br Materials methods br Results
Materials & methods
Results Demographic and clinical features are listed in Table 1. From the prospective NET database we consecutively included 252 patients: 162 patients with TC, 29 patients with AC and 61 patients with LCNEC. The median follow-up time was 48 months (42–54 months) calculated according to the reverse Kaplan Meier method . Median age at diagnosis was 69 (19–89) years. Median age was higher in AC and LCNEC compared to TC (p = 0.046). Gender distribution varied amongst the subtypes with TC and AC showing a significant female predominance with 73% and 72%, respectively and LCNEC with 46% males and 54% females (p = 0.024).
Discussion In this study of 252 patients the distribution of tumour subtype consisted of 64% with TC, 12% AC and 24% LCNEC. This correlates well with prior studies describing a 10:1 relationship between frequencies of TC and AC and the fact that TC represent approximately 70–80% of neuroendocrine lung tumours . TC presented with centrally located tumours in 58% of patients whereas both AC and LCNEC presented with peripherally located tumours in the majority of patients, 52% and 64% respectively. This finding correlates well with prior studies describing TC as often centrally located and AC and LCNEC as often peripherally located . Prior studies have found median age at diagnosis in TC as low as 45 years whereas our study found a median age at diagnosis for TCs of 68 years . In the AC group we found a median age of 72 years compared to prior studies describing a median age of 55 for patients with AC . Median age in LCNEC patients was 69 years; this corresponds to previously described assumptions that LCNEC often occur in the seventh decade [17,21]. This study describes a female predominant distribution in both TC and AC with female percentages of 73% and 72%, respectively. Of LCNEC patients, 54% were female in Pimozide to prior studies that found a male predominance of these tumours . Moreover, the low number of patients with functioning tumours (only 2) is surprisingly low compared to previous findings in other studies . The role of Ki67 in BP-NETs has been debated and still remains a field of controversy. Some studies have investigated Ki67 as a prognostic factor and its role in overall survival, but final data to support this theory is still lacking. Several studies suggest that Ki67, because of its qualities in distinguishing low-grade and high-grade tumours in small biopsies or in cases with crush artefacts, merely should be seen as an adjunct diagnostic marker in cooperation with the mitotic count and necrosis in the initial workup. Other studies have suggested that Ki67 may potentially function as an independent meaningful prognostic marker in BP-NETs [, , ]. We found that 20% in the TC group presented with Ki67 proliferation index between 5 and 10%. This may suggest that the current WHO classification should be changed for TC to include Ki67 up to 10%. Although we were not able to find an independent prognostic value of mitotic count, it still remains the most important feature for classification of lung NETs. A previous study by Beasley et al. showed a significantly worse overall survival in patients with AC with a mitotic count between 6–10 mitoses/2mm2 compared to those with 2–5 mitoses/2mm2 . We performed a similar test for AC patients comparing mitotic count with 2–5 and 6–10 mitoses/2mm2, however we did not find any significant difference in overall survival between the two groups, which could be due to the relatively low number of patients with AC compared to the study by Beasley et al (29 vs. 106 patients with AC). The WHO diagnostic criteria from 2015 recommend analysis of immunohistochemical markers (CgA, synaptophysin and CD56) to confirm neuroendocrine differentiation. CgA and synaptophysin are considered the two most valuable markers in the diagnostic process. Zahel et al demonstrated a highly sensitive but not perfect role of synaptophysin and CgA in diagnosis of BP-NETs . None of these markers are suitable for distinguishing between TC and AC, nor has it been proven that any specific immune marker holds prognostic value when it comes to BP-NETs. In line with this, we did not find any significant prognostic value in any of the investigated immunohistochemical markers in this study. However, we did find that the expression of TTF-1 in TC and AC were positive in 68% and 84% respectively. This finding challenges the conception in the WHO guidelines applicable for BP-NETs, where TTF-1 is described as “mostly negative” in TC and AC .