Regional Lymphatic Status in Oral Squamous Cell Carcinoma: A Brief Review

International Journal of Biomedicine 15(4) (2025) 639-644 http://dx.doi.org/10.21103/Article15(4)_RA3 BRIEF REVIEW INTERNATIONAL JOURNAL OF BIOMEDICINE Regional Lymphatic Status in Oral Squamous Cell Carcinoma: A Brief Review A. D. Dadamov1, 2*, A. M. Gizatullina1, Sh. N. Yakubov1, R. Kh. Nabiev1, Zh. E. Dusmatov1 Tashkent State Medical University, Tashkent, Uzbekistan Tashkent Regional Branch of the Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology, Tashkent, Uzbekistan 1 2 Abstract Oral squamous cell carcinoma (OSCC) is a common type of head and neck malignancy, leading to high morbidity and mortality rates. This brief review focuses on the regional lymphatic status in patients with OSCC. The lymphatic system plays a key role in the dissemination of malignant cells from the primary tumor. Tumor cell migration into the lymphatic system is a complex process involving multiple mechanisms and interactions within the tumor microenvironment. This multistep process is associated with the complex role of lymphatic endothelial cells in the tumor microenvironment, lymphangiogenesis, lymphatic invasion, and the modulation of the immune response. Despite recent advances, the precise role of the regional lymphatic system in the progression of OSCC remains unclear, highlighting the need for further in-depth study.(International Journal of Biomedicine. 2025;15(4):639-644.) Keywords: oral cancer • lymph node • lymphangiogenesis • lymphovascular invasion • metastases For citation: Dadamov AD, Gizatullina AM, Yakubov ShN, Nabiev RKh, Dusmatov ZhE. Regional Lymphatic Status in Oral Squamous Cell Carcinoma: A Brief Review. International Journal of Biomedicine. 2025;15(4):639-644. doi:10.21103/ Article15(4)_RA3 Abbreviations CT, computed tomography; DWI, diffusion-weighted imaging; DCE-PWI, dynamic contrast-enhanced perfusion-weighted imaging; DKI, diffusion kurtosis imaging; DTI, diffusion tensor imaging; FGF, fibroblast growth factor; LVI, lymphovascular invasion; LN, lymph node; LEC, lymphatic endothelial cell; LLNs, lingual lymph nodes; LYVE-1, lymphatic vessel endothelial hyaluronic acid receptor 1; MRS, magnetic resonance spectroscopy; MRI, magnetic resonance imaging; OSCC, oral squamous cell carcinoma; RLS, regional lymphatic status; VEGF, vascular endothelial growth factor. O ral squamous cell carcinoma (OSCC), originating from the flat squamous cells that line the mouth, lips, and tongue, accounts for more than 90% of all oral malignancies.1 OSCC dramatically impacts patients’ quality of life, resulting in high morbidity and mortality rates. Early diagnosis and complete tumor removal are considered the mainstays of treatment for OSCC.2,3 Despite improvements in diagnosis and treatment over the past 30 years, the five-year survival rate for OSCC remains only 50%.4,5 Cervical lymph node (LN) involvement (N-status) is one of the most important independent prognostic factors in OSCC.6,7 This review focuses on the regional lymphatic status (RLS) of patients with OSCC. Regional lymphatic status in patients with oral cavity carcinoma is crucial for determining the stage of the disease, prognosis, and treatment strategy. The drainage and transport functions of the lymphatic system are essential to oral cancer, as they serve as the primary pathway for metastasis. Lymphatic endothelial cells (LECs), a specialized subset of endothelial cells, play multiple roles in the tumor microenvironment in addition to lining lymphatic vessels.8,9 Lymphatic endothelial cells interact with innate and adaptive immune cells in both tissues and lymph nodes. These cells produce chemokines to attract immune cells to lymph nodes; specifically, CCL21 is involved in recruiting dendritic cells, which, in turn, promotes lymph node enlargement.10-12 640 A. D. Dadamov et al. / International Journal of Biomedicine 15(4) (2025) 639-644 Lymphatic endothelial cells play a crucial role in the formation of new lymphatic vessels observed in highly active tumors, a process known as tumor-associated lymphangiogenesis.13 Tumor-associated lymphangiogenesis also involves various lymphangiogenic factors secreted by tumor cells or host cells present in the tumor microenvironment. These include vascular endothelial growth factor (VEGF) C and D, known primarily for stimulating lymphatic vessel growth, angiopoietin-2, fibroblast growth factor (FGF), and others.14 Importantly, the discovery of specific markers for LEC, such as the lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1) and podoplanin (D2-40), has enabled the distinction between lymphatic and blood vessels.15-17 LYVE-1 exhibits a high degree of lymphatic vessel specificity and has been an essential component in numerous studies on tumor-induced lymphangiogenesis.17,18 Furthermore, LYVE-1 is closely associated with lymph node metastasis in OSCC.19 The complex role of lymphatic endothelial cells in the tumor microenvironment and recent advances in this field require in-depth study. The lingual, sublingual, and submental nodes provide lymphatic drainage from the tongue and surrounding tissues, playing a crucial role in local immunity. Lymphatic metastases in oral cavity carcinoma are a sign of a more aggressive course of the disease and make the prognosis less favorable. Lymphovascular invasion (LVI), in which cancer cells invade the lumen of endothelial-lined lymphatic and blood vessels, is considered an important step in lymph node metastasis.8,20 Lymphatic invasion is the main mechanism by which cancer cells in oral squamous cell carcinoma disseminate to regional lymph nodes.21 Blood vessel invasion is considered a secondary route of distant metastasis, although it does not appear to be associated with lymph node metastasis.22 Michikawa et al.23 reported a multivariate analysis of 63 patients with oral tongue squamous cell carcinoma, which showed that lymphatic vessel invasion was an independent risk factor for the presence of lymph node metastasis, although blood vessel invasion was not. Several retrospective studies have also reported a significant positive association between LVI and lymph node metastasis.24,25 A meta-analysis by Huang et al.21 included 36 studies involving 17,109 patients with squamous cell carcinoma. It concluded that LVI can serve as a prognostic indicator of metastasis and prognosis in OSCC. In oral carcinoma, due to its location and the characteristics of the vessels and lymphatic pathways that pass through the glossopharyngeal neuromuscular complex, metastasis and lymphatic drainage occur under high pressure, which can influence the rate of tumor growth and dissemination.26 Recently, numerous studies have shown that abnormal tumor vasculature can create significant pressure on the tumor microenvironment, collectively referred to as hydrostatic stress.27 Typically, fluid stress is generated by blood flow and interstitial blood flow, which includes microvascular fluid pressure, inter (...truncated)