Simone Ribero

Genetic epidemiology of melanoma

The field of melanoma genetics is moving at great pace with new platforms to investigate single nucleotide polymorphism, genome sequencing, gene expression, and methylation. Melanoma incidence is still rising mainly because of screening campaigns, which has increased the number of reported melanomas.However, mortality due to melanoma is not decreasing. Many cutaneous phenotypic risk factors have been linked to melanoma, but the association with UV radiation is very complex. The level of vitamin D affects both the risk of melanoma and prognosis, but more studies are needed. The genetics of melanoma involves genes involved in pigmentation and naevi, as well as genes involved in the cell cycle and senescence, which have been identified via genome-wide association studies over the last 10 years. One area of research highly relevant to melanoma is telomere biology with further links to reduced senescence. At the somatic level, new gene pathways are being explored with many new therapeutic targets, and boosting immune responses against the tumour appears to offer the best long-term outcome.

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

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.

Nonsentinel Lymph Node Status in Patients With Cutaneous Melanoma: Results From a Multi-Institution Prognostic Study

PURPOSE We investigated whether the nonsentinel lymph node (NSLN) status in patients with melanoma improves the prognostic accuracy of common staging features; then we formulated a proposal for including the NSLN status in the current melanoma staging system. PATIENTS AND METHODS We retrospectively collected the clinicopathologic data of 1,538 patients with positive SLN status who underwent completion lymph node dissection (CLND) at nine Italian centers. Multivariable Cox regression survival analysis was used to identify independent prognostic factors. Literature meta-analysis was used to summarize the available evidence on the prognostic value of the NSLN status in patients with positive SLN. RESULTS NSLN metastasis was observed in 353 patients (23%). After a median follow-up of 45 months, NSLN status was an independent prognostic factor for melanoma-specific survival (hazard ratio [HR] = 1.34; 95% CI, 1.18 to 1.52; P < .001). NSLN status efficiently stratified the prognosis of patients with two to three positive lymph nodes (n = 387; HR = 1.39; 95% CI, 1.07 to 1.81; P = .013), independently of other staging features. Searching the literature, this patient subgroup was investigated in other two studies. Pooling the results (n = 620 patients; 284 NSLN negative and 336 NSLN positive), we found that NSLN status is a highly significant prognostic factor (summary HR = 1.59; 95% CI, 1.27 to 1.98; P < .001) in patients with two to three positive lymph nodes. CONCLUSION These findings support the independent prognostic value of the NSLN status in patients with two to three positive lymph nodes, suggesting that this information should be considered for the routine staging in patients with melanoma.

Association of Histologic Regression in Primary Melanoma With Sentinel Lymph Node Status: A Systematic Review and Meta-analysis

Importance The prognostic significance of regression in primary melanoma has been debated for many years. There is no consensus regarding the need for sentinel lymph node (SLN) biopsy when regression is present within the primary tumor. Objective To review the evidence that regression may affect SLN status. Data Sources A systematic review was performed by searching in MEDLINE, Scopus, and the Cochrane Library from January 1, 1990, through June 2014. Study Selection All studies that reported an odds ratio (OR) or data on expected and observed cases of SLN positivity and histologic regression were included. Data Extraction and Synthesis Primary random-effects meta-analyses were used to summarize ORs of SLN positivity and histologic regression. Heterogeneity was assessed using the χ2 test and I2 statistic. To assess the potential bias of small studies, we used funnel plots, the Begg rank correlation test, and the Egger weighted linear regression test. The methodologic quality of the studies was assessed according to the Strengthening of Reporting of Observational studies in Epidemiology (STROBE) checklist, and 2 different meta-analyses were performed based on those criteria. Main Outcomes and Measures Summary ORs of histologic regression of primary melanoma and SLN status. Results Of the 1509 citations found in the search, 94 articles were reviewed, and 14 studies comprising 10 098 patients were included in the analysis. In the combined 14 studies, patients with regression had a lower likelihood to have SLN positivity (OR, 0.56; 95% CI, 0.41-0.77) than patients without regression. On the basis of study quality, we found that patients with regression enrolled in high-quality studies had a lower likelihood to have SLN positivity (OR, 0.48; 95% CI, 0.32-0.72) compared with results of low-quality studies (OR, 0.73; 95% CI, 0.53-1.00). Examination of the funnel plot did not provide evidence of publication bias. Conclusions and Relevance The results of this analysis showed that the risk of SLN positivity was significantly lower in patients with histologic regression compared with those without. Regression may be used in these cases to make a selection of which patients should be the most appropriate for this procedure.

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.

Number of Excised Lymph Nodes as a Quality Assurance Measure for Lymphadenectomy in Melanoma

IMPORTANCE Although the number of excised lymph nodes (LNs) represents a quality assurance measure in lymphadenectomy for many solid tumors, the minimum number of LNs to be dissected has not been established for melanoma. OBJECTIVE To investigate the distribution of the number of excised LNs in a large patient series (N = 2526) to identify values that may serve as benchmarks for monitoring the quality of lymphadenectomy in patients with melanoma. DESIGN, SETTING, AND PARTICIPANTS A retrospective multicenter study was conducted (1992-2010) in tertiary referral centers for treatment of cutaneous melanoma. Medical records on 2526 patients who underwent lymphadenectomy for regional LN metastasis associated with cutaneous melanoma were examined. EXPOSURE Patients had undergone lymphadenectomy for regional LN metastasis. MAIN OUTCOMES AND MEASURES The mean, median, and 10th percentile of the number of excised LNs were calculated for the axilla (3 levels), neck (≤3 or ≥4 dissected levels), inguinal, and ilioinguinal LN fields. RESULTS After 3-level axillary (n = 1150), 3-level or less neck (n = 77), 4-level or more neck (n = 135), inguinal (n = 209), and ilioinguinal (n = 955) dissections, the median (interquartile range [IQR]) and mean (SD) number of excised LNs were as follows: 3-level axillary dissection, 20 (15-27) and 22 (8); 3-level or less neck, 21 (14-33) and 24 (15); 4-level or more neck, 29 (21-41) and 31 (14); inguinal, 11 ( 9-14) and 12 (5); and ilioinguinal, 21 (16-26) and 22 (4). A total of 90% of the patients had 12, 7, 14, 6, and 13 excised LNs (10th percentile of the distribution) after 3-level axillary, 3-level or less neck, 4-level or more neck, inguinal, and ilioinguinal dissections, respectively. More excised LNs were detected in younger (21 for those <54 years of age and 19 for ≥54 years, P < .001) and male (21 for male sex and 19 for female sex, P < .001) patients from high-volume institutions (21 for volume of ≥300 vs 18 for volume <300, P < .001) with a more recent year of diagnosis (21 for years 2002-2010 vs 18 for years 1992-2001, P < .001), LN micrometastasis vs macrometastasis (20 vs 19, P = .005), and more positive LNs (R² = 0.03, P < .001); however, the differences between median values were small. CONCLUSIONS AND RELEVANCE These minimum numbers of excised LNs are reproducible across the institution, patient, and tumor factors evaluated. They can be taken into consideration when monitoring the quality of lymphadenectomy in melanoma and can represent entry criteria for randomized trials investigating adjuvant therapies.

The number of excised lymph nodes is associated with survival of melanoma patients with lymph node metastasis

BACKGROUND Although the number of excised LNs has been associated with patient prognosis in many solid tumors, this association has not been widely investigated in cutaneous melanoma. This study aims to evaluate the association between the number of excised regional lymph nodes (LNs) and melanoma-specific survival. PATIENT AND METHODS Clinico-pathological data from 2507 patients with LN metastasis treated at nine Italian centers were retrospectively collected. RESULTS The number of excised LNs correlated with younger age (P < 0.001), male sex (P < 0.001), neck LN field (P < 0.001), LN micrometastasis (P < 0.001) and number of positive LNs (P < 0.001). The number of excised LNs was an independent prognostic factor (HR = 0.85; P = 0.002) after adjustment for other staging features. Upon subgroup analysis, the number of excised LNs had a significant prognostic value in patients bearing 1.01-2.00 mm (HR = 0.79; P = 0.032) and 2.01-4.00 mm (HR = 0.71; P < 0.001) thick melanomas, primary tumors showing ulceration (HR = 0.86; P = 0.033) and Clark level V of invasion (HR = 0.86; P = 0.010), LN micrometastasis (HR = 0.83; P = 0.014) and two to three positive LNs (HR = 0.71; P = 0.001). Finally, this study investigated the influence of the number of excised LNs on patient staging: only when ≥11 nodes were excised the AJCC N stage could stratify prognosis (P < 0.001). Considering the number of excised LNs for each lymphatic field, at least 14, 11, 10 and 12 LNs were needed to stage patients according to the AJCC N stage after a lymphadenectomy of the neck, axilla, inguinal and ilioinguinal LN fields, respectively. CONCLUSIONS The number of excised LNs can be considered for risk stratification of patients with regional LN metastasis from cutaneous melanoma. We demonstrated that a minimum number of LNs is required for the correct staging of patients. Further research is needed to evaluate the effectiveness of the minimum number of LNs to be dissected.

Regression in cutaneous melanoma: a comprehensive review from diagnosis to prognosis

Histological regression in primary cutaneous melanoma occurs in 10–35% of cases. Although a large body of literature exists to suggest that histological regression serves very little purpose in predicting biologic behaviour with melanoma, recognizing the presence of regression at clinical and histological ground may still retain some value in grading melanoma aggressiveness. In the current review, a comprehensive overview of the main aspects of regression will be provided. Histologically, many classifications have been reported so far, but all of them only agreed on the presence of an infiltrate of lymphocytes admixed with pigment‐laden macrophages underlying an atrophic epidermis with flattened rete ridges. Upon dermoscopy, regression is also named Blue White Scar‐like areas and could be variably admixed with granularity or peppering. Almost fully regressed lesions represent a main diagnostic issue in dermoscopy, and thus, confocal microscopy can be of help to identify whether the tumour is melanocytic or not. The clinical utility of regression as a prognostic factor has been challenged recently. Nowadays, evidences showed that it is less likely associated to SLN metastases.

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

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).

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.