Clinicopathological Characteristics and Mutations Driving Development of Early Lung Adenocarcinoma: Tumor Initiation and Progression

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), to overt invasive adenocarcinoma with a lepidic pattern. This stepwise development is supported by the clinicopathological and molecular characteristics of these tumors. In the 2015 World Health Organization classification, AAH and AIS are both defined as preinvasive lesions, whereas MIA is identified as an early invasive adenocarcinoma that is not expected to recur if removed completely. Recent studies have examined the molecular features of lung adenocarcinoma tumorigenesis and progression. EGFR-mutated adenocarcinoma frequently develops via the multistep progression. Oncogene-induced senescence appears to decrease the frequency of the multistep progression in KRAS- or BRAF-mutated adenocarcinoma, whose tumor evolution may be associated with epigenetic alterations and kinase-inactive mutations. This review summarizes the current knowledge of tumorigenesis and tumor progression in early lung adenocarcinoma, with special focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF) as well as on its molecular pathogenesis and progression.

Keywords: CDKN2A (p16); HNF4A; NKX2-1 (TTF-1) amplification; Napsin A; Noguchi classification; TP53 (p53); de novo pathway; immunohistochemistry; molecular pathological epidemiology; terminal respiratory unit (TRU)-lineage.

Figure 1

Morphology of AAH (hematoxylin and eosin staining). (A) Low magnification (Scale bar = 1000 µm). (B) High magnification (Scale bar = 100 µm). AAH, atypical adenomatous hyperplasia.

Figure 2

Morphology of AIS (Noguchi type A; A–C) and AIS, sclerosing type (Noguchi type B; D–G). AIS at low magnification (Noguchi type A) [(A) HE staining and (B) EVG staining] and (C) high magnification (HE staining). AIS, sclerosing type, at low magnification (Noguchi type B) [(D) HE staining and (E) EVG staining] and high magnification [(F) HE staining and (G) EVG staining]. A, B, D, and E: Scale bar = 1000 µm. C, F, and G: Scale bar = 100 µm. AIS, adenocarcinoma in situ; EVG, Elastic van Gieson; HE, hematoxylin and eosin.

Figure 3

Morphology of MIA. MIA at low magnification ((A) HE staining and (B) EVG staining) (Scale bar = 1000 µm). Lepidic component of MIA at high magnification ((C) HE staining) and the invasive component ((D) HE staining and (E) EVG staining) (Scale bar = 100 µm). EVG, Elastic van Gieson; HE, hematoxylin and eosin; MIA, minimally invasive adenocarcinoma.

Figure 4

AAH develops from normal alveolar type II cells or club (Clara) cells after mutations in EGFR, KRAS, and BRAF. EGFR-mutated AAH progresses to AIS, followed by invasive adenocarcinoma after EGFR/TTF-1 amplification. KRAS- or BRAF-mutated AAH rarely progresses to AIS or invasive adenocarcinoma, but can do so after the inactivation of TP53/CDKN2A (p16) or other genomic events (dotted arrows). KRAS- or BRAF-mutated invasive adenocarcinoma may arise from normal lung epithelium via a de novo pathway that involves KRAS or BRAF mutations and other genomic events. Solid arrows indicate progression. AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; amp, amplification; inact, inactivation; mut, mutation.