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Genetically Altered Fields as Origin of Locally Recurrent Head and Neck Cancer

Purpose: Surgeons treating patients with head and neck squamous cell carcinoma (HNSCC) rely heavily on histology to decide whether the resection margins are tumor free and subsequent adjuvant treatments can be omitted. However, despite the presence of tumor-free margins, 10–30% of HNSCC patients still develop a locally recurrent tumor. Evidence is available that recurrent cancer develops from either (a) outgrowth of a relatively small number of tumor cells that have not been detected by the pathologist or (b) a precursor lesion in which additional genetic alterations have led again to invasive cancer. Experimental Design: In a retrospective study on 13 HNSCC cases, we analyzed the primary tumor, its surrounding histologically tumor-free resection margins, and local recurrences for loss of heterozygosity (22 microsatellite markers on 6 chromosomes) and TP53 mutations to determine the origin of the recurrent cancer. Results: A precursor lesion was absent in 5 of 13 (39%) cases, and the genetic similarity of the primary and recurrent cancer was high, providing evidence that residual cancer cells were the origin of recurrence. For the remaining eight cases (61%) a genetically related precursor lesion (field) was detected, and for five of these cases, evidence was found that both the primary and recurrent carcinoma originated from this field. The remaining three cases were less conclusive. Conclusions: This study explains the pathobiology of locally recurrent HNSCC in patients with histologically tumor-free resection margins and indicates that the development of novel therapies to decrease the local recurrence rates in HNSCC should not only be focused on eradicating residual cancer cells but also on the precursor lesions that are left behind.