Thick Primary Cutaneous Melanoma Research Articles

The Impact of Clinical and Histopathological Factors on Disease Progression and Survival in Thick Cutaneous Melanomas.

Thick cutaneous melanomas (Breslow depth > 4 mm) are locally advanced tumors, generally associated with poor prognosis. Nevertheless, these tumors sometimes display unpredictable behavior. This study aims to analyze clinical and histopathological features that can influence the prognosis of thick melanomas. This is a retrospective study on 94 thick primary cutaneous melanomas diagnosed between 2012 and 2018 that were followed-up for at least five years to assess disease progression and survival. We evaluated the age, gender, tumor location, histological subtype, Breslow depth, Clark level, resection margins, mitotic index, the presence/absence of ulceration, necrosis, regression, microsatellites, neurotropism, lymphovascular invasion, and the pattern of tumor-infiltrating lymphocytes, and their association with disease progression and survival. By conducting univariate analysis, we found that progression-free survival (PFS) was significantly associated with female gender, the superficial spreading melanoma (SSM) subtype, mitotic index, necrosis, microsatellites, and perineural invasion. Overall survival (OS) was significantly associated with female gender, Breslow depth, SSM subtype, necrosis, microsatellites, and perineural invasion. Through multivariate Cox proportional hazards regression, we found that the only factors associated with PFS were Breslow depth, necrosis, microsatellites, and perineural invasion, while the factors associated with OS were Breslow depth, necrosis, microsatellites, and perineural invasion. Certain histopathological features such as Breslow depth, necrosis, microsatellites, and perineural invasion could explain differences in disease evolution. This is one of the first studies to demonstrate an association between necrosis and perineural invasion and outcomes in patients with thick melanomas. By identifying high-risk patients, personalized therapy can be provided for improved prognosis.

Vascular endothelial growth factor/semaphorin-3A ratio and SEMA3A expression in cutaneous malignant melanoma.

Breslow thickness and Clark level are still important factors for cutaneous melanoma, but do not provide a precise prognosis in all cases. It is necessary to find new factors capable of a more accurate prediction of the tumor course. Angiogenesis is essential for tumor development and progression and is regulated by vascular endothelial growth factor A (VEGF-A) and semaphorins (SEMA), in particular, SEMA3A inhibits angiogenesis by affecting VEGF signaling. However, the prognostic role of angiogenetic factors remains unclear. To date, no information is available on SEMA3A in human melanoma. Microvessel density, immunohistochemical and mRNA VEGF and SEMA3A expression level in 60 thin (Breslow thickness ≤ 1.0 mm), 60 intermediate (1.1-4.0 mm) and 50 thick (>4.0 mm) primary human cutaneous melanomas were investigated and related to clinical/pathological parameters and disease-specific survival. No positive association between Breslow thickness, Clark level, metastasis presence and survival was identified; Clark level was poorly related to survival. VEGF and microvessel density were significantly higher in intermediate and thick melanomas and related to Breslow thickness and Clark level but not to metastasis status and survival. On the contrary, SEMA3A was significantly reduced in intermediate and thick melanomas and associated to metastasis and poor survival. VEGF/SEMA3A ratio was higher in the worst prognosis, resulting the most closely related factor with metastasis and survival. SEMA3A expression and VEGF/SEMA3A ratio turned out to be valuable prognostic biomarkers in patients affected by cutaneous melanoma, in particular with Breslow thickness >1 mm. SEMA3A might serve as a candidate tumor suppressor in cutaneous melanoma therapy.

MiRNAs as Potential Prognostic Biomarkers for Metastasis in Thin and Thick Primary Cutaneous Melanomas.

The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinical-pathological factors. MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR. A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm2 Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma.

Sentinel Lymph Node Biopsy in Patients With Thick Primary Cutaneous Melanoma.

BackgroundThe clinical value of sentinel lymph node biopsy (SLNB) in patients with thick melanoma is uncertain. The purpose of this study was to investigate the correlations between survival and lymph node status in thick melanomas.MethodsOf a total of 736 melanoma patients registered between 2000 and 2016, 50 presented with thick melanomas (≥ 4.0 mm) without distant metastatic disease. All patients were examined with a whole-body magnetic resonance imaging, or computed tomography, and positron emission tomography-computed tomography depending on the incorporation of the new technology in our medical institutions. They were studied according to the following procedure: 1) preoperative determination of regional lymph node along with the estimation and localization of sentinel lymph node (SLN) (dynamic isotope lymphography); 2) intraoperative localization and SLNB (lymphatic mapping); and 3) histopathology. Patient and tumor features were collected.ResultsMean follow-up was 40 months, and 37% had a follow-up ≥ 5 years. A positive SLN was identified in 28 patients (56%). No significant difference in melanoma-specific overall survival was observed in terms of the primary tumor site. Hazard ratios (HRs) were statistically significant for SLNB-positive group and mitotic rate (MR) > 3 mm2, but not for presence of ulceration. Mortality risk in the SLN-positive group was almost fourfold greater than that in the SLN-negative group at any time of follow-up.ConclusionsSLN status, along with MR, can provide valuable prognostic information in patients with thick primary cutaneous melanoma.

The Prognostic Significance of Sentinel Lymph Node Status for Patients with Thick Melanoma.

Sentinel lymph node biopsy (SLNB) is recommended for patients with intermediate-thickness melanoma, but the use of SLNB for patients with thick melanoma is debated. This report presents a single-institution study investigating factors predictive of sentinel lymph node (SLN) metastasis and outcome for thick-melanoma patients . A retrospective review of a single-institution database from 1997 to 2012 identified 147 patients with thick primary cutaneous melanoma (≥4mm) who had an SLNB. Clinicopathologic characteristics were correlated with nodal status and outcome. The median age of the patients was 67years, and 61.9% of the patients were men. The median tumor thickness was 5.5mm, and 54 patients (36.7%) had a positive SLN. Multivariable analysis showed that only tumor thickness significantly predicted SLN metastasis (odds ratio 1.14; 95% confidence interval (CI) 1.02-1.28; P=0.02). The overall median follow-up period was 34.6months. Overall survival (OS) and melanoma-specific survival (MSS) were significantly worse for the positive versus negative-SLN patients. Multivariable analysis showed that age [hazard ratio (HR) 1.04; 95% CI 1.01-1.07; P=0.02] and SLN status (HR 2.24; 95% CI 1.03-4.88; P=0.04) significantly predicted OS, whereas only SLN status (HR 3.85; 95% CI 2.13-6.97; P<0.01) significantly predicted MSS. Tumor thickness predicts SLN status in thick melanomas. Furthermore, SLN status is prognostic for OS and MSS in thick-melanoma patients, with positive-SLN patients having significantly worse OS and MSS. These findings show that SLNB should be recommended for thick-melanoma patients, particularly because detection of SLN metastasis can identify patients for potential systemic therapy and treatment of nodal disease at a microscopic stage.

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

Role of obesity on the thickness of primary cutaneous melanoma.

Thick primary cutaneous melanoma (PCM) is associated with older age, male sex, being single, a low educational level, self-detection and general practice detection, nodular melanoma (NM) and acral lentiginous melanoma (ALM) types; and are found in the head-neck and lower limb locations. Obesity plays a direct role on melanoma tumour growth, as it has been shown in animal models, but its role in the thickness of PCM remains unknown. We investigated the impact of obesity on the thickness of invasive PCM. A cross-sectional study was performed in a prospective cohort for which we collected several clinical and histological data already known to be associated with thick PCM and the Body Mass Index from new cases of invasive PCM which were referred to the dermatology department in Valence. Four hundred and twenty-seven patients were studied. In an univariate analysis, thick PCM was associated with low educational level, obesity, identification by the patient or the general practitioner (GP), location on the cephalic extremity, in a non-visible area of the body, the NM and ALM type, and an ulceration. In a multivariate analysis, NM, ulceration, topography of the melanoma and identification of the melanoma by the patient or GP were significantly associated with thick melanoma. When including only clinical features in the model, low educational level, mode of melanoma identification and obesity were significantly associated with a risk of thick melanoma. Obesity is a clinical independent risk factor of thick PCM. For health policies, governments should pay greater attention to detect melanoma in obese patients. Our results encourage the basic research on tumoural growth mechanisms due to obesity in melanoma.

Sentinel Lymph Node Biopsy in Patients with Thick Primary Cutaneous Melanoma: Patterns of Use and Underuse Utilizing a Population-Based Model

Background. Sentinel lymph node biopsy (SLNB) for thick cutaneous melanoma is supported by national guidelines. We report on factors associated with the use and underuse of SLNB for thick primary cutaneous melanoma. Methods. The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for thick primary cutaneous melanoma from 2004 to 2008. We used multivariate logistic regression models to predict use of SLNB. Results. Among 1,981 patients, 833 (41.8%) did not undergo SLNB. Patients with primary melanomas of the arm (OR 2.07, CI 1.56–2.75; P < 0.001), leg (OR 2.40, CI 1.70–3.40; P < 0.001), and trunk (OR 1.82, CI 1.38–2.40; P < 0.001) had an increased likelihood of receiving a SLNB, as did those with desmoplastic histology (OR 1.47, CI 1.11–1.96; P = 0.008). A decreased likelihood of receiving SLNB was noted for advancing age ≥ 60 years (age 60 to 69: OR 0.58, CI 0.33–0.99, P = 0.047; age 70 to 79: OR 0.32, CI 0.19–0.54, P < 0.001; age 80 or more: OR 0.10, CI 0.06–0.16, P < 0.001) and unknown race/ethnicity (OR 0.21, CI 0.07–0.62; P = 0.005). Conclusions. In particular, elderly patients are less likely to receive SLNB. Further research is needed to assess whether use of SLNB in this population is detrimental or beneficial.

Prevalence of sentinel lymph node evaluation in patients with thick primary cutaneous melanoma.

e19013 Background: Sentinel lymph node biopsy (SLNB) was developed for intermediate thickness melanoma. Its use for thick cutaneous melanoma is controversial. We aimed to report on clinical and pathologic factors associated with the overuse of SLNB for thick primary cutaneous melanoma. Methods: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for thick primary cutaneous melanoma (known Breslow thickness &gt; 4.00 mm) from 2004 to 2008. We excluded patients with mucosal melanoma, those without a biopsy-proven diagnosis, those diagnosed at autopsy, patients whose lymph node evaluation was unknown or other than SLNB “yes” or SLNB “no”. We used multivariate logistic regression models to predict use of SLNB. Covariates examined included: age sex, race/ethnicity, Breslow depth, tumor histology, tumor location, and ulceration status. Likelihood of undergoing sentinel lymph node biopsy was reported as odds ratios (OR) with 95% confidence intervals (CI); significance was set at p ≤ 0.05. Results: Among 1,981 patients with thick cutaneous melanoma, 1,158 (58.2%) received a SLNB. On multivariate analysis, patients with primary melanomas of the arm (OR 2.07, CI 1.56-2.75; p&lt;0.001), leg (OR 2.40, CI 1.70-3.40; p&lt;0.001) and trunk (OR 1.82, CI 1.38-2.40; p&lt;0.001) had an increased likelihood of receiving a SLNB, as did those with desmoplastic histology (OR 1.47, CI 1.11-1.96; p=0.008). Conclusions: A significant number of patients with thick melanomas receive a SLNB, even though this procedure was not developed for this patient population. We have identified predictors associated with the use of SLNB. These include: arm, leg and trunk primary sites and desmoplastic histology. Further research to assess whether use of SLNB in this population is detrimental or beneficial is needed.

The role of sentinel lymph node biopsy in patients with thick melanoma. A single centre experience

AimsTo evaluate the role, if any, of sentinel lymph node mapping (SLNM) with biopsy (SLNB) in patients with thick cutaneous melanoma. MethodsConsecutive patients with thick (Breslow ≥4 mm) cutaneous melanoma, undergoing SLNB were identified from a departmental database comprising 550 patients in total from 2000 to 2010. Factors examined included demographic data, histological subtype, site and depth of lesion, percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), complications, further lymphadenectomy, and follow-up (disease free and overall survival), where available. ResultsSixty-four eligible patients (37 men, 27 women) underwent primary excision and SLNM. Median patient age was 59 years (range 8–82 years). Mean Breslow depth was 7 mm (range 4–19 mm). Thirty melanomas were located on the limbs, 19 on the head and neck and 15 on the trunk. Twenty-three (35%) were ulcerated. Of the 57 patients who had a sentinel node identified, 18 (31%) had metastatic melanoma identified. The mean survival time for patients with a negative SLN was 79 months versus 18 months for those with a positive node. Patients with a negative SLN have a 5 year disease free survival of 79% versus 11% (p < 0.001) and an overall 5 year survival rate of 85% versus 32% when compared to node positive patients. ConclusionsThe status of the SLN is predictive of disease recurrence and overall survival in patients with a thick primary cutaneous melanoma. This modality should be employed, where applicable, in this cohort of patients.

Humoral immune response to a therapeutic polyvalent cancer vaccine after complete resection of thick primary melanoma and sentinel lymphadenectomy.

A therapeutic polyvalent cancer vaccine (Canvaxin vaccine; CancerVax Corp, Carlsbad, CA) induces antibodies to a glycoprotein tumor-associated antigen (TA90). However, endogenous immune responses to TA90 have also been reported. This study examined anti-TA90 antibody responses with respect to the survival of patients who received adjuvant vaccine immunotherapy after resection of thick (> or = 4 mm) primary cutaneous melanoma. Serum specimens were obtained from 54 patients immediately before and then 1, 2, 4, and 6 months after wide local excision of thick primary cutaneous melanoma and sentinel lymphadenectomy. All patients were offered adjuvant therapies with the vaccine, high-dose interferon, or other agents. An enzyme-linked immunosorbent assay was used to determine serial serum titers of immunoglobulin G (IgG) and IgM antibodies against TA90. These titers were correlated with clinical course. Forty-three patients chose vaccine therapy, and 11 patients chose postoperative observation. Preoperative anti-TA90 IgG and IgM titers were similar for vaccine and observation groups (P =.184). At a median follow-up of 26 months, univariate analysis of Cox regression showed that disease-free survival and overall survival of vaccine patients were significantly correlated with maximal IgM response (P =.0006 and.006, respectively) but not with maximal IgG response (P =.73 and.95, respectively). Neither response predicted survival in the observation group. Postoperative vaccine therapy may enhance IgG and IgM immune responses to TA90 after surgical resection, but only the IgM response is correlated with improved survival. These findings may become useful to guide selection of patients for postoperative adjuvant therapy of high-risk melanoma.

Prognostic factors in patients with thick cutaneous melanoma (&gt; 4 mm)

The current study was conducted to examine the role of multiple clinical and histologic factors in the prognostic assessment of patients with thick primary melanoma (> 4 mm, classified as T4). A retrospective analysis was performed in 329 patients with T4 cutaneous melanomas who were seen at the University of California at San Francisco Melanoma Center between 1978 and 2000. Fourteen histopathologic features were recorded prospectively by a single dermatopathologist. In addition, 9 clinical factors were analyzed. Several histologic factors were found to have a significant impact on the survival of patients with T4 melanoma. On univariate analysis, tumor thickness, ulceration, mitotic rate, microsatellites, vascular involvement, and histogenetic type of the primary tumor all were found to have a significant impact on the overall survival rate. Regional lymph node involvement reduced the overall survival of T4 patients dramatically. The 5-year overall survival of patients with lymph node-negative T4 disease was 61%, compared with 30% for those with lymph node-positive disease. When lymph node status was taken into account, tumor thickness, vascular involvement, and ulceration all remained independent predictors of overall survival on multivariate Cox regression analysis. Neither age, gender, nor anatomic location appeared to affect the recurrence-free or overall survival rates. Patients with thick primary cutaneous melanomas (> 4 mm) comprise a heterogeneous group. The presence or absence of lymph node involvement, vascular involvement, and ulceration appears to result in significantly divergent overall survival rates in this patient cohort. Consideration of these factors has important implications in the management of patients with T4 melanoma.

Emergence of alpha 5 beta 1 fibronectin- and alpha v beta 3 vitronectin-receptor expression in melanocytic tumour progression.

Cell adhesion is crucial in the process of tumour progression. As integrins are important receptor molecules involved in cell adhesion, we studied the distribution of the alpha 1-6, alpha v, alpha IIb, beta 1, beta 3, and beta 4 integrin subunits in tissue sections of common naevocellular naevi (n = 22), dysplastic naevi (16), thin (24) and thick primary cutaneous melanomas (28), and melanoma metastases (25). We found correlated expression of alpha 1/alpha 2, of alpha 4/alpha 5/beta 3, and of alpha 6/beta 4. Decrease of alpha 6 and beta 4, and increase of alpha 4 and alpha v were found to be correlated with melanoma progression. Furthermore, expression of alpha 5 and beta 3 was detected only in primary melanoma and melanoma metastasis. Our findings indicate that during melanoma progression alterations in integrin expression occur, the most striking being emergence of alpha 5 beta 1 fibronectin and alpha v beta 3 vitonectin receptor.

Silver-stained nucleoli and nucleolar organizer region counts are of no prognostic value in thick cutaneous malignant melanoma.

Nucleolar organizer regions (NORs) can be stained by a simple one-step silver technique; the black dots formed are termed AgNORs. Often AgNORs are tightly clustered, appearing as one silver-stained nucleolus (AgNu). We have assessed this technique as a possible prognostic indicator for thick (greater than 3.0 mm) primary cutaneous malignant melanoma (CMM). Three groups were studied: (A) seven thick CMM that had not metastasized 8-20 years after excision; (B) three thick CMM that developed metastases 6-9 years after excision; and (C) twelve CMM that presented with metastases or developed them within 4 years of excision. Two methods of counting silver-stained black dots in nuclei were employed: one method counted easily discernible black dots consisting of AgNus and dispersed AgNORs; the other attempted to count actual AgNORs both dispersed and clustered within AgNus. Scores per nucleus by the first method were 1.5-6.7 in group A, 1.1-2.6 in group B, and 1.4-5.4 in group C. AgNOR counts by the second method were 6.2-13.0 in group A, 5.4-8.9 in group B, and 5.3-10.5 in group C. No significant difference was present between groups for scores by either method. Due to the subjectively, technical difficulty, non-reproducibility, and tedium associated with the second method of attempting to count individuals AgNORs, the first method is recommended. It is concluded that this technique is of no value in predicting prognosis for CMM.