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1.
Acta Derm Venereol ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32945339

RESUMO

Locoregional lymph node recurrences of primary trunk melanoma can occur in basins not identified during sentinel lymph node biopsy. However, the factors associated with recurrences in non-sentinel lymph node basins are unknown. To evaluate these factors, this observational retrospective study examined the patterns of first lymph node recurrence and the factors associated with recurrence in non-sentinel lymph node basins. A total of 305 patients with primary trunk melanoma who had undergone sentinel lymph node biopsy from 2000 to 2015 were evaluated. Twenty-three patients presented locoregional lymph node recurrence; 8 of which (34.8%) were in non-sentinel lymph node basins. Non-sentinel lymph node recurrences were more frequent in patients with positive sentinel lymph nodes and in those patients whose number of tumour-involved nodes was > 3. These results suggest that clinical examination and ultrasound surveillance should be performed on all potential lymph node drainage basins of trunk melanomas.

2.
Melanoma Res ; 30(5): 500-510, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32898390

RESUMO

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.

3.
J Dermatol ; 47(9): 1058-1062, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32537762

RESUMO

Polarized dermoscopy enables visualization of linear shiny white structures in melanomas, thought to be due to the existence of fibrosis in the dermis. Our objective was to establish the existence of two types of linear shiny white structures and assess their association with different histological structures. We performed a cross-sectional study including all non-acral, non-facial melanomas from our hospital with linear shiny white structures. The outcome variable was the type of linear shiny white structures: shiny white streaks and white strands. We evaluated their association with explanatory variables that may affect the reflectance of melanomas and Breslow index. We used χ2 statistics and also calculated the sensitivity and specificity of each linear shiny white structure to predict those variables. We detected linear shiny white structures in 118 melanomas. Regarding shiny white streaks, we only found a statistically significant positive relationship with fibrosis in the papillary dermis. Regarding white strands, we found statistically significant and positive relationships with hyperkeratosis, Breslow index of 0.8 mm or more and acanthosis. Sensitivity and specificity study revealed that the presence of shiny white streaks was the most sensitive (81.7%) and specific (72.3%) for fibrosis in the papillary dermis, and presence of white strands was the most sensitive (91.1%) and specific (85.7%) for hyperkeratosis.

4.
Dermatol Ther (Heidelb) ; 10(4): 769-777, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535811

RESUMO

INTRODUCTION: Keratinocyte tumors (KT) are frequently observed. Surgery is the treatment gold standard. In some cases, a surgical approach might not be the best option. Radiotherapy (RT) and systemic treatments can frequently cause side effects or be contraindicated. Intralesional methotrexate (MTX) can be a conservative yet effective alternative. We decided to evaluate the effectiveness and safety of intralesional chemotherapy with MTX for the treatment of squamous cell carcinoma (SCC), keratoacanthoma (KA), and basal cell carcinoma (BCC). METHODS: All patients had a histologically confirmed diagnosis of BCC, SCC, or KA and no indication to surgery or RT. MTX was injected subcutaneously proceeding from the periphery of the lesion toward the center. Different protocols in terms of dose, frequency, and length of treatment were used to compare them. Treatment efficacy was evaluated in terms of tumor size reduction. Patients were divided into three groups: responders (improvement of more than 50%), partial responders (< 50%), and non-responders (no improvement or worsening). All data were analyzed using the chi-squared test (χ2). RESULTS: Thirty-five patients were included. Twenty-one patients suffered from SCC, 12 from KA, and 2 from BCC. KA showed a higher response rate than SCC and BCC. For AK, 92% of patients had a complete resolution; 8% were partial responders. For SCC, 47.6% of cases were responders and 14.3% partial responders, while 38% non-responders. All BCCs showed no improvement. A treatment protocol of weekly injections, performed for 4 to 6 weeks, was the most efficient. Doses of 25 mg/ml per session seemed to be most effective. About one third of our patients developed side effects with mild anemia being the most frequent. CONCLUSIONS: For selected cases, intralesional MTX can be a safe and effective option for the treatment of KT, especially in case of KA and, to a lesser extent, SCC.

5.
Sci Rep ; 10(1): 8005, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409749

RESUMO

Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of PTCH1 and TP53 and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcription levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 58.6% and TP53 in 31.4% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59.2% and 38.2% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. Increased reverse transcriptase subunit expression was observed in tumors with TERT promoter mutations and not with THOR methylation. Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter.

8.
PLoS Genet ; 15(11): e1008490, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730655

RESUMO

Despite genetics being accepted as the primary cause of familial aggregation for most diseases, it is still unclear whether afflicted families are likely to share a single highly penetrant rare variant, many minimally penetrant common variants, or a combination of the two types of variants. We therefore use recent estimates of SNP heritability and the liability threshold model to estimate the proportion of afflicted families likely to carry a rare, causal variant. We then show that Polygenic Risk Scores (PRS) may be useful for identifying families likely to carry such a rare variant and therefore for prioritizing families to include in sequencing studies with that aim. Specifically, we introduce a new statistic that estimates the proportion of individuals carrying causal rare variants based on the family structure, disease pattern, and PRS of genotyped individuals. Finally, we consider data from the MelaNostrum consortium and show that, despite an estimated PRS heritability of only 0.05 for melanoma, families carrying putative causal variants had a statistically significantly lower PRS, supporting the idea that PRS prioritization may be a useful future tool. However, it will be important to evaluate whether the presence of rare mendelian variants are generally associated with the proposed test statistic or lower PRS in future and larger studies.


Assuntos
Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Melanoma/genética , Análise de Sequência de DNA , Alelos , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Melanoma/epidemiologia , Melanoma/patologia , Herança Multifatorial/genética , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
11.
Melanoma Res ; 29(6): 664-667, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31469708

RESUMO

The aim of this study is to evaluate the relation between 25-hydroxyvitamin D levels at diagnosis and pathological characteristics in primary invasive melanoma. A cross-sectional study was designed based on a series of 204 consecutive patients diagnosed of invasive melanomas in the 2013-2017 period at a single institution. 25-hydroxyvitamin D serum levels at diagnosis were assessed, and three groups were defined by vitamin D status: deficiency, insufficiency, and sufficiency. Clinical and pathological characteristics were compared between the groups by Chi-square test. Logistic regression models were performed to evaluate the association between vitamin D status and Breslow thickness, ulceration, and tumor mitotic rate. A significant association between vitamin D levels at diagnosis and location, tumor mitotic rate, and ulceration was found; and a borderline association with Breslow thickness and BMI. Deficient levels were found in 7.8% of patients and increased the risk of presenting ulcerated tumors [odds ratio: 6.8 (95% confidence interval: 1.5-29.7; P = 0.012)] and with a tumor mitotic rate greater than 1 mitosis/mm [odds ratio: 6.0 (95% confidence interval: 1.4-25.1; P = 0.014)]. A marginal increased risk of tumor thickness greater than 1 mm was also observed [odds ratio: 3.7 (95% confidence interval: 1.0-13.9; P = 0.057)]. Our study suggests a role of vitamin D levels in melanoma aggressiveness and raises the question as to whether vitamin D levels should be monitored, or even supplemented, in people with low yearly sun exposure.

12.
Eur J Cancer ; 118: 10-34, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288208

RESUMO

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer collaborated to develop recommendations on diagnosis and treatment of BCC. A new classification into 'easy-to-treat (common) BCC and 'difficult-to-treat' BCC is proposed. Diagnosis is based on clinicodermatoscopic features for 'easy-to-treat' BCCs. Histopathological confirmation is mandatory in ambiguous lesions and in BCCs located in high-risk areas. The first-line treatment of 'easy-to-treat' BCC is complete surgery. Microscopically controlled surgery shall be offered for high-risk BCC, recurrent BCC and BCC in critical anatomical sites. Topical therapies (5% imiquimod, 5% fluorouracil) and destructive approaches (curettage, electrocautery, cryotherapy, laser ablation) should be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial BCC and thin nodular BCC. The therapy for a 'difficult-to-treat' BCC should preferentially be discussed by a multidisciplinary tumour board. Hedgehog inhibitors, vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCCs. Immunotherapy with anti-programmed cell death 1 (PD-1) antibodies is a promising therapeutic option, currently being investigated in clinical trials. Radiotherapy represents a valid alternative to surgery for BCC on the face, especially in elderly patients. In patients with naevoid basal cell carcinoma syndrome (NBCCS), close surveillance and regular skin examinations are required to diagnose and treat BCCs at early stage. Long-term follow-up is recommended in patients with high-risk BCC subtypes, high-risk sites, multiple BCCs and NBCCS.

14.
Cancer Med ; 8(9): 4235-4244, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31215168

RESUMO

Mitotic rate is no longer considered a staging criterion for thin melanoma in the 8th edition of the American Joint Committee on Cancer Staging Manual. The aim of this observational study was to identify prognostic factors for thin melanoma and predictors and prognostic significance of sentinel lymph node (SLN) involvement in a large multicenter cohort of patients with melanoma from nine tertiary care hospitals. A total of 4249 consecutive patients with thin melanoma diagnosed from January 1, 1998 to December 31, 2016 were included. The main outcomes were disease-free interval and melanoma-specific survival for the overall population and predictors of SLN metastasis (n = 1083). Associations between survival and SLN status and different clinical and pathologic variables (sex, age, tumor location, mitosis, ulceration, regression, lymphovascular invasion, histologic subtype, Clark level, and Breslow thickness) were analyzed by Cox proportional hazards regression and logistic regression. SLN status was the most important prognostic factor for melanoma-specific survival (hazard ratio, 13.8; 95% CI, 6.1-31.2; P < 0.001), followed by sex, ulceration, and Clark level for patients who underwent SLNB. A mitotic rate of >2 mitoses/mm2 was the only factor associated with a positive SLN biopsy (odds ratio, 2.9; 95% CI, 1.22-7; P = 0.01. SLN status is the most important prognostic factor in thin melanoma. A high mitotic rate is associated with metastatic SLN involvement. SLN biopsy should be discussed and recommended in patients with thin melanoma and a high mitotic rate.

15.
JAMA Dermatol ; 155(7): 782-788, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066867

RESUMO

Importance: Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. Objective: To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. Design, Setting, and Participants: A retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n = 96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component. Interventions: All biopsy specimens were evaluated for the presence of certain histologic characteristics. Main Outcomes and Measures: Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the χ2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. Results: In total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P = .02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P = .049), nests (OR, 3.0; 95% CI, 1.1-8.6; P = .04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P = .07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients. Conclusions and Relevance: These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.

16.
JAMA Dermatol ; 155(6): 679-687, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042264

RESUMO

Importance: The lymphatic and the hematogenous pathways have been proposed for disease progression in cutaneous melanoma, but association with recurrence has not been studied separately to date. Objective: To identify the risk factors associated with lymphatic and hematogenous metastasis. Design, Setting, and Participants: This retrospective cohort study included 1177 patients with malignant melanoma treated at Instituto Valenciano de Oncología, València, Spain. Data were retrieved from the melanoma database from January 1, 2000, through December 31, 2015, and analyzed from June 1 to 30, 2018. Exposure: Malignant melanoma at stages I to II. Main Outcomes and Measures: Analyses of survival free of lymphatic and hematogenous metastasis were performed using Kaplan-Meier curves and Cox proportional hazards regression. Results: For the 1177 patients included in the study analysis (51.1% women; median age at diagnosis, 55 years [interquartile range, 42-68 years), median follow-up was 75 months (interquartile range, 33-121 months); 108 (9.2%) developed lymphatic metastasis, and 108 (9.2%) developed hematogenous metastasis. In the multivariate analysis, being older than 55 years (hazard ratio [HR], 1.9; 95% CI, 1.2-3.1), tumor in the head/neck (HR, 1.7; 95% CI, 1.0-2.9) and acral locations (HR, 2.4; 95% CI, 1.3-4.5), greater Breslow thickness (HR for >4.00 mm, 5.4; 95% CI, 2.4-12.4), and presence of vascular invasion (HR, 3.2; 95% CI, 0.9-10.6) were associated with lymphatic spreading. Hematogenous metastasis was associated with greater Breslow thickness (HR for >4.00 mm, 10.4; 95% CI, 3.6-29.7), the absence of regression (HR, 0.1; 95% CI, 0.0-1.0), TERT promoter mutations (HR, 2.9; 95% CI, 1.5-5.7), and BRAF mutations (HR, 1.9; 95% CI, 1.1-3.6). Conclusions and Relevance: Risk factors associated with lymphatic and hematogenous metastasis differ. Follow-up and adjuvant treatment strategies may therefore need to be adapted to individual clinical, histopathologic, and molecular characteristics.


Assuntos
Metástase Linfática/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco
18.
Cancers (Basel) ; 11(4)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30934988

RESUMO

Survival predictions are currently determined on the basis of NRAS/BRAF mutations, even though TERT promoter mutations have been recently associated with a poor prognosis in stage I-II melanomas. Usually, it is not recommended to perform a mutational test on primary melanoma, as the results do not always reflect the mutational status of metastases. In particular, trunk melanomas have been reported to have an unfavourable prognosis. A series of 105 advanced melanoma patients were analysed by TERT promoter Sanger sequencing. Univariate/multivariate binary logistic regression models were performed using progression to a visceral site as the dependent variable and patient/tumour characteristics as covariates. Performance of the model was assessed in an external independent primary melanoma patients' dataset. Male gender (odds ratio (OR), 344; 95% CI, 1.12⁻10.6; p = 0.031), AJCC (American Joint Committee on Cancer) classification (OR, 022; 95% CI, 0.07⁻0.67; p = 0.008), SLNB (Sentinel Lymph Node Biopsy) status (OR, 3.05; 95% CI, 1.06⁻8.78; p = 0.039) and TERT-mutated trunk lesions (OR, 3.78; 95% CI, 1.35⁻10.6; p = 0.011) were significantly associated with the risk of developing a visceral spreading as first site of progression using multivariate logistic regression analysis. These results were confirmed in the external validation control group. Therefore, in trunk primary melanomas, due to their high risk of progression to visceral sites, we encourage somatic TERT mutation analysis at diagnosis to identify those patients who would potentially benefit from a more intensive follow-up protocol and a prompt initiation of therapy.

19.
Oncotarget ; 10(16): 1546-1548, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30899422
20.
J Natl Cancer Inst ; 111(12): 1314-1322, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30863861

RESUMO

BACKGROUND: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness. METHODS: Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided. RESULTS: In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P < .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis). CONCLUSIONS: T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma.

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