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Melanoma: HELP
Articles by Martin C. Mihm
Based on 50 articles published since 2010
(Why 50 articles?)
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Between 2010 and 2020, M. Mihm wrote the following 50 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 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 --

2 Review Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. 2016

Lee, Nayoung / Zakka, Labib R / Mihm, Martin C / Schatton, Tobias. ·Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. Electronic address: tschatton@bwh.harvard.edu. ·Pathology · Pubmed #27020390.

ABSTRACT: The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice.

3 Review Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy. 2016

Wiesner, Thomas / Kutzner, Heinz / Cerroni, Lorenzo / Mihm, Martin C / Busam, Klaus J / Murali, Rajmohan. ·Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. Electronic address: wiesnert@me.com. · Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria; Dermatopathologie Friedrichshafen, Friedrichshafen, Germany. · Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. · Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States. ·Pathology · Pubmed #27020384.

ABSTRACT: Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

4 Review Reflections on the Histopathology of Tumor-Infiltrating Lymphocytes in Melanoma and the Host Immune Response. 2015

Mihm, Martin C / Mulé, James J. ·Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. mmihm@partners.org James.Mule@moffitt.org. · Translational Science, Melanoma Research and Treatment, Moffitt Cancer Center, Tampa, Florida. mmihm@partners.org James.Mule@moffitt.org. ·Cancer Immunol Res · Pubmed #26242760.

ABSTRACT: In the past five decades, the role for lymphocytes in host immune response to tumors has been shown, at least in some patients, to be a critical component in disease prognosis. Also, the heterogeneity of lymphocytes has been documented, including the existence of regulatory T cells that suppress the immune response. As the functions of lymphocytes have become better defined in terms of antitumor immunity, specific targets on lymphocytes have been uncovered. The appreciation of the role of immune checkpoints has also led to therapeutic approaches that illustrate the effectiveness of blocking negative regulators of the antitumor immune response. In this Masters of Immunology article, we trace the evolution of our understanding of tumor-infiltrating lymphocytes and discuss their role in melanoma prognosis from the very basic observation of their existence to the latest manipulation of their functions with the result of improvement of the host response against the tumor.

5 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.

6 Review Progression of cutaneous melanoma: implications for treatment. 2012

Leong, Stanley P L / Mihm, Martin C / Murphy, George F / Hoon, Dave S B / Kashani-Sabet, Mohammed / Agarwala, Sanjiv S / Zager, Jonathan S / Hauschild, Axel / Sondak, Vernon K / Guild, Valerie / Kirkwood, John M. ·Center for Melanoma Research and Treatment and Department of Surgery, California Pacific Medical Center, San Francisco, CA, USA. leongsx@cpmcri.org ·Clin Exp Metastasis · Pubmed #22892755.

ABSTRACT: The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials.

7 Review AJCC melanoma staging update: impact on dermatopathology practice and patient management. 2011

Piris, Adriano / Mihm, Martin C / Duncan, Lyn M. ·Dermatopathology Unit, Pathology Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ·J Cutan Pathol · Pubmed #21385199.

ABSTRACT: Changes in the 2010 American Joint Commission on Cancer melanoma staging guidelines include the evaluation of primary tumor mitotic index (mitogenicity) and the recognized prognostic significance of a single melanoma cell in a sentinel lymph node. These revised criteria have important practice implications for dermatopathologists as well as for dermatologists, oncologists and surgeons who treat patients with cutaneous melanoma.

8 Clinical Trial Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2014

Hodi, F Stephen / Lawrence, Donald / Lezcano, Cecilia / Wu, Xinqi / Zhou, Jun / Sasada, Tetsuro / Zeng, Wanyong / Giobbie-Hurder, Anita / Atkins, Michael B / Ibrahim, Nageatte / Friedlander, Philip / Flaherty, Keith T / Murphy, George F / Rodig, Scott / Velazquez, Elsa F / Mihm, Martin C / Russell, Sara / DiPiro, Pamela J / Yap, Jeffrey T / Ramaiya, Nikhil / Van den Abbeele, Annick D / Gargano, Maria / McDermott, David. ·Authors' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu. · Massachusetts General Hospital Cancer Center; Departments of. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; · Authors' Affiliations: Departments of Medical Oncology. · Biostatistics, and. · Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and. · Mount Sinai Medical Center, New York, New York. · Pathology and. · Tufts University; Miraca Life Sciences, Newton, Massachusetts; · Surgery, Brigham and Women's Hospital; · Imaging, Dana-Farber Cancer Institute; · Beth Israel-Deaconess Medical Center, Boston; ·Cancer Immunol Res · Pubmed #24838938.

ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.

9 Clinical Trial Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. 2011

Butler, Marcus O / Friedlander, Philip / Milstein, Matthew I / Mooney, Mary M / Metzler, Genita / Murray, Andrew P / Tanaka, Makito / Berezovskaya, Alla / Imataki, Osamu / Drury, Linda / Brennan, Lisa / Flavin, Marisa / Neuberg, Donna / Stevenson, Kristen / Lawrence, Donald / Hodi, F Stephen / Velazquez, Elsa F / Jaklitsch, Michael T / Russell, Sara E / Mihm, Martin / Nadler, Lee M / Hirano, Naoto. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. marcus_butler@dfci.harvard.edu ·Sci Transl Med · Pubmed #21525398.

ABSTRACT: Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.

10 Clinical Trial The performance of MelaFind: a prospective multicenter study. 2011

Monheit, Gary / Cognetta, Armand B / Ferris, Laura / Rabinovitz, Harold / Gross, Kenneth / Martini, Mary / Grichnik, James M / Mihm, Martin / Prieto, Victor G / Googe, Paul / King, Roy / Toledano, Alicia / Kabelev, Nikolai / Wojton, Maciej / Gutkowicz-Krusin, Dina. ·Total Skin and Beauty Dermatology, Birmingham, Alabama, USA. ·Arch Dermatol · Pubmed #20956633.

ABSTRACT: OBJECTIVE: To demonstrate the safety and effectiveness of MelaFind, a noninvasive and objective computer-vision system designed to aid in detection of early pigmented cutaneous melanoma. DESIGN: A prospective, multicenter, blinded study. The diagnostic performance of MelaFind and of study clinicians was evaluated using the histologic reference standard. Standard images and patient information for a subset of 50 randomly selected lesions (25 melanomas) were used in a reader study of 39 independent dermatologists to estimate clinicians' biopsy sensitivity to melanoma. SETTING: Three academic and 4 community practices in the United States with expertise in management of pigmented skin lesions. PATIENTS: A total of 1383 patients with 1831 lesions enrolled from January 2007 to July 2008; 1632 lesions (including 127 melanomas-45% in situ-with median Breslow thickness of invasive lesions, 0.36 mm) were eligible and evaluable for the study end points. MAIN OUTCOME MEASURES: Sensitivity of MelaFind; specificities and biopsy ratios for MelaFind and the study investigators; and biopsy sensitivities of independent dermatologists in the reader study. RESULTS: The measured sensitivity of MelaFind was 98.4% (125 of 127 melanomas) with a 95% lower confidence bound at 95.6% and a biopsy ratio of 10.8:1; the average biopsy sensitivity of dermatologists was 78% in the reader study. Including borderline lesions (high-grade dysplastic nevi, atypical melanocytic proliferations, or hyperplasias), MelaFind's sensitivity was 98.3% (172 of 175), with a biopsy ratio of 7.6:1. On lesions biopsied mostly to rule out melanoma, MelaFind's average specificity (9.9%) was superior to that of clinicians (3.7%) (P=.02). CONCLUSION: MelaFind is a safe and effective tool to assist in the evaluation of pigmented skin lesions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00434057.

11 Article New insights into naevoid melanomas: a clinicopathological reassessment. 2017

Cook, Martin G / Massi, Daniela / Blokx, Willeke A M / Van den Oord, Joost / Koljenović, Senada / De Giorgi, Vincenzo / Kissin, Eleanor / Grant, Megan / Mandal, Amit / Gremel, Gabriela / Gaudy, Caroline / Viros, Amaya / Dhomen, Nathalie / Khosrotehrani, Kiarash / Marais, Richard / Green, Adele C / Mihm, Martin C. ·Histopathology, Royal Surrey County Hospital, Guildford, UK. · Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK. · Division of Clinical Medicine, University of Surrey, Guildford, Surrey, UK. · Members of EORTC Melanoma Group Pathology Working Group, Florence, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands. · Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium. · Department of Pathology, Erasmus University Medical Centre, Rotterdam, the Netherlands. · Department of Dermatology, University of Florence, Florence, Italy. · Eleanor Kissin, Department of Plastic Surgery, St George's Hospital, London, UK. · Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · The University of Queensland, UQ Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Brigham and Women's Hospital, Boston, MA, USA. ·Histopathology · Pubmed #28741688.

ABSTRACT: AIMS: Because the term 'naevoid melanoma' has variable clinical and pathological interpretations, we aimed to clarify the features of melanomas referred to as naevoid. METHODS AND RESULTS: A review was undertaken of 102 melanomas diagnosed histopathologically as naevoid melanomas and ascertained by European Organization for Research and Treatment of Cancer Melanoma Group Subcommittee pathologists from their records. We found these could be classified morphologically into three groups. Thirteen melanomas were overlying genuine naevi and were therefore excluded. Of the 89 melanomas considered to be naevoid, 11 presented clinically as exophytic papillomatous nodules with little junctional component and composed of small atypical cells showing numerous mitoses and no change with depth; we termed these 'papillomatous naevoid' melanomas. The other 78 were flat or only slightly raised, and had a superficial spreading melanoma-like component with maturation to a small cell, but still an atypical, dermal component; we termed these 'maturing naevoid' melanomas. We showed that papillomatous and maturing naevoid melanomas also have differing immunochemical profiles. Preliminary clinical follow-up suggested different outcomes for these two naevoid melanoma types. CONCLUSIONS: Melanomas that have been classified as naevoid melanomas comprise two types with distinct clinical, histopathological and immunohistochemical features that may also be prognostically significant.

12 Article The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential. 2017

Muhlbauer, Aaron / Momtahen, Shabnam / Mihm, Martin C / Wang, James / Magro, Cynthia M. ·Department of Pathology, Loyola University Medical Center, Maywood, IL, USA. · Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. · Department of Pathology, Brigham and Women's Cancer Center, Harvard Medical School, USA. · Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address: cym2003@med.cornell.edu. ·Ann Diagn Pathol · Pubmed #28648937.

ABSTRACT: BACKGROUND: FISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma. METHOD: 73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010-2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6. RESULTS: The study was composed of 50 females and 23 males with an age range of 1-73 and a mean age of 35years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis. CONCLUSION: Despite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4-probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome.

13 Article 5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms. 2017

Lee, Jonathan J / Vilain, Ricardo E / Granter, Scott R / Hu, Nina R / Bresler, Scott C / Xu, Shuyun / Frank, Alexander H / Mihm, Martin C / Saw, Robyn P M / Fletcher, Christopher D / Scolyer, Richard A / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Melanoma Institute Australia, North Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Discipline of Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. ·J Cutan Pathol · Pubmed #28032662.

ABSTRACT: BACKGROUND: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms. METHODS: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data. RESULTS: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001). CONCLUSIONS: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.

14 Article Neuropeptide Y expression in primary cutaneous melanoma. 2017

Pérez Tato, B / Juarranz, Á / Nájera, L / Mihm, M C / Fernández, P / Gilaberte, Y / González, S. ·Dermatology Service, Mostoles University Hospital, Madrid, Spain. · Department of Biology, Faculty of Sciences, Autonomous University of Madrid, Madrid, Spain. · Pathology Service, Puerta de Hierro University Hospital, Madrid, Spain. · Dermatology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Dermatology Service, San Jorge Hospital, Huesca, Spain. · Department of Medicine and Medical Specialities, Alcalá University, Madrid, Spain. · Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. ·J Eur Acad Dermatol Venereol · Pubmed #27427400.

ABSTRACT: BACKGROUND: Neuropeptide Y (NPY) is involved in the carcinogenesis of different tumours, especially neural crest-derived tumours. OBJECTIVE: The aim of our study is to investigate the expression of NPY on melanoma and its relation with prognostic histological parameters and survival. METHODS: This is a retrospective observational study of two independent series, with a total of 79 primary melanomas, diagnosed in two independent University Hospitals in Spain, from January 2000 to December 2004. RESULTS: We found a significant higher expression of NPY on superficial spreading melanoma and lentigo maligna (40%) (P = 0.030). Thinner tumours were associated with higher NPY expression (Clark level, P = 0.003; Breslow level, P = 0.012). Melanomas with low NPY expression were associated with intense cell proliferation (Ki-67, P = 0.034), high density of peritumoral mast cell infiltrates (P = 0.033) and low E-cadherin expression (P = 0.031). Melanomas with high NPY expression exhibited significant differences in terms of relapse time (median: 114 vs. 68 months, P = 0.008) and overall survival (114 vs. 74 months, P = 0.004). CONCLUSION: High expression of NPY was associated with better prognostic histological parameters, low peritumoral mast cells density, presence of adhesion proteins and better outcome.

15 Article Lethal melanoma in children: a clinicopathological study of 12 cases. 2016

Prieto-Granada, Carlos N / Lezcano, Cecilia / Scolyer, Richard A / Mihm, Martin C / Piris, Adriano. ·Department of Pathology and Dermatology, Moffitt Cancer Center/University of South Florida, Tampa, FL, United States. Electronic address: Carlos.prietogranada@gmail.com. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. · Melanoma Institute Australia, North Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Dermatology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. ·Pathology · Pubmed #27956274.

ABSTRACT: Melanoma in children is rare, representing 3% of paediatric malignancies and <1% of all melanomas. Very few detailed descriptions of bona fide lethal childhood melanomas exist in the literature. We performed a retrospective clinicopathological review of 12 paediatric (≤16 years) melanoma patients who died of metastatic disease, including detailed assessment of architectural and cytomorphological features. There were nine prepubertal patients (median age 7 years old) and three postpubertal cases (median age 15 years old). The patients died on average 45.7 months after diagnosis with the prepubertal subcohort showing a relatively longer time from diagnosis to death. The tumours were bulky (average tumour thickness=10mm), showed brisk mitotic activity (average mitotic count per mm

16 Article Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group. 2016

Lott, Jason P / Elmore, Joann G / Zhao, Ge A / Knezevich, Stevan R / Frederick, Paul D / Reisch, Lisa M / Chu, Emily Y / Cook, Martin G / Duncan, Lyn M / Elenitsas, Rosalie / Gerami, Pedram / Landman, Gilles / Lowe, Lori / Messina, Jane L / Mihm, Martin C / van den Oord, Joost J / Rabkin, Michael S / Schmidt, Birgitta / Shea, Christopher R / Yun, Sook Jung / Xu, George X / Piepkorn, Michael W / Elder, David E / Barnhill, Raymond L / Anonymous1940868. ·Cornell Scott-Hill Health Center, New Haven, Connecticut. · Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address: jelmore@u.washington.edu. · Division of Dermatology, University of Washington School of Medicine, Seattle, Washington. · Pathology Associates, Clovis, California. · Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington. · Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · University of Surrey Division of Clinical Medicine, Surrey, United Kingdom. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Department of Pathology, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil. · Department of Pathology and Dermatology, University of Michigan Hospital and Health Systems, Ann Arbor, Michigan. · Departments of Anatomic Pathology and Cutaneous Oncology, Moffitt Center, and Department of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa, Florida. · Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, University Hospitals Katholieke Universiteit Leuven, Leuven, Belgium. · Rabkin Dermatopathology Laboratory PC, Tarentum, Pennsylvania. · Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. · Section of Dermatology, University of Chicago Medicine, Chicago, Illinois. · Department of Dermatology, Chonnam National University School of Medicine, Gwangju, Korea. · Department of Pathology and Lab Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · Department of Pathology, Institut Curie and Faculty of Medicine, University of Paris Descartes, Paris, France. ·J Am Acad Dermatol · Pubmed #27189823.

ABSTRACT: BACKGROUND: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. OBJECTIVE: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions. METHODS: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. RESULTS: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91. LIMITATIONS: This was a small sample size of experienced pathologists in a testing situation. CONCLUSION: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.

17 Article Decreased tumor-infiltrating lymphocytes in nodular melanomas compared with matched superficial spreading melanomas. 2016

Lin, Richard L / Wang, Thomas J / Joyce, Cara J / Mihm, Martin C / Murphy, George F / Lian, Christine G / Lin, Jennifer Y. ·aHarvard Medical School bMihm Cutaneous Pathology Consultative Service cProgram in Dermatopathology, Department of Pathology dDepartment of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts eDepartment of Biostatistics, Tulane University, New Orleans, Louisiana, USA. ·Melanoma Res · Pubmed #26974966.

ABSTRACT: Melanoma causes over 9000 deaths annually in the USA. Among its subtypes, nodular melanoma leads to a disproportionate number of fatalities compared with superficial spreading melanoma, the most common subtype. Recent breakthroughs in melanoma research have indicated a strong connection between melanoma virulence and the immune system. We hypothesize that the aggression of nodular melanoma may, in part, be because of decreased recognition by the immune system, as represented by a decreased presence of tumor-infiltrating lymphocytes (TILs), compared with its superficial spreading counterpart. Indeed, TILs on a primary melanoma have been used as a marker for immune response and have prognostic value for survival and sentinel lymph node status. After matching melanoma cases by age, sex, and Breslow thickness, we found significantly fewer TILs in nodular melanomas than in superficial spreading melanomas. This association was prominent in thin (≤2 mm) melanomas and was no longer significant in thick (>2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma.

18 Article Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma. 2015

Lee, Jonathan J / Cook, Martin / Mihm, Martin C / Xu, Shuyun / Zhan, Qian / Wang, Thomas J / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Histopathology, Royal Surrey County Hospital, Guildford, United Kingdom. · Cancer Research UK, Manchester Institute, Manchester, United Kingdom. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Oncotarget · Pubmed #26462027.

ABSTRACT: Melanomas in the vertical growth phase (VGP) not infrequently demonstrate cellular heterogeneity. One commonly encountered subpopulation displays small cell/nevoid morphology. Although its significance remains unknown, such subpopulations may pose diagnostic issues when faced with differentiating such changes from associated nevus or mistaking such regions for nevic maturation (pseudomaturation). That 'loss' of the epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is a hallmark for melanoma and correlates with virulence prompted us to explore the diagnostic utility and biological implications of 5-hmC immunohistochemistry (IHC) in melanomas with small cell/nevoid subpopulations. Fifty-two cases were included in this study, including melanomas with small cell/nevoid subpopulations (MSCN) or melanomas with pre-existing nevus (MPEN). Semiquantitative and computer-validated immunohistochemical analyses revealed invariable, uniform loss of 5-hmC in the conventional melanoma component. By contrast, the nevic components in MPEN cases demonstrated strong nuclear immunopositivity. In MSCN cases, there was partial to complete loss of 5-hmC restricted to these nevoid areas. Based on recent data supporting tight correlation between 5-hmC loss and malignancy, our findings indicate a potential 'intermediate' biological nature for small cell/nevoid subpopulations. Because 5-hmC assisted in differentiating such regions from associated nevus, the use of 5-hmC as an adjunct to microstaging in difficult cases showing VGP heterogeneity should be further explored.

19 Article Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. 2015

Kleffel, Sonja / Posch, Christian / Barthel, Steven R / Mueller, Hansgeorg / Schlapbach, Christoph / Guenova, Emmanuella / Elco, Christopher P / Lee, Nayoung / Juneja, Vikram R / Zhan, Qian / Lian, Christine G / Thomi, Rahel / Hoetzenecker, Wolfram / Cozzio, Antonio / Dummer, Reinhard / Mihm, Martin C / Flaherty, Keith T / Frank, Markus H / Murphy, George F / Sharpe, Arlene H / Kupper, Thomas S / Schatton, Tobias. ·Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, The Rudolfstiftung Hospital, 1030 Vienna, Austria. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, Innsbruck Medical University, 6020 Innsbruck, Austria. · Department of Dermatology, University of Bern, 3010 Bern, Switzerland. · Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA; School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Electronic address: tschatton@bwh.harvard.edu. ·Cell · Pubmed #26359984.

ABSTRACT: Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

20 Article Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas. 2015

Lee, Jonathan J / Sholl, Lynette M / Lindeman, Neal I / Granter, Scott R / Laga, Alvaro C / Shivdasani, Priyanka / Chin, Gary / Luke, Jason J / Ott, Patrick A / Hodi, F Stephen / Mihm, Martin C / Lin, Jennifer Y / Werchniak, Andrew E / Haynes, Harley A / Bailey, Nancy / Liu, Robert / Murphy, George F / Lian, Christine G. ·Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, EBRC Suite 401, Boston, MA 02115 USA. · Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02215-5450 USA. ·Clin Epigenetics · Pubmed #26221190.

ABSTRACT: BACKGROUND: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. RESULTS: Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. CONCLUSIONS: Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma.

21 Article Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential. 2015

Yazawa, Erika M / Geddes-Sweeney, Jenna E / Cedeno-Laurent, Filiberto / Walley, Kempland C / Barthel, Steven R / Opperman, Matthew J / Liang, Jennifer / Lin, Jennifer Y / Schatton, Tobias / Laga, Alvaro C / Mihm, Martin C / Qureshi, Abrar A / Widlund, Hans R / Murphy, George F / Dimitroff, Charles J. ·Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Dermatology, The Warren Albert Medical School, Brown University, Providence, Rhode Island, USA. · Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA. Electronic address: cdimitroff@rics.bwh.harvard.edu. ·J Invest Dermatol · Pubmed #25756799.

ABSTRACT: Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening antitumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity, and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely dysplastic nevi, as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAM(KD)) or ST6GalNAc2-overexpressing (ST6(O/E)) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAM(KD) or ST6(O/E) melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1/melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.

22 Article BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations. 2015

Piris, Adriano / Mihm, Martin C / Hoang, Mai P. ·Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114; Department of Dermatology, Brigham and Women's Hospital, Massachusetts General Hospital, Boston, MA 02114; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114. · Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114; Department of Dermatology, Brigham and Women's Hospital, Massachusetts General Hospital, Boston, MA 02114. · Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114. Electronic address: mhoang@mgh.harvard.edu. ·Hum Pathol · Pubmed #25479927.

ABSTRACT: BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene whose mutations have recently been reported to increase susceptibility for the development of uveal melanoma, cutaneous atypical and epithelioid melanocytic lesions, clear cell renal cell carcinoma, and other tumors. Screening for BAP1 mutation/loss/inactivation and BRAFV600E mutation can be done by immunohistochemistry. We investigated BAP1 and BRAFV600E expression in 193 sporadic melanocytic lesions (11 dermal nevi, 20 congenital nevi, 40 primary and nondesmoplastic melanomas, 40 desmoplastic melanomas, 23 metastatic melanomas, 17 Spitz nevi, 19 atypical Spitz nevi, 8 atypical Spitz tumors, 14 proliferative nodules arising in congenital nevi, 1 nevus during pregnancy) and 30 melanocytic lesions from 3 patients with family history of uveal melanoma and BAP1 germline mutation. Most sporadic melanocytic lesions exhibited positive BAP1 nuclear staining, except for 1 proliferative nodule arising in congenital nevus, 1 desmoplastic, 1 nevoid, and 2 metastatic melanomas. BRAFV600E positivity was demonstrated in 80% of dermal, 5% of congenital, 6% of Spitz, and 5.5% of atypical Spitz nevi; 29% of proliferative nodules arising in congenital nevi; and 24% of primary and nondesmoplastic and 35% of metastatic melanomas. Combined BAP1 loss and BRAFV600E staining was seen in 67% of BAP1 tumor syndrome-associated lesions and in none of the sporadic melanocytic proliferations including Spitz and atypical Spitz nevi and atypical Spitz tumors, with the exception of 1 primary melanoma. The combined BAP1-BRAFV600E+ immunoprofile appears to be a constant feature of BAP1 tumor syndrome-associated melanocytic lesions, and the designation of Spitz nevi or variants thereof appears to be inaccurate for this group of lesions.

23 Article Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics. 2014

Magro, Cynthia M / Abraham, Ronnie M / Guo, Ruifeng / Li, Shibo / Wang, Xuan / Proper, Steven / Crowson, A Neil / Mihm, Martin. ·Department of Pathology and Laboratory Medicine, Room F-309, 1300 York Avenue, Weill Medical College of Cornell University, New York, NY, USA. · Department of Pathology and Laboratory Medicine, Room F-309, 1300 York Avenue, Weill Medical College of Cornell University, New York, NY, USA, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA. · Department of Pathology. · Genetics Laboratory, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, USA. · Center for Dermatology and Skin Surgery, Tampa, FL, USA. · Regional Medical Laboratories, Tulsa, OK, USA. · Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Eur J Dermatol · Pubmed #25118781.

ABSTRACT: BACKGROUND: Deep penetrating nevi (DPN) are a relatively uncommon subtype of melanocytic nevi. A small subset of these lesions exhibit atypical features (cytologic and architectural atypia, mitotic activity) seen in melanoma. These lesions we term the deep penetrating nevus-like borderline tumor. Unequivocal melanomas can show overlapping morphologic features of DPN, which have been termed plexiform melanomas. PATIENTS AND METHODS: 40 cases of DPN-like borderline tumor were identified along with 6 cases of plexiform melanoma. Clinical follow up was obtained, along with cytogenetic analysis in the form of fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization (CGH). RESULTS: The DPN-like borderline tumor cases included 24 females and 16 males. Of sentinel lymph node biopsies performed, 1/3 of cases showed lymph node involvement. All patients where an aggressive clinical approach was adopted remain free of disease. All 6 DPN-like borderline tumor cases tested by CGH showed normal cytogenetics, as did 7 of 9 cases tested by FISH. Of the plexiform melanomas, 4/6 patients died of disease. In 3 cases there was morphologic progression from a DPN-like borderline tumor to overt melanoma. In one case of progression, cytogenetics was normal in the DPN-like borderline tumor and then abnormal in the progressed melanoma. CONCLUSION: DPN-like borderline tumors are melanocytic tumors associated with a high incidence of regional lymph node disease and exhibiting the potential for melanoma progression despite a normal cytogenetic profile. Patients with these lesions should be aggressively managed, with at least complete re-excision and consideration of sentinel node biopsy, regardless of cytogenetic data.

24 Article Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up. 2014

Gerami, Pedram / Busam, Klaus / Cochran, Alistair / Cook, Martin G / Duncan, Lyn M / Elder, David E / Fullen, Douglas R / Guitart, Joan / LeBoit, Philip E / Mihm, Martin C / Prieto, Victor G / Rabkin, Michael S / Scolyer, Richard A / Xu, Xiaowei / Yun, Sook Jung / Obregon, Roxana / Yazdan, Pedram / Cooper, Chelsea / Weitner, Bing Bing / Rademaker, Alfred / Barnhill, Raymond L. ·*Department of Dermatology †Robert H. Lurie Cancer Center †††Department of Preventive Medicine and the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL ‡Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY §Department of Pathology and Laboratory Medicine, Dermatopathology, UCLA Medical Center, Los Angeles ‡‡Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, CA ¶Pathology Service, Massachusetts General Hospital, Boston, MA #Department of Pathology, University of Pennsylvania, Philadelphia ¶¶Rabkin Dermatopathology Laboratory, P.C., Tarentum, PA Departments of **Pathology ††Dermatology, University of Michigan Medical Center, Ann Arbor, MI §§Department of Pathology, Section of Dermatopathology ∥∥Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX ∥Department of Histopathology, Royal Surrey County Hospital & Division of Clinical Medicine, University of Surrey, Guildford, Surrey, UK ##Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Melanoma Institute Australia and The University of Sydney, NSW, Australia ***Departments of Dermatology, Chonnam National University Medical School, Gwangju, Korea. ·Am J Surg Pathol · Pubmed #24618612.

ABSTRACT: Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors.

25 Article Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. 2014

Balch, Charles M / Thompson, John F / Gershenwald, Jeffrey E / Soong, Seng-Jaw / Ding, Shouluan / McMasters, Kelly M / Coit, Daniel G / Eggermont, Alexander M M / Gimotty, Phyllis A / Johnson, Timothy M / Kirkwood, John M / Leong, Stanley P / Ross, Merrick I / Byrd, David R / Cochran, Alistair J / Mihm, Martin C / Morton, Donald L / Atkins, Michael B / Flaherty, Keith T / Sondak, Vernon K. ·Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA, balch@asoeditorial.org. ·Ann Surg Oncol · Pubmed #24531700.

ABSTRACT: PURPOSE: We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. METHODS: The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. RESULTS: Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20-40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). CONCLUSIONS: Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.

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