Tumor spread, in general, is the most important factor determining outcome in almost all malignant tumors. Lung tumors are unique with respect to potential routes for tumor dissemination, as apart from vascular, nodal, and distant spread of tumor cells, tumor spread through air spaces (STAS) might also occur. However, morphologic criteria for STAS and its prognostic impact have not been defined yet. We evaluated a series of 569 resected pulmonary adenocarcinomas (ADCs) for predefined morphologic criteria of limited and extensive STAS and correlated our findings with clinical, morphologic, molecular, and outcome data. Limited (21.6%) or extensive (29%) STAS was present in roughly half of all ADCs. The presence and type of STAS was tightly linked to specific growth patterns (P<0.001). STAS was much more prevalent in high-stage (P<0.001), nodal-positive (P<0.001) ADC with distant metastasis (P=0.010). STAS was associated with lower rates of EGFR (P=0.009) but higher rates of BRAF (P=0.016) mutations. Furthermore, STAS was associated with significantly reduced overall (P=0.020) and disease-free survival (P=0.004), which was growth pattern but not stage independent. We analyzed morphologic characteristics of a yet underestimated type of tumor spread of pulmonary ADC through air spaces. STAS is a novel morphologic prognosticator, which should be further validated and considered for implementation in routine diagnostic evaluation and reporting.

Recent studies in lung adenocarcinoma established a clinically relevant histomorphology-based classification. In contrast, no morphological classifiers have yet been implemented into routine diagnostics for lung squamous cell carcinoma (SQCC). However, morphology-based characteristics putatively impacting on survival have been proposed.We analysed a cohort of 541 SQCC patients with complete clinical follow-up data for morphological characteristics (keratinisation, tumour cell budding, size of tumour cell nests, nuclear size and stromal content). Morphological characteristics were correlated with clinical data and patient outcome.Keratinisation, budding, stromal content and tumour cell nest size, but not nuclear size, were associated with distinct clinicopathological characteristics and survival. SQCC patients with keratinisation, small cell nest size, high stromal content and extensive budding had shorter overall survival. A combined grading scheme composed of the two most reliable validated prognostic markers, i.e. budding and nest size, resulted in an age-, stage- and sex-independent prognosticator for overall survival with a hazard ratio of 1.6 for grade 2 tumours and a hazard ratio of 3.7 for grade 3 tumours when compared with grade 1 neoplasms (p<0.001).Morphological characteristics of SQCC have significant prognostic impact and could constitute the basis for a diagnostically relevant future SQCC grading scheme.

Our data support the introduction of cpADC as a novel category into future morphology based on pulmonary ADC classifications. Further international studies are required to validate the reported clinicopathological associations of the cribriform pattern.

Minimally invasive diagnostic techniques are increasingly being used to obtain specimens for pathological diagnosis and prediction. Referring to lung cancer, both endobronchial and endoesophageal ultrasound are used worldwide as diagnostic routine methods. Consequently, an increasing number of pathological samples are cytological and fewer are histological. On the other hand, the requirements for specific and sensitive tumor subtyping complemented by predictive analyses are steadily increasing and are an essential basis for evidence-based treatment decisions. In this article we focus on the cell block method as a helpful tool for diagnostic and predictive analyses in lung cancer and point out its advantages and disadvantages in comparison to conventional cytological and biopsy specimens. Furthermore, we retrospectively analyze the diagnostic results of the cell block method in a high-volume center over 5 years. The main advantages of cell blocks are the availability of established and validated protocols, archiving and the opportunity to have serial sections from the same specimens to provide or repeat molecular analyses. Actually, in case of tumor progression, even additional biomarkers can be tested using the original cell block when re-biopsies are not feasible. The cell block method should be considered as a reliable, complimentary approach to conventional cytological or biopsy procedures, which is helpful to fulfill the increasing requirements of high-quality diagnostics and prediction.