Poorly differentiated resectable pancreatic cancer: Is upfront resection worthwhile?

Article (PDF Available)inSurgery 152(3 Suppl 1):S112-9 · July 2012with80 Reads
DOI: 10.1016/j.surg.2012.05.017 · Source: PubMed
Abstract
Poorly differentiated, resectable pancreatic ductal adenocarcinoma is associated with early recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocarcinoma according to histologic grading. A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma between 1990 and 2008 were analyzed via the use of different histologic grading. Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients. Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%, respectively. Only the presence of symptoms was a significant clinical predictor of G3 status (P = .035). G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2, and G3 neoplasms (P < .0001). Median disease-free survival was 63, 14, and 9 months for G1, G2, and G3 pancreatic ductal adenocarcinoma (P < .0001). Adjuvant therapy improved disease-specific survival in G2 (P < .04) and G3 (P < .0001) pancreatic ductal adenocarcinoma, with a greater survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116). G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3 PDAC can be considered as possible targets for neoadjuvant treatment.
Poorly differentiated resectable
pancreatic cancer: Is upfront resection
worthwhile?
Stefano Crippa, MD,
a,c
Stefano Partelli, MD,
a,c
Giuseppe Zamboni, MD,
b
Giuliano Barugola, MD,
a,c
Paola Capelli, MD,
b
Marco Inama, MD,
a
Claudio Bassi, MD,
a
Paolo Pederzoli, MD,
a
and
Massimo Falconi, MD,
a
Verona and Negrar, Italy
Background. Poorly differentiated, resectable pancreatic ductal aden ocarcinoma is associated with early
recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate
clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocar-
cinoma according to histologic grading.
Methods. A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma
between 1990 and 2008 were analyzed via the use of different histologic grading.
Results. Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3)
pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients.
Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific
survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%,
respectively. Only the presence of symp toms was a significant clinical predictor of G3 status (P = .035).
G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural
invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2,
and G3 neoplasms (P < .0001). Median disease-free survival was 63, 14, and 9 months for G1, G2,
and G3 pancreatic ductal adenocarcinoma (P < .0001). Adjuvant therapy improved disease-specific
survival in G2 (P < .04) and G3 (P < .0001) pancreatic duc tal adenocarcinoma, with a greater
survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116).
Conclusion. G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival
after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is
greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3
PDAC can be considered as possible targets for neoadjuvant treatment. (Surgery 2012;152:S112-9.)
From the Departments of Surgery,
a
and Pathology,
b
University of Verona, Verona, Italy; and Clinical and
Research PhD Program in Surgery,
c
University of Verona and Ospedale ‘‘Sacro Cuore-Don Calabria,’’ Negrar
(VR), Italy
THE OPTIMAL APPROACH of localized pancreatic ductal
adenocarcinoma (PDAC) represents an area of in-
tense investigation. Operative resection is the only
treatment with potentially curative intention, but
the survival benefit afforded by pancreatectomy
alone is minimal.
1-4
In resected PDAC, T stage, N
and R status, and tumor grade are the main
prognostic factors for survival.
1-20
The ability of
the patient to receive adjuvant therapy after resec-
tion is a favorable predictor of survival as well.
21-23
Notwithstanding, limited improvements in long-
term survival have been observed in large clini cal
trials of adjuvant therapy.
21,24-28
Nevertheless,
20–30% of resected patients will die of disease
within 12 months from resection, even if adjuvant
therapy is delivered.
4
These deaths can be attrib-
uted to aggressive neoplasms with unrecognized
or rapidly progressive metastatic disease.
In the last decade, it has become clear that most
patients with resectable PDAC have micrometastatic
disease at diagnosis.
29
Neoadjuvant chemotherapy
or chemoradiation offers ear ly treatment for micro-
metastases, limiting operative exploration to
patients with stable or responding disease.
29-31
No
randomized, controlled trial, however, has demon-
strated the superiority of preoperative over
Giuseppe Zamboni and Massimo Falconi are currently Chair-
men of the Departments of Pathology and Surgery, Ospedale
‘Sacro Cuore-Don Calabria,’ Negrar (VR), Italy.
Accepted for publication May 11, 2012.
Reprint requests: Stefano Crippa, MD, Department of Surgery,
Ospedale ‘Sacro Cuore-Don Calabria,’ University of Verona,
Via Don Sempreboni, 5-37024 Negrar (VR), Italy. E-mail: ste.
crippa@libero.it.
0039-6060/$ - see front matter
Ó 2012 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.surg.2012.05.017
S112 SURGERY
postoperative treatment, and indications for neoad-
juvant versus adjuvant treatment are a matter of de-
bate.
21-23,29
In our experience, high preoperative
levels of CA 19.9, a long duration of symptoms,
and the presence of G3 neoplasms have been inde-
pendent predictors of early deaths.
4
Because G3
grading is associated with a poor prognosis in several
studies,
1-20
patients with resec table, poorly differen-
tiated PDAC may benefit from neoadjuvant treat-
ment. The aim of the present study is to describe
the clinicopathologic characteristics and survival
of PDAC according to histologic grading with a spe-
cific focus on poorly differentiated (G3) pancreatic
cancer.
METHODS
Prospectively collected data of patients who
underwent surgical resection for histologically
confirmed PDAC between January 1990 and Janu-
ary 2009 were reviewed retrospectively. Adenocar-
cinomas histological ly different from PDACC were
excluded from the present analysis as well as
invasive adenocarcinomas arising in the back-
ground of an intraductal papillary mucinous neo-
plasm. The following data were collected for each
patient: demographics (age and sex), presenting
symptoms, intraoperative and postoperative data,
complications, pathology, and information regard-
ing adjuvant chemotherapy and/or radiotherapy.
Diagnostic workup included a high-quality, com-
puted tomography and/or magnetic resonance
imaging, and laboratory tests including carcino-
embryonic antigen and CA 19.9. Formal pancreatic
resection was performed if intraoperative explora-
tion confirmed any of the following: (1) no distant
metastases; (2) no involvement of celiac trunk,
hepatic artery, or superior mesenteric artery; and
(3) no involveme nt of portal vein/superior mes-
enteric vein or encasement <1808 of these vessels.
Patients who underwent resection after neoadju-
vant chemotherapy/chemoradiation for stage IIB
or stage III PDAC were excluded from this study.
Postoperative mortality was defined as in-
hospital death or death within 30 days of opera-
tion. For the purpose of the study, patients who
died because of operative-related complications
were excluded from the analysis as well.
Intraoperative evaluation of the resection mar-
gins was performed routinely, and when positive,
the resection was extended whenever possible.
Quality of resection was determined according to
the R-classification by the International Union
Against Cancer. Tumor (T), nodal status (N) and
grade (G) were determined using standard TNM
classification according to AJCC classification.
32
Histopathologic grading of PDACC included
32,33
:
(1) G1, well-differentiated neoplasms; (2) G2,
moderately differentiated neoplasms; (3) G3,
poorly differentiated neoplasms. Undifferenti-
ated/anaplastic pancreatic carcinomas (n =7)
were excluded from the present analysis. After
2000, adjuvant treatment was considered in all pa-
tients who experienced a good recovery within 8
weeks from operation. According to ongoing clin-
ical trials, some patients were randomi zed in the
European Study Group for Pancreatic Cancer (ES-
PAC) 1 and ESPAC 3 clinical trials.
24,28
The follow-up schedule was described else-
where.
4
Recurrence was defin ed as the presence
of locoregional disease (ie, recurrence in the pan-
creatic remnant, peripancreatic tissue, or lymph
nodes metastases) or of metastatic disease (ie, liver
metastases, peritoneal carcinoma tosis) by radio-
logic imaging techniques. Tumor recurrence was
confirmed histologically whenever possible.
Follow-up was updated on June 2011.
Statistical analysis. Distributions of continuous
variables are reported as median and interquartile
range (IQR; 25th, 75th percentiles). Categorical
variables are presented as numbers and percent-
ages. The comparison between subgroups was
performed with the Student t test or Mann-
Whitney U test for continuous variables. Qualita-
tive data were comp ared by the v
2
test or Fisher
exact test when necessary. Disease-specific survival
(DSS) was defined as the time from resection to
disease-related death and was censored at the last
follow-up date if no events had occurred. Survival
probability was estimated according to the
Kaplan-Meier method. Univariate and multivariate
analyses were performed by the Cox regression
model to evaluate predictors of mortality. Statisti-
cal analyses were performed in SPSS 16.0 for Win-
dows software (SPSS Inc, Chicago, IL). P values
were considered significant when less or equal
than .05.
RESULTS
Study population and overall survival. During
the study period, 510 patients underwent resection
for a histologi cally confirmed PDAC. Eight pa-
tients (1.6%) died of operative-related complica-
tions and were excluded from the study. Of the
remaining 502 patients who constitute the study
population, 291 (58%) were males with a median
age of 63 years (IQR 55, 68 years). PDAC was
detected incidentally in 58 (11.5%) individuals.
The most common presenting symptoms included
jaundice (63%), abdominal pain (58%), weight
loss (53%), and new-onset or worsening diabetes
Surgery
Volume 152, Number 3S
Crippa et al S113
(20%). M edian serum CA 19.9 value was 110 U/
mL (IQR 28, 346 U/mL). Well-differentiated (G1)
neoplasms were found in 23 patients (4.5%),
moderately differentiated (G2) in 310 (62%),
and poorly differentiated in 169 (33.5%).
A logistic regression model showed that adju-
vant therapy, N status, grading, and R status were
independent predictors of DSS (Table I). At a me-
dian follow-up of 23 months, the median DSS was
24.5 months (95% confidence interval [95% CI]
21.8–27.2) for the entire cohort. The 1-, 2-, and
5-year DSS rates were 81%, 52%, and 21%, respec-
tively (Fig 1, A). The median disease-free survival
(DFS) was 13 months (95% CI 11.4–14.7). The
1-, 2, and 5-year DFS rates were 54%, 33% and
18%, respectively (Fig 1, B).
Clinical predictors of poorly differentiated (G3)
PDAC. On univa riate analysis, only the presence of
symptoms was a clinical predictor of G3 status (P =
.035; Table II). The rate of incidentally discovered
neoplasms was 35% for G1 PDAC, 12% for G2, and
7% for G3 PDACC (P < .001).
Perioperative and pathologic data in patients
with G1, G2, and G3 grading. Table III shows peri-
operative and pathologic data in the entire cohort
and in patients with G1, G2, and G3 neoplasms.
The most common operation was pancreatoduode-
nectomy, with an increased rate of distal pancreatec-
tomies in G1 group. Overall morbidity, abdominal
complications, pancreatic fistula, and adjuvant ther-
apy did not differ among the 3 groups.
In the entire cohort, 70% of patie nts underwent
adjuvant treatment according to different proto-
cols mainly based on gemcitabine or fluorouracil/
folinic acid. Twenty-two patients were enrolled in
the ESPAC-1 trial, whereas another 31 were ran-
domized to ESPAC-3. G1 neoplasms were smaller
in size than G2 (20 vs 30 mm, P = .013) and G3 (20
vs 28 mm, P = .002) PDAC. An R0 resection was
accomplished in 61% of patients, whereas R1 and
R2 margins were present in 29% and 10%, respec-
tively. There was a trend toward increased R2 resec-
tions from G1 (no R2 resection) to G2 (8%) and
G3 (15%) PDAC. The rate of T1/T2 tumor s was
significantly greater in G1 than G2 and G3 tumors,
whereas T4 PDAC was found only in these 2 latter
groups. Overall, 393 patients (78%) had lymph
node metastases. G3 neoplasms were characterized
by a greater rate of lymph node metastases and of
microvascular and perineural invasion.
Survival accordi ng to histologic grading and the
role of adjuvant therapy. After a median follow-up
of 23 months, the median DSS was 77 months
(95% CI 1.02–153.31) for G1, 26 months (95% CI
22.18–29.68) for G2, and 20 months (95%
CI 16.16–23.90) for G3 PDA C (P < .0001). The
1-, 2-, and 5-year DSS rates were 100%, 83%, and
56% for G1; 86%, 54%, and 19% for G2; and
67%, 40%, and 18% for G3 PDACC, respectively
(Fig 2, A).
Figure 2, B shows the DFS for G1, G2, and G3
PDAC. Median DFS was 63 months (95% CI 8.3–
118) for G1, 14 months (95% CI 11.8–16.2) for
G2, and 9 months (95% CI 6.9–11.1) for G3
PDCA (P < .0001). The 1-, 2-, and 5-year DFS rates
were 87%, 77% and 52% for G1; 52%, 34%, and
17% for G2; and 45%, 25% and 14% for G3
PDAC, respectively.
The impact on survival of adjuvant therapy was
different in the 3 groups. Among patients with G1
PDACC, adjuvant therapy did not improve DSS
(P = .251). In the G2 group, median DSS was 29
months in patients who underwent adjuvant treat-
ment and of 19 months in the absence of adjuvant
therapy (P = .039). This difference in DSS became
even more evident for patients with G3 neoplasms,
where median DSS was 22 months after resection
followed by adjuvant treatment compared with 12
months for patients who underwent surgical resec-
tion alone (P < .0001). Patients with G3 PDAC
undergoing adjuvant treatment had a 2-fold
survival-benefit compared with patients with G2
PDAC (hazard ratio 1.33 vs 2.11).
DISCUSSION
Despite our efforts to understand the biology of
PDAC and to improve approaches to treatment,
survival of patients with PDAC remains disappoint-
ing,
34,35
with 5-year survival rates after resection
with curative intent of <20%.
3,6,10,12-15
Indeed, in
the present study, the 5-year DSS 20.5% was the
same. Clinicians have pursued different strategies
to increase the number of long-term survivors.
First, pancreatic resections have become safe,
with low mortality rates of <5%.
2,6,9,36-38
Second,
different randomiz ed controlled trials have investi-
gated the rol e of adjuvant therapy in resected
PDAC.
24-28
Adjuvant treatment improves survival
compared with resection alone, but the median
overall survival ranged from 17 to 26 months,
24-28
with ‘early’ (within 12 months from resection) re-
currence rates of about 20–30%.
4
Third, some in-
vestigators have explored neoadjuvant treatment
as an alternative approach in resectable PDAC.
29-31
The rationale for neoadjuvant therapy includes
early treatment of micrometastatic disease, im-
provement of R0 resection rate, and identification
of patien ts with an aggressive tumor biology and/
or poor physiologic reserve in whom resection
offers no survival advantage.
Surgery
September 2012
S114 Crippa et al
Because indications for neoadjuvant therapy are
debated and this approach is still considered
investigational for patients with resectable PDAC,
the preoperative identification of the subset of
patients who are likely to benefit from neoadju-
vant treatment would be clinically important.
21
In
this light, a previous study from our Institution
showed that G3 grading, preoperative CA 19.9
Table I. Multivariate analysis of prognostic factors for disease-specific survival in the entire cohort of 502
patients with PDAC
Hazard ratio (multivariable) 95% CI P (multivariable)
Adjuvant therapy
No 1
Yes 0.543 0.422–0.699 <.0001*
CA 19.9 U/mL
<200 1
>200 1.136 0.898–1.436 .289
Histologic size, mm
<30 1
>30 1.317 1.024–1.693 .082
T stage
T1 1
T2 1.936 0.519–7.216 .325
T3 2.500 0.771–8.105 .127
T4 2.052 0.594–7.083 .256
N status
N0 1
N1 1.418 1.101–1.991 .009*
Perineural invasion
No 1
Yes 0.731 0.498–1.072 .109
Microvascular invasion
No 1
Yes 1.107 0.805–1.522 .533
Grading
G1 1
G2 2.245 1.147–4.394 .018 *
G3 3.118 1.576–6.168 .001 *
R status
R0 1
R1 1.504 1.164–1.944 .002*
R2 2.752 1.972–3.929 <.0001*
*Statistically significant.
CI, Confidence interval; PDAC, pancreatic ductal adenocarcinoma.
Fig 1. (A) Disease-specific survival for the entire cohort of 502 patients who underwent resection for histologically con-
firmed pancreatic ductal adenocarcinoma. (B) Disease-free survival for the entire cohort of 502 patients who underwent
resection for histologically confirmed pancreatic ductal adenocarcinoma.
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Volume 152, Number 3S
Crippa et al S115
level >200 U/mL, and preoperative symptoms of
more than 40 days were independent predictors
of early death.
4
Histologic G3 grading has been
recognized largely as an independent, poor prog-
nostic factor for PDAC.
1-20
In this study, we sought
to investigate the cl inicopathologic characteristics
and survival of resected PDAC according to tumor
grading and analyzing G3 PDAC in particular. As
expected, multivariate analysis identified adjuvant
therapy, N status, R status, and histologic grading
as independent predictors of DSS for the entire
cohort.
Our data showed that well-differentiated histo-
logic grading is an uncommon finding in patients
with PDAC. In this group of 502 resected patients,
only 23 (4.5%) had a G1 neoplasm; the remaining
patients had G2 (62%) or G3 (33.5%) cancers. G2
and G3 PDAC, compared with G1, had a larger
pathologic size, a greater rate of T3/T4 tumors,
and more lymph node metastases and microvascu-
lar/perineural invasion. Focusing specifically on
G3 neoplasms, we found that they had the greatest
rates of nodal metastases (83%), microvascular
invasion (85%), and perineural (88%) invasion.
Interestingly, R0 resection rates decreased as
histologic grading increased from G1 (74%), to
G2 (62%), and to G3 (57 %). Conversely, no R2
resections were reported among G1 neoplasms,
whereas R2 resections occurred in 8% in G2
neoplasms and doubled to 15% in G3 neoplasms.
Therefore, PDAC of G3 grading---a poor prognos-
tic factor by itself---is characterized by a relevant
presence of other pathologic factors associated
with poor prognosis.
Table II. Univariate analysis for clinical and laboratory predictors of G3 status of PDAC
n % Odds ratio 95% CI P (Univariate)
Age, years
<60 201 40 1 .303
>60 301 60 1.222 0.834 1.791
Sex
Male 291 58 1.285 0.880 1.876 .194
Female 211 42 1
Presence of symptoms
No 58 11.5 1 .035*
Yes 444 88.5 2.053 1.053 4.005
Pain
No 291 58 1 .231
Yes 211 42 1.260 0.863 1.840
Weight loss
No 236 47 1 .385
Yes 266 53 1.182 0.810 1.723
Jaundice
No 191 38 1 .084
Yes 311 63 1.416 0.954 2.100
Diabetes
No 402 80 1 .603
Yes 100 20 1.133 0.707 1.817
Site of neoplasm
Body/tail 94 19 1 .177
Head 408 81 1.407 0.857 2.310
Tumor size (radiology)
<30 mm 371 74 1 .307
>30 mm 131 26 1.247 0.816 1.904
CA 19.9 U/mL
<200 321 64 1 .242
>200 181 36 1.265 0.853 1.865
CEA, ng/mL
<10 482 96 1 .451
>10 20 4 1.474 0.538 4.040
*Statistically significant.
CEA, Carcinoembryonic antigen; CI, confidence interval; PDAC, pancre atic ductal adenocarcinoma.
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September 2012
S116 Crippa et al
Survival analysis confi rmed the poor outcome of
G3 PDAC after resection. Median DSS was an
impressive 77 months for the 23 patients with G1
neoplasm compared with 26 months for G2 and
just 20 months for G3 PDAC. The 2-year DSS for
G3 PDAC was only 40% and decreased to 18%
after 5 years. The poor prognosis for poorly
differentiated neoplasms is shown clearly by DFS;
Table III. Comparison of perioperative and pathologic data of patie nts with G1, G2, and G3 PDAC
Variable
Entire cohort
(n = 502),
n (%)
G1 group
(n = 23),
n (%)
G2 group
(n = 310),
n (%)
G3 group
(n =169),
n (%)
P
(G1 vs
G2)
P
(G1 vs
G3)
P
(G2 vs
G3)
Operation
PD 399 (79.5%) 14 (61%) 245 (79%) 140 (83%)
DP 89 (18%) 9 (39%) 55 (18%) 25 (15%) .084 .014* .594
Total pancreatectomy 14 (2.5%) 10 (3%) 4 (2%)
Postoperative morbidity 85 (37%) 10 (43.5%) 111 (36%) 64 (38%) .482 .060 .711
Abdominal complications 155 (31%) 10 (43.5%) 95 (31%) 50 (30%) .213 .177 .838
Pancreatic fistula 82 (16%) 5 (22%) 54 (18%) 23 (14%) .616 .306 .270
Adjuvant therapy 350 (70%) 17 (74%) 212 (68%) 121 (72%) .581 .817 .466
Median histologic size
(IQR), mm
25 (20;32) 20 (16;25) 30 (20;30) 28 (20;35) .013* .002* .080
R status
R0 307 (61%) 17 (74%) 193 (62%) 97 (57%)
R1 143 (29%) 6 (26%) 91 (29%) 46 (27%) .291 .107 .063
R2 52 (10%) 26 (8%) 26 (15%)
T stage
T1 11 (2%) 5 (22%) 4 (1%) 2 (1%)
T2 23 (5%) 5 (22%) 15 (5%) 3 (2%) <.0001* <.0001* .118
T3 412 (82%) 13 (56%) 261 (84%) 138 (82%)
T4 56 (11%) 30 (10%) 26 (15%)
N1 status 393 (78%) 14 (61%) 239 (78%) 140 (83%) .054 .011* .195
Median number of
lymph nodes evaluated (IQR)
21 (14;29) 16 (14.5;23) 21 (14;29) 22 (12;29) .361 .431 .9
Microvascular invasion 385 (77%) 8 (35%) 233 (75%) 144 (85%) <.0001* <.0001 * .010*
Perineural invasion 436 (87%) 14 (60%) 273 (88%) 149 (88%) <.0001* <.0001* 1
*Statistically significant.
DP, Distal pancreatectomy; IQR, interquartile range; PD, pancreatoduodenectomy; PDAC, pancreatic ductal adenocarcinoma.
Fig 2. (A) Disease-specific survival curves comparing resected patients according to histologic grading. (B) Disease-free
survival curves comparing resected patients according to histologic grading.
Surgery
Volume 152, Number 3S
Crippa et al S117
median DFS was only 9 months for G3 PDAC
compared wit h 63 and 14 months for G1 and G2
PDAC, respectively. When examined 2 years after
resection, only 1 of 4 patients with G3 PDAC
remains free of disease. Remarkably, a predictive
model for G3 PDAC including CA 19.9 level >200
U/mL and a duration of symptoms more than 40
days showed a probability of ‘early’ cancer-related
death of 60%, 75%, and 90% after R0, R1, and R2
resections, respectively.
4
An important observation of the present study is
the different impact of adjuvant therapy on survival
in the 3 groups. Overall, 70% of patients in this
series underwent adjuvant treatme nt with no sub-
stantial differences among G1 (74%), G2 (68%),
and G3 (72%) neoplasms. Although adjuvant ther-
apy did not significantly improve DSS in G1 PDAC
(P = .251), the impact of adjuvant therapy on DSS
was clearly important in patients with G2 (adjuvant
therapy: 29 months, no-adjuvant therapy 19 months,
P = .039) and G3 PDAC (adjuvant therapy 22
months, no-adjuvant therapy 12 months, P <
.0001). The lack of benefit of adjuvant treatment
in G1 neoplasms might be ascribed to the relatively
low number of patients (n = 23) in this group; yet,
when we compared the G2 and G3 groups, we found
that patients with G3 neoplasms undergoing adju-
vant treatment had a 2-fol d survival-benefit com-
pared with patients with G2 tumors (hazard ratio
1.33 vs 2.11). In our study, 30% of patients did not
receive adjuvant treatment, and this rate may ap-
proach as much as 56% in some studies. Inability
to undergo adjuvant therapy is related to early
cancer-recurrence or to delayed recovery after resec-
tion, especially after pancreatoduodenectomy.
11,39
No specific clinical predictors of G3 status were
found. Only the presence of symptoms was associ-
ated with G3 PDAC, but this finding can be very
nonspecific and subjective. Unfortunately, we have
detailed data regarding radiologic predi ctors of
poorly differentiation such as the presence of
necrosis within the tumor.
40
The preoperative diagnosis of PDAC can be
obtained safely with the use of minimally invasive
techniques such as endoscopic ultrasonography-
guided fine-needle aspiration or even core bi-
opsy.
41,42
In poorly differentiated carcinomas , the
nuclei are overtly malignant and enlarged with
strong anisonucleosis.
33
These 2 features have a
sensitivity of 98% and specificity of 100% for G3
PDAC.
41
Although the interpretation of cytology
smears after endoscopic ultrasonography/fine-
needle aspiration might be problematic for G1 ne-
oplasms, the cytologic diagnosis of G3 PDAC is
usually feasible and reliable.
33
On the basis of our study, neoadjuvant treat-
ment may be con sidered in G3 PDAC instead of
upfront exploration for resection. Both DSS and
DFS after resection of G3 PDAC were disappoint-
ing; G3 PDAC was associated with the greatest rate
of other poor prognostic factors, including lymph
node metastases and R2 resection. Because adju-
vant treatments imp roved survival for patients with
G3 PDAC, and 30% of these patients were unable
to undergo any therapy largely because of
operation-related complications, these patients
represent an ideal target for neoadjuvant treat-
ment. Neoadj uvant approach can also avoid use-
less resection in a population at high risk for early
failure after resection.
In conclusion, G3 PDAC is associate d with a
short DFS after resection and more often with
other poor prognostic factors, particularly lymph
node metastases and R2 resections. The benefit of
adjuvant therapy is greater in G3 than in G1 and
G2 PDAC. On the basis of these findings, G3 PDAC
can be considered as a possible target of neo-
adjuvant treatment. A preoperative cytologic/his-
tologic assessment of PDAC with grading should
become a part of the preoperative work-up of
patients with clinically resectable PDAC.
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    • "We found that, while T cells and myeloid cells were rare in normal, non-neoplastic pancreatic parenchyma (Figure 1A), both cell types were present both within the stroma and adjacent to carcinoma cells throughout PDA tumors (Figure 1B&C). Since tumor differentiation in PDA has been shown to impact survival,[26] we categorized tumors based upon standard histological criteria into well- to moderately (well-mod) differentiated or poorly differentiated. We determined the average numbers of CD3+ and CD11b+ cells in regions containing carcinoma cells and found that T cells were significantly more prevalent than myeloid cells in both well-mod differentiated (p<0.0001) and poorly differentiated tumors (p = 0.03; Figure 1D). "
    [Show abstract] [Hide abstract] ABSTRACT: The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA. We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood. In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg. Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.
    Full-text · Article · May 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Objectives: This study aimed to determine the impact of a standardized pathological protocol on resection margin status after pancreaticoduodenectomy (PD) for ductal adenocarcinoma. Methods: A total of 150 patients operated during 2008-2010 were included in a prospective multicentre study using a 'quality protocol'. Multicolour inking by the surgeon identified three resection margins: the portal vein-superior mesenteric vein margin (PV-SMVm) or mesenterico-portal vein groove; the superior mesenteric artery margin (SMAm), and the posterior margin. Resection margins were stratified by 0.5-mm increments (range: 0-2.0 mm). Pancreatic neck, bile duct and intestinal margins were also analysed. Correlations between histopathological factors and survival in the 0-mm resection margin group were analysed. Results: Thirty-six patients (24%) had a PV-SMV resection (PV-SMVR). An analysis of resections categorized according to margin distances of 0 mm, <1.0 mm, <1.5 mm and <2.0 mm confirmed R1 resections in 35 (23%), 91 (61%), 94 (63%) and 107 (71%) patients, respectively. The most frequently invaded resection margin was the PV-SMVm (35% of all patients) and PV-SMVR was the only factor correlated with a higher risk for at least one 0-mm positive resection margin on multivariate analysis (P < 0.001). Two-year progression-free survival (PFS) and median PFS time in patients with R0 and R1 resections (at 0 mm), respectively, were 42.0% and 26.5%, and 19.5 months and 10.5 months, respectively (P = 0.02). A positive PV-SMVm and SMAm had significant impact on PFS, whereas a positive posterior margin had no impact. Conclusions: Pancreaticoduodenectomy requiring PV-SMVR was associated with a higher risk for R1 resection. The standardization of histopathological analysis has a clinically relevant impact on PFS data.
    Full-text · Article · Mar 2013
  • [Show abstract] [Hide abstract] ABSTRACT: The role of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in pancreatic ductal adenocarcinoma is debated. We retrospectively assessed the value of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in addition to conventional imaging as a staging modality in pancreatic cancer. (18)Fluoro-deoxyglucose positron emission tomography/computed tomography was performed in 72 patients with resectable pancreatic carcinoma after multi-detector computed tomography positron emission tomography was considered positive for a maximum standardized uptake value >3. Overall, 21% of patients had a maximum standardized uptake value ≤3, and 60% of those had undergone neoadjuvant treatment (P=0.0001). Furthermore, 11% of patients were spared unwarranted surgery since positron emission tomography/computed tomography detected metastatic disease. All liver metastases were subsequently identified with contrast-enhanced ultrasound. Sensitivity and specificity of positron emission tomography/computed tomography for distant metastases were 78% and 100%. The median CA19.9 concentration was 48.8U/mL for the entire cohort and 292U/mL for metastatic patients (P=0.112). The widespread application of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in patients with resectable pancreatic carcinoma seems not justified. It should be considered in selected patients at higher risk of metastatic disease (i.e. CA19.9>200U/mL) after undergoing other imaging tests. Neoadjuvant treatment is significantly associated with low metabolic activity, limiting the value of positron emission tomography in this setting.
    Article · Apr 2014
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