Should We Stop Assessing Intraoperative Frozen Section Marrow Margins During Ewing Sarcoma Resection?

Ewing sarcoma is a rare and highly aggressive pediatric bone cancer that is histologically composed of small, round blue cells. These histologic findings can make it difficult to assess intraoperative frozen section bone marrow margins because the bone marrow that regenerates after preoperative chemotherapy has a similar appearance, especially on frozen section analysis. Prior studies have more broadly questioned the utility of intraoperative assessment of bone marrow margins using frozen sections during the resection of bone sarcomas; however, to our knowledge, no prior study has specifically characterized the accuracy or clinical utility of evaluating bone marrow margins on frozen sections during long bone Ewing sarcoma resection.

(1) How accurate is the assessment of intraoperative bone marrow margins using frozen sections during the resection of long bone Ewing sarcoma? (2) What changes to the prespecified surgical plan were made in response to positive intraoperative assessments of bone marrow margins? (3) Is intraoperative assessment of bone marrow margins on frozen sections associated with improved survival free from local recurrence, development of metastatic disease, or Ewing sarcoma-specific death?

Sixty-four patients who underwent primary resection of a conventional Ewing sarcoma of a long bone at our institution were analyzed. In this cohort, 81% (52 of 64) of patients had frozen bone marrow margins assessed intraoperatively. There were no identifiable reasons for why some patients had or did not have a frozen section performed, and we could not detect differences in demographic or surgical features between patients who did versus those who did not have intraoperative margins assessed. Intraoperative margins were assessed as negative on frozen sections in 88% (46 of 52) of patients and positive in the remaining 12% (6 of 52) of patients. To determine the rates of false-positive and false-negative intraoperative assessments, the results of intraoperative frozen sections were compared with the assessments of those same initial intraoperative margins as reviewed on final pathology reports. In patients with positive intraoperative assessment of bone marrow margins on frozen sections, we reviewed the surgical records and operative notes to determine whether additional bony resection was performed or if any other changes were made to the prespecified operative plan as a result of the concern for a positive intraoperative margin. Data were available on all study endpoints in 86% (55 of 64) of patients at a minimum follow-up time of 2 years. Kaplan-Meier curves and log-rank tests were used to compare survival free from local recurrence, development of metastatic disease, and Ewing sarcoma-specific death between patients with intraoperative margin assessment and those without. We also compared these same oncologic outcomes between patients whose margins were called positive versus negative intraoperatively.

All bone marrow margins that were assessed as negative on intraoperative frozen sections were confirmed to be negative when examined on final pathology reports (100% [46 of 46]). All bone marrow margins that were assessed as positive on intraoperative frozen sections were actually negative when the same tissue margins were examined on final pathology results (6 of 6) and confirmed by re-review by an experienced bone pathologist for this study. Five of those six patients had an additional, unnecessary bone resection; in the sixth patient, the orthopaedic surgeon documented a high suspicion for false-positive intraoperative assessment and did not perform additional resection. When comparing patients who had an intraoperative margin assessed by frozen section versus those who did not, there were no differences in local recurrence-free survival at 2 years (93% [95% confidence interval (CI) 81% to 99%] versus 100% [95% CI 72% to 100%]; p = 0.99), development of metastatic disease-free survival at 2 years (85% [95% CI 71% to 94%] versus 78% [95% CI 40% to 97%]; p = 0.62), or Ewing sarcoma-specific death-free survival at 2 years (91% [95% CI 78% to 97%] versus 100% [66% to 100%]; p = 0.99). Similarly, when comparing patients whose margins were true negatives versus false positives intraoperatively, there were no differences in local recurrence-free survival at 2 years (92% [95% CI 79% to 98%] versus 100% [95% CI 54% to 100%]; p = 0.99), development of metastatic disease-free survival at 2 years (86% [95% CI 71% to 95%] versus 80% [95% CI 28% to 99%]; p = 0.56), or Ewing sarcoma-specific death-free survival at 2 years (90% [95% CI 77% to 97%] versus 100% [95% CI 54% to 100%]; p = 0.99).

During long bone Ewing sarcoma resection, in a study of our patients, routine assessment of intraoperative bone marrow margins on frozen sections appears to provide no demonstrable clinical benefit and may lead to excessive resection of normal bone. If an orthopaedic surgeon has a specific concern for a positive bone marrow margin, then an intraoperative frozen section may certainly still be warranted. However, in the era of modern MRI imaging, routine intraoperative assessment of bone marrow margins using frozen sections is likely unnecessary in this setting and may be omitted to save time and cost.

Level III, diagnostic study.