Increased Incidence of Well-Differentiated Thyroid Cancer Associated with Hashimoto Thyroiditis and the Role of the PI3k/Akt Pathway

Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0536, USA.
Journal of the American College of Surgeons (Impact Factor: 5.12). 06/2007; 204(5):764-73; discussion 773-5. DOI: 10.1016/j.jamcollsurg.2006.12.037
Source: PubMed


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.
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.
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.
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.

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Available from: Shawn D Larson, Jan 08, 2014
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    • "PI3K-p85, mTOR and PTEN, constituents of the PI3K pathway, are highly expressed in HT and do not exhibit any expression in normal thyroid cells. Larson et al. [24] reported the expression of components of the PI3K pathway after immunohistochemical evaluation of HT and PTC thyroid tissue and normal thyroid tissue. While p-Akt, Akt1 and Akt2, components of the PI3K pathway, were highly expressed in HT and TC cells, they did not detect any expression in normal follicular cells [24, 25]. "
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    ABSTRACT: Aim of the study Important signalling pathways play fundamental roles in the pathogenesis of thyroid carcinoma (TC). PTEN, mTOR, PI3K-p85 and K-Ras are the principal factors involved in these signalling pathways. To immunohistochemically examine the expressions of PI3K, mTOR and PTEN in patients suffering from follicular TC, papillary TC or variants thereof, as well as to investigate KRAS mutations via PCR to determine their clinical and prognostic relevance to differentiated thyroid cancer. Material and methods The expression of PTEN, PI3K-p85 and mTOR was immunohistochemically examined, and the mutation of K-Ras was examined via PCR. The results obtained were compared to the clinico-pathologic characteristics of the patients. Results A significant correlation was found between p85 expression and lymphovascular invasions and between PTEN expression and multifocality (p = 0.048 and p = 0.04, respectively), and a correlation between p85 and capsular invasion was found, with a borderline statistical significance (p = 0.056). No expression of PTEN, p85 or Mtor was detected in normal tissue. K-Ras mutation was examined in 66 of the 101 patients (57.4%), and the percentage of patients exhibiting a K-Ras mutation was 17.4%. All of the patients exhibiting a K-Ras mutation were women (p = 0.047). The disease-free survival was 44.6 months (95% CI: 37.9–51.3) and was statistically significantly higher in the group that displayed level 1 or lower expression of p85 (p = 0.043). Conclusions The expression levels of the aforementioned markers were significantly higher in TC cells than in normal tissue. A significant correlation was detected between K-Ras mutation and gender. This study demonstrates that p85 and PTEN are markers that should be evaluated in further studies of TC.
    Contemporary Oncology / Wspólczesna Onkologia 07/2014; 18(4):234-40. DOI:10.5114/wo.2014.43803 · 0.22 Impact Factor
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    • "Although Wenzhou is an iodine-sufficient area, determining the correlation between HT and PTC in terms of iodine intake is difficult because no information on iodine intake was available in the majority of patients studied. Some molecular mechanisms, such as the PI3K/Akt or RET/RAS/ERK pathways may also contribute to tumorigenesis [20,46]. At present, no evidence suggests that HT is a premalignant lesion for PTC. "
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    ABSTRACT: Background To confirm whether clinical and biochemical parameters or Hashimoto’s thyroiditis (HT) could predict the risks of malignancy among subjects who underwent thyroidectomy, as well as to determine the influence of HT on the biological behavior of papillary thyroid cancer (PTC). Methods A total of 2,052 patients who underwent initial thyroidectomy were enrolled between June 2006 and August 2008. Serum free T4, free T3, thyrotropin (TSH), thyroglobulin, thyroglobulin antibody, antimicrosomal antibody, tumor-associated status, and thyroid disorders were documented. Results Binary logistic regression analysis was performed to define the risk predictors for thyroid cancer. Finally, calcification, HT, TSH, and age, were entered into the multivariate model. Multivariate logistic regression analysis revealed the risk of thyroid cancer increases in parallel with TSH concentration within normal range, and the risk for malignancy significantly increased with serum TSH 1.97–4.94 mIU/L, compared with TSH less than 0.35 mIU/L (OR = 1.951, 95% CI = 1.201–3.171, P = 0.007). Increased risks of thyroid cancer were also detected among the patients with HT (OR = 3.732, 95% CI = 2.563–5.435), and microcalcification (OR = 14.486, 95% CI = 11.374–18.449). The effects of HT on the aggressiveness of PTC were not observed in extrathyroidal invasion (P = 0.347), capsular infiltration (P = 0.345), angioinvasion (P = 0.512), and lymph node metastases (P = 0.634). Conclusions The risk of malignancy increases in patients with higher level TSH within normal range, as well as the presence of HT and microcalcification. No evidence suggests that coexistent HT alleviates the aggressiveness of PTC.
    World Journal of Surgical Oncology 03/2013; 11(1):56. DOI:10.1186/1477-7819-11-56 · 1.41 Impact Factor
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    • "On the other hand, it cannot be at the same time an independent prognostic factor indicating a lower number of recurrences or the presence of nodal metastases. This common transformation path of thyroid cells in papillary thyroid cancer and Hashimoto thyroiditis has been also attempted to be explained by similarities in activation of the metabolic cycle of tyrosine kinases (PI3k/Akt pathway) and overexpression of p63 protein that leads to apoptosis inhibition [26, 27]. "
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    ABSTRACT: Aims Conflicting data have been reported with regard to Hashimoto thyroiditis (HT) and risk of malignancy. The aim of this study was to evaluate coexistence of papillary thyroid cancer (PTC) with HT. Patients and methods This is a retrospective cohort study in which HT was diagnosed in 452 (F/M ratio = 405:47, median age 53.5 ± 12.1 years) of 7,545 patients qualified for thyroidectomy throughout the years 2002 to 2010. Pathological reports were reviewed to identify prevalence of PTC in HT vs. non-HT patients. Results PTC was diagnosed in 106 of 452 (23.5 %) HT patients vs. 530 of 7,093 (7.5 %) non-HT patients (p < 0.001). Metastases to level VI lymph nodes were observed in 81 of 106 (76.4 %) patients with PTC in HT vs. 121 of 530 (22.8 %) patients with PTC in non-HT disease (p < 0.001). Conclusions HT was associated with a threefold increase of PTC prevalence as compared to other non-HT thyroid diseases, and the spread of PTC to level VI lymph nodes was four times more frequent in HT than in non-HT patients.
    Langenbeck s Archives of Surgery 10/2012; 398(3). DOI:10.1007/s00423-012-1021-x · 2.19 Impact Factor
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