Informed consent and a risk-based approach to oncologic surgery in a cancer center during the COVID-19 pandemic.

BACKGROUND: Cancer patients configure a risk group for complications or death by COVID-19. For many of them, postponing or replacing their surgical treatments is not recommended. During this pandemic, surgeons must discuss the risks and benefits of treatment, and patients should sign a specific comprehensive Informed consent (IC). OBJECTIVES: To report an IC and an algorithm developed for oncologic surgery during the COVID-19 outbreak. METHODS: We developed an IC and a process flowchart containing a preoperative symptoms questionnaire and a PCR SARS-CoV-2 test and described all perioperative steps of this program. RESULTS: Patients with negative questionnaires and tests go to surgery, those with positive ones must wait 21 days and undergo a second test before surgery is scheduled. The IC focused both on risks and benefits inherent each surgery and on the risks of perioperative SARS-CoV-2 infections or related complications. Also, the IC discusses the possibility of sudden replacement of medical staff member(s) due to the pandemic; the possibility of unexpected complications demanding emergency procedures that cannot be specifically discussed in advance is addressed. CONCLUSIONS: During the pandemic, specific tools must be developed to ensure safe experiences for surgical patients and prevent them from having misunderstandings concerning their care.

Hereditary melanoma: a five-year study of Brazilian patients in a cancer referral center - phenotypic characteristics of probands and pathological features of primary tumors.

BACKGROUND: Approximately five to 10% of all melanomas occur in families with hereditary predisposition and the main high-risk melanoma susceptibility gene is the CDKN2A. OBJECTIVES: To describe, after a five-years study, the clinical data of patients (probands) from familial melanoma kindreds, and the pathological characteristics of their melanoma. METHODS: The inclusion criteria were melanoma patients with a family history of melanoma or pancreatic cancer (first- or second-degree relatives) or patients with multiple primary melanomas (MPM). RESULTS: A total of 124 probands were studied, where 64 were considered familial cases and 60 MPM. Mean age at diagnosis was 50 years. Our results show that the following characteristics were prevalent: skin phototype I/II (89.5%), sunburn during childhood (85.5%), total number of nevi ≥50 (56.5%), Breslow thickness ≤1.0mm (70.2%), tumors located on the trunk (53.2%) and superficial spreading melanomas (70.2%). STUDY LIMITATIONS: Analyses of probands' relatives will be demonstrated in future publication. CONCLUSIONS: Our findings are in agreement with previous familial melanomas reports. Fifteen new melanomas in 11 patients were diagnosed during follow up, all of which were ≤1.0 mm. This is the largest dataset of Brazilian melanoma prone kindreds to date, thus providing a complete database for future genetic studies.

Hereditary melanoma: a five-year study of Brazilian patients in a cancer referral center - phenotypic characteristics of probands and pathological features of primary tumors

Abstract: BACKGROUND: Approximately five to 10% of all melanomas occur in families with hereditary predisposition and the main high-risk melanoma susceptibility gene is the CDKN2A. OBJECTIVES: To describe, after a five-years study, the clinical data of patients (probands) from familial melanoma kindreds, and the pathological characteristics of their melanoma. METHODS: The inclusion criteria were melanoma patients with a family history of melanoma or pancreatic cancer (first- or second-degree relatives) or patients with multiple primary melanomas (MPM). RESULTS: A total of 124 probands were studied, where 64 were considered familial cases and 60 MPM. Mean age at diagnosis was 50 years. Our results show that the following characteristics were prevalent: skin phototype I/II (89.5%), sunburn during childhood (85.5%), total number of nevi ≥50 (56.5%), Breslow thickness ≤1.0mm (70.2%), tumors located on the trunk (53.2%) and superficial spreading melanomas (70.2%). STUDY LIMITATIONS: Analyses of probands' relatives will be demonstrated in future publication. CONCLUSIONS: Our findings are in agreement with previous familial melanomas reports. Fifteen new melanomas in 11 patients were diagnosed during follow up, all of which were ≤1.0 mm. This is the largest dataset of Brazilian melanoma prone kindreds to date, thus providing a complete database for future genetic studies.

Agreement between Perometry and Sequential Arm Circumference Measurements in Objective Determination of Arm Volume.

BACKGROUND: Limb circumference measurements (CM) and perometry are the preferred methods for objectively measuring arm volume in lymphedema surgery research. Understanding the measurement bias involved in these measuring systems is important to properly interpret and compare studies and their results. METHODS: Arm volumes from 91 patients were measured using sequential girths and the truncated cone formula (CM) and with the use of an automated perometer (perometry). The absolute volume of the largest arm (V), the volume difference between the arms (VD), and the relative difference between them (percentage of excess volume [PEV]) were calculated with both methods. The agreement between methods was assessed by the Pearson's correlation test and the Bland-Altman's method. RESULTS: Correlations were strong for V (r = 0.99), VD (r = 88), and PEV (r = 0.86). Volumes measured by perometry were, on average, 10.6 mL smaller than volumes calculated from CM, while their limits of agreement (LOA) ranged from -202 to 181 mL. The LOA represents the range we could expect the arm volumes measured with the two methods to differ by chance alone, 95% of the times. For VD, LOA was -101 to 141 mL, with a mean difference of 19.9 mL, while PEV had a mean difference of 0.9%, with LOA ranging from -5 to 6.8%. CONCLUSION: There is considerable measurement error between arm volume estimated by perometry and by CM. Volumes calculated with these methods should be compared with caution. Furthermore, we observed an increasingly relevant measurement bias in outcomes that are mathematically derived from arm volumes.

Reflectance confocal microscopy features of BRAF V600E mutated thin melanomas detected by immunohistochemistry.

The classification of melanoma into four histological subtypes has been questioned regarding its clinical validity in providing relevant information for treatment for metastatic tumors. Specific genetic alterations are associated with particular clinical and histopathological features, suggesting that these could be helpful in refining existing melanoma classification schemes. We analyzed BRAF V600E mutated melanomas to explore the Reflectance confocal microscopy (RCM) utility as a screening aid in the evaluation of the most appropriate patients for genetic testing. Thus, 32 melanomas were assessed regarding their BRAF V600E mutational status. Experts blinded to dermoscopic images and V600E immunohistochemistry results evaluated RCM images regarding previously described melanoma features. BRAF positive melanomas were related to younger age (p = 0.035), invasive melanomas (p = 0.03) and to the presence of hiporreflective cells (p = 0.02), epidermal nests (p = 0.02), dermal-epidermal junction nests (p = 0.05), edged papillae (p = 0.05), and bright dots (p = 0.05), and to absence of junctional thickening due to isolated cells (p = 0.01) and meshwork (p = 0.02). This study can not characterize other mutations in the BRAF, because the immunohistochemistry is specific to the type V600E. The findings should encourage the genetic evaluation of BRAF mutation. This study highlights the potential of RCM as a supplementary tool in the screening of BRAF-mutated melanomas.

Epigenetic signature of differentially methylated genes in cutaneous melanoma

Background: Cutaneous melanoma (CM) is the most aggressive subtype of skin cancer, with increasing incidence over the past several decades. DNA methylation is a key element of several biological processes such as genomic imprinting, cell differentiation and senescence, and deregulation of this mechanism has been implicated in several diseases, including cancer. In order to understand the relationship of DNA methylation in CMs, we searched for an epigenetic signature of cutaneous melanomas by comparing the DNA methylation profiles between tumours and benign melanocytes, the precursor cells of CM. Methods: We used 20 primary CMs and three primary cell cultures of melanocytes as a discovery cohort. The tumours mutational background was collected as previously reported. Methylomes were obtained using the HM450K DNA methylation assay, and differential methylation analysis was performed. DNA methylation data of CMs from TCGA were recovered to validate our findings. Results: A signature of 514 differentially methylated genes (DMGs) was evident in CMs compared to melanocytes, which was independent of the presence of driver mutations. Pathway analysis of this CM signature revealed an enrichment of proteins involved in the binding of DNA regulatory regions (hypermethylated sites), and related to transmembrane signal transducer activities (hypomethylated sites). The methylation signature was validated in an independent dataset of primary CMs, as well as in lymph node and distant metastases (correlation of DNA methylation level: r > 0,95; Pearson's test: p < 2.2e-16). Conclusions: CMs exhibited a DMGs signature, which was independent of the mutational background and possibly established prior to genetic alterations. This signature provides important insights into how epigenetic deregulation contributes to melanomagenesis in general (AU)

Role of rare germline copy number variation in melanoma-prone patients.

AIM: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition. PATIENTS & METHODS: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays. RESULTS: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2). CONCLUSION: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.

Absence of Tumor-Infiltrating Lymphocyte Is a Reproducible Predictive Factor for Sentinel Lymph Node Metastasis: A Multicenter Database Study by the Brazilian Melanoma Group.

AIMS: The aim of this study is to confirm the function of tumor-infiltrating lymphocytes (TILs) in sentinel lymph node (SLN) metastasis. MATERIALS AND METHODS: This retrospective study included 633 patients with invasive melanoma who underwent sentinel lymph node biopsy in 7 referral centers certified by the Brazilian Melanoma Group. Independent risk factors of sentinel node metastasis (SNL) were identified by multiple logistic regression. RESULTS: SLN metastasis was detected in 101 of 633 cases (16.1%) and in 93 of 428 patients (21.7%) when melanomas ≤ 1mm were excluded. By multiple logistic regression, the absence of TILs was as an independent risk factor of SLN metastasis (OR = 1.8; 95%CI: 1.1-3.0), in addition to Breslow index (greater than 2.00 mm), lymph vascular invasion, and presence of mitosis. CONCLUSION: SLNB can identify patients who might benefit from immunotherapy, and the determination of predictors of SLNB positivity can help select the proper population for this type of therapy. The absence of TILs is a reproducible parameter that can predict SLNB positivity in melanoma patients, since this study was made with several centers with different dermatopathologists.

Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma.

Approximately 10 % of all cutaneous melanoma cases occur in a familial context. The major susceptibility gene for familial melanoma is CDKN2A. In Latin America, genetic studies investigating melanoma predisposition are scarce. The aim of this work was to investigate germline CDKN2A point mutations and genomic rearrangements in a cohort of 59 Brazilian melanoma-prone patients. Screening of CDKN2A alterations was performed by sequencing and multiplex ligation probe amplification. Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions. Although this study adds to the literature on melanoma susceptibility in Latin America, it is limited by the small size of the cohort. Our findings suggest that stringent inclusion criteria led to a substantially increased rate of CDKN2A mutation detection. This consideration should be taken into account when referring patients for genetic screening in a setting of limited budget, such as in developing countries.

A review of the epidemiology and treatment of Merkel cell carcinoma.

Merkel cell carcinoma is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Articles in English, French, Italian, Portuguese, and Spanish from the last 20 years were identified in MEDLINE and reviewed. The key word "Merkel" was used for the search, relevant articles were selected, and their references were examined. The most important articles related to epidemiology, genesis and treatment were reviewed. The incidence of Merkel cell carcinoma is increasing due to the advancing age of the population, higher rates of sun exposure and an increasing number of immunocompromised individuals. With regard to etiology, the recently described Merkel Cell polyomavirus is thought to play a role. Either local or regional surgical intervention remains the standard of care, but adjuvant radiotherapy or radiotherapy as a primary treatment have been discussed as reasonable therapeutic options. An update on this rare neoplasia is essential because of its increasing incidence and changing treatment options.

A review of the epidemiology and treatment of Merkel cell carcinoma

Merkel cell carcinoma is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Articles in English, French, Italian, Portuguese, and Spanish from the last 20 years were identified in MEDLINE and reviewed. The key word "Merkel" was used for the search, relevant articles were selected, and their references were examined. The most important articles related to epidemiology, genesis and treatment were reviewed. The incidence of Merkel cell carcinoma is increasing due to the advancing age of the population, higher rates of sun exposure and an increasing number of immunocompromised individuals. With regard to etiology, the recently described Merkel Cell polyomavirus is thought to play a role. Either local or regional surgical intervention remains the standard of care, but adjuvant radiotherapy or radiotherapy as a primary treatment have been discussed as reasonable therapeutic options. An update on this rare neoplasia is essential because of its increasing incidence and changing treatment options.

Vulvar melanoma: report on eleven cases and review of the literature.

CONTEXT AND OBJECTIVE: Vulvar melanoma is a rare disease. We describe the experience of a single institution and review the literature. DESIGN AND SETTING: Retrospective study at the Department of Gynecology, Hospital do Cancer A. C. Camargo. METHODS: Eleven patients with vulvar melanoma attended between January 1987 and December 2006 were reviewed regarding clinicopathological characteristics, surgical therapy and follow-up. RESULTS: The initial symptoms were vulvar lesions, pruritus, pain and bleeding. The median age was 64.8 years. The median depth of invasion was 3.08 mm. The staging ranged from IB to IIIC (American Joint Committee on Cancer, 2002). All the patients underwent vulvectomy. Two patients did not undergo primary elective lymphadenectomy. Bilateral inguinal lymphadenectomy was performed on five patients, and one had unilateral inguinal lymphadenectomy. Sentinel lymph node investigation was performed on three patients. Five patients had locoregional recurrence. Prolonged survival was only achieved in the absence of lymph node involvement. The median follow-up was 56 months. The median disease-free survival was 15 months and the median overall survival was 29 months. CONCLUSIONS: The prognosis for patients with vulvar melanoma is generally poor, with a high tendency towards regional and distant recurrence. Depth of invasion and lymph node involvement are the most important prognostic factors. In most cases, resection of the lesion with adequate margins may replace vulvectomy. Elective inguinal femoral lymphadenectomy remains the standard lymph node staging procedure. Sentinel lymph node investigation is feasible and should be performed by a multidisciplinary team with experience of this method.

Vulvar melanoma: report on eleven cases and review of the literature / Melanoma de vulva: relato de onze casos e revisão da literatura

CONTEXT AND OBJECTIVE: Vulvar melanoma is a rare disease. We describe the experience of a single institution and review the literature. DESIGN AND SETTING: Retrospective study at the Department of Gynecology, Hospital do Cancer A. C. Camargo. METHODS: Eleven patients with vulvar melanoma attended between January 1987 and December 2006 were reviewed regarding clinicopathological characteristics, surgical therapy and follow-up. RESULTS: The initial symptoms were vulvar lesions, pruritus, pain and bleeding. The median age was 64.8 years. The median depth of invasion was 3.08 mm. The staging ranged from IB to IIIC (American Joint Committee on Cancer, 2002). All the patients underwent vulvectomy. Two patients did not undergo primary elective lymphadenectomy. Bilateral inguinal lymphadenectomy was performed on five patients, and one had unilateral inguinal lymphadenectomy. Sentinel lymph node investigation was performed on three patients. Five patients had locoregional recurrence. Prolonged survival was only achieved in the absence of lymph node involvement. The median follow-up was 56 months. The median disease-free survival was 15 months and the median overall survival was 29 months. CONCLUSIONS: The prognosis for patients with vulvar melanoma is generally poor, with a high tendency towards regional and distant recurrence. Depth of invasion and lymph node involvement are the most important prognostic factors. In most cases, resection of the lesion with adequate margins may replace vulvectomy. Elective inguinal femoral lymphadenectomy remains the standard lymph node staging procedure. Sentinel lymph node investigation is feasible and should be performed by a multidisciplinary team with experience of this method.

CONTEXTO E OBJETIVO: Melanoma de vulva é uma doença rara. Descrevemos a experiência de uma instituição e revisamos a literatura. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo no Departamento de Ginecologia do Hospital do Câncer A. C. Camargo. MÉTODOS: De Janeiro de 1987 a Dezembro de 2006, foram revisados aspectos clínico-patológicos, tratamento cirúrgico e acompanhamento de 11 pacientes com melanoma de vulva. RESULTADOS: Lesão vulvar, prurido, dor e sangramento foram sintomas iniciais. A idade mediana foi 64,8 anos. A mediana da profundidade de invasão foi 3.08 mm. O estadiamento variou de IB a IIIC (American Joint Committee on Cancer, 2002). Todas as pacientes foram submetidas a vulvectomia. Duas pacientes não foram submetidas a linfadenectomia eletiva primária. A linfadenectomia inguinal bilateral foi realizada em cinco pacientes e uma foi submetida à linfadenectomia inguinal unilateral. A pesquisa do linfonodo sentinela foi realizada em três casos. Cinco tiveram recidiva locorregional. A sobrevida prolongada esteve relacionada com a ausência de comprometimento linfonodal. O tempo mediano de acompanhamento foi de 56 meses. A sobrevida mediana livre de doença foi de 15 meses e a sobrevida mediana global de 29 meses. CONCLUSÕES: O prognóstico das pacientes com melanoma de vulva geralmente é ruim, com tendência a recorrência regional e à distância. A profundidade de invasão e envolvimento linfonodal são os principais fatores prognósticos. Na maioria dos casos a ressecção da lesão com margens adequadas pode substituir a vulvectomia. A linfadenectomia inguino-femoral eletiva ainda é o procedimento padrão para estadiamento linfonodal. Pesquisa do linfonodo sentinela é factível e deve ser realizada por equipe multidisciplinar com experiência no método.

Dupla drenagem para cadeias linfonodais distintas, detectada por técnica de biópsia de linfonodo sentinela em pacientes com melanoma cutâneo: relato de dois casos / Double drainage to distinct lymphonodal basins detected by sentinel lymph node biopsy in cutaneous melanoma patients: report of two cases

Os principais méritos da biópsia de linfonodo sentinela em pacientes com melanoma cutâneo residem na possibilidade de serem evitadas linfadenectomias radicais desnecessárias e de permitir a correta identificação da cadeia de drenagem linfática, principalmente quando o tumor se localiza em áreas de drenagem ambígua. Atualmente já foi incorporada como fator prognóstico, sendo importante dado para o correto estadiamento do paciente. No presente relato são apresentados dois casos em que a utilização desta técnica foi extremamente útil, sobretudo por ter identificado a presença de drenagem linfática para duas cadeias linfáticas distintas. é importante que o dermatologista esteja consciente da correta indicação da técnica, para poder orientar da melhor forma possível seus pacientes.