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      Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma

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          Abstract

          Purpose

          The Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) was proposed for predicting the metastatic potential of pheochromocytoma and paraganglioma to overcome the limitations of the Pheochromocytoma of the Adrenal Scaled Score (PASS). However, to date, no study validating the GAPP has been conducted, and previous studies did not include mutations in the succinate dehydrogenase type B (SDHB) gene in the score calculation. In this retrospective cohort study, we validated the prediction ability of GAPP and assessed whether it would be improved by inclusion of the loss of SDHB immunohistochemical staining.

          Methods

          We divided the tumors into non-metastatic and metastatic groups based on the presence of synchronous or metachronous metastases. The GAPP score and PASS at the initial operation were measured. Moreover, we combined some GAPP parameters with the immunohistochemical staining of SDHB to obtain a modified GAPP (M-GAPP) score.

          Results

          Metastasis occurred in 15/72 (20.8%) patients, with a mean follow-up of 43.5 months. Loss of SDHB staining was more frequent ( P = 0.044) in the metastatic group. The GAPP score ( P = 0.006), PASS ( P = 0.003), and M-GAPP score ( P<0.001) were all higher in the metastatic group. Twelve of 40 (30.0%) moderately or poorly differentiated tumors, as defined by the GAPP score, and 12/34 (35.3%) tumors with a PASS ≥4 were metastatic. Conversely, 10/19 (52.6%) tumors with an M-GAPP score ≥3 were metastatic. The area under the curve of the M-GAPP score (0.822) was significantly higher than that of the GAPP (0.728) ( P = 0.012), but similar to that of the PASS (0.753) ( P = 0.411). The GAPP ( P = 0.032) and M-GAPP scores ( P = 0.040), but not PASS ( P = 0.200), negatively correlated with metastasis-free survival.

          Conclusion

          The GAPP was validated, and M-GAPP, a combination of some GAPP parameters and loss of SDHB staining, might be useful for the prediction of the metastatic potential of pheochromocytoma and paraganglioma.

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          Most cited references14

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          Index for rating diagnostic tests.

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            • Article: found

            Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma.

            Phaeochromocytomas (PHEO) and paragangliomas are rare catecholamine-producing tumours. Although 10-30% of these tumours metastasise, histopathological criteria to discriminate malignant from benign tumours have not been established; therefore, reliable histopathological markers predicting metastasis are urgently required. A total of 163 tumours, including 40 metastatic tumours, collected by the Phaeochromocytoma Study Group in Japan (PHEO-J) were analysed using a system called grading system for adrenal phaeochromocytoma and paraganglioma (GAPP). The tumours were scored based on GAPP criteria as follows: histological pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki67 labelling index and catecholamine type. All tumours were scored from 0 to 10 points and were graded as one of the three types: well-differentiated (WD, 0-2 points), moderately differentiated (MD, 3-6 points) and poorly differentiated (PD, 7-10 points). GAPP scores of the non-metastatic and metastatic groups were 2.08±0.17 and 5.33±0.43 (mean±s.e.m., P<0.001) respectively. There was a significant negative correlation between the GAPP score and the interval until metastasis (r=-0.438, P<0.01). The mean number of years until metastasis after the initial operation was 5.5±2.6 years. The study included 111 WD, 35 MD and 17 PD types. The five-year survival of these groups was 100, 66.8 and 22.4% respectively. In addition, negative immunoreactivity for succinate dehydrogenase gene subunit B (SDHB) was observed in 13 (8%) MD or PD tumours and ten of the 13 (77%) had metastases. Our data indicate that a combination of GAPP classification and SDHB immunohistochemistry might be useful for the prediction of metastasis in these tumours.
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              The diagnosis and management of malignant phaeochromocytoma and paraganglioma.

              Malignant phaeochromocytomas are rare tumours accounting for ~10% of all phaeochromocytomas; the prevalence of malignancy among paragangliomas is higher, especially those associated with succinate dehydrogenase subunit B gene mutations. Although a subset of these tumours has metastatic disease at initial presentation, a significant number develops metastases during follow-up after excision of an apparently benign tumour. Clinical, biochemical and histological features cannot reliably distinguish malignant from benign tumours. Although a number of recently introduced molecular markers have been explored, their clinical significance remains to be elucidated from further studies. Several imaging modalities have been utilised for the diagnosis and staging of these tumours. Functional imaging using radiolabelled metaiodobenzylguanidine (MIBG) and more recently, (18)F-fluorodopamine and (18)F-fluorodopa positron emission tomography offer substantial sensitivity and specificity to correctly detect metastatic phaeochromocytoma and paraganglioma and helps identify patients suitable for treatment with radiopharmaceuticals. The 5-year mortality rate of patients with malignant phaeochromocytomas and paragangliomas greater than 50% indicates that there is considerable room for the improvement of currently available therapies. The main therapeutic target is tumour reduction and control of symptoms of excessive catecholamine secretion. Currently, the best adjunctive therapy to surgery is treatment with radiopharmaceuticals using (131)I-MIBG; however, this is very rarely curative. Chemotherapy has been used for metastatic disease with only a partial and mainly palliative effect. The role of other forms of radionuclide treatment either alone or in combination with chemotherapy is currently evolving. Ongoing microarray studies may provide novel intracellular pathways of importance for proliferation/cell cycle control, and lead to the development of novel pharmacological agents.

                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: Resources
                Role: Data curationRole: Resources
                Role: Data curationRole: InvestigationRole: Resources
                Role: Data curationRole: InvestigationRole: Resources
                Role: Data curationRole: InvestigationRole: Resources
                Role: Data curationRole: InvestigationRole: Resources
                Role: Data curationRole: InvestigationRole: Resources
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                8 November 2017
                2017
                : 12
                : 11
                : e0187398
                Affiliations
                [1 ] Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
                [2 ] Department of Endocrinology, Inha University School of Medicine, Incheon, Korea
                [3 ] Division of Endocrinology and Metabolism, Department of Medicine, Gyeongsang National University School of Medicine, Jinju, Korea
                [4 ] Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
                [5 ] Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
                2nd medical school of Charles University, CZECH REPUBLIC
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ Joint senior authors

                Author information
                http://orcid.org/0000-0003-0496-247X
                Article
                PONE-D-17-24744
                10.1371/journal.pone.0187398
                5678867
                29117221
                49f86718-2645-4156-9424-6ec22f929bbb
                © 2017 Koh et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 June 2017
                : 26 September 2017
                Page count
                Figures: 3, Tables: 7, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100005006, Asan Institute for Life Sciences, Asan Medical Center;
                Award ID: 2016-0840
                Award Recipient :
                This study was supported by grants from the Asan Institute for Life Sciences, Seoul, Republic of Korea (project no. 2016-0840). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Endocrine Tumors
                Pheochromocytomas
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Neurological Tumors
                Glioma
                Paragangliomas
                Medicine and Health Sciences
                Neurology
                Neurological Tumors
                Glioma
                Paragangliomas
                Research and Analysis Methods
                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
                Research and Analysis Methods
                Immunologic Techniques
                Immunohistochemistry Techniques
                Medicine and Health Sciences
                Oncology
                Metastasis
                Medicine and Health Sciences
                Oncology
                Basic Cancer Research
                Metastasis
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amines
                Catecholamines
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amines
                Catecholamines
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Biogenic Amines
                Catecholamines
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurotransmitters
                Biogenic Amines
                Catecholamines
                Biology and Life Sciences
                Biochemistry
                Hormones
                Catecholamines
                Biology and Life Sciences
                Anatomy
                Histology
                Medicine and Health Sciences
                Anatomy
                Histology
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Staining
                Cytoplasmic Staining
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Staining
                Negative Staining
                Custom metadata
                Although all participants provided written informed consents for this study, some participants did not agree to secondary use of their individual data. Therefore, we have included the participant-level data of those who did not object to secondary data use (N = 37) as a supporting information file. Additional data may be partially provided upon contacting the corresponding author of this manuscript.

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