This review summarizes the changes in the 5th edition of the WHO Classification of
Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification
has divided thyroid tumors into several new categories that allow for a clearer understanding
of the cell of origin, pathologic features (cytopathology and histopathology), molecular
classification, and biological behavior. Follicular cell-derived tumors constitute
the majority of thyroid neoplasms. In this new classification, they are divided into
benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular
adenoma but also variants of adenoma that are of diagnostic and clinical significance,
including the ones with papillary architecture, which are often hyperfunctional and
oncocytic adenomas. For the first time, there is a detailed account of the multifocal
hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular
goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the
best to describe this enigmatic entity. Low-risk follicular cell-derived neoplasms
include non-invasive follicular thyroid neoplasm with papillary-like nuclear features
(NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular
tumor. Malignant follicular cell-derived neoplasms are stratified based on molecular
profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological
subtypes, represent the BRAF-like malignancies, whereas invasive encapsulated follicular
variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies.
This new classification requires detailed subtyping of papillary microcarcinomas similar
to their counterparts that exceed 1.0 cm and recommends not designating them as a
subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited.
Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC.
The term "Hürthle cell" is discouraged, since it is a misnomer. Oncocytic carcinoma
is discussed as a distinct entity with the clear recognition that it refers to oncocytic
follicular cell-derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic
nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis
and ≥ 5 mitoses per 2 mm2). High-grade follicular cell-derived malignancies now include
both the traditional poorly differentiated carcinoma as well as high-grade differentiated
thyroid carcinomas, since both are characterized by increased mitotic activity and
tumor necrosis without anaplastic histology and clinically behave in a similar manner.
Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell
carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary
thyroid carcinomas derived from thyroid C cells retain their distinct section, and
there is a separate section for mixed tumors composed of both C cells and any follicular
cell-derived malignancy. A grading system for medullary thyroid carcinomas is also
introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number
of unusual neoplasms that occur in the thyroid have been placed into new sections
based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the
salivary gland type are now included in one section classified as "salivary gland-type
carcinomas of the thyroid." Thymomas, thymic carcinomas and spindle epithelial tumor
with thymus-like elements are classified as "thymic tumors within the thyroid." There
remain several tumors whose cell lineage is unclear, and they are listed as such;
these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular
thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal
tumor associated with DICER1 mutations. As in all the WHO books in the 5th edition,
mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic
malignancies are discussed separately. The current classification also emphasizes
the value of biomarkers that may aid diagnosis and provide prognostic information.