Paolo Fava

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.

Skin metastases of malignant melanoma: a clinical and prognostic survey.

Skin metastases are a frequent event in the natural history of malignant melanoma, both in the early and late phases of disease progression. In this study, we reviewed our database of 4865 melanoma patients, who were diagnosed and followed up prospectively over a 30-year period at our institution. Statistical analyses were focused on patients with secondary involvement of the skin. Seven hundred and thirty-three of the 4030 patients that met the inclusion criteria (18.2%) developed cutaneous metastases; the skin was involved as first site in 413 patients (56.3%) and after regional lymph node spreading in 208 (28.4%) patients. In a lower number of patients, cutaneous metastases developed only in advanced stages of the disease. Skin metastases were mainly locoregional, when arising as the first site of relapse (89.3%) and/or in patients with a primary melanoma of the lower limbs; in contrast, disseminated metastases are more often observed after a visceral involvement and for primary melanomas of the trunk. Moreover, despite a lower disease-free survival rate (1.3 vs. 2.9 years), we showed a significantly longer time to progression to visceral involvement for the group of patients with cutaneous locoregional metastases (62.5 vs. 17.8 months). The site of primary melanoma is strictly related to the pattern of cutaneous recurrence. The disparity in clinical outcome between patients with locoregional or disseminated skin metastases should therefore be taken into consideration in their management.

Zosteriform Cutaneous Metastases: A Literature Meta‐Analysis and a Clinical Report of Three Melanoma Cases

BACKGROUND Despite frequent skin involvement with solid tumors, zosteriform metastases are a rare, not well‐defined entity, with only few cases published in literature. The unifying characteristic is merely topographic: cutaneous lesions were distributed along dermatomes, despite the variety of clinical features, including vesicobullous, papular, and nodular lesions. Several theories have been proposed to explain the pathogenetic mechanism of zosteriform dissemination, even if none was adequately proved. OBJECTIVE In this article, we report three new cases of patients with melanoma with skin zosteriform metastases and present a meta‐analysis of literature data. METHODS AND MATERIALS We collected all Entrez‐PubMed articles about zosteriform skin metastasis since 1970 and reviewed 56 cases, including our own taken from a 4,774‐patient series. RESULTS The histotypes mainly implicated were melanoma (18%); lymphoma (14%); breast cancer (12%); squamous cell carcinoma (12%); and digestive (10.7%), respiratory (10.7%), and urinary tumors (7%), with other histotypes accounting for 14%. In only one case in our series did we describe a typical herpetiform pattern, whereas in the others we found papulonodular lesions with a dermatomeric distribution. CONCLUSION Cutaneous metastases with zosteriform pattern are rare and show a wide clinicopathologic spectrum that could affect the disease course.

Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab

PURPOSE The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab. EXPERIMENTAL DESIGN The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, β2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively. RESULTS Median survival was 8.3, 4.9 and 7.1 months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months. CONCLUSION Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation.

Heterogeneity of Circulating CD4+ Memory T-Cell Subsets in Erythrodermic Patients: CD27 Analysis Can Help to Distinguish Cutaneous T-Cell Lymphomas from Inflammatory Erythroderma

Background: Chronic dermatoses, as well as Sézary syndrome (SS), the erythrodermic and leukaemic cutaneous T-cell lymphoma, display a T-cell memory pattern. Recent findings suggest that different memory T-cell subsets can be recognized based on CD27 and CD45RO/RA expression. No data are reported as to CD27 expression in SS. Objectives: To evaluate different memory T-cell subsets, i.e. central memory (TCM), effector memory (TEM) and terminally differentiated cells in SS and inflammatory erythroderma (IE). Materials and Methods: Forty SS and 137 IE patients were included. CD27 and CD45RO/CD45RA expression was analysed by flow cytometry on peripheral blood lymphocytes and immunohistochemistry.Results: A significantly higher expression of the CD4+CD27+CD45RA– TCM subset was observed in SS whilst IE patients were characterized by increased CD4+CD27–CD45RA– TEM levels. The Vβ-restricted population was homogeneously CD4+CD26–CD27+ in the SS subjects. Conclusions: SS and IE are characterized by a different memory T-cell subset expression; CD27 expression could be used as an additional diagnostic tool in the differential diagnosis.

Extracorporeal photopheresis for the treatment of erythrodermic cutaneous T‐cell lymphoma: a single center clinical experience with long‐term follow‐up data and a brief overview of the literature

Extracorporeal photopheresis (ECP) is a therapeutic procedure in which leukapheresed peripheral blood mononuclear cells are exposed to ultraviolet A in the presence of the photosensitizer 8‐methoxypsoralen and then reinfused. Several guidelines recommend ECP as a treatment of choice in erythrodermic primary cutaneous T‐cell lymphomas (E‐CTCL). However, the level of evidence is low due to the rarity of this disease and the lack of randomized controlled trials. We performed a review of the English literature, restricting our analysis to studies including erythrodermic patients and more than 10 cases. Based on these criteria, we identified 28 studies, with a total of 407 patients. The median response rate in erythrodermic patients was 63% (range 31–86%), with a complete response rate ranging between 0 and 62% (median 20%). In our experience, we treated 51 patients with E‐CTCL since 1992. A clinical response was obtained in 32 of 51 patients (63%), with a 16% complete response rate. The median time for response induction was eight months (range: 1–23). The median response duration was 22.4 months (range six months to 11 years). The treatment was generally well tolerated without systemic toxicities grade III–IV. The pretreatment parameters significantly associated with a higher likelihood to obtain a clinical response were the B‐score in the peripheral blood, CD4/CD8 ratio, and amount of circulating CD3+CD8+ cells. Literature data together with our personal experience clearly support the clinical activity and tolerability of ECP in patients with E‐CTCL. Prospective controlled clinical trials are strongly recommended to better document the evidence.

Melanoma of unknown primary site: a 33-year experience at the Turin Melanoma Centre.

Unknown melanoma occurs as metastasis to skin, nodes or viscera, without a detectable cutaneous primary tumour. We reviewed our database of 4881 melanoma patients, diagnosed and followed up prospectively for a 33-year period. We identified 93 cases of metastatic melanoma without evidence of primary; however, five of these patients had a history of a previous excision of a presumed benign lesion without histological examination and were excluded from analyses. At diagnosis, metastases were cutaneous in 35.3% of cases, nodal in 43.2% and visceral in 17% of cases; in 4.5% of patients, both skin and nodes were involved. In all cases, clinical inspection and staging procedures performed at diagnosis of metastatic disease failed to identify a primary melanoma. In 11 cases (11.8%), extensively regressed pigmented lesions (without evidence of melanoma cells at the histological examination) were documented; moreover, we identified in our series five patients with unknown primary affected by vitiligo. The 5-year and 10-year overall survival rates were 49.6 and 41.4%, respectively, with a median of 4.9 years. The 5-year and 10-year time to progression rates were 39.4 and 32.3%, respectively, with a median of 2.3 years. Survival was longer in females and showed significant differences among patients with skin, lymph node or visceral involvement at diagnosis. In melanoma patients, unknown primary represents a not so rare event, with an uncertain origin. We confirmed the relatively good prognosis of unknown primary melanoma patients, a fact that has to be taken into consideration for their management.

Radiotherapy and immune checkpoints inhibitors for advanced melanoma

INTRODUCTION The therapeutic landscape of metastatic melanoma drastically changed after the introduction of targeted therapies and immunotherapy, in particular immune checkpoints inhibitors (ICI). In recent years, positive effects on the immune system associated to radiotherapy (RT) were discovered, and radiation has been tested in combination with ICI in both pre-clinical and clinical studies (many of them still ongoing). We here summarize the rationale and the preliminary clinical results of this approach. MATERIALS AND METHODS In the first part of this review article, redacted with narrative non-systematic methodology, we describe the clinical results of immune checkpoints blockade in melanoma as well as the biological basis for the combination of ICI with RT; in the second part, we systematically review scientific publications reporting on the clinical results of the combination of ICI and RT for advanced melanoma. RESULTS The biological and mechanistic rationale behind the combination of ICI and radiation is well supported by several preclinical findings. Retrospective observational series and few prospective trials support the potential synergistic effect between radiation and ICI for metastatic melanoma. CONCLUSION RT may potentiate anti-melanoma activity of ICI by enhancing response on both target and non-target lesions. Several prospective trials are ongoing with the aim of further exploring this combination in the clinical setting, hopefully confirming initial observations and opening a new therapeutic window for advanced melanoma patients.

Gauze-based negative pressure wound therapy: a valid method to manage pyoderma gangrenosum

Pyoderma gangrenosum (PG) is an uncommon ulcerative, non‐infective chronic inflammatory skin disorder of unknown aetiology. Systemic therapies are necessary to control the associated medical diseases, and, due to the inflammatory nature of PG, topical or systemic immunosuppressant agents are effective, but wound healing is usually slow. Negative wound pressure therapy (NPWT) has become an important tool for the management of complex skin ulcers, and usage in PG has been recently described in the literature: we present four cases of classic PG in which NPWT in association with systemic therapy achieved wound healing and a drastic pain reduction.

Disease progression in melanoma patients with negative sentinel lymph node: does false-negative specimens entirely account for this phenomenon?

Background  Sentinel lymph node (SLN) status is the most important prognostic factor for subjects with primary melanoma thicker than 1 mm.