Laryngeal cancer presents a significant public health challenge in China, with rising incidence and mortality rates over recent decades.As one of the most common malignant tumors of the head and neck, it accounts for nearly one-third of all head and neck cancers (1) and has a significant impact on global health. In 2022, an estimated 103,216 individuals are projected to die from laryngeal cancer worldwide, with age-standardized incidence and mortality rates of 3.9 and 2.1 per 100,000, respectively (2). Total laryngectomy is the primary treatment for patients with locally advanced laryngeal cancer; however, it inevitably impacts laryngeal functions, including phonation, swallowing, and respiration. To enhance the quality of life for patients, it is crucial to investigate prognostic factors for individuals with middle and late stage laryngeal cancer and to implement appropriate preventive and therapeutic measures.

Biomarkers are defined as physiological characteristics that can be objectively assessed and serve as indicators of pathological processes, risk, and pharmacological responses to therapy (3, 4). Recent studies have shown that the red blood cell distribution width (RDW) parameter in routine blood counts is strongly associated with the prognosis of various tumors. Red blood cell distribution width (RDW) is a marker of changes in red blood cell size. RDW contributes to cancer development through inflammatory responses in the microenvironment and has diagnostic and prognostic value for various tumor types, including lung, liver, prostate, esophageal cancers, and chronic lymphocytic leukemia (5–10). It is also considered a biomarker potentially involved in endothelial dysfunction (11), oxidative stress, and inflammatory processes in vascular diseases (3, 12).Hemoglobin (Hb) is one of the most important indicators in routine blood tests, reflecting the human body’s ability to produce red blood cells while also assisting in the diagnosis and treatment of various diseases. Studies have shown that hemoglobin levels correlate with prognosis in the treatment of various tumors. Hb serves as a diagnostic indicator of anemia and is also utilized for prognostic assessment in patients with lung cancer (13). Low Hb levels are recognized as a prognostic marker in patients with oral squamous cell carcinoma (14). Additionally, combining Hb with RDW has been shown to correlate with prognosis in various tumors (6, 7). In this paper, we analyze the clinicopathological characteristics and prognostic data of patients who underwent total laryngectomy to explore the potential connection between RDW, the Hb/RDW ratio (HRR), clinicopathological characteristics, and survival, aiming to identify a more convenient, reliable, and cost-effective index for the diagnosis and treatment of laryngeal cancer.

The prevalence of laryngeal cancer is 1-2% among all cancer types (15). It is the second most prevalent malignant neoplasm of the upper respiratory system, following lung carcinoma (16). Every stage of tumor development is accompanied by an inflammatory response, in addition to raising the risk of cancer (17), chronic inflammation is closely linked to the onset of cancer. Inflammation and immune system activation are pivotal in tumor development, growth, and progression (18). RDW and HRR are measurable indices of systemic inflammatory response employed in the prognosis and diagnosis of diverse malignancies. Currently, no standardized criteria exist for their ideal cut-off levels. The principal techniques for ascertaining these values involve computations derived from ROC curves and crucial values defined in prior research.

In this study, the predicted values of RDW and HRR for OS in patients who underwent total laryngectomy for laryngeal cancer, as shown by our ROC curve, are 13.75 and 10.79, respectively. Medine Kara et al. discovered that elevated RDW increased postoperative mortality by 4.6 times in laryngeal cancer patients, with an acceptable cutoff value of 14.05 for death prediction based on ROC analysis (18). Other investigations revealed an appropriate cutoff value of 13.5% for tongue cancer (4). The found HRR value for nasopharyngeal cancer was 0.97 (19), which closely corresponds with the threshold value determined in our investigation. Factors like tumor kind, case quantity, treatment variability, and selection bias impede the standardization of a precise ideal cutoff value. Nonetheless, credible studies can provide a legitimate spectrum of alternatives for establishing acceptable RDW and HRR criteria.

In this study, we analyzed the clinical characteristics of two subgroups: the low RDW group (RDW < 13.75) and the high RDW group (RDW ≥ 13.75), as well as the low HRR group (HRR < 10.79) and the high HRR group (HRR ≥ 10.79). Our findings indicated that preoperative RDW was associated with TNM clinical stage, cervical lymph node metastasis, and vascular infiltration. Additionally, the preoperative HRR was significantly correlated with gender, histologic grade, TNM clinical stage, cervical lymph node metastasis, and vascular infiltration. Additionally, Medine Kara’s study indicated that RDW served as a predictor of postoperative mortality in laryngeal cancer, with elevated RDW increasing postoperative mortality by 4.6 times in these patients (18). Marcus K’s study revealed that elevated RDW was associated with nonspecific complications after laryngectomy, including deep vein thrombosis, pneumonia, cardiac events, and difficulties in extubation (20). Marcin Miszczyk’s research indicated that patients with RDW ≥ 13.5% had markedly reduced overall survival in comparison to those with RDW < 13.5%. The study determined that a pretreatment RDW of > 13.5% is a significant predictor of reduced overall survival in individuals with squamous cell carcinoma of the tongue (4).Yakup Bozkaya’s study demonstrated that low HRR was an independent variable affecting OS and disease-free survival in patients with locally advanced nasopharyngeal carcinoma (19).

These findings highlight the important role of RDW and HRR in evaluating the prognosis of patients with head and neck tumors, as well as their potential in predicting disease progression and overall patient outcomes. In this study, the RDW group showed a substantial correlation with TNM clinical stage, cervical lymph node metastasis, and vascular infiltration, with statistically significant differences noted. Statistically significant differences were identified between the HRR group and gender, histologic grade, TNM clinical stage, cervical lymph node metastasis, and vascular infiltration. The favorable outcomes from the univariate analysis were incorporated into the multivariate COX regression model. This investigation showed that RDW, histologic grade, smoking status, TNM clinical stage, and vascular infiltration were significantly associated with OS in patients undergoing total laryngectomy, with RDW identified as an independent prognostic factor for OS in this cohort. Consequently, this study concludes that RDW and HRR are straightforward, cost-effective, and readily identifiable markers. Additionally, this study is the inaugural publication that explicitly investigates HRR as a biomarker in the peripheral blood of patients undergoing total laryngectomy. This study indicates potential markers of laryngeal cancer progression, offering a valuable diagnostic basis for clinical practice; however, the prognostic predictive value of HRR is inferior to that of RDW.

Despite the association of increased RDW and low HRR with adverse prognostic outcomes, their precise mechanisms remain ambiguous. The correlation between erythrocytes, tumor prognosis, and immunological function is intricate and multifarious. In the tumor microenvironment, erythrocyte precursors can develop into myeloid cells that inhibit T-cell immunity (21). Concurrently, erythrocytes may potentially associate with cytokines that facilitate tumor proliferation and angiogenesis (22). Metabolic byproducts, such as lactic acid, might modify the pH of the tumor microenvironment, so indirectly affecting tumor growth (23). Moreover, direct interaction between erythrocytes and tumor cells might augment the invasive and migratory properties of malignancies (21). HRR, as a hematological indicator, denotes the ratio of HB to RDW. Low HRR values generally signify diminished hemoglobin levels and elevated RDW. This may be linked to chronic inflammation, which not only inhibits erythropoietin synthesis (24) but also modifies erythrocyte production and metabolism, hence reducing erythrocyte longevity (25, 26). Moreover, malnutrition, especially deficits in iron, folate, and vitamin B12, in conjunction with oxidative stress—which compromises erythrocytes and heightens their fragility—are substantial factors contributing to increased RDW. Hb, indicative of indicative of erythrocyte production capacity, frequently signifies a worse prognosis when levels are diminished. This process may arise from anemia leading to tumor hypoxia, which induces resistance to radiation and accelerates tumor angiogenesis.

However, this study has several limitations. Firstly, it is a retrospective case study that covers a restricted number of cases from a single center, hence impacting the generalizability of the findings. Secondly, HPV infection has been identified as a considerable risk factor for laryngeal cancer; however, HPV status was not assessed in this investigation due to absent data. In addition, the follow-up duration was somewhat short, and solely the OS metric was incorporated;disease-free survival, progression-free survival, and other critical prognostic markers in oncology patients were not considered. Consequently, additional prospective research with bigger sample numbers across other centers and geographies is essential to corroborate these findings in the future.

In conclusion, preoperative RDW and HRR are prognostic risk factors for overall survival (OS) in patients undergoing total laryngectomy, with RDW serving as an independent predictor of prognosis. Preoperative RDW showed significant associations with TNM clinical stage, cervical lymph node metastasis, and vascular infiltration, while preoperative HRR was significantly associated with gender, histologic grade, TNM clinical stage, cervical lymph node metastasis, and vascular infiltration. RDW and HRR, as simple and effective biomarkers, are closely associated with the occurrence and progression of laryngeal cancer, thereby providing clinicians with robust support in patient management and the development of treatment strategies.