RESUMEN
BACKGROUND: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown. METHODS: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment. CONCLUSIONS: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients. LAY SUMMARY: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.
Asunto(s)
Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Adulto , Humanos , Escisión del Ganglio Linfático , Melanoma/patología , Melanoma/cirugía , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/cirugía , Espera VigilanteRESUMEN
Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.
Asunto(s)
Melanoma/diagnóstico , Melanoma/genética , Regiones Promotoras Genéticas/genética , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Telomerasa/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/genética , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND AND OBJECTIVES: Tumor mitotic rate (TMR) is an important prognostic variable for patients with thin melanoma. However it remains unclear what the significance of TMR is for more deeply invasive melanoma pathologically staged with a sentinel lymph node biopsy. We sought to determine the prognostic value of TMR in clinically node-negative T2 melanoma patients staged with sentinel lymphadenectomy. METHODS: A prospective IRB-approved database of cutaneous melanoma patients treated from 09/01/1997-03/01/2011 was used to identify patients with T2 melanoma staged with a SLN. Associations were evaluated using Fisher's Exact test, and Kaplan-Meier analysis. RESULTS: Three hundred thirteen T2 patients were included. 19% had ulceration, 11% a positive sentinel node (SLN), and 10% recurred. 44% of patients had TMR ≥ 1/mm(2). TMR ≥ 1/mm(2) did not predict SLN status. TMR ≥ 1/mm(2) was significantly associated with recurrence in SLN negative patients; only 3% of those with TMR < 1/mm(2) developed a recurrence compared to 16% of those with TMR ≥ 1/mm(2) (P < 0.0001). CONCLUSIONS: Although TMR ≥ 1/mm(2) is not associated with risk of SLN involvement in T2 melanoma, it is a significant risk factor for recurrence when SLN negative. As such, TMR could be used to stratify follow-up regimens in SLN negative T2 patients.
Asunto(s)
Escisión del Ganglio Linfático , Melanoma/patología , Mitosis , Recurrencia Local de Neoplasia/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Anciano , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Úlcera Cutánea/patologíaRESUMEN
Cutaneous melanoma can be lethal even if detected at an early stage. Epigenetic profiling may facilitate the identification of aggressive primary melanomas with unfavorable outcomes. We performed clustering of whole-genome methylation data to identify subclasses that were then assessed for survival, clinical features, methylation patterns, and biological pathways. Among 89 cutaneous primary invasive melanomas, we identified three methylation subclasses exhibiting low methylation, intermediate methylation, or hypermethylation of CpG islands, known as the CpG island methylator phenotype (CIMP). CIMP melanomas occurred as early as tumor stage 1b and, compared with low-methylation melanomas, were associated with age at diagnosis ≥65 years, lentigo maligna melanoma histologic subtype, presence of ulceration, higher American Joint Committee on Cancer stage and tumor stage, and lower tumor-infiltrating lymphocyte grade (all P < 0.05). Patients with CIMP melanomas had worse melanoma-specific survival (hazard ratio = 11.84; confidence interval = 4.65â30.20) than those with low-methylation melanomas, adjusted for age, sex, American Joint Committee on Cancer stage, and tumor-infiltrating lymphocyte grade. Genes hypermethylated in CIMP compared with those in low-methylation melanomas included PTEN, VDR, PD-L1, TET2, and gene sets related to development/differentiation, the extracellular matrix, and immunity. CIMP melanomas exhibited hypermethylation of genes important in melanoma progression and tumor immunity, and although present in some early melanomas, CIMP was associated with worse survival independent of known prognostic factors.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Islas de CpG/genética , Metilación de ADN/genética , Humanos , Melanoma/genética , Fenotipo , Neoplasias Cutáneas/genética , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown. STUDY DESIGN: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared. RESULTS: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin-only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86). CONCLUSIONS: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.
Asunto(s)
Metástasis Linfática/diagnóstico , Melanoma/terapia , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Cutáneas/terapia , Espera Vigilante/estadística & datos numéricos , Adulto , Anciano , Quimioterapia Adyuvante/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto , Estudios de Seguimiento , Humanos , Escisión del Ganglio Linfático/normas , Escisión del Ganglio Linfático/estadística & datos numéricos , Metástasis Linfática/terapia , Masculino , Melanoma/diagnóstico , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Selección de Paciente , Pronóstico , Puntaje de Propensión , Radioterapia Adyuvante/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/estadística & datos numéricos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Espera Vigilante/normasRESUMEN
BACKGROUND: The follow-up of patients with cutaneous melanoma is controversial. Current recommendations suggest routine history and physical examination every 3 to 6 months for the first 3 years and correlate studies including laboratory tests and radiographic imaging. However, the utility of these recommendations are unclear. The purpose of this study was to determine the impact of routine imaging on the method of detection of first recurrence in patients with stage II and sentinel lymph node-positive stage III melanoma. METHODS: We analyzed a prospective database of all cutaneous melanoma patients treated at our institution from 1997 to 2005 who had at least 2 years of follow-up. The method of detection of initial recurrence was analyzed. RESULTS: One hundred eighteen patients with stage II (n = 83) or III (n = 35) melanoma who were followed for at least 2 years were identified. Forty-three of these patients developed recurrence (median time to recurrence, 14 months). Site of first recurrence was as follows: 4 local, 17 in transit, 7 regional lymph node, and 15 distant. Twenty-nine recurrences (67%) were either patient detected or symptomatic. Eleven (26%) were detected by the physician at routine follow-up. Only three (7%) were identified by imaging (two chest X-ray and one brain magnetic resonance imaging) in an otherwise asymptomatic patient. CONCLUSIONS: Two-thirds of all initial recurrences of cutaneous melanoma were either detected by a patient or were symptomatic, with most of the remainder detected during routine physical examination. Routine imaging added little value in the detection of initial recurrence.
Asunto(s)
Melanoma/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging, even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screening, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristic curve = 0.996, sensitivity = 96.6%, and specificity = 100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.
Asunto(s)
Biomarcadores de Tumor/genética , Metilación de ADN , Epigenómica/métodos , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Algoritmos , Islas de CpG/genética , Diagnóstico Diferencial , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Nevo/diagnóstico , Nevo/genética , Nevo/patología , Curva ROC , Estudios Retrospectivos , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.
RESUMEN
Tumor mitotic rate (TMR) is a known prognostic variable in thin melanoma patients. Its significance in stage II melanoma patients is yet to be demonstrated. Retrospective analysis of a prospective melanoma database from 9/1997 to 7/2015 was performed. All stage II melanoma, with documented TMR, and six months of follow-up were included. We evaluated the association of clinicopathologic variables, TMR, as a continuous and categorical variable with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling. We used a statistical model, X-tile, to develop optimal categorizations of TMR. A total of 265 patient characteristics are included in this study. Recurrences occurred in 82 (30.9%) patients, including 5 local, 41 regional, and 36 distant patients. In multivariate model, ulceration, Breslow, and continuous TMR were associated with worse RFS\OS. Continuous TMR demonstrated worse RFS (hazards ratio [HR] 1.02 (1.00-1.05)) and OS (HR 1.02 (1.00-1.04)), whereas dichotomized TMR (≥1 vs <1) was not significant. TMR >10.4 mitoses/mm2 has a 5-year RFS\OS of 27.2 and 44.3 per cent, respectively, compared with 57.4 and 71.4 per cent, respectively, for TMR <3.2 mitoses/mm2. Continuous TMR predicts incidence of recurrence in stage II melanoma. We propose a new categorization method developed by statistical modeling for optimal stratification that may guide surveillance for this disparate patient population.
Asunto(s)
Melanoma/patología , Recurrencia Local de Neoplasia/patología , Ganglio Linfático Centinela/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Mitosis , Recurrencia Local de Neoplasia/epidemiología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Patients with stage II melanoma have a considerable risk for recurrence. Current guidelines are imprecise as to optimal follow-up. We hypothesized that by examining recurrence patterns, we could help to better inform guidelines. STUDY DESIGN: We queried IRB-approved melanoma databases of Thomas Jefferson University and University of North Carolina, identifying 581 patients with stage II melanoma between 1996 and 2015 with at least 1 year of follow-up. Data included location of first recurrence and how recurrence was detected (ie patient symptom, physician examination, or routine surveillance imaging). Cox regression with backward elimination was used for multivariable analysis. RESULTS: One hundred and seventy-one patients had a recurrence (29.4%), the incidence increased considerably by stage sub-group. Significant predictors of recurrence included male sex (p = 0.003), ulceration (p = 0.03), and stage (p < 0.001). On multivariable analysis, male sex and stage continued to be significant (p < 0.01). For overall survival, regression, ulceration, stage, and age were significant predictors of survival. Stage, regression, and age remained significant by multivariable analysis. Patient symptoms were the most frequent mode of detection (40%), followed by physician examination (30%) and surveillance imaging (26%)-this did not differ significantly by stage. Regional nodes were the most common site of recurrence (30%), followed by lung (27%) and in-transit (18%). CONCLUSIONS: The majority of recurrences in stage II melanoma are detected by patients and their physicians and rarely by routine imaging. As such, clinical follow-up and patient education are critical factors in detection of recurrence. With the prevalence of regional nodal recurrences, ultrasound might prove to be an important strategy in early recurrence detection.
Asunto(s)
Melanoma/patología , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/terapia , Adulto JovenRESUMEN
Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+ with older age relative to the wild type (BRAF-/NRAS-) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction < 0.05) but inversely associated with BRAF V600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis.
Asunto(s)
GTP Fosfohidrolasas/genética , Melanoma/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas B-raf/genética , Receptor de Melanocortina Tipo 1/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Australia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estados UnidosRESUMEN
BACKGROUND: Retrieval of fewer than 10 lymph nodes at axillary dissection (ALND) for breast cancer can represent anatomic variation or inadequate dissection. We postulated that despite aggressive ALND, a lower lymph node count is more frequent after neoadjuvant chemotherapy. METHODS: Patients who received neoadjuvant chemotherapy followed by ALND were compared with patients who received surgery first. All patients received a level I and II ALND at a single institution by one of the breast surgeons. The number of nodes retrieved at ALND was dichotomized into categories (< 10 and > or = 10), and compared using Fisher exact test. RESULTS: A total of 143 neoadjuvant and 170 surgery-first patients were studied. Patients treated with neoadjuvant chemotherapy were significantly more likely to have fewer than 10 lymph nodes retrieved at ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%, P = .003). CONCLUSIONS: A low lymph node count is more common in patients after treatment with neoadjuvant chemotherapy and should not be assumed to represent an incomplete ALND.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Terapia Neoadyuvante , Invasividad Neoplásica/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Axila , Neoplasias de la Mama/cirugía , Femenino , Humanos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/cirugía , Metástasis Linfática/patología , Metástasis Linfática/prevención & control , Mastectomía/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Probabilidad , Pronóstico , Estudios Prospectivos , Biopsia del Ganglio Linfático Centinela , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
BACKGROUND: In patients with breast cancer who choose mastectomy with immediate reconstruction, the sentinel lymph node (SLN) status on permanent histology may complicate treatment if a metastasis is found. The purpose of this study was to determine how performing an SLN biopsy (SLNB) before the definitive operation would influence subsequent surgical procedures. METHODS: Our SLN database was searched for patients who underwent staged SLNB with subsequent mastectomy between 2001 and 2004. RESULTS: Twenty-five patients with 27 breast cancers underwent SLNB before mastectomy. Of them, 9 of 27 (33%) were node positive. All 9 patients underwent modified radical mastectomy. Three node-positive patients did not undergo immediate reconstruction. Of the remaining 6 node-positive patients, 5 underwent reconstruction with autologous tissue rather than a tissue expander. In contrast, 6 of 16 (37%) node-negative patients underwent reconstruction with a tissue expander. CONCLUSIONS: Staged SLNB assists in selecting the appropriate operation in patients who are considering immediate reconstruction.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Lobular/patología , Biopsia del Ganglio Linfático Centinela/métodos , Adulto , Anciano , Axila , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal no Infiltrante/terapia , Carcinoma Lobular/terapia , Femenino , Humanos , Escisión del Ganglio Linfático , Metástasis Linfática , Mamoplastia , Mastectomía , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia AdyuvanteRESUMEN
PURPOSE: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. EXPERIMENTAL DESIGN: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. RESULTS: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0-G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten(null)/Braf(V600E)) melanomas. CONCLUSIONS: We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Pten(null)/Braf(V600E) mouse melanoma model supports this possibility.
Asunto(s)
Melanoma/enzimología , Proteínas Tirosina Quinasas/biosíntesis , Neoplasias Cutáneas/enzimología , Animales , Antineoplásicos/farmacología , Western Blotting , Línea Celular Tumoral , Modelos Animales de Enfermedad , Electroforesis en Gel Bidimensional , Técnicas de Silenciamiento del Gen , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Melanoma/patología , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Neoplasias Cutáneas/patología , Análisis de Matrices Tisulares , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
IMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN, SETTING, AND PARTICIPANTS: A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 [1.1-7.7]) or BRAF (3.1 [1.2-8.5]) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 [0.3-3.0]) or BRAF (0.6 [0.2-1.7]) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higherAJCC stage primary melanomas.
Asunto(s)
Biomarcadores de Tumor/genética , GTP Fosfohidrolasas/genética , Melanoma/genética , Proteínas de la Membrana/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor , Masculino , Melanoma/enzimología , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Melanoma/terapia , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Nueva Gales del Sur , Oportunidad Relativa , Fenotipo , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Factores de Tiempo , Microambiente Tumoral , Estados UnidosRESUMEN
BACKGROUND: Follow-up of patients with sentinel lymph node-positive stage III melanoma uses history, physical exam, and cross-sectional imaging. The aim of this study was to evaluate positron emission tomographic (PET)/computed tomographic (CT) scans in the detection of recurrence. METHODS: From 2003 to 2009, a single-institution prospective database of all cutaneous melanoma patients was used to identify sentinel lymph node-positive stage III patients with disease-free survival >1 year and 1 restaging PET/CT scan. RESULTS: Thirty-eight patients were identified, with a median follow-up period of 27.5 months. Seven (18%) developed recurrence (median time to recurrence, 25 months). Recurrences were detected as follows: 3 by patients, 1 by physician, 1 by PET/CT scan and lactate dehydrogenase, 1 by PET/CT scan, and 1 by brain magnetic resonance imaging. One hundred eight follow-up PET/CT scans were performed. Two of 38 patients had asymptomatic metastases detected by routine restaging PET/CT scan, and there were 9 scans with false-positive results. CONCLUSIONS: With short follow-up, the utility of routine PET/CT scans in identifying unsuspected recurrence in patients with sentinel lymph node-positive stage III melanoma appears minimal.
Asunto(s)
Melanoma/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Estadificación de Neoplasias/métodos , Tomografía de Emisión de Positrones/métodos , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología , Adulto JovenRESUMEN
IMPORTANCE Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.OBJECTIVE To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.DESIGN, SETTING, AND PARTICIPANTS Survival analysis with a median follow-up of 7.6 years.The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma(GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.MAIN OUTCOMES AND MEASURES Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.RESULTS Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex,nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally ofa higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios[ORs] [95%CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95%CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a;P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95%CI, 1.4-3.0)(P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.
Asunto(s)
Melanoma/mortalidad , Melanoma/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Adulto , Anciano , Australia/epidemiología , Canadá/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Melanoma Amelanótico/mortalidad , Melanoma Amelanótico/patología , Persona de Mediana Edad , Índice Mitótico , Estadificación de Neoplasias , Sistema de Registros , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
Patients with sentinel lymph node (SLN) positive melanoma have a significant recurrence risk. We sought to examine variables associated with development of early recurrence. A prospective institutional review board-approved database of cutaneous melanoma patients treated from 2003 to 2010 was used to identify SLN positive stage III patients with 1 year of follow-up. The Kaplan-Meier method, and logistic regression were used to evaluate variables associated with early recurrence. Seventy-four patients were identified. Twenty-four (32%) had an early recurrence. Five variables were highly significantly associated with early recurrence: location of head/neck, Breslow depth greater than two, ulceration, number of lymph nodes positive ≥ 2, and largest lymph node metastasis > 1 mm. Using these five variables, a numerical risk score was created from 0 to 5 to determine if an early recurrence occurred as the number of risk factors increased. The proportion of patients with early recurrence increased in linear fashion with increasing risk score (P < 0.0001). These data suggest that SLN positive stage III melanoma patients have a significant risk of early recurrence, which is associated with several defined variables and increases with the number of risk factors present. These data may be useful in stratifying patients to level of recurrence risk and adjusting follow-up schedules.
Asunto(s)
Melanoma/patología , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/etiología , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Técnicas de Apoyo para la Decisión , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Metástasis Linfática , Masculino , Melanoma/mortalidad , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Adulto JovenRESUMEN
BACKGROUND: Melanoma excisions frequently are associated with significant soft-tissue defects, creating the need for complex closures. These closures could be performed by either surgical oncologists or plastic surgeons. We sought to quantify the relative value units (RVUs) and describe the practice patterns of 2 academic surgical subspecialties after a melanoma excision. METHODS: After institutional review board approval, a retrospective data analysis of a billing database was conducted on all melanoma patients undergoing an excision and closure by surgical oncology and plastic surgery departments in 2007. Data were obtained using billing records for Current Procedural Terminology diagnosis codes. RVUs were used to quantify the value added to each practice from these closures. The surgical oncologist and patient decided if a plastic surgeon was needed. RESULTS: A total of 270 closures were performed, 53 (19.9%) primary and 217 (80.1%) complex. The surgical oncologists performed most complex closures (188; 86.6%), and the plastic surgeons performed the remainder (29; 13.4%), generating a total of 1,921 RVUs (1,630 by the surgical oncologists and 291 by the plastic surgeons). For analysis, complex closures were divided among 4 anatomic sites: trunk, upper extremity, lower extremity, and head and neck. Most closures by the surgical oncologists were adjacent tissue rearrangements (155; 82%) and the remainder were skin grafts (33; 18%). Closures by the plastic surgeons were more likely to be a full-thickness skin graft (P < .0027) in the head and neck region (P < .0001), with a higher associated median RVU/case (10.15 compared with 8.44 for the surgical oncologists; P < .0002). CONCLUSIONS: At our institution, the majority of melanoma closures were performed by surgical oncologists. However, plastic surgery often was involved in more complex closures in the head and neck. This data set quantifies the RVUs added and describes the types of closures performed in an academic melanoma practice.
Asunto(s)
Procedimientos Quirúrgicos Dermatologicos , Oncología Médica/estadística & datos numéricos , Melanoma/cirugía , Procedimientos de Cirugía Plástica/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Neoplasias Cutáneas/cirugía , Cirugía Plástica/estadística & datos numéricos , Centros Médicos Académicos , Adulto , Anciano , Femenino , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante de Piel , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Atypical melanocytic neoplasms present a therapeutic dilemma. Current consensus is to perform a sentinel lymph node (SLN) biopsy as part of management. However, it is unclear whether this is required in all patients. We present our experience with sentinel lymphadenectomy in these patients and examine the clinical and pathologic variables associated with a positive SLN. STUDY DESIGN: A prospectively maintained melanoma database was queried for patients with controversial melanocytic lesions. All patients between January 1997 and January 2009 were included. Demographic and pathologic information was collected and correlated with results of SLN biopsy. RESULTS: Thirty-one patients underwent SLN biopsy. Median patient age was 19 years (range 5 to 59 years) and median tumor Breslow depth was 1.35 mm. Five patients (16%) had a positive SLN. Those with a positive SLN were younger (median 11 vs 23.5 years, p = 0.02) and had a greater Breslow depth (median 1.90 vs 1.09; p = 0.03) than those who were SLN negative. Median follow-up was 16 months for patients with at least 6 months of follow-up time and there have been no recurrences identified. CONCLUSIONS: We report an SLN positive rate of 16% in patients with atypical melanocytic tumors. Younger age and greater Breslow depth are associated with having a positive SLN. These results confirm earlier work demonstrating the importance of SLN biopsy in this disease and highlight the need to measure Breslow depth in these lesions so that they can be appropriately stratified as to the need for SLN biopsy.