To investigate the clinicopathological characteristics and potential diagnostic pitfalls of bronchiolar adenoma (BA) combined with lung adenocarcinoma (LUAD) in the same lesion.

We analyzed eight cases of BA combined with LUAD from our hospital pathology department between July 2020 and January 2022, and summarized their clinical data, radiological features, histopathological characteristics and immunohistochemical phenotypes.

Upon macroscopic examination, the lesions were characterized by gray-white or gray-brown solid nodules with well-defined borders, measuring 0.6-1.8cm in maximum diameter. The incidence of proximal-type BA (6/8) was higher than that of distal-type BA (2/8), and they combined with different stages of LUAD, including adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and invasive mucinous adenocarcinoma (IMA). Immunohistochemistry showed that cytokeratin 5/6 and P40 were positive in the continuous basal cell layer in BA, but only scattered positive basal cells were seen at the junction of BA and LUAD. TTF-1 was positive in proximal-type BA ciliated cells in five cases and in LUAD cells in seven cases, and weakly positive in some basal cells. One case of IMA and mucinous cells of BA were TTF-1 negative. There was partially positive Napsin-A expression in BA luminal cells and LUAD cells of all cases except IMA.

There is no obvious boundary when BA and LUAD are in the same lesion. The luminal epithelial cells in the area where the two components migrate toward each other are atypical and lack a continuous underlying basal cell layer. Microscopic diagnosis should be aided by immunohistochemistry.

Bronchiolar adenoma/ciliated muconodular papillary tumour (BA/CMPT) is a benign peripheral lung tumour composed of bilayered bronchiolar-type epithelium containing a continuous basal cell layer; however, the similarities in imaging and tissue biopsy findings at histopathology between BA/CMPT and malignant tumours, including lung adenocarcinoma, pose significant challenges in accurately diagnosing BA/CMPT preoperatively. This difficulty in differentiation often results in misdiagnosis and unnecessary overtreatment. The objective of this article is to provide a comprehensive and systematic review of BA/CMPT, encompassing its clinical manifestations, pathological basis, imaging features, and differential diagnosis. By enhancing healthcare professionals' understanding of this disease, we aim to improve the accuracy of preoperative BA/CMPT diagnosis. This improvement is crucial for the development of appropriate therapeutic strategies and the overall improvement of patient prognosis.

Bronchiolar adenoma (BA) is a rare tumor of the bronchioles with a double-layer structure, including the basal cell layer and the superficial cell layer, and it has a good prognosis. However, the concept of a putative variant of BA has been proposed in the recent literature.

Data on 17 cases of BA were collected from our center. The clinical data, morphology, immunophenotype, and molecular changes were retrospectively analyzed. We also collected the molecular changes in BA reported in the previous literature and summarized the putative driver mutations of BA.

Out of 17 BAs, 13 were classic cases with a double-layer structure, including 9 proximal-type and 4 distal-type BAs. Of note, we also identified 3 cases that lacked a continuous basal cell layer, including 2 cases of mixed-type BA with monolayered lesions (basal cells were undetected in some areas) and 1 case of a monolayered BA-like lesion (basal cells were completely undetected). The immunohistochemical findings of monolayer cell lesions were closer to those of minimally invasive adenocarcinoma. We also found one case in which BA transformed into invasive adenocarcinoma accompanied by mutations in the TP53, JAK2, NF1 and RB1 genes. Combined with the previous literature, the most common putative driver gene mutations in 62 BA lesions were EGFR (25/62; 41%) and BRAF (21/62; 34.4%).

Typical BA has a double-layer cell structure; however, there is also a putative variant of BA, which has a monolayer cell structure and lacks the basal cell layer. Transformation from BA into invasive adenocarcinoma is unusual but can occur.

To describe the histologic features of bronchiolar adenoma/ciliated muconodular papillary tumors (BA/CMPTs) and analyze the pitfalls in diagnosis from frozen sections. A total of 208 frozen and permanent sections of BA/CMPTs from Shanghai Chest Hospital from July 2018 to July 2021 were retrospectively analyzed. The median age of BA/CMPT patients was 65 years (15 to 79 y), and women accounted for 61.62% (122/198). The median size of BA/CMPTs was 0.6 cm (range 0.2 to 2 cm), of which 88.94% were small (≤1 cm, 185/208). In terms of location, the right lower lobe accounted for 44.23% (92/208), and the left lower lobe accounted for 33.65% (70/208). In 10 patients with 2 independent BA/CMPTs, 5 lesions were located in the left lower lobe and 4 in the right lower lobe. A total of 86.06% of the CT images of BA/CMPT showed solid/subsolid nodules (179/208). Among 208 tumors, 68.75% were distal type (143/208), and 31.25% were proximal type (65/208). The qualitative error rate of frozen sections was 21.33% (32/150), of which the distal type accounted for 75% (24/32); most of them were misdiagnosed as invasive adenocarcinoma during frozen diagnosis. The frozen diagnosis of BA/CMPTs might result in misdiagnosis as invasive adenocarcinoma. A careful search for characteristics of BA/CMPT, such as bilayer epithelial cells with basal cells and a lack of cellular atypia and invasive growth patterns, may be helpful for frozen diagnosis.

Pulmonary salivary gland-type tumors (SGT) represent a small but distinct group of primary lung neoplasms. These types of tumors originate from the submucosal bronchial glands of the tracheobronchial tree. Pulmonary SGTs differ greatly in the incidence of individual tumors from salivary gland tumors of the head and neck. Additionally, the vast majority of pulmonary SGT are malignant. Recently, pathologic diagnosis has significantly improved with the application of molecular diagnostic technologies. However, the current knowledge of benign SGTs is limited; moreover, tumor diversity and overlapping morphological features of SGT represent diagnostic challenges such as correct tumor categorization and their accurate differentiation from malignant lesions. Compounding this inherent difficulty has been the recent introduction of new variants, including sialadenoma papilliferum (SP). Pulmonary SP is very rare, with limited reports available, and most of the initial diagnoses rendered so far were incorrect, resulting in inappropriate treatment. Several cases of SP have recently been reported. This review will serve to update practicing pathologists on the morphology, immunophenotype, and molecular characteristics of SP and its mimics.

The clinicopathological features, immunohistochemical characteristics, and genetic mutation profile of two unusual cases of distal bronchiolar adenoma are retrospectively analyzed and the relevant literature is reviewed.

Case 1 was a 63-year-old female patient who had a mixed ground-glass nodule, with mild cells in morphology, visible cilia, and bilayer structures in focal areas. Immunohistochemical staining for P63 and cytokeratin (CK)5/6 revealed the lack of a continuous bilayer structure in most areas, and no mutations were found in epidermal growth factor receptor, anaplastic lymphoma kinase, ROS1, Kirsten rat sarcoma, PIK3CA, BRAF, human epidermal growth factor receptor-2 (HER2), RET, and neuroblastoma RAS genes. Case 2 was a 58-year-old female patient who presented with a solid nodule, in which most cells were observed to be medium sized, the nuclear chromatin was pale and homogeneous, local cells had atypia, and cilia were found locally. Immunohistochemical staining for P63 and CK5/6 showed no expression of these proteins in mild cell morphology whereas the heteromorphic cells showed a bilayer structure. The same nine genes as above were analyzed, and HER2 gene mutation was identified.

Some unresolved questions remain to be answered to determine whether the lesion is a benign adenoma or a part of the process of malignant transformation from benign adenoma of the bronchial epithelium. Furthermore, whether lesions with atypical bilayer structures are similar to atypical hyperplastic lesions of the breast remains to be elucidated. Moreover, clarity on whether these lesions can be called atypical bronchiolar adenoma and whether they are invasive precursor lesions is needed. Future studies should examine the diagnostic significance of HER2 gene mutation as a prognostic indicator.

Bronchiolar adenoma (BA) is a rare benign lung tumor that shows proliferation of bland bronchiolar-type epithelium containing a continuous layer of basal cells. This tumor entity has been newly added to the recent World Health Organization (WHO) classification 5th edition. This entity encompasses a spectrum of lesions: the classic ciliated muconodular papillary tumor (CMPT) and the non-classic CMPT. Although BA is reported to have driver mutations including BRAF V600E, EGFR, and KRAS, the molecular profile of BA is still incompletely understood. Five resected BAs at our institutions were analyzed. The BA lesions were subdivided into two groups: three proximal-type BAs and two distal-type BAs. NRAS codon 12/13 mutation and EML4 exon 20-ALK exon 20 fusion were found in two of the three proximal-types. BRAF V600E mutation was found in one of the two distal-types. Two cases coexisted with lung adenocarcinoma, with EGFR exon 19 deletion and KRAS mutation, respectively. No recurrence was observed at a median of 12 months (range 2-84 months) of follow-up. BA has uncommon variants of mutation seen in lung adenocarcinoma. NRAS mutation and ALK fusion partner has not been reported previously. The present cases may reinforce the distinctive biology of BA from lung adenocarcinoma.

Alpha-fetoprotein-producing gastric cancer (AFPGC) is associated with high invasion and poor prognosis, but has not been well-documented due to its rarity. To develop the understanding of AFPGC, and further facilitate its clinical decision-making and treatment, we performed clinicopathological and molecular characterization of AFPGC and its two major subtypes, namely, gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC). The clinicopathological and molecular characteristics of AFPGC patients (n = 54) were mainly investigated by immunohistochemistry and next-generation sequencing (NGS) approaches. AFPGC exhibited a higher incidence of lymphatic and vascular invasion than conventional gastric adenocarcinoma (CGA). Despite various morphological patterns, there was mostly no evident difference in clinicopathological characteristics between the GAED and HAC subtypes. Target-enriched NGS profiling of disease mutation landscapes discovered 17 differentially mutated genes between AFPGC and CGA. The AFPGC patients carrying ZNF217 mutations had poorer overall survival than the ZNF217 wildtype. Furthermore, ATR showed a significantly higher mutation rate in GAED than in HAC. Overall, our study of clinicopathological characteristics shed light on the differences between CGA and AFPGC, as well as the relationships between the GAED and HAC subtypes of AFPGC. Furthermore, mutation landscape profiling revealed potential diagnostic and prognostic markers for AFPGC and its two subtypes.

The 2021 World Health Organisation (WHO) Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are 1) broader emphasis on genetic testing than in the 2015 WHO Classification, 2) a chapter entirely dedicated to the classification of small diagnostic samples, 3) continued recommendation to document percentages of histological patterns in invasive non-mucinous adenocarcinomas, with utilization of these features to apply a formal grading system, as well as using only invasive size for T-factor size determination in part lepidic non-mucinous lung adenocarcinomas as recommended by the 8^th Edition TNM Classification, 4) recognition of spread through airspaces (STAS) as a histological feature with prognostic significance, 5) moving lymphoepithelial carcinoma to squamous cell carcinomas, 6) update on evolving concepts in lung neuroendocrine neoplasm classification, 7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT) as a new entity within the adenoma subgroup, 8) recognition of thoracic SMARCA4-deficient undifferentiated tumor, and 9) inclusion of essential and desirable diagnostic criteria for each tumor.

Bronchiolar adenomas (BAs)/ciliated muco-nodular papillary tumors (CMPTs), are small, peripheral lung nodules arising predominantly in the elderly that follow a benign course. They can be mistaken for adenocarcinomas on frozen section. Immunohistochemistry (IHC) for basal cell markers highlights the continuous layer of basal cells underlying the tumor cells in BAs. BAs are further subdivided into proximal-type and distal type. Six BAs were retrieved from the pathology archives. The cases were classified based on morphology into proximal and distal BAs. The clinical and radiological features were reviewed. Immunohistochemistry and special stains were performed. The most common radiological picture of BA/CMPT was of a solid nodule with SUV_max < 3 as seen in 60% cases. 40% cases showed cavitation on CT. On histological examination, four cases were morphologically classified as proximal BAs and two as distal BAs. In proximal BAs, TTF1 was focally positive only in the basal cells in three of four. The mucin stained acidic. In distal BAs, TTF1 was diffusely positive in both basal and luminal cells. There was scant intracellular neutral mucin. Both the distal BAs had concomitant neuroendocrine tumors in the same lobe. Though the number of cases evaluated in this study is too low to be statistically significant, this study provides additional evidence to the concept of BA classification based on site specific histology and supplementary immunohistochemistry and reiterates the radiological features that may help distinguish it from malignant lesions.