In an important update for clinicians, the 2022 World Health Organization (WHO) classification of endocrine and neuroendocrine tumors introduced significant changes that impact diagnosis, grading, and prognostication.
In a review published in the Journal of Clinical Pathology, Carl Christofer Juhlin, MD, PhD, explained how this revision aims to improve accuracy in identifying and assessing these complex lesions by offering advanced diagnostic tools, refined nomenclature, and new grading systems.
The latest classification brings fresh clarity and complexity to endocrine pathology, emphasizing the integration of histological features, immunohistochemical markers, and molecular analyses. The ability to more accurately stratify thyroid, adrenal, parathyroid, and gastroenteropancreatic neuroendocrine tumors is now a critical aspect of pathology practice. Pathologists, in collaboration with clinicians, are expected to use a combination of microscopic assessment, immunohistochemistry, and, where appropriate, genetic testing to navigate the evolving landscape of endocrine neoplasia, the author explained.
For example, the diagnosis of atypical parathyroid tumors (APT) has been refined. APTs are now clearly differentiated from benign adenomas due to their potential for malignancy, driven by the loss of parafibromin—a protein encoded by the CDC73 gene. This mutation is a hallmark of tumors with increased recurrence risks, and immunohistochemistry for parafibromin is becoming essential in diagnosing these lesions. Additionally, markers such as Ki-67, galectin-3, and PGP9.5 are now recommended to assess APT aggressiveness.
The classification of thyroid tumors has also undergone substantial revision, particularly with the introduction of new subtypes of papillary thyroid carcinoma (PTC). Clinicians are now tasked with recognizing various PTC subtypes, as they differ significantly in terms of prognosis. A more detailed understanding of tumor genetics—particularly BRAF, RAS, and RET mutations—paved the way for more accurate prognostication.
In addition, the concept of high-grade thyroid carcinoma (DHGTC), encompassing aggressive forms of PTC, follicular thyroid carcinoma (FTC), and oncocytic thyroid carcinoma (OTC), has been solidified. These tumors exhibit features such as elevated mitotic activity or tumor necrosis and are considered more aggressive than other differentiated thyroid carcinomas.
The 2022 updates also offer new insights into adrenal tumors, with changes to the terminology for non-functional adrenal lesions. For example, the term nodular adrenocortical hyperplasia has been replaced by sporadic nodular adrenocortical disease, reflecting a more accurate understanding of these lesions as neoplastic rather than hyperplastic.
For pheochromocytomas and paragangliomas (PPGLs), which originate from the adrenal medulla and parasympathetic ganglia, the new classification highlights the importance of genetic screening. Identifying specific gene mutations associated with PPGLs can inform prognostication and guide treatment strategies, as these lesions often exhibit hereditary patterns. Immunohistochemistry for markers including SDHB, SDHA, and FH is crucial in identifying genetic mutations linked to an increased risk of metastasis.
A key development in the latest WHO classification is the inclusion of neuroendocrine tumors (NETs) across all organs. This expansion reflects the growing recognition that neuroendocrine differentiation is not limited to endocrine glands, but extends to multiple anatomical sites, including the gastrointestinal tract, lung, and skin. Clinicians are now encouraged to perform immunohistochemical tests to visualize hormone production, which may aid in identifying clinically silent disease.
Moreover, the classification now solidifies the concept of stratifying highly proliferative neuroendocrine tumors (Ki-67 index >20%) into grade 3 neuroendocrine carcinoma (NEC) or NET, based on a combination of clinical, morphological, and molecular factors. This change is designed to improve risk stratification and optimize treatment decisions.
Despite the wealth of new tools and guidelines, the implementation of the 2022 WHO classification will not be without challenges, the author noted. As the terminology evolves, pathologists and clinicians need to adapt to the changes in tumor nomenclature and diagnostic criteria, particularly for rare or ambiguous cases. While molecular biomarkers hold immense potential, the classification still emphasizes the integration of traditional histopathological methods with emerging technologies, rather than relying solely on genetic testing.
Collaboration between pathologists, endocrinologists, oncologists, and surgeons will be crucial to ensure that these updates translate into better patient outcomes. With a growing emphasis on personalized medicine, the updated classification is designed to enhance diagnostic accuracy and provide more tailored prognostic information.
