Defining Factors That Allow for a More Personalized Approach to Stage I NSCLC.

Our understanding of lung cancer biology has grown dramatically in the past 20 years. It is no longer regarded as a single disease but rather as a diverse oncologic landscape with wide variation in molecular biology, mutations, malignant potential, and prognosis. Unfortunately, none of this increased knowledge is currently reflected in the lung cancer staging system. In 2022, lung cancer staging remains dependent on tumor size, invasion to adjacent structures, and spread to regional nodes or distant locations. Our staging system is agnostic to any molecular data, which is becoming more intriguing as we have entered an era where so many treatment decisions are based on a tumor’s molecular signature.

Adenocarcinoma is currently the lung cancer cell type with the greatest understanding of its biological diversity and where that diversity has the most significant impact on treatment and prognosis. In 2011, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society provided a structure to better understand the histologic heterogeneity of pulmonary adenocarcinomas by organizing them into the following five subtypes: lepidic, acinar, papillary, solid, and micropappillary. This work also defined adenocarcinoma in situ and minimally invasive adenocarcinoma described as small (<3 cm), solitary adenocarcinomas consisting of purely lipid growth without invasion or with an invasion of less than 0.5 cm. Clear definitions for these very early adenocarcinomas are important because numerous series reveal an absence of nodal involvement and 100% disease-specific survival after resection, allowing us to think differently about extent of resection and need for nodal evaluation at the time of resection. The International Association for the Study of Lung Cancer pathology committee brought this work one step further in 2020 and defined a pathologic grading system for pulmonary adenocarcinoma based on predominant histologic pattern and the proportion (<20% or >20%) of high-grade histologic pattern. This grading system is highly predictive for survival in stage I cohorts and more advanced cohorts. Despite the strong prognostic nature of this histologic subclassification, it is currently included in our staging system.

Adenocarcinomas of the lung are somewhat unique in the fact that their appearance on computed tomography (CT) scan can predict histologic subclassification. A strong association exists between the percent of ground glass on CT scan and lepidic-predominant histologic features. The accompanying work by Hamada et al. takes the presence of ground-glass components in a tumor nodule on CT scan one step further and suggests that any ground-glass components on CT scan tumor should serve as a marker for a mixed tumor and that mixed tumors are distinct from solid tumor. In stage I, mixed tumors have a different histologic profile and improved overall and recurrence-free survival compared with solid tumors. Their work suggests that prognostication is improved with the addition of this ground-glass component to the current T descriptor of the lung cancer staging system.

Unfortunately, adding new variables to the lung cancer staging is challenging. It requires incredible levels of rigor and validation to assure prognostication across the wide spectrum of the disease and throughout the world. The staging also needs to hold true for both pathologic and clinically staged patients. At the same time, the increased molecular and biological diversity of lung cancer needs to be accounted for when discussing prognosis and treatment. On some levels, this has happened in advanced disease without associated changes to the staging system. Patients on stage IV with driver mutations are treated differently and have unique prognosis to those without actionable mutations. One would never describe an EGFR or ALK-mutated patient simply as a “patient with stage IV disease,” and the qualifier “EGFR-mutated” or “ALK-mutated” is almost always included when discussing their disease due to obvious differences in treatment, prognosis, and research questions that make this a unique cohort. Maybe the same needs to occur in stage I disease with regard to CT appearance. Is it time for the lexicon of early stage disease to also reflect the biological diversity that exists? When describing a cancerous nodule on CT scan, maybe we need to do more than simply refer to it as a “stage I cancer.” Hamada et al. suggest that describing it as a “stage I solid tumor” or “stage I ground glass containing tumor” would be far more specific and prognostic. This type of distinction could allow for consideration of a more personalized treatment approach and discussion of prognosis. It would also allow us to ask more meaningful research questions and better stratify patients within clinical trials. The treatment and prognosis in advanced NSCLC have evolved by dividing a single very large group into multiple smaller cohorts with unique molecular characteristics. Leveraging the strong association between CT appearance and molecular characteristic in early stage disease could allow us to do the same in stage I disease and similarly improve survival with a more personalized approach to prognosis and treatment.

CRediT Authorship Contribution Statement

Jessica S. Donington: Conceptualization, Writing—original draft, Writing—review and editing.