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Melanoma: HELP
Articles by Dr. Richard Scolyer
Based on 271 articles published since 2008

Between 2008 and 2019, R. Scolyer wrote the following 271 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11
1 Guideline Data set for pathology reporting of cutaneous invasive melanoma: recommendations from the international collaboration on cancer reporting (ICCR). 2013

Scolyer, Richard A / Judge, Meagan J / Evans, Alan / Frishberg, David P / Prieto, Victor G / Thompson, John F / Trotter, Martin J / Walsh, Maureen Y / Walsh, Noreen M G / Ellis, David W / Anonymous3190770. ·*Melanoma Institute Australia Disciplines of †Pathology **Surgery, Sydney Medical School, The University of Sydney Departments of ‡Tissue Pathology and Diagnostic Oncology ††Melanoma and Surgical Oncology, Royal Prince Alfred Hospital §Royal College of Pathologists of Australasia, Sydney, NSW ¶¶Royal Adelaide Hospital and Flinders University, Adelaide, SA, Australia ∥Department of Pathology, Ninewells Hospital and Medical School, Dundee, Scotland ¶Cedars-Sinai Medical Center, Los Angeles, CA #Departments of Pathology and Dermatology, University of Texas-MD Anderson Cancer Center, Houston, TX ‡‡Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB ∥∥Department of Pathology, Capital District Health Authority and Dalhousie University, Halifax, NS, Canada §§Royal Victoria Hospital, Belfast, UK. ·Am J Surg Pathol · Pubmed #24061524.

ABSTRACT: An accurate and complete pathology report is critical for the optimal management of cutaneous melanoma patients. Protocols for the pathologic reporting of melanoma have been independently developed by the Royal College of Pathologists of Australasia (RCPA), Royal College of Pathologists (United Kingdom) (RCPath), and College of American Pathologists (CAP). In this study, data sets, checklists, and structured reporting protocols for pathologic examination and reporting of cutaneous melanoma were analyzed by an international panel of melanoma pathologists and clinicians with the aim of developing a common, internationally agreed upon, evidence-based data set. The International Collaboration on Cancer Reporting cutaneous melanoma expert review panel analyzed the existing RCPA, RCPath, and CAP data sets to develop a protocol containing "required" (mandatory/core) and "recommended" (nonmandatory/noncore) elements. Required elements were defined as those that had agreed evidentiary support at National Health and Medical Research Council level III-2 level of evidence or above and that were unanimously agreed upon by the review panel to be essential for the clinical management, staging, or assessment of the prognosis of melanoma or fundamental for pathologic diagnosis. Recommended elements were those considered to be clinically important and recommended for good practice but with lesser degrees of supportive evidence. Sixteen core/required data elements for cutaneous melanoma pathology reports were defined (with an additional 4 core/required elements for specimens received with lymph nodes). Eighteen additional data elements with a lesser level of evidentiary support were included in the recommended data set. Consensus response values (permitted responses) were formulated for each data item. Development and agreement of this evidence-based protocol at an international level was accomplished in a timely and efficient manner, and the processes described herein may facilitate the development of protocols for other tumor types. Widespread utilization of an internationally agreed upon, structured pathology data set for melanoma will lead not only to improved patient management but is a prerequisite for research and for international benchmarking in health care.

2 Guideline EANM-EORTC general recommendations for sentinel node diagnostics in melanoma. 2009

Chakera, Annette H / Hesse, Birger / Burak, Zeynep / Ballinger, James R / Britten, Allan / Caracò, Corrado / Cochran, Alistair J / Cook, Martin G / Drzewiecki, Krzysztof T / Essner, Richard / Even-Sapir, Einat / Eggermont, Alexander M M / Stopar, Tanja Gmeiner / Ingvar, Christian / Mihm, Martin C / McCarthy, Stanley W / Mozzillo, Nicola / Nieweg, Omgo E / Scolyer, Richard A / Starz, Hans / Thompson, John F / Trifirò, Giuseppe / Viale, Giuseppe / Vidal-Sicart, Sergi / Uren, Roger / Waddington, Wendy / Chiti, Arturo / Spatz, Alain / Testori, Alessandro / Anonymous1200637. ·Department of Plastic Surgery and Burns Unit, Rigshospitalet, Copenhagen, Denmark. annette.hougaard.chakera@live.dk ·Eur J Nucl Med Mol Imaging · Pubmed #19714329.

ABSTRACT: The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to "general consensus" and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.

3 Editorial Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond. 2018

Gershenwald, Jeffrey E / Scolyer, Richard A. ·Departments of Surgical Oncology and Cancer Biology, Unit 1484, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jgershen@mdanderson.org. · Melanoma and Skin Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jgershen@mdanderson.org. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. ·Ann Surg Oncol · Pubmed #29850954.

ABSTRACT: -- No abstract --

4 Editorial Advances in melanoma: revolutionary progress delivering improved patient management and outcomes. 2016

Scolyer, Richard A / Vilain, Ricardo E / Mihm, Martin C. ·Melanoma Institute Australia, North Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address: richard.scolyer@sswahs.nsw.gov.au. · School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, Australia; Hunter Cancer Research Alliance (HCRA), Calvary Mater Newcastle, Waratah, Australia; Division of Anatomical Pathology, Pathology North (Hunter), New Lambton Heights, NSW, Australia. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. ·Pathology · Pubmed #27020382.

ABSTRACT: -- No abstract --

5 Editorial Multiple primary cutaneous melanomas: recent studies highlight features associated with more indolent behaviour. 2013

Murali, Rajmohan / Scolyer, Richard A / Armstrong, Bruce K. · ·Pathology · Pubmed #23255028.

ABSTRACT: -- No abstract --

6 Editorial Can we better identify thin cutaneous melanomas that are likely to metastasize and cause death? 2012

Murali, Rajmohan / Scolyer, Richard A / Thompson, John F. · ·Ann Surg Oncol · Pubmed #22777079.

ABSTRACT: -- No abstract --

7 Editorial Surgical strategies and histopathologic issues in the management of lentigo maligna. 2009

Stretch, Jonathan R / Scolyer, Richard A. · ·Ann Surg Oncol · Pubmed #19322612.

ABSTRACT: -- No abstract --

8 Review Impact of genomics on the surgical management of melanoma. 2018

Ferguson, P M / Long, G V / Scolyer, R A / Thompson, J F. ·Melanoma Institute Australia, Sydney, New South Wales, Australia. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. · Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. ·Br J Surg · Pubmed #29341162.

ABSTRACT: BACKGROUND: Although surgery for early-stage melanoma offers the best chance of cure, recent advances in molecular medicine have revolutionized the management of late-stage melanoma, leading to significant improvements in clinical outcomes. Research into the genomic drivers of disease and cancer immunology has not only ushered in a new era of targeted and immune-based therapies for patients with metastatic melanoma, but has also provided new tools for monitoring disease recurrence and selecting therapeutic strategies. These advances present new opportunities and challenges to the surgeon treating patients with melanoma. METHODS: The literature was reviewed to evaluate diagnostic and therapeutic advances in the management of cutaneous melanoma, and to highlight the impact of these advances on surgical decision-making. RESULTS: Genomic testing is not required in the surgical management of primary melanoma, although it can provide useful information in some situations. Circulating nucleic acids from melanoma cells can be detected in peripheral blood to predict disease recurrence before it manifests clinically, but validation is required before routine clinical application. BRAF mutation testing is the standard of care for all patients with advanced disease to guide therapy, including the planning of surgery in adjuvant and neoadjuvant settings. CONCLUSION: Surgery remains central for managing primary melanoma, and is an important element of integrated multidisciplinary care in advanced disease, particularly for patients with resectable metastases. The field will undergo further change as clinical trials address the relationships between surgery, radiotherapy and systemic therapy for patients with high-risk, early-stage and advanced melanoma.

9 Review Trajectories of premalignancy during the journey from melanocyte to melanoma. 2018

Colebatch, Andrew J / Scolyer, Richard A. ·Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Australia; Melanoma Institute of Australia, The University of Sydney, North Sydney, Australia; Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. ·Pathology · Pubmed #29132722.

ABSTRACT: A stepwise progression from melanocytic precursors to cutaneous melanoma is a well-established model, based on decades of careful observation and morphological analysis. The steps identified are benign melanocytic naevus, dysplastic naevus, 'radial growth phase' melanoma (including melanoma in situ) and 'vertical growth phase' melanoma (also termed tumourigenic melanoma). Recent genomic data have refined the understanding of the steps of melanoma development and their relationship to one another. These data support the existence of dysplastic naevi as distinct lesions; suggest the importance of clonal dynamics in the precursor steps of melanoma; and confirm the carcinogenic role of ultraviolet radiation throughout early melanoma development and progression. In this review, the steps of melanoma development and progression are summarised and discussed in the context of recent genomic studies. This new understanding of melanoma pathogenesis that has been facilitated through careful correlation of morphological and molecular features will allow the identification and development of robust biomarkers to assist in more accurate diagnosis and prognostication of melanocytic tumours.

10 Review Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next? 2016

Welsh, Sarah J / Rizos, Helen / Scolyer, Richard A / Long, Georgina V. ·Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, 2 Technology Place, Sydney, NSW 2109, Australia; Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia. · Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia. · Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: georgina.long@melanoma.org.au. ·Eur J Cancer · Pubmed #27232329.

ABSTRACT: Treatment of BRAF-mutant metastatic melanoma with mitogen-activated protein kinase (MAPK) pathway targeted therapies (BRAF/MEK inhibitors) and immune checkpoint inhibitors has revolutionised management and improved outcomes for patients with advanced stage disease. However, acquired resistance to MAPK inhibitor therapy develops in the majority of patients at approximately 12 months and multiple mechanisms lead to resistance. Understanding the mechanisms of resistance is therefore critical for the development of more effective therapeutic strategies in BRAF-mutant melanoma. Recently, several distinct mechanisms of resistance to BRAF-inhibition have been proposed based on data obtained in experimental melanoma cell models and small series of human tumour samples. These include reactivation of the MAPK pathway resulting in continued extracellular signal-regulated kinase activation and activation of parallel signalling pathways including the PI3K-mTOR (phosphoinositide 3-kinase-mammalian target of rapamycin) pathway. Alterations in how the cells of the immune system respond to melanoma cells treated with targeted therapy may also influence response and progression. In this review, we discuss these mechanisms and identify potential therapeutic strategies to overcome resistance which, in turn, will lead to improved outcomes for patients with metastatic melanoma.

11 Review Critical Assessment of Clinical Prognostic Tools in Melanoma. 2016

Mahar, Alyson L / Compton, Carolyn / Halabi, Susan / Hess, Kenneth R / Gershenwald, Jeffrey E / Scolyer, Richard A / Groome, Patti A. ·Division of Cancer Care and Epidemiology, Cancer Research Institute, Queen's University, Kingston, ON, Canada. · Arizona State University, Phoenix, AZ, USA. · School of Medicine, Mayo Clinic, Rochester, MN, USA. · Department of Biostatistics and Bioinformatics, Alliance Statistics and Data Center, Duke University, Durham, NC, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Melanoma Institute Australia, Sydney, NSW, Australia. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Division of Cancer Care and Epidemiology, Cancer Research Institute, Queen's University, Kingston, ON, Canada. groomep@queensu.ca. ·Ann Surg Oncol · Pubmed #27052645.

ABSTRACT: The 7th edition American Joint Committee on Cancer (AJCC) melanoma staging system classifies patients according to prognosis. Significant within-stage heterogeneity remains and the inclusion of additional clinicopathologic and other host- and tumor-based prognostic factors have been proposed. Clinical prognostic tools have been developed for use in clinical practice to refine survival estimates. Little is known about the comparative features of tools in melanoma. We performed a systematic search of the scientific published literature for clinical prognostic tools in melanoma and web-based resources. A priori criteria were used to evaluate their quality and clinical relevance, and included intended clinical use, model development approaches, validation strategies, and performance metrics. We identified 17 clinical prognostic tools for primary cutaneous melanoma. Patients with stages I-III and T1 or thin melanoma were the most frequently considered populations. Seventy-five percent of tools were developed using data collected from patients diagnosed in 2006 or earlier, and the well-established factors of tumor thickness, ulceration, and age were included in 70 % of tools. Internal validity using cross-validation or bootstrapping techniques was performed for two tools only. Fewer than half were evaluated for external validity; however, when done, the appropriate statistical methodology was applied and results indicated good generalizability. Several clinical prognostic tools have the potential to refine survival estimates for individual melanoma patients; however, there is a great opportunity to improve these tools and to foster the development of new, validated tools by the inclusion of contemporary clinicopathological covariates and by using improved statistical and methodological approaches.

12 Review Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists. 2016

Kakavand, Hojabr / Wilmott, James S / Long, Georgina V / Scolyer, Richard A. ·Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia. · Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Electronic address: richard.scolyer@sswahs.nsw.gov.au. ·Pathology · Pubmed #27020392.

ABSTRACT: The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the exciting prospect of combining them to further improve survival rates and this is currently being investigated in clinical trials. Ultimately it may be the responsibility of the pathologist to identify which therapy or combination of therapies is most likely to benefit individual patients.

13 Review Identification, Review, and Systematic Cross-Validation of microRNA Prognostic Signatures in Metastatic Melanoma. 2016

Jayawardana, Kaushala / Schramm, Sarah-Jane / Tembe, Varsha / Mueller, Samuel / Thompson, John F / Scolyer, Richard A / Mann, Graham J / Yang, Jean. ·School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia. · The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. Electronic address: sarah-jane.schramm@sydney.edu.au. · The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Melanoma Institute Australia, Sydney, NSW, Australia; Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Melanoma Institute Australia, Sydney, NSW, Australia; Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. ·J Invest Dermatol · Pubmed #26763444.

ABSTRACT: In metastatic melanoma, it is vital to identify and validate biomarkers of prognosis. Previous studies have systematically evaluated protein biomarkers or mRNA-based expression signatures. No such analyses have been applied to microRNA (miRNA)-based prognostic signatures. As a first step, we identified two prognostic miRNA signatures from publicly available data sets (Gene Expression Omnibus/The Cancer Genome Atlas) of global miRNA expression profiling information. A 12-miRNA signature predicted longer survival after surgery for resection of American Joint Committee on Cancer stage III disease (>4 years, no sign of relapse) and outperformed American Joint Committee on Cancer standard-of-care prognostic markers in leave-one-out cross-validation analysis (error rates 34% and 38%, respectively). A similar 15-miRNA biomarker derived from The Cancer Genome Atlas miRNA-seq data performed slightly worse (39%) than these current biomarkers. Both signatures were then assessed for replication in two independent data sets and subjected to systematic cross-validation together with the three other miRNA-based prognostic signatures proposed in the literature to date. Five miRNAs (miR-142-5p, miR-150-5p, miR-342-3p, miR-155-5p, and miR-146b-5p) were reproducibly associated with patient outcome and have the greatest potential for application in the clinic. Our extensive validation approach highlighted among multiple independent cohorts the translational potential and limitations of miRNA signatures, and pointed to future directions in the analysis of this emerging class of markers.

14 Review Atypical Spitzoid neoplasms: a review of potential markers of biological behavior including sentinel node biopsy. 2014

McCormack, Christopher J / Conyers, Rachel K / Scolyer, Richard A / Kirkwood, John / Speakman, David / Wong, Nick / Kelly, John W / Henderson, Michael A. ·aPeter Macallum Cancer Institute, East Melbourne bVictorian Melanoma Service, Alfred Hospital, Prahran cDepartment of Paediatrics, Murdoch Children's Research Institute, Royal Children's Hospital, The University of Melbourne, Parkville dThe Royal Children's Hospital, Flemington Road, Parkville, Victoria eMelanoma Institute Australia , Royal Prince Alfred Hospital, The University of Sydney, Sydney, New South Wales, Australia fDepartment of Medicine, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. ·Melanoma Res · Pubmed #24892957.

ABSTRACT: Atypical cutaneous melanocytic lesions, including those with Spitzoid features, can be difficult to categorize as benign or malignant. This can lead to suboptimal management, with potential adverse patient outcomes. Recent studies have enhanced knowledge of the molecular and genetic biology of these lesions and, combined with clinicopathological findings, is further defining their biological spectrum, classification, and behavior. Sentinel node biopsy provides important prognostic information in patients with cutaneous melanoma, but its role in the management of melanocytic lesions of uncertain malignant potential (MELTUMP) is controversial. This paper examines the role of molecular testing and sentinel node biopsy in MELTUMPs, particularly atypical Spitzoid tumors.

15 Review Genetic alterations and personalized medicine in melanoma: progress and future prospects. 2014

Griewank, Klaus G / Scolyer, Richard A / Thompson, John F / Flaherty, Keith T / Schadendorf, Dirk / Murali, Rajmohan. ·Affiliations of authors: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany (KGG, DS) · Royal Prince Alfred Hospital, Camperdown, NSW, Australia (RAS) · University of Sydney, Camperdown, NSW, Australia (RAS, JFT) · Melanoma Institute Australia, North Sydney, NSW, Australia (RAS, JFT) · Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, MA (KTF) · Department of Pathology, and Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (RM). ·J Natl Cancer Inst · Pubmed #24511108.

ABSTRACT: High-throughput sequencing technologies are providing new insights into the genetic alterations involved in melanomagenesis. It appears likely that most genetic events important in the pathogenesis of melanoma will be discovered over the next few years. Genetic analysis is also increasingly being used to direct patient care. In parallel with the discovery of new genes and the elucidation of molecular pathways important in the development of melanoma, therapies targeting these pathways are becoming available. In other words, the age of personalized medicine has arrived, characterized by molecular profiling of melanoma to identify the relevant genetic alterations and the abnormal signaling mechanisms involved, followed by selection of optimal, individualized therapies. In this review, we summarize the key genetic alterations in melanoma and the development of targeted agents against melanomas bearing specific mutations. These developments in melanoma serve as a model for the implementation of personalized medicine for patients with all cancers.

16 Review Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. 2014

Schatton, Tobias / Scolyer, Richard A / Thompson, John F / Mihm, Martin C. ·Department of Dermatology, Brigham and Women's Hospital and Transplantation Research Center, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. ·Methods Mol Biol · Pubmed #24258985.

ABSTRACT: The role of the tumor-infiltrating lymphocyte (TIL) and its relationship to prognosis has been most extensively studied in malignant melanoma. The purpose of this chapter is to discuss in depth the immunobiology and molecular aspects of lymphocyte function in general and particularly TIL function in the context of antimelanoma immunity. Emphasis is placed upon the role of these inflammatory mediators in the enhancement and impairment of progression of this often fatal human cancer. In addition, the analysis of TILs in melanoma and their direct relationship to prognosis as well as their effect on the positivity of the sentinel lymph node will be discussed. Furthermore, details of lymph node responses to metastatic melanomas and their prognostic significance will be clarified. Finally, the importance of TILs for the evaluation of therapeutic response and how TIL immunobiology could critically inform the design of novel melanoma immunotherapeutic protocols will be elucidated.

17 Review Radiotherapy for lentigo maligna: a literature review and recommendations for treatment. 2014

Fogarty, G B / Hong, A / Scolyer, R A / Lin, E / Haydu, L / Guitera, P / Thompson, J. ·Melanoma Institute Australia, Poche Centre, 40 Rocklands Road, North Sydney, NSW, 2060, Australia; Genesis Cancer Care, Mater Sydney Radiation Oncology Centre, Mater Hospital, 25 Rocklands Road, North Sydney, NSW, 2060, Australia. ·Br J Dermatol · Pubmed #24032599.

ABSTRACT: Lentigo maligna (LM) incidence is increasing. LM frequently involves the face near critical anatomical structures and as a consequence clinical management is challenging. Nonsurgical therapies, including radiotherapy (RT), are increasingly used. Evidenced-based treatment guidelines are lacking. We conducted a review of previously published data analysing RT treatment of LM. A search of PubMed, Embase and Medline databases to June 2012 identified nine clinical studies that examined the use of RT for LM treatment in at least five patients. Nine studies described 537 patients with LM treated with definitive primary RT, between 1941 and 2009, with a median reported follow-up time of 3 years. Eight articles could be reviewed for oncological outcome data. There were 18 recurrences documented in a total of 349 assessable patients (5%). Salvage was successful in the majority of recurrent LM cases by using further RT, surgery or other therapies. Progression to LM melanoma (LMM) occurred in five patients (five out of 349, 1.4%) who all had poor outcomes. There were five marginal recurrences documented out of 123 assessable patients (4%). There were eight in-field recurrences documented with either LM (five) or LMM (three) out of 171 assessable patients (5%). A series of recommendations were then developed for RT parameters for treatment of LM. These parameters include treatment volume, dose, dose per fraction and outcome measures. These may be of use in prospective data collection.

18 Review Lymphatic biomarkers in primary melanomas as predictors of regional lymph node metastasis and patient outcomes. 2013

Pasquali, Sandro / van der Ploeg, Augustinus P T / Mocellin, Simone / Stretch, Jonathan R / Thompson, John F / Scolyer, Richard A. ·Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. sandro.pasquali@unipd.it ·Pigment Cell Melanoma Res · Pubmed #23298266.

ABSTRACT: Recently developed lymphatic-specific immunohistochemical markers can now be utilized to assess intratumoral and/or peritumoral lymphatic vessel density (LVD), to detect lymphatic vessel invasion (LVI) by melanoma cells and to identify lymphatic marker expression in melanoma cells themselves. We systematically reviewed the available evidence for the expression of lymphatic markers as predictors of regional node metastasis and survival in melanoma patients. The currently available evidence suggests that LVD (particularly in a peritumoral location) and LVI are predictors of sentinel node metastasis and poorer survival. Nevertheless, adherence to international guidelines in the conduct and reporting of the studies was generally poor, with wide methodologic variations and heterogeneous findings. Larger, carefully conducted and well-reported studies that confirm these preliminary findings are required before it would be appropriate to recommend the routine application of costly and time-consuming immunohistochemistry for lymphatic markers in the routine clinical assessment of primary cutaneous melanomas.

19 Review Tumours associated with BAP1 mutations. 2013

Murali, Rajmohan / Wiesner, Thomas / Scolyer, Richard A. ·Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. MuraliR@mskcc.org ·Pathology · Pubmed #23277170.

ABSTRACT: BAP1 (BRCA1-Associated Protein 1) was initially identified as a protein that binds to BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway. Germline mutations of BAP1 confer increased susceptibility for the development of several tumours, including uveal melanoma, epithelioid atypical Spitz tumours, cutaneous melanoma, and mesothelioma. However, the complete tumour spectrum associated with germline BAP1 mutations is not yet known. Somatic BAP1 mutations are seen in cutaneous melanocytic tumours (epithelioid atypical Spitz tumours and melanoma), uveal melanoma, mesothelioma, clear cell renal cell carcinoma, and other tumours. Here, we review the current state of knowledge about the functional roles of BAP1, and summarise data on tumours associated with BAP1 mutations. Awareness of these tumours will help pathologists and clinicians to identify patients with a high likelihood of harbouring germline or somatic BAP1 mutations. We recommend that pathologists consider testing for BAP1 mutations in epithelioid atypical Spitz tumours and uveal melanomas, or when other BAP1-associated tumours occur in individual patients. Tumour tissues may be screened for BAP1 mutations/loss/inactivation by immunohistochemistry (IHC) (demonstrated by loss of nuclear staining in tumour cells). Confirmatory sequencing may be considered in tumours that exhibit BAP1 loss by IHC and in those with equivocal IHC results. If a BAP1 mutation is confirmed in a tumour, the patient's treating physician should be informed of the possibility of a BAP1 germline mutation, so they can consider whether genetic counselling and further testing of the patient and investigation of their family is appropriate. Recognition and evaluation of larger numbers of BAP1-associated tumours will also be necessary to facilitate identification of additional distinct clinico-pathological characteristics or other genotype-phenotype correlations that may have prognostic and management implications.

20 Review Review and cross-validation of gene expression signatures and melanoma prognosis. 2012

Schramm, Sarah-Jane / Campain, Anna E / Scolyer, Richard A / Yang, Yee Hwa / Mann, Graham J. ·Sydney Medical School, The University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia. graham.mann@sydney.edu.au ·J Invest Dermatol · Pubmed #21956122.

ABSTRACT: In melanoma, there is an urgent need to identify novel biomarkers with prognostic performance superior to traditional clinical and histological parameters. Gene expression-based prognostic signatures offer promise, but studies have been challenged by sample scarcity, cohort heterogeneity, and doubts about the efficacy of such signatures relative to current clinical practices. Motivated by new studies that have begun to address these challenges, we reviewed prognostic signatures derived from gene expression microarray analysis of human melanoma tissue. We used REMARK-based criteria to select the most relevant studies and directly compared their signature gene lists. Through functional ontology enrichment analysis, we observed that these independent data sets converge in part upon immune response processes and the G-protein signaling NRAS-regulation pathway, both important in melanoma development and progression. The signatures correctly predicted patient outcome in independent gene expression data sets with some notably low misclassification rates, particularly among studies involving more advanced-stage tumors. This successful cross-validation indicates that gene expression analysis-based signatures are becoming translationally relevant to care of melanoma patients, as well as improving understanding of the aspects of melanoma biology that determine patient outcome.

21 Review Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. 2011

Scolyer, Richard A / Long, Georgina V / Thompson, John F. ·Melanoma Institute Australia, Sydney, NSW, Australia. richard.scolyer@sswahs.nsw.gov.au ·Mol Oncol · Pubmed #21482206.

ABSTRACT: In the initial period after melanoma was recognised as a disease entity in the early 1800's, it was subclassified on the basis of its presumed origin (from a precursor naevus, from a melanocytic precursor lesion acquired during adult life or in previously blemish-fee skin). In 1967 the eminent American pathologist, Dr Wallace Clark, proposed a histogenetic classification for melanoma in which the disease was subdivided predominantly on the basis of histopathological features of the intra-epidermal component of the tumour adjacent to any dermal invasive component. The subtypes were superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) and nodular melanoma (NM). Whilst additional entities, including acral lentiginous melanoma, mucosal melanoma, desmoplastic melanoma and naevoid melanoma have since been recognised, SSM, LMM and NM remain in the latest (2006) version of the WHO melanoma classification. Clark's histogenetic classification has been criticised because the criteria upon which it is based include clinical features (such as the site of the melanoma) and non-tumourous histopathological features (such as the character of the associated epidermis and the degree of solar elastosis) and also because of overlap in defining features, lack of an independent association with patient outcome and minimal relevance as a determinant of clinical management. However, such criticisms fail to acknowledge its importance in highlighting the myriad of clinical and histological guises of melanoma, which if not recognized by clinicians and pathologists will inevitably lead to a delay in diagnosis and a concomitant adverse clinical outcome. Recently, mutually exclusive oncogenic mutations in melanomas involving NRAS (15-20%), BRAF (50%), CKIT (2%), and GNAQ/GNA11 (50% of uveal melanomas) have been identified. This might herald the beginning of a new molecular classification of melanoma in which the biologically distinct subsets share a common oncogenic mechanism, behave clinically in a similar fashion and require similar clinical management. These discoveries are already being successfully exploited as therapeutic targets in clinical trials of metastatic melanoma patients with promising activity. Whilst there remains much to be discovered in this rapidly evolving field, there is already great optimism that more rational and effective therapies for melanoma patients will soon be widely available.

22 Review Nevus/Melanocytoma/Melanoma: an emerging paradigm for classification of melanocytic neoplasms? 2011

Zembowicz, Artur / Scolyer, Richard A. ·Department of Pathology, Lahey Clinic, Burlington, Massachusetts, USA. dr.z@DermatopathologyConsultations.com ·Arch Pathol Lab Med · Pubmed #21366452.

ABSTRACT: CONTEXT: Until recently, the prevailing paradigm in classification and clinical management of melanocytic proliferations mandated dichotomous classification of all melanocytic lesions as either entirely benign (nevus) or entirely malignant (melanoma). However, some diagnostically challenging lesions cannot be unequivocally classified as nevus or melanoma by histologic evaluation of the primary tumor. Such lesions have been referred to as borderline or melanocytic tumors of uncertain malignant potential. OBJECTIVE: To review and update the problem of diagnostically difficult melanocytic proliferations and recent concepts regarding borderline melanocytic tumors. DATA SOURCES: Published literature and personal experience of the authors. CONCLUSIONS: Preliminary evidence indicates that it may be appropriate to expand the classification scheme of melanocytic neoplasms to include a third diagnostic category of melanocytic lesions of intermediate malignant potential that are capable of metastasis to regional lymph nodes but have limited potential for distant spread. We propose the term melanocytoma for this group of lesions. We believe that a nevus/melanocytoma/melanoma paradigm may provide a useful intellectual framework to understand, research, and clinically manage borderline melanocytic tumors.

23 Review Melanoma pathology: important issues for clinicians involved in the multidisciplinary care of melanoma patients. 2011

Scolyer, Richard A / Prieto, Victor G. ·Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2050, Australia. richard.scolyer@sswahs.nsw.gov.au ·Surg Oncol Clin N Am · Pubmed #21111957.

ABSTRACT: Histologic analysis remains the gold standard for diagnosis of melanoma. The pathology report should document those histologic features important for guiding patient management, including those characteristics on which the diagnosis was based and also prognostic factors. Pathologic examination of sentinel lymph nodes provides very important prognostic information. New techniques, such as comparative genomic hybridization and fluorescence in situ hybridization are currently being studied to determine their usefulness in the diagnosis of melanocytic lesions. Recent molecular studies have opened new avenues for the treatment of patients with metastatic melanoma (ie, targeted therapies) and molecular pathology is likely to play an important role in the emerging area of personalized melanoma therapy.

24 Review Histologically ambiguous ("borderline") primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy. 2010

Scolyer, Richard A / Murali, Rajmohan / McCarthy, Stanley W / Thompson, John F. ·Melanoma Institute Australia, Sydney, NSW, Australia. richard.scolyer@sswahs.nsw.gov.au ·Arch Pathol Lab Med · Pubmed #21128774.

ABSTRACT: It is well recognized that the pathologic diagnosis of melanocytic tumors can sometimes be difficult. For some atypical melanocytic tumors that do not display clear-cut features of malignancy, it may be difficult or impossible to exclude a diagnosis of melanoma; this includes those showing some resemblance to Spitz nevi, blue nevi, deep penetrating nevi, and possible nevoid melanomas. When there is uncertainty about whether a primary melanocytic tumor is a nevus or a melanoma, we recommend that a second opinion be sought from one or more experienced colleagues. If diagnostic uncertainty persists, the evidence for or against the various differential diagnostic considerations should be presented in the pathology report and a "most likely" or "favored" diagnosis given. Molecular testing of the primary tumor by using techniques such as comparative genomic hybridization or fluorescence in situ hybridization may assist in establishing a diagnosis of melanoma if multiple chromosomal aberrations are identified. However, these tests require further independent validation and are not widely available at present. Complete excision of the lesion is probably mandatory, but plans for further management should be formulated on a case-by-case basis. While the safest course of action will usually be to manage the tumor as if it were a melanoma (taking into account the tumor's thickness and other prognostic variables), this may not always be appropriate, particularly if it is located in a cosmetically sensitive site such as the face. In some cases, it may be appropriate for the surgical oncologist to convey the diagnostic uncertainty to patients and to present them with management choices so that they can decide whether they wish to be managed aggressively (as for a melanoma) or conservatively. While a sentinel lymph node biopsy may be recommended on the basis of the primary tumor characteristics, the clinical significance of lymph node involvement for these tumors is not yet clear, and it may not have the same prognostic implications as nodal involvement from an unequivocal "conventional" melanoma.

25 Review Fine-needle biopsy of metastatic melanoma: clinical use and new applications. 2010

Murali, Rajmohan / Thompson, John F / Uren, Roger F / Scolyer, Richard A. ·Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. rajmohan.murali@sswahs.nsw.gov.au ·Lancet Oncol · Pubmed #20106719.

ABSTRACT: Fine-needle biopsy (FNB) is a minimally invasive and accurate means of diagnosing metastatic melanoma. The judicious use of FNB, with a multidisciplinary approach involving pathologists, radiologists, treating clinicians, and other health professionals, can achieve efficient and cost-effective management of patients with melanoma who are suspected of having metastatic disease. The FNB procedure is well-tolerated and has the potential to readily provide fresh tumour material for the performance of molecular, genetic, and proteomic analyses. These analyses are likely to become more important in the future for the diagnosis of metastatic melanoma, for establishing prognosis, and for identifying patients with metastatic melanoma in whom targeted therapy (so-called personalised treatment) is most likely to be effective. In this review, the role of FNB as an important diagnostic modality in the management of suspected metastatic melanoma is described and other diagnostic and research applications of FNB are discussed.