From tumor regression to molecular diagnostics—modern lung pathology

Lung cancer continues to be the most common tumorrelated cause of death. Within the scope of neoadjuvant therapy concepts for non-small cell lung cancer (NSCLC), the following grading of therapy-induced tumor regression was established over 20 years ago: RG I: no or only spontaneous tumor regression in the tumor bed of the primary tumor and in the regional lymph nodes. RG II: morphological evidence of therapy-induced tumor regression with: RG IIa: more than 10% of viable tumor cells in the tumor bed of the primary tumor and/ or regional lymph nodes presenting more than focal microscopic disease; RG IIb: maximum of 10% of viable tumor cells in the tumor bed of the primary tumor and/ or regional lymph nodes presenting only focal microscopic disease. RG III: complete tumor regression without evidence of viable tumor in the tumor bed of the primary tumor and in the regional lymph nodes. Applying this regression grading, a statistically significant longer median survival time could be demonstrated for patients with stage III NSCLC and a maximum of 10% of viable tumor tissue in the resection specimens after neoadjuvant therapy (regression grade IIb/III) than for patients with tumors of regression grade I or IIa. In a corresponding trial, the extent of tumor regression (regression grade I/IIa versus regression grade IIb/III) could be established as an independent prognostic factor for patients treated with tumor resection (1-5). Recently, the International Association for the Study of Lung Cancer (IASLC) has also developed multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens following neoadjuvant therapy. In these recommendations, major pathologic response (MPR) is defined as the reduction of viable tumor to the amount beneath an established clinically significant cutoff based on prior evidence according to the individual histologic type of lung cancer and a specific therapy. The historical definition of MPR for all histologic types of lung cancer is ≤10% of viable tumor with no viable tumor required for complete pathologic response (CPR) (6). The definitions of MPR and CPR therefore largely match those of regression grades IIb and III, respectively.