Molecular markers of lymph node metastases in oral cancer

Abstract

Cervical lymph node metastasis occurs frequently in patients with oral squamous-cell carcinoma (OSCC) and is a major determinant of prognosis and treatment planning. Accurate lymph node staging is therefore crucial. Current preoperative clinical assessment of the lymph nodes by physical examination and imaging is suboptimal. Depending on the techniques used, in approximately 20% to 40% of all patients with HNSCC, nodal metastases remain undetected during diagnostic work-up. Establishing optimal treatment of patients who are clinically assessed as having non-metastasizing (N0) disease is therefore challenging. If no nodal metastasis is detected, the preferred treatment in many centers is to electively treat the neck, in addition to treating the primary tumor in all patients. An alternative is to refrain from additional neck treatment, closely observe the patient (watchful waiting), and only treat the necks of patients who develop clinically apparent metastases during follow-up. Whichever strategy is chosen, suboptimal treatment may be given. The primary treatment of OSCC is surgery, in most cases followed by (chemo)radiotherapy on indication. Neck dissection is therefore also the most frequent mode for treatment of the neck in OSCC. In the case of elective neck dissection, the 60% to 80% of patients who are clinically assessed as N0 (cN0) and are indeed free of metastases receive unnecessary treatment of the neck, causing morbidity, including shoulder dysfunction, pain, lymphedema, contour changes, and lower lip paresis, even in more conservative types of selective neck dissection. Conversely, watchful waiting results in undertreatment of the 20% to 40% of patients with occult metastases, which may result in an unfavorable prognosis in the case of delayed treatment. Because there is no conclusive evidence to indicate which approach is best, the management of patients who are clinically assessed as having N0 disease is one of the major issues in the management of OSCC in particular, which is reflected in the different approaches between centers. Treatment of the N0 neck, both surgically and by radiotherapy, would greatly benefit from improved preoperative assessment of lymph node metastasis, which is the goal of this thesis. One of the studies in this thesis describes the validation of a gene expression signature for distinguishing metastasizing (N+) from non-metastasizing (N0) OSCC and oropharynx (OPSCC) in a large (n=222) multicenter Cohort. The signature performed well on the most relevant subset of early-stage (cT1-T2N0) OSCC (n=101), with an NPV of 89%. Several genes from this signature (KLK5, KLK7, SPINK5 and CTSK) were evaluated for their association with lymph node metastases as a solitary predictive marker. Especially CTSK shows promising first result with a NPV of 89% in the clinically relevant group of cT1-T2N0 OSCC, however these results need further validation in a larger cohort. The results presented in this thesis indicate that molecular markers for predicting lymph node metastasis in OSCC, after application in a prospective study, may usefully be implemented in a clinical setting.