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

Abstract

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.

Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus

“…An intrinsic problem with these approaches, however, remains that genetic changes that are specifically linked to clinical failures may only reflect late progression and do not allow identification of chromosomal loci that play a role in the earlier phase of carcinogenesis. Moreover, the different outcomes, distant metastasis, locoregional recurrence as a result of residual cancer cells, or second-field tumors (Tabor et al, 2001(Tabor et al, , 2004, are very different biologically entities and are most likely associated with different genetic changes. The majority of loci presented here showed losses or gains in HPV-negative tumors and no apparent changes in HPV-positive tumors.…”

The clinical relevance of microsatellite alterations in head and neck squamous cell carcinoma: a critical review

“…19,33,53 Some primary and recurrent HNSCC originate from the same precursor lesion that contains genetically related features to the tumors, including LOH. 54 Overall, studies in HNSCC have shown that deletions at chromosome arms 3p, 4p, 8p and 9p represent early genetic changes and that loss at 18q, 17p and 11qter is associated with neoplastic progression. 33,34,36,45,48,55 Dysplastic regions in the head and neck region that show more LOH seem to be more at risk for neoplastic evolution.…”

Proteomic analysis reveals successive aberrations in protein expression from healthy mucosa to invasive head and neck cancer

“…These early p53 alterations have been more frequently observed in patients suffering from multiple cancers compared to those with only one tumor (Waridel et al, 1997;Homann et al, 2001), in agreement with the field model . In cytogenetic studies, allelic imbalances/loss of heterozygosity (LOH) and chromosomal aneuploidy have been detected in tumors and mucosal biopsies of tumor patients (Soder et al, 1995;Bedi et al, 1996;Califano et al, 1996;Ai et al, 1999;Partridge et al, 2000;Braakhuis et al, 2002;Tabor et al, 2004). Chromosomal aneuploidy appears to precede malignant transformation as indicated by findings of monosomy and trisomy in histologically normal squamous mucosa (Ai et al, 2001;Wolf et al, 2004).…”