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Cancer Epidemiology, Biomarkers & Prevention
Differences in Survival by Histologic Type of
Pancreatic Cancer
Megan Dann Fesinmeyer,1,2 Melissa A. Austin,1,2,3 Christopher I. Li,2,3
Anneclaire J. De Roos,2,3 and Deborah J. Bowen1,2
1
Institute for Public Health Genetics, University of Washington; 2Division of Public Health Sciences, Fred Hutchinson
Cancer Research Center; and 3Department of Epidemiology, University of Washington, Seattle, Washington
Abstract
Objective: Although pancreatic cancer has an extremely high
case fatality rate, little is known about differences in
mortality by histologic types. We examined median survival
and risk of mortality for endocrine pancreatic tumors and two
types of exocrine tumors, adenocarcinomas, and mucinous
tumors.
Method: This analysis included 35,276 pancreatic cancer
cases reported to the nine population-based cancer
registries participating in the Surveillance, Epidemiology,
and End Results program from 1973 to 2000. Survival
among cases with pancreatic adenocarcinomas, mucinous
tumors, and endocrine tumors were compared using
Kaplan-Meier plots. Comparative risks of mortality were
evaluated using multivariate adjusted Cox regression
models.
Results: Endocrine pancreatic cancer cases had a median
survival of 27 months compared with a median survival of 4
months for adenocarcinoma and mucinous tumor cases.
Compared with adenocarcinoma cases, endocrine tumor cases
had a 0.28-fold lower risk of mortality [95% confidence
interval (95% CI), 0.26-0.30], and mucinous tumor cases had a
0.88-fold lower risk (95% CI, 0.84-0.91). These results were
similar for men and women. Within histologic types,
advanced tumor stage, older diagnosis age, surgery, and
Black race were associated with increased risks of mortality,
whereas female sex and more recent year of diagnosis were
associated with decreased risks.
Conclusion: This study confirms the clinical observation that
patients with endocrine pancreatic cancer survive longer than
patients with exocrine tumors. A better understanding of
these differences could contribute to identifying the underlying causes of pancreatic cancer and to improving survival
rates across all histologic types. (Cancer Epidemiol Biomarkers Prev 2005;14(7):1766 – 73)
Introduction
Pancreatic cancer is a leading cause of cancer mortality in the
United States; it is the fourth and fifth most common cause of
cancer death among men and women, respectively (1).
Although several risk factors for pancreatic cancer have been
identified, including smoking (2), age (3), family history (4),
and diabetes (5), this knowledge has not led to substantial
improvements in the early detection or survival of pancreatic
cancer cases (6). In addition, most studies of pancreatic cancer
survival focus on survival after surgery and are thus not
generalizable to all cases.
Similar to cancers arising in other organs, pancreatic tumors
are classified according to their cell type of origin, structure, and
behavior. The pancreas is a multifunctional organ consisting of a
variety of cell types (6). The exocrine pancreas is comprised of
duct cells and acinar cells that produce a combination of gastric
enzymes needed for digestion (7). In contrast, the endocrine
pancreas contains h cells and other types of endocrine cells that
produce hormones, including insulin, that are dispersed
throughout the body and that are required for glucose
metabolism (8).
The majority of exocrine pancreatic cancers are adenocarcinomas. These tumors originate in the epithelial cells lining the
pancreatic duct, form gland-like structures, and account for
f90% of all pancreatic cancers (9, 10). Mucinous tumors,
another type of exocrine pancreatic cancer, is the second most
common histologic type of pancreatic cancer, accounting for
Received 2/16/ 05; revised 4/21/ 05; accepted 4/29/ 05.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Requests for reprints: Melissa A. Austin, Department of Epidemiology and Institute for Public
Health Genetics, School of Public Health and Community Medicine, University of
Washington, HSB F-363, Box 357236, 1959 Northeast Pacific Avenue, Seattle, WA 98195-7236.
Phone: 206-543-0709; Fax: 206-685-9651. E-mail: [email protected]
Copyright D 2005 American Association for Cancer Research.
<10% of all tumors. Mucinous tumors are usually less invasive
at diagnosis than other types of exocrine pancreatic cancer
(11). These tumors form sac-like structures, secrete mucin, and
typically arise from the pancreatic ductal epithelium (11).
Cancers of the endocrine pancreas are less common, occurring
at a rate of about five per million person-years, and accounting
for <5% of all pancreatic cancers (12). These tumors arise from
pancreatic islet cells, including h cells and a cells (8). Rather
than ablating endocrine function in the pancreas, these tumors
often produce pancreatic hormones at high levels (13). Tumors
of this type include insulinomas and gastrinomas and are
often detected due to the symptoms caused by excessive
hormone levels (12).
Although disparities in survival time between endocrine
and exocrine pancreatic cancer have been noted clinically,
these differences have not been quantified. Furthermore,
survival differences among subtypes of exocrine pancreatic
cancer (adenocarcinomas and mucinous tumors) have not
been reported. The few studies that have evaluated pancreatic
cancer survival by histologic type were not population-based
and were restricted to pancreatic cancer cases receiving
surgery thus limiting their generalizability (14-16). The
purpose of this study was to quantify the median survival
times and compare the risks of mortality for cases diagnosed
with adenocarcinomas, mucinous tumors, and endocrine
carcinomas of the pancreas using population-based data from
the National Cancer Institute’s Surveillance, Epidemiology,
and End Results (SEER) program from 1973 to 2000. In
addition, we sought to identify risk factors associated with
mortality within each histologic type.
Patients and Methods
Case Selection. Pancreatic cancer cases diagnosed from
January 1973 to December 2000 were ascertained from the nine
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Cancer Epidemiology, Biomarkers & Prevention 1767
population-based cancer registries that participated in the
SEER program over this period (17). These registries serve the
states of Connecticut, Hawaii, Iowa, New Mexico, and Utah
and the metropolitan areas of Atlanta, Detroit, San FranciscoOakland, and Seattle-Puget Sound. All registries contain data
on cancers diagnosed from January 1973 onward, with the
exception of the Seattle-Puget Sound and Atlanta registries,
which contain data on cancers diagnosed from 1974 onward
and 1975 onward, respectively. It is estimated that >95% of all
incident cancer cases in the populations under surveillance are
ascertained. Further operational details and methods used by
the SEER program are provided elsewhere (18).
In total, 64,649 potentially eligible cases were identified from
the SEER registries. Those with an unknown survival time (n =
2,691), a diagnosis age of <20 years (n = 32), nonmalignant
disease (n = 47), unstaged tumors (n = 10,751), rare histologic
types of pancreatic cancer based on their four-digit International Classification of Diseases for Oncology, 3rd Edition (ICD-O3) histology code (n = 1,397), or a nonspecific histology (n =
14,455) were excluded. The remaining 35,276 cases of
pancreatic cancer that were included in the analysis were
divided into three histologic type groups based on their ICDO-3 codes: (a) adenocarcinomas (n = 31,357; 89% of total; ICDO-3 codes 8140, 8141, 8143, 8144, 8190, 8211, 8261, 8262, 8263,
8290, 8440, 8503, 8560, and 8570), (b) mucinous tumors (n =
2,865; 8% of total; ICD-O-3 codes 8470, 8471, 8472, 8473, 8480,
and 8481), and (c) endocrine tumors (n = 1,054; 3% of total;
ICD-O-3 codes 8150, 8151, 8152, 8153, 8154, 8155, and 8246).
It is worth noting that 93% of the mucinous tumor cases
were categorized as mucinous adenocarcinoma or mucinproducing adenocarcinomas (ICD-O-3 codes 8480 and 8481,
respectively).
Survival and Mortality Analyses between Histologic
Types. Survival time was measured in months from date of
diagnosis until date of death. Nondeaths were censored at the
follow-up cutoff date for the SEER data set (December 31,
2000), or the date the case was last known to be alive. SEER
registries obtain survival time for cancer cases by reviewing
medical records and death certificates to obtain dates of
diagnosis, death, and last known follow-up. Because pancreatic cancer is often fatal at diagnosis, a large number of cases
had a SEER-assigned survival time of 0 month (n = 3,080; 8.6%
of total), indicating that the case survived for <1 month. To
minimize any bias that could result from excluding these cases
from the analysis, cases with a survival time of zero were each
assigned a survival time of 0.5 month.
We used Stata version 8.2 (Stata Corp., College Station, TX;
ref. 19) for all descriptive and statistical analyses. To compare
survival in the three histologic types, we plotted Kaplan-Meier
curves for 5-year survival. The assumption of proportional
hazards was confirmed using plots of the log cumulative
hazards for each histologic type (data not shown). Cox
regression was then used to compare risks of mortality for
the three case groups and to calculate hazard ratios (HR) and
95% confidence intervals (95% CI; ref. 20). In these analyses,
cases with adenocarcinoma served as the reference group.
Several potential confounding variables were defined a
priori and were included in the multivariate Cox model, coded
as categorical variables. These variables were age at diagnosis
(<50, 50-59, 60-69, 70-79, and >80 years), year of diagnosis
(1973-1976, 1977-1980, 1981-1984, 1985-1988, 1989-1992, 19931996, and 1997-2000), SEER historic stage (local, regional, or
distant), race (White, Black, Asian/Pacific Islander, and other/
unknown), SEER registry, and gender. Another measure of
tumor progression, tumor grade, was not included in these
analyses due to the large percentage of cases with ungraded
tumors (50-79% of all cases with different histology types in
this data set). Because previous studies found differences in
pancreatic cancer mortality for men and women (21, 22), we
tested for effect modification by gender. Gender was found to
be an effect modifier of the association between histologic type
and risk of mortality by likelihood ratio testing (P < 0.001),
comparing a model containing a multiplicative interaction
term for gender and histology with a model without the
interaction term. Thus, the mortality analyses were repeated
stratified by gender.
Mortality Analyses Stratified by Histologic Type. We used
Cox regression to identify risk factors associated with
mortality within each of the three histologic types. The risk
factors examined were tumor stage, age at diagnosis, calendar
year at diagnosis, gender, and race in multivariate adjusted
models, using the definitions of covariates provided above.
Test for trend analyses for ordered variables (tumor stage, age
at diagnosis, and calendar year at diagnosis) were done using
grouped linear variables in the multivariate-adjusted models.
Analysis of Surgery Subgroup. Given the generally short
survival time of pancreatic cancer, cases that survive long
enough to receive surgical treatment are highly selected and
are thus not likely to represent all pancreatic cancer cases.
However, for comparison with other studies, we conducted an
analysis of the association between surgery and pancreatic
tumor survival. The three surgery classification groups
included in the analysis were (a) any partial or total
pancreatectomy, including the Whipple procedure (ref. 6; a
total or partial pancreatectomy with a subtotal gastrectomy
and duodenectomy, either with or without a splenectomy); (b)
other cancer-directed surgery (including local excision of
tumor); and (c) no cancer-directed surgery or no surgery
(including cases who only received biopsies). HRs were
calculated comparing recipients of pancreatectomy and other
cancer-directed surgery with patients who did not receive
surgery. Subjects with an unknown surgery status (n = 14,692)
were excluded from this analysis.
Results
Demographic characteristics of the three pancreatic cancer
histologic types are presented in Table 1. The mean age at
diagnosis was similar for both adenocarcinomas and mucinous
tumors (67.3 and 66.7 years, respectively), whereas endocrine
tumor patients had a somewhat younger mean age at
diagnosis (58.0 years). In general, the number of cases
diagnosed with each histologic type increased over the course
of our study. Nearly equal numbers of women and men were
diagnosed with mucinous tumors, whereas more men than
women were diagnosed with endocrine tumors and adenocarcinomas. Distributions by race were similar within histologic types, although a slightly lower proportion of endocrine
tumor cases were Black. In general, the proportion of cases
with each histologic type were similarly distributed throughout the SEER sites. Distributions of localized, regional, and
distant tumor stages were also similar within each of the three
groups, with more than two thirds of the cases having distant
disease.
Finally, surgery status was known for 58.3% of cases,
although this proportion varied by histologic type as surgery
status was known for 57.8% of the adenocarcinoma cases,
58.5% of the mucinous tumor cases, and 75.7% of the endocrine
tumor cases (Table 1). The percentage of cases that received
either a pancreatectomy or other cancer-directed surgery also
differed by histologic type, ranging from 11.1% of adenocarcinoma cases to 17.6% of mucinous tumor cases and to 29.2%
of endocrine tumor cases.
Survival and Mortality between Histologic Types. At all
time points in the follow-up period, survival rates among
endocrine pancreatic cancer cases were higher than for either
adenocarcinoma or mucinous tumor cases (Fig. 1). For
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1768 Pancreatic Cancer Survival by Histologic Type
Table 1. Demographic characteristics of pancreatic cancer cases by histologic type
Adenocarcinoma
(n = 31,357)
Age at diagnosis
<50
50-59
60-69
70-79
80+
Mean (SD)
Year of diagnosis*
1973-1976
1977-1980
1981-1984
1985-1988
1989-1992
1993-1996
1997-2000
Gender
Male
Female
Race
White
Black
Asian/Pacific Islander
Other/Unknown
SEER registry
San Francisco
Connecticut
Detroit
Hawaii
Iowa
New Mexico
Seattle-Puget Sound
Utah
Atlanta
SEER historic stage
Localized
Regional
Distant
Surgery status
No cancer-directed surgery
Other cancer-directed surgery
Pancreatectomy
Unknown surgery
Mucinous tumors
(n = 2,865)
Endocrine tumors
(n = 1,054)
Total
(n = 35,276)
n (%)
3,050
6,530
11,265
10,541
3,890
67.0 (11.5)
n
2,472
5,776
10,027
9,514
3,568
67.3
(%)
(7.9)
(18.4)
(32.0)
(30.3)
(11.4)
(11.3)
n
261
514
972
840
278
66.7
(%)
(9.1)
(17.9)
(33.9)
(29.3)
(9.7)
(11.4)
n
317
240
266
187
44
58.0
(%)
(30.1)
(22.8)
(25.2)
(17.7)
(4.2)
(14.6)
3,078
3,959
4,451
4,601
4,696
5,043
5,529
(9.8)
(12.6)
(14.2)
(14.7)
(15.0)
(16.1)
(17.6)
306
384
382
361
448
469
515
(10.7)
(13.4)
(13.3)
(12.6)
(15.6)
(16.4)
(18.0)
85
106
103
123
202
186
249
(8.0)
(10.0)
(9.8)
(11.7)
(19.2)
(17.7)
(23.6)
3,469
4,449
4,936
5,085
5,346
5,698
6,293
16,299 (52.0)
15,058 (48.0)
1,420 (49.6)
1,445 (50.4)
581 (55.1)
473 (44.9)
18,300
16,976
26,009 (83.5)
3,521 (11.3)
1,622 (5.2)
205
2,422 (85.2)
283 (10.0)
137 (4.8)
23
906 (86.4)
93 (8.9)
50 (4.8)
5
29,337
3,897
1,809
233
5,260
4,970
6,490
1,435
4,395
1,702
3,978
1,144
1,983
(16.8)
(15.9)
(20.7)
(4.6)
(14.0)
(5.4)
(12.7)
(3.7)
(6.3)
452
529
498
103
393
134
382
133
241
(15.8)
(18.5)
(17.4)
(3.6)
(13.7)
(4.7)
(13.3)
(4.6)
(8.4)
165
123
181
50
164
67
152
61
91
(15.7)
(11.7)
(17.2)
(4.7)
(15.6)
(6.4)
(14.4)
(5.8)
(8.6)
5,877
5,622
7,169
1,588
4,952
1,903
4,512
1,338
2,315
2,760 (8.8)
8,911 (28.4)
19,686 (62.8)
239 (8.3)
645 (22.5)
1,981 (69.1)
121 (11.5)
245 (23.2)
688 (65.3)
3,120
9,801
22,355
16,083 (88.8)
135 (0.7)
1,891 (10.4)
13,248
1,382 (82.4)
38 (2.3)
257 (15.3)
1,188
565 (70.8)
57 (7.1)
176 (22.1)
256
18,030
230
2,324
14,692
*The Seattle-Puget Sound and Atlanta SEER registries did not contribute cases until January 1, 1974 and January 1, 1975, respectively.
example, at 24 months, 51.6% of endocrine cases were alive
compared with only 4.6% of adenocarcinoma cases and 8.6% of
mucinous tumor cases. Median survival of endocrine pancreatic cancer cases was f2 years longer than for adenocarcinoma
or the mucinous tumor cases (27 versus 4 months, respectively,
Table 2). Compared with adenocarcinoma cases, patients with
endocrine tumors and mucinous tumors had reduced adjusted
risks of mortality (HR, 0.28; 95% CI, 0.26-0.30 and HR, 0.88;
95% CI, 0.84-0.91, respectively).
Among mucinous tumor cases, the relative decrease in
adjusted risk of mortality compared with adenocarcinoma
cases was slightly greater among women (HR, 0.84; 95% CI,
0.79-0.89; Table 2) than among men (HR, 0.91; 95% CI, 0.860.97), although this difference was within the limits of chance.
In endocrine tumor cases, the adjusted HRs were nearly
identical in both genders (men: HR, 0.28; 95% CI, 0.26-0.31 and
women: HR, 0.27; 95% CI, 0.24-0.30). However, women with
endocrine tumors had a substantially longer median survival
compared with men (37 versus 23 months).
Mortality within the Adenocarcinoma Cases. Table 3A
presents median survival times and adjusted HRs for mortality
among adenocarcinoma cases. Age at diagnosis, year of
diagnosis, gender, race, tumor stage, and surgery were all
related to risk of mortality in this group. Specifically, risk of
mortality increased in each ascending category of age at
diagnosis (P trend < 0.001), with corresponding decreases in
median survival time. Patients diagnosed with adenocarcinoma in later calendar years had a decreased risk of mortality
compared with cases diagnosed in the earliest time interval.
This risk reduction increased in each time interval, culminating
with a 27% reduction in risk of mortality in cases diagnosed in
the 1997 to 2000 interval compared with those diagnosed
between 1973 and 1976 (P trend < 0.001).
The median survival times for men and women differed
slightly (3 months for men and 4 months for women), and the
adjusted reduction in risk associated with female gender was
8% in adenocarcinoma cases (P < 0.001). Compared with
Whites, who had a median survival of 4 months, Blacks had a
median survival of 3 months and an 1.11-fold (95% CI, 1.071.15) increased adjusted risk of mortality. Asian/Pacific
Islanders were not different from Whites with respect to
survival or risk of mortality. Compared with patients with
localized adenocarcinoma, patients diagnosed with regional or
distant adenocarcinoma had 1.17-fold (95% CI, 1.12-1.22) and
2.43-fold (95% CI, 2.33-2.54) increases in risk of mortality,
respectively (P trend < 0.001).
Compared with adenocarcinoma cases who received no
cancer-directed surgery, who had a median survival of 4
months, cases who received a partial or complete pancreatectomy had a median survival of 13 months (the longest median
survival of any of the adenocarcinoma strata analyzed) and an
0.53-fold (95% CI, 0.50-0.57) reduced adjusted risk of mortality.
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Cancer Epidemiology, Biomarkers & Prevention 1769
of 6 months, but their adjusted reduction in risk of mortality
was not different from that of Whites. The risk of mortality
associated with stage increased in each higher stage and was
greatest in cases with distant tumors, who had a 4.64-fold (95%
CI, 3.90-5.52) increased risk of mortality compared with cases
with localized tumors (P trend < 0.001).
Compared with cases who received no cancer-directed
surgery, who had a median survival of 4 months, cases who
received a partial or complete pancreatectomy had a median
survival of 24 months and a 0.39-fold (95% CI, 0.32-0.47)
reduced adjusted risk of mortality. Cases receiving other
cancer-directed surgeries experienced similar improvements in
survival time and risk of mortality compared with patients
receiving no surgery.
Figure 1. Kaplan-Meier curves comparing percent survival for 5 years
in the pancreatic cancer histologic types: adenocarcinoma (n =
31,357, solid line), mucinous tumors (n = 2,865, dotted line), and
endocrine tumors (n = 1,054, dashed line).
Cases receiving other cancer-directed surgery also experienced
improvements in survival time compared with cases receiving
no surgery, with a median survival of 8 months and a 0.70-fold
(95% CI, 0.58-0.83) decreased adjusted risk of mortality.
Mortality within Mucinous Tumor Cases. Table 3B
presents median survival times and adjusted HRs for mortality
among mucinous tumor cases. Similar to adenocarcinoma
cases, age at diagnosis, year of diagnosis, gender, race, tumor
stage, and surgery were all related to risk of mortality.
Cases with mucinous tumors diagnosed in all age groups
after age 50 had increased risks of mortality compared with
cases diagnosed before age 50 (P trend < 0.001). Cases diagnosed
at age 80 or older had the greatest risk of mortality (HR, 2.55;
95% CI, 2.12-3.07). Risk of mortality decreased for cases in each
ascending year of diagnosis, with the greatest reduction
observed among cases diagnosed from 1997 to 2000, who
had a 0.68-fold (95% CI, 0.59-0.80) reduction in risk of mortality
compared with patients diagnosed from 1973 to 1976 (P trend <
0.001). The median survival times for men and women differed
slightly for mucinous tumors (3 months for men and 4 months
for women), and females in this group had a 0.87-fold (95% CI,
0.80-0.94) adjusted reduction in risk of mortality. Compared
with Whites, who had a median survival of 4 months, Blacks
had a shorter median survival of 3 months, and a 1.33-fold
(95% CI, 1.16-1.53) increased adjusted risk of mortality. Asian
or Pacific Islander cases had a slightly longer median survival
Mortality within the Endocrine Tumor Cases. Table 3C
presents median survival times and adjusted HRs for mortality
among endocrine tumor cases. Age at diagnosis, year of
diagnosis, gender, race, tumor stage, and surgery were again
all related to risk of mortality in this group. The risk of
death among cases with endocrine tumors increased with age
(P trend < 0.001), culminating in a 5.79-fold (95% CI, 4.06-8.27)
increased risk of mortality in patients diagnosed at age 80 or
older compared with patients diagnosed before age 50.
Median survival durations and the magnitudes of the HRs
tended to increase over time compared with cases diagnosed
from 1973 to 1976 (P trend < 0.001). The median survival was
more than a year longer among women with endocrine tumors
compared with men with these tumors (37 versus 23 months,
respectively), and females had a 0.81-fold (95% CI, 0.70-0.94)
adjusted reduction in risk of mortality. Race was not associated
with adjusted risk of mortality in endocrine tumor cases,
although median survival differed somewhat by race. Distant
endocrine tumors had a 3.33-fold (95% CI, 2.50-4.45) increased
risk of mortality compared with localized tumors, but no
increase in risk was found for regional tumors. However,
median survival was 29 months shorter (70 versus 99 months)
for regional tumors compared with localized tumors, and
advanced tumor stage was associated with increased adjusted
risk of mortality (P trend < 0.001).
Compared with subjects who received no cancer-directed
surgery, who had a median survival of 21 months, cases who
received a partial or complete pancreatectomy had a median
survival of 97 months and a 0.48-fold (95% CI, 0.36-0.65)
reduced adjusted risk of mortality. Patients receiving other
cancer-directed surgery experienced even better survival and
reductions in mortality: fewer than 50% of these cases died
before the end of the study period and had a 0.31-fold (95% CI,
0.19-0.51) reduced adjusted risk of mortality compared with
cases receiving no surgery.
Table 2. Median survival times and adjusted HRs for mortality by histologic type of pancreatic cancer and gender
Histologic type
All pancreatic cancer cases
Adenocarcinoma
Mucinous
Endocrine
Men
Adenocarcinoma
Mucinous
Endocrine
Women
Adenocarcinoma
Mucinous
Endocrine
n at risk
Person-years
at risk
No. deaths
Median
survival (mo)
HR* (95% CI)
31,357
2,865
1,054
18,480
2,276
3,542
30,217
2,658
759
4
4
27
1.00 (reference)
0.88c (0.84-0.91)
0.28c (0.26-0.30)
16,299
1,420
581
9,229
913
1,763
15,726
1,346
428
3
3
23
1.0 (reference)
0.91c (0.86-0.97)
0.28c (0.26-0.31)
15,058
1,445
473
9,250
1,363
1,779
14,491
1,312
331
4
4
37
1.0 (reference)
0.84c (0.79-0.89)
0.27c (0.24-0.30)
*Hazard ratio defined as the instantaneous risk of death compared to the adenocarcinoma histologic type, adjusted for age at diagnosis, year of diagnosis, SEER
registry, SEER historic stage, and race. Hazard ratios that include all cases are also adjusted for gender.
c95% CI = 95% confidence interval.
bP < 0.01.
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1770 Pancreatic Cancer Survival by Histologic Type
Table 3.
n at risk
Person-years
at risk
No.
deaths
Median
survival (mo)
HR* (95% CI)
P-value
for trend
A. Adjusted HRs for mortality by SEER historic stage, age at diagnosis, year of diagnosis, and surgery status among adenocarcinoma cases
Age at diagnosis (y)
<50
50-60
60-70
70-80
>80
Year of diagnosis
1973-1976
1977-1980
1981-1984
1985-1988
1989-1992
1993-1996
1997-2000
Gender
Male
Female
Race
White
Black
Asian/Pacific Islander
SEER historic stage
Localized
Regional
Distant
Surgery status
No cancer-directed surgery
Pancreatectomy
Other cancer-directed surgery
2,472
5,776
10,027
9,514
3,568
1,956
4,089
6,315
4,881
1,238
2,335
5,521
9,678
9,211
3,472
5
5
4
3
2
1.00 (reference)
1.11c (1.06-1.16)
1.23c (1.18-1.29)
1.50c (1.43-1.57)
2.08c (1.97-2.20)
<0.001
3,078
3,959
4,451
4,601
4,696
5,043
5,529
1,715
2,171
2,759
2,804
3,082
3,199
2,749
3,070
3,954
4,431
4,569
4,643
4,943
4,607
3
3
3
3
4
4
4
1.00 (reference)
0.92c (0.88-0.96)
0.90c (0.86-0.94)
0.89c (0.85-0.93)
0.82c (0.79-0.86)
0.80c (0.76-0.83)
0.73c (0.70-0.77)
<0.001
16,299
15,058
9,229
9,250
15,726
14,491
3
4
1.00 (reference)
0.92c (0.90-0.94)
26,009
3,521
1,622
15,333
1,951
1,094
25,114
3,399
1,515
4
3
4
1.00 (reference)
1.11c (1.07-1.15)
0.94 (0.88-1.01)
2,760
8,911
19,686
3,175
8,051
7,253
2,603
8,369
19,245
7
7
2
1.00 (reference)
1.17c (1.12-1.22)
2.43c (2.33-2.54)
16,083
1,891
135
9,138
2,809
152
15,340
1,537
121
4
13
8
1.00 (reference)
0.53c (0.50-0.57)
0.70c (0.58-0.83)
<0.001
B. Adjusted HRs for mortality by SEER historic stage, age at diagnosis, year of diagnosis, and surgery status among mucinous
Age at diagnosis (y)
<50
261
414
218
6
1.00 (reference)
b
50-60
514
461
474
4
1.20 (1.02-1.41)
60-70
972
700
910
4
1.37c (1.18-1.59)
70-80
840
604
786
3
1.65c (1.42-1.92)
>80
278
97
270
2
2.55c (2.12-3.07)
Year of diagnosis
1973-1976
306
177
305
3
1.00 (reference)
1977-1980
384
228
383
3
1.01 (0.87-1.17)
1981-1984
382
224
378
3
0.98 (0.84-1.14)
1985-1988
361
328
352
4
0.92 (0.79-1.07)
b
1989-1992
448
568
418
4
0.85 (0.73-0.98)
b
1993-1996
469
437
436
4
0.86 (0.74-0.99)
1997-2000
515
314
386
5
0.68c (0.59-0.80)
Gender
Male
1,420
913
1,346
3
1.00 (reference)
Female
1,445
1,363
1,312
4
0.87c (0.80-0.94)
Race
White
2,422
1,896
2,261
4
1.00 (reference)
Black
283
171
269
3
1.33c (1.16-1.53)
Asian/Pacific Islander
137
185
108
6
0.86 (0.67-1.10)
SEER historic stage
Localized
239
735
156
16
1.00 (reference)
Regional
645
769
575
8
2.00c (1.67-2.40)
Distant
1,981
772
1,927
3
4.64c (3.90-5.52)
Surgery status
No cancer-directed surgery
1,382
893
1,305
4
1.00 (reference)
Pancreatectomy
257
655
151
24
0.39c (0.32-0.47)
x
0.30c (0.18-0.50)
Other cancer-directed surgery
38
192
17
cases
C. Adjusted HRs for mortality by SEER historic stage, age at diagnosis, year of diagnosis, and surgery status among endocrine
Age at diagnosis (y)
<50
317
1,532
190
51
1.00 (reference)
50-60
240
939
164
41
1.20 (0.97-1.49)
60-70
266
695
202
17
1.89c (1.54-2.31)
70-80
187
349
161
12
2.81c (2.25-3.49)
>80
44
27
42
2
5.79c (4.06-8.27)
Year of diagnosis
1973-1976
85
402
80
11
1.00 (reference)
1977-1980
106
511
94
23
0.90 (0.66-1.23)
1981-1984
103
466
94
32
0.77 (0.57-1.06)
1985-1988
123
529
103
23
0.74 (0.55-1.00)
tumor cases
<0.001
<0.001
<0.001
<0.001
<0.001
Table 3.
(Continued on the following page)
Cancer Epidemiol Biomarkers Prev 2005;14(7). July 2005
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Cancer Epidemiology, Biomarkers & Prevention 1771
Table 3. (Cont’d)
n at risk
Person-years
at risk
No.
deaths
Median
survival (mo)
HR* (95% CI)
P-value
for trend
C. Adjusted HRs for mortality by SEER historic stage, age at diagnosis, year of diagnosis, and surgery status among endocrine tumor cases
1989-1992
1993-1996
1997-2000
Gender
Male
Female
Race
White
Black
Asian/Pacific Islander
SEER historic stage
Localized
Regional
Distant
Surgery status
No cancer-directed surgery
Pancreatectomy
Other cancer-directed surgery
b
202
186
249
771
566
297
156
126
106
32
34
26
0.69 (0.52-0.91)
0.59c (0.44-0.79)
b
0.65 (0.47-0.88)
581
473
1,763
1,779
428
331
23
37
1.00 (reference)
b
0.81 (0.70-0.94)
906
93
50
3,056
349
114
648
71
37
27
30
17
1.00 (reference)
1.08 (0.83-1.41)
1.45 (0.93-2.25)
121
245
688
686
1,302
1,553
55
138
566
99
70
15
1.00 (reference)
1.29 (0.94-1.78)
3.33c (2.50-4.45)
565
176
57
1,874
634
345
438
59
19
21
97
1.00 (reference)
0.48c (0.36-0.65)
0.31c (0.19-0.51)
x
<0.001
*HRs for each risk factor are adjusted for all other factors in the table.
cP < 0.001.
bP < 0.05.
xNo median survival reported because >50% of all cases in the cell were alive by December 31, 2000.
Discussion
The analyses presented here quantitatively show that survival
time among pancreatic cancer cases varies by histologic type in
a large, population-based setting. Specifically, patients diagnosed with cancer of the endocrine pancreas survive f2 years
longer, on average, than those diagnosed with exocrine
pancreatic cancer, including both adenocarcinoma and mucinous tumor cases. This result concurs with qualitative clinical
observations of decreased mortality among endocrine pancreatic cancer cases compared with exocrine pancreatic cancer
cases. After adjustment for age at diagnosis, gender, diagnosis
year, stage, race, and SEER registry, there was a 0.28-fold
decreased adjusted risk of mortality for endocrine tumors, and
a 0.88-fold decreased adjusted risk of mortality for mucinous
tumors compared with adenocarcinomas, although mucinous
cases did not have a longer unadjusted median survival time.
These decreased adjusted risks of mortality were similar
among men and women, although the median survival time
for women with endocrine cancer was considerably longer
than it was for men (37 versus 23 months, respectively).
Whereas there are many published accounts of survival in
specific patient subgroups (14-16, 23), we are not aware of any
previous, population-based reports comparing survival between endocrine and exocrine pancreatic tumors. A previous
analysis of data on 100,313 pancreatic cancer cases in the
National Cancer Database estimated 5-year survival rates for
different tumor stages and courses of treatment, but the
National Cancer Database is not population-based, and that
analysis did not examine survival within or between histologic
types (24). Although differences in methodology preclude
direct comparison between the National Cancer Database
study and the results presented here, both studies found that
surgery is associated with increased survival and documented
that more advanced tumors are associated with decreased
survival.
At this time, there is no known explanation for the
difference in survival time between cases with exocrine and
endocrine tumors, but tumors of the exocrine pancreas may be
more lethal than endocrine tumors due to their cellular or
molecular behavior. For example, pancreatic adenocarcinomas
often block the pancreatic duct, resulting in jaundice and
cachexia (25). In contrast, endocrine pancreatic tumors often
overproduce normally occurring substances such as insulin
and glucagons (13). How these histologic differences influence
survival remains to be determined by basic science research
studies.
Our observation that risks of mortality declined from 1973 to
2000 in each histologic type of pancreatic cancer suggests that
some progress has been made in the diagnosis and/or
treatment of the disease over this time period. For adenocarcinomas, this improvement has been modest, with only a slight
increase in median survival time over the 28-year period (3
months in 1973-1976 versus 4 months in 1997-2000). The
statistically significant decrease in risk of mortality over this
same time period may be due to the large sample size in this
analysis and may not represent a clinically significant improvement. A similar trend towards slight improvement in survival
and risk of mortality over time was also seen in mucinous
tumors. However, for endocrine tumors, increased survival
times and reductions in risk of mortality over time have been
more dramatic, as median survival times have improved from
11 months in 1973 to 1976 to 26 months in 1997 to 2000.
It is unclear why women with endocrine tumors survive >1
year longer than their male counterparts (37 versus 23
months). This finding suggests that hormonal factors may
affect endocrine pancreatic cancer survival, as they are also
related to the incidence of several other types of cancer(26, 27).
In addition, several studies have found an association between
hormones and reproductive factors and the incidence of
exocrine pancreatic cancer. In the Nurse’s Health Study,
increased parity was significantly associated with a reduced
risk of exocrine pancreatic cancer, with an average of 10%
reduction in risk associated with each additional birth (28). In
the Enhanced Cancer Surveillance project based in Canada,
use of oral contraceptives was associated with a 0.36-fold (95%
CI, 0.13-0.96) reduction in risk of exocrine pancreatic cancer
(29). No epidemiologic study to date has investigated the role
of hormonal factors in relation to endocrine pancreatic cancer
risk, and no study has addressed the association between
hormonal factors and pancreatic cancer survival. Furthermore,
no prior studies have compared survival in men versus
women diagnosed with different pancreatic cancer histologies.
Thus, additional investigations aimed at furthering our
understanding of the etiology of endocrine pancreatic tumors,
especially differential risk by gender, are needed.
Cancer Epidemiol Biomarkers Prev 2005;14(7). July 2005
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1772 Pancreatic Cancer Survival by Histologic Type
This analysis provides evidence of increased mortality risk
among Blacks with exocrine pancreatic cancer compared with
Whites. Previous analyses have not found consistent differences in pancreatic cancer mortality by race, including two
studies using SEER data (30, 31). Unlike the results reported
here, neither of these studies used SEER data from all nine
registries in operation from 1973 to 2000. One of these studies
found a higher incidence of pancreatic cancer in Blacks than
Whites but reported no difference in risk of mortality (30).
This is in contrast to our findings of a HR of 1.11 (95% CI,
1.07-1.15) and 1.33 (95% CI, 1.16-1.53) for Blacks compared
with Whites with adenocarcinoma and mucinous tumors,
respectively. The difference may be attributable to the fact
that the previous study excluded all cases with unknown
treatment, which constituted 41.6% of our sample. In a study
using SEER centers with a large proportion of Asians,
unadjusted median survival was longer in Asians than
Whites, a finding that is not consistent with our results. This
difference could be due to the inclusion of cases with
unknown tumor stage in that study (11.1% of their sample;
ref. 31), whereas we excluded such cases. Also in that study,
median survival time in pancreatic cancer cases was slightly
shorter among Black women than White women after
adjustment for age, diagnosis year, tumor stage, tumor grade,
and morphology, in agreement with our unadjusted median
survival results. If the increased mortality risk for pancreatic
cancer in Blacks is confirmed in future studies, there are at
least two possible explanations to consider.
First, poorer health outcomes for Black versus White cancer
cases have been reported in many types of cancer, including
colorectal, breast, lung, and prostate cancers (32). Furthermore,
a higher proportion of Black Americans than White Americans
have no health insurance (33), and uninsurance or underinsurance has been associated with decreased survival time in
several cancer types (34-36). These trends might also be
expected to apply to pancreatic cancer cases. However, SEER
does not collect data on social or economic variables; thus, it
was not possible to investigate the interaction of socioeconomic risk factors with race on survival in this data set. In addition,
prognostic biomarker profiles may vary between Whites and
Blacks. Cases with K-ras mutations in the paraortic lymph
nodes have shorter survival times than cases with lymph
nodes free of K-ras mutations (37). Although the proportion of
cases with K-ras mutations was similar in Whites and Blacks in
one study (38), the prognostic value of specific K-ras and other
mutations in Blacks and Whites warrant investigation as
possible mechanisms influencing survival.
In this study, among partial or complete pancreatectomy or
other cancer-directed surgery recipients, median survival was
considerably greater than among cases receiving no cancerdirected surgery, no surgery, and with unknown surgery
status in all histologic types. Previous research on pancreatic
cancer survival has focused on cohorts of patients who have
undergone pancreatic resection, rather than all diagnosed
cases. For example, a recent study of pancreatic adenocarcinoma patients who underwent pancreatic resection reported a
median survival of 13.6 months and a 5-year survival of 14.6%
(14). In that study, treatment type, large tumor size, advanced
stage, and high grade were each associated with decreased
5-year survival. This result is similar to our finding that tumors
diagnosed at an advanced stage were associated with an
increased risk of mortality and concurs with our report of a
13-month median survival in adenocarcinoma cases undergoing pancreatectomy.
The survival analyses conducted here, comparing cancerdirected surgery recipients with patients receiving no surgery,
suggest that surgery increases survival time. However, surgery
is generally offered to patients who have a better prognosis
and less advanced disease. Thus, even if surgery conveyed no
true survival benefit, the subgroup of patients who receive
surgery are likely to live longer than those patients who were
not surgical candidates. Adjustment for stage may not be
sufficient to remove this bias, because prognosis can vary
within each tumor stage. In addition, the proportion of patients
who did not receive surgery varied between histologic types;
thus, a direct comparison of surgery effects between histologic
types is probably not valid. Whereas this analysis may
overestimate the quantitative benefit of surgery, the large
reduction in risk of mortality and increase in median survival
in all histologic types suggests that surgery provides a survival
benefit to pancreatic cancer patients.
Another implication of the results presented here is that the
high case fatality rate of pancreatic cancer may introduce bias
into population-based studies of cancer survivors, caused by a
combination of recruitment of cases with less rapidly fatal
pancreatic cancer types, and the unavailability of patients with
more advanced disease. In particular, studies that recruit
survivors of pancreatic cancer are likely to overrepresent cases
with endocrine tumors and underrepresent cases with adenocarcinoma. Recent data analyses from the Cancer Genetics
Network, a multisite national registry, illustrate this important
bias (39). The Cancer Genetics Network uses SEER to identify
cancer cases from six different cancer sites: melanoma,
pancreatic, kidney, lung, thyroid, and non-Hodgkin’s lymphoma, using identical recruitment and data collection methods
for all cancer sites. Cancer Genetics Network researchers found
that response rates (number of completed interviews over
number of possibly eligible respondents) vary dramatically
among the six cancer sites, from a low of 23% for pancreatic
cancer to 51% for kidney cancer to 74% for bladder cancer. A
major reason for this variation is the number of deceased
cancer patients by the time of attempted contact. In contrast,
completion rates (number of completed interviews divided by
the number of eligible, contacted respondents) among patients
from the six cancer sites varied much less, with a range of 78%
to 96%. These results underscore the importance of rapid case
recruitment strategies in pancreatic cancer research to better
understand the underlying causes of all forms of pancreatic
cancer. Conversely, it is important for physicians to realize that
there are less fatal forms of pancreatic cancer that may benefit
from surgery. For example, endocrine tumor cases who do not
receive surgery have a median survival time of 21 months, but
median survival time increases to 97 months among those
cases who receive a pancreatectomy.
Whereas the population-based design of this study enhances
the generalizability of its results, the noncentralized nature of
SEER data collection at different geographic sites is a limitation
of this study. Reviews of pathology reports and the recording
of histology codes was conducted by a large number of SEER
staff over 28 years at nine sites, using medical records and
death certificates with varying levels of completeness and
accuracy. In addition, histopathologic diagnoses were made by
a large number of pathologists and physicians, with perhaps
different methods of diagnosing pancreatic tumors and
classifying their histology. Thus, there is likely to be some
degree of misclassification not only by histologic type but also
for the other variables collected by SEER that were used in this
analysis. This data set is also limited by the small number of
available potential confounding variables that could be related
to survival following a pancreatic cancer diagnosis such as
smoking status, alcohol use, comorbidities such as diabetes,
access to health care, and socioeconomic status. Furthermore, it
is important to note that excluding 14,455 cases with no known
histology could bias the results, if survival time or underlying
histologic type is related to missing data for the histology
variable. It is possible that cases who die quickly may be more
likely to have an unrecorded histologic type because they
undergo fewer diagnostic procedures before dying. Thus,
excluding these cases from the survival analyses may result in
an overestimation of survival time for pancreatic cancer cases
Cancer Epidemiol Biomarkers Prev 2005;14(7). July 2005
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Cancer Epidemiology, Biomarkers & Prevention 1773
overall. However, if the distribution of underlying histologic
types is similar both in cases with known and unknown
histology, then the between-histologic type comparisons are
valid.
In summary, this large, population-based, quantitative
analysis confirms the clinical observation of increased median
survival time in endocrine pancreatic cancer compared with
either pancreatic adenocarcinoma or mucinous pancreatic
tumors (27 versus 4 months, respectively). Furthermore, a
larger percentage of endocrine than exocrine cases survived at
all time points up to 5 years after diagnosis. Among patients
with endocrine tumors, women survived substantially longer
than men (37 versus 23 months, respectively). Within
histologic types, advanced tumor stage, older diagnosis age,
surgery, and Black race were associated with increased risk of
mortality, whereas female sex and more recent year of
diagnosis were associated with decreased risk. Although
selection bias may be present, the results also suggest that
surgery provides survival benefit. Better understanding of
these differences in survival could contribute to identifying the
underlying causes of pancreatic cancer and increasing survival
among all histologic types.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
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Differences in Survival by Histologic Type of Pancreatic
Cancer
Megan Dann Fesinmeyer, Melissa A. Austin, Christopher I. Li, et al.
Cancer Epidemiol Biomarkers Prev 2005;14:1766-1773.
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