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Management of solid and cystic lesions of the pancreas 299
resection. For cystic lesions, treatment strategies usually require careful c haracterization as to the nature of
the cyst and its potential for malignancy or malignant
transformation. Treatment may range fro m no further
intervention to surveillance with serial imaging or
surgical resection. A critical component in all diagnostic
and t reatment planning is the requirement for collaboration among members of a multidisciplinary team
that includes surgeons, gastroenter ologists , radiologists,
interventional ra diol ogists, medical oncologist, rad iotherapists, and pathologists.
During the last 10–20 years, such multidisciplinary
involvement has facilitated the development of strict
radiographic criteria for classifying pancreatic lesions
(biopsy proven or not) into degrees of resectability, identifying criteria for resection of pancreatic neuroendocrine
tumors, and selecting patients with IPMN or other cystic
lesions for continued observation or resection. The overall
management of each of these is discussed in this chapter
with emphasis on localized lesions considered for surgical
resection.
22.2.1 Management of adenocarcinoma
of the pancreas
22.2.1.1 Risk factors
Several risk factors for pancreatic adenocarcinoma are
fairly well established [4]. A history of tobacco smoking
unequivocally increases the risk of pancreatic cancer.
Some studies also suggest increased risk with use of
smokeless tobacco products [5] or exposur e to secondhand smoke. Type 2 diabetes mellitus, obesity, and
metabolic syndrome have all been associated with an
increasedriskofpancreaticadenocarcinoma.Ofnote,
recent evidence has demonstrated a potential protective effect for diabetics whose blood glucose is controlled using metf ormin compared with an increased
risk for diabetics managed with sulfonylureas or
insulin [6–9].
Other risk factors include hepatitis B virus infection,
any form of chronic pancreatitis, or a history of gastric
bypass surgery. Lastly, a growing number of inherited
cancer syndromes put carriers at increased risk for pancreatic cancer. These include BRCA1, BRCA2, Peutz–
Jeghers syndrome, germline p16 mutations (seen in
familial atypical mole and melanoma), PALB-2 mutations [10], and those identified as having documented
genetic mutations seen in hereditary nonpolyposis colon
cancer (HNPCC) [11].
22.2.1.2 Presenting signs and symptoms
With the exception of obstructive jaundice, which is a
common presenting symptom of patients with adenocarcinoma in the head of the pancreas, symptoms of pancreatic cancer are often nonspecific and include vague or
poorly characterized abdominal pain or back pain. Both of
these are often attributed to other causes such as
gallbladder disease, peptic ulcer disease or acid reflux,
or to musculoskeletal problems. Other potential signs of
pancreatic cancer include unexplained venous thromboembolism, steatorrhea, weight loss, or night sweats; the
latter are usually harbingers of advanced disease.
22.2.1.3 Imaging studies
Given the current rates of microscopically positive
surgical margins in pancreatic cancer resections
(>40%), high-quality cross-sectional CT or MR imaging
must be a component of clinical staging [12].
Importantly, for patients who present with obstructive jaundice, biliary decompression with a percutaneous transhepatic catheter (PTC) or endobiliary
stent should ideally be performed after acquisition of
dynamic phase thin-cut helical imaging. Preprocedure
imaging wi ll avoid inflammatory changes that could
result from instrumentation [13].
Adequate imaging is imperative to understand the
relationship between a tumor and the mesenteric vasculature. Currently, CT scanners of various resolutions
remain in use, many of which use a slice thickness of
5 mm. Our current standard for pancreatic imaging is to
use slices no farther apart than 2.5 mm, and preferably as
thin as 0.6 mm. Another nuance of CT imaging is the
appropriate timing of contrast dye to obtain arterial and
venous images; this is easily mistimed. It is our experience
that the use of narrow cuts on CT scan will find potential
metastases that have been missed on scans with lower
resolution. A frequent difficulty is the assessment of
indeterminate potential metastases in the lungs or liver.
While MRI may occasionally identify these as benign or
malignant, even this tool is imperfect.
Imaging may also offer clues to the underlying tumor
histology. Ductal adenocarcinomas are usually poorly
demarcated, low-density lesions with minimal peripheral
enhancement. They can be associated with evidence of
pancreatic ductal obstruction with or without upstream
pancreatic atrophy, and in general, regional adenopathy
is prominent but not typically bulky. In pancreatic neuroendocrine tumors (pNETs), the tumor mass may be
300 Chapter 22
Table 22.1 Comparison of survival in patients with positive and
negative surgical margins.
Overall survival
(months)
Author Year R0 R1
Milikan [102] 1999 17 8
Sohn [16] 2000 19 12
Benassai [103] 2000 26 9
Neoptolemos [19] 2001 17 11
Takai [20] 2003 23 8
fairly bulky and somewhat better delineated and have
more enhancement than most adenocarcinomas. pNETs
are not associated with pancreatic ductal obstruction and
do not cause pancreatic atrophy. However, lymph node
metastases are often bulky and can also show evidence of
enhancement, particularly on the arterial phase of the
scan. Similarly, acinar cell carcinomas are generally more
enhancing and associated with bulky adenopathy. In
addition, they can appear more heterogeneous than
either adenocarcinoma or pNETs.
22.2.1.4 Staging of pancreatic cancer: the
emergence of “borderline resectable”
disease
Pancreatic adenocarcinoma is notorious for local invasion
and metastatic spread to other organs at the time of
diagnosis in the majority of patients (>80%). Even
patients whose tumors have been discovered with no
visible metastases still have a high likelihood of recurrence after surgery. The two largest pitfalls have been
surgery that results in positive margins and the development of distant metastases. Even the most recent studies
demonstrate recurrence rates of over 70% within three
years in resected pancreatic cancer patients [14].
How, then, does one avoid this outcome? The importance of achieving negative margins as a result of surgery
cannot be overstated. In multiple prior series, patient
survival was uniformly longer in those patients achieving
a negative margin. These are noted in Table 22.1 [15–20].
Our observation is that patients who have undergone an
R1 resection recur fairly rapidly and are often too debilitated after surgery to take effective chemotherapy. For
this reason, we have tried to identify patients at higher
risk for positive margins and recurrence, labeling them
“borderline resectable” [21].
There is no broad consensus definition of borderline
resectable disease, and at present, multiple sets of
criteria have been suggested (Table 22.2). The minimal
disease activity (MDA) criteria also include p atients
with suspected extrapancreatic disease (“bord erli ne
group B”) or comorbid conditions (“borderline group
C”) that would increase the risk of surgery (Box 22.1;
Figure 22.1, Figure 22.2, Figure 22.3, Figure 22.4, and
Figure 22.5). Katz and others have pr eviously assess ed
the prevalence of b orderli ne resectable pancreatic cancer. In a review of 2454 patients evaluated between
1999 and 2006, 1 60 (7%) patients were classifi ed as
borderline resectable [22].
The National Comprehensive Cancer Network’s
(NCCN) expert panel on pancreatic cancer is in general
Table 22.2 Comparison of borderline resectable pancreatic cancer among different organizations.
AHPBA-SSAT-SSO MD Anderson NCCN Intergroup (Alliance A021101)
SMV-PV
SMA
CHA Abutment or
Celiac trunk No abutment or
CHA, common hepatic artery; PV, portal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein.
Abutment,
encasement or
occlusion
Abutment
short-segment
encasement encasement
encasement
Occlusion
Abutment
Abutment or
short-segment
Abutment No abutment or
Abutment with
impingement or
narrowing
Abutment
Abutment or shortsegment encasement
encasement
Interface between tumor and vessel measuring >180° of
the vessel circumference or reconstructable occlusion
or both
Interface between tumor and vessel measuring <180° of
the circumference of the vessel wall
Reconstructable, short-segment interface between tumor
and vessel of any degree
Interface between tumor and vessel measuring <180° of
the circumference of the vessel wall
Management of solid and cystic lesions of the pancreas 301
Box 22.1 M.D. Anderson criteria for borderline resectable pancreatic cancer, with examples
Borderline group A: anatomical criteria
Abutment or encasement of a short segment of the hepatic artery w/o celiac artery
involved
Abutment of the SMA by <180°
Short segment occlusion of the SMV, PV or SMV/PV confluence
Celiac trunk abutment (includes GDA involvement with hepatic artery extension)
Borderline group B: suspected extrapancreatic disease
Lymph node involvement on imaging
CA 19-9 >1000 in the absence of biliary obstruction
Borderline group C: anatomically resectable with comorbid disease
ECOG 3 performance status
Significant comorbid conditions
ECOG, European Cooperative Oncology Group; GDA, gastroduodenal artery; PV, portal
vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein.
agreement with preoperative therapy for borderline
resectable patients; however, there is no consensus on
what should qualify as standard treatment. Retrospective
data accumulated at the MD Anderson Cancer Center
Figure 22.1 CT image from a 56-year-old man whose CHA
arose off the SMA and was encased by tumor (shown). After
neoadjuvant FOLFIRINOX and chemoradiation, the tumor was
smaller. He was taken to the OR after six months of
neoadjuvant therapy. The tumor was noted to still be at the
CHA, which was resected and replaced by a graft. Three
months later a local recurrence and liver metastases
were noted.
suggest that a sequence of chemotherapy followed by
chemoradiation, and ultimately resection, may be appropriate for patients with borderline resectable pancreatic
cancer. One example of a patient successfully treated in
this fashion is given in Figure 22.6. A retrospective study
of 84 patients with category A borderline resectable
disease found that 32 were ultimately able to undergo
resection after initial chemotherapy and/or radiation. All
Figure 22.2 CT image from a different 56-year-old man whose
tumor was noted to contact the SMA (shown) by 180°. After
neoadjuvant chemotherapy only a partial response was seen.
He then proceeded to radiation.
302 Chapter 22
Figure 22.3 CT image from a 65-year-old man who
presented with a 4.8 cm tumor encircling the SMV and
narrowing the splenoportal confluence (shown). His tumor
progressed through chemotherapy with subsequent
complete venous occlusion seen four months after starting
therapy, with collateral formation and ascites
requiring paracentesis.
but one patient had an R0 resection. Overall median
survival of the entire group was 21 months, and the
survival of those patients whose neoadjuvant treatment
allowed surgery was 40 months [23]. Takahashi and
colleagues also found that they were able to get a significant number of patients (43 of 80) with anatomically
borderline PC to the operating room with the use of
gemcitabine-based chemoradiation [24]. All but one
had a margin negative resection; the five-year survival
rate of this group was 34%.
In another example, Kim et al. treated 39 borderline
resectable pancreatic cancer (PC) patients with gemcitabine and oxaliplatin along with chemoradiation [25]. Of
these 39, 30 completed treatment and 24 underwent
resection. The median survival for this group as a whole
was 18.4 months; the 24 patients who ultimately underwent resection survived a median of 25.4 months. By
comparison, survival of a simultaneous cohort of resectable patients was 26.5 months for all patients and
Figure 22.4 CT image from a 52-year-old man with a 4.4 cm
mass at the pancreatic head, abutting the PV, PV/SMV
confluence, and encasing the gastroduodenal artery (shown).
He responded to FOLFIRINOX and then underwent
chemoradiation. At surgery, tumor extended to the portal vein,
duodenal wall, and bile duct. He remains free of visible disease
one year postoperatively.
44.7 months for those patients who ultimately underwent resection.
Our current work with borderline PC patients
revolves around the FOLFIRINOX regimen, pioneered
by Conroy and others in the metastatic setting [26]. In
its initial phase III trial, this regimen offered a superior
response rate and superior overall survival time when
compared with gemcitabine. Given its promise (albeit
also its toxicity), we have begun a phase II study at the
MD Anderson Cancer Center offering initial FOLFIRINOX followed b y chemoradiation. A par allel multicenter trial is now under way. However, unanswered
questions remain: is this too toxic for patients looking
to u ndergo surgery? Will there be an unacceptable risk
of infection in patients with bil iary stent? Would a more
tolerable regimen, such as gemcitabine with nab-paclitaxel [27], offer a better outcome in the long term?
Ongoing clinical trials will help define the best strategy
for such patients.
Figure 22.5 CT image from a 58-year-old man with a 3.1 cm
mass at the head of the pancreas, with enlarged nodes in the
hepatic arterial station (shown). The primary tumor improved
with FOLFIRINOX; the nodes remained stable. He completed
radiation and underwent surgery six months after diagnosis.
He later developed a recurrence with malignant ascites.
Management of solid and cystic lesions of the pancreas 303
22.2.1.5 Preoperative prognostication of
pancreatic adenocarcinoma
While there are some patients whose medical condition
encourages or demands early surgery (e.g. gastric outlet
obstruction, biliary obstruction not amenable to stent
placement), these patients are generally in worse shape
than nonurgent patients. In one small series, these
patients generally had more anorexia and weight loss,
more fatigue, and a higher rate of infections than those
patients sufficiently healthy to delay chemotherapy in
favor of neoadjuvant chemoradiation [28]. In this group,
only 61% of patients went on to adjuvant chemotherapy,
as opposed to 84% of patients with good Eastern Cooperative Oncology Group (ECOG) performance status (PS)
(ECOG 0–1) who began neoadjuvant chemoradiation in a
nonurgent fashion. We observed that patients with ECOG
PS 2–3 had, on average, longer hospital stays (24 vs
11 days, P = 0.002) than the ECOG 1–2 patients, largely
because of complications. This group was also less likely
than healthier patients to begin adjuvant treatment
because of poor performance status (22% vs 84%).
The carbohydrate antigen (CA) 19-9 tumor marker
may also serve as a tool for preoperative prognostication.
Figure 22.6 (a) CT image from a 66-year-old woman with a pancreatic cancer considered borderline resectable owing to SMA
involvement. (b) The same patient after three months of FOLFIRINOX chemotherapy, with regression. She is now planned
for surgery.
304 Chapter 22
In the RTOG 9704 study [29], a baseline CA 19-9 of >90
suggested a shorter median survival than those patients
lower than this cut-off (10- vs 21-month median survival). A smaller study of 111 patients using a CA 19-9
cut-off of 120 U/mL likewise found better survival among
patients with lower preoperative values (35.6 vs
17.4 months, P = 0.044) [30]. It is important to note that
CA 19-9 will be unreliable in the setting of elevated bilirubin, though corrective formulas have been proposed. Additionally, undetectable CA 19-9levelsarefoundinpatients
who lack the Lewis (a) blood antigen, and likewise may not
be helpful in prognostication in these patients [31].
DPC4/SMAD4 status may also suggest prognosis: in
one rapid autopsy series of 76 patients, only two of nine
(22%) nonmetastatic patients had loss of DPC4 staining,
compared with 16 of 22 (78%) with widely metastatic
disease [32]. A second series of pancreas cancer patients
likewise found that SMAD4 is lost in 70% of PC specimens
and that such patients are more likely to develop metastases in the first year after surgery (51.4% vs 13%) [33].
This group found that SMAD4 status was similar in
preoperative and postoperative samples, suggesting
that it may be used as a predictive marker. Recent
work in our own group likewise demonstrates that
73% of intact localized cancer patients had positive
DPC4/SMAD4 staining, while 71% of patients with distant spread had loss of DPC4/SMAD4 [34]. It is our
opinion that DPC/SMAD4 testing remains an underutilized prognostic factor in such patients.
Pancreatic tumors frequently demonstrate activation of
the JAK/STAT pathway, resulting in interleukin (IL)-6
production and systemic inflammation. The modified
Glasgow Prognostic Score (mGPS) is one marker of
such inflammation. One point each is assigned for elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<3.5 g/dL). In one early study, an elevated GPS – on
multivariate analysis with age and tumor stage – was
found to be associated with poor survival [35]. When
studied in a population of potentially resectable pancreatic cancer patients, median survival decreases with
increasing mGPS score. Scores of 0, 1, and 2 were associated with survival durations of 37.2, 11.5, and 7.3 months,
respectively. This effect was independent of age, stage,
nodal status, and margin status [36]. Jamieson et al. had
similar observations evaluating a different cohort of
patients undergoing surgery for pancreatic ductal adenocarcinoma, finding that an elevated GPS was associated
with lower survival (hazard ratio [HR] 2.26) [37].
A consensus statement of pancreatic surgeons has
observed that the GPS has now been validated in more
than 60 studies of organ-specific cancers, involving more
than 30 000 patients from 13 different countries, and
endorses its use to obtain further validation on its potential benefit for survival with surgery, although not for
prediction of resectability [38]. We do note that the GPS
parallels our own observation of low albumin as a poor
prognostic marker and a means of categorizing patients
into borderline group C.
22.2.1.6 Adjuvant trials in pancreatic
adenocarcinoma
For over 25 years, solid lesions of the pancreas have
generally been managed with upfront surgical resection.
This has often been done when there has been a suspicion
of adenocarcinoma without biopsy confirmation. What
can be learned from a number of adjuvant trials and single
institutional reports with upfront surgical resection of
adenocarcinoma of the pancreas is briefly summarized
below.
• Six months of systemic chemotherapy with either
gemcitabine or fluorouracil/folinic acid (leucovorin)
modestly improves median survival and five-year survival compared with observation alone.
• Chemoradiation has often been a component of adju-
vant therapy, particularly in North America, but there
are no definitive randomized data to support its use as a
necessary component of adjuvant therapy.
• Although data are limited, perhaps as many as 40–50%
of patients taken to the operating room for resection of
pancreatic cancer do not undergo adjuvant therapy,
based on discovery of radiographically occult metastases, an unresectable tumor, or poor recovery from
surgery.
• Margin-positive resections are associated with worse
survival than R0 resections.
• Elevated CA 19-9 levels postoperatively confer a poor
prognosis.
• No meaningful improvement in survival has been
observed in median or overall survival with an upfront
surgical approach to pancreatic adenocarcinoma.
For a review of this subject, see the paper by Wolff
et al. [39].
Even after successful surgery, pancreatic cancer
patients suffer a high rate of relapse and death.
Randomized studies from the last decade (Table 22.3)
demonstrate that the median survival of patients treated
Management of solid and cystic lesions of the pancreas 305
Table 22.3
with chemotherapy, even under the best of circumstances, is generally no better than 24 months. Fiveyear survival after surgery approximates 25% and often
less [14,40–43]. The use of adjuvant chemotherapy has
generally been shown to have a small but beneficial effect.
A recently published meta-analysis of adjuvant chemotherapy and chemoradiation studies to date has shown
improvements in survival for those patients treated with
fluorouracil and gemcitabine, with hazard ratios of 0.65
and 0.59 respectively when compared with observation
alone [44]. Chemoradiation resulted in worsened survival than fluorouracil or gemcitabine (HR 1.69, 1.86
respectively). Major limitations in interpreting these
studies include the heterogeneity of patients included
for selection and the absence of uniform criteria for
surgical resection prior to enrollment into these adjuvant
studies.
Survival among pancreatic adenocarcinoma patients after adjuvant chemotherapy.
Study Author Chemotherapy # Pt Median survival
(months)
ESPAC-1 Neoptolemos [40] 5-FU 147 20.1 26% 21%
Observation 142 15.5 13% 8%
CONKO-001 Oettle [14] Gemcitabine 179 22.8 38%
Observation 175 20.2 18%
ESPAC-3 Neoptolemos [41] Fluorour acil 551 23 20% 3%
Gemcitabine 537 23.6 19% 2%
RTOG 9704 Regine [42] Gem/RT/Gem 221 20.5
FU/RT/FU 230 16.9
JSAP-02 Ueno [43] Gemcitabine 58 22.3 29% 24%
Observation 60 18.4 23% 11%
FU, fluorouracil; RT, radiation therapy.
∗∗
∗∗
Three-year
survival
∗
∗
25% 10%
21% 7%
Five-year overall
survival
majority of patients who present with a radiographically
resectable tumor. Third, it provides a relevant time period
to observe underlying tumor biology, and with restaging
studies performed after preoperative therapy, a subset of
patients will be discovered to have interval development
of metastatic disease. Fourth, it facilitates careful observation of the patient proceeding through a course of
anticancer therapy. Patients with pancreatic cancer are
often older (peak age of onset 60–70 years), and they may
have other comorbidities or generalized deconditioning
that is not apparent on initial surgical evaluation. Chemotherapy or chemoradiation offers a selection mechanism
to better identify patients who may not be able to tolerate
a pancreaticoduodenectomy, or other pancreatic cancer
resections.
A sequential series of preoperative the rapy trials
performed at the MD Anderson Cancer Center coupled
with reports from other trials have provided valuable
22.2.1.7 Neoadjuvant trials in pancreatic
adenocarcinomas
Similar to other solid tumors, to include breast, esophageal, and rectal cancer, several institutions began investigating the role of preoperative or neoadjuvant therapy
for the treatment of potentially resectable pancreatic
cancer. Given the biology of pancreatic cancer, such a
strategy has sound logic. First, it provides for delivery of
cytotoxic therapy (historically as fluorouracil [5-FU]based chemoradiation) to an intact and relatively wellperfused tumor and surrounding microenvironment.
Second, it provides for early treatment of microscopic
metastatic disease, almost certainly present for the
information as to the potential merits of preoperative
therapy.
• Approximately 15% of patients treated with pre-
operative therapy will develop radiographic evidence
of metastatic disease within 6–12 weeks of presentation
with resectable disease. This spares one in seven potential surgical patients from a morbid surgical procedure.
• An additional 10% of patients will have radiographi-
cally occult metastatic disease found at the time of
staging laparoscopy or laparotomy after neoadjuvant
treatment.
• Roughly 5% of patients who embark on preoperative
therapy will be considered to have unacceptable
21%
10%
306 Chapter 22
surgical risk based on clinical observations made during
preoperative treatment.
• R0 resection rates are generally higher with the use of
preoperative therapy compared with upfront surgical
resections performed at the same institutions [45].
• Radiation may also reduce the incidence of fistula
formation after surgery [46].
• An undisturbed blood supply offers the theoretical
advantage of better distribution of chemotherapy to
the tumor, and less hypoxia (with attendant HIF
expression) may result in less chemoresistance [47].
A rigorous application of this approach was conducted at
the MD Anderson Cancer Center [48]. This study is
noteworthy in that the investigators applied a specific
definition of potentially resectable disease. Patients were
included if there was no evidence of extrapancreatic
disease; if there was no evidence of tumor extension to
the superior mesenteric artery (SMA) or celiac axis; and if
there was no evidence of occlusion of the superior mesenteric vein (SMV) or SMV-portal vein (PV) confluence.
Tumor abutment and encasement of the SMV, in the
absence of vessel occlusion or extension to the SMA, was
considered resectable. Treatment included weekly gem-
2
citabine at a dose of 400 mg/m
for a total of seven doses.
Radiation was given over a 10-day course at a dose of
3 Gy/day. A total of 86 patients were treated; 74 were
found to be resectable, among whom nine patients had
metastases; an additional patient dropped out. The
remaining 64 underwent surgery. The median survival
of all patients was 22.7 months, but it reached 34 months
for those patients who ultimately did undergo surgery.
The five-year survival for these patients was 36%, which
equates to 27% for the whole group. This compares
favorably with any of the studies of adjuvant chemotherapy presented in Table 22.2 and has the added advantage of having prevented unhelpful surgery in a sizeable
minority of patients.
The same investigators also asked whether the
sequence of chemotherapy, chemoradiation, and surgery
would be valuable to potentially resectable patients [49].
Here, gemcitabine and cisplatin were given every other
week for four doses prior to the initiation of chemoradiation. In this study, 90 patients were enrolled, 79
completed neoadjuvant treatment, and 52 ultimately
underwent resection. The median survival of resected
patients was 31 months, but survival of all patients was
only 17.9 months. Although the study enrolled a separate
population from the earlier study, the authors concluded
that the additional chemotherapy did not add to the effect
of chemoradiation.
Our current approach to patients with potentially
resectable PC is a course of neoadjuvant chemoradiation
followed by surgery. We believe that the strategy allows
the identification of distant metastases, while not compromising care of the primary tumor itself. As evidence of
this, we observe that only one patient of the 176 in the
two aforementioned studies actually had progression of
the primary tumor precluding resection; the other
patients were all excluded from surgery because of metastatic disease.
22.2.1.8 Approach to patients with presumed
adenocarcinoma of the pancreas
In patients discovered to have a solid lesion involving the
pancreas, dual-phase helical CT or contrast-enhanced
MR of the abdomen and pelvis should be obtained. In
addition, NCCN guidelines recommend plain chest X-ray
or CT imaging of the chest. Laboratory studies should
include a measurement of serum CA 19-9 level. For those
patients with lesions in the liver, lung, or peritoneum
suspicious for metastatic spread, biopsy of a metastatic site
is preferred to determine histology and confirm the presence of metastatic disease. In the absence of metastatic
disease, many centers still perform image-guided biopsy
of the pancreatic lesion as part of diagnosis and staging,
preferably utilizing endoscopic ultrasonography with fine
needle aspiration to minimize the risk of peritoneal
seeding or needle tract seeding that is more likely with
percutaneous biopsy. However, in some centers, when
high-quality imaging demonstrates a clearly resectable
solid lesion of the pancreas without evidence of metastatic
spread, surgical resection without prior biopsy is often
recommended.
Laparoscopy remains an additional tool to rule out
occult peritoneal metastatic disease not identified on
cross-sectional imaging. Recent studies comparing laparoscopy to high-resolution CT imaging have been
reported. In one example of 136 patients where the
greater sac was inspected laparoscopically, with no mobilization of viscera, three (2%) had radiographically occult
disease [50]. Subsequent laparotomy identified an additional 12 patients (9%), occurring at the posterior liver,
lesser sac, retroperitoneum, and proximal jejunal mesentery. In a second group of 138 patients undergoing open
staging, 15 had radiographically occult metastases. Of
these, six would have been hidden from sight with
Management of solid and cystic lesions of the pancreas 307
standard staging laparoscopy, had it been performed. The
investigators do note that a more extensive laparoscopic
evaluation would have found the majority of these
metastases. Other investigators have similarly noted
that the sensitivity of CT for peritoneal and liver surface
metastases may be as low as 42% [51], but have also
noted that an elevated CA 19-9 may accompany such
findings. In our own practice, we tend to reserve laparotomy for patients who have elevated CA 19-9, who have a
mediocre performance status, or who are otherwise
deemed at higher surgical risk.
The current standard of care for solid lesions that meet
radiographic criteria for surgical resectability with no
evidence of metastasis is an attempt at upfront surgical
resection. In the case of pancreatic head lesions, inking of
the SMA or uncinate margin is a critical component of
pathological staging. While preoperative therapy for
resectable pancreatic adenocarcinoma has shown promising results, neoadjuvant chemotherapy, chemoradiation, or both are still considered investigational and
should preferably be delivered in the context of a clinical
trial. Importantly, for those patients being considered for
preoperative treatment, biopsy confirmation of malignancy is advised. As noted above, for patients who present
with equivocal evidence of metastatic disease to the liver
or peritoneum, or for patients who have a CA 19-9 over
500–1000 (with normal bilirubin level), staging laparoscopy prior to laparotomy is advised. However, in borderline pancreatic cancer (whether for anatomical reasons,
suspected metastases, or poor performance status), biopsy
confirmation is recommended. If adenocarcinoma is confirmed, preoperative treatment should be considered
in most situations irrespective of the availability of a
clinical trial.
There has been recent interest in the use of laparoscopic
resection of pancreas body and tail lesions. There is yet
relatively little literature comparing these with formal
open resection. While there are no randomized trials, a
number of retrospective studies have evaluated laparoscopic resection with open resection. The largest such
comparison evaluated 212 patients who underwent distal
pancreatectomy; 11% of these had been laparoscopic
resections. These investigators noted less blood loss
(790 vs 422 mL) and shorter length of stay (11 vs
7 days). R1 margin rates were similar between the groups
(27% vs 26%) though the tumors in the laparoscopic
group tended to be smaller (4.5 vs 3.5 cm, P = ns). Fewer
patients in the laparoscopic group underwent adjuvant
chemotherapy though reasons for this are not given. As
expected, absence of adjuvant chemotherapy, positive
margins, and involved nodes correlated with worsened
survival; the type of resection did not, with similar survival regardless of surgery type.
This study’s findings are similar to a later one again
retrospectively comparing outcomes of patients treated
laparoscopically (n = 8) with open surgery (n = 22); this
was not a randomized comparison [52]. In this smaller
cohort, R0 margins were achieved in seven of eight
laparoscopically treated patients and in 12 of 14 patients
treated with open surgery. A longer operative time was
noted in the laparoscopic group, but hospital stay was
shorter (8 vs 12 days). Three-year survival was similar
between the groups. These data suggest that laparoscopic
surgery may be appropriate for carefully selected patients,
though a randomized study (not yet performed) would be
valuable information.
22.2.2 Management of pancreatic
neuroendocrine tumors
Neuroendocrine tumors (NETs) represent only 3% of
pancreatic cancers ; however, they are important to
recognize. A number of fundamental differences
between pancreatic adenocarcinomas and neuroendocrine tumors lead physicians to take a different
surgical and medical approach to these cancers. There
are differences in prognostic factors between NETs and
adenocarcinomas, differences in staging and biomarker
availability, in the use of radioimaging to define tumor
extent, a nd in the role of neoadjuvant chemotherapy
and metastatectomy. Unlike adenocarcino mas, some of
these tumors are metabolically active, pro ducing hormones such as gastrin, insulin or glucagon, while others
are nonfunctional.
22.2.2.1 Risk factors
Neuroendocrine tumors can arise from a number of
different sites, including the foregut (lungs, stomach,
pancreas), midgut (jejunum, ileum, appendix), and
hindgut (distal colon) [53]. One retrospective study at
a large academic medical center found a slight male
predominance (55% vs 45%); this was also seen in
evaluation of the SEER database [3]. Unlike patients
with adenocarcinoma, cigarette smoking, BMI, and alcohol consumption were not found to be significant risk
factors for NET. There was an increased incidence of
diabetes mellitus in these patients (odds ratio [OR]
308 Chapter 22
2.8); however, many of these were diagnosed with diabetes around the time of their cancer diagnosis.
There are some inheritable predispositions for pancreatic NET. While uncommon, the most frequent of these
aberrations is MEN1 syndrome [54]. This is an autosomal
dominant syndrome resulting in pituitary adenomas,
parathyroid hyperplasia, and pancreatic neuroendocrine
tumors; however, multiple mutations have been identified that may result in this syndrome. Other associated
syndromes (also rare) include von Hippel–Lindau syndrome [55], von Recklinghausen disease, neurofibromatosis type 1, and tuberous sclerosis (TSC); this
last gene was found to be mutated in roughly 9% of
pancreatic NETs.
22.2.2.2 Signs and symptoms of pancreatic NETs
Pancreatic neuroendocrine tumors may be either functional (i.e. hormone producing) or nonfunctional. Fully
40% of patients are diagnosed incidentally. Both may
cause symptoms resulting from the local effect of the
tumor – abdominal or back pain (typically T10 level),
early satiety, and duodenal obstruction. They may cause
jaundice if obstructing the bile duct. Functional tumors
may cause specific effects related to the hormone produced. Insulinomas may cause episodic hypoglycemia,
often with confusion, palpitations, or tremulousness.
Conversely, glucagonomas may cause diabetes mellitus,
anemia, weight loss, diarrhea, chelitis, and necrolytic
migratory erythema. Gastrinomas arising from the pancreas may result in peptic ulcer disease, and VIPomas may
cause watery diarrhea, weight loss, and hypokalemia.
22.2.2.3 Diagnosis and staging
A growing recognition of the different biology of pNET
and adenocarcinoma prompted alternative classification
schemes. An early version of this was put forward by the
World Health Organization [56,57], which classified
tumors into benign, indeterminate, and malignant
behavior. Each of these classifications was based on tumor
size, mitoses per high power field (HPF), KI-67, perineural or vascular invasion. More recently, both the European Neuroendocrine Tumor Society (ENETS) and the
American Joint Committee on Cancer (AJCC) have proposed more detailed staging systems. The purpose of both
staging systems is to offer prognostic information to
patients and clinicians specific to pancreatic endocrine
tumors as a distinct entity from the more broad classification of carcinoid tumors as well as from exocrine
pancreatic tumor (e.g. adenocarcinomas). The ENETS
staging system [58], published in 2006, was derived
from a consensus conference and stages patients into a
TNM system. In this system, T1 tumors are those <2 cm,
T2 range from 2 to 4 cm, T3 tumors exceed 4 cm or invade
the duodenum or bile duct, and T4 tumors are those that
invade adjacent organs or blood vessels. Overall stage
progresses from stage I (T1N0) to stage IIIA (T4N0).
Lymph node-positive tumors (N1) are designated as stage
IIIB, and the presence of metastases de fines stage IV.
The AJCC system is based on the exocrine pancreas
staging system and differs from the ENETS system as more
broadly including resectable cancer as stage I, while
designating tumor abutting the celiac axis or SMA without involved nodes as stage IIB. Stage III in the ENETS
system includes all patients with node-positive disease,
while the AJCC system lists T1–T3/N1 tumors as stage
IIB [59]. They are both prognostic for relapse: five-year
relapse-free survival rates for stages I–III respectively
were 90%, 73%, and 66% using the AJCC system, and
100%, 84%, and 75% using the ENETS system. There is
no current consensus in favor of one over the other.
Both systems also differ from the previous WHO classification by excluding reference to the proliferation rate
of the tumors. However, this does remain of prognostic
importance. Two separate means of testing this aspect of
cell biology are KI-67 immunolabeling and counting of
mitoses on slides. These two methods have recently been
compared [60], with the finding that there can be discordance between the two systems. One third of tumors
deemed to be grade 1 on mitotic rate alone (<2 mitoses/10
HPF) were actually grade 2 by KI-67 analysis (3–20% KI67 positive cells). These tumors were larger and more
aggressive than those found to be grade 1 on both measures. In a smaller number of tumors, the opposite (grade
1 KI-67/grade 2 WHO) was true; these tumors did not
differ histologically from uniform grade 1 tumors. Ellison
et al. have offered a point system to combine the ENETS/
AJCC staging with proliferation index, patient age, and
sex into a prediction of patient survival [61].
22.2.2.4 Imaging studies
Pancreatic NETs may have characteristic imaging features
on CT [62]. Smaller tumors tend to be more homogeneous, while larger tumors may be more heterogeneous,
with areas of cystic change, necrosis, and calcification.
Well-differentiated pNETs tend to be well circumscribed,
particularly compared with the more amorphous
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