Evolution of the histologic classification of thyroid neoplasms and its impact on clinical management

Abstract

The vast majority of low grade follicular cell derived thyroid carcinomas follows an indolent clinical course and is associated with very low mortality. Risk stratification using multiple clinical and pathologic characteristics has become the standard of care to guide appropriate management and avoid overtreatment. Over the past few decades, the field of thyroid pathology has witnessed several major changes that significantly impacted upon patients' care. These are: 1) The reclassification of non-invasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features; 2) the diagnosis of Hurthle cell carcinoma based on the presence of capsular and vascular invasion; 3) a detailed definition of poorly differentiated thyroid carcinoma, taking into consideration mitosis and necrosis; and 4) the emphasis on a detailed pathologic analysis such as the extent of vascular invasion and extrathyroidal extension. This review describes these histological concepts and details the history, rationale, and clinical impacts of such changes. These shifts in the classification and characterization of thyroid carcinoma provided a platform supporting therapy de-escalation. In addition several lessons were learned from these changes especially from the misclassification of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma. We hope that the lessons learned will help better classify tumors in the future whether arising in the thyroid or other organs.

Keywords: Extensive vascular invasion; Extrathyroidal extension; Hurthle cell carcinoma; Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP); Poorly differentiated thyroid carcinoma.

Figure 1. Timeline depicting the changes in the histologic definition and classification of well differentiated thyroid carcinoma

The references pertaining to the above time points are as follows,: Lindsay S [8], Chen and Rosai [9], Williams ED et al. [80], Zhu et al. [28], Wreesmann et al. [29], Liu J et al. [22], the Cancer Genome Atlas Research Network [57], Nikiforov Y et al. [34]. PTC, papillary thyroid carcinoma; FA: Follicular adenoma; FC, follicular carcinoma; WDT-UMP, well differentiated tumor of uncertain malignant potential”; FVPTC, follicular variant of papillary thyroid carcinoma; EFVPTC, encapsulated follicular variant of papillary thyroid carcinoma; TCGA, the cancer genome atlas research network; NIFTP, noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Figure 2. Diagram and microscopic pictures of the subtypes of follicular variant of papillary thyroid carcinoma (FVPTC)

This tumor has encapsulated (commonly RAS mutated) and infiltrative (most frequently BRAF mutated) forms. The encapsulated FVPTC (EFVPTC) can be further classified based on the invasive status. The former non-invasive EFVPTC is now reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) to emphasize the indolent nature of this lesion. (A) The tumor is composed entirely of follicular architecture and exhibits nuclear features of papillary thyroid carcinoma, e.g. nuclear membrane irregularity, nuclear enlargement, chromatin clearing, and nuclear grooves. (B) A NIFTP is an encapsulated/well-circumscribed tumor without evidence of capsular or vascular invasion. C: Infiltrative FVPTC showing tumor follicles (arrow) invading in between non-neoplastic follicles.

Figure 3

Microscopic pictures of a 4 cm encapsulated Hurthle cell carcinoma with microscopic extensive VI (7 foci) in a 44 year old male without distant disease at presentation. The patient developed bone and lung metastasis 3 years after diagnosis: A: low power view of the tumor (T) and its capsule (C) with several intra and extracapsular vessels filled with tumor (arrows). B: Medium power view of the Hurthle cells growing in nested/trabecular pattern. C: Medium power view of a tumor thrombus (arrow) hanging in the lumen of an intracapsular vessel. D: High power view showing the tumor thrombus covered by endothelial cells (arrow). In some classification schemes, this tumor would be labeled as minimally invasive. Reprinted with permission from reference [47].

Figure 4

Extensive vascular invasion (VI) is correlated with decreased recurrence free survival in 267 patients with encapsulated low grade follicular cell derived carcinoma (log-rank test, p < 0.001). In contrast patients with no or focal VI (<4 vessels) have a very good outcome. Modified from reference [47] with permission.

Figure 5

Adverse outcome (defined as the presence of disease at last follow-up) according to degree of extra-thyroid extension (ETE) in papillary thyroid carcinoma cases with adequate follow-up. Only patients with gross ETE (15 cases) had an adverse outcome. There was no survival difference between patients without ETE (11 cases) and those with microscopic (micro) ETE (31 cases). Reprinted with permission from reference [75].

Figure 6

Stepwise molecular pathogenesis of thyroid carcinomas. Genetic profiles of papillary thyroid carcinoma (PTC), poorly differentiated thyroid carcinomas (PDTC), and anaplastic carcinoma (ATC) reveal a stepwise progression of thyroid carcinoma characterized by increased mutation burden and greater frequency of mutation in TERT promoter, TP53, EIF1AX, PIK3CA-AKT-mTOR pathway, SWI/SNF complex, mismatch repair genes, and histone methyltransferases (HMTs). Microscopic pictures of H&E sections from PTC (top left), ATC (top right), and PDTC (top center) with upper picture representing PDTC diagnosed by the MSKCC criteria only and lower picture showing PDTC fulfilling both MSKCC and Turin proposal. Below are the rates of genetic alterations in each histotype. Reprinted with permission from reference [58].