Girard et al1 reported in CHEST (January 2010) a comparison analysis of seven patients with multiple lung adenocarcinomas benchmarked on the epidermal growth factor receptor (EGFR) and Kirsten-rat sarcoma 2 viral oncogene homolog clonality status, which we read with interest and has instigated some reflections. Martini-Melamed (MM) criteria outlined a clinical and diagnostic classification of multiple primary lung cancers (MPLCs)2; today, American College of Chest Physicians (ACCP) guidelines provided a new MPLC classification.3 Both MM and ACCP criteria are used to classify an MPLC case as primary metastatic or true synchronous/metachronous multiple. Furthermore, none of these criteria incorporate information on molecular status to distinguish multiple primary from metastatic disease. The new diagnostic algorithm described by Takamochi and colleagues4 is based on the assessment of EGFR-Kirsten-rat sarcoma 2 viral oncogene homolog to achieve a correct definition of the clonality status among multiple lung adenocarcinomas and, in turn, is used as a differential diagnosis criterion. With this algorithm, Takamochi and colleagues4 could easily detect significant discrepancies in existing clinical criteria in 36 patients they thoroughly examined to assess the difference between true primary and metastatic disease. Similar evidence was reported in Girard et al,1 thus, confirming the inherent limitations of the MM/ACCP criteria. Moreover, Takuwa et al5 advocated for molecular-based stratification criteria by detailing a case of multiple synchronous lung adenocarcinomas harboring an L858R mutation within exon 21 of EGFR in the middle-lobe tumor and subcarinal nodes but not in the upper-lobe tumor. In the setting where MM/ACCP criteria are taken into account, the diagnosis of N2 nodal involvement defines synchronous multiple tumors as metastatic lesions; however, these data might suggest that the number of multiple primary adenocarcinomas could be higher than what is observed if only MM/ACCP criteria are taken into account. On the other hand, very few reports compare the clonality status of primary tumors and lymph node metastases6: of 56 non-small cell lung cancers, the molecular appearance in the primary cancer and its lymph node metastasis were concordant in 92.9% and 69.6% by p53 and EGFR status, respectively.