Histopathologic and molecular approach to staging of multiple lung nodules.

Distinguishing multiple primary lung cancers from intrapulmonary metastases in patients with synchronous multifocal lung adenocarcinomas can be challenging. The most recent 8th edition American Joint Committee on Cancer staging manual (AJCC staging manual) distinguishes four disease patterns in patients with multiple lung nodules: (I) two or more distinct and histologically different masses (considered unrelated and staged as individual cancers); (II) multiple ground-glass or part-solid nodules, histologically of with lepidic growth pattern (considered separate tumors, T staged based on highest T stage lesion); (III) patchy areas of ground-glass and consolidations, histologically often invasive mucinous adenocarcinomas (considered single tumor with diffuse "pneumonic-type" involvement); and (IV) separate nodules with the same histologic features based on comprehensive histologic subtyping (considered intrapulmonary metastases). Histologic and molecular features, in conjunction with clinical and radiological information, can all be tools to assist with staging of multiple nodules. Histologic features of adenocarcinomas are best characterized using comprehensive histologic subtyping (percentage of lepidic, acinar, solid, papillary and micropapillary pattern). Genomic alterations are commonly assessed using fluorescence in-situ hybridization and next generation sequencing (NGS). The AJCC considers exactly matching breakpoints by comparative genomic hybridization (CGH) as the only evidence for intrapulmonary metastases, and clearly different histologic types or subtypes as the only evidence for separate primary tumors. Similar histologic subtypes or the same biomarker pattern are considered merely relative arguments in favor of a single tumor source. When assessing multifocal lung cancer, pathologists should consider, and carefully weigh the importance of, molecular testing results in addition to the tumor's histologic features. For many cases encountered in routine clinical practice, absolute certainty cannot be reached as to whether they represent multiple primary cancers or intrapulmonary metastases. Classification of difficult cases often benefits from multidisciplinary discussion.