New developments in the therapy for NETs: risk stratification
Neuroendocrine tumors (NETs) represent a rare and diverse group of tumors with predominant location in the gastro-entero-pancreatic and bronchopulmonary system. At initial diagnosis 50% of the patients present with metastatic disease whereas more than 80% develop metastases in the course of the disease with liver metastases as the most frequent ones. In consideration of the variable and sometimes indolent tumor growth behaviour, risk stratification is an important need for therapeutic decision making. Patient prognosis is currently best reflected by different classification systems according to WHO 2000/2010 and ENETS TNM staging system1. These are based upon prognostic determinants such as histological differentiation (well-differentiated NET/neuroendocrine carcinoma and poorly differentiated neuroendocrine carcinoma) and biological/pathomorphological signs of malignancy, and more recently on the TNM staging and grading system. Grading of the tumor based on the proliferation index as measured by Ki67 immunostaining (G1<2%, G2 320%, G3>20%) next to staging seems to be the strongest predictor of survival2. Location of the primary tumor in the pancreas (compared to GI), high liver tumor burden/extended disease and carcinoid heart disease as well as highly elevated circulating chromogranin A, are worse prognostic parameters. In contrast, surgery of liver metastases and removal of the primary tumor are reported to be beneficial for patient outcome. By integrating these and additional significant prognostic factors, a nomogram can be developed to better assess an individual patients disease-specific survival3. However, it warrants prospective evaluation. Molecular imaging by 18F FDG PET may be helpful in identifying more dedifferentiated tumours and its prognostic value has to be validated in the future4. More recently molecular tissue markers (e.g. FGF13, TSC-2, and PTEN expression) were identified to predict survival in pancreatic NET5. In summary WHO/TNM classification provide currently the best tool to stratify patients, however specific and reliable molecular markers have to be identified to better select patients for specific treatments and determine surveillance strategies.
1. Rindi et al. Virchows Arch 449(4) 2006.
2. Pape et al. Cancer 113(2) 2008.
3. Modlin et al. Neuroendocrinol 92(3) 2010.
4. Binderup et al. Clin Cancer Res 16(3) 2010.
5. Missiaglia et al. J Clin Oncol 28(2) 2010.