Koos Boeve

22 Chapter 1 Early detection and treatment of local recurrences and second primaries is challenging. Since clinical manifestation might be lacking, field cancerization and residual cells are not recognized during surgery, clinical examination or histopathological assessment and consequently detection is delayed until conversion into a local recurrence or second primary tumour. In some cases there is clinical manifestation of field cancerization (e.g. leukoplakia), and in this particular cases therapy is limited by the extensiveness of the field cancerization. The intra-oral clinical examination, during follow-up after treatment of the first primary tumour, might be limited by postoperative fibrosis induced by surgery or irradiation [73] and as a result of reconstruction of the resection area of the first primary with tissue from extra-oral donor sites. To prevent patients for local recurrences or second primary tumours, histopathological predictive characteristics have been studied. Close (1-5 mm) or involved (<1 mm) resection margins of the tumour, perineural and lymphovascular invasion, grade of differentiation, tumour infiltration depth and tumour pattern of invasion have been reported as predictive for local recurrence [74-76]. Even in cases with free resectionmargins (>5 mm) [75,77], a local recurrence rate of 8% to 11% is reported [77,78]. Other studies analysed the detection of minimal residual cancer or preneoplastic fields usingmolecular markers in surgical resection margins [76,79]. Although some promising results of molecular tumour biomarkers with 100% positive predictive values for local recurrences [79], robust validation in several trials with clearly defined margins and sufficient power is lacking [80]. Currently, patients with involved or close resection margins, or T3-T4 staged tumours are treated with adjuvant radiotherapy, chemotherapy or a surgical re-resection to lower the risk for a local recurrence [81]. Moreover, preneoplastic regions located adjacent to the resection area could be removed using laser therapy [82]. Due to the clinical invisibility, removal of the total preneoplastic field is uncertain. For example, oral leukoplakia is a clinically visible type of field cancerization with an annual malignant transformation risk of 1% [83]. Even if these visible leukoplakia fields are removed completely with carbon dioxide laser surgery, a local recurrence risk of 3-40% for oral leukoplakia was reported in a systematic review [83]. Therefore, after treatment of the first primary tumour, all OSCC patients are clinically assessed according to a strict follow-up scheme starting with a 6 week interval followed by three and six months intervals in the Netherlands. Biomarkers for diagnosis and monitoring of recurrent disease in OSCC using liquid biopsies Although field cancerization and residual tumours cells are often clinically invisible, their already existing (epi)genetic alterations might be detectable and used as biomarker to monitor OSCC patients in order to diagnose local recurrences in an early stage [46].