UTMB patient demographics
Between January 1, 1987, and December 31, 2002, 812 patients underwent thyroid resection at UTMB. Of these, 260 patients were identified as having primary thyroid cancer, HT, or HT associated with thyroid cancer (162, 52, and 46 patients, respectively). The remaining 552 patients had diagnoses other than thyroid cancer or HT and were excluded from the study. Two patients with primary thyroid lymphoma, one patient with insular thyroid carcinoma (an unusual poorly differentiated cancer), and one patient with Hürthle cell carcinoma without definitive evidence of follicular cell involvement were excluded from further analysis. There was a total of 161 women (78.9%) and 43 men (21.1%) with a median age of 40 (range 7–79). Caucasians represented 49% of all patients, followed by Hispanic (33.2%), African American (13.9%), and Asian/Pacific Islander (3.5%). Total thyroidectomy was performed in 55.8% of resections and 99 patients (38.4%) underwent lymph node dissection with an average of 7.5 nodes removed. Primary thyroid malignancy was identified in 204 patients (25.1%); PTC was the most common histological type identified (87.6%), followed by FTC (10.4%), medullary (0.5%) and anaplastic (1.5%). Median tumor size was 2.0 cm (range 0.09 – 9.0 cm) and 83.7% of patients had tumor confined to the thyroid. Lymph node metastases were present in 70 patients (34%), 4 patients (2.0%) had evidence of distant metastases, and 137 (68.8%) had Stage I disease (Stage II: 10.6%; III: 14.1%; IV: 6.5%).
Comparison of UTMB patients with the SEER database
Demographics for patients with thyroid cancer resected at UTMB and those recorded in the SEER database are presented in . A search of the SEER database identified 22,647 patients with PTC, FTC and poorly differentiated (medullary and anaplastic) thyroid cancer during the study period. The two populations had a similar ratio of female patients, median tumor size and histological type. The median age was slightly higher in SEER patients (44 vs. 40; p=0.004). Racial and clinical stage distributions were also noted to be statistically different (p<0.0001 for both factors) between the two populations. UTMB had fewer Caucasian and Asian patients and a higher number of African-American and Hispanic patients compared to the SEER database consistent with the demographic make-up of the state of Texas. While the histological type was similar, the stage distributions differed between the 2 populations. The majority of SEER patients were designated Stage I (83.7%) followed by Stage II (7.7%), whereas 68.8% of UTMB patients were Stage I followed by Stage III (14.1%).
Comparison of UTMB patient demographics with SEER Database.
To further examine these populations, patients were stratified by gender and histological type of cancers (). The frequency of histological type by gender was similar between the UTMB and SEER patients. There were no statistical differences when these two groups were compared for an association between thyroid cancer and the populations controlling for gender (p=0.19). UTMB and SEER patients were then stratified by race and histological type (). Again, the frequency of histological type by race was similar between the two populations with no association between thyroid cancer when controlling for race (p=0.21).
Comparison of sex & frequency of thyroid cancer for UTMB and SEER patients.
Comparison of race & frequency of thyroid cancer in UTMB and SEER patients.
Comparison of HT and HT associated with thyroid cancer
lists univariate prognostic factors for UTMB patients with thyroid cancer stratified by the presence or absence of HT. Overall, 98 patients were identified as having pathological changes consistent with HT (37.7%), 86 (88%) were with a median age of 44 (range 14–73). Of these cases, 46 patients (47%) had associated thyroid malignancy (all histological types). PTC was the most common histological type (74%), followed by FTC (19.6%), lymphoma (4.3%), and anaplastic thyroid cancer (2.2%). Patients with HT and associated cancer were similar to patients with thyroid cancer alone in regards to median age (41 to 39; p=0.64), racial distribution (p=0.61) and median tumor size (2.15 to 1.90 cm; p=0.29). A significantly higher percentage of women had HT and associated thyroid cancer when compared to thyroid cancer alone (90.7 vs. 75.5, respectively; p=0.03). While the overall racial distribution was similar (p=0.61), we observed that Hispanic patients had a lower incidence of HT and associated cancer compared to cancer alone (25.6% vs. 35.5%). Meanwhile, Caucasians and African-American had a slightly higher incidence of HT and associated cancer and thyroid cancer alone (53.5% vs. 47.7%, 18.6% vs. 12.3%, respectively).
Univariate prognostic variables in UTMB patients with well-differentiated thyroid cancer (PTC/FTC) stratified by the presence of HT.
The presence of positive lymph nodes and extrathyroid tumor extension were also assessed. Six patients (14%) with HT and associated thyroid cancer had extrathyroid extension compared to 38 (24.5%) patients with thyroid cancer alone; however, this was not statistically significant (p=0.14). The percentage of patients with positive lymph nodes between the groups was also not statistically significant (27.9 vs. 35.1; p=0.38). There was no statistical difference in clinical stage between patients with HT and cancer and cancer alone. Patients with HT alone had a higher median age when compared to patients with HT and cancer (48 vs. 41, respectively). Our patients with HT and associated thyroid cancer were similar to UTMB thyroid cancer patients with respect to demographics and prognostic variables; however, there was a significantly higher percentage of women with HT and associated cancer. Overall, UTMB patients with HT were approximately 3 times more likely to have well-differentiated thyroid cancer when compared to patients with no HT (odds ratio 2.96; 95% CI: 1.9 – 4.6).
Expression of the PI3K pathway components in HT, papillary carcinoma, and corresponding normal thyroid
Histologically normal samples from patients undergoing thyroid resection for laryngeal carcinoma (control; n=10), HT (n=8), PTC (n=8), or HT associated with well-differentiated cancer (PTC; n=8) were analyzed for expression patterns of the PI3K/Akt pathway components p-Akt, Akt1, Akt2, and the tumor suppressor PTEN, the natural PI3K inhibitor. Stained specimens were then reviewed by a pathologist and graded according to expression levels. These results are summarized in . Samples were compared to H&E staining of normal, HT, HT -associated thyroid cancer and thyroid cancer alone (data not shown).
Summary of IHC staining results.
Representative tissue staining patterns from selected patients are shown in – . Similar sections of normal thyroid, thyroid with HT, HT with associated thyroid cancer and well-differentiated thyroid cancer alone were chosen to better illustrate changes in the expression of various proteins. These samples were representative of all specimens analyzed. Phosphorylated Akt was not expressed in the control tissue (). Histologically, HT is characterized by diffuse lymphocytic infiltration, parenchymal atrophy, and fibrosis, leading to a derangement in follicular cells referred to as Hürthle cell change, with an increase in cell size, acidophilic staining, shrinking of the follicular spaces, and sparse colloid deposition. In contrast to control thyroid tissues, HT specimens showed high levels of p-Akt expression within infiltrating lymphocytes and Hürthle cell changes with both a cytoplasmic and nuclear distribution (). There was no expression in normal follicular cells. Phosphorylated Akt expression was also found to be high in HT associated thyroid cancer within papillary carcinoma cells, within areas of Hürthle cell changes and within infiltrating lymphocytes (); residual normal follicles had no expression. Thyroid cancer alone (PTC) was noted to have p-Akt expression to a lesser extent again with a cytoplasmic and nuclear distribution ().
Immunohistochemical analysis of representative thyroid tissues stained for p-Akt expression
Immunohistochemical analysis of representative thyroid tissues stained for PTEN
We next analyzed specimens for Akt1 and Akt2 isoform expression. No Akt1 or Akt2 expression was noted in control thyroid tissues ( and , respectively). Similar to p-Akt, Akt1 and Akt2 expression in HT alone ( and , respectively) and HT associated thyroid cancer specimens ( and , respectively) was high in areas of infiltrating lymphocytes and Hürthle cell changes with a cytoplasmic and nuclear distribution. There was no expression of either Akt isoforms in normal follicular cells. There was significant expression of Akt1 and Akt2 within papillary carcinoma cells with a distinct absence of staining within normal follicular cells ( and , respectively).
Immunohistochemical analysis of representative thyroid tissues stained for Akt1 expression
Immunohistochemical analysis of representative thyroid tissues stained for Akt2 expression
Finally, we analyzed specimens for the tumor suppressor protein PTEN (). In contrast to p-Akt, Akt1 and Akt2, PTEN expression was expressed in normal thyroid specimens (). There was positive PTEN cytoplasmic and nuclear expression in the follicular cells lining the thyroid follicles. PTEN expression in HT specimens was similar to p-Akt, Akt1 and Akt2 expression with high expression within infiltrating lymphocytes and areas of Hürthle cell changes (). Similar to control tissues, the distribution was both cytoplasmic and nuclear. HT-associated thyroid cancer specimens had PTEN expression in infiltrating lymphocytes and areas of Hürthle cell changes; there was little, if any, PTEN expression in papillary carcinoma cells (). Papillary carcinoma specimens had no PTEN expression ().
In summary, the PI3K pathway components p-Akt, Akt1, and Akt2 were highly expressed in HT, HT-associated thyroid cancer and thyroid cancer alone with no expression noted in normal follicular cells. Conversely, the tumor suppressor PTEN was expressed in normal thyroid, with slightly increased expression in infiltrating lymphocytes and within areas of Hürthle cell change, but there was little, if any, expression of PTEN noted in papillary carcinoma cells (). These results, demonstrating increased PI3K activation and Akt isoform expression in areas of inflammation and cancer, suggest a possible common molecular mechanism between these two processes.