Ann Surg Oncol (2020) 27:2888–2901

https://doi.org/10.1245/s10434-020-08350-8

ORIGINAL ARTICLE – HEPATOBILIARY TUMORS

The Impact of Preoperative CA19-9 and CEA on Outcomes

of Patients with Intrahepatic Cholangiocarcinoma
Amika Moro, MD1, Rittal Mehta, MPH, BDS1, Kota Sahara, MD1,2, Diamantis I. Tsilimigras, MD1,
Anghela Z. Paredes, MD, MS1, Ayesha Farooq, MBBS1, J. Madison Hyer, MD1, Itaru Endo, MD, PhD2,
Feng Shen, MD3, Alfredo Guglielmi, MD4, Luca Aldrighetti, MD5, Matthew Weiss, MD6,
Todd W. Bauer, MD7, Sorin Alexandrescu, MD8, George A. Poultsides, MD9, Shishir K. Maithel, MD10,
Hugo P. Marques, MD11, Guillaume Martel, MD12, Carlo Pulitano, MD13, Olivier Soubrane, MD14,
Bas G. Koerkamp, MD15, Kazunari Sasaki, MD16, and Timothy M. Pawlik, MD, MPH, PhD, FACS1
1
Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James
Comprehensive Cancer Center, Columbus, OH; 2Department of Gastroenterological Surgery, Yokohama City University
School of Medicine, Yokohama, Japan; 3Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China;
4
Department of Surgery, University of Verona, Verona, Italy; 5Department of Surgery, Ospedale San Raffaele, Milan,
Italy; 6Department of Surgery, Johns Hopkins Hospital, Baltimore, MD; 7Department of Surgery, University of Virginia,
Charlottesville, VA; 8Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania; 9Department of Surgery,
Stanford University, Stanford, CA; 10Department of Surgery, Emory University, Atlanta, GA; 11Department of Surgery,
Curry Cabral Hospital, Lisbon, Portugal; 12Department of Surgery, University of Ottawa, Ottawa, Canada; 13Department of
Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia; 14Department of Hepatobiliopancreatic
Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France; 15Department of Surgery, Erasmus
University Medical Centre, Rotterdam, The Netherlands; 16Department of General Surgery, Cleveland Clinic Foundation,
Cleveland, OH

ABSTRACT CA19-9/low CEA (10.0%), or high CA19-9/high CEA

Background. The objective of the current study was to
assess the impact of serum CA19-9 and CEA and their
combination on survival among patients undergoing sur-
gery for intrahepatic cholangiocarcinoma (ICC).
Methods. Patients who underwent curative-intent resec-
tion of ICC between 1990 and 2016 were identified using a
multi-institutional database. Patients were categorized into
four groups based on combinations of serum CA19-9 and
CEA (low vs. high). Factors associated with 1-year mor-
tality after hepatectomy were examined.
Results. Among 588 patients, 5-year OS was considerably
better among patients with low CA19-9/low CEA (54.5%)
compared with low CA19-9/high CEA (14.6%), high
 Society of Surgical Oncology 2020
First Received: 30 August 2019;
Published Online: 20 March 2020
T. M. Pawlik, MD, MPH, PhD, FACS
e-mail: tim.pawlik@osumc.edu
(0%) (P \ 0.001). No difference in 1-year OS existed
between patients who had either high CA19-9 (high CA19-
9/low CEA: 70.4%) or high CEA levels (low CA19-9/high
CEA: 72.5%) (P = 0.92). Although patients with the most
favorable tumor marker profile (low CA19-9/low CEA)
had the best 1-year survival (87.9%), 15.1% (n = 39) still
died within a year of surgery. Among patients with low
CA19-9/low CEA, a high neutrophil-to-lymphocyte ratio
(NLR) (odds ratio 1.09; 95% confidence interval 1.03-1.64)
and large size tumor (odds ratio 3.34; 95% confidence
interval 1.40–8.10) were associated with 1-year mortality
(P \ 0.05).
Conclusions. Patients with either a high CA19-9 and/or
high CEA had poor 1-year survival. High NLR and large
tumor size were associated with a greater risk of 1-year
mortality among patients with favorable tumor marker
profile.
The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic…
Typically originating from malignant transformation of
the bile duct epithelium, intrahepatic cholangiocarcinoma
(ICC) is the second most common primary liver malig-
nancy.1 The incidence of ICC has increased worldwide
over the past several decades.2,3 Although curative-intent
resection remains the mainstay of treatment for patients
who present with operable disease, 5-year overall survival
(OS) ranges from 20 to 55% after surgical resection.4–6 In
addition, more than one-half of patients experience a
recurrence within 2 years of surgery.7 Because outcomes
following surgery vary considerably, surgery may not be
the best immediate treatment option for all patients who
present with ICC. Rather, a subset of patients may be more
appropriately treated with neoadjuvant systemic or
locoregional therapies.8 Identification and selection of
patients at lower risk for early recurrence, and therefore
more likely to benefit from surgical resection, remains
poorly defined. As such, some patients may inappropriately
undergo surgery first when neoadjuvant therapy may have
been a preferred treatment approach.
Tumor markers are traditional tools used to assist in
diagnosis, estimate prognosis, as well as identify recur-
rence.9 Carbohydrate antigen (CA) 19-9 is the most
frequently used biomarker in the management of ICC.
Although not formally included in the 8th edition Ameri-
can Joint Committee on Cancer (AJCC) staging system,
CA19-9 was noted to be an important prognostic factor in
the manual.10 Carcinoembryonic antigen (CEA), a well-
known tumor marker for colorectal and other adenocarci-
nomas, also has recently gained attention as a potential
tumor marker for hepatobiliary cancers.11–14 The impact of
CA19-9 and CEA on prognosis have been reported among
patients with pancreatic adenocarcinoma and colorectal
cancer, respectively.15–18 In contrast, the association of
preoperative CA19-9 and CEA levels on long-term out-
comes of patients with ICC has not been thoroughly
examined. In particular, previous studies have proposed
disparate cutoff values for CA19-9 and CEA and have
largely involved small, single-center experiences.19–21
How CA19-9 and CEA levels relate to prognosis, as well as
long-term outcomes among patients with different levels of
these tumor markers (e.g., high CEA, low CA19-9, or
various combinations) has not been defined. As such, the
objective of the current study was to determine the optimal
cutoff values for CA19-9 and CEA to categorize patients
into distinct OS prognostic groups based on these serum
tumor markers. Such data may help to determine which
patients may be the best candidates for upfront hepatic
resection versus preoperative chemotherapy as an optimal
treatment sequencing strategy.
2889
METHODS
Data Sources and Study Population
Patients who underwent resection of ICC between Jan-
uary 1990 and December 2016 were identified in a multi-
institutional database from 16 centers: The Ohio State
University Comprehensive Cancer Center, Columbus, OH;
Johns Hopkins Hospital, Baltimore, MD; Stanford
University, Stanford, CA; University of Virginia, Char-
lottesville, VS; Winship Cancer Institute, Emory
University, Atlanta, GA; Cleveland Clinic Foundation,
Cleveland, OH; Fundeni Clinical/Institute, Bucharest,
Romania; Scientific Institute San Raffaele, Vita-Salute San
Raffaele University, Milan, Italy; University of Verona,
Verona, Italy; Curry Cabral Hospital, Lisbon, Portugal;
Beaujon Hospital, Clichy, France; Erasmus University
Medical Centre, Rotterdam, Netherlands; University of
Ottawa, Ontario, Canada; Eastern Hepatobiliary Surgery
Hospital, Shanghai, China; Yokohama City University
School of Medicine, Yokohama, Japan; Royal Prince
Alfred Hospital, University of Sydney, Sydney, Australia.
Patients who had concurrent extrahepatic disease at the
time of hepatectomy, underwent palliative-intent liver
resection or had macroscopically incomplete resection
(R2) were excluded. Patients who lacked information on
CA19-9 or CEA were also excluded from the cohort. The
Institutional Review Board of all the participating institu-
tions approved the study.
Patient demographic and clinicopathologic data inclu-
ded age, body mass index (BMI), sex, region of the
institution (i.e., western or western), preoperative liver
function data (i.e., albumin, bilirubin), preoperative neu-
trophil-to-lymphocyte ratio (NLR), tumor markers (i.e.,
preoperative serum level of CA 19-9 and CEA), tumor
morphology (i.e., tumor size, number of tumor nodules),
preoperative lymph node status, type of resection (i.e.,
major or minor hepatectomy), resection margin status,
location of the tumor, presence of cirrhosis, vascular
invasion, perineural invasion, histological grade, morpho-
logical type (i.e., mass-forming [MF], intraductal growth
[IG], periductal infiltrating [PI]), regional lymph node
status according to AJCC 8th edition, and the receipt of
adjuvant chemotherapy.10,22 Major hepatectomy was
defined as the resection of three or more Couinaud seg-
ments.23 Vascular invasion was defined as major (invasion
of the first- and second-order branches of the portal vein or
hepatic arteries, or as invasion of one or more of the three
hepatic veins) or microvascular (invasion of smaller
intraparenchymal vascular structures identified histologi-
cally).10 The primary endpoint was OS, which was defined
as the time interval between initial hepatectomy and the
date of death or last follow-up.
2890 A. Moro et al.

Determination of Cutoffs using the X-tile Software TABLE 1 Baseline characteristics of patients undergoing curative-
intent surgery for ICC
To identify thresholds of CA19-9 and CEA that opti- All patients (n = 588)
mally differentiated OS among patients above and below
Characteristics Patient number (%)
certain threshold values, X-tile software version 3.6.1, a
bio-informatics tool produced by Camp et al. was Age, median (IQR), yr 58 (50–67)
used.24–28 X-tile software was created to determine cutoffs BMI, median (IQR), kg/m2 24.4 (21.7–27.4)
on the basis of biomarkers to subset the population into Sex
clinically relevant groups and is a valuable tool for out- Male 355 (60.4)
comes based cutoff generation. Although there are several Female 233 (39.6)
ways to determine cutoffs, X-tile specifically allows for the Region of the institution
illustration and identification of subgroups by giving dif- Western 225 (38.3)
ferent numbers between the optimal ranges of tumor Eastern 363 (61.7)
markers as the cutoff. The v2 score and P values were then Preoperative jaundice
calculated using these numbers as the cutoffs; values No 536 (91.9)
associated with maximum Chi square score and minimum Yes 47 (8.1)
p value were then used as the final cutoff point.25 Cut- Serum albumin, median (IQR), g/dL 4.2 (3.9–4.5)
points were made in X-tile and were cross-validated with Total bilirubin, median (IQR), mg/dL 7.2 (0.7–13.2)
Monte-Carlo simulations. Cross-validation with 1000 ran- NLR, median (IQR) 2.7 (2.0–3.9)
dom populations in the entire cohort was performed to Size of tumor, median (IQR), cm 5.6 (3.8–8.0)
identify the appropriate thresholds of CA19-9 and CEA.25 Number of tumor nodules (IQR) 1 (1–1)
CA19-9, median (IQR), IU/mL 39.7 (15.8–174.1)
Statistical Analysis
CEA, median (IQR), ng/mL 2.5 (1.5–4.2)
Preoperative lymph node status
Continuous and categorical variables were presented as
Negative 433 (80.9)
median with interquartile ranges (IQR) and frequencies
Suspicious 69 (12.9)
(%), respectively. Differences among continuous values
Positive 33 (6.2)
were assessed with Kruskal–Wallis analysis, whereas
Type of resection
associations among categorical values were assessed with
Minor hepatectomy 300 (51.7)
Chi square test. To assess survival, Kaplan–Meier survival
Major hepatectomy 280 (48.3)
curves were evaluated using the log-rank test. Logistic
Resection margin
regression analyses were conducted to identify factors that
R0 524 (89.6)
were associated with 1-year mortality after hepatectomy.
R1 61 (10.4)
Patients who were censored within 1 year after liver
resection were excluded from the logistic regression anal- Location
yses. Clinicopathological parameters significant (P \ 0.05) Unilobar 506 (87.2)
in the bivariate logistic regression were included in the Bilobar 74 (12.8)
multivariable analyses. Subsequently, a backward step Cirrhosis
selection was used to eliminate nonsignificant variables No 498 (86.5)
using a p value \ 0.10. Results were reported as odds ratio Yes 78 (13.5)
(OR) and 95% confidence intervals (CI). A p value \ 0.05 Vascular invasion
(two-tailed) was defined as statistically significant for all No 399 (68.3)
tests. All multivariable analyses were conducted on com- Yes 185 (31.7)
plete case data. Statistical analysis was performed using Perineural invasion
SPSS Version 25.0 (IBM Corporation). No 456 (84.1)
Yes 86 (15.9)
RESULTS Histological grade
Well to moderate 507 (88.0)
Patient Clinicopathological Characteristics Poor to undifferentiated 69 (12.0)
Morphologic type
A total of 588 patients were included in the analytic MF, IG 520 (91.2)
cohort (Table 1). Median age at the time of surgery was PI, MF ? PI 50 (8.8)
58 years (interquartile range [IQR] 50–67), and more than
The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic… 2891

TABLE 1 continued one-half of patients were male (n = 355, 60.4%). Median

All patients (n = 588)
tumor number and tumor size were 1 (IQR 1–1) and 5.6 cm
(IQR 3.8–8.0), respectively, whereas median preoperative
Characteristics Patient number (%) albumin and NLR levels were 4.2 g/dL (IQR 3.9–4.5) and
AJCC 8th edition N category 2.7 (IQR 2.0–3.9), respectively. In assessing preoperative
Nx 419 (71.4) tumor markers, median preoperative CA19-9 and CEA
N0 94 (16.0) levels were 39.7 IU/mL (IQR 15.8–174.1) and 2.5 ng/mL
N1 74 (12.6) (IQR 1.5–4.2), respectively. Roughly half of patients
Adjuvant chemotherapy underwent a minor hepatectomy (n = 300, 51.7%) with the
No 470 (80.9) majority having an R0 resection (n = 524, 89.6%). On final
Yes 111 (19.1) pathological analysis, most patients had a mass-forming or
intraductal growth morphologic ICC subtype (n = 520,
IQR interquartile range; BMI body mass index; ICC intrahepatic 91.2%), and well-to-moderately differentiated tumor grade
cholangiocarcinoma; NLR neutrophil-to-lymphocyte ratio; CA car-
bohydrate antigen; CEA carcinoembryonic antigen; MF mass- (n = 507, 88.0%). A minority of patients received adjuvant
forming; IG intraductal growth; PI periductal infiltrating; AJCC chemotherapy (n = 111, 19.1%). After a median follow up
American Joint Committee on Cancer of 21.4 months (IQR 11.2–38.4), 248 patients (42.2%)
patients had died.

A B
1.0 1.0
CA19-9 < 176.3 CEA < 9.6
p < 0.001 p < 0.001
Probability of overall survival
Probability of overall survival

CA19-9 ≥ 176.3 CEA ≥ 9.6

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2

0.0 0.0
0 12 24 36 48 60 0 12 24 36 48 60
Months after hepatectomy Months after hepatectomy
Number at risk (number censored) Number at risk (number censored)
442 (0) 347 (41) 230 (110) 147 (165) 84 (213) 56 (236) 528 (0) 399 (52) 257 (128) 161 (188) 93 (240) 59 (266)
146 (0) 86 (16) 41 (34) 19 (42) 11 (47) 5 (50) 60 (0) 34 (5) 15 (16) 5 (20) 2 (20) 2 (20)

FIG. 1 Overall survival of patients with ICC stratified by CA19-9 (a) and CEA (b) levels

FIG. 2 Kaplan-Meier curve 1.0 Low CA19-9 & Low CEA *

comparing the overall survival Low CA19-9 & High CEA
**
of patients who have low CA19-
Probability of overall survival

High CA19-9 & Low CEA ****

9/low CEA, low CA 19-9/high 0.8 High CA19-9 & High CEA ***
CEA, high CA19-9/low CEA, * p <0.001
and high CA19-9/high CEA 0.6 ** p=0.92
*** p=0.18
**** p=0.08

0.4

0.2

0.0
0 12 24 36 48 60
Months after hepatectomy
Number at risk (number censored)
416 (0) 331 (39) 222 (104) 143 (158) 83 (205) 55 (228)
112 (0) 69 (13) 35 (24) 19 (30) 11 (35) 5 (38)
26 (0) 17 (2) 9 (6) 5 (7) 2(8) 2 (8)
34 (0) 18 (3) 7 (10) 0 (12)
2892 A. Moro et al.

TABLE 2 Comparison of patient characteristics stratified based on level of CA19-9 and CEA
All patients (N = 588), Patient number (%)
Characteristics Low CA19-9 & Low High CA19-9 & Low Low CA19-9 & High High CA19-9 & High P value
CEA = 416 CEA N = 112 CEA N = 26 CEA N = 34

Age, median (IQR), year 58 (49–67) 60 (51–69) 61 (52–65) 61 (52–66) 0.47

BMI, median (IQR), kg/ 24.4 (22.0–27.2) 24.0 (21.5–27.6) 24.5 (20.6–27.2) 23.1 (20.6–28.4) 0.83
m2
Sex
Male 254 (61.1) 64 (57.1) 17 (65.4) 20 (58.8) 0.83
Female 162 (38.9) 48 (42.9) 9 (34.6) 14 (41.2)
Region of the institution
Western 158 (38.0) 54 (48.2) 8 (30.8) 5 (14.7) 0.004
Eastern 258 (62.0) 58 (51.8) 18 (69.2) 29 (85.3)
Preoperative jaundice
No 396 (95.9%) 89 (80.2%) 23 (88.5%) 28 (84.8%) \ 0.001
Yes 17 (4.1%) 22 (19.8%) 3 (11.5%) 5 (15.2%)
Serum albumin, median 4.2 (4.0–4.5) 4.1 (3.8–4.4) 4.1 (3.8–4.3) 4.1 (3.8–4.5) 0.045
(IQR), g/dL
Total bilirubin, median 8.2 (0.7–13.7) 2.7 (0.6–10.9) 9.7 (1.0–14.6) 6.9 (1.1–14.5) 0.15
(IQR), mg/dL
NLR, median (IQR) 2.7 (1.9–3.5) 3.0 (2.1–4.3) 2.7 (2.0–3.5) 3.4 (2.4–4.3) 0.03
Size of tumor, median 5.2 (3.6–7.5) 7.0 (4.5–9.0) 6.6 (4.5–11.0) 6.4 (4.0–9.3) 0.001
(IQR), cm
Number of tumor nodules 1 (1–1) 1 (1–1) 1 (1–1) 1 (1–1) 0.73
(IQR)
Preoperative lymph node
status
Negative 320 (84.4%) 72 (71.3%) 19 (76%) 22 (73.3%) 0.09
Suspicious 41 (10.8%) 19 (18.8%) 4 (16%) 5 (16.7%)
Positive 18 (4.7%) 10 (9.9%) 2 (8%) 3 (10%)
Type of resection
Minor hepatectomy 240 (58.5) 36 (32.4) 12 (46.2) 12 (36.4) \ 0.001
Major hepatectomy 170 (41.5) 75 (67.6) 14 (53.8) 21 (63.6)
Resection margin
R0 377 (91.3) 97 (86.6) 20 (76.9) 30 (88.2) 0.08
R1 36 (8.7) 15 (13.4) 6 (23.1) 4 (11.8)
Location
Unilobar 50 (12.2) 18 (16.2) 3 (11.5) 3 (9.1) 0.63
Bilobar 360 (87.8) 93 (83.8) 23 (88.5) 30 (90.9)
Cirrhosis
No 339 (83.1) 102 (93.6) 24 (96.0) 33 (97.1) 0.003
Yes 69 (16.9) 7 (6.4) 1 (4.0) 1 (2.9)
Vascular invasion
No 294 (71.2) 69 (61.6) 16 (61.5) 20 (60.6) 0.15
Yes 119 (28.8) 43 (38.4) 10 (38.5) 13 (39.4)
Perineural invasion
No 335 (86.8) 76 (76.8) 20 (80.0) 25 (78.1) 0.06
Yes 51 (13.2) 23 (23.2) 5 (20.0) 7 (21.9)
Histological grade
Well to moderate 364 (89.2%) 92 (83.6%) 21 (84%) 30 (90.9%) 0.36
Poor to undifferentiated 44 (10.8%) 18 (16.4%) 4 (16%) 3 (9.1%)
The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic… 2893

TABLE 2 continued
All patients (N = 588), Patient number (%)
Characteristics Low CA19-9 & Low High CA19-9 & Low Low CA19-9 & High High CA19-9 & High P value
CEA = 416 CEA N = 112 CEA N = 26 CEA N = 34

Morphologic type
MF, IG 384 (93.9) 85 (83.3) 22 (88.0) 29 (85.3) 0.004
PI, MF ? PI 25 (6.1) 17 (16.7) 3 (12.0) 5 (14.7)
AJCC 8th edition N
category
Nx 312 (75.2) 70 (62.5) 13 (50.0) 24 (70.6) \ 0.001
N0 50 (12.0) 26 (23.2) 8 (30.8) 10 (29.4)
N1 53 (12.8) 16 (14.3) 5 (19.2) 0 (0)
Adjuvant chemotherapy
No 349 (84.3) 74 (68.5) 22 (84.6) 25 (75.8) 0.002
Yes 65 (15.7) 34 (31.5) 4 (15.4) 8 (24.2)
Overall survival, median 25.5 (13.6–45.2) 15.4 (7.7- 26.9) 15.8 (9.2–25.4) 12.4 (6.4–18.6) \ 0.001
(IQR), month
Bold values denote statistical significance (P \ 0.05)
IQR interquartile range, BMI body mass index, ICC intrahepatic cholangiocarcinoma, NLR neutrophil-to-lymphocyte ratio, CA carbohydrate
antigen, CEA carcinoembryonic antigen, MF mass-forming, IG intraductal growth, PI periductal infiltrating, AJCC American Joint Committee on
Cancer

Impact of CA19-9 and CEA on Overall Survival
Using the X-tile software, the optimal cutoff value to
differentiate OS was CA19-9 and CEA was 176.3 IU/mL
and 9.6 ng/mL, respectively. Applying these cutoff values,
marked differences in long-term prognosis among patients
with low versus high CA19-9 and CEA values were noted
(5-year OS: low CA19-9, 52.0% vs. high CA19-9: 12.8%,
respectively; P \ 0.01) (5-year OS: low CEA: 46.0% vs.
high CEA: 6.7%, respectively; P \ 0.01) (Figs. 1a and b).
In examining various combinations of CA19-9 and
CEA, four groups were investigated: low CA19-9/low
CEA; n = 416 [70.1%], high CA19-9/low CEA; n = 112
[19.1%], low CA19-9/high CEA; n = 26 [4.4%], high
CA19-9/high CEA; n = 34 [5.8%]. Patients with a preop-
erative low CA19-9/low CEA had a 5-year OS (54.5%) that
was considerably better than patients who had either low
CA19-9/high CEA (14.6%) or high CA19-9/low CEA
(10.0%), respectively. Of note, among patients who had a
high CA19-9/high CEA, median OS was 15.6 months
(95% CI 7.6-25.5) (Fig. 2). Patients who presented with
high preoperative CA19-9, irrespective of CEA level,
tended to have more aggressive clinicopathological char-
acteristics, including a higher tumor number, size, and the
presence of jaundice (all P \ 0.05; Table 2).
There was no difference in 1-year survival among
patients who had either a high preoperative CA19-9 or
CEA level (high CA19-9/low CEA: 70.4% vs. low CA19-
9/high CEA: 72.5% vs. high CA19-9/high CEA: 57.5%).
Among patients with high CA19-9 or high CEA, multi-
variable analysis revealed that low serum albumin (OR
3.92; 95% CI 1.40-10.99) and tumor size [ 5 cm (OR
2.49; 95% CI 1.28-4.84) were independently associated
with higher odds of 1-year mortality (Table 3). Of note,
while patients who had the most favorable tumor marker
profile of low CA19-9/low CEA had the best 1-year sur-
vival (87.9%), more than 1 in 10 patients (n = 39, 15.1%)
still died within a year of surgery. Among patients with a
low CA19-9/low CEA, higher NLR (OR 1.09; 95% CI
1.03–1.64) and tumor size [ 5 cm (OR 3.34; 95% CI
1.40–8.10) were associated with greater odds of 1-year
mortality (Table 4).
To understand the relative impact of the CA19-9 and
CEA on 1-year mortality, additional multivariable analyses
were performed that adjusted for BMI, NLR, tumor size,
and vascular invasion (Table 5). Of note, CA19-9 and CEA
remained strongly associated with 1-year mortality even
after controlling for these factors. Specifically, patients
with high CA19-9/low CEA (OR 3.38; 95% CI 1.72–6.64)
or low CA19-9/high CEA (OR 5.12; 95% CI 1.71–15.37)
had approximately threefold and fivefold higher odds of
1-year mortality compared with patient with low CA19-9/
low CEA, respectively. In addition, patients with high
CA19-9/high CEA levels also had higher odds of 1-year
mortality compared with patients with low CA19-9/low
CEA levels (OR 4.60; 95% CI 1.79–11.81; Table 5).
2894 A. Moro et al.

TABLE 3 Logistic regression analysis of perioperative prognostic factors associated with 1-year mortality among patients with high CA19-9 or
high CEA
Variable Bivariate analysis Multivariable analysis
Odds ratio (95% CI) P value Odds ratio (95% CI) P value

Age 1.03 (0.99–1.06) 0.07

BMI 1.11 (1.02–1.21) 0.017 1.10 (0.99–1.21) 0.06
Sex
Male Ref
Female 0.85 (0.43–1.68) 0.64
Region of the institution
Western Ref
Eastern 1.40 (0.69–2.84) 0.36
Preoperative jaundice
No Ref
Yes 1.32 (0.55–3.18) 0.54
Low serum albumin* 2.43(1.34–4.42) 0.004 3.92 (1.40–10.99) 0.009
Total bilirubin 1.01(0.97–1.06) 0.67
NLR 1.13(0.99–1.29) 0.05
Size of tumor (cm)
B5 Ref
[5 3.12 (1.33–7.33) 0.009 2.49 (1.28–4.84) 0.007
Number of tumor nodules 1.02 (0.75–1.38) 0.91
Preoperative lymph node status
Negative Ref
Suspicious 0.47 (0.18–1.28) 0.24
Positive 0.83 (0.26–2.61) 0.76
Type of resection
Minor hepatectomy Ref
Major hepatectomy 0.86 (0.43–1.70) 0.66
Resection margin
R0 Ref
R1 2.14 (0.86–5.34) 0.10
Location
Unilobar Ref
Bilobar 0.73 (0.29–1.84) 0.51
Cirrhosis
No Ref
Yes 1.91 (0.94–3.85) 0.07
Vascular invasion
No Ref
Yes 1.90 (0.84–4.27) 0.12
Perineural invasion
No Ref
Yes 1.18 (0.49–2.81) 0.71
Histological grade
Well to moderate Ref
Poor to undifferentiated 1.77 (0.73–4.30) 0.20
Morphologic type
MF, IG Ref
PI, MF ? PI 0.57 (0.20–1.66) 0.30
The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic…
TABLE 3 continued
Variable Bivariate analysis
Odds ratio (95% CI)
AJCC 8th edition N category
Nx Ref
N0 0.98 (0.45–2.12)
N1 0.47 (0.14–1.51)
Adjuvant chemotherapy
No Ref
Yes 0.53 (0.24–1.19)
Bold values denote statistical significance (P \ 0.05)
BMI body mass index, ICC intrahepatic cholangiocarcinoma, NLR neutrophil-to-lymphocyte ratio, CA carbohydrate antigen, CEA carcinoem-
bryonic antigen, MF mass-forming, IG intraductal growth, PI periductal infiltrating, AJCC American Joint Committee on Cancer
*Odds ratio changes based on the decrease of serum albumin level
**Patients who were censored within 1 year after liver resection (18 patients) were excluded from the analysis
DISCUSSION
Although there have been improvements in the nonop-
erative systemic and locoregional therapies, surgical
resection remains the only potentially curative treatment
option for patients with ICC.29,30 Tumor markers play an
important role in the management of many patients with
cancer, because these values are readily available, inex-
pensive, and can be obtained preoperatively.31 Previous
studies have demonstrated that tumor markers, such as
CA19-9 and CEA, may have prognostic importance for
patients with pancreatic and colorectal cancer.15–18 While
few studies have examined the importance of these markers
among patients with ICC, the data have been scant and are
largely derived from small, single-center case series.19–21
The current study was important, because we were able to
define specific cutoff values for CA19-9 (176.3 IU/mL)
and CEA (9.6 ng/mL) that categorized patients into distinct
prognostic groups. In addition, unlike any previous study,
we characterized the impact of CA19-9 relative to CEA. Of
note, patients with either high preoperative CA19-9 or
CEA levels had poor short- (1-year) and long-term (5-year)
survival—regardless of whether CA19-9 or CEA was ele-
vated. In fact, even among patients with discordant tumor
markers, prognosis was poor (5-year OS; low CA19-9/high
CEA, 14.6%; high CA19-9/low CEA, 10.0%). In contrast,
patients with both a low preoperative CA19-9 and CEA
had a substantially better 1- and 5-year survival. Despite
the better outcomes compared with patients who had a high
CA19-9 or CEA, more than one in ten patients with low
preoperative CA19-9/CEA died within 1 year following
curative-intent resection of ICC. Importantly, we noted that
2895
Multivariable analysis
P value Odds ratio (95% CI) P value
0.43
0.21
0.12
NLR and large tumor size ([ 5 cm) were useful prognostic
factors among patients who had both a low CA19-9 and
CEA.
Preoperative tumor markers have been associated with
postoperative prognosis among patients with various types
of malignancies.11,13,32,33 Previous studies have failed to
report specific cutoff values for CA19-9 levels and have
simply noted an association of rising CA19-9 with poor
prognosis.19–21 In the current study, using the bioinfor-
matics X-tile software tool, we were able to delineate
specific cutoff values to categorize patients into distinct
prognostic groups. Ferrone et al. had previously reported
that a CA19-9 [ 200 IU/mL was associated with worse
long-term survival among patients with pancreatic adeno-
carcinoma, even after adjusting for stage.34 In a separate
study, Liu et al.35 reported that a CA19-9 cutoff value of
250.9 IU/mL was associated with poor prognosis among
patients with gallbladder carcinoma. In the current study,
we identified a similar cutoff value of 176.3 IU/mL as
being associated with a particularly poor prognosis among
patients undergoing resection of ICC. Approximately 10%
of the population are, however, genotypically negative for
Lewis blood group antigen and therefore do not have the
ability to synthesize CA19-9.36 As such, CA19-9 may not
be an appropriate tumor marker for all patients. Recently,
CEA, which is established as a tumor marker especially in
gastrointestinal malignancies, has been increasingly used
as a tumor marker for hepatobiliary malignancies.11,13,14 In
the current study, patients who had either a high preoper-
ative CA19-9 or CEA level had a similar poor prognosis
(1-year OS: high CA19-9/low CEA, 70.4% vs. low CA19-
9/high CEA, 72.5%). These data demonstrate that the use
2896 A. Moro et al.

TABLE 4 Logistic regression analysis of perioperative prognostic factors associated 1-year mortality among patients with low CA19-9/low
CEA
Variable Bivariate analysis Multivariable analysis
Odds ratio (95% CI) P value Odds ratio (95% CI) P value

Age 0.99 (0.97–1.02) 0.47

BMI 1.05 (0.98–1.12) 0.18
Sex
Male Ref
Female 0.77 (0.40–1.48) 0.43
Region of the institution
Western Ref
Eastern 1.09 (0.57–2.11) 0.78
Preoperative jaundice
No Ref
Yes 1.29 (0.28–5.99) 0.75
Low serum albumin* 1.63 (0.90–2.96) 0.11
Total bilirubin 0.99 (0.95–1.04) 0.72
NLR 1.11 (1.04–1.17) \ 0.001 1.09 (1.03–1.64) 0.005
Size of tumor (cm)
B5 Ref
[5 2.18 (1.11–4.28) 0.02 3.34 (1.40–8.10) 0.006
Number of tumor nodules 1.45 (0.82–2.57) 0.20
Preoperative lymph node status
Negative Ref
Suspicious 0.66 (0.19–2.26) 0.92
Positive 0.51 (0.06–3.97) 0.66
Type of resection
Minor hepatectomy Ref
Major hepatectomy 0.83(0.44–1.59) 0.58
Resection margin
R0 Ref
R1 1.02 (0.34–3.06) 0.97
Location
Unilobar Ref
Bilobar 1.01 (0.37–2.71) 0.98
Cirrhosis
No Ref
Yes 1.91 (0.94–3.85) 0.07
Vascular invasion
No Ref
Yes 1.37 (0.70–2.66) 0.36
Perineural invasion
No Ref
Yes 1.59 (0.66–3.85) 0.31
Histological grade
Well to moderate Ref
Poor to undifferentiated 1.16 (0.43–3.14) 0.77
Morphologic type
MF, IG Ref
PI, MF ? PI 0.32 (0.04–2.45) 0.27
The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic…
TABLE 4 continued
Variable Bivariate analysis
Odds ratio (95% CI)
AJCC 8th edition N category
Nx Ref
N0 1.67 (0.69–4.08)
N1 1.81 (0.77–4.22)
Adjuvant chemotherapy
No Ref
Yes 0.13 (0.02–0.91)
Bold values denote statistical significance (P \ 0.05)
BMI body mass index, ICC intrahepatic cholangiocarcinoma, NLR neutrophil-to-lymphocyte ratio, CA carbohydrate antigen, CEA carcinoem-
bryonic antigen, MF mass-forming, IG intraductal growth, PI periductal infiltrating, AJCC American Joint Committee on Cancer
*Odds ratio changes based on the decrease of serum albumin level
**Patients who were censored within 1 year after liver resection (39 patients) were excluded from the analysis
of CEA as a tumor marker among patients with ICC was
both informative and predictive of prognosis. In turn,
measurement of CEA should be considered in the preop-
erative workup of patients with ICC.
Patients with an elevated CA19-9 and/or CEA generally
had a poor prognosis; however, certain clinicopathological
factors conferred an even worse outcome. Specifically, on
multivariable analysis, low serum albumin and larger
tumor size were both associated with a particularly poor
outcome. In fact, an elevated CA19-9 and/or CEA among
patients who also had a low preoperative serum albumin or
larger tumor ([ 5 cm) was associated with a 2.50-fold and
3.92-fold higher odds of 1-year mortality, respectively.
Serum albumin level is a well-recognized indicator of
preoperative nutritional status and liver function. In addi-
tion, some investigators have noted that albumin may act as
an antioxidative and have protective features among cancer
patients.37,38 For example, Akgul et al.39 reported that low
serum albumin levels increased overall risk of death among
cancer patients. Tumor size is another factor that has been
recognized as a relevant prognostic factor among patients
with ICC. The latest 8th edition of the AJCC staging
manual has recognized the importance of tumor size
through the revision of the T categories into T1a and T1b
using the 5-cm cutoff point.10 These data were consistent
with the results of the current study. Of note, tumor size
was independently associated with 1-year mortality among
patients with either high CA19-9 or CEA (OR 3.92; 95%
CI 1.40-10.99; Table 3). Collectively, the data suggest that
patients with high tumor markers who have low serum
albumin levels and larger tumor size are the least likely to
benefit from surgery with a high chance of death within the
first year. As such, these patients may be better served with
neoadjuvant therapies before surgical consideration to
better define the biology of disease.
2897
Multivariable analysis
P value Odds ratio (95% CI) P value
0.64
0.47
0.03 0.24 (0.03–1.84) 0.17
While patients with both a low preoperative CA19-9 and
CEA had a much better prognosis, one in ten of these
patients still died within the first year following surgery. Of
note, NLR and larger tumor size were the variables that
were associated with 1-year mortality among patients who
had both a low preoperative CA19-9 and CEA level. NLR
is a systemic inflammatory response marker, which has
been correlated with tumor progression and prognosis for
several different types of cancer.40–43 Specifically,
inflammation can play an important role in tumorigenesis
and tumor progression and neutrophils play a significant
role in this process.44–46 Neutrophils can both enhance
tumor growth and promote cancer progression by inhibiting
immune response of the specific cellular immune system
and the effect of activated lymphocytes.44–48 To this point,
Sia et al. reported a subset of ICC tumors that were more
associated with inflammation that had a worse prognosis,
possibly due to activation of several oncogenic pathways.49
Additionally, large tumor size was independently associ-
ated with a higher risk of early death within the first year
following surgery among patients with low preoperative
CA19-9 and CEA levels (OR 3.34; 95% CI 1.40–8.10;
Table 4). As such, assessment of NLR and tumor size
should be particularly informative among patients with low
CA19-9 and CEA to better inform and predict prognosis
among this subset of patients.
There are several limitations that should be considered
when interpreting the data. Similar to other multi-institu-
tional cohort studies, patient selection, diagnosis,
and surgical techniques, may have somewhat varied. In
addition, given the retrospective design of the study,
residual selection bias was possible. In particular, patients
with extremely high CA19-9 or CEA levels may have been
preferentially excluded from surgical consideration. Data
in the current study were derived from a surgical dataset; as
2898 A. Moro et al.

TABLE 5 Logistic regression analysis of perioperative prognostic factors associated with 1-year mortality
Variable Bivariate analysis Multivariable analysis
Odds ratio (95% CI) P value Odds ratio (95% CI) P value

Age 0.99 (0.97–1.01) 0.34

BMI 1.06 (1.01–1.12) 0.023 1.14 (1.06–1.22) \ 0.001
Sex
Male Ref
Female 0.85 (0.54–1.34) 0.48
Region of the institution
Western Ref
Eastern 1.19 (0.74–1.90) 0.47
Preoperative jaundice
No Ref
Yes 2.11 (1.03–4.35) 0.04
Low serum albumin* 2.24 (1.50–3.36) \ 0.001
Total bilirubin 0.99 (0.97–1.02) 0.71
NLR 1.10 (1.05–1.16) \ .001 1.12 (1.06–1.19) \ 0.001
Tumor marker group
Low CA19-9/Low CEA Ref Ref
High CA19-9/Low CEA 3.20 (1.90–5.40) \ 0.001 3.38 (1.72–6.64) \ 0.001
Low CA19-9/High CEA 3.51 (1.42–8.65) 0.006 5.12 (1.71–15.37) 0.003
High CA19-9/High CEA 5.78 (2.68–12.50) 0.017 4.60 (1.79–11.81) 0.001
Size of tumor (cm)
B5 Ref
[5 2.55 (1.57–4.14) \ 0.001 3.11 (1.58–6.11) 0.001
Number of tumor nodules 1.18 (0.91–1.54) 0.22
Preoperative lymph node status
Negative Ref
Suspicious 0.74 (0.35–1.56) 0.43
Positive 1.09 (0.43–2.77) 0.86
Type of resection
Minor hepatectomy Ref
Major hepatectomy 1.16 (0.75–1.79) 0.51
Resection margin
R0 Ref
R1 1.79 (0.94–3.40) 0.08
Location
Unilobar Ref
Bilobar 1.29 (0.68–2.44) 0.44
Cirrhosis
No Ref
Yes 1.63 (0.92–2.86) 0.09
Vascular invasion
No Ref
Yes 1.62 (1.03–2.56) 0.038 1.62 (0.89–2.99) 0.118
Perineural invasion
No Ref
Yes 1.59 (0.87–2.90) 0.13
Histological grade
Well to moderate Ref
The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic…
TABLE 5 continued
Variable Bivariate analysis
Odds ratio (95% CI)
Poor to undifferentiated 1.69 (0.91–3.13)
Morphologic type
MF, IG Ref
PI, MF ? PI 0.70 (0.29–1.71)
AJCC 8th edition N category
Nx Ref
N0 1.71 (0.97–3.00)
N1 1.13 (0.57–2.23)
Adjuvant chemotherapy
No Ref
Yes 0.54 (0.28–1.05)
Bold values denote statistical significance (P \ 0.05)
BMI body mass index, ICC intrahepatic cholangiocarcinoma, NLR neutrophil-to-lymphocyte ratio, CA carbohydrate antigen, CEA carcinoem-
bryonic antigen, MF mass-forming, IG intraductal growth, PI periductal infiltrating, AJCC American Joint Committee on Cancer
*Odds ratio changes based on the decrease of serum albumin level
**Patients who were censored within 1 year after liver resection (57 patients) were excluded from the analysis
such, comparison of surgical versus nonsurgical patients
was not feasible. The cutoffs of CA19-9 and CEA sug-
gested in the context of this study are different from those
reported using traditional methods in the study by Sasaki
et al.11 Specifically, the software (X-tile) used to determine
cutoffs in the current study was designed to optimize out-
come-based cut-points and, thus, may better reflect which
levels should be considered low or high. However, future
studies should validate these cutoffs in independent exter-
nal cohorts.
CONCLUSIONS
Patients who had either a high preoperative CA19-9 or
CEA had a very poor outcome with a 1-year survival of
only 64.9%. Both CA19-9 and CEA were associated with
outcomes, suggesting that both tumor markers may be
prognostically informative for patients undergoing surgery
for ICC. These data are important given that 10% of
patients will be genotypically negative for Lewis blood
group antigen and therefore do not have the ability to
synthesize CA19-9. In addition, patients with a high CA19-
9/CEA who had a low albumin or large tumor size fared
particularly poorly. While patients who have both a low
preoperative CA19-9 and CEA level traditionally are
considered as in a ‘‘good’’ prognostic group, a subset of
these patients were identified who had poor short-term
outcomes. Specifically, a high NLR and large tumor size
were associated with a much higher risk of mortality within
the first year following curative-intent resection. Data from
2899
Multivariable analysis
P value Odds ratio (95% CI) P value
0.10
0.43
0.06
0.73
0.07
the current study should help to inform clinicians about the
relative merits of using serum laboratory values, such as
CA19-9, CEA, NLR, as well as albumin in estimating
patient prognosis among patients with ICC. Specifically,
while tumor markers should not be used to preclude
patients from surgery, preoperative data, such as tumor
markers, may help to identify which patients may benefit
from a different initial treatment strategy—such as the use
of neoadjuvant chemotherapy. Similar to pancreatic cancer,
the use of preoperative chemotherapy among ICC patients
with high tumor markers may allow for a better biologic
selection of patients who are more likely to benefit versus
those unlikely to benefit from upfront surgical resection.
DISCLOSURES The authors declare no conflicts of interest.
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