BA is a newly described tumor defined by Chang et al. , which is a more extensive terminology than that of CMPT. It has not been well recognized by pathologists and cannot be classified according to the 2015 WHO classification system . A total of 26 previous studies about this family of neoplasms were searched in the literature, plus the cases in the present study, from which 99 cases of BA /CMPT were reported. The clinicopathological features of these cases are summarized in Table 3.
BA often affects middle-aged to elderly adults from East Asia (77/99, 77.8%), with the median age being 64 years old (range from 19 to 84 years old). The incidence rate of male and female is similar, being close to 1:1.3. BA occurs almost exclusively in the peripheral lungs. Chest CT images showed peripheral solid mass, part-solid nodules, or ground-glass opacity with an irregular border, and some of the patients showed a central cavity [3, 6, 9, 10, 16, 17, 19, 21, 23, 24]. The median diameter was 0.9 cm (range 0.2 to 4.5 cm), mostly between 0.2 and 2 cm. Only two cases were 3.5 cm and 4.5 cm in diameter .
Typically, the tumor is a pale mucinous nodule with an irregular border and sometimes a central cavity is found in the resected specimens. Histologically, BA /CMPT displays diverse morphological patterns including adherence, glandular, papillary, and micropapillary architecture, with abundant mucin around the tumor and the mucinous pool spreading into the adjacent alveolar spaces. The tumor is mainly composed of mucous and basal cells, while ciliated columnar cells may be present or absent. A few cells showed apical cytoplasmic snouts similar to club (Clara) cells . The tumor cells lacked nuclear atypia, mitosis, and necrosis. Chang et al.  reported 25 lesions from 21 patients, with most of the lesions being flat and only seven lesions containing focal papillary architecture. They categorized the lesions into two groups: proximal-type and distal-type based on the morphological and IHC similarities of the bronchiolar structures. The classical CMPT belongs to the proximal-type BA and the TTF1 staining is negative or weakly positive. However, for distal-type BAs, the TTF1 and Napsin A show diffuse positivity.
Some cases revealed discontinuous (skipping) growth patterns, which resembled the spread of tumors through air spaces and micropapillary tufts detached in the alveolar cavity, which is similar to micropapillary adenocarcinoma. Chang et al.  hypothesized that these cells were interconnected with each other in 3-dimensional spaces because these skip lesions do not extend away for more than a few alveoli and the basal cells were always present. However, these microscopic features of BA /CMPT may be an extreme diagnostic challenge for pathologists, especially when studying intraoperative frozen sections.
Immunohistochemically, the three types of cells strongly expressed CK7, and always expressed CEA, HNF4α, MUC1, MUC5B, and MUC5AC [3, 5, 9, 11, 12, 15], which is consistent with primary lung adenocarcinoma. The ciliated columnar cells were focally positive for MUC5AC, whereas the mucous cells lacked staining for MUC5AC. Some of the cases showed positive membrane staining for β-catenin . The tumor cells were always negative for CK20, CDX-2, P53, MUC2, and MUC6, and had a low ki-67 index, usually less than 10% (often less than 1%) [2, 3, 5, 9-12, 15, 17]. The basal cells were positive for p63 and CK5/6.
Previously reported gene mutations of BA CMPT are summarized in Table 4. Several molecular alterations have been identified in BAs, including BRAF, EGFR, KRAS, ALK rearrangement, AKT1, and HRAS (Table 4). Consistent with these, we performed molecular analysis on our four cases and found EGFR, BRAF, and AKT1 mutations. To the best of our knowledge, this is the first study to report the existence of ERBB2 mutation in BA CMPT. As shown in Figure 3, the most common mutation was BRAFV600E (38%), followed by EGFR (15%), KRAS (12%), ALK rearrangement (4%), AKT1 (4%), HRAS (1%), BRAFG606R (1%), and ERBB2 (1%).
Human epidermal growth factor receptor 2 (HER2/ERBB2) is a receptor tyrosine kinase of the ERBB family, which plays a significant role in cancer development and progression, especially in breast, ovarian, and gastric cancers. The overexpression of HER2 protein is associated with poor prognosis. Recent studies have shown that the HER2 mutation is a distinct subset of lung adenocarcinomas. ERBB2 mutations are exclusive to EGFR/KRAS/ALK mutations and represent 6% of EGFR/KRAS/ALK negative specimens of non-small cell lung cancers (NSCLC). In NSCLCs, the most common mutations of ERBB2 are in-frame insertions in exon 20 and are more frequent among non-smokers . There is some overlap on genetic changes between BA and NSCLC. However, for all patients, there was no recurrence or metastasis after 2–120 months of follow-up. However, this type of disease often leads to misdiagnosis because they may morphologically mimic mucinous adenocarcinoma.
Of the 99 patients, 23 were originally diagnosed with adenocarcinoma (23.0%) [6, 17-19, 5, 21, 23, 24] and two were suspected of having malignant tumors (2.0%) . Furthermore, some cases were only pathologically descriptive diagnoses. Therefore, pathologists must distinguish BA /CMPT from malignant tumors, especially during intraoperative diagnosis. The well-differentiated mucinous adenocarcinoma can have ciliated columnar cells especially when adenocarcinoma infiltrates into the bronchioles; however, basal cells are never present. Evidence support of malignancy should be carefully ruled out and immunohistochemical analysis highlighting basal cells with p63 and/or CK5/6 is helpful. Otherwise, solitary peripheral ciliated glandular papilloma, mixed squamous cells, and glandular papilloma and mucoepidermoid carcinoma must be considered as differential diagnoses.
In conclusion, we reported four cases of BAs and detected the mutation of ERBB2 exon 20 insertion for the first time. BA /CMPT is a rare peripheral tumor that exhibits characteristics similar to those of adenocarcinoma, including morphological and genetic changes. At present, BA shows benign biological features that might be due to the limited number of cases. The pathogenesis and biological behavior of BA /CMPT must be examined further in future research and requires the study of more cases and longer follow-up times.