ORIGINAL ARTICLE – PANCREATIC TUMORS
Impact of Tumor Grade on Prognosis in Pancreatic Cancer:
Should We Include Grade in AJCC Staging?
Nabil Wasif, MD1, Clifford Y. Ko, MD, MSHS2,3, James Farrell, MD4, Zev Wainberg, MD5, Oscar J. Hines, MD2,
Howard Reber, MD2, and James S. Tomlinson, MD, PhD2,3
1John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA;2Department of Surgery, David Geffen
School of Medicine at UCLA, Los Angeles, CA;3Department of Surgery, Greater Los Angeles VA Healthcare System, Los
Angeles, CA;4Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA;5Division of
Hematology, David Geffen School of Medicine at UCLA, Los Angeles, CA
Background. AJCC staging of pancreatic cancer (PAC) is
used to determine prognosis, yet survival within each stage
shows wide variation and remains unpredictable. We
of this variation and that the addition of grade to current
AJCC staging would provide improved prognostication.
Methods. The Surveillance,
Results (SEER) database (1991–2005) was used to identify
8082 patients with resected PAC. The impact of grade on
overall and stage-specific survival was assessed using Cox
regression analysis. Variables in the model were age, sex,
tumor size, lymph node status, and tumor grade.
Results. For each AJCC stage, survival was significantly
worse for high-grade versus low-grade tumors. On multi-
variate analysis, high tumor grade was an independent
predictor of survival for the entire cohort (hazard ratio
[HR] 1.40, 95% confidence interval [95% CI] 1.31–1.48) as
well as for stage I (HR 1.28, 95% CI 1.07–1.54), stage IIA
(HR 1.43, 95% CI 1.26–1.61), stage IIB (HR 1.38, 95% CI
1.27–1.50), stage III (HR 1.28, 95% CI 1.02–1.59), and
stage IV (HR 1.58, 95% CI 1.21–2.05) patients. The
addition of grade to staging results in a statistically sig-
nificant survival discrimination between all stages.
Conclusions. Tumor grade is an important prognostic
variable of survival in PAC. We propose a novel staging
Epidemiology, and End
system incorporating grade into current AJCC staging for
pancreas cancer. The improved prognostication is more
reflective of tumor biology and may impact therapy deci-
sions and stratification of future clinical trials.
The American Joint Commission on Cancer (AJCC)
tumor node metastasis (TNM) staging system is the ‘‘lan-
guage of cancer’’ by which physicians communicate about
the disease process.1Staging ensures an objective, repro-
ducible classification of the extent of disease and is our
most important determinant of treatment recommendations.
For research purposes, clinical trials depend on staging for
appropriate patient stratification upon which accurate
measurement of the treatment effect under study can be
performed. Perhaps most importantly to the patient, staging
is our best tool to provide prognostic information in our
effort to manage patient expectations in the context of a
suggested treatment plan.
Current staging for pancreatic cancer is based on the 6th
edition of the AJCC Cancer Staging Manual, published in
2002 (Table 1).2This update has been validated for pan-
creatic cancer using the National Cancer Database (NCDB)
and shown to have good survival discrimination between
stages.3However, because survival within a particular
stage is highly variable, the Memorial Sloan Kettering
Cancer Center (MSKCC) developed a nomogram to better
predict the likelihood of disease-specific survival after
initial resection for pancreatic carcinoma.4This nomogram
incorporates additional factors into the predictive model
not included in traditional TNM staging, one of which is
the degree of differentiation or grade of the tumor. Pre-
dictions by the nomogram discriminated better than AJCC
stage, suggesting that incorporation of additional variables
No financial disclosures or conflicts of interest for any of the authors.
? The Author(s) 2010. This article is published with open access
First Received: 19 April 2009;
Published Online: 27 April 2010
J. S. Tomlinson, MD, PhD
Ann Surg Oncol (2010) 17:2312–2320
would improve accuracy. This nomogram was indepen-
dently validated by the group at Massachusetts General
Hospital on a cohort of 424 patients.5
Several other multivariate analyses have shown that
tumor grade is an important prognostic indicator after
resection of pancreatic cancer.6–11Grade is a measure of the
degree of differentiation of the tumor. Differentiation refers
to the morphologic and functional resemblance between a
tumor cell and a normal cell of the same tissue. Malignant
neoplasms range from well differentiated (low grade) to
undifferentiated (high grade); in general, the more undif-
ferentiated the tumor, the more aggressive the malignant
biology.12For pancreatic adenocarcinomas, histologic
grade is based on the extent of glandular differentiation. If
[95% of the tumor is composed of glands then it is clas-
sified as being well differentiated, 50%–95% is moderately
differentiated, and\50% is poorly differentiated.2
The aim of this study was to use a population-based
database providing significant power to assess the impact of
tumor grade on prognosis after resection for pancreatic
cancer. We hypothesized that some of the variability in
survival within the same AJCC stage might be the result of
differences in tumor grade. Our goal was to assess the
significance of tumor grade as a predictive factor indepen-
dent of known adverse predictors of survival. Furthermore,
we sought to develop a novel staging system that would
incorporate grade into the existing TMN system in hopes of
providing improved staging that is more reflective of the
underlying tumor biology and associated survival.
The National Cancer Institute’s Surveillance, Epidemi-
ology, and End Results (SEER) tumor registry database was
used for this study. SEER contains more than 3 million
cases from 17 geographic sites, covering approximately
26% of the U.S. population. The database was designed to
reflect the overall characteristics of the U.S. population and
is regarded as a model population-based tumor registry.
Quality control is an important component of the SEER
program; the current standard for accuracy of the data in the
registry is an error rate of less than 5%.13SEER Program
registries routinely collect data on patient demographics
(e.g., age, sex), primary tumor characteristics (e.g., size,
extent, grade), nodal staging (number of nodes examined,
number of positive nodes), surgery performed (pancreati-
coduodenectomy vs distal pancreatectomy), vital status, and
survival. Although information on radiation therapy is
recorded, no information on chemotherapy is reported. The
November 2007 update was used for this study, providing
TABLE 1 American Joint
Committee on Cancer (AJCC)
6th edition TNM staging system
for pancreatic cancer
T stage (primary tumor)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor limited to pancreas and B2 cm
Tumor limited to pancreas and[2 cm
Tumor extends beyond pancreas
T4 Tumor extends beyond pancreas and involves the celiac axis or superior mesenteric artery
N stage (regional lymph nodes)
NXRegional nodes cannot be assessed
N0No regional lymph node metastasis
N1 Regional lymph node metastasis
M stage (distant sites)
MXDistant metastasis cannot be assessed
Stage 0TisN0 M0Localized
Stage IA T1N0M0 Localized
Stage IBT2N0 M0 Localized
Stage IIA T3 N0M0 Locally invasive
Stage IIB T1–3N1M0 Locally invasive
Stage III T4 Any NM0 Unresectable
Stage IVAny T Any NM1 Distant metastasis
Grade in Pancreatic Cancer 2313
information from 1973 to 2005.14As a population-based
study with no patient identifiers involved, our study was
exempt from institutional research board review.
The study period was from 1991 to 2005. The ICD-10
histology codes 8000, 8010, 8020, 8021, 8140, 8141, and
8500 were used to identify all patients with a diagnosis of
adenocarcinoma of the pancreas. Patients who did not
undergo cancer-directed surgery were excluded from the
analysis. Also excluded were patients with no histological
confirmation of the diagnosis and cases identified from
autopsy reports only. Although no specific field for AJCC
stage in pancreatic cancer is provided in the SEER data-
base, the information to accurately stage patients is present
in other data fields. Using extent of disease (EOD) data
fields, we were able to determine stage according to the 6th
edition of the AJCC Staging Manual, as our group and
others have done so previously.15,16Complete TNM data
were available for 7627 out of 8082 patients (94.4%) using
the EOD codes. In the SEER database, tumor grade is
coded as 1 (well differentiated), 2 (moderately differenti-
ated), 3 (poorly differentiated), or 4 (undifferentiated).
Tumor grade was recorded for 7086 out of 8082 patients
Kaplan–Meier curves and log-rank tests were used to
identify differences in overall survival, defined as duration
of survival after initial resection of pancreatic carcinoma.
Predictors of survival after surgical resection for the entire
cohort were identified by Cox regression analysis using
proportional hazards modeling. Variables included in the
model were age, sex, tumor size, lymph node status, and
tumor grade. Only patients with complete data were
included in the multivariate analysis. Thus, 5935 of 8082
patients were eligible for inclusion in the multivariate
analysis. A separate multivariate analysis was performed to
identify predictors of survival for stages I, IIA, IIB, III, and
IV individually. Stages IA and IB were combined together
to ensure adequate numbers for analysis. For stages I, IIA,
and IIB variables in the model were age, sex, tumor size,
and tumor grade only. Lymph node status was not included
because by definition all patients in stages I and IIA are
node negative and patients in stage IIB are node positive.
In our study, grade was redefined as a dichotomous, cate-
gorical variable: tumor grades 1 (well differentiated) and 2
(moderately differentiated) were combined into a ‘‘low-
grade’’ group and tumor grades 3 (poorly differentiated)
and 4 (undifferentiated) into a ‘‘high-grade’’ group. Cate-
gorical variables were compared between low-grade and
high-grade groups using chi-square analysis. Differences
between continuous variables were determined using t test.
Significance levels were set at P\.05 and confidence
intervals were 95%. All tests were two-tailed. Predictors of
high tumor grade were identified using logistic regression
analysis. Factors included in the model were sex, tumor
size, lymph node status, and presence of extrapancreatic
invasion. Patients with incomplete data were excluded
from regression analysis. All statistical analysis was per-
formed using SPSS 16.0 statistical software (SPSS Inc.,
Our study population consisted of 8082 patients who
underwentresection of pancreatic
Demographic, tumor, and treatment characteristics of the
entire cohort as well as low-grade and high-grade groups
are detailed in Table 2. A total of 996 (12%) patients did
not have tumor grade recorded. Significant differences
were seen between the high-grade and low-grade cohort
with regard to sex, tumor size, lymph node involvement,
number of positive nodes, AJCC stage, and reception of
For each AJCC stage classification, survival was sig-
nificantly worse with high-grade (3 or 4) versus low-grade
(1 or 2) tumors (Fig. 1). Multivariate analysis of the entire
cohort identified the following independent predictors of
adverse outcome: increasing age, male sex, tumor size
[2 cm, lymph node positivity, and high tumor grade.
Importantly, the hazard ratio (HR) associated with high
tumor grade (HR = 1.4) was of a similar magnitude and
significance when compared with tumor size (HR = 1.37)
and node status (HR = 1.38). When each stage was ana-
independent predictor of survival across all stages
(Table 3). Interestingly, in the stage IV patients who
underwent a resection, grade was the only independent
prognostic variable (HR = 1.58).
Predictors of high tumor grade were tumor size[2 cm
(odds ratio [OR] 1.39, 95% confidence interval [95% CI]
1.18–1.65, P\.001), positive lymph nodes (OR 1.24, 95%
CI 1.08–1.42, P = .002), and peripancreatic invasion (OR
1.20, 95% CI 1.03–1.41, P = .02). Female sex was a
protective factor (OR .85, 95% CI .74–.97, P = .013).
Tumor grade (G) was incorporated into AJCC (TNM)
staging system to generate a novel TNMG staging system
for 6862 out of 8082 patients (84.9%). This TNMG staging
differs from the AJCC staging by advancing a patient to the
next higher stage level in the presence of high tumor grade
(Table 4). For instance a high-grade stage IIA tumor in the
TNM staging system would now be a stage IIB tumor in
grade remained an
2314N. Wasif et al.
the novel TNMG system. By restaging patients in this
manner, the impact of grade on survival can be realized, as
demonstrated by a 2-month improvement in median sur-
vival of stage IIA patients simply by advancing patients
with high-grade tumors and associated worse survival into
stage IIB. Excellent discrimination in overall survival
between stages is also seen in this novel TNMG staging
classification and appears to be durable throughout all time
points as the curves remain separate through 5 years
The aim of this study was to use a population-based
tumor registry to assess the impact of tumor grade on
prognosis after surgical resection for pancreatic cancer. We
believe that the variability in survival within each AJCC
stage may be attributed to factors not currently incorpo-
rated into the staging system, one of which is tumor grade.
Our data show that within each AJCC stage, high tumor
grade is an independent and significant predictor of adverse
TABLE 2 Demographic,
tumor and treatment
Percentages may not add up to
100 due to rounding
AJCC American Joint
Committee on Cancer
aLow grade included grades 1
and 2; high grade included
grades 3 and 4. Excluded from
these 2 columns were 996
patients for whom data were
Demographics All patients
(n = 8082)
(n = 4491)
(n = 2595)
Mean ± SD 65.2 ± 11.065.2 ± 10.865.3 ± 10.9
Black9.9 9.9 9.2
Tumor location (%)NS
Head85.6 85.7 85.4
Tail 9.4 9.19.7
Type of surgery (%)NS
Whipple procedure 82.482.282.7
Distal pancreatectomy 9.39.4 9.2
Total pancreatectomy 18.104.22.168
Tumor size (cm)
Mean ± SD 3.5 ± 1.9 3.4 ± 1.83.7 ± 2.1
Lymph node status (%)
AJCC state (%)
IA 4.3 5.22.7
III 6.86.5 7.4
IV 6.75.2 9.1
Number of nodes examined NS
Mean ± SD 9.8 ± 8.09.8 ± 8.0 9.8 ± 8.0
Median 8.08.0 8.0
Number of positive nodes .006
Mean ± SD 2.9 ± 2.6 2.9 ± 2.5 3.1 ± 2.7
Radiation (%) .001
Yes 42.7 44.240.2
Grade in Pancreatic Cancer 2315
outcome. When patients are restaged with grade incorpo-
rated into a novel TNMG staging system, excellent
discrimination in survival between stages is seen.
The largest series on surgical resection for pancreatic
cancer in the literature includes 1423 patients who under-
went pancreaticoduodenectomies at the Johns Hopkins
Medical Institutions.8Among other variables, the authors
report histologic grade as an independent predictor of
survival on multivariate analysis, with a hazard ratio of 1.6.
Other single-institution studies have confirmed this on both
univariate and multivariate analysis with a hazard ratio that
varies between 1.14 and 2.56.9–11Our population-based
a. Stage I
Low grade, n = 605, median 25 mos.
High grade, n = 245, median 17 mos.
p = 0.001
40 50 2030 10
b. Stage IIA
Low grade, n = 1122, median 18 mos.
High grade, n = 577, median 13 mos.
p = 0.000
40 502030 10
c. Stage IIB
Low grade, n = 2103, median 15 mos.
High grade, n = 1295, median 11 mos.
p = 0.000
40 5020 30 10
d. Stage III
Low grade, n = 281, median 13 mos.
High grade, n = 188, median 9 mos.
p = 0.016
40 5020 30 10
e. Stage IV
Low grade, n = 226, median 8 mos.
High grade, n = 232, median 5 mos.
p = 0.000
FIG. 1 Kaplan-Meier survival curves stratified by grade for patients with stage I (a), stage IIA (b), stage IIB (c), stage III (d), and stage IV (e)
2316N. Wasif et al.
study reports a hazard ratio of 1.40 for high tumor grade,
which falls well within the range reported in the literature.
Largely in concert with published studies, we found
tumor size [2 cm, lymph node positivity, age, and male
sex as adverse prognostic factors for the entire cohort.
Tumor size and lymph node involvement are well-known
prognostic indicators for pancreatic cancer and, along with
distant metastases, form the trifecta of the current TNM-
based AJCC staging for pancreatic cancer. Many studies
have shown that patients with a tumor larger than 2 cm or
lymph node involvement have a significantly lower median
and 5-year survival.6–11,17–21Other studies show that
patients who are elderly have a worse outcome than
younger patients after surgical resection of pancreatic
cancer.22,23Similarly, we also show that males have poorer
survival than females, which may be related to the presence
of lower-grade tumors in females as demonstrated by our
Especially pertinent to the context of our study are
clinical trials for adjuvant treatment of pancreatic cancer.
In the CONKO-001 trial of adjuvant gemcitabine versus
observation after resection of pancreatic cancer, the median
overall survival was 22.8 months in the gemcitabine group
and 20.2 months in the observation group (P = .005).24
Similarly in the ESPAC-1 trial, adjuvant chemotherapy
with 5-fluorouracil/leucovorin had a statistically significant
benefit over observation with respect to median survival
(20.1 vs 15.5 months, P = .009).25Lastly, the RTOG 97–
04 trial randomized patients to chemoradiotherapy using
5FU versus chemoradiotherapy with gemcitabine. The
results demonstrated a 3.7-month difference in median
survival in favor of the chemoradiotherapy/gemcitabine
TABLE 3 Cox regression analyses
Patient groupHazard ratio (95% CI)
Entire cohort (n 5 5935)
Male 1.07 (1.00–1.13) .035
Positive 1.38 (1.30–1.47)
Tumor size (cm)
Stage I (n 5 845)
Tumor size (cm)
1.50 (1.17–1.91) .001
\.001 1.72 (1.31–2.26)
High 1.28 (1.07–1.54) .007
Stage IIA (n 5 1501)
Tumor size (cm)
Stage IIB (n 5 3140)
Tumor size (cm)
TABLE 3 continued
Patient group Hazard ratio (95% CI)
Stage III (n 5 384)
1.19 (.86–1.64) .29
1.81 (1.28–2.57) .001
High1.28 (1.02–1.59) .032
Stage IV (n 5 270)
n = patients with all variables available for regression analysis
Grade in Pancreatic Cancer2317
regimen.26In none of these trials were patients stratified by
grade. Given the magnitude of difference in median sur-
vival in these adjuvant trials and the potential impact of
grade on survival, it is feasible that stratifying upon grade
could alter the median survival difference and possibly the
significance of these trial results. We have shown that
stratifying AJCC stage IIB resected tumors (node positive)
by grade demonstrates a 4-month improvement in median
survival for node-positive, low-grade tumors compared
with node-positive, high-grade tumors, which is compara-
ble to the difference in median survival seen in the trial
results quoted previously. Some may argue that randomi-
zation would automatically adjust for this factor; however,
given the degree to which most trials in pancreatic cancer
are underpowered, the risk for bias resulting from inaccu-
rate stratification becomes much greater with such an
influential factor such as grade. This study shows that high
tumor grade (HR 1.40) has a larger impact on survival than
both node positivity (HR 1.38) and tumor size[2 cm (HR
1.37), both of which are part of the current AJCC staging
system and are used to risk stratify patients routinely.
Our data make a strong case for inclusion of tumor grade
into current staging for pancreatic cancer; therefore, we
proposed a novel TNMG staging system. With the addition
of grade to the current AJCC staging system, we are better
able to tease out the ‘‘best case scenario’’ patients in stage
IA (low-grade tumors,\2 cm, node negative and localized
to the pancreas) and show an improvement in median
survival of 3 months compared with stage IA in TNM
staging (\2 cm, node negative and localized). We can also
identify the ‘‘bad actors’’ in stage IIA (high-grade tumors,
node negative, and locally invasive) and move them to
stage IIB in TNMG staging; again an improvement in
median survival of 2 months compared with stage IIA in
TNM staging. Furthermore, dividing stage IV patients into
stage IVA (low grade with median survival 8 months) and
stage IVB (high grade with median survival 5 months)
provides better risk stratification in the very patient popu-
lation most likely to enroll in future clinical trials to
evaluate potential new therapies. Moreover, in support of
ourcontention that discrimination
improved with TNMG staging, the overall ‘‘spread’’ in
median survival for TNMG staging is 25 months (range
5–30 months), which compares with 21 months with TNM
staging (range 6–27 months).
TABLE 4 Restaging according
to TNMG classification
0 70 60
405020 30 10
IA IB IIA IIBIII
FIG. 2 Kaplan-Meier survival curves based on TNMG classification
showing excellent discrimination between stages
2318N. Wasif et al.
Importantly, we demonstrate that not only does addition
of tumor grade makes sense given its significant and
independent impact on survival, but it can be added to the
existing TNM staging system in a relatively simple man-
ner. In other words, the novel TNMG staging system
proposed does not create a more complex staging system
but rather builds upon the existing AJCC staging system
with improved reflection of the underlying biology and
associated impact on survival. This is not a trivial point as
more complex staging systems such as the previously
mentioned nomograms have not been widely adopted in
spite of improved prognostication.
Tumor grade is already part of staging for prostate
cancer, sarcomas, and certain bone tumors. For a prog-
nostic factor to be included in the staging system, it must
explain some of the heterogeneity associated with the
expected course and outcome of a disease.1Our analysis
shows that tumor grade in pancreatic cancer meets this
criterion. Pathology studies of pancreatic cancer have
examined a scoring system based on grade, similar to
Gleason score for prostate cancer, and have shown good
predictive ability as well as reproducibility.27Similarly
Eltoum et al. devised a cytologic grading system for biopsy
specimens obtained by endoscopic ultrasound-guided fine-
needle aspiration to predict survival in patients with pan-
The use of population-based data has several inherent
limitations. Even though the database is checked regularly
for discrepancy and reportedly has 95% accuracy, the
possibility of coding errors remains. Furthermore, we
cannot account for variability among SEER regions in
pathology protocols used to assess tumor grade, as well as
interobserver variability among pathologists. As mentioned
previously, no information on chemotherapy is provided in
the database so we were unable to assess the impact of
adjuvant therapy. Additionally, margin status is not recor-
ded in SEER. Nevertheless, the use of a population
database enables us to study a large contemporary sample
of patients and make significant statistical conclusions
relevant to the general population, which is not possible in
In this study we use the SEER cancer registry to show
that tumor grade is a significant and independent prog-
nostic factor for survival after resection of pancreatic
adenocarcinoma. In fact, high tumor grade has a greater
impact on survival in pancreatic cancer than known poor
prognostic factors such as lymph node positivity and tumor
size, which form the basis of our current staging system.
We believe inclusion of tumor grade into AJCC staging for
pancreatic cancer would enhance the current system and
provide better survival prognostication reflective of the
aggressive biology associated with high-grade tumors.
These findings may have implications for adjuvant therapy
decision making as well as risk stratification of patients
entering future clinical trials.
(Goldschmied) Research Laboratories of the John Wayne Cancer
Institute at Saint John’s Health Center. Supported by funding from
QVC and the Fashion Footwear Association of New York Charitable
Foundation (New York, NY), the Margie and Robert E. Petersen
Foundation (Los Angeles, CA), Mrs. Lois Rosen (Los Angeles, CA),
and the Associates for Breast and Prostate Cancer Studies (Santa
Monica, CA). Supported by funding from the Family of Robert Novick
(Los Angeles, CA), Ruth and Martin H. Weil Fund (Los Angeles, CA),
and the Wrather Family Foundation (Los Alamos, CA).
Supported by grants from the Gonda
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
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