Background Histopathologic analysis remains the gold standard for the pathologic diagnosis of melanoma. Numerous histologic criteria are used to diagnose melanoma, but none alone are sufficient to ...establish this diagnosis. Therefore, differentiating between benign pigmented lesions and melanoma may be controversial. Although several studies have examined the interobserver variability in the pathological diagnosis of melanoma, the prevalence of discordant diagnoses of melanocytic neoplasms is unknown. Objective We sought to examine the discordance rate of melanoma diagnoses referred to our pigmented lesion clinic, a subset of the University of California, San Francisco (UCSF) Department of Dermatology and Comprehensive Cancer Center Melanoma Center during a 2-year period. Methods A total of 392 new patients given a diagnosis of thin melanoma (melanoma in situ, stage IA, stage IB) or benign nevus were referred in 2006 and 2007, with initial diagnoses rendered by an outside dermatopathologist or surgical pathologist. Subsequently, these specimens were re-evaluated by routine histopathologic examination at the UCSF Dermatopathology Service and a distinct diagnosis was rendered. The two available diagnoses were compared, and discordance was defined as the lack of agreement between two pathologists when rendering a benign versus malignant versus ambiguous diagnosis. Results The discordance rate of melanomas and nevi between the referring centers and UCSF was 14.3%. Limitations This review was limited in that there were few patients with benign pigmented lesions referred to the pigmented lesion clinic at UCSF. Conclusion The level of discordance in the routine histopathologic interpretation of melanocytic neoplasms can be high.
The Gene Expression Signatures of Melanoma Progression Haqq, Christopher; Nosrati, Mehdi; Sudilovsky, Daniel ...
Proceedings of the National Academy of Sciences - PNAS,
04/2005, Letnik:
102, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma ...progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma.
Background A minority of patients with T1 melanoma will have a positive sentinel lymph node (SLN) biopsy (SLNB) finding. Identifying who will develop metastatic disease is important in determining ...prognosis and treatment. Objective We sought to identify clinical and histologic features predictive of a positive SLNB result and determine its prognostic significance in patients with T1 melanoma. Methods Clinical and histologic parameters were evaluated in 484 patients with T1 melanoma for their ability to predict a positive SLNB result. The impact of various factors on SLN positivity was evaluated. SLN status was examined as a predictor of overall survival. Results In all, 34 patients had a positive SLNB finding. Four factors predicted a higher risk of SLN positivity: age 43 years or younger, Breslow depth 0.8 mm or greater, tumors on the lower extremity and trunk, and tumor-infiltrating lymphocyte level. By multivariate analysis, low tumor-infiltrating lymphocytes ( P = .0015) and decreasing age ( P = .0058) independently predicted SLN positivity. If 0 to 2 of these factors were present, the rate of a positive SLNB result was 3%; this increased to 15% with 3 factors present and to 30% if all 4 factors were present ( P < .002). SLN-positive patients had significantly decreased survival ( P = .003), and SLN status was the most powerful predictor of survival ( P = .009). Limitations Our data analysis includes patients from 1994 to 2007 and therefore information on mitotic rate, a recently defined T1b criterion, is not recorded for all patients. Conclusions Combining clinical and histologic prognostic factors may help identify subgroups of T1 patients at higher risk of SLN positivity. SLN status has significant prognostic impact in patients with thin melanomas.
Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the ...oncogenic effects of BPTF in melanoma.
The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided.
shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents.
These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.
The histopathological diagnosis of melanoma can be challenging. No currently used molecular markers accurately distinguish between nevus and melanoma. Recent transcriptome analyses have shown the ...differential expression of several genes in melanoma progression. Here, we describe a multi-marker diagnostic assay using 5 markers (ARPC2, FN1, RGS1, SPP1, and WNT2) overexpressed in melanomas. Immunohistochemical marker expression was analyzed in 693 melanocytic neoplasms comprising a training set (tissue microarray of 534 melanomas and nevi), and 4 independent validation sets: tissue sections of melanoma arising in a nevus; dysplastic nevi; Spitz nevi; and misdiagnosed melanocytic neoplasms. Both intensity and pattern of expression were scored for each marker. Based on the differential expression of these 5 markers between nevi and melanomas in the training set, a diagnostic algorithm was obtained. Using this algorithm, the lesions in the validation sets were diagnosed as nevus or melanoma, and the results were compared with the known histological diagnoses. Both the intensity and pattern of expression of each marker were significantly different in melanomas compared to nevi. The diagnostic algorithm exploiting these differences achieved a specificity of 95% and a sensitivity of 91% in the training set. In the validation sets, the multi-marker assay correctly diagnosed a high percentage of melanomas arising in a nevus, Spitz nevi, dysplastic nevi, and misdiagnosed lesions. The multi-marker assay described here can aid in the diagnosis of melanoma.
Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the ...precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression ofMITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression.
To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or ...low-dose IFNα-2b versus observation.
Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median. A multimarker index was then developed to combine marker expression levels by counting for each patient the number of markers with high expression. The impact of the multimarker index on relapse-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier analysis, and both univariate and multivariate Cox regression analyses.
By Kaplan-Meier analysis, high multimarker expression scores were significantly predictive of RFS (
< 0.001) and OS (
< 0.001). Stepwise multivariate Cox regression analysis with backward elimination that included routine clinical and histologic prognostic factors revealed high multimarker expression scores and tumor thickness as the only factors significantly and independently predicting RFS and OS. Stepwise multivariate Cox regression analyses that also included treatment type and number of positive lymph nodes generated identical results for both RFS and OS. In the molecularly defined low-risk subgroup, patients treated with high-dose IFN had a significantly improved RFS compared with patients in the other two subgroups (
< 0.05).
These results validate the independent impact of combined expression levels of SPP1, RGS1, and NCOA3 on survival of melanoma in a prospectively collected cohort.
.
Diet and Melanoma in a Case-Control Study MILLEN, Amy E; TUCKER, Margaret A; HARTGE, Patricia ...
Cancer epidemiology, biomarkers & prevention,
06/2004, Letnik:
13, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background: Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable
risk factors. This study investigates risk related to dietary factors, ...which are potentially modifiable. Methods: Newly diagnosed
patients with melanoma ( n = 502) were recruited from pigment lesion clinics and controls ( n = 565) were recruited from outpatient clinics. To investigate the relationship between melanoma and dietary factors in this
case-control study, study subjects were requested to complete a food frequency questionnaire, which assessed diet over the
previous year. Using logistic regression, odds ratios (ORs) for melanoma were computed for nutrient and alcohol intake. Results:
Persons in high versus low quintiles of energy-adjusted vitamin D, α-carotene, β-carotene, cryptoxanthin, lutein, and lycopene
had significantly reduced risk for melanoma (ORs ≤ 0.67), which remained after adjustment for presence of dysplastic nevi,
education, and skin response to repeated sun exposure. Addition of micronutrients from supplements did not add an additional
reduction in risk. High alcohol consumption was associated with an increased risk for melanoma, which remained after adjustment
for confounders OR (95% confidence interval) in highest versus lowest quintiles, 1.65 (1.09-2.49). Conclusions: Diets consisting
of foods rich in vitamin D and carotenoids and low in alcohol may be associated with a reduction in risk for melanoma. These
analyses should be repeated in large, prospective studies.
Purpose: To determine the prognostic significance of a multimarker assay incorporating expression levels of three molecular markers
in primary cutaneous melanoma.
Experimental Design: We assessed ...expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of
395 patients. For each marker, we identified optimal cut-points for expression intensity to predict disease-specific survival
(DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative overexpression of all three markers was
embodied in a multimarker index, and its prognostic effect on DSS and SLN status was assessed using Cox regression, Kaplan-Meier
analysis, and logistic regression. The prognostic effect of this multimarker assay on DSS was assessed in an independent cohort
of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections.
Results: Increasing multimarker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient
cohort. Multivariate logistic regression analysis revealed multimarker expression scores as an independent predictor of SLN
status ( P = 0.001). Multivariate Cox regression analysis showed the independent effect of the multimarker index on DSS ( P < 0.001). The multimarker index was the most significant factor predicting DSS when compared with other clinical and histologic
factors, including SLN status ( P = 0.002). Multimarker expression scores were also the most significantly predictive of DSS in the independent cohort ( P = 0.01).
Conclusions: These results describe a multimarker assay with independent prognostic effect on the prediction of survival associated with
melanoma in two distinct cohorts. (Clin Cancer Res 2009;15(22):6987–92)
Individualized approaches to prognosis are crucial to effective management of cancer patients. We developed a methodology to assign individualized 5-year disease-specific death probabilities to 1,222 ...patients with melanoma and to 1,225 patients with breast cancer. For each cancer, three risk subgroups were identified by stratifying patients according to initial stage, and prediction probabilities were generated based on the factors most closely related to 5-year disease-specific death. Separate subgroup probabilities were merged to form a single composite index, and its predictive efficacy was assessed by several measures, including the area (AUC) under its receiver operating characteristic (ROC) curve. The patient-centered methodology achieved an AUC of 0.867 in the prediction of 5-year disease-specific death, compared with 0.787 using the AJCC staging classification alone. When applied to breast cancer patients, it achieved an AUC of 0.907, compared with 0.802 using the AJCC staging classification alone. A prognostic algorithm produced from a randomly selected training subsample of 800 melanoma patients preserved 92.5% of its prognostic efficacy (as measured by AUC) when the same algorithm was applied to a validation subsample containing the remaining patients. Finally, the tailored prognostic approach enhanced the identification of high-risk candidates for adjuvant therapy in melanoma. These results describe a novel patient-centered prognostic methodology with improved predictive efficacy when compared with AJCC stage alone in two distinct malignancies drawn from two separate populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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