BA is a newly entity defined by Chang et al.[18], which is a more extensive terminology than CMPT. It has not been well recognized by pathologists and could not be classified according to 2015 WHO classification system [28]. So far, 26 English literatures about this family of neoplasms are searched, plus our cases, there are 99 cases have been reported. The clinicopathologic features of these cases were summarized in Table 2.
BA often affect middle-aged to elderly adults from East Asia (77/99, 77.8%), with the median age of 64 years old (range from 19 to 84 years old). Expect one patient is 19 years’ old [10], the remaining are range from 31 to 84 years old. The incidence rate of male and female was similar, close to 1:1.3. It occurs almost exclusively in peripheral lung. Chest computed tomography (CT) shows peripheral solid, part-solid nodules or ground-glass opaque (GGO) with an irregular border, part of the patients show a central cavity on the CT images [3,6,9,10,16,17,19,21,23,24]. The median diameter was 0.9cm (range 0.2 to 4.5cm), mostly between 0.2 to 2cm. Only two cases were 3.5cm and 4.5cm in diameter [11].
Grossly, the tumor is a pale mucinous nodule with irregular border and sometimes a central cavity in resected specimens. Histologically, BA displays a diverse morphological pattern such as adherence, glandular, papillary, micropapillary architecture, with abundant mucin around the tumor and the mucinous pool spreading into adjacent alveolar spaces. The tumor mainly composed of mucous cells and basal cells, whereas ciliated columnar cells could present or absent. A few cells showed apical cytoplasmic snouts like club (Clara) cells [18]. The tumor cells lacked nuclear atypia, mitosis, and necrosis. Chang et al. reported 25 lesions from 21 patients [18], most lesions were flat and only 7 lesions contained focal papillary architecture. They categorized the lesions into 2 groups: proximal-type and distal-type based on the morphologic and IHC similarity with the bronchiolar structures. The classical CMPT belongs to the proximal-type BA and the TTF1 staining is negative or weakly positive. But for distal-type BAs, TTF1 and Napsin A showed diffuse positivity.
Some cases revealed discontinuous (skipping) growth pattern which is resembling Tumor Spread Through Air Spaces (STAS) and micropapillary tufts detached into the alveolar cavity which is similar to the micropapillary adenocarcinoma. Chang et al. hypothesized that these cells being interconnected with each other in 3-dimensional spaces [18], because these skip lesions do not extend away for more than a few alveoli. Anyway, the basal cells were always present. However, these microscopic features of BA may be an extremely diagnostic challenge for pathologists, especially for intraoperative frozen sections.
Immunohistochemically, the three types of cells are strongly expressed CK7, always express CEA, HNF4α, MUC1, MUC5B and MUC5AC [3,5,9,11,12,15], consistent with the primary lung adenocarcinoma. The ciliated columnar cells are focally positive for MUC5AC, while the mucous cells lacked staining for MUC5AC. Some of the cases are positive membrane staining for β-catenin [9]. The tumor cells always negative for CK20, CDX-2, P53, MUC2 and MUC6 and have a low ki-67 index, usually less than 10% (often less than 1%) [2,3,5,9-12,15,17]. The basal cells are positive for p63 and CK5/6.
Previous reported gene mutations of BA were summarized in Table 3. Until now, several molecular alterations have been identified in BAs, including BRAF, EGFR, KRAS, ALK rearrangement, AKT1, and HRAS (Table 3). Consistent with them, we performed molecular analysis on the 4 cases and found EGFR, BRAF and AKT1 mutations. Importantly, ERBB2 mutation was first described in our present cohort. As showed in Figure 2, 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%).
Again, it’s the first time that ERBB2 exon 20 insertion has been reported in BA. 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. Overexpression of HER2 protein associated with poor prognosis. Recent research shows that HER2 mutations is a distinct subset of lung adenocarcinomas. ERBB2 mutations are exclusive to EGFR/KRAS/ALK mutations, representing 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 were more frequent among non-smokers [29]. It is obvious that there is some overlap on genetic changes between BA and NSCLC. But of all the patients, there are 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 all the 99 patients, twenty-three were diagnosed with adenocarcinoma originally (23.0%) [6,17-19,5,21,23,24], two were suspected of malignant tumors (2.0%) [6]. Furthermore, some cases were just pathologically descriptive diagnosis. So it's important for pathologist to distinguish BA from malignant tumors, especially in intraoperative diagnosis. The well-differentiated mucinous adenocarcinoma could have ciliated columnar cells especially when adenocarcinoma infiltrates into bronchioles, but never present basal cells. Evidence support to malignancy should be carefully ruled out, and immunohistochemistry highlighted basal cells with p63 and/or CK5/6 is helpful. Otherwise, solitary peripheral ciliated glandular papilloma, mixed squamous cell and glandular papilloma and mucoepidermoid carcinoma needs to be considered as differential diagnosis.
In conclusion, we reported four cases of BAs and detected the mutation of ERBB2 exon 20 insertion for the first time. BA is likely a rare peripheral tumor, and exhibit characteristics similar to adenocarcinoma, including morphological and genetic changes. At present, BA shows benign biological feature might due to the limited number of cases. The pathogenesis and biological behavior of BA need to be further clarified, requiring more cases and longer follow-up.