Incidental papillary microcarcinoma of the thyroid--further evidence of a very low malignant potential: a retrospective clinicopathological study with up to 30 years of follow-up.

BACKGROUND: Despite the frequent occurrence of papillary microcarcinoma (PMC) of the thyroid, no consensus on its malignant potential or its treatment exists. The objective of this study was to analyze the clinicopathological characteristics of a retrospective cohort of consecutive patients with PMC treated in a single institution during a 30-year period and to study the incidence rates of PMC in all patients operated on for thyroid diseases during this period. METHODS: Demographic data, clinical characteristics, histological workup of the resected glands, histopathological features, treatment, and follow-up data were studied. RESULTS: Between 1975 and 2004, [corrected] 759 PMCs were detected in 28,197 patients who received thyroidal surgery. The detection rate of PMC was significantly determined by the accuracy of the histological examination. Only 5 patients with PMC presented with clinically apparent lymph node metastases and 754 were incidental PMCs. Mean follow-up was 88±2 (range, 11-639) months. Only three patients experienced recurrence in cervical lymph nodes, all of whom presented with clinically suspect cervical nodes. No patient died of disease. Clinically apparent lymph node metastases and stage pT3 were significantly associated with recurrence. CONCLUSIONS: Incidentally detected PMC, even when multifocal, is a biologically indolent tumor that seldom if ever progresses. In contrast, clinically occult PMC detected due to clinically suspected and histological confirmed lymph node metastases or extrathyroidal growth may show a more aggressive course with disease recurrence and an eventual poorer prognosis.

Carbonic anhydrase IX overexpression is associated with diminished prognosis in esophageal cancer and correlates with Her-2 expression.

BACKGROUND: Carbonic anhydrase IX (CAIX), a transmembrane glycoprotein, seems to play a key role in the adaption of tumor cells to hypoxia. This study was designed to investigate the clinical role of CAIX and its association with Her-2 in a large cohort of adeno- (AC) and squamous cell carcinomas (SCC) of the esophagus and their metastases. METHODS: Expression of CAIX and Her-2 was investigated immunohistochemically in formalin fixed, paraffin-embedded tissue from 330 esophageal cancers (182 ACS, 148 SCCs). Corresponding lymph node metastases in 137 cases, distant metastases in 34 cases, and local recurrences in 14 cases were analyzed for CAIX expression. RESULTS: A total of 147 cases (44.5%) showed strong CAIX expression (AC: 46.7%; ACC: 41.9%). CAIX status of the primary tumor influenced CAIX expression in corresponding lymph node metastases (P<0.001, linear regression). High CAIX-expression was an independent prognostic factor for shorter overall and disease-free survival (P≤0.05, Cox regression). Twenty-nine ACs (15.9%) and 6 SCCs (4.1%) showed Her-2 overexpression. In AC, a significant positive correlation between the Her-2 status and CAIX expression was found (P=0.009, chi-square test). CONCLUSIONS: High CAIX expression is associated with shorter survival in esophageal cancer, and the hypoxic phenotype seems to be preserved at least during formation of lymph node metastases. Inhibition of CAIX might reduce the ability of tumor cells to establish disseminated disease. In Her-2 overexpressing ACs, blocking of this tyrosine kinase, e.g., by monoclonal antibodies, might induce this effect.

Increase of papillary thyroid microcarcinoma and a plea for restrictive treatment: A retrospective study of 1,391 prospective documented patients.

BACKGROUND: The incidence of papillary thyroid microcarcinomas (PMCs) has increased sharply and therefore the lack of consensus for treatment has become a clinical dilemma. Our aim was to evaluate a less-radical approach. METHODS: This study includes 1,391 patients with PMC treated at a single surgical referral center in the endemic goiter area in Austria. Data, including long-term follow-up examinations with a median follow-up time of 7 years, were collected from the institutional surgery database. RESULTS: Of the 1,391 patients, 947 (68.1%) had a near-total or total thyroidectomy; 1,090 patients (78.3%) had no lymphadenectomy, and 1,136 patients (81.7%) did not receive radioiodine treatment. Twenty-one patients (1.5%) underwent reoperation, 5 because of lymph node recurrence (0.4%), 16 with clinically benign recurrence, including 4 cases of another PMC. There were no recurrences in the thyroid bed and no disease-related deaths. Risk factors for lymph node recurrences were nonincidental finding, nodal metastases at presentation, young age, aggregate tumor size, and subcapsular tumor localization. Multifocality, sex, maximum tumor size, and the extent of surgery were not relevant factors. CONCLUSION: Nodal recurrence is rare and reoperation cured all patients. Micrometastases are not of clinical relevance. The postoperative findings of most PMCs suggest that, even if multifocal, a limited approach without completion thyroidectomy, lymphadenectomy and radioiodine treatment is sufficient. In case of pre- or intraoperative clinically suspected nodal metastases or postoperatively diagnosed risk factors we propose the standard radical procedure. Routine preoperative cervical lymph node sonography is advisable before any thyroid surgery.

Thrombocytes Correlate with Lymphangiogenesis in Human Esophageal Cancer and Mediate Growth of Lymphatic Endothelial Cells In Vitro.

Recent data provide evidence for an important role of thrombocytes in lymphangiogenesis within human malignant disease. The aim of this study was to investigate the role of thrombocytes in lymphangiogenesis in human esophageal cancer. Perioperative peripheral blood platelet counts (PBPC) were evaluated retrospectively in 320 patients with esophageal cancer, comprising 184 adenocarcinomas (AC), and 136 squamous cell carcinomas (SCC). Data on lymphangiogenesis evaluated by anti-podoplanin immunostaining were available from previous studies, platelets within the tumor tissue were assessed by CD61 immunostaining. For in vitro studies, human lymphatic endothelial cells (LECs) were isolated and co-cultured with peripheral blood platelets. Stromal thrombocytic clusters (STC) were evident in 82 samples (25.6%), and vascular thrombocytic clusters (VTC) in 56 (17.5%). STC and VTC were associated with a significantly higher PBPC at investigation of all cases. The presence of STC was associated with higher lymphatic microvessel density (p<0.001), PBPC and STC were associated with lymphovascular invasion of tumor cells in a regression model. The presence of STCs was associated with shorter DFS of all patients (p = 0.036, Breslow test), and VTC with shorter DFS in in SCC (p = 0.025, Breslow test). In cell culture, LEC proliferation was enhanced by co-culture with human platelets in a dose- and time-dependent manner mediated by the release of PDGF-BB and VEGF-C. Platelets play an important role in lymphangiogenesis and lymphovascular invasion in esophageal cancer, influencing prognosis. So the disruption of signaling pathways between platelets, tumor cells and lymphatic endothelium might be of benefit for patients.

RAF-kinase inhibitor protein (RKIP) downregulation in esophageal cancer and its metastases.

Raf kinase inhibitor protein (RKIP) is an inhibitor of Raf-mediated activation of mitogen-activated protein (MAP) kinase (MEK)-MAP kinase and is considered as an important tumor suppressor. RKIP-expression was investigated retrospectively in 321 esophageal cancers [179 adenocarcinomas (ACs), 142 squamous cell carcinomas (SCCs)]. RKIP-expression was further investigated in 41 precursor lesions consisting of 14 cases of non-dysplastic Barrett's mucosa, 5 low grade dysplasias (LGD), and 12 high grade dysplasias (HGD) as well as, 4 cases with low grade and 6 cases with high-grade squamous cell dysplasia. Corresponding lymph node metastases were investigated in 140 patients, distant metastases in 29, and local recurrences in 12. High RKIP-expression was significantly more common in Barrett's mucosa without dysplasia and in LGD compared to HGD (p = 0.047, χ(2) test) and invasive AC (p < 0.001, χ(2) test). In 187 primary esophageal cancers (58.3 %) RKIP was downregulated (AC: 51.4 %; SCC: 66.9 %). RKIP status of primary tumors influenced RKIP expression in corresponding lymph node and distant metastases (p < 0.05, linear regression). Downregulation of RKIP was associated with shorter overall survival (OS) and disease free survival (DFS) in all tumors (p ≤ 0.05, Cox regression). In AC, downregulation of RKIP was an independent prognostic factor for OS and DFS (p ≤ 0.05, Cox regression), while in SCC it reached significance only in univariate analysis (p ≤ 0.05, log-rank test). In conclusion, downregulation of RKIP is associated with shorter survival in esophageal cancers, and RKIP status of tumor cells seems to be preserved at the formation of metastases. Inhibition of RKIP-downregulation might reduce the ability of esophageal cancers to establish disseminated disease.

The incidence of lymphocytic thyroid infiltration and Hashimoto's thyroiditis increased in patients operated for benign goiter over a 31-year period.

The incidence of Hashimoto's thyroiditis (HT) seems to have increased over the last several decades. Since there is a lack of recent studies in the literature that evaluate this phenomenon on a histological basis, we aimed to assess the incidence of lymphocytic thyroid infiltration (LTI) in our large surgical patient collective over a 31-year period. In our study, a total of 1,050 patients who had undergone uni- or bilateral thyroid surgery for benign goiter were included (150 patients in each group, during 1979 to 2009). The stored histological sections of the removed thyroid specimens were re-analyzed, including routine grading of LTI severity on a scale of 0-4, according to Williams and Doniach. Positive correlations were seen for the incidences of LTI grading (0-4) (r = 0.077, p = 0.013) and HT (r = 0.044, p = 0.078) over the years. Furthermore, when comparing the years 1979-1989 and 1994-2009, i.e., before and after the second iodine prophylaxis had been introduced in Austria, a higher incidence of HT was found for the later years (2 out of 450, 0.4%, vs. 6 out of 600, 1.0%, respectively; p < 0.0001). In conclusion, the data demonstrate that the incidence of LTI and HT has increased substantially over the last 31 years.

Expression of Her-2 in carcinomas of the esophagus.

The human epidermal growth factor receptor-2 gene (HER-2) encodes for a membrane-bound tyrosine kinase (Her-2), which is overexpressed in various human cancers. Her-2-targeted therapy has recently been shown to be beneficial for patients with advanced gastric cancer. Her-2 protein expression was investigated in 341 esophageal carcinomas [152 squamous cell carcinomas (SCC), 189 adenocarcinomas (AC)], 39 cases of Barrett mucosa, and 11 cases of squamous cell dysplasia. HER-2 gene amplification was assessed by colorimetric in-situ hybridization. Positive Her-2 status was found in 15.3% of ACs and 3.9% of SCCs. Positive Her-2-status was more common in dysplastic Barrett mucosas compared with nondysplastic ones (P=0.04). In 26% of the patients with ACs who had received neoadjuvant chemotherapy (n=39), the Her-2 status of pretherapeutic biopsies was different compared with subsequent surgical specimens. There was no statistically significant correlation between Her-2 status and patients' survival. Although Her-2 overexpression is rare in SCCs, it is found in 15.3% of ACs, where amplification of HER-2 gene and overexpression of Her-2 protein seem to be early events in carcinogenesis. The evaluation of Her-2 status in tumor biopsies and in particular in the context with possible alterations after neoadjuvant treatment can potentially lead to false Her-2-staging. Although Her-2-overexpression in esophageal cancer seems to have no influence on patients' survival, these subtypes of esophageal ACs have to be considered as targets for an anti-Her-2 therapy.