Publications by authors named "Gilles Landman"

51 Publications

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited.

Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates.

Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis.

Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

Sarcoidosis with necrobiosis-lipoidica-like skin lesions: A challenge for the dermatologist.

Health Sci Rep 2021 Mar 21;4(1):e200. Epub 2020 Dec 21.

Dermatology Service of Faculdade de Medicina do ABC ABC University of Medicine Santo André Brazil.

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http://dx.doi.org/10.1002/hsr2.200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752159PMC
March 2021

IMPDH-Based Cytoophidium Structures as Potential Theranostics in Cancer.

Mol Ther 2020 07 11;28(7):1557-1558. Epub 2020 Jun 11.

Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1016/j.ymthe.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335744PMC
July 2020

Demographic, Clinical, and Pathologic Features of Patients With Cutaneous Melanoma: Final Analysis of the Brazilian Melanoma Group Database.

JCO Glob Oncol 2020 04;6:575-582

Brazilian Melanoma Group, São Paulo, São Paulo, Brazil.

Purpose: National epidemiologic data on melanoma are scarce in Brazil. The current work presents final demographic, clinical, and pathologic results from the Brazilian Melanoma Group database to detail how patients with melanoma present at diagnosis.

Methods: The online database includes patients diagnosed between 1982 and 2015 and evaluated at their centers of origin between 2001 and 2016. The primary objective was to describe the demographic, clinical, and pathologic characteristics of the patients, and secondary objectives were to investigate the association between clinical and pathologic variables of interest.

Results: A total of 1,596 patients were included. Median age was 52 years, 57% were women, and the majority were identified as white. Invasive melanoma was diagnosed in 1,297 patients, mostly localized, whereas 299 (19%) had in situ disease (TisN0M0). Only 165 patients had initial lymph node involvement. Fitzpatrick skin types I or II were slightly more frequent with in situ melanoma (73%) than with invasive disease (67%; = .054). The median Breslow thickness was 0.95 mm, Clark levels 2 and 3 comprised nearly 70% of cases, and ulceration was present in 18% of patients. The mitotic rate was significantly associated with the presence of ulceration and both vascular and perineural invasion but not with margin positivity, whereas histologic regression was associated with both intratumoral and peritumoral inflammatory infiltrates.

Conclusion: Despite the limitations of an observational, registry-based study, the current results provide a general profile of patients with cutaneous melanoma in Brazil at the time of diagnosis.
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http://dx.doi.org/10.1200/JGO.20.00005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193775PMC
April 2020

Pigmented epithelioid melanocytoma: A case report.

J Cutan Pathol 2020 Feb;47(2):109-112

Department of Dermatology, ABC Medical School, São Paulo, Brazil.

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http://dx.doi.org/10.1111/cup.13584DOI Listing
February 2020

IMP dehydrogenase rod/ring structures in acral melanomas.

Pigment Cell Melanoma Res 2020 05 13;33(3):490-497. Epub 2020 Jan 13.

Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH-based RR structures. Forty-five ALM paraffin-embedded tissue samples and 59 melanocytic nevi were probed with anti-IMPDH2 antibody. Both the rod- and ring-shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR-positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR-positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR-positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR-positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR-low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.
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http://dx.doi.org/10.1111/pcmr.12854DOI Listing
May 2020

BRAFV600E and KIT immunoexpression in early-stage melanoma.

An Bras Dermatol 2019 17;94(4):458-460. Epub 2019 Oct 17.

Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.

Melanoma is widely known as the most lethal skin cancer. Specific tumor-related mortality can be significantly reduced if diagnosis and treatment are properly performed during initial phases of the disease. The current search for biomarkers in early-stage melanomas is a high-priority challenge for physicians and researchers. We aimed to assess the immunoexpression of BRAFV600E and KIT in a case series consisting of 44 early-stage melanomas. Formalin-fixed paraffin-embedded samples were systematically evaluated using a semi-quantitative method based on scores of percentage and intensity for immunostained tumor cells. We observed significant concordance between BRAFV600E and KIT immunoexpression in thin invasive melanomas. Our findings corroborate previous evidence showing abnormal expression of proteins associated with MAPK intracellular signaling pathway in early-stage melanomas.
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http://dx.doi.org/10.1590/abd1806-4841.20198349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007021PMC
October 2019

Intratumor Heterogeneity of KIT Gene Mutations in Acral Lentiginous Melanoma.

Am J Dermatopathol 2020 Apr;42(4):265-271

Departamento de Patologia, Universidade Federal de São Paulo, São Paulo, Brazil; and.

Melanoma is an aggressive skin malignancy, and the acral lentiginous melanoma (ALM) subtype affects non-sun-exposed sites such as the volar surface of the hands and feet and the subungual region and is most common in Asians, Hispanics, and Afro-descendants. The presence of different clones within the same tumor seems to influence the aggressiveness of tumors. Patients with mutations in the KIT gene have shown a good response to tyrosine kinase inhibitor therapy. We tested the hypothesis of intratumor heterogeneity through analysis of KIT gene mutations in ALM and determined the correlation between KIT mutations and demographic, clinical, and histopathological variables. Twenty-five ALM samples were examined. We selected up to four different regions per tumor for sequencing by the Sanger method for analysis of KIT gene exon 11 and exon 13 mutations. Advanced lesions were predominant, and the main histopathological characteristics of lesions were Breslow index >4.0 mm (17/25, 68%), Clark level IV/V (21/25, 84%), ulceration (16/25, 64%), and >3 mitoses/mm (8/25, 32%). KIT gene mutations were detected in 11/25 cases (44%), and all these 11 cases displayed intratumor heterogeneity, that is, at least 2 tumor regions had different mutational profiles. The predicted effect of most mutations detected was detrimental to protein function. No significant correlations between histopathological variables and either KIT mutations or intratumor heterogeneity were observed. The hypothesis of intratumor heterogeneity of KIT gene mutations in acral lentiginous melanoma was supported.
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http://dx.doi.org/10.1097/DAD.0000000000001475DOI Listing
April 2020

αEβ7 Expression Increases With the Extent of Cutaneous Involvement in Mycosis Fungoides.

Am J Dermatopathol 2019 Sep;41(9):630-636

Department of Pathology, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil.

Background: Cell adhesion molecules are essential to lymphocyte migration in neoplastic and inflammatory skin diseases. Our aim was to investigate possible differences in cell adhesion molecule expression between mycosis fungoides (MF) and inflammatory skin diseases (drug reactions and allergic contact dermatitis).

Methods: We selected 33 biopsies from patients with MF and 10 biopsies of patients with inflammatory skin diseases from Department of Pathology-Universidade Federal de São Paulo (UNIFESP) from January 1997 to December 2013. Expression of α4β1 integrin and αEβ7 integrin was assessed by immunohistochemistry in intraepidermal lymphocytes by counting 4 microscopic epidermal fields (×400) and comparing those between the 2 groups.

Results: We observed increased expression of integrin αEβ7 in intraepidermal lymphocytes in advanced stages of MF (T3 and T4). αEβ7 expression was detected in intraepidermal dendritic cells of MF and inflammatory diseases samples. The expression of E-cadherin in epidermal cells in MF outlined Pautrier microabscesses, whereas in inflammatory diseases, spongiosis reduced its expression in keratinocytes.

Conclusions: The findings presented here support the idea that the lymphocyte migratory mechanism observed in neoplasms is similar to that of inflammatory processes of the skin.
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http://dx.doi.org/10.1097/DAD.0000000000001397DOI Listing
September 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Th17/Treg imbalance in COPD progression: A temporal analysis using a CS-induced model.

PLoS One 2019 10;14(1):e0209351. Epub 2019 Jan 10.

Department of Clinical Medicine, Laboratory of Experimental Therapeutics, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

Background: The imbalance between pro- and anti-inflammatory immune responses plays a pivotal role in chronic obstructive pulmonary disease (COPD) development and progression. To clarify the pathophysiological mechanisms of this disease, we performed a temporal analysis of immune response-mediated inflammatory progression in a cigarette smoke (CS)-induced mouse model with a focus on the balance between Th17 and Treg responses.

Methods: C57BL/6 mice were exposed to CS for 1, 3 or 6 months to induce COPD, and the control groups were maintained under filtered air conditions for the same time intervals. We then performed functional (respiratory mechanics) and structural (alveolar enlargement) analyses. We also quantified the NF-κB, TNF-α, CD4, CD8, CD20, IL-17, IL-6, FOXP3, IL-10, or TGF-β positive cells in peribronchovascular areas and assessed FOXP3 and IL-10 expression through double-label immunofluorescence. Additionally, we evaluated the gene expression of NF-κB and TNF in bronchiolar epithelial cells.

Results: Our CS-induced COPD model exhibited an increased proinflammatory immune response (increased expression of the NF-κB, TNF-α, CD4, CD8, CD20, IL-17, and IL-6 markers) with a concomitantly decreased anti-inflammatory immune response (FOXP3, IL-10, and TGF-β markers) compared with the control mice. These changes in the immune responses were associated with increased alveolar enlargement and impaired lung function starting on the first month and third month of CS exposure, respectively, compared with the control mice.

Conclusion: Our results showed that the microenvironmental stimuli produced by the release of cytokines during COPD progression lead to a Th17/Treg imbalance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209351PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328193PMC
September 2019

Association between frontal fibrosing alopecia and linear scleroderma "coup de sabre".

Australas J Dermatol 2019 Aug 6;60(3):e256-e258. Epub 2019 Jan 6.

Faculdade de Medicina do ABC, São Paulo, Brazil.

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http://dx.doi.org/10.1111/ajd.12979DOI Listing
August 2019

Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly.

Cancer Immunol Immunother 2019 Feb 14;68(2):269-282. Epub 2018 Nov 14.

Department of Clinical and Experimental Oncology, Universidade Federal de São Paulo, Rua Diogo de Faria, 824, 5° andar, Hemocentro, CEP 04037-002, Sao Paulo, Brazil.

Aging immune deterioration and Epstein-Barr (EBV) intrinsic mechanisms play an essential role in EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV + DLBCLe) pathogenesis, through the expression of viral proteins, interaction with host molecules and epigenetic regulation, such as miR-155, required for induction of M1 phenotype of macrophages. This study aims to evaluate the relationship between macrophage polarization pattern in the tumor microenvironment and relative expression of miR-155 in EBV + DLBCLe and EBV-negative DLBCL patients. We studied 28 EBV + DLBCLe and 65 EBV-negative DLBCL patients. Tumor-associated macrophages (TAM) were evaluated by expression of CD68, CD163 and CD163/CD68 ratio (degree of M2 polarization), using tissue microarray. RNA was extracted from paraffin-embedded tumor samples for miR-155 relative expression study. We found a significantly higher CD163/CD68 ratio in EBV + DLBCLe compared to EBV-negative DLBCL. In EBV-negative DLBCL, CD163/CD68 ratio was higher among advanced-staged/high-tumor burden disease and overexpression of miR-155 was associated with decreased polarization to the M2 phenotype of macrophages. The opposite was observed in EBV + DLBCLe patients: we found a positive association between miR-155 relative expression and CD163/CD68 ratio, which was not significant after outlier exclusion. We believe that the higher CD163/CD68 ratio in this group is probably due to the presence of the EBV since it directly affects macrophage polarization towards M2 phenotype through cytokine secretion in the tumor microenvironment. Therapeutic strategies modulating miR-155 expression or preventing immuno-regulatory and pro-tumor macrophage polarization could be adjuvants in EBV + DLBCLe therapy since this entity has a rich infiltration of M2 macrophages in its tumor microenvironment.
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http://dx.doi.org/10.1007/s00262-018-2273-2DOI Listing
February 2019

Radiotherapy-induced Pemphigus Foliaceous: a rare adverse effect of breast cancer therapy.

Int J Dermatol 2018 Dec 20;57(12):e165-e167. Epub 2018 Sep 20.

Pathology Department, Universidade Federal de São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1111/ijd.14248DOI Listing
December 2018

Immunoexpression of BAP1, ROS1, and ALK in Spitzoid Melanocytic Tumors.

Int J Surg Pathol 2018 Sep 6;26(6):514-520. Epub 2018 Apr 6.

2 Universidade Federal de São Paulo, São Paulo, Brazil.

Background: Spitzoid tumors are a heterogeneous group of melanocytic neoplasms that frequently imposes diagnostic difficulties. Lately, several advances in molecular biology afforded significant discoveries on the pathogenesis of these tumors. BAP1 (BRCA-1 associated protein-1) inactivation and anomalous expression of kinase translocation-related proteins are among the main criteria launched by new classification proposals. Our aim was to systematically assess the immunoexpression of BAP1, ROS1 (receptor tyrosine kinase c-Ros oncogene 1), and ALK (anaplastic lymphoma receptor tyrosine kinase) proteins in an unpublished series of spitzoid tumors.

Methods: Retrospective study based on 47 formalin-fixed paraffin-embedded tissue samples from 3 different institutions. BAP1, ROS1, and ALK immunostains were performed in all cases. We included 27 Spitz tumors without significant abnormality, 15 atypical spitzoid tumors, and 5 spitzoid melanomas.

Results: We observed loss of BAP1 nuclear immunolabeling in 4.3% of evaluable cases (2/46), both of them atypical spitzoid tumors. The proportional frequency of BAP1-inactivated cases among atypical spitzoid tumors was 14.2% (2/14). No immunoexpression of ROS1 or ALK was found.

Conclusions: Our study revealed 2 additional BAP1-inactived cases and described its respective frequency. The absence of anomalous expression of translocation-related proteins ALK and ROS1 in this series, composed predominantly of low-grade/low-risk tumors, indicates that translocated spitzoid lesions may not be as prevalent as initially suggested, at least in some populations. Furthermore, our findings encourage additional investigation on unequal occurrence of such immunomarkers among different diagnostic categories of spitzoid neoplasms.
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http://dx.doi.org/10.1177/1066896918768089DOI Listing
September 2018

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.

J Invest Dermatol 2017 12 19;137(12):2606-2612. Epub 2017 Aug 19.

Melanoma Institute Australia, Westmead, New South Wales, Australia; Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, New South Wales, Australia.

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.
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http://dx.doi.org/10.1016/j.jid.2017.07.829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701856PMC
December 2017

Marker Protein Expression Combined With Expression Heterogeneity is a Powerful Indicator of Malignancy in Acral Lentiginous Melanomas.

Am J Dermatopathol 2017 Feb;39(2):114-120

Departamento de Patologia, Universidade Federal de São Paulo, São Paulo, Brazil.

Patients And Methods: Samples of acral lentiginous melanomas (ALMs) were obtained from the Department of Pathology at Escola Paulista de Medicina-Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. Demographic, clinical, and follow-up data were obtained from the charts of Hospital São Paulo. From 2 tissue microarrays containing 60 nevi and quadruplicate samples of ≥1.0-mm of 49 ALM, sections were stained to evaluate SCF, KIT, BRAF, CYCLIND1, MYC, and PTEN immunohistochemical protein expression.

Results: Nevi and ALM from 2006 to 2010 were reviewed and collected. All specimens were in the vertical growth phase, and histopathological parameters indicated that tumors were at an advanced stage at diagnosis. Average tumor thickness was 6.95 mm, 63% were ulcerated, average mitotic index was 5 mitotic cells per mm, and 43% were at Clark's level V. Compared with nevi, the χ test showed that ALM significantly correlated with SCF protein expression (P = 0.001) and expression heterogeneity (P < 0.000). Similar findings were observed for KIT (P = 0.005, P = 0.003, respectively), MYC (P < 0.000, P < 0.000), and PTEN (P = 0.005, P < 0.000). Malignancy did not correlate with BRAF and CYCLIN D1 expression (P = 0.053 and P = 0.259, respectively), but it did significantly correlate with their heterogeneous expression (P < 0.000, P = 0.024, respectively). Combined protein expression had an odds ratio of greater malignancy when BRAF and MYC were positive and/or heterogeneously expressed (OR of 78 and 95, respectively).

Discussion And Conclusion: We show that marker protein expression, when combined with heterogeneous expression as shown by immunohistochemistry, is a powerful indicator of malignancy in ALMs, especially, when protein pairs are combined.
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http://dx.doi.org/10.1097/DAD.0000000000000635DOI Listing
February 2017

Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group.

J Am Acad Dermatol 2016 Aug 14;75(2):356-63. Epub 2016 May 14.

Department of Pathology, Institut Curie and Faculty of Medicine, University of Paris Descartes, Paris, France.

Background: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care.

Objective: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions.

Methods: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated.

Results: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91.

Limitations: This was a small sample size of experienced pathologists in a testing situation.

Conclusion: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.
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http://dx.doi.org/10.1016/j.jaad.2016.04.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958559PMC
August 2016

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

PLoS One 2016 9;11(2):e0148160. Epub 2016 Feb 9.

Medical School, São Paulo Federal University, São Paulo, Brazil.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148160PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747578PMC
July 2016

Hypomelanotic melanoma mimicking pigmented Bowen disease.

J Am Acad Dermatol 2016 Jan;74(1):e11-3

Dermaimage Medical Associates, São Paulo, Brazil; Cutaneous Oncology Department, AC Camargo Cancer Center, São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2015.09.052DOI Listing
January 2016

Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma.

Genet Med 2016 07 17;18(7):727-36. Epub 2015 Dec 17.

Unidad de Lesiones Pigmentadas, Cátedra de Dermatología, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.

Purpose: CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America.

Methods: CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained.

Results: Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients.

Conclusion: The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first- or second-degree relatives.Genet Med 18 7, 727-736.
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http://dx.doi.org/10.1038/gim.2015.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940430PMC
July 2016

Update on Thin Melanoma: Outcome of an International Workshop.

Adv Anat Pathol 2016 Jan;23(1):24-9

*Department of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland †Department of Dermatology, University of Chicago, IL ‡Dermatopathology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA **Departments of Dermatology and Pathology, University of Michigan, Ann Arbor, MI §§Myriad Genetic Laboratories Inc., Salt Lake City, UT ∥∥Departments of Pathology and Cell Biology and Dermatology, University of South Florida Morsani College of Medicine, Tampa, FL ¶¶Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, PA §Departement de Biopathologie, Centre Léon Bérard, Lyon ##Department of Pathology, Institut Curie, Paris, France ∥Escola Paulista de Medicina, Universidade de São Paulo, Brasil ¶Department of Molecular Immunology and Cell Biology, Life and Medical Sciences Institute, University of Bonn, Germany #Laboratory of Translational Cell and Tissue Research and University Hospitals, University of Leuven, KUL, Leuven, Belgium ††Department of Molecular Oncology, CRUK Manchester Institute Royal Surrey County Hospital, Guildford, UK ‡‡Department of Dermatology, Chonnam National University Medical School, Gwangju, Korea.

The following communication summarizes the proceedings of a 1-day Workshop of the International Melanoma Pathology Study Group, which was devoted to thin melanoma. The definitions and histologic criteria for thin melanoma were reviewed. The principal differential diagnostic problems mentioned included the distinction of thin melanoma from nevi, especially from nevi of special site, irritated nevi, inflamed and regressing nevi, and dysplastic nevi. Histologic criteria for this analysis were discussed and the importance of clinico-pathologic correlation, especially in acral sites, was emphasized. Criteria for the minimal definition of invasion were also discussed. In addition, a new technique of m-RNA expression profiling with 14 genes was presented and facilitated the distinction of thin melanomas from nevus in histologically obvious cases. However, for particular nevi, it was not obvious why the results indicated a malignant lesion. Despite many molecular and other ancillary investigations, Breslow thickness remains the most important prognostic factor in thin melanoma. The prognostic significance of radial (horizontal) and vertical growth phases, Clark level, regression, and mitotic rate were also discussed. Because of the increasing frequency of thin melanomas, there is a great need to develop more refined predictors of thin melanomas with worse clinical outcome.
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http://dx.doi.org/10.1097/PAP.0000000000000100DOI Listing
January 2016

Grape juice concentrate (G8000™) modulates apoptosis but not oxidative stress following rat colon carcinogenesis induced by azoxymethane.

Toxicol Mech Methods 2015 Feb 22;25(2):91-7. Epub 2015 Jan 22.

Department of Pathology .

Objectives: The aim of this study was to evaluate if grape juice concentrate is able to protect against experimental colon carcinogenesis.

Material And Methods: For this purpose, a total of 35 male Wistar rats were randomly distributed into seven groups: G1: SHAM animals receiving only saline; G2: animals receiving 15 mg/kg azoxymethane (AOM); G3: animals receiving 1% grape juice concentrate 2 weeks before the administration of AOM; G4: animals receiving 2% grape juice concentrate 2 weeks before the administration of AOM; G5: animals receiving 1% grape juice concentrate 4 weeks after the last administration of AOM; G6: animals receiving 2% grape juice concentrate 4 weeks after the last administration of AOM; G7: animals receiving only 2% grape juice concentrate.

Results: The group that received 2% grape juice concentrate before induction with AOM showed the decreased expression of Bcl-2 compared to those animals that were induced by AOM (positive control). Regarding Bax, animals that received grape juice at 2% decreased Bax immunoexpression when compared to AOM group. Furthermore, animals that intake grape juice at 1% after induced by AOM decreased Bax immunoexpression as well. 8-OHdGLI did not show significant statistically differences (p > 0.05) among groups.

Conclusion: In summary, our results demonstrate that grape juice is able to modulate rat colon carcinogenesis as a result of induction of apoptosis.
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http://dx.doi.org/10.3109/15376516.2014.989556DOI Listing
February 2015

Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma.

Fam Cancer 2014 Dec;13(4):645-9

Department of Skin Cancer, AC Camargo Cancer Center, São Paulo, Brazil.

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.
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http://dx.doi.org/10.1007/s10689-014-9736-1DOI Listing
December 2014

Expression of E-cadherin and β-catenin in basaloid and conventional squamous cell carcinoma of the oral cavity: are potential prognostic markers?

BMC Cancer 2014 Jun 3;14:395. Epub 2014 Jun 3.

Department of Clinic and Surgery, School of Dentistry, Alfenas Federal University, 700, CEP 37130-000 Alfenas, MG, Brazil.

Background: Basaloid squamous cell carcinoma presents with a preference for the head and neck region, and shows a distinct aggressive behavior, with frequent local recurrences, regional and distant metastasis. The alterations in the cadherin-catenin complex are fundamental requirements for the metastasis process, and this is the first study to evaluate the immunostaining of E-cadherin and β-catenin in oral basaloid squamous cell carcinoma.

Methods: Seventeen cases of this tumor located exclusively in the mouth were compared to 26 cases of poorly differentiated squamous cell carcinoma and 28 cases of well to moderately differentiated squamous cell carcinoma matched by stage and tumor site. The immunostaining of E-cadherin and β-catenin were evaluated in the three groups and compared to their clinicopathological features and prognosis.

Results: For groups poorly differentiated squamous cell carcinoma and basaloid squamous cell carcinoma, reduction or absence of E-cadherin staining was observed in more than 80.0% of carcinomas, and it was statistically significant compared to well to moderately differentiated squamous cell carcinoma (p = .019). A strong expression of β-catenin was observed in 26.9% and 20.8% of well to moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma, respectively, and in 41.2% of basaloid squamous cell carcinoma. The 5-year and 10-year overall and disease-free survival rates demonstrated no significant differences among all three groups.

Conclusions: The clinical and biological behavior of three groups of the oral cavity tumors evaluated are similar. E-cadherin and β-catenin immunostaining showed no prognostic value for basaloid and conventional squamous cell carcinomas.
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http://dx.doi.org/10.1186/1471-2407-14-395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049437PMC
June 2014

Tungiasis under dermoscopy: in vivo and ex vivo examination of the cutaneous infestation due to Tunga penetrans.

An Bras Dermatol 2013 Jul-Aug;88(4):649-51

Dermatology Department, University of São Paulo, Medical School, Clinics Hospital, São Paulo(SP), Brazil.

The female flea Tunga penetrans is responsible for a cutaneous parasitosis known as Tungiasis. We report the clinical case of a 12 year-old Caucasian boy who sought treatment in a dermatological private office due to a painful lesion in the plantar area and whose dermoscopic examination, without skin contact, allowed the visualization of parasite's movement inside the skin. The diagnosis of tungiasis is clinical, but it can be aided by in vivo and ex vivo dermoscopic examination of the lesion.
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http://dx.doi.org/10.1590/abd1806-4841.20132071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760950PMC
April 2014

TNF-alpha and melphalan modulate a specific group of early expressed genes in a murine melanoma model.

Cytokine 2013 May 25;62(2):217-25. Epub 2013 Mar 25.

Laboratório de Inflamação e Câncer, Fundação Antônio Prudente, Hospital AC Camargo, São Paulo, Brazil.

Background: Cutaneous melanoma displays high morbidity and mortality rates. Isolated limb perfusion with melphalan (Mel) is used for the treatment of non-resectable, locally advanced extremity melanomas. When combined with tumor necrosis factor alpha (TNF-alpha) treatment, the complete response varies between 70% and 90%. The mechanisms underlying the effects of Mel and TNF-alpha are not completely understood. We evaluated the impact of systemic Mel and TNF-alpha administration on tumor growth, analyzed the morphological changes promoted by each treatment, and identified early expressed genes in response to Mel and TNF-alpha treatment, either alone or in combination, in a murine melanoma model.

Methods: Six- to eight-week-old male mice were subcutaneously inoculated with B16F10 melanoma cells and then intravenously injected with TNF-alpha, melphalan or a combination of both drugs when the tumors reached 1.0 cm(2). Tumor growth was monitored every other day, and histological analysis was performed when the tumors reached 3.0 cm(2). Total RNA was extracted from the resected tumors and submitted to amplification, labeling and hybridization on an oligonucleotide microarray (Fox Chase Cancer Center). Tumor growth and histological parameters were compared using ANOVA. Survival curves were calculated using the Kaplan-Meier method. Two-way ANOVA was used to identify differentially expressed genes among the various treatments, and Dunn's test was used for pair-wise comparisons.

Results: Systemic administration of Mel impaired tumor growth (p<0.001), improved animal survival (p<0.001), and decreased mitotic rate (p=0.049). Treatment with TNF-alpha alone had no impact, neither on tumor growth, nor on survival, but it increased necrosis (p<0.024) and decreased mitotic rates (p=0.001) in the tumors. Combined treatment with Mel and TNF-alpha had similar effects in tumor growth, survival, necrosis and mitotic rate as observed with individual treatments. Moreover, 118 genes were found differentially expressed by microarray analysis and 10% of them were validated by RT- real time PCR. In our model we found that the treatments regulate genes that play important roles in tumorigenesis such as cell adhesion (Pard3, Pecam1, Ilk, and Dlg5), proliferation (Tcfe3 and Polr1e), cell motility (Kifap3, Palld, and Arhgef6), apoptosis (Bcl2l11), and angiogenesis (Flt1 and Ptprj).

Conclusions: Our data reproduces, in mice, some of the features observed in melanoma patients treated with the combination of Mel and TNF-alpha. The identification of genes with altered expression by these drugs both individually and in combination might help in the understanding of their mechanism of action and, as a consequence, improved strategies that could impact their clinical application.
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http://dx.doi.org/10.1016/j.cyto.2013.02.022DOI Listing
May 2013

Gene network analyses point to the importance of human tissue kallikreins in melanoma progression.

BMC Med Genomics 2011 Oct 27;4:76. Epub 2011 Oct 27.

Hospital A,C, Camargo, São Paulo, Brazil.

Background: A wide variety of high-throughput microarray platforms have been used to identify molecular targets associated with biological and clinical tumor phenotypes by comparing samples representing distinct pathological states.

Methods: The gene expression profiles of human cutaneous melanomas were determined by cDNA microarray analysis. Next, a robust analysis to determine functional classifications and make predictions based on data-oriented hypotheses was performed. Relevant networks that may be implicated in melanoma progression were also considered.

Results: In this study we aimed to analyze coordinated gene expression changes to find molecular pathways involved in melanoma progression. To achieve this goal, ontologically-linked modules with coordinated expression changes in melanoma samples were identified. With this approach, we detected several gene networks related to different modules that were induced or repressed during melanoma progression. Among them we observed high coordinated expression levels of genes involved in a) cell communication (KRT4, VWF and COMP); b) epidermal development (KLK7, LAMA3 and EVPL); and c) functionally related to kallikreins (EVPL, KLK6, KLK7, KLK8, SERPINB13, SERPING1 and SLPI). Our data also indicated that hKLK7 protein expression was significantly associated with good prognosis and survival.

Conclusions: Our findings, derived from a different type of analysis of microarray data, highlight the importance of analyzing coordinated gene expression to find molecular pathways involved in melanoma progression.
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http://dx.doi.org/10.1186/1755-8794-4-76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212933PMC
October 2011