Neuroendocrine Lung Tumors: Grade Correlates with Proliferation but not Angiogenesis

Abstract

Angiogenesis has been implicated in the progression of human neoplasia from benign precursor to invasive and metastatic phenotypes. The acquisition of dominant oncogenes in preneoplastic cells in vitro and in vivo has been associated with the increased ability of tumor cells to secrete angiogenic mediators and recruit blood vessels. However, in a subset of benign lesions, high levels of angiogenesis have been found before the conversion to invasive and metastatic phenotypes. In many of these benign lesions, dominant oncogenic pathways are activated first; then as malignant potential is acquired, there is a loss of nuclear tumor suppressor genes, such as p53 and p16. We studied neuroendocrine lung tumors (NLT) ranging from typical and atypical carcinoid tumors to large cell neuroendocrine and small cell carcinomas in order to determine whether angiogenesis (as assessed by mean vessel density) and proliferation rates (as assessed by MIB-1 nuclear immunohistochemical staining) correlate with tumor type. We found that increased rates of proliferation, but not angiogenesis, correlate with tumor type. The association of increased proliferation and tumor type may prove to be clinically useful and shed light on the role of sequential oncogenic alterations in NLT.

p53, cellular proliferation, and apoptosis-related factors in thymic neuroendocrine tumors

“…Similarly, in the literature, thymic carcinomas and high-grade pulmonary neuroendocrine neoplasms tended to have a high rate of cellular proliferation, whereas thymomas and bronchopulmonary carcinoids had lower rates of cellular proliferation. 17,22,23,34,37,41,[43][44][45][46][47][48] This finding is in keeping with the observation in other thymic neoplasms that proliferative activity is linked with overexpression of p53 protein, particularly in more aggressive histologic grade tumors. 23,25 However, we found that low-grade thymic neuroendocrine tumors, which morphologically resembled typical carcinoid tumors, did not have the low labeling indices that we had previously reported in their low-grade pulmonary counterparts.…”

“…23,25 However, we found that low-grade thymic neuroendocrine tumors, which morphologically resembled typical carcinoid tumors, did not have the low labeling indices that we had previously reported in their low-grade pulmonary counterparts. 48 The high proliferation rate that frequently occurs in thymic neuroendocrine tumors could be a key factor in explaining its aggressive biological behavior.…”

Correlation between Semi-Quantitative 18F-FDG PET/CT Parameters and Ki-67 Expression in Small Cell Lung Cancer

“…There were three cases of smallcell lung cancer with a low percentage of Ki-67 expression level (below 30 %) in the present study. Even though some studies showed a high Ki-67 percentage in small-cell lung cancers [34,35], other studies showed small-cell lung cancer cases with a low percentage of Ki-67-positive cells [36,37]. Therefore, we considered the findings in the present study reliable.…”

Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors

“…Both large-cell neuroendocrine carcinomas and smallcell carcinomas demonstrated significantly higher proliferation activity than typical and atypical carcinoids (Po0.0001), and the same was true for atypical carcinoids than typical carcinoids (Po0.01), while there was no significant difference in Ki-67 expression between large-cell neuroendocrine carcinomas and small-cell carcinomas (P ¼ 0.4031), in keeping with previous studies. 34,35 These results reflect the low-grade biological features of typical carcinoid, the less aggressive behavior of atypical carcinoid and the highly malignant nature of large-cell neuroendocrine carcinoma and small-cell carcinoma.…”