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What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?

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Abstract

Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pan-genomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype–phenotype correlations for PPGLs. The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype–phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.

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Acknowledgements

We are grateful to the invitation of the Editor-in-chief, Dr. O. Mete.

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  1. Thomas G. Papathomas and Diederik P.D. Suurd should be regarded as first authors.

  2. Alfred K. Lam and Ronald R. de Krijger are senior and corresponding authors.

Authors and Affiliations

  1. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

    Thomas G. Papathomas

  2. Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, UK

    Thomas G. Papathomas

  3. Department of Surgical Oncology and Endocrine Surgery, University Medical Center Utrecht, Utrecht, The Netherlands

    Diederik P. D. Suurd & Menno R. Vriens

  4. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Karel Pacak

  5. Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston Massachusetts, USA

    Arthur S. Tischler

  6. School of Medicine, Griffith University, Gold Coast, QLD, Australia

    Alfred K. Lam

  7. Pathology Queensland, Gold Coast University Hospital, Gold Coast, QLD, Australia

    Alfred K. Lam

  8. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    Alfred K. Lam

  9. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Ronald R. de Krijger

  10. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

    Ronald R. de Krijger

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T. G. Papathomas, D. P.D. Suurd, A.K. Lam and R. R. de Krijger drafted the design of the work; T. G. Papathomas and D. P.D. Suurd performed the literature search and drafted the initial text; K. Pacak and M. R. Vriens criticised the manuscript;

A. K. Lam and R. R. de Krijger and A.S. Tischler gave input on the concepts and finalised the manuscript; all authors contributed to the final manuscript.

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Papathomas, T.G., Suurd, D.P.D., Pacak, K. et al. What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?. Endocr Pathol 32, 134–153 (2021). https://doi.org/10.1007/s12022-020-09658-7

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