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Annual review issue: An overview of 50 years of progress in endocrine pathology

After many decades of histochemical characterization of endocrine cells and tumours, the introduction of immunohistochemical staining on formalin-fixed paraffin-embedded tissues in the 1960s, along with the development of monoclonal antibody-generating technology a few years later, launched a new and exciting era that led to major advances in endocrine pathology. The ‘APUDOMA’ concept of Pearse, suggesting that there was a common histogenetic origin of all neuroendocrine cells and tumours from the neural crest cells, was quickly modified by Pearse and various other investigators, but the underlying concept regarding the common features of neuroendocrine cells and tumours was quickly supported by the use of antibodies against neuron-specific enolase, chromogranin A, and synaptophysin. The development of highly specific and sensitive radioimmunoassays for hormones contributed to the rapid advances in endocrinology and endocrine pathology. New endocrine cells, hyperplastic endocrine lesions and endocrine tumours were rapidly identified and characterized. Pioneering studies on the classification of endocrine tumours, such as those in the pituitary, thyroid C cells and adrenal cortex and medulla, led to a new classification of endocrine disease processes and tumours. In the 1970s and 1980s, the development of molecular techniques such as gene cloning and sequencing expanded our knowledge of endocrine diseases. New techniques such as transgenic and knockout rodent models led to a better understanding of the biology, physiology and pathology of endocrine tumours. Molecular techniques also revealed genes that could be labelled for in-situ hybridization to localize specific RNAs and DNAs in endocrine cells and tumours, and led to the development of probes for fluorescence and brightfield microscopy and for cytogenetic analyses. Mutational analyses provided a great deal of insight into familial diseases such as the multiple endocrine neoplasias syndromes, succinate dehydrogenase deficiencies, Carney complex and Dicer mutations in pituitary blastomas and other endocrine tumours. Newer and more sensitive methods for analysing proteins, such as mass spectrometry-based proteomic analysis, contributed to the rapid analysis of small amounts of proteins in endocrine cells and tumours. These new approaches enabled pathologists to rapidly analyse and quantify small amounts of proteins from a few slices of tissues obtained from paraffin blocks. More recently, next-generation sequencing and other molecular techniques have led to rapid advances in endocrinology and endocrine pathology. For example, the Cancer Genome Atlas analyses and related studies have elucidated the landscape of papillary thyroid carcinomas, and provided new directions for the diagnosis and treatment of endocrine tumours such as papillary thyroid carcinomas. These studies have led to new classifications of papillary thyroid carcinomas into BRAF-mutated and RAS-mutated tumour subtypes. Similar findings have been reported in adrenal cortical and medullary tumours. The pioneering studies from the Cancer Genome Atlas studies of papillary thyroid carcinomas have led to other fundamental advances in thyroid endocrine pathology, such as the development of the novel diagnostic category of non-invasive follicular neoplasms with papillary-like nuclear features, which has already had a great impact on the diagnosis and treatment of patients with the most common thyroid tumour. We can anticipate continued advances resulting from next-generation sequencing and other molecular techniques that should be directly applicable to the diagnosis and treatment of endocrine tumours in the near future. Advances in stem cell biology should lead to the treatment of globally devastating endocrine diseases such as type 2 diabetes mellitus. The future of endocrine pathology looks very bright, and we can anticipate further rapid advances in the next 50 years.