33rd Annual Scientific Meeting proceedings

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Background
Not unreasonably, many surgeons believe that successful treatment of the cancer patient will only be achieved when every vestige of cancerous cells has been removed from the body. This premise was founded during the ‘Century of the Surgeon’, which was considered to start in 1846.[1] This was a time when improvements in anaesthesia and analgesia allowed surgeons of the time to progress increasingly wider resections about the grossly visible mass with the intent of improving tumour control. Up until then – indeed from the time of Hippocrates – surgical management of cancer had been considered largely futile.[2]

In 1867, the surgeon Charles Moore FRCS presented a dissertation that reflected on the significance of an inadequate operation on the risk of cancer recurrence.[3] In his opinion, recurrence of the tumour was due to a deficiency in local control. His view, which reveals considerable foresight for the time, is evident in this quotation:

“… it must be considered that operations are not adequate merely because they have been large. Whatever be the method of operating, the one important point, both for practice and theory, is to remove the whole. The least remnant is capable of growth, and may spring up into a new tumour with all the energy of the first.”[3]

Building on this desire for surgical control over cancer, other eminent surgeons of the time including Bilroth in Germany, Handley in London, and Halsted in Baltimore, developed the concept of the ‘oncologic operation’.[2] These surgical procedures were explicitly planned and executed with the intent of eliminating all possible risk for local recurrence of the tumour. In a dogmatic desire to leave no trace of cancer in the tissues, these oncologic procedures became increasingly extensive, and focused on complete removal of affected organs and/or inclusion of definable anatomical boundaries. This strategy was indeed successful; these new oncologic procedures were credited with providing improved patient survival and even cancer cures, which had hitherto proved elusive.[4, 5]

Despite the evidential success of these new surgical strategies on local cancer control, the morbidity associated with extensive resections was an increasing concern.[2] Furthermore, some patients continued to die due to spread of cancer beyond the local site, and there was also emerging evidence that some patients could achieve equitable rates of survival and local control with a considerably smaller surgery,[6]  or when surgery was combined with other modalities such as radiation therapy.[7] In light of this new knowledge, surgical margins became more constrained about the tumour boundary. Preservation of form, function, and quality of life, without compromising survival, was the new mantra of the surgical oncologist.[8] Curative-intent surgery by wide local excision was the new paradigm, with surgical margins defined by the centimeters of tissue obtained about the tumour.[9, 10] Now, the importance of microscopic assessment of the resected tissues to determine the success of surgery became crucial;[10, 11] when a histologically complete excision was achieved, patients had a more prolonged survival and/or decreased local recurrence when compared with a resection where cancer cells remained evident at the surgical margin.[12]  The role of the histologic margin was born, and has become one of the most important parameters in cancer management.[13]

During this evolutionary journey of cancer surgery, one fundamental requirement of margin evaluation remains unanswered, namely “What surgical margin should the surgeon use to treat a particular cancer on an individual patient?”.  Numerous studies, over many different tumour types, have attempted to define the precise millimetres of normal tissue that must be observed histologically around a tumour to be certain of local control.[12, 14] However, despite these efforts, there remain a proportion of tumours that recur when margins are considered clear of residual tumour cells, and a relatively consistent proportion of tumours that do not recur even when the resection has been considered incomplete. Although the importance of a histologically tumour-free margin is obviously beneficial for the majority of patients, these outliers bring into question the methodology or accuracy of this fundament of oncologic management.

What is a tumour margin?
The definition of a tumour margin will connote different things depending on perspective. For the surgeon, it is the extent of normal tissue that is removed around the tumour at the time of surgery, whilst for the pathologist, it will be the width of tissue visible under a microscope surrounding the tumour. Finally, the tumour is not an isolated entity, but has become firmly integrated with the local host tissues. This integration is associated with subjugation of cellular and humoral components of the local tumour microenvironment that influences and supports its ongoing survival.[15, 16] The extent of this tumour microenvironment is variable, and its potential influence on tumour recurrence is only starting to be understood.

In simple terms, the surgical margin is considered the surgical dose, while the histologic margin is used to predict whether that dose was adequate to remove all microscopic disease and thereby prevent recurrence. Crucially, aspects of the tumour microenvironment and tumour: host interactions will nuance the ultimate outcome, sometimes at odds with the prediction of the pathologist. Understanding the challenges and limitations of each margin definition is essential if we are to improve the reliability of margin evaluation, and thereby predict the potential for tumour recurrence in every case.

References
Available on request