Comparison of the 7th and 8th Edition of the UICC/AJCC TNM Staging System in Primary Resected Squamous Cell Carcinomas of the Lung-A Single Center Analysis of 354 Cases.

Background: The AJCC/UICC TNM (tumor, node, metastasis) classification is a standardized system for the description of anatomical extent and stage grouping of solid malignant tumors and is regularly updated. We aimed at testing the new 2017 8th edition of the TNM classification (TNM8) compared to the former 2009 7th edition (TNM7), in pulmonary squamous cell carcinomas (pSQCC). Methods: We analyzed a clinico-pathologically well-annotated Western single-center cohort of 354 consecutive pSQCC, resected 2000-2013, without previous neoadjuvant therapy. Patients with a clinical history of SQCC of other organs were excluded to reliably exclude lung metastases. Patients in whom TNM was unclear due to multiple tumor nodules were excluded. We reevaluated all pathological records and slides and retrospectively validated pleural invasion for all cases. Raw data of our cohort are provided as Supplementary Material. Results: The stage distribution according to TNM7 was as follows: IA (2009): 59 (16.7%), IB: 75 (21.2%), IIA: 71 (20.1%), IIB: 53 (15.0%), IIIA: 79 (22.3%), IIIB: 7 (2.0%), IV: 10 (2.8%). Staging the cases according to TNM8, 7/354 (2.0%) cases were down-staged, 154 (43.5%) were upstaged; most pronounced between stages IIA(TNM7) and IIB(TNM8), and IIB(TNM7) and IIIA(TNM8). Both staging systems showed significant prognostic impact for overall survival, disease free and disease specific survival and time to recurrence, without significant differences regarding goodness-of-fit criteria (Akaike Information Criterion and Schwarz Bayesian Criterion). Conclusion: In conclusion, we show a significant stage migration between tumors staged using TNM7 and TNM8, without benefit regarding prognostication in our cohort of primary resected pSQCC.

Expression Analysis of Autophagy Related Markers LC3B, p62 and HMGB1 Indicate an Autophagy-Independent Negative Prognostic Impact of High p62 Expression in Pulmonary Squamous Cell Carcinomas.

Autophagy is involved in maintaining cellular homeostasis under stress conditions. It also plays an important role in various diseases including cancer. Pulmonary squamous cell carcinomas (pSQCC) at present lack targetable molecular alterations, and demand alternative therapeutic options. We assessed the expression levels of autophagy related proteins LC3B, p62, and HMGB1 in 271 primary resected pSQCC by immunohistochemistry, in correlation with clinical and pathological parameters, as a rationale for a potential autophagy directed therapy. LC3B, p62, and HMGB1 staining showed various patterns. LC3Bhighp62low levels, suggested to indicate intact activated autophagy, were associated with prolonged disease specific survival (DSS) and LC3Bhighp62high levels, indicating activated but late stage impaired autophagy, with shorter DSS (p = 0.024). p62high expression regardless of LC3B, however, showed an even stronger association with shorter DSS (p = 0.015) and was also an independent negative prognostic factor in multivariate analysis (HR = 2.99; 95% CI 1.38⁻6.52; p = 0.006). HMGB1 expression correlated neither with the expression of LC3B and p62, nor with patients' outcome. Different states of autophagy characterized by distinct p62 and LC3B expression patterns may be linked to patient's prognosis in pSQCC. Our results, however, point also to an autophagy independent role of p62 with an even more pronounced prognostic impact compared to autophagy related p62.

Adverse prognostic value of PD-L1 expression in primary resected pulmonary squamous cell carcinomas and paired mediastinal lymph node metastases.

Immunohistochemical assessment of programmed cell death (PD)-ligand 1 (PD-L1) expression in lung cancer in the context of therapeutically targeting the PD1/PD-L1 axis is still controversially discussed. This includes the comparability of antibody clones, prognostic value, and discrepancies between primary tumors and metastases. We assessed tumoral PD-L1 expression using clones E1L3N and SP142 in 372 primary resected pulmonary squamous cell carcinomas, including 40 paired N2 lymph node metastases, in relation with clinico-pathological parameters. PD-L1 expression was negative (<1%) in 163/372 (44%, E1L3N) or 231/370 patients (62%, SP142). Positivity of 1-<50% was observed in 135 (36%, E1L3N) or 92 patients (25%, SP142) and ≥50% in 74 (20%, E1L3N) or 47 patients (13%, SP142). PD-L1 staining correlated significantly between both antibodies (r=0.781; P<0.001). Scores correlated significantly between full-slide sections (N=40) and tissue microarrays, and between primaries and N2 metastases (P<0.001 all). CD8+ tumor infiltrating lymphocyte counts positively correlated with PD-L1 expression (P<0.001). PD-L1 ≥50% showed the best prognostic discrimination using the split-sample validation method. It was associated with shorter disease-specific survival in the observation group (E1L3N: P=0.035, SP142: P=0.002) and validation group (E1L3N: P=0.024, SP142: P=0.101) and shorter time to recurrence (observation group: E1L3N: P=0.056, SP142: P<0.001; validation group: E1L3N: P=0.036, SP142: P=0.247). Multivariate analysis showed that PD-L1 expression ≥50% determined by clone E1L3N was an independent prognostic factor in the observation group regarding disease-specific survival (HR=2.768; 95% CI=1.149-6.666; P=0.023) and time to recurrence (HR=2.164; 95% CI=1.056-4.436; P=0.035) and in the validation group (disease-specific survival: HR=1.978; 95% CI=0.928-4.214; P=0.077 and time to recurrence: HR=1.571; 95% CI=0.838-2.944; P=0.159). High PD-L1 expression was associated with adverse prognosis in pulmonary squamous cell carcinoma. Clone E1L3N was more sensitive than SP142 and superior regarding prognostication. PD-L1 expression correlated significantly between primary tumor and N2 metastases, rendering mediastinal lymph node metastases adequate for immunohistochemical assessment.