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Klaus J. Busam - One of the best experts on this subject based on the ideXlab platform.
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rates of erbb2 alterations across Melanoma subtypes and a complete response to trastuzumab emtansine in an erbb2 amplified acral Melanoma
Clinical Cancer Research, 2018Co-Authors: Klaus J. Busam, Lee S Gottesdiener, Shannon Oconnor, David B Solit, David M Hyman, Alexander N ShoushtariAbstract:Purpose: Patients with BRAF V600 wild-type Melanoma whose tumors progress on checkpoint inhibition currently have limited therapeutic options, and additional rational treatment targets are needed. ERBB2 alterations may be amenable to targeted inhibition, but the rate of ERBB2 alterations across Melanoma subtypes is not well described. Patients and Methods: All patients with nonuveal Melanoma (cutaneous, acral, mucosal, and unknown primary) whose tumors underwent multigene sequencing with MSK-IMPACT at Memorial Sloan Kettering Cancer Center (New York, NY) from 2014 to 2018 were reviewed for known or likely oncogenic somatic alterations in ERBB2 and the other known canonical driver genes BRAF, NRAS, KIT, NF1, GNAQ, and GNA11. Results: A patient with acral Melanoma resistant to checkpoint inhibition was found to have ERBB2 amplification and achieved a durable complete response to trastuzumab emtansine. Tumor sequencing results from 732 Melanoma cases were analyzed for ERBB2 and canonical driver gene alterations. ERBB2 amplifications were detected in acral (3%) and mucosal (3%) Melanomas. ERBB2 mutations were found in cutaneous (1%), acral (2%), and mucosal (2%) subtypes and frequently cooccurred with NF1 alterations. Among the 140 patients whose tumors lacked canonical driver alterations, ERBB2 amplifications were detected in acral (7%) and mucosal (6%) Melanomas. Conclusions: ERBB2 amplification is present in a minority of acral lentiginous and mucosal Melanomas. Activating mutations in ERBB2 were identified in nonuveal Melanoma subtypes and are frequently comutated with canonical drivers. HER2 could represent a therapeutically relevant target across Melanoma subtypes.
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somatic activation of kit in distinct subtypes of Melanoma
Journal of Clinical Oncology, 2006Co-Authors: John A Curtin, Klaus J. Busam, Daniel Pinkel, Boris C. BastianAbstract:PURPOSE: Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in Melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the Melanoma types with infrequent mutations of BRAF and NRAS. PATIENTS AND METHODS: We analyzed array comparative genomic hybridization data from 102 primary Melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to Melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed. RESULTS: Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary Melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of Melanomas on chronically sun-damaged skin, but not in any (0%) Melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. CONCLUSION: KIT is an important oncogene in Melanoma. Because the majority of the KIT mutations we found in Melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global Melanoma burden.
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Are all Melanomas the same? Spitzoid Melanoma is a distinct subtype of Melanoma.
Cancer, 2006Co-Authors: Jason A. Cohen, Klaus J. Busam, William S. Twaddell, Gustavo Palacios, Melissa Gill, Eyal Levit, Alan J. Halperin, M D O Joan Mones, David N. SilversAbstract:BACKGROUND Although the majority of Melanomas demonstrate high rates of mutations in B-RAF or N-RAS that result in constitutive activation of the mitogen-activated protein kinase-signaling pathway, emerging data suggest molecular differences among Melanoma subtypes. In this study, the authors evaluated the contribution of B-RAF and N-RAS mutations to the pathogenesis of Spitzoid Melanomas. METHODS In total, 33 Spitzoid Melanomas were analyzed for clinical and pathologic characteristics as well as for hot-spot mutations in the B-RAF and N-RAS genes. In the majority of patients (28 of 33 Melanomas), the tumors were confined to the skin with no evidence of metastasis (average follow-up, 32.5 mos). There were five metastasizing Melanomas (5 of 33 tumors) with regional or systemic spread. RESULTS Of 33 Spitzoid Melanomas, only 1 showed the V600E mutation in the B-RAF gene (1 of 33 tumors; 3%). It was noteworthy that none of the metastatic Spitzoid Melanomas (0 of 5 tumors; 0%), of which 2 resulted in fatal outcomes, demonstrated mutations in B-RAF or N-RAS. CONCLUSIONS In contrast to the majority of cutaneous Melanomas, activating hot-spot mutations in B-RAF or N-RAS were not involved in the pathogenesis of Spitzoid Melanoma. These data suggested that Spitzoid Melanoma is a distinct form of Melanoma with unknown genes and/or signaling pathways involved in its development. Cancer 2006. © 2006 American Cancer Society.
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distinct sets of genetic alterations in Melanoma
The New England Journal of Medicine, 2005Co-Authors: John A Curtin, Jane Fridlyand, Heinz Kutzner, Evabettina Brocker, Philip E Leboit, Klaus J. Busam, Toshiro Kageshita, Setsuya Aiba, Hetal Patel, Daniel PinkelAbstract:Background Exposure to ultraviolet light is a major causative factor in Melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of Melanoma with different susceptibility to ultraviolet light. Methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 Melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 Melanomas from skin with chronic sun-induced damage and 40 Melanomas from skin without such damage; 36 Melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal Melanomas. Results We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of Melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of...
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Distinct Sets of Genetic Alterations in Melanoma
New England Journal of Medicine, 2005Co-Authors: John A Curtin, Hetal N. Patel, Jane Fridlyand, Kwang-hyun Cho, Heinz Kutzner, Evabettina Brocker, Klaus J. Busam, Toshiro Kageshita, Setsuya Aiba, Philip E LeboitAbstract:BACKGROUND: Exposure to ultraviolet light is a major causative factor in Melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of Melanoma with different susceptibility to ultraviolet light. METHODS: We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 Melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 Melanomas from skin with chronic sun-induced damage and 40 Melanomas from skin without such damage; 36 Melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal Melanomas. RESULTS: We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of Melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, Melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral Melanoma could be distinguished from mucosal Melanoma with 89 percent accuracy. Eighty-one percent of Melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of Melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway. CONCLUSIONS: The genetic alterations identified in Melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of Melanoma and implicate CDK4 and CCND1 as independent oncogenes in Melanomas without mutations in BRAF or N-RAS.
Harald Kittler - One of the best experts on this subject based on the ideXlab platform.
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dermatoscopy of neoplastic skin lesions recent advances updates and revisions
Current Treatment Options in Oncology, 2018Co-Authors: Philipp Weber, Christoph Sinz, Philipp Tschandl, Harald KittlerAbstract:Dermatoscopy is still an active field of research. Dermatoscopic criteria for neoplastic skin lesions are constantly revised, added, or reinterpreted. The chaos and clues algorithm, which provides a reasonable diagnostic accuracy for malignant pigmented lesion while being considerably easy to learn and apply, is a good start for beginners. Chaos (asymmetry of structure or color) is a useful concept that can be found in almost all algorithms, including algorithms for acral Melanomas or nail matrix Melanomas. Sometimes chaos goes under different names like, for example, asymmetry, irregular blotch, bizarre pattern, or atypical network. Like every other dermatoscopic clue, chaos is not 100% specific or sensitive for malignancy. A small but considerable number of nodular Melanoma lack chaos. Chaos, however, is usually present in acral Melanomas even if the classic Melanoma clue for acral Melanomas, the parallel ridge pattern, is missing. Nail matrix Melanomas are also typified by chaotic arrangement of longitudinal pigmented lines of the nail plate. Chaos alone is usually not sufficient to diagnose pigmented malignant neoplasms. Important other clues are the Hutchinson sign or the micro-Hutchinson sign for nail matrix Melanomas, angulated lines and prominent skin markings for in situ Melanomas and gray circles for facial in situ Melanomas. Flat facial lesions in particular may be difficult to diagnose. A new algorithm suggests, instead of focusing on clues to Melanoma, to look for features of solar lentigo first and if they are absent to consider Melanoma in situ. Dermatoscopy also improves the diagnosis of non-pigmented neoplasms and helps to distinguish different subtypes of basal cell carcinoma and poorly and well differentiated types of squamous cell carcinoma. Finally, dermatoscopic images can be used to train automated diagnostic systems that are able diagnose pigmented lesions without the need of human experts. Although prospective trials are currently sparse, it can be expected that approved automated diagnostic systems will soon be available to support human experts in the diagnosis of cutaneous neoplasms.
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Seven Non-Melanoma Features to Rule Out Facial Melanoma.
Acta Dermato-venereologica, 2017Co-Authors: Philipp Tschandl, Harald Kittler, Elvira Moscarella, Aimilios Lallas, Vincenzo De Giorgi, Alessio Gambardella, Amélie Boespflug, Teresa Deinlein, Josep Malvehy, Susana PuigAbstract:: Facial Melanoma is difficult to diagnose and dermatoscopic features are often subtle. Dermatoscopic non-Melanoma patterns may have a comparable diagnostic value. In this pilot study, facial lesions were collected retrospectively, resulting in a case set of 339 Melanomas and 308 non-Melanomas. Lesions were evaluated for the prevalence (> 50% of lesional surface) of 7 dermatoscopic non-Melanoma features: scales, white follicles, erythema/reticular vessels, reticular and/or curved lines/fingerprints, structureless brown colour, sharp demarcation, and classic criteria of seborrhoeic keratosis. Melanomas had a lower number of non-Melanoma patterns (p
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Melanomas vs nevi in high risk patients under long term monitoring with digital dermatoscopy do Melanomas and nevi already differ at baseline
Journal of The European Academy of Dermatology and Venereology, 2017Co-Authors: Philipp Tschandl, Harald Kittler, L Hofmann, Christine Fink, Holger A HaenssleAbstract:Background What lesions to select for a most efficient dermatoscopic monitoring of patients with multiple nevi remains an unresolved issue. Objective To compare the grade of atypia of Melanomas and nevi of the same patient at baseline. Methods Prospective observational study using 236 dermatoscopic baseline images (59 quartets from 59 patients, each including one Melanoma detected during follow-up and three nevi). Dermatologists (n = 26) were asked to assess the ‘grade of dermatoscopic atypia’ on a numerical scale and to identify the Melanomas. Results On average, each dermatologist identified 24 of 59 Melanomas (40%, range: 11–37). The number of correct picks was greater for dermatologists with moderate (mean: 28) or high (mean: 28) experience compared to beginners (mean 17; P < 0.001). In three of the 59 sets, none of the 26 dermatologists identified the Melanoma. The mean grade of dermatoscopic atypia was 2.5 for nevi (95% CI: 2.4–2.6) and 3.0 for Melanomas (95% CI: 2.9–3.1, P < 0.001). Limitations Rating dermatologists were informed that each quartet of images included one Melanoma creating substantial deviation from a real-life situation. Conclusion A significant proportion of Melanomas detected during follow-up cannot be differentiated from nevi at baseline. This necessitates the additional inclusion of less atypical lesions for monitoring.
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long term evaluation of the efficacy of digital dermatoscopy monitoring at a tertiary referral center
Journal Der Deutschen Dermatologischen Gesellschaft, 2017Co-Authors: Christoph Rinner, Christoph Sinz, Philipp Tschandl, Harald KittlerAbstract:SummaryBackground and objectives We examined the value of monitoring patients with multiple nevi using sequential digital dermatoscopy imaging at a tertiary referral center. Patients and methods This is a retrospective cohort study including 2,824 patients and 23,241 monitored lesions. We calculated trends in key parameters such as the number of Melanomas and nevi monitored and excised. Results During follow-up, we excised 1,266 lesions in 709 patients, including 146 (11.5 %) Melanomas. The percentage of in situ Melanomas detected at follow-up was significantly higher than at baseline (46.6 % versus 23.4 %, p ≤ 0.001). The risk of detecting a Melanoma during follow-up was higher for patients with a Melanoma at baseline, compared to those without (relative risk: 3.59, 95 % CI: 2.15 to 6.00). The number of documented lesions showed a positive correlation with the benign/malignant ratio, and excisions at baseline decreased significantly over the course of the study period. Conclusion Digital dermatoscopy monitoring improves the detection of thin Melanomas in patients with multiple nevi. Patients with a Melanoma at baseline are at an increased risk of developing a Melanoma during follow-up and should therefore be a target group for sequential dermatoscopy imaging.
Meenhard Herlyn - One of the best experts on this subject based on the ideXlab platform.
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Melanoma
Nature Reviews Disease Primers, 2015Co-Authors: Dirk Schadendorf, Meenhard Herlyn, Claus Garbe, David E. Fisher, Jeffrey E. Gershenwald, Jean-jacques Grob, Allan Halpern, Michael A. Marchetti, Grant Mcarthur, Antoni RibasAbstract:Melanoma is one of the most common cancers in the West, and the research arena is bustling; advances in immunotherapy and genomics are reflected in the increasing survival of patients. This Primer summarizes these developments and discusses the challenges ahead. Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for Melanoma. The prognosis of patients with malignant (advanced-stage) Melanoma differs widely between countries, but public campaigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with Melanoma. For example, families with Melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic Melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous Melanomas, whereas KIT mutations are predominantly observed in mucosal and acral Melanomas. GNAQ and GNA11 mutations prevail in uveal Melanomas. Additionally, the PI3K–AKT–PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by Melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for example, nivolumab and pembrolizumab). Alongside other new drugs — namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) — these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of Melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: http://go.nature.com/vX2N9s
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a tumorigenic subpopulation with stem cell properties in Melanomas
Cancer Research, 2005Co-Authors: Dong Fang, David E. Elder, Thiennga K Nguyen, Kim Leishear, Rena Finko, Angela N Kulp, Susan Hotz, Patricia Van Belle, Xiaowei Xu, Meenhard HerlynAbstract:Recent studies suggest that cancer can arise from a cancer stem cell (CSC), a tumor-initiating cell that has properties similar to those of stem cells. CSCs have been identified in several malignancies, including those of blood, brain, and breast. Here, we test whether stem cell–like populations exist in human Melanomas. In ∼20% of the metastatic Melanomas cultured in growth medium suitable for human embryonic stem cells, we found a subpopulation of cells propagating as nonadherent spheres, whereas in standard medium, adherent monolayer cultures were established. Individual cells from Melanoma spheres (Melanoma spheroid cells) could differentiate under appropriate conditions into multiple cell lineages, such as melanocytic, adipocytic, osteocytic, and chondrocytic lineages, which recapitulates the plasticity of neural crest stem cells. Multipotent Melanoma spheroid cells persisted after serial cloning in vitro and transplantation in vivo , indicating their ability to self-renew. Furthermore, they were more tumorigenic than adherent cells when grafted to mice. We identified similar multipotent spheroid cells in Melanoma cell lines and found that the stem cell population was enriched in a CD20 + fraction of Melanoma cells. Based on these findings, we propose that Melanomas can contain a subpopulation of stem cells that contribute to heterogeneity and tumorigenesis. Targeting this population may lead to effective treatments for Melanomas.
David Polsky - One of the best experts on this subject based on the ideXlab platform.
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de novo vs nevus associated Melanomas differences in associations with prognostic indicators and survival
Journal of the National Cancer Institute, 2016Co-Authors: Rachel M Cymerman, Yongzhao Shao, Kun Wang, Yilong Zhang, Era Caterina Murzaku, Lauren A Penn, Iman Osman, David PolskyAbstract:Background: Although 20% to 30% of Melanomas are histopathologically ‘nevus associated,’ the majority of Melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of Melanoma differed in their associations with clinical and histopathologic features and patient survival. Methods: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated Melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two-sided. Results: In NYU1, de novo Melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P Conclusions: These data suggest that de novo Melanomas are more aggressive than nevus-associated Melanomas. This classification scheme may also provide a useful framework for investigations into sex differences in Melanoma outcomes.
Philip E Leboit - One of the best experts on this subject based on the ideXlab platform.
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Melanoma on Palms, Soles and Subungual Melanoma Acral Melanoma
Histological Diagnosis of Nevi and Melanoma, 2020Co-Authors: Guido Massi, Philip E LeboitAbstract:Melanomas on acral skin seem to be of two types. Those on the sun damaged dorsal surfaces of the hands (and to a lesser extent, the feet) include a number of conventional Melanomas. A more specific type is composed of Melanomas on the volar surfaces of the acra, by which we mean the hairless areas of the hands and feet (mostly the palms and soles) and nail beds. In the majority of cases, these Melanomas have a distinct lentiginous pattern of growth reminiscent of the lentigo maligna pattern of Melanoma and of those of mucous membranes. This type of Melanoma must be distinguished from melanocytic nevi found on the same sites. Melanomas of the hands and feet, and of nail beds have different epidemiology and genetic features than conventional Melanoma. Because of special considerations, we describe Melanoma on the nail apparatus separately.
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Spitz Melanoma is a distinct subset of spitzoid Melanoma.
Modern Pathology, 2020Co-Authors: Shyam S. Raghavan, Philip E Leboit, Sandra Peternel, Thaddeus W. Mully, Jeffrey P. North, Laura B. Pincus, Timothy H. Mccalmont, Boris C. BastianAbstract:Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid Melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz Melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of “spitzoid Melanomas” defined solely by their histopathologic features belong to the category of Spitz Melanoma or to other Melanoma subtypes. We assembled a cohort of 25 spitzoid Melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz Melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz Melanoma and spitzoid Melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid Melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in Melanomas of the WHO low-CSD category, were entirely absent. While the “spitzoid Melanomas” comprising our cohort were enriched for bona fide Spitz Melanomas, the majority of Melanomas fell outside of the genetically defined category of Spitz Melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.
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Melanoma with Spindle Cell
Histological Diagnosis of Nevi and Melanoma, 2013Co-Authors: Guido Massi, Philip E LeboitAbstract:The spindle cell Melanoma is not really a type of Melanoma. Fusiform melanocytes with elongated nuclei can be seen in all of the forms of invasive Melanoma. The spindle cells usually lie in compact fascicles but can be seen between thickened collagen bundles (desmoplastic Melanoma, see Chap. 36) or form individual fascicles, simulating a neural neoplasm. Perineural invasion is a fi nding that occurs much more frequently in Melanomas with spindled cells. Melanomas in which spindle cells predominate have been termed “pseudosarcomatous.” Indeed, early twentieth-century pathologists discriminated between “melanocarcinoma” and “melanosarcoma.”
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distinct sets of genetic alterations in Melanoma
The New England Journal of Medicine, 2005Co-Authors: John A Curtin, Jane Fridlyand, Heinz Kutzner, Evabettina Brocker, Philip E Leboit, Klaus J. Busam, Toshiro Kageshita, Setsuya Aiba, Hetal Patel, Daniel PinkelAbstract:Background Exposure to ultraviolet light is a major causative factor in Melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of Melanoma with different susceptibility to ultraviolet light. Methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 Melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 Melanomas from skin with chronic sun-induced damage and 40 Melanomas from skin without such damage; 36 Melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal Melanomas. Results We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of Melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of...
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Distinct Sets of Genetic Alterations in Melanoma
New England Journal of Medicine, 2005Co-Authors: John A Curtin, Hetal N. Patel, Jane Fridlyand, Kwang-hyun Cho, Heinz Kutzner, Evabettina Brocker, Klaus J. Busam, Toshiro Kageshita, Setsuya Aiba, Philip E LeboitAbstract:BACKGROUND: Exposure to ultraviolet light is a major causative factor in Melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of Melanoma with different susceptibility to ultraviolet light. METHODS: We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 Melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 Melanomas from skin with chronic sun-induced damage and 40 Melanomas from skin without such damage; 36 Melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal Melanomas. RESULTS: We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of Melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, Melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral Melanoma could be distinguished from mucosal Melanoma with 89 percent accuracy. Eighty-one percent of Melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of Melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway. CONCLUSIONS: The genetic alterations identified in Melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of Melanoma and implicate CDK4 and CCND1 as independent oncogenes in Melanomas without mutations in BRAF or N-RAS.
