- Email: [email protected]
Mycosis fungoides
Critical Reviews in Oncology/Hematology 65 (2008) 172–182
Mycosis fungoides Pier Luigi Zinzani a,∗ , Andr´es J.M. Ferreri b , Lorenzo Cerroni c a
L. and A. Seragnoli Institute of Hematology and Oncology, University of Bologna, Bologna, Italy Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy c Department of Dermatology, Medical University of Graz, Austria
b
Accepted 23 August 2007
Contents 1.
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General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Immunophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Genetic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Diagnostic criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Additional useful tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Staging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Staging system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Molecular analysis of minimal residual disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Restaging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Treatment of stage IA disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Treatment of stage IB–IIA disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Treatment of stage IIB disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Treatment of stage III disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Treatment of stage IV disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. New active drugs and therapeutic options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
173 173 173 173 173 173 173 173 174 174 174 174 175 175 175 175 175 175 175 176 176 176 177 177 177 177 178 178 178 181
Abstract Mycosis fungoides (MF) constitutes the most frequent cutaneous T-cell lymphoma. Sezary syndrome is considered by some authors to be an erythrodermic leukemic variant of MF, but is classified separately in the new WHO-EORT classification of cutaneous lymphomas. MF
∗
Corresponding author. Tel.: +39 051 6363680; fax: +39 051 6364037. E-mail address: [email protected] (P.L. Zinzani).
1040-8428/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2007.08.004
P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 65 (2008) 172–182
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usually occurs in old adults with a 2:1 male to female ratio. Its prognosis is variable and strongly conditioned by the extent and type of skin involvement and presence of extracutaneous disease. Patients with stage IA-disease have an excellent prognosis with an overall long-term life expectancy that is similar to an age-, sex-, and race-matched control population. Almost all patients with stage IA MF will die from causes other than MF, with a median survival >33 years. Only 9% of these patients will progress to more extended disease. Patients with stage IB or IIA have a median survival greater than 11 years. These patients with T2 disease have a likelihood of disease progression of 24% and nearly 20% die of MF. Subgroups with stage IB or IIA have similar prognosis. Patients with cutaneous tumors or generalized erythroderma have a median survival of 3 and 4.5 years, respectively. The majority of these patients will die of MF. Extracutaneous dissemination is observed in less than 10% of patients with patch or plaque disease and in 30–40% of patients with tumors or generalized erythrodermatous involvement. Extracutaneous involvement is directly correlated to the extent of cutaneous disease. The most commonly involved organs are lung, spleen, liver, and gastrointestinal tract. Patients with extracutaneous disease at presentation involving either lymph nodes or viscera have a median survival of <1.5 years. Patients with plaque-type or erythrodermic MF may develop cutaneous tumors with large cell histology, often expressing CD30, which share a common clonal origin as observed in their preexisting MF and are associated with a less favourable outcome. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Mycosis fungoides; Sezary syndrome; T-cell lymphoma
1. General information 1.1. Definition Mycosis fungoides (MF) constitutes the most frequent cutaneous T-cell lymphoma. Sezary syndrome is considered an erythrodermic leukemic variant of MF. Its postulated normal counterpart is a peripheral epidermotropic CD4+ T-cell. Mycosis fungoides is included in the new WHO-EORTC classification of primary cutaneous lymphomas [1]. 1.2. Incidence Mycosis fungoides (MF) is an uncommon lymphoma; however, it is the most common of the primary cutaneous lymphomas. MF constitutes 50% of all primary NHL of the skin [1]. Annual incidence is 0.29/100.000, being about 0.5% of all new cases of NHL diagnosed in the USA each year [2].
and translocations in chromosome 1 or 6 [8]. Recently, new molecular studies revealed alterations of NAV3 in MF and Sezary syndrome [9]. The significance of these features is yet unclear.
2. Pathology and biology 2.1. Morphology The tumor cells of mycosis fungoides are predominantly small cells with cerebriform nuclei, with a minority of larger cells with similar nuclei, which infiltrate the epidermis, circulate in the blood and involve the paracortex of lymph nodes. Atypical cells may be completely absent in early lesions [10]. The infiltrate is variable accompanied by interdigitating and Langerhans’ cells. The bone marrow is usually normal. Although MF presents usually with band-like, epidermotropic infiltrates, several clinicopathologic variants have been described (e.g., follicular MF, etc.).
1.3. Risk factors
2.2. Immunophenotype
The cause and risk factors of MF and Sezary syndrome are unclear. Although environmental and occupational exposures, such as exposure to solvents and chemical, have been implicated in the etiology of the disease, the most recent large case-controlled study failed to support this hypothesis [3]. A viral etiology for MF has been also suggested. There are some reports that have found human T-lymphotrophic virus-1 (HTLV-1) either in the peripheral blood or cutaneous lesions of some patients with MF or Sezary syndrome [4]. However, many studies have revealed evidence against a role of HTLV-1 [5]. At present, HTLV-1 is not considered to play any role in the etiology of MF. The role of other viruses such as cytomegalovirus is still unclear [6]. A few studies have demonstrated histocompatibility antigen associations with MF and Sezary syndrome, specifically Aw31, Aw32, B8, Bw38, and DR5 [7]. Chromosomal abnormalities have been identified in tumor cells, mostly deletions
The cells of mycosis fungoides express T-cell-associated antigens (CD2+, CD3+, CD5+), approximately one third are CD7+; most cases are CD4+, but rare CD8+ and/or CD56+ cases have been reported. CD25 is usually negative, but positive cases have been reported. S-100+ CD1a+ interdigitating and Langerhans’ cells are present [11]. Flow cytometric studies of the peripheral blood may show expansion of the CD4+ CD7− population reflective of circulating atypical lymphocytes of Sezary type [12]. 2.3. Genetic features TCR genes are clonally rearranged, but detection of a monoclonal population of T lymphocytes may be difficult in early lesions [10]. TCR gene-rearrangement studies may show evidence of clonal expansion in peripheral blood in patients with Sezary syndrome [13]. Several chromosomal
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aberrations have been described using different molecular methods, but at present a repeatable pattern has not been identified.
3. Diagnosis 3.1. Clinical presentations Mycosis fungoides (MF) usually occurs in old adults, with a median age between 55 and 60 years and a 2:1 male to female ratio, presenting with multiple cutaneous plaques or nodules, or with generalized erythroderma. Cases in children have been well documented. MF presents as an indolent cutaneous eruption with erythematosus scaly patches or plaques that often resemble common skin disorders such as atopic dermatitis or psoriasis. The initial lesions are often confined to sun-protected areas, although any skin site may be affected. There may be prominent poikiloderma (skin atrophy with slight hyperpigmentation and telangiectasia) or associated alopecia or with follicular mucinosis. In addition, several other clinical variants have been described (e.g., hypopigmented MF among others). Especially in the past, a definitive diagnosis was often preceded by a variably long period (often referred to as the “premycotic” stage) that could range from several months to several years [14]. However, the identification of precise histopathologic criteria for diagnosis of early MF allows a specific diagnosis in most cases [10,15]. As the disease progresses, patches may evolve into infiltrated plaques with a more generalized distribution, and patients may subsequently develop ulcerated or exophytic tumors. Tumors, however, develop only in a minority of the patients [1,16]. Another phase of skin involvement is generalized erythroderma. The erythema may be accompanied by either very atrophic or lichenified skin, and plaques or tumors may also be present. These patients are almost always affected by intense pruritus. If peripheral blood involvement is present, these patients are considered to have Sezary syndrome. It is controversial as to how many or what percentage of Sezary cells constitute a significant level to define Sezary syndrome. Although the original NCI classification used the criterion of greater than 5% lymphocytes for significant blood involvement [17], the current practice by many MF referral centers is to use a criterion of at least 20% lymphocytes or an absolute count of at least 1000/mm3 to define peripheral blood involvement. Precise criteria for definition of Sezary syndrome have been proposed in the new WHO-EORT classification of cutaneous lymphomas [1]. Sezary syndrome is considered by some authors to be an erythrodermic leukemic variant of MF, but is classified separately in the new WHO-EORT classification of cutaneous lymphomas [1]. Patients present with generalized erythroderma, lymphadenopathy and circulating atypical T-cells (Sezary cells) in the peripheral blood. Peripheral blood involvement may be subtle in MF or prominent in Sezary syndrome. Patients may present with all components of Sezary syndrome or may present initially with only
one component and subsequently progress to develop other clinical features of this syndrome [18]. Patients with Sezary syndrome have a worse prognosis than patients with erythrodermic MF [19]. Extracutaneous involvement is directly correlated to the extent of cutaneous disease. Cutaneous dissemination is observed in less than 10% of patients with patch or plaque disease and in 30–40% of patients with tumors or generalized erythrodermatous involvement [14]. Lymphadenopathy is usually a late occurrence, being an initial manifestation of extracutaneous dissemination. Regional lymphadenopathies especially in areas draining extensive skin involvement are the most common presentation. Visceral dissemination may develop subsequently, and the most commonly involved organs are the lungs, spleen, liver, and gastrointestinal tract [20]. In advanced stages, transformation into a large cell lymphoma may occur, with predominance of either immunoblasts, large pleomorphic, or large anaplastic cells. Some of these cases are CD30+, thus being similar to anaplastic large cell lymphoma. An association with Hodgkin’s disease and lymphomatoid papulosis has also been reported. 3.2. Diagnostic criteria Clinical criteria for early diagnosis of MF include presence of asymmetrical, irregular, persistent erythematous lesions on sun-protected areas, that do not improve with or recur after conventional treatments. Histopathologic criteria for diagnosis of early MF include the following: presence of a patchy-lichenoid or band-like lymphocytic infiltrate within an expanded, partly fibrotic papillary dermis; epidermotropism of lymphocytes (arranged either as solitary units or in small collection defined as “Pautrier’s microabscesses” or aligned along the dermo-epidermal junction); presence of atypical lymphocytes (lymphocytes larger than normal and with indented-cerebriform nuclei); presence of intraepidermal lymphocytes larger than the dermal ones; intraepidermal lymphocytes surrounded by a clear halo (“haloed lymphocytes”). It should be underlined that in some cases histopathologic features alone are non-diagnostic, and only a careful clinicopathologic corelation allows a precise diagnosis. Flow cytometric studies of the peripheral blood may show expansion of the CD4+ CD7− population reflective of circulating atypical lymphocytes of Sezary type [12]. Detection of monoclonality of the T lymphoytes by molecular techniques is a useful additional diagnostic criterion. TCR gene-rearrangement studies may show evidence of clonal expansion in peripheral blood in patients with Sezary syndrome [13]. 3.3. Additional useful tests DNA microarray studies revealed a specific “gene signature” of MF as compared to inflammatory skin disorders [21]. These results, if confirmed by larger studies, may provide valuable additional diagnostic criteria in the near future.
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4. Staging 4.1. Staging procedures Complete staging work-up for mycosis fungoides (MF) includes an accurate physical examination, with a careful description of all cutaneous lesions (especially including the scalp, palms, soles and anogenital region) and complete hematological and biochemical exams with Sezary cells analysis. Even if the “blood” classification does not modify clinical stage, it usually correlates with a more advanced T-stage (usually T4) and the presence of extracutaneous disease [14]. Routine imaging studies in patients with early stages (I to IIA) in the absence of peripheral lymphadenopathy is unproductive [22]. Lymph node biopsies must be obtained if lymphadenopathy is present, since the presence of lymph node involvement affects both the stage and prognosis. Appropriate imaging studies and histologic evaluation must confirm suspected sites of visceral involvement when possible. Significant bone marrow involvement with an infiltrative histologic pattern is never found as a rule in patients with limited skin disease, and can be observed in patients with advanced MF or with Sezary syndrome [23]. Significant bone marrow disease is usually reflected by the presence of readily detectable Sezary cells in the peripheral blood. Therefore, bone marrow biopsy is not routinely used as part of the initial staging procedure for patients with MF.
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B (blood) B0: no circulating atypical Sezary cells (< 5% of lymphocytes); B1: circulating atypical Sezary cells (≥5% of lymphocytes). The overall clinical stage is defined by the TNMB criteria as follows: Stage IA: T1 N0 M0. Stage IB: T2 N0 M0. Stage IIA: T1-2 N1 M0. Stage IIB: T3 N0-1 M0. Stage IIIA: T4 N0 M0. Stage IIIB: T4 N1 M0. Stage IVA: T1-4 N2-3 M0. Stage IVB: T1-4 N0-3 M1. The “blood” classification does not modify clinical stage. 4.3. Molecular analysis of minimal residual disease Molecular analyses by PCR have been used for detection of minimal residual disease and of early recurrences in some study, but their reliability and repeatability are yet controversial. 4.4. Restaging procedures Restaging should include all diagnostic procedures positive at time of diagnosis and initial staging.
4.2. Staging system 5. Prognosis The standard staging classification system for mycosis fungoides (MF) is the tumor, node, metastasis, blood (TNMB) system first proposed at the NCI-sponsored Workshop on cutaneous T-cell lymphomas in 1978 [17], and is summarized as follows: T (skin) T1: T2: T3: T4:
limited patch/plaque (<10% of total-skin surface); generalized patch/plaque (≥10% of total body surface); tumors; generalized erythroderma.
N (lymph node) N0: lymph nodes clinically uninvolved; N1: lymph nodes enlarged, histologically uninvolved (reactive and dermatopathic nodes); N2: lymph nodes clinically uninvolved, histologically involved; N3: lymph nodes enlarged and histologically involved. M (viscera) M0: no visceral involvement; M1: visceral involvement.
5.1. Natural history The prognosis of mycosis fungoides (MF) is variable and strongly conditioned by the extent and type of skin involvement and presence of extracutaneous disease. Patients with stage IA-disease have an excellent prognosis with an overall long-term life expectancy that is similar to an age-, sex-, and race-matched control population [1,16]. Almost all patients with stage IA MF who die will die from causes other than MF, with a median survival longer than 33 years. Only 9% of these patients will progress to more extended disease. The latter group of patients had a lower complete remission rate to initial therapy and an older mean age than the rest of stage IA patients. Patients with stage IB or IIA have a median survival greater than 11 years [24]. These patients with T2 disease have a likelihood of disease progression of 24% and nearly 20% die of causes related to MF. Subgroups with stage IB or IIA have similar prognosis. Patients with cutaneous tumors (stage IIB) or generalized erythroderma (stage III) have a median survival of 3 and 4.5 years, respectively. The majority of these patients will die of MF. The long-term outcome in patients with erythroderma is quite variable and is dependent on patient age at presentation (<65 versus >65 years), overall stage (III versus IV), and peripheral blood involvement (B0
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versus B1) [19]. The median survival can vary widely depending on the combinations of these independent prognostic factors, and three distinct prognostic subgroups have been identified, with a median survival of 10, 3.5 and 1.5 years. Patients with extracutaneous disease at presentation involving either lymph nodes (stage IVA) or viscera (stage IVB) have a median survival of less than 1.5 years. Patients with plaque-type or erythrodermic MF may develop cutaneous tumors with large cell histology, often expressing CD30. CD30+ lymphomas arising in these patients share a common clonal origin as observed in their preexisting MF [25]. These patients usually have rapid disease progression and require more intensive local or systemic therapy. Thus, transformation of MF to a large cell lymphoma is associated with an aggressive clinical course and less favourable outcome. 5.2. Prognostic factors The extent and type of skin involvement, that is T-stage, and presence of extracutaneous disease are the most important indicators of survival in patients with mycosis fungoides (MF). The long-term outcome in patients with erythroderma is quite variable and is dependent on patient age at presentation (<65 versus >65 years), overall stage (III versus IV), and peripheral blood involvement (B0 versus B1) [19]. The median survival can vary widely depending on the combinations of these independent prognostic factors, and three distinct prognostic subgroups have been identified, with a median survival of 10, 3.5 and 1.5 years. The presence of a significant number of Sezary cells in the peripheral blood (B1 condition) is not factored into the overall clinical stage; however, it usually correlates with a more advanced T-stage (usually T4) and the presence of extracutaneous disease (stage IV) [14]. The lymph node histologic grade seems to correlate with survival. Dermatopathic changes or the presence of just a small number of atypical cells (histologic grade LN-1 or LN-2) have a 5-year survival of 80%. Patients with large clusters of paracortical atypical cells (LN-3) have a 5-year survival of 30%, and those with effaced nodes (LN4) have a 5-year survival of 15% [26]. Actual lymph node involvement with MF (N2–3, stage IVA) correlates with the histologic grade of LN-3 or -4. Some genetic features have been linked to worse prognosis, including among others the finding of an identical clone in the blood and the skin [27,28].
6. Treatment 6.1. Treatment of stage IA disease For patients with T1 without extracutaneous involvement (stage IA), standard treatment plan is limited to topical therapeutic measures. The main therapeutic options for these patients are local or total-skin topical mechlorethamine hydrochloride (HN2), phototherapy ultraviolet B (UVB), psoralen and ultraviolet A (PUVA), or localized electron-
beam radiotherapy (EBRT). There is no evidence that early aggressive systemic therapy is preferable to conservative strategy in the management of limited disease [29]. Patients treated with topical HN2 had a similar long-term survival than those treated with total-skin EBRT, with a complete remission rate of 70–80% and a median time to skin clearance of 6 to 8 months. When treatment is discontinued, more than half of the patients will relapse locally, but most will respond to a resumption of therapy. Twenty percent of patients treated with topic HN2 have a durable remission (>10 years). Topical HN2 with 10–20 mg/dL strength, either in ointment base or in water, can be applied to the entire skin once daily [16]. Treatment is continued on a daily basis until complete skin clearance, which is followed by a variable duration of maintenance therapy. By this way, HN2 seems to exert its cytotoxic activity mediated by immunostimulation. Topical BCNU produces similar outcome to those obtained with HN2 [30]; however, because of its systemic absorption, the potential hematologic complications are greater and the maximum duration of treatment is limited. Local EBRT is useful for the rare patients with a single lesion. EBRT is followed by a topical HN2 maintenance regimen. The total-skin EBRT should be reserved for patients with progressive skin disease. In spite of a higher remission rate, there are no difference in survival between patients treated with topical HN2 or with EBRT [16]. UVB or PUVA are also used a standard treatment in T1 disease. After 1.5–2 h of oral psoralen, patients receive a timed exposure to UVA light in a phototherapy unit. Only the eyes are shielded routinely, however selected areas can be shielded to minimize undesired photodamage. Certain areas like scalp, perineum, and axillae may result shadowed and not receive adequate exposure. PUVA treatment is initiated thrice weekly until skin clearance is achieved, after which the frequency is gradually decreased to as infrequently as once every 2 weeks. Maintenance should be discontinued within 1 year to reduce the risk of skin carcinogenesis. With this strategy, complete remission rate is 90%, with a median time to skin clearance of 2–6 months [31–35]. An alternative to PUVA is represented by narrow-band (311 nm) UV-B phototherapy [36–40]. Erythema, pruritus, skin dryness, nausea, cataracts, and carcinogenesis are the main complications related to phototherapy [41]. Chronic complications are more common in patients treated with more topical strategies. The long-wave UVA has an advantage over UVB in its greater depth of penetration into the dermal infiltrates of MF. Other topical treatment possibilities for which experience in large, controlled studies is lacking include topical steroids, bexarotene gel, topical methotrexate, imiquimod cream, and photodynamic therapy [42–47]. Several aspects other than clinical stage strongly influence therapeutic decision. Among others, the assessment of prognostic factors, the accessibility of different approaches, the patient’s age, social problems, and the cost-benefit ratio should be taken into consideration. This is equally important for all other stage-disease in MF. Nonspecific symptomatic treatment is an integral component of the overall therapeutic regimen. Supportive measures such as
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aggressive emolliation, topical steroids, and oral antipruritics should be used as necessary. 6.2. Treatment of stage IB–IIA disease For patients with T2 without extracutaneous involvement (stage IB–IIA), the standard treatment plan is limited to topical therapeutic measures. The main therapeutic options for these patients are local or total-skin topical mechlorethamine hydrochloride (HN2), psoralen and ultraviolet A (PUVA), or total-skin electron-beam radiotherapy (EBRT). The latter should be considered as initial therapy for patients with very thickened plaques, since the effective depth of treatment of total-skin EBRT is more substantial than with either topical HN2 or PUVA. It should also be considered for patients with rapid progression and patients who failed to respond to the other strategies. A total dose of 36 Gy administered over a 10-week period, with a 1-week split after 18–20 Gy is suggested [48,49]. Some areas like the top of the scalp, the perineum, the soles of the feet, underneath of the breasts or of the panniculus of obese individuals could receive relatively lower doses. Thus, these areas should be supplemented with 6 MeV electrons to a total dose of 20 Gy [48]. Following completion of total-skin EBRT, adjuvant topical HN2 is appropriate and may be continued for at least 6 months. Totalskin EBRT produces a complete remission rate of 80–90% in these patients [49,50]. In spite of a higher complete remission rate, patients treated with total-skin EBRT do not have an improved survival compared with those treated with topical HN2 [24]. HN2 and PUVA are used with the same modalities as for stage IA patients. Complete remission rate with topical HN2 or with PUVA are 50–70% [24] and 50–80% [31–35], respectively. Patients who fail to respond to one topical therapy or who progress after an initial response may be treated with an alternative topical strategy. There is no evidence that development of resistance to one modality affects the subsequent response to an alternative topical modality [16,24]. Patients who failed to respond to a single-agent topical regimen can receive combined-modality therapy as appropriate for individual clinical use on a type 3 level evidence. This can be done by combining topical HN2 with total-skin EBRT or with PUVA; or adding interferon- (IFN-) or retinoids to those treatments [51–53]. 6.3. Treatment of stage IIB disease Standard therapeutic option for patients with stage IIB disease depends on the entity of tumors. Local electron-beam radiotherapy (EBRT) combined with topical mechlorethamine hydrochloride (HN2) or with psoralen and ultraviolet A (PUVA) are the first-choice treatments for patients with few discrete tumors. In patients with generalized tumors three effective combinations are available: total-skin EBRT plus topical HN2, PUVA plus interferonalfa, and PUVA plus retinoids. Total-skin EBRT produces a complete remission rate of 45–75% in patients with
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stage IIB MF [54,55]. In these patients the survival benefit of topical or systemic adjuvant treatment remains unclear [54,55]. More aggressive combinations like PUVA plus interferon or retinoids are suitable for individual clinical use on a type 3 level evidence, in refractory disease or tumors relapsed after the above-mentioned strategies. The addition of interferon to PUVA improved survival respect to PUVA alone [35], being associated with a complete remission rate of 33% [53]. To date, there is no evidence that a more aggressive combination using systemic chemotherapy offers superior survival outcome [56]. Focal resistant tumors can be boosted with local EBRT or orthovoltage radiation. 6.4. Treatment of stage III disease Standard therapeutic option for patients with stage III disease is low-dose psoralen and ultraviolet A (PUVA) with a low and caution increased of the UVA dose to avoid phototoxic reactions. Considering that erythrodermic MF usually presents very inflamed and itchy skin and that the skin in these patients is frequently irritated by prior topical therapies, electron-beam radiotherapy (EBRT) is usually associated with severe desquamation, even with very low doses. The combination between PUVA and interferon-alfa produces a complete remission rate of more than 60% and response duration longer than those obtained with PUVA or interferon alone [53]. In any way, there is no clear evidence that prolongation of the response duration leads to improvement in the overall survival. Photopheresis or extracorporeal photochemotherapy is suitable for individual clinical use as primary therapy for erythrodermic MF or Sezary syndrome on a type 3 level evidence [57]. It can be effective in patients without visceral involvement or with limited lymph node disease, with a 60% of overall response rate [55]. If the response to photopheresis is partial or slow, interferon alfa can be added, obtaining a significant improvement in response rate [58]. Systemic retinoids are also suitable for individual clinical use as primary therapy for erythrodermic MF or Sezary syndrome on a type 3 level evidence. Retinoids can be used alone, or more often, in combination with PUVA or interferon alfa [59,60]. Single-agent chemotherapy is most effective in patients without extracutaneous disease. Methotrexate produces a complete remission rate of 41% with doses between 5 and 50 mg/week [61]. 6.5. Treatment of stage IV disease Standard therapeutic option for patients with stage IV disease is conventional-doses systemic chemotherapy. In MF, most chemotherapy regimens result in temporary palliative control only. Chemotherapy is used alone, or in combination with radiation or interferon alfa. In spite of a complete response rate of 80–100%, the median duration of response to chemotherapy is shorter than 1 year [61,62]. The most effective and commonly used combinations are
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CHOP and CVP regimens [63]. Methotrexate, etoposide, bleomycin, vinblastine, fludarabine, and 2-deoxycoformycin are the most commonly used single-agent chemotherapy regimens in MF and Sezary syndrome [62,64,65]. Response rates and duration are lower than those reported for combination chemotherapy regimens. The purine analogs fludarabine and 2-deoxycoformycin are suitable for individual clinical use on a type R basis. In effect, these drugs seems to be active against MF with response rates as high as 50% [66–68]. Biologic therapy, interferon alfa an retinoids are suitable for individual clinical use on a type R basis, either when used alone, together or in combination with chemotherapy or topical treatment [51,53,62]. The combination fludarabine plus interferon produces a response rate of 46% with a median duration of 6 months [69]. Megavoltage photon irradiation can be used as a palliative treatment of lymph node masses. This can be associated with systemic chemotherapy or interferon alfa. High-dose chemotherapy supported by autologous bone marrow transplantation is an experimental strategy. Experience with this strategy in MF is very limited [70], and, thus, its efficacy has not been established. However, it seems that autologous or allogeneic bone marrow or stem cell transplantation represent a promising approach in tumor-stage patients; mini-allogeneic transplantation may provide the additional advantage of a “graf-versus-tumor” effect [71–75].
cytotoxic activity against various tumors [95,96]. Vorinostat (suberoylanilide hydroxamic acid-SAHA) is the first FDAapproved HDAC inhibitor for the treatment of cutaneous manifestations of cutaneous T-cell lymphomas. Vorinostat was active against solid tumors and hematologic malignancies as intravenous and oral preparations in phase I development. In two phase II trials, vorinostat 400 mg/day was safe and effective with an overall response rate of 24–30% in refractory advanced patients with cutaneous T-cell lymphomas including large cell transformation and Sezary syndrome. The common side effects of vorinostat, which are similar in all studies, include gastrointestinal symptoms, fatigue and thrombocytopenia and the most common serious event was thrombosis. Many other HDAC inhibitors, such as valproic acid [97], MS-275 [98], CI-994 [99], and FK228 [100] among others, are being investigated, but clinical experience on MF patients is still limited.
Reviewers Molina A., MD, MS, Senior Vice-President, Clinical Research and Development, Cougar Biotechnology, 10990 Wilshire Blvd, Suite 1200, Los Angeles, CA 90024, USA.
References 6.6. New active drugs and therapeutic options Anti-T-cell monoclonal antibodies are an investigational alternative on a type R basis. It was studied in small series treated with chimeric anti-helper T-cell (anti-CD4) antibody [76]. The clinical response were generally modest and short-lived. Among novel targeted therapeutic approaches to cutaneous T-cell lymphomas are the retinoids, alltrans retinoic acid (ATRA) [77] and bexarotene (Targretin) [78,79]. Other targeted therapies include the anti-CD52 antibody alemtuzumab (Campath) [80–84], DAB389 IL-2 (denileukin diftitox, ONTAK) [85,86], tumor vaccination [87,88], unmodified or 90Y-conjugated anti-Tac Pseudomonas exotoxin conjugates, and inhibitors of intracellular signal transduction factors. Further important therapeutic modalities include Gemcitabine [89,90], pegylated liposomal doxorubicin [91], pentostatin [92], etanercept [93], immunomodulation of pro-inflammatory cytokines such as interleukin (IL)-12 [94], and photopheresis with or without concurrent immunoadjuvant treatment. Due to the inadequacy of standard therapy, all patients with extracutaneous disease should be considered candidates for newer investigative therapies. An emerging class of investigational agents is represented by histone deacetylase (HDAC) inhibitors, which may restore the expression of tumor suppressor or cell cycle regulatory genes by increasing the acetylation of histones. Depsipeptide and suberoylanilide hydroxamic acid are potent histone deacetylase inhibitors and have shown in vitro and in vivo
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[72] Masood N, Russell KJ, Olerud JE, et al. Induction of complete remission of advanced stage mycosis fungoides by allogeneic hematopoietic stem cell transplantation. J Am Acad Dermatol 2002;47:140–5. [73] 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 2005;23:6163–71. [74] Olavarria E, Child F, Woolford A, et al. T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol 2001;114:624–31. [75] Soligo D, Ibatici A, Berti E, et al. Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant 2003;31:663–6. [76] Knox SJ, Levy R, Hodgkinson S, et al. Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides. Blood 1991;77:20–30. [77] Sacchi S, Russo D, Avvisati G, et al. All-trans retinoic acid in hematological malignancies, an update. GER (Gruppo Ematologico Retinoidi). Haematologica 1997;82:106–21. [78] 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 2001;19: 2456–71. [79] Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early stage cutaneous T-cell lymphoma. Arch Dermatol 2001;137:581–93. [80] Lundin J, Osterborg A, Brittinger G, et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin’s lymphomas: a phase II multicenter study. European study group of CAMPATH-1H treatment in low-grade non-hodgkin’s lymphoma. J Clin Oncol 1998;16:3257–63. [81] Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003;101:4267–72. [82] Pangalis GA, Dimopoulou MN, Angelopoulou MK, et al. Campath1H (anti-CD52) monoclonal antibody therapy in lymphoproliferative disorders. Med Oncol 2001;18:99–107. [83] Hagberg H, Lundin J, Cavallin-Stahl E, et al. Phase 2 study of alemtuzumab (Campath-1H) in patients with advanced mycosis fungoides/S`ezary syndrome. Ann Oncol 2002;13(Suppl 2):85. [84] Zinzani PL, Alinari L, Tani M, et al. Preliminary observations of a phase II study of reduced-dose alemtuzumab treatment in patients with pretreated T-cell lymphoma. Haematologica 2005;90:702–3. [85] 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 2001;19:376–88. [86] 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 2006;126:575–83. [87] Dummer R, Hassel JC, Fellenberg F, et al. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood 2004;104:1631–8. [88] Maier T, Tun-Kyi A, Tassis A, et al. Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. Blood 2003;102:2338–44. [89] Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients. J Clin Oncol 2000;18:2603–6. [90] Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer 2005;104:2437–41. [91] Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 2003;98:993–1001.
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Biographies Pier Luigi Zinzani is Coordinator of the Lymphoma Unit of the Institute of Hematology “L. and A. Ser`agnoli”, University of Bologna, Italy. Andr´es J. M. Ferreri is Coordinator of the Unit of Lymphoid Malignancies and Vice Director of the Medical Oncology Unit, San Raffaele Scientific Institute, Milan, Italy. Lorenzo Cerroni is Head of the Lymphoma Unit and Directoir of the Research Unit Dermatopathology of the Department of Dermatology, Medical University of Graz, Austria.
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Mycosis fungoides Pier Luigi Zinzani a,∗ , Andr´es J.M. Ferreri b , Lorenzo Cerroni c a
L. and A. Seragnoli Institute of Hematology and Oncology, University of Bologna, Bologna, Italy Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy c Department of Dermatology, Medical University of Graz, Austria
b
Accepted 23 August 2007
Contents 1.
2.
3.
4.
5.
6.
General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Immunophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Genetic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Diagnostic criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Additional useful tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Staging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Staging system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Molecular analysis of minimal residual disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Restaging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Treatment of stage IA disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Treatment of stage IB–IIA disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Treatment of stage IIB disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Treatment of stage III disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Treatment of stage IV disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. New active drugs and therapeutic options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
173 173 173 173 173 173 173 173 174 174 174 174 175 175 175 175 175 175 175 176 176 176 177 177 177 177 178 178 178 181
Abstract Mycosis fungoides (MF) constitutes the most frequent cutaneous T-cell lymphoma. Sezary syndrome is considered by some authors to be an erythrodermic leukemic variant of MF, but is classified separately in the new WHO-EORT classification of cutaneous lymphomas. MF
∗
Corresponding author. Tel.: +39 051 6363680; fax: +39 051 6364037. E-mail address: [email protected] (P.L. Zinzani).
1040-8428/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2007.08.004
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usually occurs in old adults with a 2:1 male to female ratio. Its prognosis is variable and strongly conditioned by the extent and type of skin involvement and presence of extracutaneous disease. Patients with stage IA-disease have an excellent prognosis with an overall long-term life expectancy that is similar to an age-, sex-, and race-matched control population. Almost all patients with stage IA MF will die from causes other than MF, with a median survival >33 years. Only 9% of these patients will progress to more extended disease. Patients with stage IB or IIA have a median survival greater than 11 years. These patients with T2 disease have a likelihood of disease progression of 24% and nearly 20% die of MF. Subgroups with stage IB or IIA have similar prognosis. Patients with cutaneous tumors or generalized erythroderma have a median survival of 3 and 4.5 years, respectively. The majority of these patients will die of MF. Extracutaneous dissemination is observed in less than 10% of patients with patch or plaque disease and in 30–40% of patients with tumors or generalized erythrodermatous involvement. Extracutaneous involvement is directly correlated to the extent of cutaneous disease. The most commonly involved organs are lung, spleen, liver, and gastrointestinal tract. Patients with extracutaneous disease at presentation involving either lymph nodes or viscera have a median survival of <1.5 years. Patients with plaque-type or erythrodermic MF may develop cutaneous tumors with large cell histology, often expressing CD30, which share a common clonal origin as observed in their preexisting MF and are associated with a less favourable outcome. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Mycosis fungoides; Sezary syndrome; T-cell lymphoma
1. General information 1.1. Definition Mycosis fungoides (MF) constitutes the most frequent cutaneous T-cell lymphoma. Sezary syndrome is considered an erythrodermic leukemic variant of MF. Its postulated normal counterpart is a peripheral epidermotropic CD4+ T-cell. Mycosis fungoides is included in the new WHO-EORTC classification of primary cutaneous lymphomas [1]. 1.2. Incidence Mycosis fungoides (MF) is an uncommon lymphoma; however, it is the most common of the primary cutaneous lymphomas. MF constitutes 50% of all primary NHL of the skin [1]. Annual incidence is 0.29/100.000, being about 0.5% of all new cases of NHL diagnosed in the USA each year [2].
and translocations in chromosome 1 or 6 [8]. Recently, new molecular studies revealed alterations of NAV3 in MF and Sezary syndrome [9]. The significance of these features is yet unclear.
2. Pathology and biology 2.1. Morphology The tumor cells of mycosis fungoides are predominantly small cells with cerebriform nuclei, with a minority of larger cells with similar nuclei, which infiltrate the epidermis, circulate in the blood and involve the paracortex of lymph nodes. Atypical cells may be completely absent in early lesions [10]. The infiltrate is variable accompanied by interdigitating and Langerhans’ cells. The bone marrow is usually normal. Although MF presents usually with band-like, epidermotropic infiltrates, several clinicopathologic variants have been described (e.g., follicular MF, etc.).
1.3. Risk factors
2.2. Immunophenotype
The cause and risk factors of MF and Sezary syndrome are unclear. Although environmental and occupational exposures, such as exposure to solvents and chemical, have been implicated in the etiology of the disease, the most recent large case-controlled study failed to support this hypothesis [3]. A viral etiology for MF has been also suggested. There are some reports that have found human T-lymphotrophic virus-1 (HTLV-1) either in the peripheral blood or cutaneous lesions of some patients with MF or Sezary syndrome [4]. However, many studies have revealed evidence against a role of HTLV-1 [5]. At present, HTLV-1 is not considered to play any role in the etiology of MF. The role of other viruses such as cytomegalovirus is still unclear [6]. A few studies have demonstrated histocompatibility antigen associations with MF and Sezary syndrome, specifically Aw31, Aw32, B8, Bw38, and DR5 [7]. Chromosomal abnormalities have been identified in tumor cells, mostly deletions
The cells of mycosis fungoides express T-cell-associated antigens (CD2+, CD3+, CD5+), approximately one third are CD7+; most cases are CD4+, but rare CD8+ and/or CD56+ cases have been reported. CD25 is usually negative, but positive cases have been reported. S-100+ CD1a+ interdigitating and Langerhans’ cells are present [11]. Flow cytometric studies of the peripheral blood may show expansion of the CD4+ CD7− population reflective of circulating atypical lymphocytes of Sezary type [12]. 2.3. Genetic features TCR genes are clonally rearranged, but detection of a monoclonal population of T lymphocytes may be difficult in early lesions [10]. TCR gene-rearrangement studies may show evidence of clonal expansion in peripheral blood in patients with Sezary syndrome [13]. Several chromosomal
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aberrations have been described using different molecular methods, but at present a repeatable pattern has not been identified.
3. Diagnosis 3.1. Clinical presentations Mycosis fungoides (MF) usually occurs in old adults, with a median age between 55 and 60 years and a 2:1 male to female ratio, presenting with multiple cutaneous plaques or nodules, or with generalized erythroderma. Cases in children have been well documented. MF presents as an indolent cutaneous eruption with erythematosus scaly patches or plaques that often resemble common skin disorders such as atopic dermatitis or psoriasis. The initial lesions are often confined to sun-protected areas, although any skin site may be affected. There may be prominent poikiloderma (skin atrophy with slight hyperpigmentation and telangiectasia) or associated alopecia or with follicular mucinosis. In addition, several other clinical variants have been described (e.g., hypopigmented MF among others). Especially in the past, a definitive diagnosis was often preceded by a variably long period (often referred to as the “premycotic” stage) that could range from several months to several years [14]. However, the identification of precise histopathologic criteria for diagnosis of early MF allows a specific diagnosis in most cases [10,15]. As the disease progresses, patches may evolve into infiltrated plaques with a more generalized distribution, and patients may subsequently develop ulcerated or exophytic tumors. Tumors, however, develop only in a minority of the patients [1,16]. Another phase of skin involvement is generalized erythroderma. The erythema may be accompanied by either very atrophic or lichenified skin, and plaques or tumors may also be present. These patients are almost always affected by intense pruritus. If peripheral blood involvement is present, these patients are considered to have Sezary syndrome. It is controversial as to how many or what percentage of Sezary cells constitute a significant level to define Sezary syndrome. Although the original NCI classification used the criterion of greater than 5% lymphocytes for significant blood involvement [17], the current practice by many MF referral centers is to use a criterion of at least 20% lymphocytes or an absolute count of at least 1000/mm3 to define peripheral blood involvement. Precise criteria for definition of Sezary syndrome have been proposed in the new WHO-EORT classification of cutaneous lymphomas [1]. Sezary syndrome is considered by some authors to be an erythrodermic leukemic variant of MF, but is classified separately in the new WHO-EORT classification of cutaneous lymphomas [1]. Patients present with generalized erythroderma, lymphadenopathy and circulating atypical T-cells (Sezary cells) in the peripheral blood. Peripheral blood involvement may be subtle in MF or prominent in Sezary syndrome. Patients may present with all components of Sezary syndrome or may present initially with only
one component and subsequently progress to develop other clinical features of this syndrome [18]. Patients with Sezary syndrome have a worse prognosis than patients with erythrodermic MF [19]. Extracutaneous involvement is directly correlated to the extent of cutaneous disease. Cutaneous dissemination is observed in less than 10% of patients with patch or plaque disease and in 30–40% of patients with tumors or generalized erythrodermatous involvement [14]. Lymphadenopathy is usually a late occurrence, being an initial manifestation of extracutaneous dissemination. Regional lymphadenopathies especially in areas draining extensive skin involvement are the most common presentation. Visceral dissemination may develop subsequently, and the most commonly involved organs are the lungs, spleen, liver, and gastrointestinal tract [20]. In advanced stages, transformation into a large cell lymphoma may occur, with predominance of either immunoblasts, large pleomorphic, or large anaplastic cells. Some of these cases are CD30+, thus being similar to anaplastic large cell lymphoma. An association with Hodgkin’s disease and lymphomatoid papulosis has also been reported. 3.2. Diagnostic criteria Clinical criteria for early diagnosis of MF include presence of asymmetrical, irregular, persistent erythematous lesions on sun-protected areas, that do not improve with or recur after conventional treatments. Histopathologic criteria for diagnosis of early MF include the following: presence of a patchy-lichenoid or band-like lymphocytic infiltrate within an expanded, partly fibrotic papillary dermis; epidermotropism of lymphocytes (arranged either as solitary units or in small collection defined as “Pautrier’s microabscesses” or aligned along the dermo-epidermal junction); presence of atypical lymphocytes (lymphocytes larger than normal and with indented-cerebriform nuclei); presence of intraepidermal lymphocytes larger than the dermal ones; intraepidermal lymphocytes surrounded by a clear halo (“haloed lymphocytes”). It should be underlined that in some cases histopathologic features alone are non-diagnostic, and only a careful clinicopathologic corelation allows a precise diagnosis. Flow cytometric studies of the peripheral blood may show expansion of the CD4+ CD7− population reflective of circulating atypical lymphocytes of Sezary type [12]. Detection of monoclonality of the T lymphoytes by molecular techniques is a useful additional diagnostic criterion. TCR gene-rearrangement studies may show evidence of clonal expansion in peripheral blood in patients with Sezary syndrome [13]. 3.3. Additional useful tests DNA microarray studies revealed a specific “gene signature” of MF as compared to inflammatory skin disorders [21]. These results, if confirmed by larger studies, may provide valuable additional diagnostic criteria in the near future.
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4. Staging 4.1. Staging procedures Complete staging work-up for mycosis fungoides (MF) includes an accurate physical examination, with a careful description of all cutaneous lesions (especially including the scalp, palms, soles and anogenital region) and complete hematological and biochemical exams with Sezary cells analysis. Even if the “blood” classification does not modify clinical stage, it usually correlates with a more advanced T-stage (usually T4) and the presence of extracutaneous disease [14]. Routine imaging studies in patients with early stages (I to IIA) in the absence of peripheral lymphadenopathy is unproductive [22]. Lymph node biopsies must be obtained if lymphadenopathy is present, since the presence of lymph node involvement affects both the stage and prognosis. Appropriate imaging studies and histologic evaluation must confirm suspected sites of visceral involvement when possible. Significant bone marrow involvement with an infiltrative histologic pattern is never found as a rule in patients with limited skin disease, and can be observed in patients with advanced MF or with Sezary syndrome [23]. Significant bone marrow disease is usually reflected by the presence of readily detectable Sezary cells in the peripheral blood. Therefore, bone marrow biopsy is not routinely used as part of the initial staging procedure for patients with MF.
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B (blood) B0: no circulating atypical Sezary cells (< 5% of lymphocytes); B1: circulating atypical Sezary cells (≥5% of lymphocytes). The overall clinical stage is defined by the TNMB criteria as follows: Stage IA: T1 N0 M0. Stage IB: T2 N0 M0. Stage IIA: T1-2 N1 M0. Stage IIB: T3 N0-1 M0. Stage IIIA: T4 N0 M0. Stage IIIB: T4 N1 M0. Stage IVA: T1-4 N2-3 M0. Stage IVB: T1-4 N0-3 M1. The “blood” classification does not modify clinical stage. 4.3. Molecular analysis of minimal residual disease Molecular analyses by PCR have been used for detection of minimal residual disease and of early recurrences in some study, but their reliability and repeatability are yet controversial. 4.4. Restaging procedures Restaging should include all diagnostic procedures positive at time of diagnosis and initial staging.
4.2. Staging system 5. Prognosis The standard staging classification system for mycosis fungoides (MF) is the tumor, node, metastasis, blood (TNMB) system first proposed at the NCI-sponsored Workshop on cutaneous T-cell lymphomas in 1978 [17], and is summarized as follows: T (skin) T1: T2: T3: T4:
limited patch/plaque (<10% of total-skin surface); generalized patch/plaque (≥10% of total body surface); tumors; generalized erythroderma.
N (lymph node) N0: lymph nodes clinically uninvolved; N1: lymph nodes enlarged, histologically uninvolved (reactive and dermatopathic nodes); N2: lymph nodes clinically uninvolved, histologically involved; N3: lymph nodes enlarged and histologically involved. M (viscera) M0: no visceral involvement; M1: visceral involvement.
5.1. Natural history The prognosis of mycosis fungoides (MF) is variable and strongly conditioned by the extent and type of skin involvement and presence of extracutaneous disease. Patients with stage IA-disease have an excellent prognosis with an overall long-term life expectancy that is similar to an age-, sex-, and race-matched control population [1,16]. Almost all patients with stage IA MF who die will die from causes other than MF, with a median survival longer than 33 years. Only 9% of these patients will progress to more extended disease. The latter group of patients had a lower complete remission rate to initial therapy and an older mean age than the rest of stage IA patients. Patients with stage IB or IIA have a median survival greater than 11 years [24]. These patients with T2 disease have a likelihood of disease progression of 24% and nearly 20% die of causes related to MF. Subgroups with stage IB or IIA have similar prognosis. Patients with cutaneous tumors (stage IIB) or generalized erythroderma (stage III) have a median survival of 3 and 4.5 years, respectively. The majority of these patients will die of MF. The long-term outcome in patients with erythroderma is quite variable and is dependent on patient age at presentation (<65 versus >65 years), overall stage (III versus IV), and peripheral blood involvement (B0
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versus B1) [19]. The median survival can vary widely depending on the combinations of these independent prognostic factors, and three distinct prognostic subgroups have been identified, with a median survival of 10, 3.5 and 1.5 years. Patients with extracutaneous disease at presentation involving either lymph nodes (stage IVA) or viscera (stage IVB) have a median survival of less than 1.5 years. Patients with plaque-type or erythrodermic MF may develop cutaneous tumors with large cell histology, often expressing CD30. CD30+ lymphomas arising in these patients share a common clonal origin as observed in their preexisting MF [25]. These patients usually have rapid disease progression and require more intensive local or systemic therapy. Thus, transformation of MF to a large cell lymphoma is associated with an aggressive clinical course and less favourable outcome. 5.2. Prognostic factors The extent and type of skin involvement, that is T-stage, and presence of extracutaneous disease are the most important indicators of survival in patients with mycosis fungoides (MF). The long-term outcome in patients with erythroderma is quite variable and is dependent on patient age at presentation (<65 versus >65 years), overall stage (III versus IV), and peripheral blood involvement (B0 versus B1) [19]. The median survival can vary widely depending on the combinations of these independent prognostic factors, and three distinct prognostic subgroups have been identified, with a median survival of 10, 3.5 and 1.5 years. The presence of a significant number of Sezary cells in the peripheral blood (B1 condition) is not factored into the overall clinical stage; however, it usually correlates with a more advanced T-stage (usually T4) and the presence of extracutaneous disease (stage IV) [14]. The lymph node histologic grade seems to correlate with survival. Dermatopathic changes or the presence of just a small number of atypical cells (histologic grade LN-1 or LN-2) have a 5-year survival of 80%. Patients with large clusters of paracortical atypical cells (LN-3) have a 5-year survival of 30%, and those with effaced nodes (LN4) have a 5-year survival of 15% [26]. Actual lymph node involvement with MF (N2–3, stage IVA) correlates with the histologic grade of LN-3 or -4. Some genetic features have been linked to worse prognosis, including among others the finding of an identical clone in the blood and the skin [27,28].
6. Treatment 6.1. Treatment of stage IA disease For patients with T1 without extracutaneous involvement (stage IA), standard treatment plan is limited to topical therapeutic measures. The main therapeutic options for these patients are local or total-skin topical mechlorethamine hydrochloride (HN2), phototherapy ultraviolet B (UVB), psoralen and ultraviolet A (PUVA), or localized electron-
beam radiotherapy (EBRT). There is no evidence that early aggressive systemic therapy is preferable to conservative strategy in the management of limited disease [29]. Patients treated with topical HN2 had a similar long-term survival than those treated with total-skin EBRT, with a complete remission rate of 70–80% and a median time to skin clearance of 6 to 8 months. When treatment is discontinued, more than half of the patients will relapse locally, but most will respond to a resumption of therapy. Twenty percent of patients treated with topic HN2 have a durable remission (>10 years). Topical HN2 with 10–20 mg/dL strength, either in ointment base or in water, can be applied to the entire skin once daily [16]. Treatment is continued on a daily basis until complete skin clearance, which is followed by a variable duration of maintenance therapy. By this way, HN2 seems to exert its cytotoxic activity mediated by immunostimulation. Topical BCNU produces similar outcome to those obtained with HN2 [30]; however, because of its systemic absorption, the potential hematologic complications are greater and the maximum duration of treatment is limited. Local EBRT is useful for the rare patients with a single lesion. EBRT is followed by a topical HN2 maintenance regimen. The total-skin EBRT should be reserved for patients with progressive skin disease. In spite of a higher remission rate, there are no difference in survival between patients treated with topical HN2 or with EBRT [16]. UVB or PUVA are also used a standard treatment in T1 disease. After 1.5–2 h of oral psoralen, patients receive a timed exposure to UVA light in a phototherapy unit. Only the eyes are shielded routinely, however selected areas can be shielded to minimize undesired photodamage. Certain areas like scalp, perineum, and axillae may result shadowed and not receive adequate exposure. PUVA treatment is initiated thrice weekly until skin clearance is achieved, after which the frequency is gradually decreased to as infrequently as once every 2 weeks. Maintenance should be discontinued within 1 year to reduce the risk of skin carcinogenesis. With this strategy, complete remission rate is 90%, with a median time to skin clearance of 2–6 months [31–35]. An alternative to PUVA is represented by narrow-band (311 nm) UV-B phototherapy [36–40]. Erythema, pruritus, skin dryness, nausea, cataracts, and carcinogenesis are the main complications related to phototherapy [41]. Chronic complications are more common in patients treated with more topical strategies. The long-wave UVA has an advantage over UVB in its greater depth of penetration into the dermal infiltrates of MF. Other topical treatment possibilities for which experience in large, controlled studies is lacking include topical steroids, bexarotene gel, topical methotrexate, imiquimod cream, and photodynamic therapy [42–47]. Several aspects other than clinical stage strongly influence therapeutic decision. Among others, the assessment of prognostic factors, the accessibility of different approaches, the patient’s age, social problems, and the cost-benefit ratio should be taken into consideration. This is equally important for all other stage-disease in MF. Nonspecific symptomatic treatment is an integral component of the overall therapeutic regimen. Supportive measures such as
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aggressive emolliation, topical steroids, and oral antipruritics should be used as necessary. 6.2. Treatment of stage IB–IIA disease For patients with T2 without extracutaneous involvement (stage IB–IIA), the standard treatment plan is limited to topical therapeutic measures. The main therapeutic options for these patients are local or total-skin topical mechlorethamine hydrochloride (HN2), psoralen and ultraviolet A (PUVA), or total-skin electron-beam radiotherapy (EBRT). The latter should be considered as initial therapy for patients with very thickened plaques, since the effective depth of treatment of total-skin EBRT is more substantial than with either topical HN2 or PUVA. It should also be considered for patients with rapid progression and patients who failed to respond to the other strategies. A total dose of 36 Gy administered over a 10-week period, with a 1-week split after 18–20 Gy is suggested [48,49]. Some areas like the top of the scalp, the perineum, the soles of the feet, underneath of the breasts or of the panniculus of obese individuals could receive relatively lower doses. Thus, these areas should be supplemented with 6 MeV electrons to a total dose of 20 Gy [48]. Following completion of total-skin EBRT, adjuvant topical HN2 is appropriate and may be continued for at least 6 months. Totalskin EBRT produces a complete remission rate of 80–90% in these patients [49,50]. In spite of a higher complete remission rate, patients treated with total-skin EBRT do not have an improved survival compared with those treated with topical HN2 [24]. HN2 and PUVA are used with the same modalities as for stage IA patients. Complete remission rate with topical HN2 or with PUVA are 50–70% [24] and 50–80% [31–35], respectively. Patients who fail to respond to one topical therapy or who progress after an initial response may be treated with an alternative topical strategy. There is no evidence that development of resistance to one modality affects the subsequent response to an alternative topical modality [16,24]. Patients who failed to respond to a single-agent topical regimen can receive combined-modality therapy as appropriate for individual clinical use on a type 3 level evidence. This can be done by combining topical HN2 with total-skin EBRT or with PUVA; or adding interferon- (IFN-) or retinoids to those treatments [51–53]. 6.3. Treatment of stage IIB disease Standard therapeutic option for patients with stage IIB disease depends on the entity of tumors. Local electron-beam radiotherapy (EBRT) combined with topical mechlorethamine hydrochloride (HN2) or with psoralen and ultraviolet A (PUVA) are the first-choice treatments for patients with few discrete tumors. In patients with generalized tumors three effective combinations are available: total-skin EBRT plus topical HN2, PUVA plus interferonalfa, and PUVA plus retinoids. Total-skin EBRT produces a complete remission rate of 45–75% in patients with
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stage IIB MF [54,55]. In these patients the survival benefit of topical or systemic adjuvant treatment remains unclear [54,55]. More aggressive combinations like PUVA plus interferon or retinoids are suitable for individual clinical use on a type 3 level evidence, in refractory disease or tumors relapsed after the above-mentioned strategies. The addition of interferon to PUVA improved survival respect to PUVA alone [35], being associated with a complete remission rate of 33% [53]. To date, there is no evidence that a more aggressive combination using systemic chemotherapy offers superior survival outcome [56]. Focal resistant tumors can be boosted with local EBRT or orthovoltage radiation. 6.4. Treatment of stage III disease Standard therapeutic option for patients with stage III disease is low-dose psoralen and ultraviolet A (PUVA) with a low and caution increased of the UVA dose to avoid phototoxic reactions. Considering that erythrodermic MF usually presents very inflamed and itchy skin and that the skin in these patients is frequently irritated by prior topical therapies, electron-beam radiotherapy (EBRT) is usually associated with severe desquamation, even with very low doses. The combination between PUVA and interferon-alfa produces a complete remission rate of more than 60% and response duration longer than those obtained with PUVA or interferon alone [53]. In any way, there is no clear evidence that prolongation of the response duration leads to improvement in the overall survival. Photopheresis or extracorporeal photochemotherapy is suitable for individual clinical use as primary therapy for erythrodermic MF or Sezary syndrome on a type 3 level evidence [57]. It can be effective in patients without visceral involvement or with limited lymph node disease, with a 60% of overall response rate [55]. If the response to photopheresis is partial or slow, interferon alfa can be added, obtaining a significant improvement in response rate [58]. Systemic retinoids are also suitable for individual clinical use as primary therapy for erythrodermic MF or Sezary syndrome on a type 3 level evidence. Retinoids can be used alone, or more often, in combination with PUVA or interferon alfa [59,60]. Single-agent chemotherapy is most effective in patients without extracutaneous disease. Methotrexate produces a complete remission rate of 41% with doses between 5 and 50 mg/week [61]. 6.5. Treatment of stage IV disease Standard therapeutic option for patients with stage IV disease is conventional-doses systemic chemotherapy. In MF, most chemotherapy regimens result in temporary palliative control only. Chemotherapy is used alone, or in combination with radiation or interferon alfa. In spite of a complete response rate of 80–100%, the median duration of response to chemotherapy is shorter than 1 year [61,62]. The most effective and commonly used combinations are
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CHOP and CVP regimens [63]. Methotrexate, etoposide, bleomycin, vinblastine, fludarabine, and 2-deoxycoformycin are the most commonly used single-agent chemotherapy regimens in MF and Sezary syndrome [62,64,65]. Response rates and duration are lower than those reported for combination chemotherapy regimens. The purine analogs fludarabine and 2-deoxycoformycin are suitable for individual clinical use on a type R basis. In effect, these drugs seems to be active against MF with response rates as high as 50% [66–68]. Biologic therapy, interferon alfa an retinoids are suitable for individual clinical use on a type R basis, either when used alone, together or in combination with chemotherapy or topical treatment [51,53,62]. The combination fludarabine plus interferon produces a response rate of 46% with a median duration of 6 months [69]. Megavoltage photon irradiation can be used as a palliative treatment of lymph node masses. This can be associated with systemic chemotherapy or interferon alfa. High-dose chemotherapy supported by autologous bone marrow transplantation is an experimental strategy. Experience with this strategy in MF is very limited [70], and, thus, its efficacy has not been established. However, it seems that autologous or allogeneic bone marrow or stem cell transplantation represent a promising approach in tumor-stage patients; mini-allogeneic transplantation may provide the additional advantage of a “graf-versus-tumor” effect [71–75].
cytotoxic activity against various tumors [95,96]. Vorinostat (suberoylanilide hydroxamic acid-SAHA) is the first FDAapproved HDAC inhibitor for the treatment of cutaneous manifestations of cutaneous T-cell lymphomas. Vorinostat was active against solid tumors and hematologic malignancies as intravenous and oral preparations in phase I development. In two phase II trials, vorinostat 400 mg/day was safe and effective with an overall response rate of 24–30% in refractory advanced patients with cutaneous T-cell lymphomas including large cell transformation and Sezary syndrome. The common side effects of vorinostat, which are similar in all studies, include gastrointestinal symptoms, fatigue and thrombocytopenia and the most common serious event was thrombosis. Many other HDAC inhibitors, such as valproic acid [97], MS-275 [98], CI-994 [99], and FK228 [100] among others, are being investigated, but clinical experience on MF patients is still limited.
Reviewers Molina A., MD, MS, Senior Vice-President, Clinical Research and Development, Cougar Biotechnology, 10990 Wilshire Blvd, Suite 1200, Los Angeles, CA 90024, USA.
References 6.6. New active drugs and therapeutic options Anti-T-cell monoclonal antibodies are an investigational alternative on a type R basis. It was studied in small series treated with chimeric anti-helper T-cell (anti-CD4) antibody [76]. The clinical response were generally modest and short-lived. Among novel targeted therapeutic approaches to cutaneous T-cell lymphomas are the retinoids, alltrans retinoic acid (ATRA) [77] and bexarotene (Targretin) [78,79]. Other targeted therapies include the anti-CD52 antibody alemtuzumab (Campath) [80–84], DAB389 IL-2 (denileukin diftitox, ONTAK) [85,86], tumor vaccination [87,88], unmodified or 90Y-conjugated anti-Tac Pseudomonas exotoxin conjugates, and inhibitors of intracellular signal transduction factors. Further important therapeutic modalities include Gemcitabine [89,90], pegylated liposomal doxorubicin [91], pentostatin [92], etanercept [93], immunomodulation of pro-inflammatory cytokines such as interleukin (IL)-12 [94], and photopheresis with or without concurrent immunoadjuvant treatment. Due to the inadequacy of standard therapy, all patients with extracutaneous disease should be considered candidates for newer investigative therapies. An emerging class of investigational agents is represented by histone deacetylase (HDAC) inhibitors, which may restore the expression of tumor suppressor or cell cycle regulatory genes by increasing the acetylation of histones. Depsipeptide and suberoylanilide hydroxamic acid are potent histone deacetylase inhibitors and have shown in vitro and in vivo
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Biographies Pier Luigi Zinzani is Coordinator of the Lymphoma Unit of the Institute of Hematology “L. and A. Ser`agnoli”, University of Bologna, Italy. Andr´es J. M. Ferreri is Coordinator of the Unit of Lymphoid Malignancies and Vice Director of the Medical Oncology Unit, San Raffaele Scientific Institute, Milan, Italy. Lorenzo Cerroni is Head of the Lymphoma Unit and Directoir of the Research Unit Dermatopathology of the Department of Dermatology, Medical University of Graz, Austria.
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