Pathological and imaging features of pulmonary invasive mucinous adenocarcinoma—a retrospective cohort study

Introduction

Lung cancer is one of the most common malignant tumors worldwide, and its incidence and mortality rates continue to increase each year (1). An estimated 2.2 million new lung cancer cases and 1.8 million lung cancer-related deaths were recorded in 2020 (2). Lung cancer ranks second in terms of incidence among all malignant tumors in both males and females, and has the highest mortality rate of all cancers (3). Recent developments in imaging and pathological understandings have revealed an intricate correlation between the imaging manifestations of lung nodules and their growth patterns and pathological features (4). The imaging and pathological characteristics of adenocarcinoma in situ, minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma provide significant guidance for clinical treatment (5,6).

However, the polymorphism of tumors and the limitations of our understanding often lead to delayed diagnosis and treatment for certain lung nodules (7). For example, pulmonary invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with a 5-year survival of 69.2% after surgery, which accounts for approximately 2–10% of lung adenocarcinomas (8). The clinical challenge for IMA is how to improve the diagnostic and therapeutic efficacy. Due to the lack of clinical specificity, it is easily misdiagnosed as inflammatory nodules, tuberculosis, pulmonary diffuse lesions, or hamartomas which delayed a timely treatment, leading to a poor prognosis. Therefore, it is of significance how to apply current imaging technologies and ascertain its pathological and imaging characteristics to distinguish it from other benign diseases (9). This study sought to analyze the relationship between the pathological features of pulmonary IMA cases and computed tomography (CT) signs to improve the understanding, diagnosis, and treatment of lung mucinous cancer. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-526/rc).

Methods

A retrospective analysis was conducted on patients diagnosed with IMA of the lung, confirmed via surgery, biopsy, or bronchoscopy, at Zhoushan Hospital in Zhejiang Province from January 2014 to December 2021. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Zhoushan Hospital in Zhejiang Province (No. 2022-438). Informed consent was obtained from all the patients through an opt-out option available on the Hospital’s website as authorized by the Institutional Review Board.

Definition

According to the histological features, the IMA is characterized by abundant mucin (10). IMA is classified into three types: pure mucinous, mixed mucinous, and mucinous-absent. In the pure mucinous type, only mucinous cells are observed under the microscope. The mixed mucinous type features an attached-wall, papillary, acinar, and solid tumor cells with more than 10% mucinous cells. The mucinous-absent type is featured with the absence of mucous cells, but still can detect more than 10% of mucin expresses.

Inclusion and exclusion criteria

To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) have received a pathological diagnosis of pulmonary MIA through surgery or biopsy samples; and (II) have undergone a chest CT scan. Patients were excluded from the study if they had incomplete data, or were unable to provide informed consent.

Outcomes

The primary objective of the study was to assess the prevalence of various types of CT findings to conduct a detailed analysis of the radiological features observed in patients. The secondary objectives of the study were to evaluate the prevalence of different pathological types, and to conduct an in-depth examination of the molecular characteristics of IMA. This comprehensive approach sought to draw correlations between radiological patterns and the specific pathological and molecular profiles of MIA, thereby enriching our understanding of the disease’s heterogeneity and contributing to more personalized diagnostic and treatment strategies.

Statistical analyses

Statistical analysis was performed using GraphPad Prism (version 6.0). Quantitative data were presented as mean ± standard deviation. Categorical data were presented as numbers and percentages.

Results

A total of 136 patients were enrolled in this study (Table 1). Among them, 58 were male, and 78 were female. The patients had an average age of 63.0±9.7 years (range, 44–78 years). In relation to the types of lesions, 88 were nodular, 31 were inflammatory, 15 were mass-like, and 2 were diffuse. In terms of location, the lesions were located in the right upper lobe in 30 cases, the right middle lobe in 14 cases, the right lower lobe in 37 cases, the left upper lobe in 17 cases, and the left lower lobe in 38cases. Peripherally located lesions were identified in 126 cases, while centrally positioned lesions were identified in 10 cases.

The study identified the following three pathological types: pure mucinous (82 cases or 60.3%); mixed mucinous (22 cases or 16.2%); and mucinous-absent (32 cases or 23.5%) (Figure 1). Figure 2 illustrates the pathological characteristics of pulmonary IMA; Figure 2A displays mucous cells filled with mucus in their cytoplasm; Figure 2B shows tumor cells clustered together; Figure 2C depicts mucus secreting from mucous cells; Figure 2D illustrates the potential for the early spread of tumor cells through the airways, facilitated by mucus flow; Figure 2E highlights the tumor’s limited ability to destroy tissue, if the pulmonary vessels remain intact; Figure 2F shows that the bronchi are relatively unaffected by the tumor.

Figure 1 Pathogenic types of pulmonary invasive mucinous adenocarcinoma. (A) Simple mucinous type (hematoxylin-eosin staining; magnification: 40×). (B) Mixed mucinous type (hematoxylin-eosin staining; magnification: 40×). (C) Mucinous-absent type (hematoxylin-eosin staining; magnification: 40×). Red arrow: tumor cells; green arrow: mucus; blue arrow: other tumor cells.

Figure 2 Pathogenic features of pulmonary invasive mucinous adenocarcinoma. (A) The tumor is composed of mucous cells with cytoplasm containing abundant mucus (hematoxylin-eosin staining; magnification: 40×). (B) The tumor cells are clustered (hematoxylin-eosin staining; magnification: 40×). (C) Mucus secreted from mucous cells (hematoxylin-eosin staining; magnification: 40×). (D) The tumor cells can easily disseminate quickly through the airways, drifting away with the mucus (hematoxylin-eosin staining; magnification: 40×). (E) The tumor tissue exhibits weak destructive power; the pulmonary vessels remain intact (hematoxylin-eosin staining; magnification: 40×). (F) Bronchi relatively intact (hematoxylin-eosin staining; magnification: 40×). Red arrow: tumor cells; green arrow: mucus; blue arrow: intact pulmonary artery; black arrow: intact bronchi.

Then, we compared the molecular features of mucinous lung cancer to those of typical adenocarcinoma. As shown in Table 2, patients afflicted with mucinous lung cancer showed much lower levels of thyroid transcription factor-1 (15%) than those with usual adenocarcinoma (over 80%). However, cytokeratin 20 was more common in the mucinous lung cancer cases (50%) than the usual adenocarcinoma cases (about 5%). The K-RAS mutation was prevalent in 75% of the mucinous lung cancer cases, which contrasted sharply to its occurrence in a mere 15% of the usual adenocarcinoma cases. Epidermal growth factor receptor mutations were rarer in the mucinous lung cancer cases (less than 5%) than the usual adenocarcinoma cases (about 50%).

Table 3 shows how the CT scan features and types were distributed across the patients studied. The CT scans revealed various signs, including bubble-like signs in 88 patients, ground-glass nodules in 43 patients, a halo sign in 40 patients, spiculation in 20 patients, pleural retraction in 15 patients, and tree-in-bud signs in 8 patients. Notably, the nodular type features were identified in a majority of cases (64.7% or 88 patients). The inflammatory type emerged as the second most common type, with 31 patients (22.8%), followed by the mass type, which manifested in 15 patients (11.1%). The least common type was the diffuse type, which was observed in only 2 patients (1.5%).

Discussion

This study investigated 136 cases of pulmonary IMA patients, of which the mucinous type was identified as the most frequent pathological type and nodular type in the CT classification. Pulmonary IMA is a subtype of lung adenocarcinoma characterized by malignant epithelial tumors with gland-like differentiation or mucin production from a histopathological perspective. In the early stages of mucinous adenocarcinoma, the morphology and arrangement of the tumor cells are different from those of non-mucinous adenocarcinoma, and are characterized by the clustering of mucous gland epithelium (11). As the tumor grows, the cell clusters enlarge and form acini, which can secrete a large amount of mucin that permeates the surrounding lung tissue. The mucin can carry tumor cells outward and cause dissemination in the airways. Therefore, it has the capacity for early close-range spread, and in later stages, it can disseminate to distant lung parenchyma, with limited destruction of bronchi and blood vessels (12).

Primary pulmonary IMA can occur in any part of the lung. It is mainly distributed in the periphery of the lung, but it is more common in the lower lobes than the upper lobes, which are the most common sites (13,14). In our study, more than half of the cases occurred in the lower lobes or the dependent parts of each lobe due to the gravitational effect of the mucin, which resembles water flowing downwards. Additionally, the fissure lines of the upper lobes are often pronounced, which is an obstruction caused by the accumulation of mucin. Due to the weight of the mucin, the elastic fibers of the interlobar pleura can also relax.

The imaging manifestation of pulmonary nodules is closely related to the growth patterns and pathological characteristics of the nodules, with the pathological basis determining the imaging features (15). Bubble-like or reticular signs represent one of the primary radiological manifestations of pulmonary IMA (16). Additionally, mucin induces the partial blockage of the small bronchioles, leading to the formation of small bubbles. In small, disseminated foci, small cavities may be evident, and thin-layer scanning can reveal more tiny cavities. The increased pressure caused by mucin cell secretion or alveolar rupture allows mucin to permeate the surrounding tissues, creating a ground-glass appearance around the nodules (17). In addition, mucin can also flow through the pores of Kohn and the Lambert channels (18). The uneven density in the nodules, which is attributed to the gravitational effect on the mucin, results in the nodules or masses being lighter at the top and denser below. This effect also causes the interlobar fissures to appear more pronounced. Pulmonary IMA demonstrates minimal damage to blood vessels and bronchi due to the less destruction to matrix (19,20). Radiologically, this can manifest as tree-in-bud or dried branch sign changes. In our study, the speculation of spiculation and pleural retraction signs were 14.70% and 11.02%, respectively. In comparison to pulmonary infiltrative adenocarcinoma, pulmonary IMA displays features such as pleural traction, pleural indentation, occasional speculation, and subtle interlobular septal indentation; however, its contractile force is less than that of infiltrative adenocarcinoma. This is primarily because the tumor boundary observed on CT scans often represents the extent of mucin permeation rather than the actual tumor boundary.

This study had several limitations. First, the small number of cases in the study limits its ability to comprehensively depict the imaging and pathological characteristics of pulmonary IMA. Second, the data were collected from a single clinical facility, which may limit the generalizability of the findings. Finally, comparisons were not conducted due to the small sample size.

Conclusions

This study found a significant correlation between the pathological features of pulmonary IMA and its radiological presentations. These findings emphasize the importance of adopting integrated diagnostic approaches.

Acknowledgments

Funding: This work was supported by grants from the Zhoushan Municipal Science and Technology Bureau, Zhejiang Province (No. 2023C31001).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-526/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-526/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-526/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-526/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Zhoushan Hospital in Zhejiang Province (No. 2022-438). Informed consent was obtained from all the patients through an opt-out option available on the Hospital’s website as authorized by the Institutional Review Board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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