Preoperative Serum CA19-9 and Dissected Peripancreatic Tissue Margin as Determiners of Long-Term Survival in Pancreatic Cancer

ORIGINAL ARTICLE – HEPATOBILIARY AND PANCREATIC TUMORS

Preoperative Serum CA19-9 and Dissected Peripancreatic TissueMargin as Determiners of Long-Term Survival in PancreaticCancer

Mina Waraya, MD, Keishi Yamashita, MD, PhD, Hiroyuki Katagiri, MD, PhD, Kenichiro Ishii, MD, PhD,

Yoshihito Takahashi, MD, PhD, Kazunori Furuta, MD, PhD, and Masahiko Watanabe, MD, PhD, FACS

Department of Surgery, Medical School, Kitasato University Hospital, Sagamihara, Kanagawa, Japan

ABSTRACT

Background. Pancreatic cancer, a particularly deadly

form of malignancy, has increased in the last decade

worldwide. The purpose of this study is to identify markers

for determining and identifying possible long-term survi-

vors in cases of advanced pancreatic cancer.

Patients and methods. 117 patients with pancreatic ductal

carcinoma, including 89 with invasive tubular adenocar-

cinoma of the pancreas, Japan Pancreas Society (JPS) stage

III–IVb patients, who underwent tumor resection between

1986 and 2006.

Results. Univariate prognostic analyses of the 5-year

disease-specific survival (DSS) revealed that JPS stage

(P \ 0.0001), preoperative serum carbohydrate antigen

19-9 (CA19-9) level (preCA19-9; P \ 0.0001), dissected

peripancreatic tissue margin (DPM; P \ 0.0001), residual

tumor (R factor; P = 0.0007), lymph node metastasis den-

sity over 10% (ND10; P = 0.006), volume of the stromal

connective tissue (stroma factor; P = 0.008), growth pattern

(P = 0.01), and histology (P = 0.03) were all significantly

associated with poor outcome in advanced pancreatic can-

cer. Multivariate logistic analysis confirmed that preCA19-9

[P = 0.0006, relative risk (RR) = 2.16] and DPM

(P = 0.04, RR = 1.62) were prognostic factors that

remained, independent of JPS stage (P = 0.001). The higher

preCA19-9 was, the worse the prognosis was. Astonishingly,

among JPS stage III cases, 76.9% of the patients with

preCA19-9 below 37 U/ml survived more than 5 years. This,

combined with an analysis of DPM, allowed us to identify

those with the potentiality for long-term survival.

Conclusion. Our results reveal for the first time that it is

possible with JPS stage III–IVb invasive tubular adeno-

carcinomas of the pancreas to differentiate prognostic

groups and potential survival rates, like with other cancers.

Pancreatic cancer is responsible for 34,000 deaths per

year in the USA, and is the fourth most common cause of

death from cancer, a position higher than its rate of incidence

(tenth) because of its dismal prognosis.1 In Japan, prevalence

of pancreatic cancer has increased in the last decade to

become the fifth leading cause of cancer death in men and the

sixth in women.2 Surgical resection has provided the only

chance for cure or long-term survival, despite the develop-

ment of multidisciplinary treatments. Resection rates have

increased due to recent advances in surgical techniques and

the application of extensive surgery. However, postoperative

prognosis has still been dismal due to commonly occurring

liver metastasis, local recurrence, and peritoneal dissemi-

nation. It is important to be able to predict prognosis

precisely after pancreatectomy for assessment of therapeutic

effect, consideration of administering adjuvant therapy, and

providing information to the patient.

The most common staging system used for pancreatic

cancer is the tumor–node–metastasis (TNM) classification.

This system was developed by the International Union

against Cancer (UICC) and is similar to that used by the

Japan Pancreas Society (JPS). However, TNM staging

does not offer an adequately broad picture of a patient’s

prognosis. Previous studies proposed that the prognostic

factors for pancreatic cancer were tumor size, differentia-

tion, lymph node metastasis density (ND), large vessel

involvement, resection margin status, and tumor markers

Electronic supplementary material The online version of thisarticle (doi:10.1245/s10434-009-0415-7) contains supplementarymaterial, which is available to authorized users.

� Society of Surgical Oncology 2009

First Received: 15 December 2008;

Published Online: 5 March 2009

M. Watanabe, MD, PhD, FACS

e-mail: [email protected]

Ann Surg Oncol (2009) 16:1231–1240

DOI 10.1245/s10434-009-0415-7

http://dx.doi.org/10.1245/s10434-009-0415-7

[CA19-9 and carcinoembryonic antigen (CEA)].3–6 More-

over, a number of molecular markers such as K-ras,

S100A6, and SMAD4 have also been shown to have

potential for prognostic value following resection.7–10 The

aim of this study was to determine which characteristics or

clinicopathological factors point to an increased possibility

of a long-term survival prognosis.

PATIENTS AND METHODS

Registration of Patients

Between January 1, 1986 and December 31, 2006, 117

patients with primary pancreatic carcinoma underwent

pancreatectomy with D0–D3 lymph node dissection at the

Surgical Department of Kitasato University Hospital.

Among the 117 cases, 106 patients had tubular adenocar-

cinoma; the other 11 patients had invasive mucinous

cystadenocarcinoma (n = 2), invasive carcinoma origi-

nating in an intraductal tumor (n = 3), papillary

adenocarcinoma (n = 4), mucinous carcinoma (n = 1),

and adenosquamous carcinoma (n = 1). Among the 106

tubular adenocarcinoma patients, 10 had double cancer

with life-threatening phenotype, and so we excluded them

from our analysis. Among the remaining 96 pancreatic

tubular adenocarcinoma patients, 6 were classified as JPS

stage 0–II (stage 0, n = 1; stage I, n = 2; stage II, n = 3);

the potential for analysis of survival rates was limited to the

small number of patients in this group, so analysis was

therefore performed to the largest group: those with JPS

stages III–IVb. Our patient distribution was consistent with

the nationwide registry, where most cases are classified as

JPS advanced stage (stages III–IVb), a classification

applicable to 96.2% of patients in our study.11 Of these

remaining 90 patients with invasive tubular adenocarci-

noma of the pancreas, clinicopathological characteristics

and prognosis were available for 89 patients (Fig. 1).

According to patient records, 67 patients underwent

pancreatoduodenectomy (PD), among whom 29 patients

underwent pylorus-preserving pancreatoduodenectomy

(PpPD). Twenty patients underwent distal pancreatectomy

(DP), and two patients underwent total pancreatectomy

(TP). Seventy-nine percent of patients (n = 72) had node

dissection in the form of D2 (n = 32) or D2 plus para-

aortic lymph node sampling dissection (n = 40). Eight

percent of patients (n = 6) had D3 field dissection between

1991 to 2004, but no patient underwent D3 field dissection

after the randomized control trial in Japan revealed that

extended lymph node dissection did not prolong survival.12

Thirty-seven patients (42%) received empirical adjuvant

therapy, comprising 34 patients who received chemotherapy

and 3 patients who received radiotherapy. Another 21 patients

(23%) received therapy for the remnant tumor, comprising 20

patients who received chemotherapy and 1 patient who

received radiotherapy. The chemotherapy regimens consisted

mostly of 5-fluorouracil (5-FU)-based chemotherapy [5-FU

only (n = 3), 5-FU/cisplatin (n = 9), or 5-FU/adriamycin/

mitomycin-C/nimustine hydrochloride (n = 2) as venous,

portal, or arterial infusion and tegafur/uracil (UFT) (n = 11)

or 5’-deoxy-5-fluorouridine (5’DFUR) (n = 3) as oral ther-

apy], and others were mitomycin-C (n = 7) or gemcitabine

(n = 18) as venous or arterial infusion. Radiotherapy con-

sisted of 1.8 Gy per day to total dose of 50 Gy.

We used both the fifth edition of the Japan Pancreas

Society (JPS) and the sixth edition of the UICC staging

systems for evaluating the prognosis of pancreatic can-

cer.13,14 The difference between these two staging systems

is the definition of the T factor and N factor. Most patients

with UICC stage IIA/IIB were JPS stage III–IVa and

patients with UICC stage III were JPS stage IVa or IVb

(Supplemental Table 1).

JPS and UICC Classification Differences

Previous articles have explained the differences between

JPS and UICC classification in detail, so we point out only

the gist.

Pancreatic carcinomasn = 117

Pancreatic tubularadneocarcinomas

n = 96

Pancreatic invasive tubularadenocarcinomas between

JPS stage III to IVbn = 90

Patients withinformation for all

clinicopathologic factorn = 89

Univariate and multivariateanalysis for independent

prognostic factors

Pancreatic tubularcarcinomas

n = 106

Invasive carcinoma originatingin an intraductal tumor, invasivemucinous cystadenocarcinoma,

papillary adenocarcinoma,and mucinous carcinoma

n = 11

Double cancer with lifethreatening phenotype

n = 10

Japan Pancreas Society (JPS)early stage (stage 0–II)

n = 6

FIG. 1 Flowchart of patient selection

1232 M. Waraya et al.

In the JPS edition, the T category is specified by

determining local invasion of the pancreas and adjacent

structures as absent or present for eight local extension

factors. The descriptions of JPS Tis, T1, and T2 are the

same as those of the UICC sixth edition. JPS T3 is a tumor

in which one or more of intrapancreatic common bile duct

(CH), duodenum (DU), serosa (S), and retropancreatic

tissue (RP) factors are positive, irrespective of tumor size.

JPS T4 is a tumor in which one or more of portal venous

system (PV), arterial system (A), extrapancreatic nerve

plexus (PL), and other organs (OO) factors are positive.

UICC T3 is a tumor that extends beyond the pancreas but

without involvement of the celiac axis or superior mesen-

teric artery. UICC T4 is a tumor that involves the celiac

axis or superior mesenteric artery.

In the JPS edition, the status of lymph node metastasis is

divided into four categories, N0–3, according to whether

metastasis is present in lymph node group 1–3, defined on

the basis of lymph flow. The presence of distant metastasis

is defined as metastasis to the distant organs, peritoneum or

distant lymph nodes in the JPS and UICC classification.

Clinicopathological Factors

All histological and other clinicopathological factors

were judged independently and blindly by histopatholo-

gists, and all histopathologic factors from the General

Rules for the Study of Pancreatic Cancer (JPS fifth edition)

were abstracted from the medical records. The volume of

the stromal connective tissue in cancer (stroma factor) is

classified into three categories: medullary type, small in

volume; scirrhous type, large in volume; intermediate type,

which is neither medullary nor scirrhous. Lymphatic per-

meation (ly) and vascular permeation (v) are defined as ly0,

1, 2, 3 and v0, 1, 2, 3 by infiltrative grade. However, this

classification is subjective; therefore, we classified ly and v

in terms of absence or presence.

The dissected peripancreatic tissue margin (DPM)

includes every surgical margin other than pancreatic cut

end margin (PCM) and bile duct cut end margin (BCM),

i.e., anterior and posterior pancreatic, especially along the

vessels, and can be judged intraoperatively by pathologists.

Currently, lymph node metastatic progression, as lymph

node metastasis density (ND), has been demonstrated to be

one of the most potent predictors of survival.6,15,16 In this

study, we determined optimal cutoff ratio value (6.6%) on

receiver–operating characteristic (ROC) curve analysis

based on prognosis (sensitivity 64%, specificity 78%) (data

not shown), and so defined ND cutoff level as 10% above

or below.

CA19-9 is a carbohydrate antigen with the sialylated

Lewis (sLe)a blood group, and individuals with an Lea-b-

genotype (lacking the Lewis antigen glycosyltransferase)

are unable to synthesize CA19-9 (about 5–7% of the gen-

eral population). CA19-9 expresses on a mucin, a high-

molecular-mass (200–1,000 kD) glycoprotein complex in

serum. The recommended upper limit of normal for CA19-

9 level is 37 U/ml, when CA19-9 levels were determined

and defined from the standard deviations of normal, healthy

people by using a chemiluminescent enzyme immunoassay

kit manufactured by Fujirebio Limited (Tokyo, Japan). In

this study, 89 patients had documented preoperative serum

CA19-9 levels, which were obtained just before operation,

avoiding the effects of obstructive jaundice and/or

inflammation of the hepatobiliary tree. Forty-four patients

had obstructive jaundice before surgery and 41 patients

were treated with biliary juice drainage. Among these 41

patients, 23 patients obtained a normal total bilirubin level,

but 18 patients, after draining of biliary juice, were still

above the upper limit of normal before surgery: the range

of total bilirubin (T.Bil.)/direct bilirubin (D.Bil.) was

reduced from 8.6/6.8–1.6/0.9 to 29.9/24.4–4.4/3.9 mg/dl.

The three other patients with obstructive jaundice had

operations without biliary juice drainage (range of T.Bil./

D.Bil.: 1.6/1.1- 4.3/4.2 mg/dl).

Statistical Analysis

Kaplan–Meier method was used for the 5-year disease-

specific survival (DSS) analysis, and the difference in

survival rate was assessed by log-rank test.17 DSS was

measured from date of operation to date of death or last

follow-up. Patients who died from causes other than pan-

creatic cancer (n = 16) and those with more than

60 months survival were regarded as censored or excluded

at the time of death or 60 months, respectively.

The variables that had prognostic potential suggested by

univariate analysis (P \ 0.05) were subjected to multi-

variate analysis with the logistic model.18 A value of

P \ 0.05 was considered to indicate statistical significance.

All statistical analyses were done with the SAS software

package StatView, version 5.0 (SAS Institute, Cary, NC).

RESULTS

Patient Characteristics and Univariate Prognostic

Analysis in Advanced Pancreatic Cancer (JPS stage

III–IVb)

The characteristics of 89 pancreatic cancer patients in

this study (44 men and 45 women) are summarized in

Table 1. Median age was 63 years (range 39–85 years).

Comparison of the 5-year DSS curves according to stage

revealed that stratification was more homogeneous in the

JPS classifications of stage III–IVb (UICC stage IIA–IV)

Determiners of Long-Term Survival in Pancreatic Cancer 1233

TABLE 1 Distribution of

clinical and pathological factors

and univariate prognostic

analysis in 89 patients

undergoing tumor resection of

stage III–IVb pancreatic

invasive tubular

adenocarcinoma

Variable Number DDS (%) DSS average survival (months) P valuea

Age (years)

\65/C 65 51/38 57/43 15.4/20.3 NS

Gender

Male/female 44/45 49/51 21.0/21.4 NS

Portion

head/body/tail 68/15/6 76/17/7 16.6/22.1/13.8 NS

Growth pattern

nodular/other 35/54 39/61 22.3/14.1 0.01

Histology

well/moderately/poor 36/35/18 40/39/21 21.1/16.5/11.4 0.03

Mode of histological infiltration (INF)

alpha/beta/gamma 1/57/31 1/64/35 60.0/19.0/12.8 NS

Volume of stromal connective tissue (stroma factor)

medullary/intermediate/scirrhous 1/52/36 2/58/40 31.7/20.0/13.0 0.008

Lymphatic permeation (ly)

absence/presence 5/84 6/94 23.6/16.9 NS

Vascular permeation (v)


Perineural invasion (ne)


Intraductal progression (mpd)


Tumor size (cm)

B2/2 \ ts B 4/4 \ ts B 6/\ 6 13/61/13/2 14/68/14/4 24.3/16.8/14.5/6.1 NS

Intrapancreatic common bile duct invasion (CH)


Duodenal invasion (DU)


Serosal invasion (S)


Retropancreatic tissue invasion (RP)


Portal venous system invasion (PV)


Arterial system invasion (A)


Extrapancreatic nerve plexus invasion (PL)

absence/presence 72/17 81/19 18.6/11.9 0.005

Invasion of other organs (OO)


T factor

1/2/3/4 1/3/58/27 2/3/65/30 1.2/12.4/21.1/10.4 0.009

Lymph node metastasis (N)

0/1/2,3 23/34/32 26/38/36 21.7/21.0/10.2 0.005

ND factor

ND \ 10/ND10 50/39 56/44 20.5/13.2 0.006

Peritoneal dissemination (P)



than in the UICC classifications (Supplemental Fig. 1).

Therefore, we adopted the JPS classification staging system

for patient prognosis in our study. Table 1 also presents the

univariate prognostic factors of the 89 JPS stage III–IVb

patients on 5-year DSS: JPS stage (P \ 0.0001), preoper-

ative serum CA19-9 level (preCA19-9; P \ 0.0001),

distant metastasis (M factor; P \ 0.0001), dissected peri-

pancreatic tissue margin (DPM; P \ 0.0001), residual

tumor (R factor; P = 0.0007), peritoneal dissemination (P

factor; P = 0.0008), hepatic metastasis (H factor;

P = 0.004), lymph node metastasis (N factor; P = 0.005),

extrapancreatic nerve plexus (PL factor; P = 0.005),

lymph node metastasis density over 10% (ND10;

P = 0.006), volume of the stromal connective tissue

(stroma factor; P = 0.008), T factor (P = 0.009), growth

pattern (P = 0.01), and histology (P = 0.03), which were

all significantly associated with poor outcome in advanced

pancreatic cancer.

Multivariate Prognostic Analysis in Advanced

Pancreatic Cancer (JPS Stage III–IVb)

The eight variables that had prognostic potential sug-

gested by the univariate analysis (P \ 0.05): JPS stage,

preCA19-9, DPM, R factor, ND10, stroma factor, growth

pattern, and histology, were subjected to multivariate

analysis, in which staging factors were excluded, i.e., M

factor, P factor, H factor, N factor, T factor, and PL factor.

This analysis revealed that preCA19-9 (P = 0.0006,

RR = 2.16) and DPM (P = 0.04, RR = 1.62) were the

only remaining prognostic factors independent of JPS stage

(P = 0.001) (Table 2). Kaplan–Meier curves of the two

independent prognostic factors are shown in Fig. 2. Mul-

tivariate analysis including staging factors could not be

performed by the SAS software package StatView, version

5.0, because too many relative factors would have to be

included for analysis.

Prognostic Impact of preCA19-9

A Kaplan–Meier curve for 89 patients was constructed

to analyze survival discrepancies between patients with

preCA19-9 levels above or below each cutoff line, and

when log-rank P value for the 5-year DSS remained almost

constantly above 28 U/ml (Fig. 3a). This result indicated

that, the higher preCA19-9 was, the worse the prognosis

was, and preCA19-9 was the ideal prognostic marker in

pancreatic tubular adenocarcinoma (Fig. 3b). We also

calculated preCA19-9 cutoff levels of 30 U/ml on receiver–

operating characteristic (ROC) curve analysis, with 90%

sensitivity and 44% specificity for death events (Fig. 3c).

These numerical values were almost equal for 37 U/ml

TABLE 1 continued

DSS disease-specific survival,

NS not significanta log-rank test

Variable Number DDS (%) DSS average survival (months) P valuea

Hepatic metastasis (H)


Distant metastasis (M)

absence/presence 71/18 78/22 19.4/8.9 \0.0001

Pancreatic cut end margin (PCM)

negative/positive 74/14 83/17 18.1/12.7 NS

Bile duct cut end margin (BCM)

negative/positive 68/1 98/2 16.7/14.6 NS

Dissected pancreatic tissue margin (DPM)

negative/positive 48/41 53/47 22.0/11.8 \0.0001

Residual tumor (R factor)

0/1/2 35/40/14 38/44/18 23.6/14.3/10.3 0.0007

Stage (JPS)

III/IVa/IVb 39/26/24 43/29/28 25.6/13.2/8.3 \0.0001

Operation

PD/DP/TP 67/20/2 75/22/3 16.8/16.6/13.3 NS

Lymph node dissection (D)

0,1/2/2 ? a/3 11/32/40/6 12/36/44/8 20.9/18.6/16.5/8.9 NS

Postoperative therapy (including adjuvant therapy)


Preoperative serum CA19-9

B37/[ 37 U/ml 23/66 26/74 30.6/12.7 \0.0001


(Fig. 3d), therefore in this study we defined the optimal

preCA19-9 cutoff level as 37 U/ml. When we divided

preCA19-9 levels into greater or less than 37 U/ml, the 23

patients with preCA19-9 levels of less than 37 U/ml

(preCA19-9 lower) had a 5-year DSS rate of 60.0% com-

pared with 4.0% for the 66 patients with levels greater than

37 U/ml (preCA19-9 higher) (P \ 0.0001) (Fig. 2a).

Combination of Independent Prognostic Factors

for Prediction of Long-Term Survival of Advanced

Pancreatic Tubular Adenocarcinoma

(JPS Stage III–IVb)

We validated combinations of preCA19-9 and DPM:

(A) lower and absence, (B) lower and presence or higher

and absence, and (C) higher and presence. First, in

total cases of advanced pancreatic cancer (JPS stage

III–IVb), these combinations or groupings were signifi-

cantly associated with prognosis (P \ 0.0001) (Fig. 4a).

Next, we subanalyzed prognosis according to each stage

(Fig. 4b–d). These groupings showed significant associa-

tion with prognosis in either stage III (P = 0.0004) or

stage IVa (P = 0.01), but not in stage IVb. The combina-

tion of preoperative serum CA19-9 and DPM could predict

long-term survival outcomes for pancreatic tubular

adenocarcinoma.

In stage III, group A showed the best prognosis (5-year

DSS = 88.9%), but groups B and C were characteristic of

stage IV (19.4%; 9.1%) (Fig. 4b). In stage IVa, the 5-year

DSS of groups A and B was 40% and 11.3%, respectively,

whereas in group C it was 0% (Fig. 4c).

DISCUSSION

A normal level of serum CA19-9 is defined as under 37

U/ml, which was estimated based on the standard deviation

of the distribution of normal persons. In terms of prognosis,

we obtained specific cutoff value as 28 U/ml or 30 U/ml in

this study, and, interestingly, these numerical values were

not significant different for 37 U/ml (Fig. 3d). Therefore, in

TABLE 2 Multivariate analysis of factors associated with disease-

specific survival of JPS stage III–IVb invasive tubular adenocarci-

noma of pancreas

Variable P value RR 95% CI

Stage (JPS) 0.001

Stage III Reference

Stage IVa 0.001 1.96 1.29–2.97

Stage IVb 0.005 1.9 1.21–2.98

Preoperative serum CA19-9 0.0006 2.16 1.39–3.36

DPM presence 0.04 1.62 1.02–2.59

ND10 NS 1.38 0.95–1.38

Growth pattern NS 1.07 0.73–1.57

Histology NS

Well Reference

Moderately NS 1.14 0.77–1.69

Poor 0.01 1.76 1.09–2.84

Stroma NS – –

R NS

R0 Reference

R1 NS 1.04 0.64-1.71

R2 NS 1.03 0.55-1.91

CI confidence interval, RR relative risk

1.0

0.8

0.6

0.4

0.2

0 70Months

4020 50 603010

ProportionSurviving

a Preoperative Serum CA19-9

Lower (n = 23)Higher (n = 66)

p < 0.0001

1.0

0.8

0.6

0.4

0.2

0 70Months

4020 50 603010

ProportionSurviving

b DPM

Absence (n = 48)Presence (n = 41)

p < 0.0001

FIG. 2 Disease-specific survival of pancreatic invasive tubular adenocarcinomas between JPS stage III to IVb. a preCA19-9; b dissected

peripancreatic tissue margin (DPM)


this study we reasoned to define the optimal preCA19-9

cutoff level as 37 U/ml.

Previous studies showed that high serum CA19-9 levels,

from over 150 to 1,000 U/ml, are of prognostic significance

in pancreatic cancer, as in our study (Fig. 3a).15,19–23 How-

ever, this current study demonstrates that preCA19-9 status,

and in particular a threshold or cutoff value of 37 U/ml, is a

significant prognostic factor in advanced pancreatic tubular

adenocarcinoma. Intriguingly, a ROC curve preliminarily

analyzed in the current study determined that the optimal

cutoff value of preCA19-9 for prognosis was 30 U/ml

(sensitivity 90% and specificity 44% for death prediction, as

shown in Fig. 3c), which correlates closely with the cutoff

value determined by studies of distribution in healthy indi-

viduals. These findings indicate that CA19-9 deviation from

the normal range has significant relevance in pancreatic

cancer clinics. A recent study focused on pancreatic cancer

did not reveal prognostic significance of preCA19-9 equal to

or greater than 37 U/ml.22 This may be due to the difference

in methodology between that study and the current one. In

this current study preCA19-9 was taken for analysis just

before surgery, thereby avoiding the effects of obstructive

jaundice and inflammation of the hepatobiliary tree. Hence,

the preCA19-9 obtained in our study may more clearly

represent cancer cells than the CA19-9 of previous reports,

as the effects of biliary obstruction have been avoided.

We also investigated several cutoff values for preCA19-

9 using P value for patient prognosis to determine the best

optimized cutoff value. Generally, this analysis has the

shape of an earthenware mortar, i.e., as the horizontal axis

shifts right, the vertical axis shifts down and up (because of

bias).24 Log-rank plots of both cutoff value and P value as

shown in Fig. 3a revealed that, when the horizontal axis

(level of preCA19-9) was higher than 28 U/ml, the vertical

0.5

0.4

0.3

0.2

0

0.1

0 103,000

CA19-9 (U/ml)

10,00050 1,00025

P Value

a

1.0

0.8

0.6

0.4

0.2

0 70

Months

4020 50 603010

ProportionSurviving

b

CA19-9 1–103,000 (n = 89)CA19-9 100–103,000 (n = 51)CA19-9 1,000–103,000 (n = 13)CA19-9 10,000–103,000 (n = 4)

1.0

0.8

0.6

0.4

0.2

0 70

Months

4020 50 603010

ProportionSurviving

d

CA19-9 > 28 or 30 (n = 70)CA19-9 > 37 (n = 66)

p = 0.8

1.0

0.8

0.6

0.4

0.2

0 1.0

1-Specificity

0.40.2 0.8 0.90.3 0.6 0.70.50.1

Sensitivity

c

FIG. 3 Preoperative serum CA19-9 cutoff level for 5-year survival.

a Identification of optimal cutoff level. The optimal cutoff level is 28

U/ml because statistical significance (P \ 0.005) occurs mostly

between 28 and 103,000 U/ml. b Prognosis difference for preCA19-

9 levels; if preCA19-9 cutoff level is higher, survival rate is

remarkably lower. c preCA19-9 ROC curve pointed to 30 U/ml

(sensitivity 0.90, specificity 0.44). d PreCA19-9 level between 28 U/

ml or 30 U/ml, and 37 U/ml has no statistical difference


axis (P value) remained in the lower right space. This

meant that preCA19-9 value was statistically significant for

prognosis if preCA19-9 cutoff level was higher than 28 U/

ml, and hence was an ideal biomarker. Such ideal prog-

nostic biomarkers have never been reported in pancreatic

cancer, and we must now take careful note of preCA19-9

levels in actual clinics. In the present study, 13 patients

showed preCA19-9 levels over 1,000 U/ml, a group com-

posed of JPS stage III (n = 3), IVa (n = 3), and IVb

(n = 7) patients, and their average survival was only

4.7 months after operation. Nine of the 13 cases recognized

distant metastasis (liver metastasis in seven patients and

bone or lung metastasis in the remaining two patients) on

average within 3.5 months (range 1–7 months), while the

other four patients died due to other diseases. Of the 13

patients, only 11 could be examined for postoperative

serum CA19-9 for follow-up purposes within 3 months,

given the other two patients’ extreme short-term survival

outcomes. All 11 cases showed elevated serum CA19-9

during the clinical course. Recent publications regarding

both gastric and colorectal cancer (CRC) in our institute

had shown prognostic relevance only in stage IV dis-

ease.25,26 Persistent elevation of CA19-9 in serum during

the clinical course therefore plays an important role in

determining a dismal prognosis in noncurative disease.

This connection can now also be seen in stage III pancre-

atic cancer. Conversely, pancreatic cancer, which has been

believed to be a noncurative disorder despite curative

operation, can be seen as ‘‘curative,’’ like gastric or CRC, if

serum CA19-9 is not elevated.

Serum CA19-9 itself may be associated with the poor

outcomes of invasive tubular adenocarcinoma of the pan-

creas from our results. This would allow for the classical

hypothesis that serum CA19-9 enhances extravasation and

1.0

0.8

0.6

0.4

0.2

0 70Months

4020 50 603010

ProportionSurviving

a JPS Stage III, IVa, IVb

Group A (n = 17)Group B (n = 37)Group C (n = 35)

p < 0.0001

p = 0.004

p = 0.0005

1.0

0.8

0.6

0.4

0.2

0 70Months

4020 50 603010

ProportionSurviving

c JPS Stage IVa


p = 0.01

NS

NS

1.0

0.8

0.6

0.4

0.2

0 70Months

4020 50 603010

ProportionSurviving

b JPS Stage III


p = 0.0004p = 0.008

NS

1.0

0.8

0.6

0.4

0.2

0 70Months

4020 50 603010

ProportionSurviving

d JPS Stage IVb


p = 0.4

FIG. 4 Combination of independent prognostic factors and progno-

sis. We assigned combinations of preCA19-9 and DPM (lower and

absence; lower and presence or higher and absence; and higher and

presence) to the staging groups A, B, and C. a Prognosis of JPS stage

III–IVb, b JPS stage III, c JPS stage Iva, d JPS stage IVb


metastasis by interaction with E-selectin expressed on

endothelium.27 Recent publications additionally propose

emerging mechanisms of serum CA19-9 involving

systemic dissemination of cancer cells. (1) Mucins

expressing CA19-9 were associated with the induction of

inflammatory molecules such as interleukin-6 (IL-6) and

prostaglandin (PGE2) in human cancer, and such inflam-

matory status is a prerequisite for systemic metastasis.28,29

(2) P-selectin, another specific ligand for serum CA19-9,

may be involved in promoting tumor aggregation with

platelets, leading to systemic cancer spread.30,31 Matsum-

oto et al. actually showed that blocking serum CA19-9 by

cimetidine is beneficial to CRC patients’ outcomes, and

therefore, antagonism with CA19-9 inhibitors might have

great potential to inhibit tumor metastasis.32,33

Resection status (R factor) has produced mixed results

as a prognostic factor.34–39 In this study, R factor was

eliminated as an independent prognostic factor, while

DPM, one part of R factor, was used. Of the 41 patients

with DPM present, 38 patients (93%) had positive retro-

pancreatic tissue margin, suggesting that DPM actually

represents retropancreatic tissue invasion. Previous studies

have emphasized the importance of tumor-free retroperi-

toneal tissue for patient survival after the resection of

ductal adenocarcinoma of the head of the pancreas.11,40,41

On the other hand, Luttges et al. and Westgaard et al. could

not demonstrate significant difference according to retro-

peritoneal tissue margin status, therefore it was necessary

to establish whether the retroperitoneal margin status was

significant for prognosis.42,43 Both preCA19-9 and DPM

can be informative during surgery (histopathologists can

diagnose DPM intraoperatively with a quick histopatholo-

gical diagnosis), and the information may influence

operative procedures during the operation.

Surgical margin status may, however, simply represent

an invasive phenotype of pancreatic cancer, rather than the

result of operative treatment. If so, we must identify the

oncogene involved in such malignancy for novel molecular

targeting. Reflecting this possibility, randomized trials

actually concluded that the addition of extended lym-

phadenectomy and retroperitoneal soft tissue clearance did

not significantly improve patient prognosis.12,44–47 Never-

theless, surgical resection has provided the only chance for

long-term survival in pancreatic cancer, and in consider-

ation of the present study, an attempt at complete clearance

of retroperitoneal tumor tissue (DPM absence) may be

worthwhile for those patients with putative pathological

stage III–IVa, when preCA19-9 levels are in the lower

range.

Finally, this is a retrospective study over 20 years with

89 patients included for analysis. So, this study might

suffer from bias, i.e., change in treatment strategy such

as range of lymph node dissection and application of

chemoradiotherapy, and learning curve. Prospective vali-

dation is further needed to clarify the relationship between

preCA19-9 and DPM, and prognosis in invasive tubular

adenocarcinoma of the pancreas.

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Preoperative Serum CA19-9 and Dissected Peripancreatic Tissue Margin as Determiners of Long-Term Survival in Pancreatic Cancer

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