Transforming patient care with a revised classification for lung adenocarcinomas

In a groundbreaking large-scale study, the International Association for the Study of Lung Cancer (IASLC) addresses the challenge of accurately classifying pulmonary adenocarcinomas. Their modified classification system, supported by biomarker analysis, enhances reproducibility and aligns better with the clinical reality compared to the current WHO classification.

Patients diagnosed with resected adenocarcinoma in situ (AIS) generally achieve a cure. However, accurately determining the extent of invasion in these cases is essential for staging, and this poses a challenge using the existing criteria outlined in the WHO classification. Recognising this difficulty, the pathology panel of the International Association for the Study of Lung Cancer (IASLC) embarked on a study aimed at refining the current classification. The goal was to create a more precise classification system supported by biomarker analysis.

Methods

This study included two retrospective cohorts of patients with resected pulmonary adenocarcinoma measuring up to 3 cm (n=70), diagnosed between 2011 and 2016, from the San Raffaele Scientific Institute, Milan, Italy (n=35) and OLVG Hospital, Amsterdam, the Netherlands (n=35). The modified classification factored in iatrogenic collapsed adenocarcinoma in situ, identified through elastin and cytokeratin 7 staining. Pathologists assessed the cases according to the WHO criteria (round 1) and, after a one-hour tutorial, according to the modified classification (round 2). Based on feedback from 41 peers in the first two rounds, which included scores and heatmaps highlighting the underlying histology of hotspots of invasion, another round was conducted according to the modified classification (round 3). The primary endpoints were the kappa score and recurrence-free survival (RFS) after 5 years. To distinguish between patients diagnosed with AIS and those with invasive cancer without metastases, a secondary endpoint involving biomarker analysis was initiated.

Results

The study drew participation from 42 pathologists across 13 countries who scored the cases in three rounds. The kappa values for the three rounds were 0.27, 0.45, and 0.62, respectively. These results indicated that the standard WHO criteria faced challenges in achieving consistent and reproducible results, while the modified classification significantly improved reproducibility. Pathologists displayed a more significant increase in competence, reflected by a higher kappa score, both when evaluated blindly (0.45) and with guidance (0.62). The outcomes suggested that the revised classification overcomes the limitations of the WHO criteria, thereby addressing concerns about inconsistent assessments. Importantly, the research revealed that cases scored with "no-invasion" consensus in the second and third rounds achieved a 100% recurrence-free survival (RFS) rate.  The diagnosis of adenocarcinoma in situ after resection with the modified classification implies that the patient is cured. Biomarker analyses associated unveiled intriguing correlations, including a low proliferation rate in adenocarcinoma in situ compared to invasive adenocarcinomas, and the presence of TP53 mutations in invasive adenocarcinomas, underscoring their role as late- stage events. Importantly, the modified classification was able to recognise 14% (10/70) AIS cases in small pulmonary adenocarcinomas.

Conclusions

These results suggest that the modified adenocarcinoma classification significantly enhances reproducibility and aligns better with the clinical reality. These findings could enable a more confident diagnosis and treatment decisions for patients with pulmonary adenocarcinomas.

Reference

Thunnissen E, et al. Invasion or No Invasion, That’s the Question. A Large Reproducibility Study in Pulmonary Adenocarcinoma, Supporting a Modified Classification. Presented at WCLC 2023; Abstract PL03.07.