate of 65% to 70% for topical mechlorethamine.77,103 Furthermore, 10-year relapse-free survival is roughly 50% for TSEBT167 compared with 34% for mechlorethamine.77 However, in this group of patients whose long-term survival is similar to healthy controls, initial treatment with TSEBT has not been associated with an overall survival advantage.166 The administration of TSEBT for patients with stage IA MF as first-line therapy remains controversial, and although some reserve TSEBT for those refractory to standard therapies, others recommend TSEBT as first-line therapy for even pauci-lesional stage IA disease. For patients with limited patches, UVB therapy results in a complete response rate of roughly 80% with a median response duration of 2 years.168,169 PUVA is appropriate for both patches and plaques, producing complete responses rates of at least 80%. Although relapse is common, most patients will respond to additional PUVA.170,171 Similar to mechlorethamine, topical BCNU produced a complete response rate of

Newly Diagnosed Patch Plaque Mycosis Fungoides Managed at Hamilton, Ontario* Stage IA n = 143 95% 2.5 62% 94% 100% 99% n = 11 100%

Stage IB

5 50% 82% 99% 94%

10 40% 66% 99% 89%

15 40% 61% 96% 76%

N/A

N/A

N/A

n = 79 89% 2.5 44% 88% 100% 99% n = 21 89%

5 22% 69% 98% 91%

10 12% 49% 91% 80%

15 12% 39% 91% 75%

N/A

N/A

N/A

PUVA, Psoralen plus ultraviolet A; TSEBT, total skin electron beam therapy. *This table contains data from Hamilton, Ontario, updated through 2004 and representative of the results of TSEBT as first-line therapy for stages IA and IB. Results shown for 222 patients receiving TSEBT alone document high rates of complete remission. For those who fail TSEBT, limited second-line therapies142 may produce prolonged remissions, as indicated by the time to second progression outcome measure. Results shown for 32 patients receiving TSEBT plus adjuvant PUVA indicate that PUVA significantly improves progression-free survival rates (p = 0.03), with follow-up under 5 years as of 2004.142

DISEASE SITES

TSEBT WITHOUT ADJUVANT THERAPY Rate of complete remission Years of follow-up Progression-free experience Time to second progression142 Cause-specific survival (death from mycosis fungoides) Overall survival (death from any cause) TSEBT WITH 60 SESSIONS OF ADJUVANT PUVA Progression-free experience

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86%, partial response rate of 12%, and 5-year relapse-free survival of 35%.105 Recurrent or refractory T1 disease can still respond to TSEBT,161 class I steroids (complete response 63%, par­ tial response 31%),101 interferon-α monotherapy (complete response 50%, partial response 35%),113 topical bexarotene (complete response 21%, partial response 42%),107 and oral bexarotene (complete response 7%, partial response 47%).123 For example, data from Hamilton showed that 70% of patients were free of disease 15 years after first-line TSEBT and secondline salvage treatments as needed.167 Extensive Patches or Plaques: T2 N0 M0 (IB) and T2 N1 M0 (IIA) TSEBT in such patients can demonstrate excellent response rates and rapid palliation. For example, complete response rates for T2 disease range from 76% to 90% (Table 79-9), compared with a complete response rate of 34% for topical mechlorethamine.77,98,161 Adjuvant therapy following TSEBT is crucial for patients with T2 disease because 10-year relapsefree survival is only 10% in those treated with TSEBT alone.167 Retrospective data from Yale University found that patients receiving adjuvant PUVA experienced a 5-year disease-free survival of 85% versus 50% for those not receiving adjuvant PUVA.97 A prospective pilot study at Hamilton documented a similar benefit (Table 79-9). Retrospective data from Stanford University showed that patients treated with TSEBT and adjuvant topical mechlorethamine experienced 10-year relapsefree survival of roughly 40% compared to 10% with TSEBT alone.98 Patients with T2 disease who are relatively asymptomatic can receive treatment similar to that recommended for T1 disease. Topical corticosteroids may also be helpful for patients with extensive patches, with data suggesting a complete response rate of 25% and partial response rate of 57%.101 Again, topical mechlorethamine is a reasonable choice for these patients, resulting in a complete response rate of 34%, partial response rate of 38%, and 10-year relapse-free survival rate of 20%.77 Similarly, BCNU produced a complete response rate of 47%, partial response rate of 37%, and 5-year relapsefree survival rate of 10%.105 As an alternative to topical chemotherapy, topical phototherapy may be considered for extensive patch or plaque disease. UVB should be reserved for extensive patch disease only because of its superficial penetration. In contrast, PUVA may be considered for patients with patches or thin plaques and has resulted in complete response rates of 60% to 100%.101,170,171 Phase II trials suggest promising improvements in both complete response rate and duration of remission when adding IFN-α to PUVA for the treatment of T2 disease.116,117,119 Cutaneous Tumors: T3 N0-1 M0 (IIB) Radiotherapy is an important treatment modality for cutaneous tumors because of its ability to treat the full thickness of deeply infiltrative lesions. For the rare patient with asymptomatic tumors involving less than 10% of the skin, either topical skin-directed therapy, along with local radiotherapy or TSEBT are reasonable first-line treatment options, with both producing a similar 5-year overall survival of roughly 50%.98 However, most patients with T3 disease present with extensive, symptomatic tumors. Such patients often benefit from TSEBT as a first-line, palliative treatment because of a superior complete response rate as compared with topical HN2 plus localized radiotherapy, 44% to 54% versus 8%.98,99 Adjuvant therapy should be strongly considered for patients after completing a course of TSEBT, even as maintenance therapy after a complete response. Retrospective data suggest that adjuvant topical mechlorethamine may improve

the duration of response, resulting in 5-year relapse-free survival of 55% compared to 30% with TSEBT alone.98 Adjuvant photopheresis is another reasonable option, with retrospective data reporting 5-year overall survival of 100% for patients receiving this modality compared with 50% in patients who did not receive adjuvant therapy.136 Other adjuvant therapies worthy of consideration include IFN-α, bexarotene, and denileukin diftitox.172 Erythroderma: T4 N0-1 M0 (III) TSEBT is an appropriate initial therapy for erythrodermic MF because of its ability to produce a rapid and sustained response, thereby ameliorating the severe cutaneous symptoms experienced by such patients. Further, data suggest that TSEBT can result in a substantial reduction in the number of malignant cells circulating in the peripheral blood, potentially altering the natural history of the disease.173,174 Retrospective data indicate that TSEBT monotherapy produced a 100% complete response rate and 5-year progression-free survival of 69% for patients with T4 N0 M0 B0 MF.100 However, when including those with blood or visceral involvement, the complete response rate dropped to 74% and only 36% remained progression-free at 5 years. Patients with erythroderma and blood or visceral involvement are particular candidates who may benefit from adjuvant photopheresis because retrospective data suggest that such treatment improves 2-year causespecific survival from 69% without EP to 100% with EP.137 For patients without access to TSEBT, several other topical treatment options exist. For example, a series of 10 patients treated with PUVA reported a complete response rate of 70% and median progression-free survival of 5 months.175 Although not studied in a randomized setting, prospective phase II experiences suggested that addition of IFN-α to PUVA may improve the duration of response, in advanced disease.115-117 Another option for T4 disease is photopheresis monotherapy because 80% of patients will experience at least some cutaneous improvement.109 Patients with a normal peripheral blood CD4/CD8 ratio appear more likely to respond.135 Total Skin Electron Therapy: Toxicity TSEBT is generally well-tolerated, and toxicity is minimized by using low daily fractions sizes176 and a shielding regimen that reduces the dose to eyes, ears, lips, hands, and feet. Common acute toxicities from TSEBT include pruritus, dry desquamation, erythema, alopecia, xerosis, bullae of the feet, edema of the hands and feet, hypohidrosis (diminished perspiration),177 and loss of fingernails and toenails.167,178 Rare acute side effects include gynecomastia in men, mild epistaxis, and mild parotiditis.167 Because of the superficial penetration of electrons, patients do not experience gastrointestinal or hematologic toxicities. In general, TSEBT does not cause serious long-term complications,179 although permanent nail dystrophy, xerosis, telangiectasias, partial scalp alopecia, and fingertip dysesthesias have been described.160 Second cutaneous malignancies including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma have been observed in patients treated with TSEBT, particularly in those exposed to multiple therapies that are themselves known to be mutagenic, such as PUVA and mechlorethamine.104,180

PALLIATION In current practice, for the majority of patients, age or performance status ultimately preclude allogeneic transplant, and therefore palliative treatment options remain a mainstay of therapy. A palliative approach usually includes novel biologic agents, cytotoxic chemotherapy, and radiation. For example, oral bexarotene has shown efficacy in patients with relapsed or refractory MF, producing an overall response rate of 57%



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for stage IIB, 32% for stage III, 44% stage IVA, and 40% for stage IVB.122 Another option, denileukin diftitox, resulted in an overall response rate of 30% for patients with treatmentrefractory stages IB to IVA disease.74 Systemic chemotherapy should also be considered and may result in complete response rates of 20% to 60%.147 Radiotherapy, including TSEBT, plays an important role in the palliation of both cutaneous and extracutaneous disease.181,182 For those patients with extensive skin disease recurrent after TSEBT, a second course of TSEBT may produce substantial palliation with acceptable toxicity.183 Typically median doses for repeat TSEBT courses after an initial course of >30 Gy tend to be lower, on the order of 18 Gy to 23 Gy. However, evidence suggests that lower doses can still achieve high rates of overall and complete response.163,184 Toxicity of repeat TSEBT is typically characterized by xerosis, telangiectasias, pigment changes, and alopecia. Criteria for retreatment include complete response to the initial course, an extended disease-free interval after the initial course, diffuse cutaneous involvement at relapse, or failure of other modalities. Localized, symptomatic skin lesions can benefit from a local radiotherapy field, with options including higher doses on the order of 20 Gy to 30 Gy, or lower doses on the order of 8 Gy in two fractions or 7 Gy in one fraction.185 Recent evidence suggests that the lower dose approach produces complete response rates in excess of 90%, and that retreatment with higher doses of radiation is safe and effective for those patients whose tumor recurs following low dose irradiation.186 Finally, patients with symptomatic nodal or visceral disease often benefit from a course of palliative megavoltage radiotherapy to a total dose of 20 Gy to 30 Gy delivered in 2-Gy to 3-Gy fractions.

complete responses in two patients with extensive MF. In 1960, Stanford University reported the first method for linear accelerator-based TSEBT.191 With a patient standing 10 feet from the end of the accelerator, two fields were treated, one directed above the patient’s head and a second directed below the patient’s feet. This approach is known as the dual-field technique. In addition, patients were treated in two positions with respect to the accelerator: anteroposterior and posteroanterior. Over time, it became clear that increasing the number of treatment positions improved dose homogeneity in the lateral dimension.192,193 Ultimately, Stanford adopted a six-treatment position technique in which patients stand in six different orientations with respect to the accelerator: anteroposterior, posteroanterior, right and left anterior oblique, and right and left posterior oblique.194 Although commonly called the “six-field” technique, it should be remembered that two fields are actually treated for each of the six treatment positions. The first clinical results of TSEBT were published in 1962 by a group from St. John’s Hospital for Diseases of the Skin in London.195 Using the dual-field, four treatment position technique developed at Stanford, all five patients treated for MF experienced “very good” responses at total doses ranging from 12 Gy to 18 Gy. However, four of five patients relapsed within 8 months and disease was difficult to control in the axillae and perineum because of underdosing. In 1971, Stanford University reported 107 patients with MF who received TSEBT between 1957 and 1968.194 Using a variety of doses, they produced a 52% complete response rate. In addition, among patients with localized patches or plaques, 30% experienced long-term disease-free survival, providing the first evidence that MF could actually be cured.

Follow Up

Target Volumes

Follow up after definitive treatment for MF is best carried out by a multidisciplinary team with expertise in CTCL. Because most patients managed with TSEBT now receive adjuvant treatment, they remain in close contact with their dermatologists every 1 month to 3 months for many years. Biopsy of clinically borderline or suspicious lesions is important to document relapse and to rule out transformation to a large-cell variant. In addition, close surveillance is required to detect treatment-related skin cancers and ensure that appropriate therapy is initiated promptly. Patients with an elevated CD4/ CD8 ratio, LDH, or soluble interleukin-2 receptor level at initial diagnosis should have these values followed closely to determine response to therapy.

The target volume for TSEBT should include the epidermis and dermis.99 The thickness of the epidermis varies from 0.05 mm to 0.50 mm and is greatest in the distal extremities. The thickness of the dermis varies from 1 mm to 4 mm and is greatest in the hands and feet. Therefore, the thickness of the skin varies from a minimum of about 2 mm on the trunk to a maximum of about 4.5 mm at the hands and soles of the feet.99 As a result, the EORTC TSEBT consensus statement recommends that the 80% isodose line should be ≥4 mm deep to the skin surface to ensure that the epidermis and dermis fall with the high-dose region. Because of their thickness, the deep margin of cutaneous tumors is often underdosed when treated with TSEBT alone and may require supplemental boosts with appropriately selected electrons to ensure adequate dose to areas typically underdosed such as axillae and perineum.

TECHNIQUES OF IRRADIATION Historical Development

Limited Superficial Radiotherapy Minimal stage IA disease should be treated with a single radiation field where possible, though abutting fields may be required at a convex surface such as the scalp, an axillary fold, breast, hand, or foot. The junction of abutting fields should be shifted during the course of treatment to improve homogeneity. Field margins can be limited by lead cut-out to only 1 cm to 2 cm beyond the visible (or palpable) clinical lesion. Electrons of 4 MeV to 16 MeV energy with appropriate bolus material are usually sufficient, and the dose should be approximately 8 Gy to 30 Gy (one to two treatments per week) with the expectation of durable response. One or several fields of 6 MeV to 16 MeV electrons can also be used to encompass the limited volumes required to palliate symptomatic skin lesions, including most tumor nodules and skin ulcers. Clinical regression can be seen at 12 Gy to 14 Gy and considered adequate for a first course of treatment, and in certain cases,

DISEASE SITES

Localized radiation was first used to treat MF in 1902, shortly after the discovery of x-rays.187 In 1939, Summerville reported treatment of extensive cutaneous MF with an “x-ray bath” of kilovoltage photons delivered with two large fields.188 A total air exposure of 900 roentgen delivered in daily fractions of 10 roentgen produced a complete response. In 1945, Levin and Behrman proposed that the total air exposure at the skin surface should be 600 roentgen to 800 roentgen for patches or plaques and 1000 roentgen to 1600 roentgen for tumors.189 The development of total skin electron beam therapy began in the early 1950s. Trump et al at the Massachusetts Institute of Technology used a Van de Graaff generator to produce a vertically oriented, stationary beam of 2.5 MeV electrons incident on a motorized couch.190 By placing the patient in the prone, supine, and lateral decubitus positions and translating the couch through the electron beam, all skin surfaces could receive a meaningful dose. This treatment approach produced

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as low as 8 Gy is acceptable.22,90,99,157 Treating with the lowest dose that induces clinical remission preserves as much radiation tolerance of the skin as possible and enables future delivery of local radiotherapy or TSEBT. Furthermore, in situations of coexisting cancer diagnoses (e.g., Hodgkin’s, breast, prostate or rectal cancers), radiation treatments for those diagnoses must be carefully planned to minimize the superficial skin exposure to preserve the option of TSEBT in the future.

Node, Viscera, and Blood Radiotherapy Nodal regions (e.g., axillary and inguinal) and some visceral organs (e.g., lungs, larynx, and brain) can be encompassed using standard beam arrangements and energies. Prescriptions are typically 20 Gy to 30 Gy in 10 to 20 fractions over 2 to 4 weeks. Several experiences using TSEBT in combination with either low dose total body irradiation196 or total nodal irradiation197,198 have been reported. However, such treatment may increase the risk of secondary malignancies or myelodysplastic syndrome198 and has not demonstrated superiority over conventional systemic agents. For patients undergoing allogeneic bone marrow transplantation, incorporation of TBI in the preparative regimen may be considered.153 TSEBT delivers a total dose to the blood and marrow of approximately 0.4 Gy in 30 or more fractions over 6 weeks to 14 weeks. In general, hematologic values remain normal during a course of TSEBT. However, for those with Sézary syndrome, the number of circulating Sézary cells may fall by 50% to 95% and, in rare instances, may remain in a sustained remission.

Modern TSEBT Technical advances since the initial Stanford and St. John’s publications have included dose escalation to 35 Gy to 36 Gy, improvements in shielding, and integration of boost

treatments to underdosed regions, culminating in the publication of a consensus statement from the EORTC regarding appropriate techniques for TSEBT (Table 79-10).161 The method of TSEBT used at our institution achieves these objectives with a ≥4 MeV modern linear accelerator using the dual-field, six-treatment position technique. The patient stands 3 meters from the electron source, and the gantry is angled up and down at 113 degrees and 67 degrees to produce the dualfields. A Lucite plate is placed in front of the patient and serves to scatter the incident electrons and attenuate x-ray contamination (Figure 79-4). TABLE 79-10 

EORTC Guidelines for Total Skin Electron Beam Therapy

• Dose inhomogeneity in air at treatment distance should be <10% within vertical and lateral dimensions. • 80% isodose line should be ≥4 mm deep to the skin surface to ensure that the epidermis and dermis fall within the high-dose region. • 80% isodose line should receive a minimum total dose of 26 Gy. • 20% isodose line should be <20 mm from the skin surface to minimize dose to underlying structures. • 30 to 36 fractions should be used to minimize acute side effects. • Total dose to bone marrow from photon contamination should be <0.7 Gy. • Patch treatments should be used to underdosed areas, such as the perineum, scalp, and soles of feet. • Internal and external eye shields should be used to ensure that the dose to the globe is not more than 15% of the prescribed skin surface dose. Adapted from Jones GW, Kacinski BM, Wilson LD, et al: Total skin electron radiation in the management of mycosis fungoides. Consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol 47:364–370, 2002.

Figure 79-4  Geometry of dual-field total skin electron beam technique.



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Figure 79-5  Treatment positions used in total skin electron beam therapy. Top row (from left to right): right anterior oblique, anteroposterior, and left anterior oblique treatment positions. Bottom row (from left to right): right posterior oblique, posteroanterior, and left posterior oblique treatment positions. Adapted and reprinted with permission from Figure 6 in Dabaja BS: Mycosis fungoides, presentation, diagnosis, and treatment strategy. In Thomas CR, Jr, editor: Radiation medicine rounds: Hematologic malignancies, New York, 2012, Demos Medical Publishing.

This technique places the dose maximum at 1 mm, the 80% isodose line at 6 mm, and the 20% isodose line at 12 mm,199 thus satisfying the EORTC criteria for TSEBT167 (Table 79-10). Photon contamination because of bremsstrahlung scattering in the machine head, intervening air, scatterers or degraders, and patient, is acceptable at 1.2%. A comparison of the depth-dose curves for a single anteroposterior treatment position and for all six treatment positions is presented graphically in Figure 79-6 and by film dosimetry in Figure 79-7.199 Using six treatment positions shifts the isodose curve toward the skin surface because of the obliquity of the incident electrons. As a result of the shielding inherent to these treatment positions, underdosed areas must be considered for supplemental treatment. Areas of potential underdosing include the shoulders, axillae, inframammary folds, folds under any

DISEASE SITES

A total of six treatment positions are designated: anteroposterior, right and left anterior oblique, posteroanterior, and right and left posterior oblique (Figure 79-5). These positions maximize skin unfolding, thereby improving dose homogeneity in the lateral dimension. Each position is treated with two fields, an upper field and a lower field to maximize dose homogeneity in the vertical dimension. For example, on cycle one, the anteroposterior, right posterior oblique, and left posterior oblique positions are treated. On cycle two, the posteroanterior, right anterior oblique, and left anterior oblique positions are treated with the same dose. Over the course of two treatment cycles, a patient will receive 2 Gy to the entire skin surface. This pattern continues, with patients receiving one to two cycles per week for classically 6 weeks to 10 weeks (Table 79-11).

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Sample Treatment Protocol

TREATMENT CYCLE Day 1 Day 2 DOSE Dose per cycle Cycles per week Total cycles Total dose BOOSTS Perineum Soles of feet BLOCKING External eye shields Internal eye shields Lip shield Lead mitt for hands Fingernail shield Foot block Testicular shield

AP, RPO, LPO treatment positions PA, RAO, LAO treatment positions 2 Gy 2 18 36 Gy 100 cGy/day, first 9 and last 9 treatment days 100 cGy/day, first 7 and last 7 treatment days First 11 cycles Last 7 cycles Cycles 1-4 Every other cycle Every other cycle, alternating with mitts Cycles 1-3, 5, 7, 9, 11, 13, 15, 17, 18 Used with perineal boost only

Data from Chen Z, Agostinelli AG, Wilson LD, et al: Matching the dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys 59:872–885, 2004. AP, Anteroposterior; LAO, left anterior oblique; LPO, left posterior oblique; PA, posteroanterior; RAO, right anterior oblique; RPO, right posterior oblique.

Figure 79-6  Depth dose curves for dual-field total skin electron beam therapy. Purple line: Depth dose curve for an anteroposterior (AP) dual-field 4 MeV electron beam incident on polystyrene, a tissueequivalent material. Note that the surface receives roughly 80%, and that the maximum dose is deposited 8 mm from the surface. Red line: Depth dose curve for dual-field, six treatment position, standard TSEBT. Because of multiple beams entering the skin surface at oblique angles, the dose delivered to the skin surface rises dramatically, and drops to 80% by 8 mm. (Graph courtesy of Zhe Chen, PhD). Adapted with permission from Figures 6 and 11 in Chen Z, Agostinelli AG, Wilson LD, et al: Matching the dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys 59:872–885, 2004.

Figure 79-7  Cross-sectional dose distribution. Axial film dosimetry for single treatment position and six treatment position technique. The dark region is proportional to the electron dose delivered to the film. Adapted with permission from Figure 5 in Chen Z, Agostinelli AG, Wilson LD, et al: Matching the dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys 59:872–885, 2004.

pannus, groin and medial thighs, perineum, and perianal area; though underdosed areas are dependent on body habitus. Obesity and idiosyncratic lateral and flatter regions or individual folds may determine other areas that are underdosed. The scalp may be underdosed, but is supplemented typically only if involved to decrease risk of alopecia. Therefore, supplemental patch fields should be guided by in vivo dosimetry along with clinical assessment and suspicion, to ensure that the surface dose is at least 50% of the prescribed TSEBT dose.200,201 The hands, and feet, as well as areas of the perineum receiving tangential beam may be overdosed as a result of a variety of factors including tissue heterogeneity (e.g., bone), high convexity, and overlap between more than three of the six primary fields.99 Thus, these regions should be shielded for a certain proportion of the treatments to reduce the total dose to 32 Gy to 36 Gy or less. Upfront planning for cyclic blocking is warranted, particularly in the context of comorbidities such as diabetes (or other vasculopathy) that may further compromise skin integrity or worsen the morbidity associated with acute radiation skin toxicity. Detailed dosimetric measurements are typically required to determine the most appropriate shielding regimen using lead or other shielding material, for a particular treatment arrangement and patient geometry (Table 79-12). Eyes may be shielded with a combination of external eye shields and lead internal eye shields.202 Although internal eye shields may cause conjunctival irritation and corneal abrasions, the risk is usually less than 1%167 (Tables 79-10 and 79-11). Because many tumors have a thickness greater than 6 mm, TSEBT alone may result in significant underdosing. As a result, for patients with bleeding, weeping, or painful tumors at presentation, an initial or concurrent boost of 10 Gy in five fractions with either 6 MeV to 16 MeV electrons or orthovoltage photons has been effective. In addition, asymptomatic plaques and tumors that persist at the end of treatment receive a similar boost to ensure adequate dose delivery at depth.

Other Radiation Management Issues Cutaneous symptoms including xerosis, pruritus, and pain from fissures or ulceration are often severe and should be managed aggressively with topical corticosteroids, emollients, oral antihistamines, and aggressive wound care with nonocclusive dressings.81 Acute skin toxicity from TSEBT usually responds to the above measures, although treatment breaks on the order of 1 week to 2 weeks may occasionally be required.203



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Dose to Anatomic Sites Using In Vivo TLD Dosimetry Dose/2-day TSEBT Treatment Cycle*

Central axis Top of head Forehead Eye Eyelid Lips Posterior neck Shoulder Axilla Hand Mid-back Umbilicus Flank Lateral thigh Perineum Top of feet Soles of feet

79 

Total Dose with Blocking and Boosts

Gy

Percentage

Gy

Percentage

2.0 2.3 2.4 0.1 — — 2.1 1.7 2.2 1.6 2.0 2.1 2.0 1.9 0.6 2.3 0

100 115 118 12 — — 104 87 109 82 100 104 99 95 31 117 0

36.0 41.4 42.5 2.2 24.5 30.0 37.4 31.3 39.2 15.6 36.0 37.4 35.6 34.2 29.0 28.5 14.0

100 115 118 6 68 83 104 87 109 43 100 104 99 95 81 79 39

Data from Chen Z, Agostinelli AG, Wilson LD, et al: Matching the dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys 59:872–885, 2004. TLD, Thermal luminescent detector; TSEBT, total skin electron beam therapy; —, not reported. *Dose using dual-field, six-treatment position setup with scalp electron reflector and eye shields.

TREATMENT CONTROVERSIES, PROBLEMS, CHALLENGES, AND FUTURE POSSIBILITIES A major challenge is the need for prospective randomized trials to compare radiation-based and nonradiation-based approaches to initial treatment. Adequately powered trials are problematic given the rarity of MF and difficulty in accruing patients. A recent Cochrane meta-analysis evaluated 14 trials that included 675 participants, the majority representing

stages IA to IIB patients. Unfortunately, the efficacy of treatments could not be directly compared among the agents studied. Disease clearance was the primary outcome in most studies, with widely heterogeneous results, ranging from 0% to 83% response for skin-directed therapies.206 This metaanalysis highlights ongoing challenges to prospectively evaluating treatment options for MF. In the absence of randomized data, treatment will continue to be guided by institutional expertise and patient preference. The clinical management of patients with MF is complex and typically requires an interdisciplinary team approach that attends to the patient as a whole. Most patients require a fairly detailed understanding of the disease, its implications and risks, and all treatment options. The majority of patients are seeking a cure, which for many is unrealistic. Improvements in quality of life are possible regardless of presenting stage. The relative contributions of various factors in determining quality of life have not been systematically explored. However, clinical experience indicates that the most salient factors are controlling symptoms; achieving remission regardless of prior clinical trajectory; using treatments that are efficient and of limited duration (so as to be less disruptive to lifestyle and personal circumstances over the long term); addressing any anxiety and depression; and providing sustained and reliable support and expertise that extends into years and even decades of follow-up. Many biologic and clinical questions pertaining to the pathophysiology and treatment of MF remain unanswered. For example, it is unclear whether the development of MF is initially driven by a specific exogenous antigen or by random mutational events occurring in activated T cells. In addition, the molecular factors that influence disease progression and response to various treatment modalities are just beginning to be elucidated. Clinically more studies with homogeneous patient populations are required to evaluate putative prognostic factors. The future will likely bring additional novel systemic therapies for MF. For example, biologic and immunologic agents including monoclonal antibodies directed against CD4, CD52, CD25, and CD30, individualized dendritic cellbased tumor vaccines, HDACi, purine nucleoside phosphorylase inhibitors, proteasome inhibitors, immunomodulatory/ immunostimulatory agents, fusion toxins, and antifolates continue to undergo investigation, with the goal of improving the

DISEASE SITES

Large bullae that develop during TSEBT should be lanced under sterile conditions and require nonocclusive dressings until they reepithelialize. As previously discussed, patients with advanced MF may experience a profound degree of immunosuppression. As a result, cutaneous and systemic infections are an important cause of morbidity and mortality. The most common infections include cellulitis resulting from Staphylococcus aureus or β-hemolytic streptococci, cutaneous herpes simplex or herpes zoster (both of which may disseminate cutaneously), bacteremia (most commonly with S. aureus), and bacterial pneumonia.35 Signs and symptoms of such infections should be evaluated promptly and treated aggressively. Independent of MF, TSEBT also suppresses cutaneous immunity, likely as a result of destruction of normal skin-homing lymphocytes and epidermal antigen presenting dendritic cells. Thus, any new eruption that develops during the course of TSEBT should be evaluated promptly, as disseminated cutaneous bacterial, fungal, and viral infections are not uncommon204,205 (Figure 79-8).

Figure 79-8  Disseminated herpes simplex during the course of total skin electron beam therapy.

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treatment of recurrent or refractory disease.207,208 Strategies for integrating novel biologics with standard therapies such as TSEBT are needed to maximize the benefits of each. For longterm disease control and cure, allogeneic stem-cell transplant is an encouraging development, with present challenges focused on developing the optimal conditioning scheme and strategies to manage the complications.

CRITICAL REFERENCES A full list of cited references is published online at www.expertconsult.com. 2. Willemze R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354–371, 1997. 20. Girardi M, Heald PW, Wilson LD: The pathogenesis of mycosis fungoides. N Engl J Med 350:1978–1988, 2004. 41. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768–3785, 2005. 53. Vergier B, de Muret A, Beylot-Barry M, et al: Transformation of mycosis fungoides: Clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneous Lymphomas. Blood 95:2212–2218, 2000. 55. de Coninck EC, Kim YH, Varghese A, et al: Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides. J Clin Oncol 19:779–784, 2001. 56. Prince HM, Whittaker S, Hoppe RT: How I treat mycosis fungoides and Sezary syndrome. Blood 114:4337–4353, 2009. 60. Vonderheid EC, Bernengo MG, Burg G, et al: Update on erythrodermic cutaneous T-cell lymphoma: Report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 46:95–106, 2002. 74. Olsen E, Duvic M, Frankel A, et al: Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19:376–388, 2001. 75. Olsen EA, Whittaker S, Kim YH, et al: Clinical end points and response criteria in mycosis fungoides and sezary syndrome: A consensus statement of the international society for cutaneous lymphomas, the united states cutaneous lymphoma consortium, and the cutaneous lymphoma task force of the european organisation for research and treatment of cancer. J Clin Oncol 29:2598–2607, 2011. 79. Olsen E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and sezary syndrome: A proposal of the international society for cutaneous lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 110:22–2007, 1713. 94. Duarte RF, Canals C, Onida F, et al: Allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sezary syndrome: A retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 28:4492–4499, 2010.

95. Duarte RF, Schmitz N, Servitje O, et al: Haematopoietic stem cell transplantation for patients with primary cutaneous T-cell lymphoma. Bone Marrow Transplant 41:597–604, 2008. 96. Duvic M, Donato M, Dabaja B, et al: Total skin electron beam and nonmyeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome. J Clin Oncol 28:2365– 2372, 2010. 97. Quiros PA, Jones GW, Kacinski BM, et al: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38:1027–1035, 1997. 98. Chinn DM, Chow S, Kim YH, et al: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43:951–958, 1999. 119. Stadler R, Otte HG, Luger T, et al: Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood 92:3578–3581, 1998. 122. Duvic M, Hymes K, Heald P, et al: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: Multinational phase II-III trial results. J Clin Oncol 19:2456–2471, 2001. 124. Talpur R, Jones DM, Alencar AJ, et al: CD25 expression is correlated with histological grade and response to denileukin diftitox in cutaneous T-cell lymphoma. J Invest Dermatol 126:575–583, 2006. 129. Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109–3115, 2007. 137. Wilson LD, Jones GW, Kim D, et al: Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J Am Acad Dermatol 43:54–60, 2000. 154. Molina A, Zain J, Arber DA, et al: Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides. J Clin Oncol 23:6163–6171, 2005. 157. Cotter GW, Baglan RJ, Wasserman TH, et al: Palliative radiation treatment of cutaneous mycosis fungoides–a dose response. Int J Radiat Oncol Biol Phys 9:1477–1480, 1983. 160. Jones GW, Tadros A, Hodson DI, et al: Prognosis with newly diagnosed mycosis fungoides after total skin electron radiation of 30 or 35 GY. Int J Radiat Oncol Biol Phys 28:839–845, 1994. 161. Jones GW, Kacinski BM, Wilson LD, et al: Total skin electron radiation in the management of mycosis fungoides: Consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol 47:364–370, 2002. 199. Chen Z, Agostinelli AG, Wilson LD, et al: Matching the dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys 59:872–885, 2004.



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Diamandidou E, Colome-Grimmer M, Fayad L, et al: Transformation of mycosis fungoides/Sezary syndrome: Clinical characteristics and prognosis. Blood 92:1150–1159, 1998. 53. Vergier B, de Muret A, Beylot-Barry M, et al: Transformation of mycosis fungoides: Clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneous Lymphomas. Blood 95:2212–2218, 2000. 54. O’Quinn RP, Zic JA, Boyd AS: Mycosis fungoides d’emblee: CD30-negative cutaneous large T-cell lymphoma. J Am Acad Dermatol 43:861–863, 2000. 55. de Coninck EC, Kim YH, Varghese A, et al: Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides. J Clin Oncol 19:779–784, 2001. 56. Prince HM, Whittaker S, Hoppe RT: How I treat mycosis fungoides and Sezary syndrome. Blood 114:4337–4353, 2009. 57. Stein M, Farrar N, Jones GW, et al: Central neurologic involvement in mycosis fungoides: Ten cases, actuarial risk assessment, and predictive factors. Cancer J 12:55–62, 2006. 58. 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1. Sander CA, Flaig MJ, Jaffe ES: Cutaneous manifestations of lymphoma: A clinical guide based on the WHO classification. Clin Lymphoma 2:86–100, discussion 101–2, 2001. 2. Willemze R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354–371, 1997. 3. Alibert JLM: Tableau du Pian Fungoide Description des Maladies de la Peau, Observees a l’Hopital Saint-Louis et Exposition des meilleurs Methodes Suivies pour leur Traitement, Paris, 1806, Barrois L’Aine & Fils. 4. Sezary A, Bouvrain Y: Erythrodermie avec presence de cellules monstreuses dans derme et sang circulant. Bull Soc Fr Dermatol Syph 45:254–260, 1938. 5. Lutzner MA, Jordan HW: The ultrastructure of an abnormal cell in Sezary’s syndrome. Blood 31:719–726, 1968. 6. 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60. Vonderheid EC, Bernengo MG, Burg G, et al: Update on erythrodermic cutaneous T-cell lymphoma: Report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 46:95–106, 2002. 61. Wilson LD, Cooper DL, Goodrich AL, et al: Impact of non-CTCL dermatologic diagnoses and adjuvant therapies on cutaneous T-cell lymphoma patients treated with total skin electron beam radiation therapy. Int J Radiat Oncol Biol Phys 28:829–837, 1994. 62. Gerami P, Rosen S, Kuzel T, et al: Folliculotropic mycosis fungoides: An aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 144:738– 746, 2008. 63. LeBoit PE: Granulomatous slack skin. Dermatol Clin 12:375–389, 1994. 64. Liu HL, Hoppe RT, Kohler S, et al: CD30+ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 49:1049–1058, 2003. 65. 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Hoppe RT, Medeiros LJ, Warnke RA, et al: CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Am Acad Dermatol 32:448–453, 1995. 85. Quiros PA, Kacinski BM, Wilson LD: Extent of skin involvement as a prognostic indicator of disease free and overall survival of patients with T3 cutaneous T-cell lymphoma treated with total skin electron beam radiation therapy. Cancer 77:7–1996, 1912. 86. Delfau-Larue MH, Dalac S, Lepage E, et al: Prognostic significance of a polymerase chain reaction-detectable dominant T-lymphocyte clone in cutaneous lesions of patients with mycosis fungoides. Blood 92:3376–3380, 1998.

87. Guitart J, Camisa C, Ehrlich M, et al: Long-term implications of T-cell receptor gene rearrangement analysis by Southern blot in patients with cutaneous T-cell lymphoma. J Am Acad Dermatol 48:775–779, 2003. 88. Beylot-Barry M, Sibaud V, Thiebaut R, et al: Evidence that an identical T cell clone in skin and peripheral blood lymphocytes is an independent prognostic factor in primary cutaneous T cell lymphomas. J Invest Dermatol 117:920–926, 2001. 89. Bakels V, Van Oostveen JW, Geerts ML, et al: Diagnostic and prognostic significance of clonal T-cell receptor beta gene rearrangements in lymph nodes of patients with mycosis fungoides. J Pathol 170:249–255, 1993. 90. Dabaja BS: Mycosis fungoides, presentation, diagnosis, and treatment strategy. In Thomas CR, Jr, editor: Radiation medicine rounds: hematologic malignancies, New York, 2012, Demos Medical Publishing. 91. Bass JC, Korobkin MT, Cooper KD, et al: Cutaneous T-cell lymphoma: CT in evaluation and staging. 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J Clin Oncol 18:2603–2606, 2000.

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