Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway

Abstract

Background: The link between inflammation and cancer is well-established, but the link between Hashimoto thyroiditis (HT) and thyroid cancer remains controversial. The purpose of our study was to determine the incidence of patients with thyroid cancer and associated HT at our institution, to correlate our patient population demographics with the Surveillance, Epidemiology and End Results (SEER) database, and to assess the expression of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in patients with HT.

Study design: Demographic and histologic data were collected from patients undergoing thyroid resection at the University of Texas Medical Branch from 1987 to 2002 and compared with the SEER database. Immunohistochemistry for phosphorylated Akt (a marker of PI3K activity), Akt isoforms and PTEN (an inhibitor of PI3K) was performed on paraffin-embedded blocks of resected thyroid tissue.

Results: Our patient population demographics and thyroid cancer incidence by histologic type were similar to patients in the SEER database. Ninety-eight (37.7%) resected specimens had pathologic changes consistent with HT; 43 (43.8%) had an associated well-differentiated thyroid cancer. Increased phosphorylated Akt, Akt1, and Akt2 expression was noted in regions of HT and thyroid cancer compared with regions of normal surrounding thyroid tissue.

Conclusions: Patients with HT were three times more likely to have thyroid cancer, suggesting a strong link between chronic inflammation and cancer development. PI3K/Akt expression was increased in both HT and well-differentiated thyroid cancer, suggesting a possible molecular mechanism for thyroid carcinogenesis.

Figure 1. Immunohistochemical analysis of representative thyroid tissues stained for p-Akt expression

(A, A′) Normal thyroid showing absent p-Akt expression in normal follicular cells lining a thyroid follicle (arrow head). (B, B′) Hashimoto’s thyroiditis showing p-Akt expression in areas of Hürthle cell changes (white arrow) compared with normal follicles (arrowhead) (black arrow indicates large germinal center). (C, C′) Hashimoto’s thyroiditis with papillary carcinoma. The black arrow indicates Hürthle cell changes in a region of Hashimoto’s thyroiditis with increased p-Akt expression. p-Akt expression is also increased in regions of papillary cancer (arrow head; white arrow points to a normal follicle). (D, D′) papillary carcinoma showing increased p-Akt expression (arrow head signifies papillary carcinoma; the white arrow indicates a normal residual follicle). (Panels A – D = 100x; panels A′ - D′ = 600x)

Figure 2. Immunohistochemical analysis of representative thyroid tissues stained for Akt1 expression

(A, A′) Absent Akt1 expression in normal follicular cells lining a thyroid follicle (arrow head). (B, B′) Hashimoto’s thyroiditis showing increased Akt1 expression in areas of Hürthle cell changes (white arrow) compared with normal follicles (arrowhead). The black arrow indicates large germinal center which also demonstrates increased Akt1 expression. (C) Hashimoto’s thyroiditis with papillary carcinoma showing increased Akt1 expression lining the entire follicle affected by papillary cancer. The black arrow indicates Hürthle cell changes in a region of Hashimoto’s thyroiditis with increased Akt1 expression. (C′) Strong Akt1 expression is noted in regions of papillary cancer on higher magnification (arrow head; white arrow points to a normal follicle). (D, D′) papillary carcinoma with strong Akt1 expression (arrow head signifies papillary carcinoma). (Panels A – D = 100x; panels A′ - D′ = 600x)

Figure 3. Immunohistochemical analysis of representative thyroid tissues stained for Akt2 expression

(A, A′) Normal thyroid showing absent Akt2 expression in normal follicular cells lining a thyroid follicle (arrow head). (B, B′) Hashimoto’s thyroiditis with multiple large germinal centers (black arrows) showing increased Akt2 expression. The arrow head in the inset indicates a normal follicle, and the white arrow signifies Hürthle cell change with strong Akt2 expression. (C, C′) Hashimoto’s thyroiditis with papillary carcinoma (the black arrow indicates Hürthle cell changes with Akt2 expression, the arrow head points to a normal follicle, and the white arrow signifies papillary carcinoma, again, with strong Akt2 expression). (D, D′) multiple regions of papillary carcinoma with increased Akt2 expression (the arrow head signifies papillary carcinoma). (Panels A – D = 100x; panels A′ - D′ = 600x)

Figure 4. Immunohistochemical analysis of representative thyroid tissues stained for PTEN

(A, A′) PTEN expression is noted in normal thyroid tissue (arrow head points to follicular cells lining a normal thyroid follicle). (B, B′) Hashimoto’s thyroiditis with PTEN expression noted in areas of inflammation and Hürthle cell changes (the arrow head in the inset indicates a normal follicle, and the white arrow signifies Hürthle cell changes). The black arrow indicates a large germinal center (C, C′) Hashimoto’s thyroiditis with papillary carcinoma. The black arrow indicates a region of Hürthle cell change with PTEN expression noted. The arrow head points to a normal follicle with PTEN expression; the white arrow signifies papillary carcinoma with absent PTEN expression. (D, D′) papillary carcinoma showing absent PTEN expression. The white arrow indicates a normal residual follicle; the arrow head signifies papillary carcinoma with absent PTEN expression. (Panels A – D = 100x; panels A′ - D′ = 600x)