A meta-analysis of margin size and local recurrence in oral squamous cell carcinoma
Introduction
Oral cavity squamous cell carcinoma (OSCC) is increasingly common worldwide [1], [2], [3] and represents an increasing burden on health services. The mainstay of treatment is primary surgery, with adjuvant radiotherapy or chemotherapy used when indicated [4], [5]. Adjuvant therapies are well researched with their use based on high quality evidence [6], [7], [8].
Surgery involves removal of the tumour with a margin of clinically uninvolved tissue, arbitrarily taken approximately 1 cm from the visible tumour edge [9], [10], with the aim of ensuring removal of microscopic tumour extension. This is not evidence based, in contrast to cutaneous SCC, where guidelines for surgical excision are based on good quality evidence about microscopic tumour spread [11], [12].
The adequacy of excision is assessed pathologically, and the pathological margin size is a major consideration in determining the need for further treatment [5]. The pathological margin is almost invariably smaller than the surgical margin due to both microscopic tumour extension and tissue shrinkage. The amount of shrinkage is yet to be accurately quantified, with figures of 9.2–75% quoted in the literature [13], [14], [15].
Guidance on pathological margins for OSCC is issued by the UK Royal College of Pathologists [16]. It categorises a margin <1 mm as involved, 1–5 mm as close and >5 mm as clear [16]. These categories do not appear to be related to risk of recurrence [9], and studies that have looked at the relationship between margin size and recurrence have shown conflicting results. Margins of <1 mm are generally acknowledged to be a poor prognosticator [17], [18], [19], but margins of other sizes have shown broad variability in their relationship with recurrence. Close margins particularly cause on-going confusion within the literature [9], [20], [21]. They are generally defined as having a prognostic significance as compared to clear margins, but suggested values vary, including <1.6 mm [9], 2 mm [19], 5 mm [22], [23], 7 mm [24], and 10 mm [25]. Furthermore, some studies have shown no prognostic significance associated with margin size [9], [22], [26].
The inconsistency in findings can be attributed at least partly to varying study designs adjusting differently for various patient, tumour and treatment related factors that may or may not influence recurrence rates [17], [26], [27]. Common confounders include the grouping of patients with cancers of the larynx and pharynx with those of the oral cavity [9], [20], [21], under the umbrella term of head and neck cancer, despite the later presentation of these more posterior tumours, and their better response to radiotherapy [18]. A second issue is the combination of patients who received adjuvant radiotherapy with those who did not in analysis of margins [17], [27], [28]. As radiotherapy is given to reduce the risk of recurrence it will confound the relationship between margin and outcome. A third issue is lack of adjustment for tumour related factors, in particular markers of disease aggression such as tumour size and depth, differentiation, invasive pattern, and perineural and lymphovascular invasion, when analysing margins [22], [27], [28]. This is of importance as more aggressive disease may require larger margins, or adjuvant treatment, to prevent recurrence.
Furthermore, many studies use survival or locoregional recurrence as primary outcome measures [19], [28], [29], [30]. Primary surgery is best assessed by its ability to prevent local recurrence, as regional or distant recurrences temporally isolated from a local recurrence are likely due to metastasis in transit at the time of, or prior to, surgery. Survival is influenced by many factors and is difficult to interpret as a marker of margin adequacy. Local recurrence rates should therefore be used as the standard measure of the effectiveness of surgery to the primary tumour.
Despite a paucity of consistent evidence about the relationship between margin size and local recurrence, close or involved margins are a key determinant of the need for adjuvant therapy [5]. Clarifying the relationship between margins and local recurrence is a priority due to the morbidity associated with both excessive surgery and unnecessary adjuvant treatment.
A systematic review has the potential to advance understanding in this area by allowing evaluation of a larger sample of patients than would be possible with primary research, whilst avoiding common confounders. As no randomised control trials in this area exist [18], a review of cohort studies, which form the majority of literature in this area, is the most appropriate method.
This review aims to determine whether a wider pathological margin reduces local recurrence rates in patients with OSCC treated by primary surgery without adjuvant therapy.
Section snippets
Methods
This review was undertaken in line with the 2009 PRISMA guidelines [31], using Cochrane methodology adapted for a review of cohort studies [32].
Medline and Embase were searched using the terms ‘head and neck cancer’, ‘squamous cell carcinoma’, ‘surgical procedures’ and ‘margins’. It was deliberately broad in covering all head and neck neoplasms to ensure retrieval of all relevant papers in all languages [18]. Reference lists of articles and reviews relevant to the research question were checked
Results
A summary of the five included studies is given in Table 1. Patient demographics were similar across studies. Follow up was greater than two years for all studies. Two studies included multiple oral cavity subsites [23], [36], one included only the buccal mucosa [38], one only the tongue [25], and one only the floor of mouth [45]. Four of the studies contained additional patients who had undergone adjuvant radiotherapy.
Table 2 gives simple summary data for each individual study. All included
Discussion
This review is the first in the area that has included a meta-analysis. A total of 539 patients were included, forming a reasonable retrospective cohort from which to make clinical assumptions about patients. However, as well as giving statistically significant findings regarding the importance of margin size, this review has also highlighted a paucity of consistency and high quality research in this area, which merits discussion as it may limit the clinical application of these results.
This
Conclusions
The reduction in risk should not be interpreted as an absence of risk in the 5 mm or greater pathological margin group, particularly given the lack of adjustment for other poor prognostic indicators in this review and the finding of local recurrence in just over 20% of this group. It could be argued that with such high local recurrence rates, this study does not identify a margin sufficient to recommend surgery alone as a treatment in patients with OSCC. Other risk factors for local recurrence
Conflict of interest statement
None of the authors have any commercial interest in the subject of study or any other conflict of interest. This work was presented as a poster at the Society of Surgical Oncology Annual Cancer Symposium 2014.
Acknowledgment
Thanks to the Anthony Long Charitable Trust for providing financial support for this study.
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