are several considerations that make the comparison of evidence in the literature and subsequent adjustment of surgical planning difficult. There are distinct and widely different concepts of what constitutes the definition of a “margin” and how the quality or magnitude of margins are reported. Margins may refer to: (i) the intraoperative margin (i.e. the normal tissue margin as measured in situ between palpable tumor and the planned incision), (ii) the width of normal tissue beyond palpable tumor and the resected edges as measured after resection and before fixation, (iii) the measured width of tissue beyond the palpable tumor after fixation, and (iv) the measured width of normal tissue between the nearest microscopic tumor cell and the resected edge as seen by a pathologist on the slide. Each of the above margin assessment methods represents very different measurements, yet it is rare for veterinary journal articles to report which of these margin assessment methods is being used or even the magnitude of the resected margin beyond a description of “wide,” “marginal,” or “incomplete.” A recent study (Terry et al. 2017) showed that there was significant difference in the measured grossly normal surgical margins following sarcoma removal after resection compared to the planned intraoperative excision margin. Therefore, surgeon intent (wide or marginal) should not be considered an acceptable means of reporting margins obtained. In addition, these same authors noted that comparison of subgross evaluation of tumor‐free margins, once sectioned and placed on a slide, was not at all comparable to the magnitude of the pathologist‐reported histological tumor‐free margin.
In human medicine, there has been a shift in margin assessment schemes from a traditional Enneking‐style margin assessment (intralesional, marginal, wide, or radical) to either a distance method (reporting the minimum distance between the nearest observed tumor cell and the inked surgical margin) or a qualitative method, where resected specimens are classified as R0 (no tumor at the inked edge), R1 (microscopic tumor at the inked edge), and R2 (residual gross disease left in patient). This highlights the important difference between surgical margins in situ versus histologic margins. Recent reports comparing the distance method to the qualitative method indicate that with osteosarcoma the distance method in combination with tumor response to chemotherapy (>90% or <90%) was the best predictor of local recurrence (Cates 2017). Conversely, in soft tissue sarcomas of the extremity, the qualitative assessment was most predictive and the distance method was not (Harati et al. 2017). It is likely, therefore, that different methods of margin assessment will have differing prognostic significance in veterinary surgical oncology.
The Influence of Sectioning
Despite histopathology universally being used to assess the completeness of surgical margins, the methods of sectioning to evaluate the completeness of margins may vary. The most common method is to perform four complete radial sections. These represent cranial, caudal, dorsal, and ventral portions of the submitted specimen. Unless the surgeon uses tissue ink to identify the surgical margin, it may be difficult for the pathologist to determine whether any one of these sections represents a surgical margin or a trimming artifact. Tissue inking improves the likelihood that the standard sections evaluated do indeed represent true surgical margins; however, in the case of radial sectioning, the area of margin examined represents only a small percentage of the actual surgical margin surface. Several reports document the fact that with more sections, there is a higher likelihood of finding a positive margin. Comprehensive margin evaluation of a 1 cm cutaneous malignancy is estimated to require greater than 4000 sections, making this an impractical means of assessing margin completeness. Tangential sectioning is an alternative method to evaluate surgical margins. Tangential sections are taken parallel to the inked edge, and represent a potentially more sensitive method to detect residual tumor at the margin because they evaluate a greater percentage of the total margin. In humans, significant differences were noted in margin reporting outcomes when tangential sectioning was compared with radial methods. The disadvantage to tangential sectioning is that it does not allow for quantification of the histologically tumor‐free distance and lacks contextual reference to the primary tumor. In one recently reported study in the veterinary literature (Dores et al. 2018), tangential sections detected a significantly higher proportion of positive margins as compared with radial sections in resected mast cell tumors. In this study, radial sections incorrectly classified 50% of the margins as being complete. Surgical oncologists should therefore understand the histologic margin status is influenced not only by the adequacy of excision but also by the method of margin assessment.
Future Directions
The quality of the margin may be more influential than the quantity. Tissue barriers such as muscle, fascia, joint capsule, cartilage, and bone are inherently resistant to tumor penetration. Most solid tumors expand within their tissue of origin initially and grow along lines of least resistance. Surgical oncologists understand that including a tissue barrier beyond where the tumor is attached will trump a larger tissue margin in the absence of that barrier in terms of the likelihood of obtaining complete margins. However, fascia, often favored as a good tissue barrier and easily identifiable to the surgeon, is frequently difficult to discern as a distinct structure on histological sections. This creates difficulty in margin interpretation especially when minimum distances between the fascial plane used as a surgical margin and the nearest tumor cell exist. Is the patient at higher risk for recurrence with a 2‐cm histologic margin of normal fat or a 2‐mm histologic margin of normal tissue that includes a defined fascial layer (per surgeon reporting)?
Human medical evidence has suggested that qualifying the peripheral growth pattern of sarcomas as either “pushing” (no infiltration into surrounding tissue beyond the pseudocapsule) or “infiltrative” (tumor pseudocapsule poorly defined or satellite nodules present) was predictive of local recurrence (Engellau et al. 2005, 2007). The “pushing” contour was seen most commonly in low‐grade sarcomas, but a significant percentage of high‐grade sarcomas also displayed this characteristic (Engellau et al. 2007). High‐grade tumors with a “pushing” growth pattern had significantly fewer local recurrences than high‐grade tumors with “infiltrative” growth patterns (Engellau et al. 2007; Lintz et al. 2012). It is therefore possible that in even high‐grade sarcomas, a pushing pattern of peripheral growth may allow a narrower resection than a tumor with an infiltrative contour. These features (pushing or infiltrative) can be seen on MRI (Iwata et al. 2014; Nakamura et al. 2017), making it conceptually possible to plan resection margins preoperatively based on tumor contour features; however, this approach has not been studied extensively in human medicine or at all in veterinary medicine.
Compartmental tumor excision has been proposed by Enneking and others as a means to diminish the risk of local recurrence in musculoskeletal sarcomas. In compartmental excision, an entire compartment of tissue is removed, for example, an entire muscle or muscle group, as opposed to circumferentially resecting en bloc. Proponents argue that wide local excision, involving an arbitrary measure of a normal tissue “cuff,” risks leaving satellite nodules beyond the resected plane, especially in high‐grade, infiltrative tumors. Indeed, compartmental tumor excision has been shown to reduce recurrences in some tumor types and may be worth considering adopting in veterinary surgical oncology.
Currently, the best‐known predictors for local recurrence of solid tumors are histologic grade and completeness of excision. These features are typically assessed after resection, although grade may be determined prior to resection if the tumor is biopsied and sufficient tissue can be evaluated. Newer technologies such as genome sequencing and proteome analysis are designed to probe deeper into the biological aggressiveness of an individual tumor. Utilization of these methods may provide more specific information, can be acquired prior to surgery, and will provide information from both the tumor and the surrounding microenvironment. The microenvironment/tumor stroma is becoming a featured player in the understanding of tumor biology, as scientists begin to understand the importance of a permissive microenvironment and its role in invasion and metastasis. These datasets may ultimately provide the most accurate assessment of biologic behavior and subsequently assist the surgeon in personalized surgical planning. These analyses may prove to be far more predictive of both local recurrence and metastatic potential
