Surgical margins – Are they important?

Introduction

It makes biological sense that completely excising a malignant neoplasm (for the sake of this article, it is assumed that a neoplasm/tumor = malignant) would be curative (Figure 1). However, there are many examples whereby a tumor is completely “excised” based on pathology reporting, and yet recurs – or conversely, where a tumor is not completely excised, and yet it does not recur (1-3). Based on this evidence, we can make the determination that complete versus incomplete excision is not the whole story. So what is the source of these seemingly paradoxical scenarios? Although this question might extend to a vast scope, some clinically important aspects are discussed in this article.

Semantics

So are surgical margins important? The non-standardized language used in veterinary surgical pathology reports and research studies has confounded our attempts to answer this question. Terms such as “clean”, “dirty”, “close”, and “narrow” – often used in pathology reports – are ambiguous and may have variable definitions depending on the interpretation (4,5). The harmonization of language to provide more concrete value, and in turn, biologically relevant information, is desperately needed. 

In human medicine, margin grading schemes such as the residual tumor classification scheme have been developed that associate a classification (e.g., R0, R1, R2) with defined macroscopic and/or histologic margin measurements. In this way, a single letter and number combination conveys a discrete, unequivocal piece of information: so for example R1 = histologically incomplete excision (4). This makes the margin status clear to the submitter, allowing them to make informed treatment decisions. Further, this standardization of margin reporting allows for more translatable prognostic studies. It must be stated that any classification scheme that is developed should be correlated with biological outcomes (e.g., disease-free intervals, survival times) which necessitates robust prospective studies. Despite the utility of such systems, nothing similar currently exists in veterinary medicine. 

Surgical specimen assessment

Much of the discrepancy between tumor margin and recurrence may be at least partially explained by consideration of the process of histopathologic evaluation of a surgical biopsy specimen, and various factors impinge on this.

Inking of surgical specimens by the submitting surgeon is ideal, as the surgeon is the person most informed as to where the true margins are. Inking is an effective means of ensuring clear and accurate identification of surgical margins (5-7). Despite the ease of inking and the valuable information provided, this is an extremely uncommon practice, yet, without this, the individual trimming a specimen can only make an educated guess as to where the surgical margin is (Figure 2). 

In addition, deformation of the excised tissue also impacts the ability of the diagnostician to identify surgical margins. Tissue deformation is the reconfiguration of tissue size, orientation, and shape that begins immediately following surgical incision, and it can introduce an unpredictable and confounding factor to margin evaluation (8,9); indeed, the translation can be so severe as to reorient the layers of the surgical specimen (5). This deformation has been most thoroughly documented in skin, where it has been shown to be impacted by anatomic location, age and other factors. As a result, the submitted tissue frequently appears very different from what the surgeon observed, complicating accurate margin assessment by the diagnostician/pathologist (Figure 3). 

Furthermore, when tumors are sampled for histopathologic evaluation, the standard sectioning technique of perpendicular sectioning allows for the pathologist to: 

i) obtain a diagnosis and 
ii) provide a distance from the neoplastic cells to the tissue (presumed surgical) margin (10). 

This distance is referred to as the “histologic tumor-free distance”, or HTFD, and is the distance traditionally described in histopathology reports. However, given that perpendicular histologic sections are approximately 5 µm in thickness and only several sections are evaluated, the pathologist is evaluating less than 1% of the total tumor margin (Figure 4). Therefore, although an HTFD may be provided, this is perhaps an inaccurate representation of the true margin. Studies have shown that different tumors have differing infiltrative patterns, which are often asymmetric, confounding the ability to identify the most representative margins to assess (Figure 5). The final diagnosis of “complete excision” (i.e., HTFD > 0) is not an absolute, but an estimate based on a reasonably limited tissue examination. More extensive margin evaluation (complete en face or tangential) is time-consuming, expensive, and of questionable practical value, though this has been and is being explored for different tumor types (3). 

Tumor biology

The term “histologic safety margin” (HSM) defines the minimal normal marginal tissue (HTFD) needed to correlate with a specific outcome, such as a reduced risk of recurrence. In human medicine, the HSM is a prioritized factor that requires rigorous and standardized investigation for each tumor type. Nonetheless, the HSM provides discrete clinical/surgical goals that correlate with patient outcomes. 

While complete excision of soft tissue sarcomas (STS) is the prioritized surgical outcome, the exact HTFD necessary to prevent/mitigate recurrence is unknown (1). Further, for many studies that have addressed this biological question, the definition of “complete excision” has varied. Multiple studies have identified that even “incomplete” excision does not imply that recurrence is inevitable, with some studies showing only around 33% recurrence in incompletely excised STS (11). STS are histologically graded on a scale of 1-3 (low-high) (12), and currently grade, and not margin status, has been shown to be a more reliable predictor of STS recurrence and biological aggressiveness (1). Nonetheless, even this grading system is imperfect and not validated, highlighting our gaps in knowledge in understanding tumor-host biology.

Conclusion

Practitioners are encouraged to explore the practice of inking a specimen’s margins prior to tissue submission; this is a simple, low-cost and effective means of communicating the location and orientation of the surgical margin which can have a valuable impact on the pathologist’s assessment. There is a distinct need for robust prospective studies and harmonization of surgical specimen evaluation, sectioning and communication, best achieved through collaboration between practitioners, surgeons, oncologists and pathologists, as each plays an integrated role in the process of patient management and diagnostics. In the future, we may need to reassess our approaches and our understanding of the utility of margin measurement in veterinary oncology, but this will surely only be appreciated through rigorous scientific assessment.

 

Further reading

Liptak JM. Histologic margins and the residual tumour classification scheme: Is it time to use a validated scheme in human oncology to standardise margin assessment in veterinary oncology? Vet. Comp. Oncol. 2020;18(1):25-35. 

 

References

1. Chiti LE, Ferrari R, Roccabianca P, et al. Surgical margins in canine cutaneous soft-tissue sarcomas: a dichotomous classification system does not accurately predict the risk of local recurrence. Animal (Open Access. J.) 2021;11(8):2367.

2. Bray JP. Soft tissue sarcoma in the dog – Part 2: surgical margins, controversies and a comparative review. J. Small Anim. Pract. 2017;58(2):63-72.

3. Dores CB, Milovancev M, Russell DS. Comparison of histologic margin status in low-grade cutaneous and subcutaneous canine mast cell tumours examined by radial and tangential sections. Vet. Comp. Oncol. 2018;16(1):125-130.

4. Liptak JM. Histologic margins and the residual tumour classification scheme: Is it time to use a validated scheme in human oncology to standardise margin assessment in veterinary oncology? Vet. Comp. Oncol. 2020;18(1):25-35.

5. Milovancev M, Russell DS. Surgical margins in the veterinary cancer patient. Vet. Comp. Oncol. 2017;15(4):1136-1157.

6. Milovancev M, Löhr CV, Bildfell RJ, et al. A comparison of microscopic ink characteristics of 35 commercially available surgical margin inks. Vet. Surg. 2013;42(8):901-908.

7. Kiser PK, Löhr CV, Meritet D, et al. Histologic processing artifacts and inter-pathologist variation in measurement of inked margins of canine mast cell tumors. J. Vet. Diagn. Investig. 2018;30(3):377-385.

8. Risselada M, Mathews KG, Griffith E. Effect of feline skin specimen preparation on postexcision and postfixation tissue shrinkage. J. Feline Med. Surg. 2016;18(12):970-975.

9. Upchurch DA, Klocke EE, Henningson JN. Amount of skin shrinkage affecting tumor versus grossly normal marginal skin of dogs for cutaneous mast cell tumors excised with curative intent. Am. J. Vet. Res. 2018;79(7):779-786.

10. Stromberg PC, Meuten DJ. Trimming tumors for diagnosis and prognosis. In: Tumors in Domestic Animals [Internet]. John Wiley & Sons, Ltd; 2016;27-43.

11. Milovancev M, Tuohy JL, Townsend KL, et al. Influence of surgical margin completeness on risk of local tumour recurrence in canine cutaneous and subcutaneous soft tissue sarcoma: A systematic review and meta-analysis. Vet. Comp. Oncol. 2019;17(3):354-364.

12. Dennis MM, McSporran KD, Bacon NJ, et al. Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs. Vet. Pathol. 2011;48(1):73-84.