Diagnostics and treatment in bronchial carcinoid tumors

At the start of this thesis there were several unanswered questions with regard to optimal patient selection for different treatments of bronchial carcinoid. Also, there were unanswered questions with regard to classification of bronchial carcinoid on small histological samples and with regard to prognostic value of several new tissue biomarkers. The aim of this thesis was to further optimize patient selection for parenchyma sparing techniques, and to explore the potential value of biomarkers in the treatment of bronchial carcinoid. Part one (chapter 2-5) of this thesis describes the classification of bronchial carcinoid on small histological samples and the use of diagnostic and prognostic biomarkers. In Chapter 2 we analyze patient selection for endobronchial treatment and underscore the importance of radiological assessment of bronchial carcinoids. Differentiation between typical and atypical carcinoid according to the current WHO classification is accomplished by obtaining the mitotic count and the presence of necrosis. As outlined above, TC is defined as a neuroendocrine tumour with less than 2 mitoses per 2 mm2 and absence of necrosis, while AC is defined by 2-10 mitoses per 2 mm2 and/or the presence of (dot-like) necrosis. However, it is known that small biopsies have limited diagnostic value for the distinction between TC and AC. In Chapter 3 and Chapter 4 we analyzed biopsy-resection paired specimens of patients referred for treatment for bronchial carcinoid to measure accuracy of pretreatment biopsies and analyze the value of tumor biopsy size. Furthermore, we describe the reliability of different immunohistochemical markers on different biopsies and resection specimens, and assessed the impact of specimen size on the accuracy of the diagnosis. Because the current classification of TC and AC only partially reflects their metastatic potential, there is a need for more accurate prognostic biomarkers for bronchial carcinoids. In Chapter 5 we investigated a combination of morphological and novel immunohistochemical markers for predicting dissemination. Part two (chapter 6-8) focuses on therapeutic strategies and patient selection for EBT. In Chapter 6 we present the results of a systematic review of the available literature on the feasibility and outcome of endobronchial treatment compared to surgical resection. We studied several endpoints such as overall survival, disease free survival, recurrence rate, complications, quality of life, and healthcare costs. Where EBT can be curative for patients with small intraluminal carcinoid tumors, tumor debulking prior to surgery may potentially result in less lung parenchyma that has to be removed during surgery to achieve complete resection of the tumor. In addition, EBT may reduce the need for sleeve resection to achieve radical margins when bulky tumors are removed. It is in Chapter 7 that we investigated whether endobronchial therapy for bronchial carcinoid, if not curative, can reduce the extent of the surgical resection and whether EBT prior to surgery is associated with increased surgical morbidity. Several letters, in reply to comments from experts in the field of treatment for bronchial carcinoid tumors, regarding published studies by our group, are bundled in Chapter 8.