Introduction
Laryngeal squamous cell carcinoma (LSCC) originates from the mucosal epithelium of the larynx and is among the most frequently occurring malignancies in the head and neck region. Unfortunately, the incidence of LSCC, along with other head and neck SCCs, has been steadily increasing. According to GLOBACAN, the Global Cancer Observatory, there is an anticipated 30% rise in the number of cancer cases by the year 2030 (1). This rise may be due to several factors, including a lack of concrete screening strategies, carcinogen consumption, and increased human papillomavirus (HPV) infections (2). Despite the increase in cases, the survival rate of LSCCs has not significantly decreased over the past few decades. On average, the 5-year survival rate is about 40-60%, regardless of the patient’s age or anatomical site of the tumor (3). Interestingly, some studies suggest that the slight improvement in survival is more related to the rise of patients with HPV-associated LSCC, which has a better overall outcome than actual advances in cancer control (2).
The prognostic factors of LSCC are typically grouped into three categories: host, tumor, and treatment, which encompass various elements such as age, gender, nutritional or performance status, tumor site, tumor histological grading, perineural/vascular invasion, and TNM staging (4). Despite this, studies have shown conflicting results regarding their accuracy in predicting patient outcomes (5). As a result, there is currently no definitive predictor of survival due to the primary tumor site’s heterogeneity, tumor behavior, and molecular mechanisms (6). For this reason, quests for discovering a more reliable prognostic parameter have been carried out.
When predicting tumor behavior and assessing its aggressiveness, it is important to consider the histopathologic findings. Tumor progression and response to treatment are also closely linked to how tumor cells interact with the microenvironment around them (7). Studies have shown that cancer cells at the tumor front tend to be more aggressive and contribute to tumor growth (8). Peritumoral tumor budding (TB) occurs when small clusters of non-glandular cancer cells appear throughout the invasive tumor front. This is associated with decreased cell adhesion and increased local invasion (9). While TB is commonly reported in colorectal cancers, it is now recognized as a reliable predictor of lymph node metastasis, advanced cancer prognosis, and response to therapy in multiple malignancies such as lung SCC, esophageal SCC, breast cancer, and pancreatic ductal adenocarcinoma (10, 11). The TBNS (tumor budding/nest size) grading system, which combines TB with cell nest size (CNS), is also considered a practical prognostic element in SCCs of various sites, including lung, oral cavity, larynx, and hypopharynx (12, 13). The adverse effect of TB on survival of LSCC, even in patients with a lower TNM staging score, have also been confirmed in previous studies (14-16). Despite the significant impact TB can have on patient survival, it has yet to be included in standard pathology reports for LSCC due to limited data and a lack of systematic scoring systems.
Hence, through this study, we aim to investigate the relationship of TB and CNS with nodal involvement and overall prognosis in patients with laryngeal SCCs to further establish the value of TB and CNS as an inexpensive, easily assessable, yet highly reliable prognostic factor.