Giuseppe Macripò

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

Merkel cell carcinoma of the skin is a malignant neuroendocrine tumour, whose prognostic criteria are a matter of dispute. Specifically, no predictor is presently available in stage I–II tumours. We collected clinical and follow-up data from 70 Merkel cell carcinomas of the skin. The same cases were studied for p63 expression by immunohistochemistry, by reverse-transcription PCR (RT-PCR) and TP63 gene status by FISH and for presence of Merkel cell polyomavirus by PCR. Stage emerged as a significant prognostic parameter (P=0.008). p63 expression, detected in 61% (43/70) of cases by immunohistochemistry, was associated with both decreased overall survival (P<0.0001) and disease-free survival (P<0.0001). Variable expression patterns of the different p63 isoforms were found only in cases immunoreactive for p63. In these latter lesions, at least one of the N-terminal p63 isoforms was detected and TAp63α was the most frequently expressed isoform. TP63 gene amplification was observed by FISH in only one case. Presence of Merkel cell polyomavirus DNA sequences was detected in 86% (60/70) of Merkel cell carcinomas and did not emerge as a significant prognostic parameter. Merkel cell carcinoma cases at low stage (stage I-II) represented over half (40/70 cases, 57%) of cases, and the clinical course was uneventful in 25 of 40 cases while 15 cases died of tumour (10/40 cases) within 34 months or were alive with disease (5/40 cases) within 20 months. Interestingly, a very strict correlation was found between evolution and p63 expression (P<0.0001). The present data indicate that p63 expression is associated with a worse prognosis in patients with Merkel cell carcinoma, and in localised tumours it represents the single independent predictor of clinical evolution.

Efficacy and Skin Toxicity Management with Cetuximab in Metastatic Colorectal Cancer: Outcomes from an Oncologic/Dermatologic Cooperation

PURPOSE The aim of this study was to investigate the efficacy of the combination of irinotecan/cetuximab and to plan related skin toxicity management with an oncologic/dermatologic team. PATIENTS AND METHODS Thirty-four patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer received cetuximab 400 mg/m2 as an initial dose and 250 mg/m2 weekly thereafter. In addition, patients received irinotecan 180 mg/m2 every 2 weeks. RESULTS Thirty-two patients were evaluated for response rate (RR) and skin toxicity to establish the best management. In our study, the responses observed with cetuximab treatment were complete response in 1 patient (3%), partial response in 11 patients (34%), disease stabilization in 6 patients (19%), and progressive disease in 14 patients (44%). Of 34 patients evaluable for cutaneous toxicity, 10 patients (29%) presented with grade 1 eruption, 13 (38%) with grade 2 eruption, and 4 (12%) with grade 3 eruption. Allergic reactions such as flushing and urticaria (grade 2) were seen in 2 patients (6%). CONCLUSION Cutaneous reactions consisted of follicular rash, xerosis, painful fissures in palms and soles, alterations in hair growth, and mucositis. In the majority of patients (80%-90%), the worst recorded skin effects were mild (grade 1) to moderate (grade 2). The incidence of severe cases (grade 3) was approximately 15%. All dermatologic effects were reversible and generally without sequelae within 4 weeks after treatment discontinuation. We observed significant correlations between degree of cutaneous toxicity and increased RR. Correct identification and treatment by oncologic/dermatologic cooperation of EGFR cutaneous side effects help to improve quality of life.

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.

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.

Prognostic differences across sexes in melanoma patients: What has changed from the past?

Differences across the sexes include epidemiological trends, distribution of clinical features and prognostic relevance in melanoma patients. The aims of this single-institution hospital-based cohort study were as follows: to assess the trends over time of the male/female ratio; to analyse the clinicopathologic features according to sex and their modifications following the introduction in 1999 of sentinel lymph node biopsy; to ascertain the metastatic pathways across sexes and the prognostic role of sex in the disease-free interval (DFI), disease-specific survival (DSS) and survival after recurrence. The patient population included 4310 stage I–II melanoma patients, diagnosed, treated and followed up in our institution from 1975. Patients were divided into two groups on the basis of the introduction of sentinel lymph node biopsy in 1999. A female prevalence was observed until 1999; thereafter, the male/female ratio approached 1 (period 1999–2003), with a subsequent increasing trend suggesting a potential male prevalence. Longer DFI and DSS were observed after 1999 and men showed greater improvement compared with women. In multivariate analyses, sex showed a lower impact on DFI and survival after recurrence following the introduction on sentinel lymph node biopsy. No sex-related differences in terms of DSS were observed before and after 1999 among patients with melanoma located on the trunk. However, among patients with primary lesions not located on the trunk, sex maintained a significant prognostic role in both groups. The results of this study suggest that in the last few years, the prognosis of men could have improved more than that in women. The changing surgical/therapeutic interventions can influence sex disparities in 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.

Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years

In many centers, Stage I–II melanoma patients are considered “cured” after 10 years of disease‐free survival and follow‐up visits are interrupted. However, melanoma may relapse also later. We retrospectively analyzed a cohort of 1,372 Stage I–II melanoma patients who were disease‐free 10 years after diagnosis. The aim of this study was to characterize patients who experienced a late recurrence and to compare them to those who remained disease‐free to identify possible predictive factors. Multivariate Cox proportional‐hazards regression analyses were carried out to evaluate the influence of different factors on the risk of recurrence. Seventy‐seven patients out of 1,372 (5.6%) relapsed, 52 in regional sites and 25 in distant ones. The majority of patients (31 out of 52) experienced late recurrence in regional lymph nodes. Brain and lung were the most common site of single distant recurrence (24% each). Patients with multiple distant metastases showed a brain and lung involvement in, respectively, 40 and 48% of cases. A Cox proportional‐hazards regression model analysis showed the independent role of age under 40 years, Breslow thickness >2 mm, and Clark Level IV/V in increasing the risk of Late Recurrence. These patients should be followed‐up for longer than 10 years. The pattern of recurrence suggests that melanoma cells can be dormant preferentially in lymph nodes, brain and lung. A particular attention should be reserved to these anatomic sites during the follow‐up after 10 years of disease‐free.

Cutaneous Melanoma Metastases Arising on a Split-Skin Graft Donor Site

A primary ulcerated melanoma on the right supraclavicular region, 2.2 mm thick, Clark level IV, of a 40year-old man was treated with surgical excision in July 2007. On October 2007, small multiple cutaneous metastases merging into a nodular lesion were localized on the surgical scar; a swelling of the right axillary lymph nodes was also present (Figure 1). The patient underwent radical node dissection associated with the excision of cutaneous metastases. The defect was repaired using a full-thickness skin graft (0.8 cm) taken with an electric dermatome from the patient’s left thigh. The histological examination confirmed the presence of melanoma cells in the skin and in six of 30 axillary lymph nodes. One month later, multiple blackbluish papulonodular lesions, ranging from 1 to 10 mm in diameter, developed on the skin graft donor site, whereas contiguous areas were uninvolved (Figure 2); similar lesions were also present in the supraclavicular engrafted site (Figure 3). Histological analyses confirmed the metastatic nature of the lesions. Computed tomography scan showed disseminated lung and liver involvement. Blood samples from this patient were positive for tyrosinase messenger RNA (mRNA) expression as tested using reverse transcriptase polymerase chain reaction (RT-PCR) technology. Despite palliative chemoimmunotherapy performed with dacarbazine, cisplatin, vindesine, interleukin-2, and alpha-interferon, the patient died in 2 months.