Background:Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts.Methods:Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. Results were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC).Results:Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007).Conclusions:Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.

Recently, a novel classification for pulmonary adenocarcinomas (ADCs) was published, the cornerstone of which is the quantification of growth patterns. Data on reproducibility in the routine diagnostic setting are lacking. 100 constitutive cases of lung ADC resection specimens from our archives were classified independently by five pulmonary pathologists and two residents according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification.The most frequent predominant pattern in our cohort was solid (37%), followed by acinar (35%), lepidic (20%), papillary (5%) and micropapillary (3%). k-values for the denomination of the predominant pattern revealed substantial agreement for pulmonary pathologists (k50.44-0.72) and fair agreement for residents (k50.38-0.47). Interobserver variability was significantly higher in cases with higher slide numbers (p50.028) and was considerably reduced after training. Intraobserver variability was low (k50.79-0.87). Papillary and micropapillary patterns were the most complicated patterns to evaluate, while evaluation of lepidic and solid tumour growth was straightforward.Our data imply that the novel classification of pulmonary ADC is applicable with acceptable interobserver variability if performed by specifically trained pathologists. Additional efforts are needed to harmonise the application of this novel and clinically important classification scheme of pulmonary ADC.

The International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed a classification for lung adenocarcinomas (ADC) based on the predominant growth pattern. This classification has been shown to have prognostic and maybe even predictive impact. However, until now, the reproducibility of this classification has not been sufficiently demonstrated. Digital images of 40 selected ADC cases were shown twice to members of the Pulmonary Pathology Working Group of the German Society of Pathology. Each time a teledialogue-based survey on the classification was performed. Between the voting procedures, salient features of the novel classification were presented and discussed in detail by its members. The mean percentages of consensual votes per pattern ranged between 59.6 and 75 %, with lepidic and solid being the pattern with the most discordant and concordant votes, respectively. The other patterns ranged in between (papillary 65.8 %; acinar 67.8 %; micropapillary 74.2 %). The extent of disagreement decreased after the educational session. This decrease, however, was heterogeneous for the different patterns with acinar being the pattern with the strongest improvement. The overall number of abstentions decreased significantly after the educational session (p < 0.001) as well. The IASLC/ATS/ERS classification of lung ADC can be applied with reasonable consensus even for difficult cases in a nationwide context. The reproducibility evidently improves following educational sessions, even among experienced lung pathologists. Worldwide harmonization is clearly the next step on the way to a clinically meaningful, internationally accepted use of this novel prognostic and potentially predictive tool in lung pathology.