Semaphorin-3F/Neuropilin-2 Transcriptional Expression as a Predictive Biomarker of Occult Lymph Node Metastases in HNSCC

SIMPLE SUMMARY: The presence of lymph neck node metastasis is the most important clinical prognostic factor in patients with head and neck squamous cell carcinoma. The expression of the semaphorin-3F and neuropilin-2 proteins is involved in the regulation of lymphangiogenesis. We analized the transcriptional expression of semaphorin-3F and neuropilin-2 in head and neck squamous cell carcinoma tumors of patients without clinical or radiology evidence of lymph node involvement treated with elective neck dissection. We found that patients with high semaphorin-3F and low neuropilin-2 had a lower risk of occult lymph node metastasis than the ones who had low semaphorin-3F or high semaphorin-3F and high neuropilin-2. If our results are validated, the expression of the SEMA3F-NRP2 axis could be used as a biomarker predicting the risk of occult lymph node metastasis, with elective neck dissections being indicated exclusively for patients at higher risk. The availability of a biomarker with the capacity to predict the presence of occult lymph node metastases would make it possible to avoid elective neck dissections in low-risk patients, with the consequent decrease in surgical time and morbidity of the treatment without impairing the oncologic outcome. ABSTRACT: The expression of the semaphorin-3F (SEMA3F) and neuropilin-2 (NRP2) is involved in the regulation of lymphangiogenesis. The present study analyzes the relationship between the transcriptional expression of the SEMA3F-NRP2 genes and the presence of occult lymph node metastases in patients with cN0 head and neck squamous cell carcinomas. We analyzed the transcriptional expression of SEMA3F and NRP2 in a cohort of 53 patients with cN0 squamous cell carcinoma treated with an elective neck dissection. Occult lymph node metastases were found in 37.7% of the patients. Patients with occult lymph node metastases (cN0/pN+) had significantly lower SEMA3F expression values than patients without lymph node involvement (cN0/pN0). Considering the expression of the SEMA3F-NRP2 genes, patients were classified into two groups according to the risk of occult nodal metastasis: Group 1 (n = 34), high SEMA3F/low NRP2 expression, with a low risk of occult nodal involvement (14.7% cN0/pN+); Group 2 (n = 19), low SEMA3F or high SEMA3F/high NRP2 expression, with a high risk of occult nodal involvement (78.9% cN0/pN+). Multivariate analysis showed that patients in Group 2 had a 26.2 higher risk of lymph node involvement than patients in Group 1. There was a significant relationship between the transcriptional expression values of the SEMA3F-NRP2 genes and the risk of occult nodal metastases.