Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach

Abstract

The fifth edition of the World Health Organization (WHO) histologic classification of thyroid neoplasms released in 2022 includes newly recognized tumor types, subtypes, and a grading system. Follicular cell-derived neoplasms are categorized into three families (classes): benign tumors, low-risk neoplasms, and malignant neoplasms. The terms "follicular nodular disease" and "differentiated high-grade thyroid carcinoma" are introduced to account for multifocal hyperplastic/neoplastic lesions and differentiated thyroid carcinomas with high-grade features, respectively. The term "Hürthle cells" is replaced with "oncocytic cells." Invasive encapsulated follicular and cribriform morular variants of papillary thyroid carcinoma (PTC) are now redefined as distinct tumor types, given their different genetic alterations and clinicopathologic characteristics from other PTC subtypes. The term "variant" to describe a subclass of tumor has been replaced with the term "subtype." Instead, the term "variant" is reserved to describe genetic alterations. A histologic grading system based on the mitotic count, necrosis, and/or the Ki67 index is used to identify high-grade follicular-cell derived carcinomas and medullary thyroid carcinomas. The 2022 WHO classification introduces the following new categories: "salivary gland-type carcinomas of the thyroid" and "thyroid tumors of uncertain histogenesis." This review summarizes the major changes in the 2022 WHO classification and their clinical relevance.

Keywords: Classification; Standards; Thyroid neoplasms; Thyroid nodule; World Health Organization.

Fig. 1.

Molecular classification and histopathological correlates in follicular cell-derived neoplasms. Thyroid neoplasms are classified as two molecular groups (BRAF^V600E-like and RAS-like) or three groups (BRAF^V600E-like, RAS-like, and non-BRAF^V600E-/non-RAS-like) based on the mutational and gene expression profiles [7,8]. The BRAF^V600E group is most commonly represented by papillary thyroid carcinoma (PTC). The BRAF^V600E-like molecular profile includes the BRAF^V600E mutation and gene fusions involving BRAF, RET, and neurotrophic receptor tyrosine kinase 1/3 (NTRK1/3). RAS-like molecular profiles include NRAS, HRAS, KRAS, EIF1AX, enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1), Dicer 1, ribonuclease III (DICER1), phosphatase and tensin homolog (PTEN) mutations, BRAFK601E, and gene fusions involving peroxisome proliferator-activated receptor gamma (PPARG) and THADA. When the three-group molecular classification is applied, PAX8::PPARG gene fusion and mutations of EIF1AX, EZH1, IDH1, SOS1, SPOP, DICER1, and PTEN genes are classified as a non-BRAF^V600E-/non-RAS-like group [8]. Encapsulated/circumscribed thyroid tumors with a predominant follicular growth pattern generally have a RAS-like molecular profile. High grade is histologically defined as the presence of ≥5 mitoses per 2 mm² and/or tumor necrosis. Y, yes; N, no; Q, questionable; PDTC, poorly differentiated thyroid carcinoma; ATC, anaplastic thyroid carcinoma; DHGTC, differentiated high-grade thyroid carcinoma; IEFVPTC, invasive encapsulated follicular variant of papillary thyroid carcinoma; WDT-UMP, well-differentiated tumor of uncertain malignant potential; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear features; FT-UMP, follicular tumor of uncertain malignant potential; FTC, follicular thyroid carcinoma; OCA, oncocytic carcinoma of the thyroid; TERT, telomerase reverse transcriptase; TP53, tumor protein p53; PAX8, paired box 8.

Fig. 2.

Decision tree for the differential diagnosis of follicular cell-derived neoplasms. The first step is to evaluate whether the tumor has nuclear features of papillary thyroid carcinoma (PTC). Tumors are then stratified according to the growth pattern, histologic differentiation, tumor capsular or vascular invasion, and high-grade histologic features. Y, yes; N, no; Q, questionable; FND, follicular nodular disease; FA, follicular adenoma; FA-P, follicular adenoma with papillary architecture; OA, oncocytic adenoma; FT-UMP, follicular tumor of uncertain malignant potential; IEFVPTC, invasive encapsulated follicular variant of papillary thyroid carcinoma; WDT-UMP, well-differentiated tumor of uncertain malignant potential; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear features; FTC, follicular thyroid carcinoma; OCA, oncocytic carcinoma of the thyroid; DHGTC, differentiated high-grade thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; ATC, anaplastic thyroid carcinoma.

Fig. 3.

Counting mitoses in a hotspot. (A) The mitotic count is assessed by counting the number of tumor cells with mitosis per 2 mm² in a hotspot (hematoxylin and eosin [H&E] stain, digital zoom ×10). (B) One high power-field of ×400 magnification using the ×40 objective lens and ×10 eyepiece has a field diameter of 0.49 to 0.53 mm in usual light microscopes (H&E stain, digital zoom ×10). Ten fields are approximately equivalent to 2 mm².

Fig. 4.

Increased mitotic activity and Ki67 index in high-grade thyroid cancers. Differentiated high-grade thyroid carcinomas can arise from hobnail papillary thyroid carcinoma (A, hematoxylin and eosin [H&E] stain, digital zoom ×100; B), tall cell papillary thyroid carcinoma (C, H&E stain, digital zoom ×100; D), and follicular thyroid carcinoma (E, H&E stain, digital zoom ×100; F). Immunohistochemical stains for Ki67 show proliferation index ≥5% (B, D, F; digital zoom ×40). High-grade medullary thyroid carcinoma shows mitotic count ≥5 per 2 mm² (G, H&E stain, digital zoom ×100) and Ki67 proliferation index ≥5% (H, digital zoom ×40). Arrowheads indicate mitotic tumor cells.

Fig. 5.

Subclassification of encapsulated follicular-derived thyroid tumors. Tumors with a non-invasive encapsulated follicular pattern include follicular adenoma and non-invasive follicular thyroid neoplasm with papillary-like nuclear features. (A) A follicular adenoma is shown (hematoxylin and eosin [H&E] stain, digital zoom ×1). (B) The minimally invasive subtype of follicular thyroid carcinoma has a tumor capsular invasion only (H&E stain, digital zoom ×10). (C) The encapsulated angioinvasive subtype is a cancer with vascular invasion regardless of capsular invasion status (H&E stain, digital zoom ×10). (D) CD31 immunostaining highlights endothelial-lined tumor emboli within the vessel (digital zoom ×40). (E) Extensive vascular invasion with ≥4 foci in extrathyroidal fibroadipose tissue is shown (H&E stain, digital zoom ×20). (F) The widely invasive subtype shows obliteration of the tumor capsule and invasion into extrathyroidal soft tissue (H&E stain, digital zoom ×10).

Fig. 6.

Follicular subtypes of papillary thyroid carcinoma (PTC). (A) Infiltrative follicular PTC shows an ill-defined infiltrative margin, follicular growth, and fibrotic stroma (digital zoom ×10). (B) Tumor cells have well-developed PTC nuclear features (digital zoom ×100). (C) Invasive encapsulated follicular variant PTC, which is now considered a separate entity and not a PTC subtype, invades through the fibrous capsule and shows a predominant follicular growth pattern (digital zoom ×10). (D) The nuclear features of invasive encapsulated follicular variant PTC are less developed than those of infiltrative follicular PTC; that is, the nuclei are rounder and more uniform (digital zoom ×100).

Fig. 7.

Tall cell and hobnail subtypes of papillary thyroid carcinoma (PTC) and encapsulated classic PTC with hobnail-like morphology. (A) Tall cell PTC shows an elongated and closely packed papillary pattern (hematoxylin and eosin [H&E] stain, digital zoom ×20). (B) The height of tumor cells is at least three times greater than their width (H&E stain, digital zoom ×100). Tumor cells have abundant eosinophilic cytoplasm and distinct cell membranes. (C) Hobnail PTC has papillary or micropapillary structures (H&E stain, digital zoom ×20). (D) Hobnail cells show enlarged hyperchromatic nuclei with reverse polarity (H&E stain, digital zoom ×100). (E) Encapsulated classic PTC shows cystic spaces and papillae lined with tumor cells having hobnail-like morphology (H&E stain, digital zoom ×20). (F) The papillary structure shows hyalinized and edematous stroma and cells with hobnailing cytomorphology (H&E stain, digital zoom ×100). The nuclear features look similar to those of classic PTC. These histologic findings are associated with ischemic and degenerative changes, and should not be diagnosed as hobnail PTC, which is an aggressive subtype.