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Page 2 of 8 Gavriilidis et al. Hepatoma Res 2023;9:23 https://dx.doi.org/10.20517/2394-5079.2023.26

INTRODUCTION
Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer that originates above the second-order bile
[1,2]
ducts . As the second most common primary biliary malignancy, iCCA represents 10%-15% of all primary
liver tumors and continues to increase in incidence worldwide . While surgical resection is the best
[3,4]
[5-7]
curative-intent treatment option, 5-year survival after surgical resection is only 20%-30% . Systemic
treatment continues to evolve in the setting of advanced disease through the use of immune checkpoint
inhibitors. As demonstrated in the TOPAZ-1 trial, durvalumab, a PD-L1 inhibitor, when added to
gemcitabine/cisplatin, significantly improved median overall survival and is now considered the new
standard of care. To this point, immune checkpoint inhibitors have demonstrated efficacy in the advanced
[8,9]
disease setting and may be used in the adjuvant treatment setting in the future . The need for improved
systemic therapy is particularly relevant to patients with iCCA as long-term outcomes following resection
are often poor and characterized by tumor recurrence in 50%-70% of patients [5,10] . One of the strongest
predictors of tumor recurrence is lymph node metastasis (LNM), which can be present in up to 40%-60% of
patients [11,12] . The presence of LNM can be difficult to assess on preoperative clinical imaging and can be
present even among patients with early-stage, small tumors [11,12] . As such, lymph node dissection (LND) has
been endorsed as the standard of care in the operative approach of patients undergoing resection of
iCCA [5,13] .

While LND has become more widely adopted in the surgical management of iCCA, the beneficial effect and
role of LND remain somewhat controversial. For example, the impact of LND on staging and prognosis, as
well as the technical aspects of LND (i.e., which nodal basins require evaluation), continue to be debated.
We herein review the role of LND as part of the surgical management of iCCA, with a particular emphasis
on LND prognostic and therapeutic value, as well as the technical aspects of LND in the treatment of iCCA.

METHODS
A comprehensive review was performed using MEDLINE/PubMed with the search dates of January 1, 1990
to March 21, 2023. Search terms included “intrahepatic cholangiocarcinoma”, “bile duct cancer”,
“lymphadenectomy”, “lymph node metastasis”, and “lymph node staging” in PubMed. Articles written in
English identified using the aforementioned search terms were included. A review of included manuscripts
was performed, and the latest, most relevant articles were included.

MAIN BODY
Lymphadenectomy technique
The incidence of LNM in patients with iCCA ranges from 20%-60%. The National Comprehensive Cancer
Network (NCCN) guidelines suggest evaluation of six lymph nodes at minimum to stage patients
adequately [14-16] . Zhang et al. reported data from a large multi-institutional experience that defined the
[14]
prognostic impact of number and station of LNM after curative-intent resection for iCCA . Among 603
patients with iCCA who underwent surgery, 40% had LNM. Median overall survival was incrementally
worse among patients without nodal disease (N0) (69.8 months) vs. 1 to 2 LNM (proposed N1) (26.0
months) versus 3 or more LNM (proposed N2) (16.0 months) [Figure 1]. LNM were more likely to be
[14]
detected, and thus patients more likely to be staged accurately, when six or more lymph nodes were
resected, which was consistent with current American Joint Committee on Cancer (AJCC) guidelines [15,16] .
Regarding nodal location and station, median OS was worse in patients who had positive lymph nodes
outside the hepatoduodenal ligament (HDL) (station 12) (15.0 months) compared with individuals who had
LNM confined to the HDL (20.0 months). In turn, the data suggested that standard lymphadenectomy of at
least six lymph nodes, with dissection of nodal station 12 and beyond, was needed to ensure adequate
staging.