Favourable prognostic role of histological regression in stage III positive sentinel lymph node melanoma patients.

BACKGROUND: Sentinel lymph node (SLN)-positive melanoma patients are a heterogeneous group of patients with survival rates ranging from ∼20 to over 80%. No data are reported concerning the role of histological regression on survival in stage III melanoma. METHODS: The study included 365 patients with positive SLN from two distinct hospitals. The model was developed on patients from 'AOU Città della Salute e della Scienza di Torino', and externally validated on patients from IRCCS of Candiolo. Survival analyses were carried out according to the presence of regression and adjusted for all other prognostic factors. RESULTS: Among patients followed at 'AOU Città della Salute e della Scienza di Torino' (n=264), the median follow-up time to death or censoring (whatever two events occurred earlier) was 2.7 years since diagnosis (interquartile range: 1.3-5.8). In all, 79 patients died from melanoma and 11 from other causes. Histological regression (n=43) was associated with a better prognosis (sub-HR=0.34, CI 0.12-0.92), whereas the other factors above showed an inverse association. In the external validation, the concordance index was 0.97 at 1 year and decreased to 0.66 at 3 years and to 0.59 at 5 years. Adding histological regression in the prognostic model increased the discriminative ability to 0.75 at 3 years and to 0.62 at 5 years. Finally, using a cutoff of 20% for the risk of death led to a net re-classification improvement of 15 and 11% at 3 and 5 years after diagnosis, respectively. CONCLUSIONS: Histological regression could lead to an improvement in prognostic prediction in patients with stage III-positive SLN melanoma.

Prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis.

The prognostic significance of histological regression in primary melanoma has been debated for many years. We aim to review the evidence to see how histological regression may affect prognosis. A systematic review was performed by searching in MEDLINE, Scopus and the Cochrane Library from 1 January 1966 to 1 August 2015. All studies reporting hazard ratios or data on survival and histological regression were included. Primary random-effects meta-analyses were used to summarize outcome measures. Heterogeneity was assessed using the χ2 -test and I2 -statistic. To assess the potential bias of small studies we used funnel plots and the Begg and Mazumdar adjusted rank correlation method. Summaries of survival outcomes were measured as hazard ratios or relative risk of death at 5 years according to the presence of histological regression of primary melanoma. In total, 183 articles were reviewed out of 1876 retrieved. Ten studies comprising 8557 patients were included. Patients with histological regression had a lower relative risk of death (0·77, 95% confidence interval 0·61-0·97) than those without. Examination of the funnel plot did not provide evidence of publication bias. The results showed that histological regression is a protective factor for survival.

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.

Ultrasound-based follow-up does not increase survival in early-stage melanoma patients: A comparative cohort study.

INTRODUCTION: Different protocols have been used to follow up melanoma patients in stage I-II. However, there is no consensus on the complementary tests that should be requested or the appropriate intervals between visits. Our aim is to compare an ultrasound-based follow-up with a clinical follow-up. PATIENTS AND METHODS: Analysis of two prospectively collected cohorts of melanoma patients in stage IB-IIA from two tertiary referral centres in Barcelona (clinical-based follow-up [C-FU]) and Turin (ultrasound-based follow-up [US-FU]). Kaplan-Meier curves were used to evaluate distant metastases-free survival (DMFS), disease-free interval (DFI), nodal metastases-free survival (NMFS) and melanoma-specific survival (MSS). RESULTS: A total of 1149 patients in the American Joint Committee on Cancer stage IB and IIA were included in this study, of which 554 subjects (48%) were enrolled for a C-FU, and 595 patients (52%) received a protocolised US-FU. The median age was 53.8 years (interquartile range [IQR] 41.5-65.2) with a median follow-up time of 4.14 years (IQR 1.2-7.6). During follow-up, 69 patients (12.5%) in C-FU and 72 patients (12.1%) in US-FU developed disease progression. Median time to relapse for the first metastatic site was 2.11 years (IQR 1.14-4.04) for skin metastases, 1.32 (IQR 0.57-3.29) for lymph node metastases and 2.84 (IQR 1.32-4.60) for distant metastases. The pattern of progression and the total proportion of metastases were not significantly different (P = .44) in the two centres. No difference in DFI, DMFS, NMFS and MSS was found between the two cohorts. CONCLUSION: Ultrasound-based follow-up does not increase the survival of melanoma patients in stage IB-IIA.

Prediction of high naevus count in a healthy U.K. population to estimate melanoma risk.

BACKGROUND: Despite recent discoveries of germline and somatic mutations in melanoma, naevus count remains the most important risk factor for melanoma. Counting naevi on the whole body is time consuming. In order to identify patients at risk for melanoma, many studies have used naevus count on selected body sites as a proxy for total body naevus count (TBNC). OBJECTIVES: The main aim of this study was to assess the predictive value of naevus count on 17 different body sites in estimating TBNC in a large cohort of healthy U.K. Caucasian female subjects. Once the site with the best predictive value for TBNC was determined, a second aim was to estimate the cut-off values of naevus counts at this anatomical site that best predict the presence of 50 or 100 naevi, respectively. METHODS: The most predictive body site for TBNC was assessed in a cohort of healthy female twins. This finding was replicated on a control group from a U.K. case-control study and a prediction model was performed afterwards. The area under the receiver operating characteristics curve was used to evaluate the best cut-off for the prediction of having a TBNC of more than 50 or 100. RESULTS: There were 3694 female twins included. The TBNC showed a steady decline after the age of 30 years (P < 0·001). The most predictive sites for TBNC were the arms and legs: the adjusted correlation coefficients were 0·50 and 0·51 (P < 0·001) for the right and left arm, respectively, and 0·49 and 0·48 for the right and left legs, respectively (P < 0·001). The arm remained the most predictive site for TBNC when replicated in a control population including both sexes. In the twin study, women with more than 11 naevi on the right arm were approximately nine times more likely to have more than 100 naevi (odds ratio = 9·38, 95% confidence interval 6·71-13·11). CONCLUSIONS: The ability to estimate TBNC quickly by counting naevi on one arm could be a very useful tool in assessing melanoma risk in primary care.

Phenotypical characterization of circulating cell subsets in pyoderma gangrenosum patients: the experience of the Italian immuno-pathology group.

BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).

Sentinel Lymph Node Biopsy in Thick-Melanoma Patients (N=350): What is Its Prognostic Role?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is currently recommended for patients with intermediate-thickness melanomas (T2-T3). Historically, T4 melanoma patients have not been considered good candidates for SLNB because of the high risk of distant progression. However, some authors suggest that T4 melanoma patients could be considered as a heterogeneous group that could benefit from SLNB. METHODS: We retrospectively analyzed 350 patients with thick (>4 mm) melanomas between 1999 and 2011. Patients were stratified into three groups depending on the results of SLNB: (1) 94 SLNB-negative; (2) 84 SLNB-positive; and (3) 172 SLNB not performed (observation group). The associations of clinical-pathologic features with the result of SLNB, disease-free interval (DFI), and disease-specific survival (DSS) were analyzed. RESULTS: Multivariate analyses confirmed a better prognosis for SLN-negative patients compared with patients in the observation group (DSS hazard ratio [HR] 0.62, p = 0.03; DFI HR 0.47, p < 0.001). The observation group was shown to have the same prognosis as the positive-sentinel lymph node group, when adjusted for principal confounders in the model. CONCLUSIONS: We confirmed that thick-melanoma patients are a heterogeneous group with different prognosis. In our experience, SLNB allowed for an appropriate stratification of patients in different survival groups. On the basis of our results, we strongly recommend the routine execution of SLNB in cases of primary melanoma thicker than 4 mm.

Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients.

BACKGROUND: The prognostic significance of regression in primary melanoma has been debated over the past few years. Once it was considered to be a negative prognostic factor, as it may have prevented proper melanoma thickness measurement, therefore affecting the staging of the tumours. For this reason, it was considered to be an indication for sentinel lymph node biopsy (SLNB) in melanoma < 1 mm. OBJECTIVES: To ascertain the utility of SLNB in thin melanoma and to clarify the role of regression in disease-free survival (DFS) and overall survival (OS) in our series. METHODS: We analysed data collected from 1693 consecutive patients with AJCC (American Joint Committee on Cancer) stage I-II melanoma. RESULTS: Globally, SLNB was performed in 656 out of 1693 patients. Regression was present in 349 patients and 223 of them were characterized by thin lesions. SLNB was performed in 104 cases of thin melanoma with regression. The majority of regional lymph node metastases were observed in patients who did not undergo SLNB (89 out of 132). Among the remaining 43 'false negative' patients only three showed regression in the primary. Using the Cox multivariate model, histological regression maintained a significant protective role [hazard ratio (HR) 0·62, P = 0·012 for DFS; HR 0·43, P = 0·008 for OS] when corrected for the principal histopathological and clinical features, despite SLNB. CONCLUSIONS: We confirmed that regression alone should not be a reason to perform SLNB in thin melanoma and, on the contrary, it can be considered a favourable prognostic factor in patients with AJCC stage I-II melanoma.

Relevance of multiple basin drainage and primary histologic regression in prognosis of trunk melanoma patients with negative sentinel lymph nodes.

BACKGROUND: Lymphatic drainage to multiple basins (MLBD) is frequently observed in patients with primary melanoma located in the trunk. Conflicting data regarding the prognostic impact of MLBD are reported. OBJECTIVE AND METHODS: We reviewed our case series of 352 patients with trunk melanoma to evaluate the pattern of basin drainage and to analyse whether different basin drainages may have different significance in negative sentinel lymph node (SLN) patients. The presence of single/multiple basin drainage, the status of SLN, the presence of melanoma regression, Breslow thickness, ulceration and type of melanoma were recorded for each patients and correlated to Disease Free Survival (DFS) and Overall Survival (OS). RESULTS: MLBD occurred in 77 patients (21.9%) and single basin lymphatic drainage (SLBD) occurred in 275 patients (79.1%). The presence of metastases in SLN was not significantly different in patients with MLBD compared to those with SLBD (26% vs. 19.6%). No differences in OS and DFS were found in SLBD/MLBD independently from SLN status. However DFS was higher in patients with MLBD and negative SLN (P = 0.0001), in addition, in patients with negative SLN and SLBD disease recurrence was 19% while was only 7% in patients with negative SLN obtained from MLBD (P = 0.03). Multivariate analysis showed that Breslow thickness <2 mm, MLBD pattern and regression of melanoma were favourable variables for DFS of patients with negative SLN. CONCLUSIONS: An accurate study of the drainage basin and of all the SLNs obtained from MLBD is recommended because of the impact in prognosis of melanoma of the trunk.

Melanoma in patients younger than 20 years.

AIM: Melanoma is rare in children and uncommon in adolescents. Clinical and prognostic factors can differ from adult population. There is often a delay in diagnosis and the therapeutic management is not unequivocally established. The aim of this study was to review our monocentric case series to establish the characteristics of the population and the possible different behaviour of the malignancy compared to adults. METHODS: From 1975 to 2011 we selected 36 out of 43 patients with a diagnosis of melanoma before the age of 20. We reported a female predominance, the most common site of primary lesions for both sexes were the lower extremities and according to adulthood population the most common histotype was Superficial Spreading Melanoma. RESULTS: None of our patients presented distant metastasis at diagnosis, but 29.4% showed a progression, and the 17.6% died during the follow-up. A significant difference based on gender was found at the multivariate analysis on Disease free survival as well as Breslow thickness, but only Breslow thickness was the only parameter that maintained a role on survival at multivariate analysis when corrected for gender and age. We performed the sentinel lymph node biopsy in 3 patients and they all resulted negative. CONCLUSION: Despite our small case series we observed some important differences of melanoma in children compared to adults. It remains difficult to establish the prognostic factors in younger melanoma patients. Similar to adults, the detection of melanoma in an early phase of development, with a low Breslow thickness, is the most important prognostic factor.

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients.

Bullous pemphigoid (BP) is the most frequent autoimmune bullous skin disease, characterised by auto-antibodies against the hemidesmosome complex. Recently, regulatory T cells (Tregs) have been implicated in the development of several autoimmune diseases; few data are available in BP, failing to demonstrate a role of this subset in disease pathogenesis. The aim of this study was to investigate the expression and phenotypes of different Tregs (CD4+ CD25brightFOXP3+ and CD8+ CD28- cells) in BP to clarify whether the depletion of this subset constitutes one mechanism of tolerance loss. The CD4+ CD25brightFOXP3 and CD8+ CD28- circulating subsets were determined by flow-cytometry in 26 untreated BP patients and compared with a group of age- and sex-matched healthy controls (HC, n = 30). Absolute and percentage values of the CD4+ CD25brightFOXP3+ cells were significantly reduced in BP compared with HC (median CD25brightFOXP3+ expression within CD4+ cells: 1.8 vs. 3.5%, p = 0.002); conversely, BP patients were characterised by a significant expansion of the CD25brightFOXP3- "activated" T-cell subset. CCR4 and CD62L were expressed on the majority of CD4+ CD25brightFOXP3+ cells (75.2 and 82.3%, respectively). No differences in the CD8+ CD28- subset were found between BP and HC. This is the first report showing a significant reduction of circulating CD4+ CD25brightFOXP3+ Treg frequency in BP patients.

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. OBJECTIVE: We focused our study on patients with disease progression after negative SLN biopsy (SLNB), with the aim of elucidating their clinical and histopathological characteristics, outcome and real incidence of false negative. METHODS: A total of 688 melanoma patients who underwent SLNB (1 May 1998-31 December 2008) were analysed; all patients had Breslow >1 mm or Breslow <1 mm and at least one of the following features: regression, ulceration and/or Clark level IV-V. RESULTS: Progression developed in 114 of 503 negative SLN patients (22.7%); the first metastatic site was regional in 64% and distant in 36% of these cases. Thirty-nine patients had nodal metastases in the SLN basin as first site of progression. High-risk melanomas (P = 0.001) and elderly patients (P = 0.0005) had an increased probability of progression. Women with a higher median age and lower limbs primary melanoma developed mainly regional skin metastases, while an increased probability of distant metastases was demonstrated in patients with primary on the trunk and axillary SLN (P = 0.003, P = 0.001 respectively). Age at diagnosis, Breslow thickness and regression showed a prognostic relevance in univariate and multivariate analyses on disease-free survival and overall survival. CONCLUSIONS: Even if SLN status remains the most important prognostic factor for melanoma patients, progressive disease after a negative SLNB is a relatively frequent event. However, in our opinion, only a part of negative SLNB patients with metastatic spreading should be considered as false negative (7.75%).

Clinical and prognostic reports from 270 patients with multiple primary melanomas: a 34-year single-institution study.

BACKGROUND: Development of more than one primary melanoma in a sole patient is frequent, accounting for 1.2-8.2% of melanoma patients in most recent series. OBJECTIVE AND METHODS: Clinical, histological and epidemiological characteristics of 270 multiple primary melanomas patients were reviewed. RESULTS: Two-hundred and seven patients (76.7%) had two melanomas, whereas in the remaining 63 the number of primary ranged from three to eight; on the whole, 639 multiple primary melanomas were identified. Synchronous melanomas developed more frequently in patients with three or more lesions; median age was significantly lower in the group of patients with more than three melanomas than in the others. Mean Breslow's thickness significantly decreases (P<0.001) from the first (1.77±1.76 mm) to subsequent primaries (0.85±1.25 mm for the second and 0.66±0.48 mm for the third melanoma). Percentage of 'in situ' melanomas was 5.6% as first diagnosis, but increased to 24.8% for the second melanoma; number of nodular melanomas was significantly lower for succeeding diagnosis. AJCC stage at diagnosis showed a statistical prognostic significance, whereas outcome and survival did not depend on the number of primary lesions. Multivariate analysis confirmed the prognostic role of Breslow's thickness, ulceration, gender and patient age, and the better prognosis of patients with multiple melanomas, respect to those with single primary melanoma. CONCLUSIONS: Skin examination and long-term follow-up are mandatory for patients affected by melanoma, with the intent to promptly diagnose not only a disease progression but also possible new primary melanomas.

Clinico-pathologic features of primary melanoma and sentinel lymph node predictive for non-sentinel lymph node involvement and overall survival in melanoma patients: a single centre observational cohort study.

OBJECTIVE: Completion Lymph Node Dissection (CLND) is the current standard of practice for patients with a positive Sentinel Lymph Node Biopsy (SLNB). Significant morbidity is associated to CLND, so we tried to evaluate which prognostic variables could predict NSLN invasion in SLN-positive patients and their impact on the overall survival (OS). METHODS: A retrospective chart review of 603 patients that had undergone SLNB for melanoma between 2000 and 2009 at our department was done. 100 SLN were positive at the histopathological analysis of SLN. Demographic variables, primary melanoma, SLN pathologic features and results of CLND were analysed. Multivariate logistic regression and OS analyses were carried out to test the prognostic relevance of clinico-pathologic variables on CLND results and disease course. RESULTS: Breslow thickness, ulceration and micro/macrometastatic pattern of SLN invasion carried a significantly independent higher likelihood of NSLN involvement; Starz classification did not maintain a statistical significance in multivariate analysis. Only one patient (4.3%) without adverse prognostic factors showed NSLN involvement, which was found in 33.3% of patients with one and 55.9% with two or more adverse parameters (p = 0.0001). OS analyses confirmed the prognostic significance of these factors. CONCLUSION: Waiting for the results of Multicenter Selective Lymphadenectomy Trial II, our study suggests a clinically useful and easily applicable means of identifying patients with an unfavourable disease course. The presence of one or more adverse factors identifies patients in whom CLND is mandatory to include thereafter in a more strict follow-up program. Moreover, the finding of no adverse prognostic indicators associated to the presence of significant co-morbidities and/or elderly age, could be useful in identifying patients not to treat by CLND.