REVIEW

published: 21 October 2021

doi: 10.3389/fonc.2021.776863

Recurrent Intrahepatic
Cholangiocarcinoma – Review
Yuki Bekki 1, Dagny Von Ahrens 1, Hideo Takahashi 2, Myron Schwartz 1
and Ganesh Gunasekaran 1,2*
1Division of Liver Surgery, Recanati/Miller Transplantation Institute, The Icahn School of Medicine at Mount Sinai,
New York, NY, United States, 2 Department of Surgery, Mount Sinai South Nassau, Oceanside, NY, United States

Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver

malignancy after hepatocellular carcinoma. While surgical resection with negative
margin is the only curative treatment, ICC has very high rate of recurrence, up to 60-
70% after curative resection. We reviewed the current data available on risk factors for ICC
recurrence, recurrence pattern (location and timing), treatment options, and future
directions. The risk factors for recurrence include elevated preoperative CA19-9,
Edited by:
presence of liver cirrhosis, nodal metastasis, positive margins, and vascular invasion.
Alessandro Vitale, Understanding different recurrence patterns, timing course, and risk factors for early
University Hospital of Padua, Italy
recurrence is important to tailor postoperative surveillance and select treatment strategies
Reviewed by:
including systemic or locoregional therapy. Re-resection can be considered for a selected
David Fuks,
Assistance Publique Hopitaux patient population at experienced centers, and can yield long-term survival. ICC remains a
De Paris, France dismal disease given the high likelihood of recurrence. Advances in our understanding of
Jong Man Kim,
Sungkyunkwan University,
the genomic landscape of ICC are beginning to identify targetable alterations in ICC in
South Korea subsets of patients that allow for personalized treatment.
*Correspondence:
Keywords: intrahepatic cholangiocarcinoma, recurrence, management, risk factors for recurrence, re-resection
Ganesh Gunasekaran
of the liver
[email protected]

Specialty section:
This article was submitted to INTRODUCTION
Surgical Oncology,
a section of the journal Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy,
Frontiers in Oncology comprising of 5-10% of all primary liver cancers (1). Likely due to increasing use of cross-sectional
Received: 14 September 2021 imaging, its incidence has been increasing in the US and worldwide in the past several decades
Accepted: 01 October 2021 (2–5). Despite advance in systemic treatment (6, 7), surgical resection with negative margins is the
Published: 21 October 2021
only curative treatment for ICC (8–13). However, even with successful resection combined with
Citation: adjuvant systemic chemotherapy, 5-year survival has ranged between 25-43% (8, 14–17) due to the
Bekki Y, Von Ahrens D, Takahashi H, high rate of recurrence. While the median survival after recurrence is approximately 12 months (14,
Schwartz M and Gunasekaran G
16), there is increasing evidence that aggressive multimodality treatment including re-resection may
(2021) Recurrent Intrahepatic
Cholangiocarcinoma – Review.
be prolong survival in selected patient populations (15, 16, 18).
Front. Oncol. 11:776863. Given the high recurrence rate, we aim to summarize the risk factors for recurrence, recurrence
doi: 10.3389/fonc.2021.776863 patterns, treatment options, and future directions in recurrent ICC management in this review.

Frontiers in Oncology | www.frontiersin.org 1 October 2021 | Volume 11 | Article 776863

Bekki et al. Recurrent Intrahepatic Cholangiocarcinoma - Review

RISK FACTORS FOR RECURRENCE AJCC recommendation, the performance and extent of
lymphadenectomy during resection of ICC remain a topic
Due to the heterogeneity of patients and tumor characteristics, of debate.
management of ICC has to be tailored to the individual patient,
including, for example, decisions about whether to employ Minimally Invasive Liver Resection
adjuvant and/or neoadjuvant therapy (19, 20). Risk factors for A recent retrospective study from a single institution used
recurrence in ICC have been extensively reported in the literature propensity score matching to demonstrate improved
and include patient, histological, and treatment factors (21–24). intraoperative and short-term outcomes, including number of
The presence of underlying liver disease such as primary sclerosing nodes retrieved and depth of resection margin, with laparoscopic
cholangitis (PSC), viral hepatitis, and cirrhosis (21, 23) is a compared to open resection for ICC (42). Median disease-free
significant risk factor for both initial ICC incidence (25–27), and survival (DFS) and overall survival (OS) were similar between the
for increased recurrence after resection. Additionally, the presence groups (DFS; 28 vs. 32 months, OS; 44 vs. 41 months). A recent
of underlying liver disease can limit the ability to perform major meta-analysis of eight retrospective cohort studies confirmed the
resection which is often necessary in ICC to achieve oncologically benefit of laparoscopic resection, showing a comparable number
optimal results (18). Elevated pretreatment carbohydrate antigen of nodes retrieved, a lower rate of positive margins, and
19-9 is a marker of tumor aggressiveness and one of major risk improved DFS compared to open resetion (43).
factors for recurrence (28, 29). On the other hand, a study based on the National Cancer
Tumor-related risk factors include both gross characteristics Database (NCDB) found that patients who underwent
like tumor size and number of lesions that are identifiable on laparoscopic resection more commonly had inadequate nodal
imaging, and surgical margin status (30–33), vascular invasion sampling (laparoscopic 61% vs. open 39%; p<0.001) (44). The
(24, 29, 33) and regional nodal metastases (17, 24, 28, 29, 34) majority of studies advocating a minimally-invasive approach are
which are only identified histologically after surgery. Several single institution, retrospective studies and are thus highly
nomograms have been reported to enable estimation of risk of heterogeneous and prone to selection bias (45, 46). At this point
recurrence based on tumor and patient risk factors (24, 29, 34). we can safely conclude that a minimallyinvasive approach is safe
Although recurrence risk is dependent on the treatment and feasible for selected patient populations at experienced centers.
strategy, there are some controversies in this area.
Routine Systemic Chemotherapy
Routine Lymphadenectomy The use of adjuvant chemotherapy after resection of ICC has
While nodal metastasis is a major risk factor for recurrence, the long been controversial, as results of trials have been mixed (47).
role of routine lymphadenectomy remains controversial in ICC The BILCAP trial, reported in 2019, demonstrated improved
management. The American Joint Committee on Cancer (AJCC) survival with adjuvant oral capecitabine therapy in a protocol-
recommends a lymphadenectomy with a minimum retrieval of 6 specified sensitivity analysis for a population comprising patients
lymph nodes for ICC (35), since microscopic nodal metastases with a mix of intra- and extrahepatic cholangiocarcinoma and
have been demonstrated in more than 40% of patients (17). gallbladder cancer, but failed to meet its primary endpoint of
However, given the complex pattern of lymphatic flow from the overall survival in the intention-to-treat analysis (7). After
liver, complete regional lymphadenectomy is challenging (36). In gemcitabine plus cisplatin was established as first-line
a meta-analysis performed by Zhou and colleagues, treatment for advanced biliary tract cancer based on the ABC-
lymphadenectomy during resection of ICC did not alter 02 trial (6), gemcitabine plus oxaliplatin (GEMOX) was studied
patient survival (37). In a review of data from the Surveillance, in the adjuvant setting in the PRODIGE 12-ACCORD 18 trial,
Epidemiology, and End Results (SEER) database (38), Kizy et al. and the regimen failed to demonstrate benefit after resection of
found similar median survival for patients with nodal metastasis biliary tract cancer (48).
treated with surgical resection or with chemotherapy alone. Although the routine use of adjuvant chemotherapy remains
On the other hand, Altman and colleagues reported a positive controversial, it is commonly employed in patients where
impact of lymphadenectomy in another SEER database study. pathology reveals high-risk features including positive lymph
While systemic chemotherapy was associated with improved nodes and/or positive margins (18, 24, 29, 34, 49, 50).
survival after resection in patients with nodal metastasis, patients While there have been no randomized trials of neoadjuvant
who did not undergo lymphadenectomy were significantly less- systemic therapy in ICC, several retrospective studies have been
likely to receive adjuvant chemotherapy (39). An international reported, especially in the setting of initially unresectable tumors.
multi-institutional study found that patients with nodal metastasis A multicenter retrospective analysis demonstrated comparable
who had ≥ three lymph nodes resected had an improved survival OS and DFS between patients who did or did not receive
compared with patients with fewer than three nodes removed, neoadjuvant chemotherapy despite the fact that the patients
suggesting a therapeutic effect of lymphadenectomy; the number of who received neoadjuvant therapy initially had more advanced
lymph nodes resected did not correlate with outcome in patients disease (20). Two retrospective studies document the potential
without nodal metastasis (40). Given the rather low sensitivity of for neoadjuvant chemotherapy to downstage initially
preoperative cross-sectional imaging to diagnose lymph node unresectable tumors to where resection becomes feasible
metastasis, routine lymphadenectomy has been advocated for (51, 52). Future studies of neoadjuvant therapy in ICC will be
staging as well as possible therapeutic effect (41). Despite the helpful, though conducting prospective trials in resectable ICC

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Bekki et al. Recurrent Intrahepatic Cholangiocarcinoma - Review

has been challenging due to the low incidence and the Re-Resection
heterogeneity of the disease. The majority of ICC recurs in the liver, and re-resection in
selected patients is associated with long-term survival (14, 22, 23,
55–57). A multi-institutional study of 400 patients with ICC
RECURRENCE PATTERN recurrence demonstrated that those who underwent re-resection
had a median survival of 26.1 months, compared to 9.6 months
The high recurrence risk and poor prognosis of ICC is in large for nonsurgical locoregional treatment and 16.8 months for
part the result of the disease only being discovered when it is systemic chemotherapy (55). Another recent multi-institutional
relatively advanced locally; tumors are commonly large, and study of 113 patients who underwent re-resection for recurrent
achieving complete resection is often technically challenging. ICC demonstrated median survival of 65.2 months (58). While
Recurrence of ICC after curative surgical resection can occur at 156 patients who underwent repeated exploration for recurrent
the resection margin, an intrahepatic site away from the margin, ICC were included in their study, 43 patients (27.6%) did not
and/or extrahepatic organs; each manifestation has unique undergo re-resection.
biology and patterns of progression. Furthermore, the timing Repeat liver resection for recurrent ICC is often challenging
of recurrence is also variable (53). Understanding different since initial ICC resections are commonly major resections, often
recurrence patterns, timing course and risk factors for early with concomitant vascular/biliary resection and reconstruction,
recurrence is important to tailor postoperative surveillance and and with lymphadenectomy around the hepatoduodenal
to select treatment strategies including adjuvant therapy. ligament (59). Patients selected for re-resection, in addition to
a technically favorable situation, typically have had a long
Recurrence Location/Organ disease-free interval (often greater than two years), less-
A multi-institutional study of 920 patients with ICC found that advanced initial stage, negative lymph nodes, and no
607 (66.0%) patients developed recurrence following curative extrahepatic disease (59, 60). There have been many single
resection. One hundred forty five patients (23.9%) recurred at the institution studies from around the world that have reported
resection margin, 178 (29.3%) recurred intrahepatically away survival benefit of re-resection, and without question there are
from the margin, 90 (14.8%) had extrahepatic-only recurrence, long-term disease-free survivors. However, the obvious selection
and 194 (32.0%) had both intra-and extrahepatic recurrence. bias inherent in operative candidates makes valid statistical
Major extrahepatic recurrence sites include lungs, lymph nodes, comparison of re-resection with other treatment modalities
peritoneum, bone, and adrenal. The different recurrence patterns impossible (14, 16, 56, 59–62).
had different time courses: intrahepatic margin recurrence and
extrahepatic-only recurrence were commonly observed within 6 Locoregional Treatment
months, while intrahepatic recurrence away from the margin The use of locoregional treatments including thermal ablation (15),
occurred gradually within 2 years (54). stereotactic body radiation therapy (SBRT) (63, 64), transarterial
chemoembolization (TACE) and intraarterial yttrium-90
Recurrence Timing radiotherapy (16, 65), has been reported with varying degrees of
The majority of ICC recurrence appears within two years of success (66), and this remains an area of active investigation.
resection, and this is commonly defined as early recurrence (22, Table 1 summarizes the treatment modalities and corresponding
23). Studies have demonstrated that recurrence patterns, risk outcomes for recurrent ICC (14, 55, 56, 58, 61, 63, 67–73). Zhang
factors, and outcomes differ significantly between patients with et al. reported comparable outcomes between thermal ablation
early vs. late recurrence. Not surprisingly, early recurrence is group and re-resection group for recurrent ICC (median OS: 21.3
associated with worse prognosis (23). Tsilimigras et al. defined and 20.3 months, respectively). However, patients with recurrent
very early recurrence (VER) as recurrence within 6 months from tumor > 3cm demonstrated a higher OS rate in the re-resection
initial resection based on distinct clinical features and more group than those in the ablation group (67). Another single center
aggressive behavior noted in this group (21). Approximately one- retrospective study also identified a tumor size (> 2cm) as a risk
quarter of patients with ICC in their series had VER, and their factor for poor survival after thermal ablation for recurrent
survival was dismal compared to those without VER (5-year OS ICC (68).
8.9% vs. 49.8%; p<0.001). TACE is another option with reasonable efficacy for
unresectable recurrent ICC. A retrospective study of 275
patients with recurrent ICC included 183 patients who
TREATMENT OF RECURRENCE underwent TACE and 92 patients who underwent microwave
ablation therapy. In their study, TACE provided longer survival
Although management of recurrent ICC is challenging and systemic after treatment than microwave coagulation therapy (median OS
therapy remains the cornerstone similar to patients who present 26.9 vs 12.1 months). Interestingly, different prognostic factors
primarily with advanced disease, several studies have reported for each treatment type were identified: the extent of tumor
benefit of incorporating aggressive locoregional treatment of progression for TACE, and the etiologic subtype for microwave
recurrent disease compared to systemic therapy alone (15, 53). ablation therapy (71).

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Bekki et al. Recurrent Intrahepatic Cholangiocarcinoma - Review

TABLE 1 | Treatment modality and survival after ICC recurrence.

Study Treatment modality No of patients Size of tumor (cm) Survival after recurrence (months)

Bartsch et al. (58) re-resection 113 – 36.8

Si et al. (56) re-resection 72 3 45.1
Zhang et al. (67) re-resection 32 5 20.3
Yoh et al. (61) re-resection 15 5 91.6
Zhang et al. (67) ablation 77 – 21.3
Chu et al. (68) ablation 40 1.5 26.6
Kim et al. (69) ablation 20 1.5 27.4
Fu et al. (70) ablation 12 3.2 30
Ge et al. (71) TACE 183 6 26.9
Goerg et al. (72) TACE 12 – 13.3*
Smart et al. (73) radiation 66* 5.6 25*
Jung et al. (63) radiation 30 – 13
Spolverato et al. (55) chemotherapy 46 3 16.8
Park et al. (14) chemotherapy 21 – 10

*Patients in both unresectable and recurrent ICC.

Intrahepatic cholangiocarcinoma, ICC; Transarterial chemoembolization, TACE.

A meta-analysis of SBRT for unresectable or recurrent mismatch repair deficiency on biopsy or surgical specimens is
cholangiocarcinoma included 11 studies with 226 patients. The now routine, and as with other tumor types, these patients have a
median OS was 13.6 months and 1-year local control rate was high rate of response to checkpoint inhibitors. While several
78.6%, suggesting that SBRT was a feasible treatment option for biomarkers of response to immunotherapy have been identified,
those patients (64). These results are in line with the study by Jung such as tumor mutation burden, presence of tumor-infiltrating
et al. reporting the median OS of 13 months after SBRT for 30 patients lymphocytes, or programmed death-ligand 1 expression status
with recurrent ICC (63). In order to apply higher dose of radiation (combined positive score) (82, 83), the response rate remains low
towards tumors and reduce radiation related toxicity, proton (12, 78), and checkpoint inhibitors are generally given together
radiation therapy have been introduced. Smart et al. demonstrated with cytotoxic chemotherapy. As with most cancers, identifying
the efficacy of proton radiation therapy for 66 patients with biomarkers or genetic signatures of ICC that predict response to
unresectable or recurrent ICC with median OS of 25 months and therapy is an area of intense research and will be integral to
2-year local control of 84% (73). Even though radiation related establishing an effective, personalized approach.
toxicity can be a barrier to dose escalation, radiation therapy
remains an effective local modality for recurrent ICC.
Although the level of evidence is limited due to the retrospective
design and potential selection bias in these studies, locoregional CONCLUSIONS
treatment for recurrent ICC was associated with prolonged survival
ICC is the second most common primary liver malignancy with
in patients with recurrent ICC (14–16, 22, 55, 59). With various
high risk of recurrence after curative resection. Risk factors for
locoregional treatment options available, comprehensive patient
recurrence have been defined, and the majority of patients will
and tumor information is needed to stratify patients to select the
have recurrent disease within 2 years of the initial resection.
treatment option including multimodal approach.
Prognosis after recurrence remains grim and treatment options
beyond systemic treatment after recurrence are limited. While it
can be technically challenging, repeat resection is a feasible and
FUTURE DIRECTIONS safe option for selected patients at experienced centers and can
result in long-term survival. Other locoregional options such as
With recent technological advances in Next Generation thermal ablation, SBRT, TACE or intraarterial radioembolization
Sequencing (NGS), genomic profiling of tumors has become increasingly being employed in conjunction with systemic therapy.
significantly easier and more affordable. As has been Sequencing of tumor DNA is now routine in patients with ICC
demonstrated in other cancer types (74, 75), molecular analysis and can identify actionable mutations and genomic alterations
of tumors can help clinicians to tailor the treatment for advanced that can help clinicians tailor treatment to manage this
or recurrent ICC (76, 77). The incidence of actionable mutations aggressive malignancy.
in patients with ICC ranges from 30-70%, with the most
common being IDH1 and FGFR-2 (12, 78, 79). Similar to
pancreatic cancer, targeting other genomic alterations such as AUTHOR CONTRIBUTIONS
DNA damage repair genes, HER2 amplification or activation,
and NTRK gene fusions can improve survival compared to YB, DA, and HT drafted the manuscript MS and GG conceived
conventional systemic chemotherapy alone (74). the study and were in charge of overall direction and planning.
Immunotherapy has revolutionized cancer treatment and is All authors reviewed the results and approved the final version of
currently being studied in ICC (80, 81). Identification of DNA the manuscript.

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Bekki et al. Recurrent Intrahepatic Cholangiocarcinoma - Review

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