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Ruff et al. Hepatoma Res 2023;9:17 https://dx.doi.org/10.20517/2394-5079.2023.18 Page 5 of 12

blood loss and decreased Pringle maneuver time [41-43] . In addition, the data demonstrated that oncologic
outcomes, such as the number of lymph nodes harvested, are comparable among patients undergoing a
minimally invasive approach [42-44] . Despite the potential benefits of MIS and comparable long-term
outcomes to open surgery, the success of the MIS approach is dependent on patient selection and surgeon
experience/expertise. In addition, the oncologic success of the MIS approach for ICCA (defined as obtaining
an adequate lymphadenectomy and R0 margin status) has been strongly associated with receipt of surgery at
high-volume centers .
[20]

Anatomic vs Non-Anatomic Resection
The role of an anatomic resection (AR) versus non-anatomic resection (NAR) for HCC has been well
established, but its role in ICCA remains controversial. A retrospective review of 702 patients with ICCA
noted that patients who underwent anatomic versus non-anatomic resection had a similar incidence of
complications (AR 26.6% versus NAR 25.1%, P = 0.634), yet 1-, 3-, and 5-year disease-free and overall
[23]
survival was better among individuals who had an AR . The benefit of anatomic resection was only noted,
however, among patients with stage IB or stage II (without microvascular invasion) cancer. A separate
retrospective study of 1,023 patients with ICCA who underwent curative-intent resection compared short-
and long-term outcomes among patients who had a major versus minor hepatectomy . Of note, overall
[45]
and recurrence-free survival were the same, but the risk of postoperative complications was higher among
patients who underwent a major (48.4%) versus minor (27.2%) hepatectomy (P < 0.001). The impact of AR
versus NAR remains debated. Therefore, the main goal of resection for ICCA should be to spare hepatic
parenchyma as long as a negative margin can be achieved.

Margin Status
A universal goal of curative intent surgery is to achieve an R0 resection margin. A positive microscopic (R1)
or macroscopic (R2) margin is associated with a higher risk of recurrence. Spolverato et al. evaluated the
relationship between margin status and survival in 583 patients from 12 major hepatopancreatobiliary
centers . Of note, one out of six patients had an R1 resection and R1 margin status was a predictor of both
[46]
shorter recurrence-free (hazard ratio 1.61, P = 0.01) and overall (hazard ratio 1.54, P = 0.01) survival versus
patients who had an R0 resection. A separate multi-institutional database study analyzed 449 patients with
ICCA who underwent surgery . In this study, again, 15.6% of patients had an R1 margin and a positive
[47]
resection margin was associated with worse overall survival (hazard ratio 2.2, P < 0.001). Multifocal disease,
vascular invasion, and lymph node metastases were also associated with worse overall survival. While the
goal of surgical resection is to always achieve an R0 margin, an R1 margin may just be reflective of worse
underlying tumor biology (e.g., larger tumors, multifocal disease, perineural or vascular invasion). To this
point, in a retrospective study of 1,105 patients with ICCA, the relationship between overall tumor burden
and margin status was examined .The tumor burden score was calculated with a formula that incorporated
[48]
tumor size and number. With increasing margin width, patients with low or medium tumor burden had
incrementally better survival. Patients with a high tumor burden did not, however, derive the same survival
benefit from increasing margin width or from an R0 resection margin. In turn, while the goal should be an
R0 margin, achieving microscopically negative margins cannot always overcome poor tumor biology.

Lymphadenectomy
Lymph node metastases are an important prognostic indicator of survival for patients with ICCA. The
National Comprehensive Cancer Network (NCCN) guidelines recommend portal lymphadenectomy at the
[49]
time of resection to ensure accurate staging [Figure 2] . In particular, at least six lymph nodes should be
evaluated. The extent of lymphadenectomy should include the dissection of lymph nodes along the
common hepatic artery and within the hepatoduodenal ligament . A SEER database study evaluated 1,496
[50]