Vieri Grandi

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model

PURPOSE Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

Role of bexarotene in the treatment of cutaneous T-cell lymphoma: the clinical and immunological sides

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of lymphoid neoplasms. The incidence of CTCLs has risen over the last three decades. The most common CTCLs are mycosis fungoides and Sèzary syndrome. Therapies for CTCLs are various and range from skin-directed therapy to chemotherapy. Retinoids have been used in CTCL treatment since the 1980s with good results. Bexarotene is the first retinoid approved by the US FDA for CTCL therapy. Since then, numerous experiences of both its efficacy and mechanism of action have been reported. The aim of this paper is to review bexarotene action on CTCLs, as well as to highlight its immunological targets.

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

Background Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

Maintenance phase in psoralen–ultraviolet A phototherapy of early-stage mycosis fungoides. A critically appraised topic

A 65‐year‐old patient affected by mycosis fungoides (MF) stage IB achieved complete remission (CR) after a cycle of PUVA phototherapy. The U.S. Cutaneous Lymphoma Consortium (USCLC) guidelines suggest that the patient should be kept in the maintenance phase, defined as a ‘period of gradual decrease of frequency of UVL [ultraviolet light] while in clinical remission before discontinuation of phototherapy’ by slowly tapering the number of psoralen–ultraviolet A (PUVA) applications over time up to clinical relapse. The USCLC guidelines also suggest a standardized schedule for the maintenance phase. Alternatively, the patient could end PUVA therapy and go straight to follow‐up.

Primary cutaneous B‐cell lymphoma other than marginal zone: clinicopathologic analysis of 161 cases: Comparison with current classification and definition of prognostic markers

Categorization of primary cutaneous B‐cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus‐based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL‐LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL‐NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a “double hit score” upon positivity for BCL2 and MYC. PCDLBCL‐NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B‐cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a “non‐germinal B‐cell” profile, whereas “germinal center” cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC‐LT, which often coexpressed MYC and BCL2. The impact of single factors on 5‐year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group—PCDLBCL‐NOS—exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.

Standardization of regimens in Narrowband UVB and PUVA in early stage mycosis fungoides: Position paper from the Italian Task Force for Cutaneous Lymphomas

UV‐based (PUVA and narrowband UVB) phototherapy is broadly and commonly used in the treatment of Cutaneous T‐cell Lymphomas (CTCL), yet unfortunately, the evidence for the efficacy of these treatments is based only on case series or prospective but non‐randomized studies. Therefore, no internationally approved guidelines exist and no standardization of schedules has been proposed. Recently, consensus guidelines have been published by the United States Cutaneous Lymphoma Consortium. The aim of this study was to review the biological and clinical evidences on PUVA and NB‐UVB in CTCL and to critically evaluate acceptability and feasibility of these guidelines in the real‐life setting from the perspective of the Cutaneous Lymphoma Task Force of the Italian Lymphoma Foundation (Fondazione Italiana Linfomi, FIL).

Moyamoya in a patient with Sneddon's syndrome.

NEUROFARBA Department, Neuroscience Section, University of Florence, Florence, Italy SOD Neurologia 2, Neuroscience Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy SOD Oculistica, Department of Translational Surgery and Medicine, Florence, Italy Department of Surgery and Translational Medicine, Division of Dermatology, University of Florence, Florence, Italy Department of Surgery and Translational Medicine, Division of Pathological Anatomy, University of Florence, Florence, Italy Stroke Unit and Neurology, Cardiovascular Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy

A literature revision in primary cutaneous B-cell lymphoma

The term “Primary Cutaneous B-Cell Lymphoma” (PCBCL) comprehends a variety of lymphoproliferative disorders characterized by a clonal proliferation of B-cells primarily involving the skin. The absence of evident extra-cutaneous disease must be confirmed after six-month follow-up in order to exclude a nodal non-Hodgkins lymphoma (NHL) with secondary cutaneous involvement, which may have a completely different clinical behavior and prognosis. In this article, we have summarized the clinico-pathological features of main types of PCBCL and we outline the guidelines for management based on a review of the available literature.

Erythroderma and non-Hodgkin T-cell lymphoma: what else, apart from Mycosis Fungoides and Sézary syndrome?

BackgroundPeripheral T-cell lymphomas, not otherwise specified (PTCL-NOS), are a rare condition characterised by specific histology, nodal presentation, and a poor prognosis. In total, 10-18% of patients present with cutaneous involvement which is regarded as a poor prognostic marker. However, cutaneous PTCL-NOS lesions have been rarely reported in the literature.ObjectivesWe sought to describe PTCLNOS cases characterised by erythrodermic dissemination to the skin.Materials & methodsThree cases of PTCL-NOS were investigated; all male, with a mean and median age of 55 and 51 years, respectively.ResultsAll patients underwent aggressive chemotherapeutic protocols with only transient improvement of the disease, and died within two years of follow-up.ConclusionsDermatologists should be reminded that erythroderma and lymph node enlargement do not represent an exclusive paradigm for erythrodermic cutaneous T-cell lymphoma, and that these features can be due to a systemic lymphoma that should be considered in the differential diagnosis.

Ingenol mebutate in the treatment of ‘Hydroxyurea-induced Squamous Dysplasia’: a single centre experience

‘Hydroxyurea‐induced Squamous Dysplasia’ (HISD) is a cutaneous side‐effect related to chronic oral treatment with Hydroxyurea. Ingenol mebutate gel is a topical drug approved for the treatment of multiple, non‐hypertrophic actinic keratoses (AK) localized within a limited cancerization field. Since HISD may be considered as a drug‐induced variant of classic AK, ingenol mebutate is likely to have therapeutic effects.