Expression of the membrane mucins MUC4 and MUC15, potential markers of malignancy and prognosis, in papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequent carcinoma of the thyroid gland and has a relatively good prognosis. However, it is important to identify PTC characteristics that indicate high risk for recurrence and metastasis. To date, overexpression of the membrane mucin, MUC1, has been investigated as a key molecular event in the pathogenesis of aggressive PTC. However, other membrane-associated mucins, matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-13 (TIMP-3), have not been studied yet. The aim of this study was to evaluate the expression levels of MUC4, MUC15, MMP-13, and TIMP-3 and their prognostic significance in PTC. METHODS: We analyzed MUC4, MUC15, MMP-13, and TIMP-3 expression in 10 PTC and 10 normal thyroid tissue samples using real-time reverse transcription-polymerase chain reaction. Tissue array blocks were obtained from 98 PTC cases. Tumor regions and nontumor regions were analyzed in tissue array blocks and immunohistochemistry studies were conducted using sectioned slides. Semiquantitative scores were correlated with clinicopathological factors of 98 PTC patients. RESULTS: MUC4- and MUC15-specific mRNA was increased by 78-fold and 4.75-fold, respectively, in PTC samples compared with normal thyroid tissues. MMP-13 and TIMP-3 gene expression levels were decreased by approximately 0.39-fold and 0.53-fold, respectively. By immunohistochemistry, MUC4 and MUC15 expression levels were increased in PTC samples compared with normal thyroid tissues (p < 0.001). MMP-13 and TIMP-3 expression levels were decreased in PTC samples compared with normal thyroid tissues (p < 0.001). High MUC4 scores were significantly correlated with small tumor size and papillary thyroid microcarcinoma subtype. High MUC15 scores were significantly correlated with age (≥45 years), distant metastasis, and multifocality. CONCLUSIONS: MUC4 and MUC15 were overexpressed in PTC, and high MUC15 expression was associated with high malignant potential. MUC15 may serve as a prognostic marker and potential novel therapeutic target in PTC.

Visually discernible [18F]fluorodeoxyglucose uptake in papillary thyroid microcarcinoma: a potential new risk factor.

CONTEXT: A significant number of papillary thyroid microcarcinomas (PTMCs), despite excellent prognosis, show aggressive features such as extrathyroidal extension (EE) and lymph node metastasis (LNM) that may not always be detected preoperatively or intraoperatively. The relapse rate appears also substantial. OBJECTIVE: To assess the value of [(18)F]fluorodeoxyglucose (FDG) uptake in PTMC as a potential risk factor for preoperative risk stratification. METHODS: This retrospective study included 87 patients (17 males and 70 females; mean age = 51.2 yr, range 29-74 yr) with a unifocal PTMC who underwent preoperative FDG-positron emission tomography (PET)/computed tomography (CT)and total thyroidectomy and central lymph node dissection. Statistical analyses were performed to compare the gender, age, tumor size, and FDG uptake in PTMC with the presence of histopathologically proven EE and central LNM (cLNM). RESULTS: Of the 87 patients, 44 (51%) had EE, and 27 (31%) had cLNM. PET/CT showed visually discernible FDG uptake in 46 PTMCs (53%). FDG positivity of PTMCs was the only significant variable correlated with both EE and cLNM; there was a significant difference in the prevalence of both EE (70 vs. 29%) and cLNM (41 vs. 19.5%) between the FDG-positive and FDG-negative groups. In contrast, other already known risk factors, i.e. gender, age, and size, showed a correlation with only one or neither of EE and cLNM. CONCLUSION: The results indicate that visual FDG positivity in PTMCs is a potential risk factor that can be useful for preoperative risk stratification. Prospective studies would be warranted to assess the long-term benefit and cost effectiveness of preoperative FDG-PET/CT.

Predicting recurrence of nonfunctioning pituitary adenomas.

CONTEXT: Nonfunctioning pituitary adenomas are commonly diagnosed as large tumors. Most are detected incidentally during imaging studies or as a result of neurological manifestations. Depending on severity, most patients with large tumors require surgery and adjunctive therapies because of the high rate of tumor recurrence. The ability to predict the recurrence of a tumor at the time of the initial surgery would be helpful in deciding whether adjunctive therapy is necessary and decreasing morbidity. We investigated the use of several cellular markers for predicting the recurrence of nonfunctioning pituitary adenomas. OBJECTIVE: A tissue array block was made using tissue from 35 cases of nonfunctioning pituitary adenomas (16 cases with early recurrence 4 yr after surgery, and nine cases without recurrence). Levels of tumor tissue cellular markers associated with cell proliferation or apoptosis were analyzed, and immunohistochemical study of cellular markers was conducted using sectioned slides from the tissue array block. RESULTS: High Ki-67 and TUNEL labeling indexes were associated with recurrent nonfunctioning pituitary adenomas. Tumors with a high level of expression of phospho-Akt, phospho-p44/42 MAPK, and PTTG1 were associated with early recurrence. However, high levels of expression of phospho-CREB and ZAC1 were inversely associated with recurrence. CONCLUSIONS: Tumors with high levels of expression of phospho-Akt and phospho-p44/42 MAPK and low levels of expression of phospho-CREB and ZAC1 should be followed closely and may require adjunctive therapy to prevent tumor recurrence.

Tumor tissue identification in the pseudocapsule of pituitary adenoma: should the pseudocapsule be removed for total resection of pituitary adenoma?

OBJECTIVE: The microsurgical pseudocapsule can be found in the transition zone between an adenoma and the surrounding normal pituitary tissue. We investigated the precise histology of the pseudocapsule. Furthermore, we evaluated the remission rate, the changes in pituitary function, and the recurrence rate after intensive resection of the pseudocapsule. METHODS: In 616 patients with pituitary adenomas (Hardy Types I-III) over a period of 14 years, we introduced intensive resection of the microsurgical pseudocapsule to achieve complete tumor removal. A combined pituitary function test and radiological study were performed on the patients before surgery, 1 year after surgery, and at subsequent 1.5-year intervals 2 to 13 years postoperatively. RESULTS: Microsurgical pseudocapsules were identified in 343 (55.7%) of 616 patients, and the distinct microsurgical pseudocapsules were observed in 180 (52.5%) of these patients. In the remaining 163 patients, the microsurgical pseudocapsules were incompletely developed. Tumor cluster infiltration was present in the pseudocapsule in 71 (43.6%) of these patients. Aggressive resection of the microsurgical pseudocapsule was more often required in larger tumors than in smaller ones. The presence of a pseudocapsule was slightly more frequent in prolactin-secreting tumors (70.9%) than in growth hormone-secreting (55.0%) and adrenocorticotropic hormone-secreting (40.0%) tumors. In the 243 patients of the total resection group who underwent combined pituitary function tests more than 2 times after surgery, the surgical remission rate was 99.1% in clinically nonfunctional tumors, 88% in growth hormone-secreting, 70.6% in prolactin-secreting, and 100% in adrenocorticotropic hormone-secreting tumors. The surgical remission rate was 86.2% in the presence of a pseudocapsule and 94.3% in the absence of a pseudocapsule. Preoperative hypopituitarism improved in 140 patients (57.6%), persisted in 47 patients (19.3%), and was aggravated in 33 patients (13.6%). There was no statistical difference in improvement or deterioration of pituitary function according to the existence or absence of the pseudocapsule. The tumor recurrence rate was 0.8% in the total resection group and was 42.1% in the subtotal resection group. CONCLUSION: We have shown that tumor tissue is frequently present within the pseudocapsule, suggesting that any tumor remnant in the pseudocapsule could be a source of recurrence and an obstacle to achieving complete remission. These results indicate that intensive resection of the pseudocapsule could result in a higher remission rate without deteriorating pituitary function.

HoxD10 gene delivery using adenovirus/adeno-associate hybrid virus inhibits the proliferation and tumorigenicity of GH4 pituitary lactotrope tumor cells.

Prolactinoma is one of the most common types of pituitary adenoma. It has been reported that a variety of growth factors and cytokines regulating cell growth and angiogenesis play an important role in the growth of prolactinoma. HoxD10 has been shown to impair endothelial cell migration, block angiogenesis, and maintain a differentiated phenotype of cells. We investigated whether HoxD10 gene delivery could inhibit the growth of prolactinoma. Rat GH4 lactotrope tumor cells were infected with adenovirus/adeno-associated virus (Ad/AAV) hybrid vectors carrying the mouse HoxD10 gene (Hyb-HoxD10) or the beta-galactosidase gene (Hyb-Gal). Hyb-HoxD10 expression inhibited GH4 cell proliferation in vitro. The expression of FGF-2 and cyclin D2 was inhibited in GH4 cells infected with Hyb-HoxD10. GH4 cells transduced with Hyb-HoxD10 did not form tumors in nude mice. These results indicate that the delivery of HoxD10 could potentially inhibit the growth of PRL-secreting tumors. This approach may be a useful tool for targeted therapy of prolactinoma and other neoplasms.

Expression and role of estrogen receptor alpha and beta in medullary thyroid carcinoma: different roles in cancer growth and apoptosis.

Medullary thyroid carcinoma (MTC) originates from parafollicular C cells. Estrogen receptor beta(ERbeta) expressionwas detected in normal parafollicular C cells and MTC tumor tissue, but ERalpha expression in MTC tumors still remains undetermined. The appearance and loss of ERalpha or ERbeta expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ERalpha, ERbeta, and Ki67, a mitotic index, in 11 human MTC tissue samples. ERalpha was detected in 10 cases (91%), and ERbeta expression was observed in 8 cases (72.7%). A majority (8/10) of ERalpha-positive tumors showing ERbeta Ki67 expression was detected in three cases (27.3%). Neither clinical parameters nor tumor node metastasis (TNM) tumor staging was correlated with the positivity for ERs or Ki67. To investigate the biological role of each ER, we used ER-negative MTC TT cells and adenoviral vectors carrying ERalpha (Ad-ERalpha), ERbeta (Ad-ERbeta), estrogen response element (ERE)-Luc (Ad-ERE-Luc), and activator protein 1 (AP1)-Luc (Ad-AP1-Luc). Estrogen stimulated and anti-estrogen, ICI 182 780, suppressed ERE reporter activity in TT cells expressing ERalpha or ERbeta, suggesting that both ERs use the same classical ERE-mediated pathway. Ad-ERalpha infection stimulated TT cell growth; in contrast, Ad-ERbeta infection suppressed their growth. Apoptosis was detected in Ad-ERbeta-infected TT cells. Estrogen and anti-estrogen suppressed AP1 activity in Ad-ERalpha-infected cells, whereas upon Ad-ERbeta infection estrogen further stimulated AP1 activity which in turn is suppressed by anti-estrogen, suggesting that each ER acts differently through a non-ERE-mediated pathway. Our results suggest that ERalpha and ERbeta may play different roles in MTC tumor growth and progression.

Nodular gastritis and pathologic findings in children and young adults with Helicobacter pylori infection.

PURPOSE: The aim of this study was to investigate the pathologic characteristics of nodular gastritis in children and young adults infected with Helicobacter pylori (H. pylori). MATERIALS AND METHODS: A total of 328 patients were enrolled in this study, and the diagnosis of H. pylori infection was done with gastroduodenal endoscopy concomitant with a CLO(TM) test and pathologic analysis of the biopsy specimens. Diagnoses of normal, superficial gastritis, nodular gastritis, and peptic ulcer disease were made from the gastroduodenal endoscopic findings. The density of H. pylori organisms in the gastric mucosa was rated as normal, mild, moderate, or marked. The pathologic findings of nodular gastritis were based on the histopathologic findings of inflammation, immune activity, glandular atrophy and intestinal metaplasia. Each of these findings was scored as either normal (0), mild (1), moderate (2), or marked (3) according to the updated Sydney system and using visual analog scales. The gastritis score was the sum of the four histopathologic scores. RESULTS: In this study, nodular gastritis (50.6%) was most common, and mild density (51.5%) H. pylori infection was also common upon microscopic examination. Intestinal metaplasia occurred in 9 patients (2.7%). CONCLUSION: Logistic regression revealed a significant increase in the incidence of nodular gastritis with gastritis score (p=0.008), but not an association with sex, age, or H. pylori density. Gastritis score was the only significant factor influencing the occurrence of nodular gastritis. Intestinal metaplasia, which was originally thought to be a pre-malignant lesion, occurred in 2.7% of the patients with H. pylori infection.