Validation of the International Tumor Budding Consensus Conference (ITBCC) 2016 recommendation in squamous cell carcinoma of the lung-a single-center analysis of 354 cases.

There are no universally accepted grading systems in pulmonary squamous cell carcinoma (pSQCC). Recently, tumor budding, cell nest size, and spread through airspaces (STAS) have been proposed as grading scheme candidates. Tumor budding is a well-established independent prognostic factor in colorectal cancer. The International Tumor Budding Consensus Conference (ITBCC) provided consensus on scoring in 2016, albeit for colorectal cancers. Here, we aimed to validate the ITBCC method in pSQCC and evaluate additional proposed grading parameters. We analyzed a fully clinico-pathologically annotated Western single-center cohort of 354 consecutive primary resected pSQCC (resected 2000-2013). Patients with SQCC of other organs were excluded to reliably exclude lung metastases. We assessed conventional grading, keratinization, STAS, and tumor budding according to ITBCC recommendations, and correlated them with clinico-pathological parameters and survival. Tumor budding was low (0-4 buds/0.785 mm2) in 41%, intermediate (5-9 buds/0.785 mm2) in 30%, and high (≥10 buds/0.785 mm2) in 29% of cases (mean bud count = 7.45 (H&E), min = 0, max = 84). Cell nests of 1, 2-4, 5-15, >15 cells were present in 68%, 20%, 5%, 7%, respectively. We detected STAS in 33% of cases, desmoplasia in 68%. Tumor budding assessed as continuous and categorized variables was highly concordant between hematoxylin and eosin (H&E) and pancytokeratin (AE1/AE3) stained slides (P < 0.001) and significantly associated with tumor size, UICC/AJCC pT, pN, stage (all P < 0.001) and presence of mediastinal lymph node metastases (H&E: P = 0.028). Tumor budding was a significant prognostic parameter for overall, disease-specific, and progression-free survival (PFS) (all P < 0.001). ITBCC tumor budding categories were independent prognostic factors for overall survival (HR = 1.581; 95% CI 1.186-2.108; P = 0.002), disease-specific survival (HR = 1.710; 95% CI 1.111-2.632; P = 0.015), and PFS (HR = 1.457; 95% CI 1.123-1.890; P = 0.005). STAS or conventional tumor grade had no prognostic value. In conclusion, we confirm tumor budding as an independent prognostic marker in pSQCC and validate the ITBCC 2016 scoring recommendations in pSQCC.