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      Assessing tumor infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group : Part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors

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      Advances in anatomic pathology
      Lymphocytes, tumor-infiltrating, Biomarkers, Cancer, Immunotherapy, Pathology

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          Abstract

          Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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          Final version of 2009 AJCC melanoma staging and classification.

          To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.
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            Effector memory T cells, early metastasis, and survival in colorectal cancer.

            The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown. We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors). Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor-node-metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-gamma, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7-CD28+CD27+) to effector memory (CD45RO+CCR7-CD28-CD27-) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival. Copyright 2005 Massachusetts Medical Society.
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              Systematic review of microsatellite instability and colorectal cancer prognosis.

              A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies. Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques. Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I(2) = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14). CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI.
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                Author and article information

                Journal
                9435676
                21145
                Adv Anat Pathol
                Adv Anat Pathol
                Advances in anatomic pathology
                1072-4109
                1533-4031
                24 June 2017
                November 2017
                01 November 2018
                : 24
                : 6
                : 311-335
                Affiliations
                [1 ]Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
                [2 ]The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
                [3 ]Breast Cancer Translational Research Laboratory/Breast International Group, Institut Jules Bordet, Brussels, Belgium
                [4 ]Department of Pathology and TCRU, GZA, Antwerp, Belgium
                [5 ]Department of Development and Regeneration, Laboratory of Experimental Urology, KU Leuven, Leuven, Belgium
                [6 ]Department of Pathology, AZ Klina, Brasschaat, Belgium
                [7 ]Department of Anatomical Pathology, St Vincent’s Hospital Melbourne, Fitzroy, Australia
                [8 ]Department of Pathology, University of Melbourne, Parkville, Australia
                [9 ]Department of Medical Oncology, Austin Health, Heidelberg, Australia
                [10 ]Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
                [11 ]School of Cancer Medicine, La Trobe University, Bundoora, Australia
                [12 ]Department of Medicine, University of Melbourne, Parkville, Australia
                [13 ]Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, Australia
                [14 ]Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands
                [15 ]Department of Pathology, School of Medicine, University of California, San Diego, USA
                [16 ]Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, USA
                [17 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, USA
                [18 ]Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
                [19 ]Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
                [20 ]Department of Pathology, GZA Ziekenhuizen, Antwerp, Belgium
                [21 ]Université Paris-Est, Créteil, France
                [22 ]INSERM, UMR 955, Créteil, France
                [23 ]Département de pathologie, APHP, Hôpital Henri-Mondor, Créteil, France
                [24 ]Department of Medicine, Clinical Division of Oncology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
                [25 ]Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
                [26 ]European Institute of Oncology, Milan, Italy
                [27 ]University of Milan, School of Medicine, Milan, Italy
                [28 ]New York University Medical School, New York, USA
                [29 ]Perlmutter Cancer Center, New York, USA
                [30 ]Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, USA
                [31 ]Molecular Oncology Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain
                [32 ]Department of Cancer Biology, Mayo Clinic, Jacksonville, USA
                [33 ]Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Australia
                [34 ]Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia
                [35 ]National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania
                [36 ]Cancer Research Institute and Department of Pathology, Beth Israel Deaconess Cancer Center, Boston, USA
                [37 ]Harvard Medical School, Boston, USA
                [38 ]Department of Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk, Belgium
                [39 ]Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
                [40 ]Academic Medical Innovation, Novartis Pharmaceuticals Corporation, East Hanover, USA
                [41 ]Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, USA
                [42 ]Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, USA
                [43 ]Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
                [44 ]Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
                [45 ]Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand, France
                [46 ]University of Auvergne UMR1240, Clermont-Ferrand, France
                [47 ]Department of Surgery, Kansai Medical School, Hirakata, Japan
                [48 ]Montefiore Medical Center, Bronx, New York, USA
                [49 ]The Albert Einstein College of Medicine, Bronx, New York, USA
                [50 ]Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea
                [51 ]Department of Pathology, Brigham and Women’s Hospital, Boston, USA
                [52 ]Department of Cancer Biology, Dana Farber Cancer Institute, Boston, USA
                [53 ]Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Providence, USA
                [54 ]Warren Alpert Medical School of Brown University, Providence, USA
                [55 ]Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center, Gliwice, Poland
                [56 ]Institute of Oncology, Gliwice Branch, Gliwice, Poland
                [57 ]Department of Medicine, Vanderbilt University Medical Centre, Nashville, USA
                [58 ]Vanderbilt Ingram Cancer Center, Nashville, USA
                [59 ]Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
                [60 ]VMscope GmbH, Berlin, Germany
                [61 ]Department of Pathology, Yale University School of Medicine, New Haven, USA
                [62 ]Service de Biostatistique et d’Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Université-Paris Sud, Université Paris-Saclay, Villejuif, France
                [63 ]German Breast Group GmbH, Neu-Isenburg, Germany
                [64 ]Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
                [65 ]Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada
                [66 ]Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada
                [67 ]Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
                [68 ]The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia
                [69 ]Australian Clinical Labs, Bella Vista, Australia
                [70 ]INSERM Unit U981, and Department of Medical Oncology, Gustave Roussy, Villejuif, France
                [71 ]Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre, France
                [72 ]Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
                [73 ]Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain
                [74 ]Department of Pathology, University Hospital Leuven, Leuven, Belgium
                [75 ]Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Doha, Qatar
                [76 ]Department of Oncology, Montefiore Medical Centre, Albert Einstein College of Medicine, Bronx, USA
                [77 ]Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
                [78 ]Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada
                [79 ]Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
                [80 ]Department of Pathology, New York University Langone Medical Centre, New York, USA
                [81 ]Directorate of Surgical Pathology, SA Pathology, Adelaide, Australia
                [82 ]Discipline of Medicine, Adelaide University, Adelaide, Australia
                [83 ]Pathology Department, Stanford University Medical Centre, Stanford, USA
                [84 ]Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, USA
                [85 ]Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands
                [86 ]Dana-Farber Cancer Institute, Boston, USA
                [87 ]Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University, New York, USA
                [88 ]Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA
                [89 ]Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
                [90 ]Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
                [91 ]European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
                [92 ]Institute of Pathology, Medical University of Graz, Austria
                [93 ]Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg, Germany
                [94 ]Research Pathology, Genentech Inc., South San Francisco, USA
                [95 ]Department of Pathology, Stanford University, Palo Alto, USA
                [96 ]Translational Sciences, MedImmune, Gaithersberg, USA
                [97 ]Translational Medicine, Merck & Co., Inc., Kenilworth, USA
                [98 ]Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA
                Author notes
                Corresponding author: Shona Hendry, Department of Anatomical Pathology, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia, shona.hendry@ 123456gmail.com , T: +61 3 9231 4542 F: +61 3 9231 4580
                Article
                PMC5638696 PMC5638696 5638696 nihpa883270
                10.1097/PAP.0000000000000161
                5638696
                28777143
                be9d31c1-2fec-4ee7-89b1-9117e81ab95a
                History
                Categories
                Article

                Lymphocytes,tumor-infiltrating,Biomarkers,Cancer,Immunotherapy,Pathology

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