Nicola Pimpinelli

WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects.

Abstract:  The new WHO/EORTC classification for cutaneous lymphomas comprises mature T‐cell and natural killer (NK)‐cell neoplasms, mature B‐cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior.

Primary cutaneous B-cell lymphoma: A unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases

The clinical presentation and course, and the morphoimmunologic features of primary cutaneous B‐cell lymphoma (CBCL) were investigated in a series of 83 patients. Fifty‐one patients were male and 32 were female (male‐to‐female ratio of 1.6:1); CBCL primarily involved the elderly (median age, 58 years). A locoregional extension of the disease was quite frequent (86.7%). The neoplastic cells showed a range of appearances reminiscent of the whole spectrum of follicular/parafollicular cells. The antigenic phenotype of tumor cells (CD19+, CD20+, CD22+, CD28+, CD10−, CD5−, MB2+, CD74+/−, CDw75+/−. MT2+/−, surface immunoglobulin+ monoclonal/−) plus the presence of admixed CD14‐ dendritic reticulum cells suggest a mantle‐zone nature for CBCL. The nonaggressive clinical behavior with a substantial tendency to remain localized to a limited area of the skin, the quite good response to nonaggressive treatment, and the dichotomy existing between the enhancement of morphoimmunologic atypism—which parallels the increasing age and growth rate of lesions—and the constant benign overall prognosis on long‐term follow‐up make CBCL a unique type of lymphoma of low‐grade malignancy. Proper recognition of CBCL is mandatory to avoid possible undertreatment or overtreatment of the patients affected.

Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop.

Cutaneous lymphomas expressing a cytotoxic or natural killer (NK) cell phenotype represent a group of lymphoproliferative disorders for which there is currently much confusion and little consensus regarding the best nomenclature and classification.

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas

PURPOSE Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. PATIENTS AND METHODS The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification. RESULTS Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). CONCLUSION Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

New and Established Topical Corticosteroids in Dermatology

Currently, topical glucocorticosteroids are the most frequently used drugs in dermatologic practice. Over the years, research has focused on strategies to optimize potency and, in particular, the anti-inflammatory and immunosuppressive capacity of these drugs, while minimizing adverse effects. However, ‘ideal’ topical corticosteroids have not yet been synthesized. They should be able to permeate the stratum corneum and reach adequate concentrations in the skin without reaching high serum concentrations. Such characteristics can be obtained by increasing the natural lipophilicity of corticosteroids, e.g. by esterification. In the past, many structural modifications have been made to improve the efficacy of topical corticosteroids to produce drugs with greater potency, although this has often been associated with a higher likelihood of adverse effects. Betamethasone dipropionate and clobetasol propionate, known as fifth-generation corticosteroids, are a typical example of potent molecules that can control specific dermatoses very rapidly, but which are associated with a high risk of topical and systemic adverse effects.Recently, steroid components have been synthesized that aim to have adequate anti-inflammatory effects and minimal adverse effects. The newest topical corticosteroids used for the treatment of different dermatoses and allergic reactions of the respiratory tract (in particular asthma) are budesonide, mometasone furoate, prednicarbate, the di-esters 17,21-hydrocortisone aceponate and hydrocortisone-17-butyrate-21-propionate, methylprednisolone aceponate, alclometasone dipropionate, and carbothioates such as fluticasone propionate. These new topical corticosteroids are evaluated in the current review, which compares the risk/benefit ratio of each molecule with established agents. The new molecules, compared with the well known and established corticosteroids, generally have a higher anti-inflammatory effect, good compliance among patients (only a once-daily application is needed), rarely induce cross-sensitivity reactions and have weak atrophogenicity.

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n = 10) but not in primary melanoma lesions (n = 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor.

Primary cutaneous follicular centre‐cell lymphoma—a lymphoproliferative disease with favourable prognosis

In this study the clinico‐pathological and immunohistological features, the methods of treatment and follow‐up data of 11 patients with follicular centre‐cell (B‐cell) lymphoma primarily presenting in the skin are reported. All the patients had nodular, tumorous and/or papulonodular skin lesions on the trunk. In nine patients the disease was confined to a circumscribed area of the back. Small papulonodular or plaque‐like lesions, as well as large nodules or tumours, were biopsied in six of 11 patients. No clear‐cut correlation between the age and clinical morphology of the lesions and their histological growth pattern was found. Interestingly, however, a different immuno‐architectural pattern was observed in large, late lesions compared to small, early lesions. Initial treatment consisted of orthovolt radiotherapy (in two patients associated with surgical excision), resulting in complete remission in all patients. Only one patient developed extracutaneous disease, which was limited to a single drainage lymph node appearing simultaneously with a cutaneous relapse. Five other patients had recurrent disease in the skin close to the initial site. The median disease‐free period was 15·5 months. On relapse, radiotherapy alone or in combination with short courses of chemotherapy was performed. This resulted in a second complete remission. All the patients are still alive and in complete remission, with a median survival of 37 months. These results confirm the favourable prognosis of patients affected with primary cutaneous follicular centre‐cell lymphoma limited to the trunk. Orthovolt radiotherapy proved to be the most suitable treatment for both initial lesions and relapses limited to the skin.

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.

HEDGEHOG‐GLI Signaling Drives Self‐Renewal and Tumorigenicity of Human Melanoma‐Initiating Cells

The question of whether cancer stem/tumor‐initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a collection of human melanomas obtained from a broad spectrum of sites and stages. We find that melanomaspheres display extensive in vitro self‐renewal ability and sustain tumor growth in vivo, generating human melanoma xenografts that recapitulate the phenotypic composition of the parental tumor. Melanomaspheres express high levels of Hedgehog (HH) pathway components and of embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that human melanomas contain a subset of cells expressing high ALDH activity (ALDHhigh), which is endowed with higher self‐renewal and tumorigenic abilities than the ALDHlow population. A good correlation between the number of ALDHhigh cells and sphere formation efficiency was observed. Notably, both pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting either SMO or GLI1 result in a significant decrease in melanoma stem cell self‐renewal in vitro and a reduction in the number of ALDHhigh melanoma stem cells. Finally, we show that interference with the HH‐GLI pathway through lentiviral‐mediated silencing of SMO and GLI1 drastically diminishes tumor initiation of ALDHhigh melanoma stem cells. In conclusion, our data indicate an essential role of the HH‐GLI1 signaling in controlling self‐renewal and tumor initiation of melanoma CSC/TIC. Targeting HH‐GLI1 is thus predicted to reduce the melanoma stem cell compartment. Stem Cells2012;30:1808–1818