Recognition of pre-invasive lung cancer lesions is important for clinical research. The most common types of lung cancer are squamous carcinoma and adenocarcinoma. In both China and North America, the incidence of lung adenocarcinoma has increased and is now the most common type of lung cancer, e.g., 58.9% of lung cancers in Shanghai in 2002-2004 were adenocarcinomas, and 86.1% in women. Atypical squamous epithelial hyperplasia has been considered as a precursor of squamous lung cancer, and the World Health Organization (WHO) has suggested that the precursor of lung adenocarcinoma is atypical adenomatous hyperplasia (AAH). The increasing popularity of chest CT has improved the detection rate of peripheral lung lesions, and regular follow-up has become a common diagnostic strategy for small nodules in the lung, which offers the possibility to improve the detection rate of pre-invasive lung adenocarcinoma. However, the current understanding of AAH is inadequate in both pathology and clinical practice. Therefore, we review the recent literature on AAH for the reference of our colleagues and hope to draw the attention of clinical, pathological and research workers. The definition of AAH is often found in surgically resected lung cancer specimens and is defined mainly from a pathological point of view.AAH refers to a focal lesion not associated with the primary lung cancer lesion, with a single row of non-invasive atypical epithelial cells lining the alveolar wall, which is a mild to moderate atypical cellular hyperplasia with limited involvement of respiratory bronchioles, resulting in a focal lesion in the peripheral alveoli, usually ≤5 mm, and There is no interstitial inflammation or fibrotic changes. Factors associated with the occurrence of AAH Statistics have shown that the incidence of AAH varies among specimens: the incidence of AAH in resected lung cancer specimens ranges from 9.3% to 21.4%, while the incidence of AAH in lung specimens resected for other reasons ranges from 4.4% to 9.6%. The incidence of AAH is higher in women than in men. The incidence of AAH in multiple lung cancers is higher than that in solitary lung cancers. Some studies have reported that AAH may be associated with a history of previous malignancies, such as rectal cancer, liver cancer, breast cancer, thyroid cancer, head and neck cancer, and malignant lymphoma. In addition, the correlation between AAH and smoking history and family tumor history is still inconclusive and needs to be further investigated. AAH is a scattered, soft, pale or yellow AAH lesion sometimes seen on lung sections, with a speckled depression in the alveolar space, often located near the pleura (Figure 1). 51% of AAH is located in the upper lobe, followed by the lower lobe (37%), and the right middle lobe (11%). The number of AAH lesions in each lung cancer patient varied from 1 to 13, with an average of 3.5. However, these AAH lesions were taken from resected tumor specimens, and it is likely that other lesions were missed, which is suspected to be an underestimation. Microscopically, AAH is a parenchymal lung lesion, often occurring in the central alveoli near the respiratory bronchioles. The histological criteria for the diagnosis of AAH are: (1) clear lesion margins with a single layer of atypical epithelial cells and no central atrophy or scar formation; (2) abundant cytoplasm with round or dome-shaped cells, similar to alveolar type II (3) The nuclei were darkly stained with prominent nucleoli, and the atypia was not as obvious as that of adenocarcinoma; (4) The alveolar septum was lined with atypical square or columnar cells, and mild fiber thickening was seen in the alveolar septum (Figure 2). It should be noted that the diagnosis of AAH cannot be made by cytology. Molecular biology of AAH The protein product of the P53 gene plays an important role in the regulation of the balance between proliferating and normal cells and can be used as a biomarker for malignant lesions, while C-erbB2 is a pro-adjuvant gene for adenocarcinoma. In one study, the rates of moderate/severe positivity, focal/weak positivity and negativity for P53 in lung cancer were 53%, 35% and 12%, respectively, while the rates of positivity in AAH lesions were lower, at 28%, 30% and 42%, respectively. In lung cancer, the rate of C-erbB2 cell membrane positivity was 65% (some cases also showed cytoplasmic positivity), only strong cytoplasmic positivity was seen in 12%, focal/weak cytoplasmic staining was 17%, and negative rate was 6%, compared with 7%, 34%, 25%, and 33% in AAH lesions, respectively. These results suggest that AAH has some genetic alterations associated with malignancy like lung cancer, but the incidence is low, which also supports AAH as a precancerous lesion. KRAS gene mutations, especially codon 12 mutations, are specific for peripheral lung cancer, which is different from bronchogenic lung cancer, suggesting a different pathway for peripheral lung carcinogenesis. The rate of KRAS codon 12 mutation in AAH alone was 15%-50%, and that in combined adenocarcinoma was about 22%-42%, and that in fine bronchoalveolar carcinoma (24%-33%) was also higher than that in AAH, suggesting that KRAS codon 12 mutation may be an early event in the development of peripheral type adenocarcinoma. Recently, there have been more studies on epidermal growth factor receptor (EGFR). Yoshida et al. in Japan reported positive expression of EGFR from AAH to invasive adenocarcinoma with an increasing trend. They suggested that EGFR plays an important role in the development of both AAH and adenocarcinoma, and its expression suggests the promotion of AAH to adenocarcinoma; EGFR had a positive expression rate of 94% in end respiratory unit type lung adenocarcinoma and 40% in AAH (2/5 cases). Clinical and imaging diagnosis AAH has no obvious clinical symptoms and signs and is detected by surgical resection of lung cancer specimens or chest CT examination, and histological diagnosis is the only way to confirm the diagnosis. AAH is more difficult to detect on X-ray chest radiographs, but high-resolution CT of the chest reveals small, round-like lesions with clear borders and faint to moderate density, in the form of homogeneous hairy or frosted glass shadows (GGO) with low translucency that do not obscure the underlying lung parenchyma, mostly under 5 mm in size (Figure 3). AAH, 50% were fine bronchoalveolar carcinomas, and 10%-25% were invasive adenocarcinomas. In the case of lung cancer, in addition to GGO manifestations, there are other lung cancer features, such as burrs, pleural traction, which may have solid granules and may be budding, mulberry, or insect-like in shape. It is noteworthy that most AAH and lung cancer occurred at the same time (91.7%), and a few were at different stages, suggesting the importance of careful exploration during serial readings and surgery. In peripheral lung adenocarcinoma, fine nodules on other sites should be used as targets for surgical exploration and postoperative follow-up. Treatment and prognosis of AAH AAH is usually found in surgically resected specimens of lung cancer, and its resection may prevent the development of lung cancer. Prior to surgery for lung adenocarcinoma, a detailed series of chest CTs should be read to look for GGO or fine nodules in areas other than the cancer. The scope of AAH resection should be small rather than large, and for GGO or fine nodules that cannot be reached by the intraoperative investigation, long-term postoperative follow-up should be performed to dynamically observe the changes. In a case of multiple adenocarcinoma, Seki et al. in Japan reported that two operations were performed within 3 years and 8 months and a total of 13 tumor-like lesions were resected, of which 10 were stage IA primary lung cancer and 3 were AAH. pathological and molecular biological examinations showed that the atypical changes in the second operation specimen were more obvious than the first one, regardless of lung cancer or AAH cells. The first specimen was negative for P53, while the second specimen was partially positive for P53 and positive for carcinoembryonic antigen (CEA). The patient had no recurrence for 2 years and 6 months afterwards. The authors suggest that the pathological and genetic changes of the two surgeries in this case support the theory that AAH is a precancerous lesion, and that surgery should not be abandoned arbitrarily for multiple lung adenocarcinoma, but should be performed under safe conditions (age, physical condition, coexisting disease, cardiopulmonary function, etc.). In 1997, Suzuki et al. reported that 137 of 1360 surgically resected lung cancer cases were associated with AAH, and no significant effect of AAH on the 5-year survival rate of all stages of lung cancer was observed (see Table). Noguchi et al. reported a 5-year survival rate of 74.6% in 236 patients with surgically resected small adenocarcinoma of the lung (≤2 cm). The histological classification of the tumors according to their growth pattern revealed that the best prognosis (100%) was found for types A and B. Type A is a limited fine bronchoalveolar carcinoma with isolated alveolar lining cell growth and thickened alveolar septa; type B is a focal fibrosis caused by intra-tumoral alveolar atrophy in addition to type A presentation. These descriptions are similar to AAH, suggesting that resection of AAH is expected to prevent the lesion from becoming cancerous. The recent development of small incision surgery and thoracoscopic surgery has reduced the surgical trauma. For small lesions near the chest wall that can be reached by minimally invasive surgery, if lung cancer cannot be excluded by examination, treatment can be decided accordingly, which may be beneficial for improving prognosis. Although there is no clear conclusion as to whether isolated AAH that is not lung cancer should be surgically resected, minimally invasive surgery is worthwhile if the patient has high risk factors for lung cancer and cancer cannot be excluded.