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INTRODUCTION: Cutaneous malignant melanomas rarely occur in the eye, usually in the eyelids or the conjunctiva. Conjunctival malignant melanomas are even rarer. Most melanomas are dark in color as they are pigmented. However, amelanotic conjunctival malignant melanomas, a scarce variant of the cancer, can be challenging to diagnose accurately. CASE PRESENTATION: We present two cases of white Caucasian Swedish-born women who were diagnosed with unilateral amelanotic malignant melanoma in the conjunctiva of the eye. In the first case, the patient was an 81-year-old woman who was suffering from redness and foreign body sensation in the left eye. The initial diagnosis was blepharitis. Three biopsies were taken, which showed malignant melanoma in the eyelid and the conjunctiva. Unfortunately, the eye and the rest of the orbit could not be saved, and the patient had to undergo an orbital exenteration. In the second case, the patient was a 50-year-old woman, and the tumor was localized in the temporal conjunctiva of the left eye. The initial diagnosis was pinguecula, but at the time of surgery, the physician suspected conjunctival intraepithelial neoplasia. The tumor was not completely removed, so adjuvant brachytherapy and local chemotherapy were used. The eye was preserved. No neck and/or lung metastasis was detected in either case at the time of diagnosis. CONCLUSIONS: Conjunctival amelanotic malignant melanomas should be suspected when tumors are present in the eye and/or the eyelids. By suspecting amelanotic malignant melanoma, the delay in treatment can be shortened. Treating them as soon as possible is essential to minimize the risk of metastasis.
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Tumeurs de la conjonctive , Mélanome achromique , Humains , Femelle , Tumeurs de la conjonctive/anatomopathologie , Tumeurs de la conjonctive/thérapie , Tumeurs de la conjonctive/diagnostic , Mélanome achromique/anatomopathologie , Mélanome achromique/diagnostic , Sujet âgé de 80 ans ou plus , Adulte d'âge moyen , Mélanome/anatomopathologie , Mélanome/diagnosticRÉSUMÉ
Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.
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Chimiokine CCL21 , Mélanome , Humains , Chimiokine CCL21/génétique , Chimiokines/sang , Épigenèse génétique , Études de suivi , Immunothérapie , Mélanome/traitement médicamenteuxRÉSUMÉ
Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). Evidence Review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0. Findings: The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma. Conclusions and Relevance: The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.
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Mélanome , Tumeurs cutanées , Humains , Tumeurs cutanées/diagnostic , Tumeurs cutanées/anatomopathologie , Mélanome/diagnostic , Mélanome/anatomopathologie , Anatomopathologistes , Consensus , Établissements de santéRÉSUMÉ
Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, microphthalmia-associated transcription factor (MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma development and progression, have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation, and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining mRNA levels of neural crest-associated genes, we found that 1 subtype had lost the expression of several lineage genes, including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.
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Mélanome , Facteur de transcription associé à la microphtalmie , ADN/métabolisme , Humains , Mélanocytes/anatomopathologie , Mélanome/anatomopathologie , Facteur de transcription associé à la microphtalmie/génétique , Facteur de transcription associé à la microphtalmie/métabolisme , Phénotype , ARN messager/métabolisme , Facteurs de transcription SOX-E/génétique , Facteurs de transcription SOX-E/métabolismeRÉSUMÉ
PURPOSE: Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC; eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy. METHODS: Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b/pT2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed. RESULTS: Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and < 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P < .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits > 1 mm in maximum dimension. CONCLUSION: Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits < 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.
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Mélanome , Tumeurs cutanées , Adulte , Humains , États-Unis , Micrométastase tumorale/anatomopathologie , Extension extranodale , Stadification tumorale , Mélanome/traitement médicamenteux , Appréciation des risques , Tumeurs cutanées/traitement médicamenteux , PronosticRÉSUMÉ
Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I−II melanoma) is watchful waiting, while >40% of patients with stage IB−IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I−II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I−II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4−96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3−84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41−6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a 'low risk' of recurrence (96.8% 5-year RFS (95%CI 91.6−98.8), n = 130), 49% as 'intermediate risk' (88.4% 5-year RFS (95%CI 83.6−91.8), n = 261), and 26% as 'high risk' (61.1% 5-year RFS (95%CI 51.9−69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I−II melanoma into two groups differentiated by RFS.
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BACKGROUND: In patients with melanoma, sentinel lymph node (SLN) status is pivotal for treatment decisions. Current routine for SLN detection combines Technetium99m (Tc99) lymphoscintigraphy and blue dye (BD). The primary aim of this study was to examine the feasibility of using a low dose of superparamagnetic iron oxide (SPIO) injected intracutaneously to detect and identify the SLN, and the secondary aim was to investigate if a low dose of SPIO would enable a preoperative MRI-evaluation of SLN status. METHODS: Patients with melanoma of the extremities were eligible. Before surgery, a baseline MRI of the nodal basin was followed by an injection of a low dose (0.02-0.5 mL) of SPIO and then a second MRI (SPIO-MRI). Tc99 and BD was used in parallel and all nodes with a superparamagnetic and/or radioactive signal were harvested and analyzed. RESULTS: Fifteen patients were included and the SLNB procedure was successful in all patients (27 SLNs removed). All superparamagnetic SLNs were visualized by MRI corresponding to the same nodes on scintigraphy. Micrometastatic deposits were identified in four SLNs taken from three patients, and SPIO-MRI correctly predicted two of the metastases. There was an association between MRI artefacts in the lymph node and the dose SPIO given. DISCUSSION: It is feasible to detect SLN in patients with melanoma using a low dose of SPIO injected intracutaneously compared with the standard dual technique. A low dose of SPIO reduces the lymph node MRI artefacts, opening up for a non-invasive assessment of SLN status in patients with cancer.
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Membres/imagerie diagnostique , Nanoparticules magnétiques d'oxyde de fer , Mélanome/imagerie diagnostique , Biopsie de noeud lymphatique sentinelle/méthodes , Noeud lymphatique sentinelle/imagerie diagnostique , Tumeurs cutanées/imagerie diagnostique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Membres/anatomopathologie , Études de faisabilité , Femelle , Humains , Lymphoscintigraphie/méthodes , Imagerie par résonance magnétique , Magnétométrie , Mâle , Mélanome/anatomopathologie , Adulte d'âge moyen , Stadification tumorale , Noeud lymphatique sentinelle/anatomopathologie , Tumeurs cutanées/anatomopathologieRÉSUMÉ
BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.
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Carcinome transitionnel , Tumeurs de la vessie urinaire , Carcinome transitionnel/traitement médicamenteux , Carcinome transitionnel/génétique , Carcinome transitionnel/chirurgie , Traitement médicamenteux adjuvant , Cisplatine , Cystectomie , Femelle , Humains , Mâle , Traitement néoadjuvant , Invasion tumorale , Études rétrospectives , Résultat thérapeutique , Tumeurs de la vessie urinaire/traitement médicamenteux , Tumeurs de la vessie urinaire/génétique , Tumeurs de la vessie urinaire/anatomopathologieRÉSUMÉ
Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P<0.005). In one case, none of 20 pathologists recognized a tumor with BRAF and TERT promoter mutations associated with fatal outcome as a conventional melanoma when only limited clinical information was provided, whereas 60% of pathologists correctly diagnosed this case when genomic information was also available. There was also a significant improvement in agreement of which lesions should be classified in the Spitz category/WHO Pathway from an average Cohen κ of 0.360 (SE=0.00921) to 0.607 (SE=0.0232) with genomics.
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Marqueurs biologiques tumoraux/génétique , Analyse de mutations d'ADN , Séquençage nucléotidique à haut débit , Mutation , Naevus à cellules épithelioïdes et fusiformes/génétique , Tumeurs cutanées/génétique , Adulte , Biopsie , Femelle , Humains , Mâle , Adulte d'âge moyen , Naevus à cellules épithelioïdes et fusiformes/mortalité , Naevus à cellules épithelioïdes et fusiformes/anatomopathologie , Naevus à cellules épithelioïdes et fusiformes/thérapie , Biais de l'observateur , Valeur prédictive des tests , Reproductibilité des résultats , Tumeurs cutanées/mortalité , Tumeurs cutanées/anatomopathologie , Tumeurs cutanées/thérapieRÉSUMÉ
BACKGROUND: The quest for diagnostic tools for the detection of cutaneous malignant melanoma (cMM) is ongoing. A challenge in cMM care is not overlooking cMM at an early stage, while simultaneously avoiding unnecessary biopsies or excisions of benign pigmented skin lesions (PSLs). A novel hyperspectral imaging (HSI) device is shown to have potential for differentiating equivocal PSLs in Asian skin types. Our objective was to assess the accuracy of the HSI device in distinguishing between cMM and benign PSLs in patients with Caucasian skin types. METHODS: Patients with Caucasian skin types (Fitzpatrick I-II), enrolled for excisional biopsies of PSLs were included and examined using the HSI device. The discrimination index (DI) was used to demonstrate the sensitivity (SE) and specificity (SP) in comparison with the re-evaluated histopathology diagnoses. RESULTS: In 186 patients, 202 pigmented skin lesions were included. The sensitivity to detect cMM was 96.7% (87/90), and the specificity for benign lesions was 42.1% (45/107). The AUC was 0.800 (95% confidence interval (CI): 0.740-0.861). CONCLUSIONS: Our novel HSI device showed a high sensitivity in detecting malignant lesions in patients with Caucasian skin types. Compared with analogous technologies, as multispectral imaging or electrical impedance spectroscopy, our device showed similar or better accuracy in differentiating cMM from benign PSLs. Therefore, it might be a useful clinical tool in skin types I-IV and where further triage of pigmented skin lesions is important.
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Mélanome , Troubles de la pigmentation , Tumeurs cutanées , Humains , Imagerie hyperspectrale , Mélanome/imagerie diagnostique , Sensibilité et spécificité , Tumeurs cutanées/imagerie diagnostiqueRÉSUMÉ
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The majority of extracellular vesicle (EV) studies conducted to date have been performed on cell lines with little knowledge on how well these represent the characteristics of EVs in vivo. The aim of this study was to establish a method to isolate and categorize subpopulations of EVs isolated directly from tumour tissue. First we established an isolation protocol for subpopulations of EVs from metastatic melanoma tissue, which included enzymatic treatment (collagenase D and DNase). Small and large EVs were isolated with differential ultracentrifugation, and these were further separated into high and low-density (HD and LD) fractions. All EV subpopulations were then analysed in depth using electron microscopy, Bioanalyzer®, nanoparticle tracking analysis, and quantitative mass spectrometry analysis. Subpopulations of EVs with distinct size, morphology, and RNA and protein cargo could be isolated from the metastatic melanoma tissue. LD EVs showed an RNA profile with the presence of 18S and 28S ribosomal subunits. In contrast, HD EVs had RNA profiles with small or no peaks for ribosomal RNA subunits. Quantitative proteomics showed that several proteins such as flotillin-1 were enriched in both large and small LD EVs, while ADAM10 were exclusively enriched in small LD EVs. In contrast, mitofilin was enriched only in the large EVs. We conclude that enzymatic treatments improve EV isolation from dense fibrotic tissue without any apparent effect on molecular or morphological characteristics. By providing a detailed categorization of several subpopulations of EVs isolated directly from tumour tissues, we might better understand the function of EVs in tumour biology and their possible use in biomarker discovery.
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Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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Mélanome/immunologie , Mélanome/thérapie , Structures lymphoïdes tertiaires/immunologie , Antigènes CD20/métabolisme , Lymphocytes B/immunologie , Lymphocytes B/métabolisme , Antigène CD274/antagonistes et inhibiteurs , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Chimiokine CXCL13/métabolisme , Humains , Mémoire immunologique/immunologie , Mélanome/génétique , Mélanome/anatomopathologie , Métastase tumorale/génétique , Métastase tumorale/anatomopathologie , Phénotype , Pronostic , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Protéomique , RNA-Seq , Récepteurs CXCR5/métabolisme , Analyse sur cellule unique , Taux de survie , Facteur de transcription TCF-1/métabolisme , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Structures lymphoïdes tertiaires/génétique , Résultat thérapeutique , Microenvironnement tumoral/immunologieRÉSUMÉ
Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra-tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.
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Hétérogénéité génétique , Mélanome/génétique , Lumière du soleil/effets indésirables , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Épithélioma in situ/génétique , Épithélioma in situ/anatomopathologie , Maladie chronique , Études de cohortes , Variations de nombre de copies de segment d'ADN/génétique , Femelle , Séquençage nucléotidique à haut débit , Humains , Mâle , Mélanome/anatomopathologie , Adulte d'âge moyen , Mutation/génétique , Invasion tumorale , Oncogènes , Transcription génétique , Jeune adulteSujet(s)
Purpura/étiologie , Scorbut/complications , Scorbut/diagnostic , Abdomen , Acide ascorbique/usage thérapeutique , Dermoscopie , Membres , Humains , Mâle , Adulte d'âge moyen , Purpura/imagerie diagnostique , Purpura/anatomopathologie , Scorbut/traitement médicamenteux , Vitamines/usage thérapeutiqueRÉSUMÉ
PURPOSE: For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome. EXPERIMENTAL DESIGN: We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data. RESULTS: Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets. CONCLUSIONS: We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.