Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal

Abstract

There is a continuous debate regarding the classification of thyroid follicular lesions and the term "well-differentiated tumor of uncertain malignant potential (WDT-UMP)" was recently introduced to cover this problematic spectrum of tumors. The objective of this study was to reappraise WDT-UMP using morphological, immunochemical, and molecular analysis and to shed more light on encapsulated thyroid follicular-patterned tumors. A total of 30 cases of WDT-UMP with equivocal papillary thyroid carcinoma-type nuclear changes (PTC-N) or focal unequivocal PTC-N were examined. As a control, follicular adenoma (n = 29), follicular carcinoma (n = 8), hyalinizing trabecular adenoma (n = 5), and PTC (n = 48) were included. HBME-1, cytokeratin 19, and galectin-3 were positive in 12 (40.0%), 10 (33.3%) and 11 (36.7%) cases of WDT-UMP, respectively. According to the positivity of those markers, significant differences were obtained between WDT-UMP and PTC encapsulated common type (P = 0.028, 0.010, and 0.004, respectively), infiltrative follicular variant (P = 0.020, 0.026, and 0.008, respectively), and infiltrative common type (P = 0.004, 0.001, and 0.005, respectively), but not between WDT-UMP and follicular adenoma or follicular carcinoma. BRAF(V600E) mutation was absent but RET/PTC1 rearrangement was found in only two (6.7%) cases of WDT-UMP. None of the 20 patients with WDT-UMP developed recurrence, with an average follow-up of 80 months. These findings indicate that WDT-UMP has a favorable outcome and is distinct from PTC in morphological, immunohistochemical, and molecular characteristics. We propose that WDT-UMP should be classified as "well-differentiated tumor with uncertain behavior".

Figure 1

Nomenclature for encapsulated thyroid follicular tumors (modified with permission from Williams’ proposal^{( 13 )}). EFV‐PTC, encapsulated follicular variant papillary thyroid carcinoma; FTA, follicular thyroid adenoma; PTC‐N, papillary thyroid carcinoma‐type nuclear changes; WDT‐UB, well‐differentiated tumor with uncertain behavior; WDT‐UMP, well‐differentiated tumor of uncertain malignant potential.

Figure 2

Comparison of morphology in different follicular thyroid lesions. (A) Normal thyroid epithelium. (B) Follicular variant papillary thyroid carcinoma, which shows typical nuclear changes of papillary thyroid carcinoma. (C,D) Well‐differentiated tumor of uncertain behavior, which shows 2–4‐times enlargement of nuclei size, ground glass features, and 3–4% of nuclear grooves, but pseudoinclusions are rare or absent. (E) Follicular thyroid adenoma, which shows 1–4‐times enlargement of nuclei size, the obvious difference is that the nuclei are hyperchromatic. (F) Hyalinizing trabecular adenoma, which is encapsulated, with trabecular growth pattern, polygonal and elongated cells, pseudoinclusions, and cytoplasmic yellow bodies. There is an accumulated hyaline substance in the basement membrane between trabeculae and alveoli. Original magnification: (C,F) ×100; (A,B,D,E) ×200.

Figure 3

Immunohistochemistry of HBME‐1, GAL‐3, CK19 in well‐differentiated tumor of uncertain behavior (WDT‐UB), follicular thyroid adenoma (FTA), and follicular variant papillary thyroid carcinoma (FV‐PTC). (A) In WDT‐UB, the reaction of the three markers increased, but was mainly in the cell membrane, and the staining was less intense. (B) In FTA, only occasional reaction with the three markers was found. (C) In infiltrative FV‐PTC, all of the three markers showed intense and diffuse reaction with the carcinoma cells. Original magnification: (A,C) ×200; (B) ×100.

Figure 4

Different expression of HBME‐1, cytokeratin 19 (CK19), and galectin‐3 (GAL‐3) in well‐differentiated tumor of uncertain behavior (WDT‐UB) and the other five groups of thyroid tumors. P‐values obtained using the chi‐square or Fisher’s exact test. C‐PTC, infiltrative common type papillary thyroid carcinoma; EC‐PTC, encapsulated common type papillary thyroid carcinoma; FTA, follicular thyroid adenoma; FTC, follicular thyroid carcinoma; IFV‐PTC, infiltrative follicular variant papillary thyroid carcinoma.

Figure 5

Sequence analysis of BRAF exon 15 in one patient (case 7) showing the wild‐type sequence (top panel), and of RET/PTC1 rearrangement (case 23) harboring H4/ret rearrangement (bottom panel).