11 Introduction and aim of thesis is based on a combination of microscopic examination, immunohistochemical analysis, and molecular/genetic analysis. Regarding NSCLC, several histopathological criteria have been linked to prognosis. For example, adenocarcinomas as a type, is associated with a better prognosis than the squamous cell carcinoma type of NSCLC5. Within the adenocarcinomas some subtypes, such as micropapillary and solid are associated with a worse prognosis6, 7. Also within the subtypes, certain patterns are associated with worse prognosis, such as the cribriform variant of acinar adenocarcinoma8. In 1960, Liebow introduced the term “bronchioloalveolar carcinoma” (BAC) to describe a well-differentiated form of adenocarcinoma that presents with one of three growth patterns: (1) a single nodular pattern, (2) a multinodular pattern, or (3) a diffuse pneumonic pattern9. However, the definition of bronchioloalveolar carcinoma remained somewhat unclear in terms of pathological criteria. As radiology, histology, and immunophenotyping knowledge advanced, it became increasingly crucial to distinguish certain subtypes of non-small cell lung cancer with a better prognosis and less invasive treatment from the conglomerate of cases. In 1995, Noguchi et al. identified subtypes that exhibited 100% long term survival. Type A demonstrated growth through replacement of alveolar lining cells, accompanied by minimal or slight thickening of the alveolar septa, and an absence of fibrotic foci within the tumors, called localized bronchioloalveolar carcinoma (LBAC). Type B followed a comparable pattern, but fibrotic foci due to alveolar collapse were evident in the tumors and was called bronchioloalveolar carcinoma with foci of collapse of alveolar structure10. In 1997, Silver and Askin examined cases that were diagnosed as having papillary or bronchioloalveolar characteristics. They identified certain cases with a worse prognosis when stricter criteria were applied, such as over 75% papillary pattern, complicated papillary growth in secondary and tertiary branches, greater cytonuclear atypia, and distortion or destruction of underlying pulmonary architecture11. However, in the 1999 edition of the WHO classification, the papillary subtype is not so strictly defined, namely as “an adenocarcinoma with a predominance of papillary structures that replace the underlying alveolar architecture”12. In the 2015 edition of the WHO classification, the term bronchioloalveolar carcinoma (BAC) was abandoned, and instead, the concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were introduced. These new concepts have been increasingly diagnosed, particularly in lesions discovered through lung cancer screening13. When surgically removed, both AIS and MIA exhibit nearly 100% 5-year survival rates. A precise and accurate diagnosis distinguishing non-invasive adenocarcinomas such as AIS and MIA from invasive carcinomas is crucial. This is because invasive adenocarcinomas may require additional therapy, while non-invasive non-mucinous adenocarcinomas can be cured through surgical resection alone, eliminating the need for further treatment. 1
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