Chapter 103: Cutaneous T-Cell Lymphoma (Mycosis Fungoides and SéZary Syndrome)

In 1806, Baron Jean-Louis Alibert described a patient who presented with skin patches that grew into plaques and mushroom-like tumors and first coined the term mycosis fungoides (MF).¹² In 1938, Sézary and Bouvrain described a syndrome of pruritus, generalized exfoliative erythroderma, and abnormal hyperconvoluted lymphoid cells in the blood.¹³ Today this condition is referred to as Sézary syndrome (SS), a condition seen in a subset of patients with MF.

Prior to the 1970s, cutaneous lymphomas were believed to be cutaneous counterparts of the systemic lymphomas. In 1975, Lutzner and associates¹⁴ suggested the term cutaneous T-cell lymphoma (CTCL), recognizing that despite the significant similarities of malignant cell morphology and phenotype to systemic T-cell lymphomas, the cutaneous lymphomas represented distinct entities. Although this definition has helped to distinguish cutaneous lymphomas from systemic disease, it has also led to inappropriately using the umbrella term CTCL interchangeably with MF. Common World Health Organization (WHO)–European Organisation for Research and Treatment of Cancer (EORTC) classification was first developed in 2005¹⁵ to resolve differences between various classifications (Table 103–1) and is currently accepted as the standard for CTCL staging and classification.¹⁶

MF is twice as common in males as in females. The median age at diagnosis is 55 years. Americans of African descent have a higher incidence of MF and a poorer prognosis than Americans of European descent. MF occurs least often in Asians and Hispanics. Evidence for a genetic predisposition (germline transmission of susceptibility) in patients with CTCL is inconclusive. An approximately 6 percent increase in incidence of CTCL per decade was documented from the early 1970s to 1998, but the incidence subsequently leveled off and stabilized, with a current incidence of approximately one per 100,000.¹⁷ Incidence is highly age-dependent, with the highest incidence of 3.6 per 100,000 of adults after the age of 70 years. Approximately 3000 new cases of MF are reported annually, comprising approximately 3 percent of all lymphomas. The mortality rate varies widely according to the stage of disease. Stage I mortality does not differ from the mortality of age-matched controls. However, stage IV patients have a 27 percent 5-year survival and 10 percent 15-year survival. Median survival of patients with SS is 1.5 years. The mortality rate of MF in the United States has been declining, possibly because of earlier diagnosis of the disease.^1,18

The etiologies of MF and SS are unknown, although epidemiologic features are suggestive of an infectious origin, including a predilection for elderly individuals and a higher-than-expected incidence in immune-suppressed patients.¹⁹ However, studies to date have failed to reveal consistent associations between any particular infectious agent and CTCL, including novel infectious agents.²⁰ A “persistent antigen stimulation” hypothesis was proposed as an initial event after MF was observed to be a disease of mature CD4+ memory T cells, but the stimulating antigen is not known.^21,22 MF also may be viewed as a disease of immune dysregulation. Tumor progression is associated with decreased antigen-specific T-cell responses and impaired cell-mediated cytotoxicity. On the other hand, improved survival is associated with intact cell-mediated immunity. Progression of MF is associated with progressive T-helper type 2 (Th2) skewing and increased production of Th2 cytokines. This alteration accounts for many of the immune abnormalities associated with advanced MF, such as hypereosinophilia, increased serum immunoglobulin (Ig) A and IgE levels, impaired natural killer (NK) cell function, and impaired cellular immunity.^23,24 Late-stage MF and SS are associated with declining immunocompetence,²⁵ resulting in severe life-threatening infections, and a high incidence of secondary malignancies. The latter increase is not attributable to prior treatment with carcinogenic agents alone.²⁶ Fifty percent of deaths among patients with MF result from infections.

Environmental factors have been suggested in the etiology of CTCL in Europe,^27,28 but have not been confirmed by epidemiologic studies in the United States.

The clinical presentation of MF is highly variable. Cutaneous manifestations of the disease result from skin infiltration by malignant cutaneous lymphocyte antigen (CLA)-positive lymphocytes and depend on the extent of skin involvement. Patients initially may present with “chronic dermatitis” that is resistant to therapy, which is often misdiagnosed as spongiotic dermatitis (so-called eczema), “psoriasis-like dermatitis,” or other chronic, nonspecific dermatoses, usually associated with pruritus. Histologically, diagnosis may be difficult, especially in the early stages of the disease and in its erythrodermic form, as the abnormal atypical infiltrate can be minimal and can be masked by normal inflammatory infiltrates in the skin, or it can be misinterpreted as a normal inflammatory infiltrate because of its mature CD4+ phenotype.

MF may progress through distinct stages of skin involvement, ranging from patch (Fig. 103–1A) to plaque (Fig. 103–1B) to tumor (Fig. 103–1C), but any type of lesion may progress or lesions may arise de novo. For descriptive purposes, the skin manifestations of MF are divided into patch stage (patch-only disease), plaque stage (both patches and plaques), and tumor stage (more than one tumor present, usually in the context of patches and plaques) (Fig. 103–1C). A patch is defined as a flat lesion with various degrees of erythema and fine scaling; it may be atrophic or poikilodermatous (Fig. 103–1D). A plaque is a well-demarcated erythematous, brownish, or violaceous lesion of at least 1 mm elevation with a variable amount of scale. Tumors are elevated at least 10 mm above the skin surface and may resemble a plaque or be dome shaped without significant scaling.

Distribution of the lesions depends on the clinical stage at presentation. In earlier stages, the lesions have a predilection for folds and non–sun-exposed body areas (“bathing trunk” distribution). In later stages, the lesions can affect the face, including development of ectropion, and other areas, such as palms and soles (keratoderma; see Fig. 103–1E). Tumors may be generalized, and ulceration is common. Progression through the stages is variable but commonly occurs over several years.²⁹ Lesions usually are associated with pruritus, which may range from mild to excruciatingly severe, leading to insomnia, weight loss, depression, and suicidal ideation. Pruritus is one of the most important quality-of-life issues for these patients.³⁰

Erythrodermic skin involvement occurs in 5 percent of patients with MF. Manifestations range from very faint to severe, with significant scaling, keratoderma, painful fissures of the hands and feet, nail dystrophy, and nail loss leading to the patient’s inability to walk and maintain daily activities. Severely inflamed skin serves as a breeding ground for bacteria and other pathogens, with resulting fevers, chills, and septicemia.^19,31 Peripheral edema of the extremities may be significant in the later stages and lead to cardiovascular compromise.

Depending on the stage of presentation, patients may present with nodal and/or blood involvement and/or visceral metastases. The earliest stages of MF (e.g., Stage IA and B), may pursue a waxing and waning course, with minimal symptoms and may not have any negative prognostic implications for a patient. The more advanced stages usually, but not inevitably, present with symptoms of the disease. The symptomatology usually reflects the site and severity of involvement and ranges from completely asymptomatic to severe pain, organ malfunction, or at the end stage disease, multi-organ failure.

There is no definitive marker for MF or SS. The diagnosis of CTCL usually is established by correlating clinical and pathologic findings. Early lesions may show polymorphic infiltration (containing mixed inflammatory cells) compatible with several benign dermatoses. Classically, MF lesions show superficial band-like (lichenoid) lymphocytic infiltrate (Fig. 103–2A). The lymphocytes may range from small to large, with characteristic convoluted (cerebriform) nuclei. The hallmark of the malignant infiltrate in MF is epidermotropism (presence of lymphocytes in the epidermis without spongiosis) with formation of the epidermal clusters of lymphocytes around Langerhans cells termed Pautrier microabscesses (Fig. 103–2B). Atypical lymphocytes line up along the dermoepidermal junction and are surrounded by a halo artifact (Fig. 103–2C), which is an important feature of early disease.³² Superficial dermal collagen may be thickened, so called ropey collagen. In more advanced stages, the infiltrate is less polymorphic, with a predominance of larger atypical cells extending deeper into the dermis; epidermotropism may be lost.³³ Transformation to large T-cell lymphoma (CD30+ or CD30−) may occur and carries a poor prognosis in the setting of MF.³⁴

Immunophenotyping plays an important role in diagnosis. The cells usually are CD3+CD4+CD45RO+CD8−, a phenotype associated with mature helper-inducer T lymphocytes. Loss of maturation markers, such as CD7 and CD26 expression on CD4+ are important markers for malignant T lymphocytes.^35,36 The cells may express T-cell activation markers, such as HLA-DR or CD25 (interleukin [IL]-2 receptor). Clonal rearrangement of the T-cell receptor (TCR) Vβ gene can be identified in approximately 90 percent of advanced cases of MF, but in only 50 percent of early stage cases.³⁷ In rare instances, the classic clinical presentation of MF may be associated with an aberrant CD4 phenotype or may have CD4−dyCD8+ T-cell phenotype^38,39 (Fig. 103–3A to C). Recent molecular studies have identified several new markers, which may prove useful as positive markers of the disease, including thymocyte selection-associated high mobility group box factor (TOX), plastin (PLS3), and killer cell immunoglobulin-like receptor KIR3DL2.^40,41,42,43 Cytogenetic abnormalities are not consistently identified, but loss of heterozygosity on 10q and microsatellite instability may be seen in advanced-stage disease.⁴⁴ A possible association exists with homozygous deletion of PTEN and CDKN2A and tumor-suppressor genes on 10p and 9p chromosomes, respectively. These may be silenced with progression of disease.^45,46

STAGING

MF is classified according to the widely accepted modified tumor, node, metastasis, blood (TNMB) classification, originally adopted in 1975 by the Mycosis Fungoides Cooperative Study Group^47,48 and revised to match modern developments in the field.¹⁶ Accurate determination of the stage in MF and SS is of utmost importance because of its prognostic significance and critical role in selecting therapy. Cutaneous lesions are classified using the T staging system (Table 103–2). The area of the skin and type of the lesions were found to correlate with patient survival and are important prognostic predictors and need to be calculated at every visit to assess disease status.⁴⁹ Prognosis varies according to tumor burden. The presence of tumors (T3) may indicate a worse prognosis than erythroderma (T4).¹⁸

The extent of extracutaneous disease usually correlates with the extent of skin involvement. In early disease, significant involvement of lymph nodes and blood is unlikely. However, lymphadenopathy is present in more than half of patients as disease advances and increases with progressive cutaneous involvement. Lymph nodes are assigned N category in the TNMB staging of MF¹⁶ (see Table 103–2). Computed tomography (CT) and positron emission tomography (PET) scans are used to assess involvement of lymph nodes.^50,51 Excisional lymph node biopsy is usually recommended to assess the extent of the disease and nodal architecture, but other techniques, including fine-needle aspiration, are selectively used as well.⁵²

Histopathologic examination of affected lymph nodes may show partial or complete effacement of normal architecture, with a monomorphic infiltrate of MF cells. However, in most cases, the nodal architecture is not effaced, and dermatopathic changes are present with varying numbers of atypical lymphocytes in the T-cell paracortical areas of the node. Even the presence of dermatopathic changes alone in the lymph nodes carries prognostic significance (see Tables 103–2 and 103–3).^53,54 Abnormal lymph nodes should be biopsied regardless of the T stage.

Metastatic disease (including patients with positive nodes) is the most significant prognostic predictor (see Tables 103–2 and 103–3). Patients with visceral involvement that includes liver, spleen, pleura, and lung have a median survival of less than 1 year.⁵⁵ Blood involvement may be an important predictor of progression and survival (Figs. 103–4 and 103–5).⁵⁶ The number of circulating Sézary cells increases with advancing disease, and the cells are particularly prominent in patients with generalized erythroderma. However, even in early stage disease, a high frequency of clonal T cells in the blood may be detected using a highly sensitive polymerase chain reaction (PCR) technique, suggesting that early systemic disease is common.⁵⁷ Blood involvement is rated as B category in the TNMB staging (see Table 103–2). For staging purposes, the B2 blood rating is equivalent to nodal involvement.^58,59 The B2 rating is defined as (1) a Sézary cell count of 1000 cells/mm³ or more; (2) a CD4-to-CD8 ratio of 10 or higher caused by an increase in circulating T cells and/or an aberrant loss or expression of pan–T-cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-cell clone in the blood determined by the Southern blot or PCR technique; or (4) a chromosomally abnormal T-cell clone. Malignant cells also can be detected using sensitive techniques such as cytogenetics or TCR gene rearrangement studies.^{60,61,62,63,64} Patients with blood involvement have a higher likelihood of lymphadenopathy and visceral involvement. Marrow infiltration is infrequently detected by biopsy despite circulating malignant cells; it is identified at autopsy in 30 to 40 percent of cases. The cytologic appearance of the malignant cells in visceral organs is similar to that of the malignant cells in the skin.⁶⁵

In the erythrodermic subset of MF, three T4 subsets can be identified (Table 103–4). In general, in SS, a triad of exfoliative erythroderma, generalized lymphadenopathy, and leukemia, has the worst prognosis among the forms of MF.

Diagnosis of MF is based on a constellation of findings, which include clinical presentation, skin and lymph node biopsies (if indicated), and blood evaluation. A number of benign dermatoses can mimic MF or SS, and may even have TCR gene rearrangements.^66,67,68,69 Such benign conditions include psoriasis and psoriasiform dermatoses (such as pityriasis rubra pilaris, seborrheic dermatitis, contact dermatitis, and eczema), intertrigo, tinea, drug eruptions, and other conditions.

Cutaneous and systemic lymphomas other than MF should be considered in the differential diagnosis. Smoldering adult T-cell leukemia/lymphoma has a number of clinical features similar to MF, but it usually can be distinguished by the presence of antibodies to human T-lymphotropic virus type 1 (HTLV-1) and by other associated findings unusual in MF. However, this distinction may be difficult.^70,71

Pagetoid reticulosis (Woringer-Kolopp disease) is a rare skin disorder that consists of solitary or localized cutaneous plaques. It affects young males almost exclusively. It has a benign course, and the prognosis is excellent.^72,73,74 It is an epidermal process, with the majority of atypical lymphocytes found within hyperplastic epidermis.⁷⁵ Although the disease usually is indolent and localized, some patients present with a disseminated form referred to as the Ketron-Goodman variant.⁷⁶ The histologic findings are similar to those found in Woringer-Kolopp disease, with predominantly epidermal involvement by malignant cells and a poor prognosis.⁷⁶ This variant is a disease of an activated T lymphocyte that only occasionally expresses the helper T-cell CD4 antigen.^77,78 Like MF, the neoplastic cells have TCR gene rearrangements.

Other mimics of CTCL, such as alopecia mucinosa, contact dermatitis, lichen planus, parapsoriasis, pediatric atopic dermatitis, pemphigus foliaceus, plaque psoriasis, pustular psoriasis, and tinea corporis, should be considered in the differential diagnosis. The diagnosis is made by appropriate investigation (e.g., potassium hydroxide skin prep) and skin biopsy. CD30+ (Ki-1) and CD30− lymphomas can mimic tumors of MF; they present as erythematous or violaceous nodules that ulcerate. The critical issue is to differentiate primary cutaneous CD30+ lymphoproliferative disorder from CD30+ large cell transformation of MF and from secondary cutaneous involvement caused by CD30+ nodal lymphoma. The course of CD30+ lymphomas of the skin is indolent, they carry a favorable prognosis and tend to regress spontaneously, whereas transformed MF and nodal lymphoma have poor prognoses. In rare instances, these lymphomas progress to systemic involvement and have the same prognosis as nodal CD30+ lymphomas.^79,80 Lymphomatoid papulosis (LyP) is a benign counterpart of CD30+ lymphoproliferative disorders of the skin with excellent prognosis. It usually presents as crops of recurrent pruritic or painful erythematous papules or nodules, which ulcerate and heal spontaneously. LyP usually runs a chronic course.⁸¹ LyP may be associated with other malignancies, particularly MF and other lymphomas, in up to 10 percent of cases. Therefore close observation and followup are recommended for patients with LyP. Low-dose oral methotrexate is the drug of choice for treatment of LyP.

A variety of therapeutic modalities produce remissions in most patients with MF. In general, MF therapy is divided into (1) skin-directed therapy (SDT) and (2) systemic therapy (Table 103–5). SDT is the mainstream therapy in early disease but also is used as an adjunct in systemic disease. Therapeutic decisions may be difficult and heavily depend on the stage at presentation. Revised practice guidelines are available on National Comprehensive Cancer Network (NCCN) website (www.nccn.org). See Fig. 103–6 for an overview of the treatment algorithm for MF/SS. In view of the protracted course of the disease and lack of curative therapies, therapeutic decisions should generally be focused on induction of long-term remissions with the least toxic agents and regimens. A number of highly effective monotherapies were recently shown to be safe and effective in patients with MF and SS in prospective clinical trials, leading to their approval by the FDA in the United States and abroad. Several novel agents are in clinical trials to test for their efficacy as monotherapy for MF. In addition, there are number of promising combination regimens being tested in clinical trials examining systemic multiagent therapies in advanced MF or SS to guide therapeutic decisions.

SKIN-DIRECTED THERAPIES

Topical Glucocorticoids

These agents are effective during early stages of MF. They are limited to temporary short-term use because of suppression of collagen synthesis (skin atrophy), striae formation, skin fragility, and secondary infections. The class of topical preparation depends on the area and the site of involvement. Ultrapotent topical glucocorticoids should not be used on the face, neck, and intertriginous areas. Topical steroids are rarely used as monotherapy, but may be effective as an additional modality for symptomatic relieve of pruritus.

Topical Tacrolimus (Protopic) Topical tacrolimus has been approved for use in atopic dermatitis. It is as effective as mid- to low-potency glucocorticoids for use on facial skin and intertriginous areas in patients with MF. A major advantage of tacrolimus compared with steroids is that it does not suppress collagen synthesis and therefore does not cause skin atrophy.⁸² However, because the use of calcineurin inhibitors in CTCL is controversial,⁸³ tacrolimus use should be limited to short-term use on small areas.

Topical Nitrogen Mustard (Mechlorethamine Hydrochloride) Topical nitrogen mustard is a topical alkylating agent used predominantly in patients with early stages of the disease (stages IA and IB), but can be used as a part of combination therapy with systemic agents in advanced stages. Prior to FDA-approval of mechlorethamine hydrochloride 0.02 percent gel in 2013,⁸⁴ it was only available through certified compounding pharmacies in forms of solution, cream or ointment of various concentrations (0.01 to 0.04 percent). The major advantage of this topical therapy is its relatively low toxicity. Disadvantages include the inconvenience of daily application to large areas of skin, allergic reactions in up to half of cases,⁸⁵ the potential for development of skin cancer,⁸⁶ and the inability to cure the disease. Therapy is usually continued for up to 12 months in responders. Frequency then is reduced to every other day for an additional 1 to 2 years. Therapy is discontinued after 3 years or when cutaneous lesions disappear completely. Mechlorethamine should not be used together with ultraviolet A (UVA) or ultraviolet B (UVB) therapy because of cumulative carcinogenic effects on the skin and significant increase in risk for skin cancer and melanoma.

Topical Carmustine (Bis-Chloroethylnitrosourea [BCNU]) BCNU is not currently widely used for treatment of MF because of its severe irritant reactions and its absorption from the skin that results in systemic toxicity. The preparation ranges from 20 to 40 mg/dL in petrolatum ointment. It is applied at night and washed off in the morning. Monitoring includes biweekly complete blood counts to identify marrow suppression. Carmustine causes irreversible skin thinning, telangiectasias, and hyperpigmentation.⁸⁷

Topical Retinoids Bexarotene (Targretin) 1 percent gel, is a topical retinoid (rexinoid) FDA-approved for treatment of MF patients who are refractory to at least one other topical therapy. It is a small lipophilic molecule related to vitamin A. It readily crosses the cytoplasmic membrane and binds to nuclear receptors (retinoid X receptors [RXRs]), resulting in changes in gene expression mediated through specific intracellular receptors, leading to maturating and apoptosis of malignant cells.⁸⁸ Complete responses of 20 percent and overall responses of 60 percent are reported.^89,90 It is applied in a thin layer to the patches and plaques twice daily. The major toxicity is irritation at the site. Oral administration of bexarotene is associated with severe birth defects. Considering potential absorption of the drug from the skin surface, bexarotene should not be given to pregnant women.

Phototherapy Phototherapy is a well-established effective treatment for MF, utilizing ultraviolet radiation of the UVA and UVB spectra. It is not FDA-approved for treatment of MF and SS because of a lack of prospective clinical trials, but is considered to be one of the most effective therapies for early disease (mainly patches and thin plaques). Phototherapy may result in complete clearing of the lesions. It was hypothesized that the mechanism of action of this therapy is Langerhans’ cells depletion from the epidermis.⁹¹

The peak of therapeutic effectiveness of UVB is within 295 to 313 nm. Conventional broad band UVB lamps emit wavelengths ranging from 280 to 330 nm, but narrow band UVB (NBUVB) emits only wavelengths 311 to 312 nm, eliminating harmful UV rays below 300 nm, which can cause erythema or severe burning and increase the risk of skin cancer.^92,93,94 Similarly, excimer lasers emitting at 308 nm can be successfully used for hard to reach areas resistant to other therapy.⁹⁵ NBUVB may be a viable alternative to psoralen with UVA radiation (PUVA) with similar response rates in a small cohort.⁹⁶ Therapy should be instituted three times per week. On average, 6 to 12 weeks are required to achieve response. Maintenance therapy is required after a response occurs for at least 2 more months, but thereafter the maintenance regimen for various light sources is not well established and depends on the personal experience of the treating physician.

The UVA spectrum ranges from 320 to 400 nm, therefore UVA light penetrates deeper than UVB, into the dermis. Phototherapy involving UVA radiation is used with psoralen and is referred to as PUVA. Psoralen is a phototoxic furocoumarin activated by UVA light. In its active form, psoralen bonds covalently and irreversibly to DNA. Therefore, psoralen activated by UVA light affects cells primarily in the epidermis and papillary dermis. A 60 percent complete remission rate and long-term remissions (>10 years) have been reported with PUVA; patients with generalized erythroderma and tumors have lower response rates than patients with plaques.^97,98,99 Psoralen usually is given at a dose of 0.6 mg/kg orally, 2 hours before the UVA light therapy. Treatments initially are given three times per week. Maintenance therapy may be given every 2 to 4 weeks for an indefinite period. Adverse effects of PUVA therapy include mild nausea, pruritus, and sunburn-like changes, with atrophy and dry skin. PUVA is not cross-resistant with other treatment modalities. Disadvantages of PUVA therapy are its necessity to visit doctor’s office frequently (from three times a week to once a month) and its expense. Long-term side effects include an increased incidence of skin cancers and melanoma.¹⁰⁰

Photodynamic Therapy Photodynamic therapy is a photochemotherapy that utilizes two properties of porphyrins: their selective accumulation in tumor sites (e.g., 5-aminolevulinic acid) and their ability to generate cytotoxic oxygen species at the tumor site after red-light irradiation. 5-Aminolevulinic acid is a natural porphyrin precursor and upon irradiation is converted in the tumor to the highly photoactive endogenous protoporphyrin IX. Red-light irradiation is safe and penetrates deep in the tissue, allowing for treatment of thick tumors. Photodynamic therapy is especially useful in patients with limited skin area involved by few tumors. The main problem with the treatment is that the pain induced during irradiation limits its use for larger areas.^101,102 It is used for therapy of MF off-label.

Electron Beam Therapy Electron beam therapy is a highly effective form of treatment of MF and can be used as a localized therapy (LEBT) to specific sites or lesions, or as radiation of the entire skin surface (total skin electron beam therapy [TSEBT]). It delivers a uniform dose from the surface to a specific depth, after which the dose falls off rapidly, sparing deeper normal tissues. It is usually delivered to penetrate only into the dermis, systemic effects are minimal, and the complete remission rate is 80 percent.^3,103,104 Twenty percent of patients remain relapse free after 3 years. The relapse rate depends on the stage of the disease, and the relapse usually is short lived (may be as short as 2 to 3 weeks) in patients with erythroderma or numerous tumors. In the past, the treatment regimen was 4 Gy per week to a total dose of 36 Gy in 8 to 9 weeks. However, low-dose electron beam therapy has been shown to be nearly as effective, eliminating the usual side effects, such as alopecia, skin atrophy, destruction of skin adnexa, dermatitis, and increased risk of cutaneous malignancy.^{105,106,107,108} The advantage of electron beam therapy is the high frequency of durable complete responses without systemic toxicity. Up to three courses of electron beam therapy can be safely administered when used in a highly fractionated fashion (1 Gy per dose).

Imiquimod (Aldara) Imiquimod is a topical immunomodulator that is extremely effective in the treatment of condylomata acuminata, actinic keratoses, basal cell carcinomas, keratoacanthomas, and other cutaneous malignancies. The mode of action is not known but is thought to be related to induction of tumor necrosis factor-α and interferons resulting in activation of a Th1-type immune response and rejection of cancer or virally infected cells. Several groups reported the effectiveness of imiquimod in early patch MF.^109,110 It should be used three times per week for 3 months. It is not FDA-approved for therapy of MF and SS.

SYSTEMIC THERAPY

Oral Retinoids

Bexarotene (Targretin) is an FDA-approved RXR-selective retinoid, or “rexinoid,” for therapy of the MF. It is a first-line systemic agent for patients without contraindications to retinoids. At the currently FDA-approved dose of 300 mg/m²/day the overall response rate to bexarotene monotherapy ranges from 45 to 57 percent with at least 2 percent complete responses.^111,112 Higher doses are associated with higher response rates and shorter time to response, but also with a higher incidence of adverse events. All patients on bexarotene rapidly develop central hypothyroidism and hyperlipidemia (most significantly hypertriglyceridemia), requiring coadministration of thyroid supplements and lipid-lowering agents. Other rare adverse events include headaches, possibly a result of pseudotumor cerebri, leucopenia, and pruritus. The majority of side effects are laboratory findings and dose-dependent; bexarotene is usually well tolerated by the patients. Its use is recommended beginning with refractory or persistent stage IA disease as well as in more advanced stages (NCCN guidelines). Standard procedures for management of patients on bexarotene therapy are reviewed.¹¹³ Bexarotene is safe to use long-term for maintenance therapy. Bexarotene and other retinoids are labeled pregnancy Category X, and must not be given to a pregnant woman or a woman who intends to become pregnant.

Other retinoids have been used for treatment of MF and SS, including isotretinoin, acitretin, etretinate (not available in United States), and all-trans retinoic acid (ATRA). Activity of these compounds in MF/SS has been demonstrated in case series or small open-label pilot studies, but there are no prospective studies formally evaluating these drugs.¹¹⁴

Histone Deacetylase Inhibitors Vorinostat is an oral histone deacetylase inhibitor (HDACi), which was FDA-approved for treatment of cutaneous manifestations of recurrent, refractory or persistent MF and SS in 2008 at the dose of 400 mg by mouth daily.¹¹⁵ Vorinostat was evaluated in an open-label phase IIb clinical trial and was shown to have an overall response rate of 30 percent. No complete responses were observed on the clinical trial. Median time to relapse in patients with advanced disease was 56 days. Median time to progression was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32 percent of patients had pruritus relief. The most common drug-related adverse events were diarrhea (49 percent), fatigue (46 percent), nausea (43 percent), and anorexia (26 percent); most were grade 2 or lower but those grade 3 or higher included fatigue (5 percent), pulmonary embolism (5 percent), thrombocytopenia (5 percent), and nausea (4 percent).

Romidepsin is a selective HDACi given as an intravenous infusion. Romidepsin was FDA-approved for therapy of CTCL based on a phase IIB clinical trial documenting an overall response rate of 34 percent, with 6 percent complete responses.¹¹⁶ The median duration of response was 13.7 months. Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Romidepsin was shown to have single-agent clinical activity with significant and durable responses in patients with CTCL.¹¹⁶ HDACi may be excellent combinational agents, potentiating effects of other therapies, possessing a radio- and photosensitizing effects. Several clinical trials are on the way examining potential combinations, including electron beam.¹⁰⁶

Interferon-α Interferon-α can be used as a single agent or combined with other systemic therapies. The response rate when interferon-α is used as a monotherapy is 50 to 70 percent at doses beginning at 3 to 5 × 10⁶ units/day or three times per week, either subcutaneously or intralesionally.¹¹⁷ Toxicity includes acute flu-like symptoms and fatigue. It is commonly used in combination with other immunotherapies (such as extracorporeal photopheresis [ECP] and phototherapy), but this practice is based on small case series and small prospective studies. It is not clear if combinations truly result in improved clinical outcomes.^10,118,119

Extracorporeal Photopheresis PUVA can be delivered by an extracorporeal technique.^120,121 White cells are collected by leukapheresis, exposed to a photoactivating drug, and irradiated with UVA. The cells then are reinfused into the patient. The effect may be both a direct cytotoxic effect on the tumor cells and an immunologic effect by activating lymphocytes against the tumor cells. Photopheresis typically is administered every 2 to 4 weeks until clearance of disease. Side effects are minimal and may be related to fluid shifts during the procedure.¹⁰⁰ A recent retrospective review suggested a survival advantage for patients treated with ECP¹²² and beneficial responses in patients with early stage MF.¹²³

Monoclonal Antibodies Alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody that targets the CD52 antigen. A response rate of 50 percent has been reported in a small cohort of patients.^124,125 Low-dose alemtuzumab was shown to be safe and effective in very elderly SS patients.¹²⁶ Alemtuzumab effectively depletes leukemic cells from blood of these patients. Very low doses on an as needed basis were reported to be effective long-term in SS patients.¹²⁷ Numerous monoclonal antibodies are in clinical trials now as single agents and in combinations, including anti–PD-1 antibodies and anti-CCR4 antibody.

Monoclonal Antibody Conjugates Brentuximab vedotin (SGN-35) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent antimicrotubule agent monomethyl auristatin E (MMAE). Following binding to CD30, brentuximab vedotin is rapidly internalized and transported to lysosomes where MMAE is released and binds to tubulin, leading to cell-cycle arrest and apoptosis. Brentuximab was recently FDA-approved for CD30+ cutaneous T-cell lymphomas, showing durable antitumor activity with a manageable safety profile in patients with relapsed/refractory primary cutaneous CD30-positive lymphoproliferative disorders.¹²⁸ The overall response rate was 73 percent, with 54 percent for MF and 100 percent for all other tumor types (LyP and primary cutaneous anaplastic large cell lymphoma [PCALCL]). Response was not correlated with level of CD30 expression at baseline in MF. Peripheral sensory neuropathy is a significant adverse event associated with brentuximab vedotin administration. Neuropathy symptoms are cumulative and dose related. Multiple ongoing trials are currently evaluating brentuximab vedotin alone or in combination with other agents in relapsed/refractory patients, as well as patients with newly diagnosed disease.

Recombinant Fusion Proteins Denileukin diftitox (DD) is an IL-2 diphtheria toxin fusion protein, which had full FDA approval in October 2008 following a phase III randomized, double-blind, placebo-controlled trial.¹²⁹ The overall response rate was 37 percent at a dose of 9 μg/kg/day and 46 percent with 18 μg/kg/day, which was statistically significant (p = 0.002) compared to placebo. Patients receiving 18 μg/kg/day had a progression-free survival of 971+ days and duration of response of 220 days. Time to response was 92 days; time to treatment failure was 169 days. Importantly, 45 percent of best responses occurred during cycle 4 and beyond, suggesting that an appropriate trial of the drug is necessary to achieve optimal responses. All complete responses occurred after four or more cycles.¹²⁹ Side effects were numerous, including a capillary leak syndrome, infection, hepatitis, increased fluid retention, rash, shortness of breath, and flu-like symptoms such as chills, fever, weakness, bone and muscle pain, headache, nausea, and vomiting. Cardiac arrhythmias and thrombotic emergencies have been reported occasionally. Usually, adverse events are most severe during the first two cycles, diminishing as the treatments continue. DD manufacturing was discontinued and a new formulation of the same product is in clinical trials at this time.

Chemotherapy Several agents have been FDA-approved for therapy of various subsets of MF and SS.

Pralatrexate is a novel antifolate with high affinity for reduced folate carrier-1, which was recently FDA-approved for therapy of transformed MF (tMF). The recommended regimen was identified as 15 mg/m² a week for 3 of 4 weeks; the response rate was 45 percent.¹³⁰ The most common grade 3 adverse event (AE) was mucositis (17 percent); the only grade 4 AE was leukopenia (3 percent). MF patients were not able to tolerate the “lymphoma” dosage of pralatrexate (30 mg/m² a week for 6 of 7 weeks) because of intolerable toxicities, including severe mucositis. It was hypothesized that the higher incidence of mucositis was a result of distribution of malignant cells from the skin and mucosal surfaces beyond visible lesions resulting in “localized” tumor necrosis in the skin with collateral damage to surrounding tissues. Administration of a single 10 to 15 mg dose of leucovorin 24 hours following pralatrexate infusion, completely abrogated these side effects and allowed therapy with 30 mg/m² without sacrificing efficacy.¹³¹

Alkylating agents used to treat MF and SS include nitrogen mustard topically or systemic cyclophosphamide, or chlorambucil. Response rates of 60 percent, with 15 percent complete remissions, have been reported.^132,133 Similar results are obtained with methotrexate 2.5 to 10 mg/day orally¹³⁴; bleomycin 7.5 to 15 mg intramuscularly given twice weekly; and doxorubicin 60 mg/m² intravenously given once per month.^135,136 Pegylated doxorubicin used in advanced MF has resulted in an overall response of 88 percent.¹³⁷ Purine analogues including fludarabine and pentostatin have response rates as high as 50 percent.^138,139,140 Gemcitabine has a similar response rate.¹⁴¹ Neither single-agent or multiagent therapy cures MF. Chemotherapy with a single agent and polychemotherapy result in a higher incidence of transformation to large cell lymphoma, which carries a worse prognosis than the original diagnosis.^142,143 Because responses to therapy are generally higher after combination therapy, single-agent chemotherapy is used rarely. However, use of multiagent chemotherapy results in increased immunosuppression and an increased risk of serious infections, leading to death in the majority of patients who develop this complication.¹⁴⁴ Combination therapy produces objective responses in greater than 80 percent of patients and complete responses in approximately one fourth of cases.^99,145 The duration of remission varies, with a median of approximately 1 year. No long-term disease-free survival has been reported.

Combined Modality Therapy Several multidrug regimens reportedly improve clinical response in patients with MF, including combination of extracorporeal photophoresis with low-dose interferon-α and oral bexarotene; prednisone and fludarabine; and PUVA and oral bexarotene.^3,146

Because in general MF is an indolent malignancy of T cells with excellent prognosis in early stages, the treatment should be conservative, with skin-directed therapies (nitrogen mustard, topical glucocorticoids, topical bexarotene) combined with light therapy, low-dose interferon, low-dose methotrexate, or other single-agent chemotherapy. The survival of patients treated with aggressive chemotherapy is not different from the survival of patients treated conservatively, but aggressive chemotherapy results in greater toxicity. Because no curative therapy exists, the goal of therapy is to prevent progression to more advanced stages and to preserve the patient’s quality of life for as long as possible.

Prognosis largely depends on the stage at presentation. Fifty percent of deaths among patients with MF result from infections. Septicemia and bacterial pneumonia are common; they usually are caused by Staphylococcus or Pseudomonas and develop from cutaneous lesions.⁵⁴ Herpes virus infections occur in up to 10 percent of patients with advanced MF. Progressive MF with widespread visceral involvement late in the course of the disease is the next most common cause of death.

CLINICAL FINDINGS

CD30+ cutaneous lymphoproliferative disorders are the second most common CTCLs after MF and represent approximately 25 percent of CTCL cases.⁸¹ PCALCL represents a spectrum of CD30+ lymphoproliferative disorders, including LyP and PCALCL as its malignant counterpart. It is defined by the presence of skin involvement without evidence of extracutaneous disease for at least 6 months after presentation.¹³ Secondary involvement of lymph nodes may not necessarily be associated with a worse prognosis.¹⁴ In some cases, distinction between LyP and PCALCL cannot be made because of discrepancies between clinical features and histologic appearance. These cases are referred to as borderline lesions, and their classification should take into consideration their clinical behavior and appearance (Fig. 103–7A).

Other CD30+ cutaneous lymphoproliferative disorders include large cell transformation of MF, systemic anaplastic large cell lymphoma (ALCL), cutaneous NK/T-cell lymphoma, and Hodgkin lymphoma. Making the distinctions between these diagnoses is critical because management and prognosis are significantly different (see “Treatment” below). The descriptive term anaplastic could be omitted from the name of this lymphoma because these lymphomas may have an anaplastic, immunoblastic, or pleomorphic cell morphology. Regardless of pathologic type, these CD30+ large cell lymphomas have a similar clinical course, treatment, and prognosis.^{81,147,148,149}

CD30+ PCALCL can occur at any age, with the peak incidence in patients in their 60s, with a slight male predominance.^79,150 PCALCL can occur anywhere on the body. The lesions are brownish to violaceous nodules or tumors, ranging in number from solitary (most commonly) to numerous with generalized involvement. They may regress spontaneously. Histopathologically, at least 75 percent of the large cells should express CD30. Most cases are CD4+, with loss of pan–T-cell markers CD2, CD3, and CD5. In rare cases, the cells are CD8+CD30+. In contrast to systemic ALCL, primary cutaneous large cell lymphoma is negative for CD15 and epithelial membrane antigen.¹⁵¹ In addition, primary cutaneous large cell lymphoma usually does not express anaplastic lymphoma kinase-1 (ALK-1) or the t(2;5) chromosomal translocation.^152,153 Presence of ALK-1 in cutaneous lesions without systemic involvement does not carry a worse prognosis.

LyP is the benign counterpart of primary cutaneous ALCL. It is characterized by crops of erythematous, dome-shaped papules or nodules that may ulcerate spontaneously. It regresses over a few months with minor sequelae such as scarring or atrophy (see Fig. 103–7B). The three main histologic types of LyP are A, B, and C. The infiltrate usually is wedge shaped with ulcer formation. The large atypical cells of type A resemble immunoblasts of Reed-Sternberg cells. These cells are surrounded by neutrophils and eosinophils. Type B cells resemble MF, with lichenoid lymphocytic infiltration of cells with cerebriform nuclei and some epidermotropism. Type C cells resemble ALCL, with sheets of large CD30+ cells in the infiltrate. The histologic distinction between LyP and the corresponding condition may be difficult, and clinical correlation is required.¹⁵⁴ In rare cases, LyP evolves into more aggressive primary cutaneous large cell lymphoma. In addition, a higher incidence of lymphoid and nonlymphoid malignancies is observed in patients with LyP.¹⁵⁵

TREATMENT

LyP is extremely responsive to low-dose methotrexate therapy, requiring 10 to 15 mg orally weekly, with noticeable clinical response within a month. Brentuximab vedotin was shown to be highly effective in patients with PCALCL and LyP (see section Monoclonal Antibody Conjugates above). Other treatment options include oral PUVA therapy, retinoids, topical and systemic glucocorticoids, and intralesional and systemic interferon-α.^81,147,154 Treatment of primary cutaneous large cell lymphoma depends on the extent of skin involvement. In cases of solitary lesions, radiotherapy is often the best initial treatment modality. A combination of PUVA and interferon-α may be considered for more disseminated disease. Combination chemotherapy should be reserved for resistant cases.^81,147,156