articulo medico

1. ORIGINAL ARTICLE
Prognostic Significance of Preoperative Tumor Markers
in Pseudomyxoma Peritonei from Low-Grade Appendiceal Mucinous
Neoplasm: a Study from the US HIPEC Collaborative
Wasay Nizam1
& Nadege Fackche1
& Bernardo Pessoa1
& Boateng Kubi1
& Jordan M. Cloyd2
& Travis Grotz3
&
Keith Fournier4
& Sean Dineen5
& Jula Veerapong6
& Joel M. Baumgartner6
& Callisia Clarke7
& Sameer H. Patel8
&
Gregory C. Wilson8
& Laura Lambert9
& Daniel E. Abbott10
& Kara A. Vande Walle10
& Byrne Lee11
& Mustafa Raoof11
&
Shishir K. Maithel12
& Maria C. Russell12
& Mohammad Y. Zaidi12
& Fabian M. Johnston1
& Jonathan B. Greer1
Received: 30 November 2020 /Accepted: 7 April 2021
# 2021 The Society for Surgery of the Alimentary Tract
Abstract
Background Tumor markers are commonly utilized in the diagnostic evaluation, treatment decision making, and surveillance of
appendiceal tumors. In this study, we aimed to determine the prognostic significance of elevated preoperative tumor markers in
patients with pseudomyxoma peritonei secondary to low-grade appendiceal mucinous neoplasm who underwent cytoreductive
surgery and hyperthermic intraperitoneal chemotherapy.
Methods Using a multi-institutional database, eligible patients with measured preoperative tumor markers [carcinoembryonic
antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), or cancer antigen 125 (CA-125)] were identified. Univariate and multi-
variate Cox-proportional hazards regression analysis assessed relationships between normal and elevated serum tumor markers
with progression-free and overall survival in the context of multiple clinicopathologic variables.
Results zTwo hundred and sixty-four patients met criteria. CEA was the most commonly measured tumor marker (97%). Patients
who had any elevated tumor marker had a higher peritoneal carcinomatosis index (PCI) as compared to those with normal range
markers. Elevated CEA and CA 19-9 levels were individually associated with longer inpatient length of stay, requirement for
intraoperative transfusion, and incomplete cytoreduction. Utilization of neoadjuvant chemotherapy, increased PCI score, elevat-
ed CA 19-9 (p = 0.007), and CA-125 levels (p = 0.01) were predictive of decreased progression-free survival on univariate
analysis. However, in a multivariate model, only elevated PCI was a statistically significant predictor of progression-free
survival.
The findings of this paper were virtually presented at the American
College of Surgeons Clinical Congress 2020 on 10/3/2020.
* Jonathan B. Greer
jgreer13@jhmi.edu
1
Department of Surgery, Johns Hopkins University, 600 N. Wolfe
Street/Blalock 609, Baltimore, MD 21287, USA
2
Division of Surgical Oncology, Department of Surgery, The Ohio
State University Wexner Medical Center, Columbus, OH, USA
3
Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic,
Rochester, MN, USA
4
Department of Surgical Oncology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA
5
Department of Gastrointestinal Oncology, Moffitt Cancer Center,
Department of Oncologic Sciences, Morsani College of Medicine,
Tampa, FL, USA
6
Division of Surgical Oncology, Department of Surgery, University of
California, San Diego, CA, USA
7
Division of Surgical Oncology, Department of Surgery, Medical
College of Wisconsin, Wauwatosa, WI, USA
8
Department of Surgery, University of Cincinnati College of
Medicine, Cincinnati, OH, USA
9
Division of Surgical Oncology, Department of Surgery, University of
Massachusetts Medical School, Worcester, MA, USA
10
Division of Surgical Oncology, Department of Surgery, University of
Wisconsin, Madison, WI, USA
11
Division of Surgical Oncology, Department of Surgery, City of Hope
National Medical Center, Duarte, USA
12
Division of Surgical Oncology, Winship Cancer Institute, Emory
University, Atlanta, USA
https://doi.org/10.1007/s11605-021-05075-1
/ Published online: 10 September 2021
Journal of Gastrointestinal Surgery (2022) 26:414–424

2. Conclusion Elevated preoperative tumor markers indicate a higher burden of disease but are not independently associated with
survival in this retrospective multi-institutional cohort. Further prospective studies are needed to clarify the utility of these
markers in this patient population.
Keywords Low-grade appendiceal mucinous neoplasm . Pseudomyxoma peritonei . Biomarkers . Tumor
Introduction
Primary appendiceal neoplasms represent a heterogeneous
group of tumors that can originate from epithelial or neuroen-
docrine cells .
1
Mucinous neoplasms arise from epithelial tis-
sue and have historically presented a diagnostic challenge for
clinicians. These tumors have been the subject of numerous
histologic classification schemes that have been frequently
modified in an effort to optimally stratify tumors by their
biologic behavior .
2
The most recent classification scheme,
developed by the Peritoneal Surface Oncology Group
International (PSOGI) in 2016,
3
categorized mucinous
appendiceal neoplasms based on their invasive or non-
invasive nature. Non-invasive mucinous neoplasms without
high-grade atypia or infiltrating features were defined as
low-grade appendiceal mucinous neoplasms (LAMN).
3, 4
These lesions represent the vast majority of all appendiceal
mucinous neoplasms and can be challenging to treat given
the rarity of these in clinical practice and their propensity for
peritoneal dissemination, leading to pseudomyxoma peritonei
(PMP) .
5
The mainstay of treatment for LAMN with PMP is
now cytoreductive surgery with hyperthermic intraperitoneal
chemotherapy (CRS/HIPEC), as opposed to repeated
debulking alone, which is a procedure with significant mor-
bidity, though in line with other major oncologic surgical in-
terventions .
6, 7
Satisfactory long-term outcomes are expected
following CRS-HIPEC .
8
Given the short-term risk of a major
surgical intervention for a potentially long-term gain, efforts
are underway to better stratify patients preoperatively to po-
tentially spare a patient from an ultimately unhelpful opera-
tion. Unfortunately, much of the data that have predicted out-
comes in this disease rely on intraoperative variables and are
therefore not relevant for preoperative risk stratification.
Tumor markers are a useful tool for clinicians and can be
applied in a multitude of ways when caring for cancer patients,
including early detection and diagnosis .
9, 10
More established
clinical practices include the use of tumor markers for disease
surveillance following definitive cancer treatment as well as
monitoring the response to therapy in cases of advanced
disease.
10
In certain GI malignancies, such as gastric and pan-
creatic cancers, tumor markers have been shown to provide
prognostic information that correlates elevated circulating
marker levels with survival,
11–13
thus providing physicians with
objective evidence that can be used to guide patient care and
management.
Whether circulating tumor marker levels can be utilized to
provide such prognostic information in patients with PMP
from LAMN is uncertain. Three different glycoproteins,
CEA, CA 19-9, and CA-125, may be secreted by neoplastic
cells into systemic circulation .
14
A recently published multi-
disciplinary recommendation from the Chicago Consensus
Working Group for the Management of Peritoneal Surface
Malignancies advocated for measuring each of these tumor
markers prior to surgical exploration .
15
A similar position
was also adopted by the Peritoneal Surface Oncology Group
International (PSOGI) that put forth a consensus recommen-
dation from 80 worldwide experts encouraging the acquisition
of preoperative baseline levels of these tumor markers in all
patients with appendiceal pseudomyxoma peritonei .
16
However, in the absence of prior uniform centralized guide-
lines, significant variations exist in their utilization. Current
literature derived from single and multi-institutional experi-
ences have found conflicting results regarding the association
of these tumor markers with overall and progression-free sur-
vival .
17–20
To address the question of preoperative utility of
these markers in CRS/HIPEC for PMP from LAMN, we uti-
lized the US HIPEC Collaborative database. We hypothesized
that elevated preoperative tumor markers will be predictive of
worse progression-free survival (PFS) following CRS/
HIPEC.
Materials and Methods
The US HIPEC Collaborative is a multi-institutional database
that contains retrospectively collected data over a 17-year pe-
riod from 2000 to 2017. Participating institutions include
Johns Hopkins University, The Ohio State University, Mayo
Clinic, MD Anderson Cancer Center, Moffitt Cancer Center,
University of California San Diego, Medical College of
Wisconsin, University of Massachusetts Medical School,
University of Wisconsin, City of Hope National Medical
Center, and Emory University. Institutional Review Board
(IRB) approval was obtained at each site. The database con-
tains patients who underwent CRS/HIPEC for peritoneal sur-
face malignancies .
21
Comprehensive information pertaining
to clinicopathologic variables and overall outcomes were col-
lected. At each site, expert gastrointestinal pathologists were
involved in the review of pathologic specimens.
415
J Gastrointest Surg (2022) 26:414–424

3. To ensure uniformity in reporting from each site, the
American Joint Committee on Cancer (AJCC) 7th edition
guidelines were used for staging .
22
Peritoneal carcinomatosis
index (PCI) and completeness of cytoreduction (CC) score, as
defined by Sugarbaker, was estimated intraoperatively by the
surgical team .
23
Demographic information and patient char-
acteristics pertaining to age, gender, race, and body mass in-
dex (BMI) were obtained. Additional variables included ASA
class, presence of symptoms prior to the operation, postoper-
ative complications, and discharge destination.
Using the database, patients with PMP from LAMN identified
on final pathologic specimens were selected. Patients undergoing
emergency procedures, palliative surgery, or surgery without cu-
rative intent were excluded. Patients that had at least one of the
above-mentioned tumor markers measured preoperatively were
then identified and retained for final analysis. Data were extracted
for the common tumor markers in appendiceal mucinous neo-
plasms (CEA, CA 19-9, CA-125). Elevated tumor marker levels
were defined according to the following cut-off values: CEA: 3
ng/ml, CA 19-9: 37 u/ml, CA-125: 37 u/ml. Tumor markers that
were drawn within 90 days of surgery were considered to be
preoperative per the database entry rules.
For both groups, categorical variables were compared using a
chi-squared analysis and continuous variables were compared
using a Student’s t-test. Given the typically long overall survival
with the disease process, PFS was chosen as the primary out-
come variable. PFS was defined as the interval from surgery to
either recurrence or progression of the disease. If a patient had
both a date of disease progression and date of disease recurrence,
the earlier of the two served as the date of progression and was
therefore used to calculate PFS. Overall survival was assessed as
a secondary outcome variable. Survival analyses were performed
with a Kaplan-Meier method and a log rank test to discern be-
tween subgroups. Univariate and multivariate Cox-proportional
hazards regression analyses were performed to assess relation-
ships between serum tumor marker levels, demographics, pa-
tient, and disease characteristics, with progression-free and over-
all survival. All tumor markers and patient variables with a p-
value < 0.2 on univariate analysis were included in the multivar-
iate analysis. Statistical significance was pre-defined at a p-value
of less than 0.05 for all variables. All statistical analysis was
performed using STATA software version 15 (StataCorp.
2017. Stata Statistical Software: Release 15. College Station,
TX: StataCorp LLC).
Results
Demographic and Disease Characteristics of the Study
Population
The database contains a total of 2372 patients who had
undergone CRS/HIPEC. From this total population, 533
(22.5%) patients with LAMN were identified. Of these,
approximately half (n = 264, 49.5%) had at least one
tumor marker recorded, and this defined our study pop-
ulation. The median age of the study population was 57
years. The majority of patients were women (61.4%)
and of white race (84.9%). The majority (63.3%) of
patients had an ASA class of III or greater and a good
baseline functional status (82.2%) with ECOG ≤ 1
(Table 1). No statistically significant differences in de-
mographics existed between patients with tumor markers
in the normal or elevated range (Table 2).
Within the study population, the median PCI was 14. The
most commonly used intraperitoneal chemotherapy agent
used was Mitomycin C. A diverting stoma was performed in
13.6% of patients. Intraoperative blood transfusion was re-
quired by 15.9% of patients and a similar number required a
postoperative blood transfusion (13.3%). A complete
cytoreduction (CC ≤ 1) was achieved in 92.1% of patients.
Preoperative Tumor Marker Assessment
CEA was the most commonly measured tumor marker (n
= 257, 97.3%), whereas CA 19-9 (n = 184, 69.6%) and
CA-125 (n = 173, 65.5%) were utilized less frequently
(Figure 1). All three markers were recorded in 148 pa-
tients (56.1%) (Figure 1). When only one tumor marker
was used, CEA was the tumor marker most frequently
used (n = 58, 22%). In comparison, no patient had solely
CA 19-9 levels measured and only 4 patients had only
CA-125 levels monitored. The most commonly elevated
tumor marker was CEA, which was elevated in 58.3% of
patients. Elevated CA 19-9 and CA-125 were noted in
25% and 29.4%, respectively. For patients with an ele-
vated CEA level, the median tumor marker level was
10.05 ng/ml and the interquartile range was 6.5–30
ng/ml. The maximum observed CEA level was 521
ng/ml. For patients with an elevated CA 19-9 level, a
median value of 115.5 u/ml was observed with an inter-
quartile range of 39–212 u/ml. Similarly, for CA-125, a
median value of 58.4 u/ml and an interquartile range of
39–98 u/ml were seen (Table 3).
Outcomes
When comparing patients with normal tumor marker levels
against those with an elevated tumor marker, the median
PCI was consistently greater in patients with elevated tu-
mor marker levels (Table 2). Patients with elevated CEA or
CA 19-9 levels were more likely to have incomplete
cytoreduction. Elevated CEA or CA 19-9 levels were also
associated with a greater need for intraoperative transfu-
sion, but no difference in postoperative transfusion re-
quirements. A greater proportion of patients with elevated
416 J Gastrointest Surg (2022) 26:414–424

4. CEA levels received either ileostomy or colostomy crea-
tion during their procedure. Overall, elevated CEA (p =
0.006) or CA 19-9 (p = 0.004) levels were also associated
with a statistically significant longer durations of stay;
however, no difference was noted in terms of ICU length
of stay. There was no difference in complication rates be-
tween those with normal tumor markers and those with
elevated tumor markers. There was also no difference not-
ed in the discharge destination noted between both groups
with most patients going home. Readmission rates between
both groups were comparable (Table 2).
Table 1 Demographics, operative, hospital course, and outcomes of
whole study population
Characteristics Whole group
(n=264)
Number %
Demographics
Age, median (IQR 1–3) 57 (49–65)
Gender
Male 102 38.6
Female 162 61.4
Race
White 223 84.5
Black 12 4.5
Other/unknown 29 11.0
BMI
Non-obese 180 68.2
Obese 84 31.8
ASA class
II 70 26.5
III 161 61.0
IV 6 2.3
Unknown 27 10.2
ECOG status
0 171 64.8
1 46 17.4
2 4 1.5
3 1 0.4
Unknown 42 15.9
Insurance status
Private 163 61.7
Government 75 28.4
Uninsured 3 1.1
Unknown 23 8.7
Operative/hospital course data
Neoadjuvant chemotherapy
No 239 90.5
Yes 25 9.5
PCI, median (IQR 1–3) 14 (8–21)
Intraperitoneal chemotherapy agent
None 15 5.7
Mitomycin C 245 92.8
Other (cisplatin/carboplatin/oxaliplatin/melphalan) 4 1.5
Type of operation/organ resections
Appendectomy 72 27.3
Ileocectomy 7 2.7
Right colectomy 86 32.6
Transverse/left/total colectomy 17 6.4
Low anterior resection 10 3.8
Ileostomy/colostomy
None 228 86.4
End ileostomy/colostomy 4 1.5
Table 1 (continued)
Characteristics Whole group
(n=264)
Number %
Diverting loop ileostomy 8 3.0
Unknown 24 9.1
Intraoperative PRBC transfusion
No 216 81.8
Yes 42 15.9
Unknown 6 2.3
Postoperative PRBC transfusion
No 202 76.5
Yes 35 13.3
Unknown 27 10.2
CC (n = 240)
0 143 59.6
1 78 32.5
2 11 4.5
3 8 3.4
Postoperative outcomes
Adjuvant chemotherapy
No 211 80.0
Yes 17 6.4
Unknown 36 13.6
Readmission (n = 263)
Yes 49 18.6
No 214 81.4
Postoperative complication (n = 263)
No 135 51.3
Yes 128 48.7
Discharge destination
Home 173 65.5
Other 7 2.7
Unknown 84 31.8
Death
Yes 19 7.2
No 233 88.3
Unknown 12 4.5
417
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5. Survival Analysis
To investigate a possible difference in survival between those
with normal range tumor markers and those with elevated
tumor markers, we utilized a Cox-proportional hazards model.
On univariate analysis, elevated CA 19-9 levels (HR: 1.49, p =
0.007) and elevated CA-125 levels (HR: 1.44, p = 0.01) were
found to be predictive of decreased PFS (Figure 2). CEA was
Table 2 Demographic characteristics and outcomes of normal and elevated tumor markers
Characteristics CEA (n = 257) CA 19-9 (n = 184) CA-125 (n = 173)
Normal
(n = 107)
Elevated
(n = 150)
P-value Normal
(n = 138)
Elevated
(n = 46)
P-value Normal
(n = 122)
Elevated
(n = 51)
P-value
Age, median (IQR 1–3) 54 (47–65) 58 (50–65) 0.233 54 (47–64) 57 (50–65) 0.307 54 (48–63) 57 (48–64) 0.167
Gender 0.614 0.794 0.175
Female 63 93 84 27 87 31
Male 44 57 54 19 35 20
Race 0.770 0.819 99 48 0.143
White 90 127 114 41 4 0
Black 4 8 5 1 19 2
Other/unknown 13 19 19 4
BMI 0.151 0.523 0.778
Normal 68 108 92 33 84 34
Elevated 39 42 46 13 38 17
Preoperative symptoms 0.727 0.932 0.264
No 58 78 73 24 64 22
Yes 49 72 65 22 58 29
PCI, median (IQR 1–3) 10 (5–14.5) 19 (12.5–25) < 0.001 12 (6–17) 25 (19–31) < 0.001 13 (7–21) 19 (12–26) 0.002
CC < 0.001 0.001 0.239
0 70 68 89 16 75 23
1 25 52 34 24 33 18
2 0 11 5 4 4 4
3 1 7 1 2 4 2
ICU LOS median (IQR 1–3) 2 (1–3) 2 (1–3) 0.412 2 (1–3) 2 (1–3) 0.987 2 (1–3) 2 (1–3) 0.877
Total LOS median (IQR 1–3) 9 (7–11) 10 (8–13) 0.006 9 (7–11) 11 (9–15) 0.004 9 (8–12) 9 (7–12) 0.937
Intraoperative transfusion 0.007 0.002 0.088
No 96 115 123 32 104 38
Yes 9 31 14 13 16 12
Postoperative 0.114 0.908 0.357
transfusion
No 86 110 112 32 87 42
Yes 10 24 15 4 17 5
Ileostomy/colostomy 0.044 0.053 0.965
No 99 124 129 39 113 47
End stoma 0 7 1 3 3 1
Loop 1 4 4 2 3 1
Postop complication 0.263 0.250 0.318
No 60 73 70 19 54 27
Yes 47 77 68 27 67 24
Surgical site infection 0.600 0.118 0.106
No 104 144 131 46 115 51
Yes 3 6 7 0 6 0
Discharge destination 0.823 0.684 0.742
Home 67 100 82 29 81 34
Other 3 4 3 2 3 0
Unknown 37 46 53 15 38 17
Readmission 0.424 0.498 0.324
No 89 119 111 39 94 43
Yes 18 31 27 7 27 8
Death 0.208 0.500
No 97 129 123 42 108 46
Yes 2 17 5 4 6 4
Unknown
Progression 0.002 0.001 0.028
No 86 91 108 27 91 30
Yes 16 45 19 17 19 15
Unknown
418 J Gastrointest Surg (2022) 26:414–424

6. not associated with a difference in PFS (HR: 1.64, p = 0.089).
Additional predictive factors of worse PFS included the ad-
ministration of neoadjuvant chemotherapy (HR: 3.35, p <
0.001), increased PCI score (HR: 1.06, p < 0.001), incomplete
cytoreduction (HR: 1.76 p = 0.008), and length of stay beyond
30 days (HR: 8.29 p = 0.043). When incorporating these fac-
tors into a multivariate model, only an increase in PCI score
retained a statistically significant association with
progression-free survival (Table 4). Elevated tumor markers
did not.
When focusing on overall survival, on univariate analysis,
incomplete cytoreduction (CC > 2) was the only variable as-
sociated with a significantly worse survival (HR: 13.91, p <
0.001). When combining additional factors that approached
statistical significance such as age (p = 0.083) and ASA class
(p = 0.099) in the multivariate model, no tumor marker was
found to have a statistically significant effect on overall sur-
vival and only incomplete cytoreduction remained statistically
significant (HR: 4.58 p = 0.037) (Table 5).
Discussion
This study explored the prognostic significance of preopera-
tive tumor markers in patients undergoing CRS/HIPEC for
PMP secondary to LAMN with respect to PFS and OS. The
goal was to see if a preoperative variable such as tumor
markers could be found to correlate with postoperative out-
comes, such that adequate preoperative risk stratification and
counseling could be done. Consistent with previous reports,
we found elevated PCI score and incomplete cytoreduction to
be independent predictors of survival. Contrary to our hypoth-
esis, none of the investigated tumor markers (CEA, CA 19-9,
or CA-125) were independent predictors of PFS or OS.
A common utility of tumor markers involves applying
them to predict disease recurrence/progression. Such a corre-
lation was not evident in our multivariate analysis, where only
increased PCI was noted to be predictive of decreased PFS,
which again is an intraoperative variable that is less helpful in
the preoperative setting. This finding aligns with results from
a previous bi-institutional study
19
but is contrary to data from
previous single-center experiences that have suggested de-
creased survival in patients with elevated CEA and CA 19-9
levels .
17, 24
These discrepancies highlight the need for further
studies to better assess this relationship. Given that tumor
recurrence is undoubtedly influenced by multiple dynamic
factors, before and after surgery, it is unlikely that a single
preoperative tumor marker level can accurately be used to
predict disease recurrence. However, tumor markers may
serve as a useful adjunct to other surveillance tools, and such
combinations may allow for earlier detection of disease recur-
rence. For instance, some authors in the event of an elevated
Table 3 Range of tumor markers
in patients with an elevated tumor
marker
Tumor marker (units) Median Interquartile range Maximum observed value
CEA (ng/ml) 10.1 6.5–30 521
CA 19-9 (u/ml) 115.5 39–212 984
CA-125 (u/ml) 58.4 39–98 275
58
4
0
33
3
18
148
0
20
40
60
80
100
120
140
160
CEA CA 125 CA 19-9 CEA & CA 19-9 CEA & CA 125 CA 125 & CA 19-9 CEA, CA 125 & CA
19-9
s
t
n
e
i
t
a
P
f
o
r
e
b
m
u
N
Measured Tumor Marker
Fig. 1 Patterns in utilization of tumor markers
419
J Gastrointest Surg (2022) 26:414–424

7. Fig. 2 a Kaplan-Meier survival
curve of elevated vs normal CEA
levels. b Kaplan-Meier survival
curve of elevated vs normal CA
19-9 levels. c Kaplan-Meier sur-
vival curve of elevated vs normal
CA-125 levels
420 J Gastrointest Surg (2022) 26:414–424

8. tumor marker advocate performing a second look laparoscopy
within 12 months of the index operation to assess residual
disease burden.
17
Correlating the prospective serial monitoring
of tumor markers pre- and postoperatively could also be uti-
lized to predict disease recurrence. Given the limitations of
this dataset, assessing this relationship was not possible; how-
ever, this would be an interesting avenue of further research.
Similar to disease progression, tumor markers did not cor-
relate with overall survival. Given that LAMN generally be-
have as slow, indolent tumors, such a relationship would be
unexpected. Overall survival was influenced by the complete-
ness of cytoreduction, a factor that has consistently been
shown to be important in patients undergoing CRS/HIPEC
for a variety of malignancies.
24–28
Given the histologic and
clinical similarities between LAMN and other mucinous epi-
thelial tumors, it is possible that the effect of other factors
influencing the overall survival of mucinous epithelial tumors
may also extend to LAMN. Such reported factors include
demographic variables such as age
29
and male sex,
24,
30
neither of which were noted to influence overall survival
in our study population. Tumor grade
29
and high PCI scores
19,
29, 30
are other factors that have been shown to affect survival.
While PCI was noted to be predictive of disease progression,
an association with overall survival was not seen in this study
population. Interestingly, chemotherapy prior to CRS/HIPEC
was found to be associated with decreased survival, although
this likely represents selection bias.
29, 30
Lastly, an interesting
consideration is the non-invasive nature of LAMN and wheth-
er the dissemination of tumor markers in a non-invasive dis-
ease is different from mucinous adenocarcinomas. While this
is an interesting biological question, it is beyond the scope of
this manuscript to speculate.
A major limitation of this study is its retrospective nature.
While the multi-institutional aggregation of data provides
Table 4 Univariate and
multivariate predictors of
progression-free survival
Clinical characteristics Univariate Multivariate
HR 95 CI% P-value HR 95 CI% P-value
Age (1-year increase in age) 1.00 0.98–1.02 0.969
Gender
Male vs female 1.31 0.78–2.18 0.298
Race
Others vs white 0.57 0.23–1.43 0.230
BMI
Obese vs non-obese 0.78 0.45–1.36 0.396
ASA class
III vs II 1.05 0.56–1.94 0.882
IV vs II 0.92 0.12–6.99 0.934
Symptoms
Yes vs No 0.89 0.54–1.48 0.664
Neoadjuvant chemotherapy
Yes vs No 3.35 1.77–6.35 < 0.001 1.89 0.88–4.06 0.099
Elevated CEA
Elevated vs normal 1.64 0.93–2.92 0.089 0.88 0.43–1.79 0.727
CA 19-9
Elevated vs normal 1.49 1.12–1.98 0.007 1.71 0.68–4.32 0.250
CA-125
Elevated vs normal 1.44 1.09–1.90 0.010 1.09 0.48–2.45 0.824
PCI (1 unit increase in PCI) 1.06 1.03–1.09 < 0.001 1.05 1.01–1.10 0.011
CC
1 vs 0 1.76 1.20–3.42 0.008 1.06 0.54–2.05 0.851
≥ 2 vs 0 0.47 0.16–1.34 0.156 0.15 0.02–1.21 0.075
Postoperative complication
Yes vs No 0.95 0.58–1.58 0.858
Length of stay
(15–30 days) vs (0–14 days) 1.34 0.71–2.53 0.371 1.26 0.59–2.67 0.552
(> 30 days) vs (0–14 days) 8.29 1.07–64.4 0.043 1.59 0.17–14.79 0.685
421
J Gastrointest Surg (2022) 26:414–424

9. significant numbers of patients, allowing this introduces the
element of institutional variations in practices. There may be
variability in the timing of acquiring tumor markers relative to
the time of therapy, which may influence our results. While
some physicians may routinely assess tumor markers, others
may be more selective in their assessment, thereby excluding
certain patients from this cohort and over-representing patients
with a higher burden of disease. This multi-institutional ap-
proach also provides a unique ability to independently analyze
specific histologies given the large dataset. Utilizing this fo-
cused approach, however, limits the ability to determine wheth-
er tumor markers can discriminate between different etiologies
of PMP. Additionally, this dataset is composed exclusively of
patients who underwent some form of surgical resection.
Therefore, those with unresectable disease were excluded from
this study. The results of this study therefore cannot be applied
to this patient population and this introduces an inherent selec-
tion bias that may have affected our observed outcomes.
Finally, the study occurred over a 17-year period during which
multiple different reporting schemes for appendiceal tumors
were introduced/modified, which may result in misclassifica-
tion bias. However, given the limited changes in the diagnostic
criteria for LAMN, we believe that the majority of eligible
patients were correctly included in this study.
Conclusion
In conclusion, the role of preoperative tumor markers in pa-
tients with PMP from LAMN undergoing CRS/HIPEC re-
quires further clarification but do not appear to correlate with
progression-free or overall survival. Given this finding, ele-
vated TM should not preclude eligible patients from consid-
eration of an operative intervention. While elevated TM do
correlate with a higher burden of disease, they were not found
to be independently associated with survival. Prospective
Table 5 Univariate and
multivariate predictors of overall
survival
Clinical characteristics Univariate Multivariate
HR 95 CI% P-value HR 95 CI% P-value
Age (1-year increase in age) 1.04 0.99–1.09 0.083 1.01 0.96–1.06 0.573
Gender
Male vs female 1.12 0.45–2.77 0.81
Race
Others vs white 1.36 0.30–6.11 0.685
BMI
Obese vs non-obese 0.75 0.27–2.11 0.592
ASA class
III vs II 1.63 0.55–4.81 0.375 2.88 0.48–17.19 0.245
IV vs II 6.57 0.70–61.6 0.099 15.20 0.84–62.59 0.065
Symptoms
Yes vs No 0.86 0.34–2.14 0.740
Neoadjuvant chemotherapy
Yes vs No 0.94 0.21–4.08 0.924
Elevated CEA
Elevated vs normal 2.52 0.87–7.27 0.087 2.88 0.22–37.3 0.417
CA 19-9
Elevated vs normal 1.35 0.79–2.33 0.27 0.87 0.07–2.50 0.993
CA-125
Elevated vs normal 1.24 0.74–2.11 0.408 1.58 0.76–2.85 0.148
PCI (1 unit increase in PCI) 1.03 0.97–1.10 0.363
CC
1 vs 0 2.71 0.54–13.69 0.226 1.73 0.29–10.23 0.545
≥ 2 vs 0 13.91 3.90–49.57 < 0.001 4.58 1.86–24.22 0.037
Postoperative complication
Yes vs No 0.78 0.31–1.93 0.585
Length of stay
(> 15 days) vs (0–14 days) 0.57 0.16–2.01 0.388
422 J Gastrointest Surg (2022) 26:414–424

10. studies monitoring serial tumor marker levels pre- and post-
operatively should be considered to further delineate a clear
role for tumor markers in predicting disease progression and
survival.
Acknowledgements The authors would like to thank local database man-
agers that were involved in data collection and maintenance of this large
database.
Author Contribution W. N.: substantial contributions towards the con-
ception and design of study, acquisition, analysis, and interpretation of
data for the work, drafted the work, made revisions, and final approval of
manuscript.
N. F.: substantial contributions towards the conception and design of
study, acquisition, analysis, and interpretation of data for the work, made
revisions, and final approval of manuscript.
B. P., B. K., J. M. C., T. G., K. F., S. D., J. V., J. M. B., C. C., S. H. P.,
G. C. W., L. L., D. E. A., K. A. V. W., B. L., M. R., S. K. M., M. C. R., M.
Y. Z., F. M. J., and J. B. G. made substantial contributions to the acqui-
sition of data for the work, interpretation and analysis of results, critical
review of manuscript, and final approval of manuscript.
Declarations
Conflict of Interest The authors declare no competing interests.
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