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Tuesday, March 11, 2008

Pancreatic Neoplasms

Pancreatic neoplasias may be broadly classified as
ductal adenocarcinomas, neuroendocrine tumors,
and cystic tumors. Pancreatic ductal adenocarcinoma
for 90% of cancers of the pancreas and will be the main
focus of this chapter.



PANCREATIC ADENOCARCINOMA
The American Gastroenterological Association (AGA) has
published guidelines on the diagnosis and treatment
of pancreatic ductal adenocarcinoma. The following
discussion integrates the AGA guidelines.
PREVALENCE
Pancreatic cancer is the fourth and fifth most common
cancer in men and women respectively. It accounts for
more than 30,000 new cases and 20,000 cancer-related
deaths each year. Most patients are more than 60 years
old (male-to-female ratio 2:1). It has the lowest 5-year
survival of any cancer because of late diagnosis and
low resection rates.
RISK FACTORS

The AGA guidelines list several genetic, environmental,
and disease-related risk factors for pancreatic adenocarcinoma.
A consistent association has been demonstrated between
cigarette smoking and the development of pancreatic
cancer. The AGA guidelines recommend cessation of
smoking for the purpose of pancreatic cancer prevention.
Dietary factors such as high meat and fish consumption also
increase the risk. Based on animal experiments, the aromatic
amines present in cigarette smoke, meats, and fish oil may
be the specific pathogenic factor predisposing to neoplastic
transformation. Occupations with a high exposure to
amines (chemistry, hairdressing, rubber work) have been
found to confer an increased risk for pancreatic cancer.
Certain diseases predispose toward pancreatic cancer,
including chronic pancreatitis, diabetes mellitus,
and hereditary cancer syndromes (eg, familial
adenomatous polyposis, hereditary dysplastic nevus
syndromes). A family history of pancreatic cancer is
another important risk factor. Hereditary pancreatitis
is a genetic disease caused by a mutation of the
cationic trypsinogen gene. Patients with this disease
develop acute recurrent pancreatitis in childhood,
which usually progresses to chronic pancreatitis and
pancreatic cancer in early adulthood.

There is no compelling evidence to support a screening
strategy for at-risk patients. However, the AGA guidelines
recommend initiating screening with CT and endoscopic
ultrasound (if the CT findings are negative) 10 years before
the earliest known case of pancreatic cancer in
families with cancer syndromes and after age 35 in
hereditary pancreatitis.

SIGNS AND SYMPTOMS

Sixty percent of pancreatic cancers develop in the
pancreatic head; 40% develop in the body and tail.
The major symptoms include abdominal pain,
anorexia, weight loss, and jaundice. The pain is
located in the epigastrium and has a quality characterized
as deep and boring. The pain may be intermittent
or constant, and is progressive. Painless jaundice
indicates a potentially resectable lesion located in
the pancreatic head. A predominance of abdominal
pain suggests neural plexus involvement, location in
the tail, unresectability, and a poor prognosis.

Pruritis and steatorrhea are suggestive of biliary
and pancreatic duct obstruction, respectively.
Physical examination findings include jaundice,
cachexia, a palpable abdominal mass, ascites,
left cervical lymphadenopathy (Virchow's node),
a palpable gallbladder (Courvoisier's sign),
and migratory superficial thrombophlebitis
(Trousseau's syndrome). Commonly observed
laboratory features of pancreatic cancer include
a mild, normocytic anemia, hypoalbuminemia,
hyperbilirubinemia, hypercalcemia, and elevated
sedimentation rate.

DIAGNOSIS

The diagnosis and staging of pancreatic cancer is
accomplished through imaging tests and pathologic diagnosis.
According to the AGA guidelines, the best initial imaging test
for diagnosis and staging of pancreatic cancer is
contrast-enhanced, dual-phase, helical computed tomography
(CT) with thin cuts through the pancreas. CT allows assessment
of the primary tumor, local invasiveness, regional lymph node
involvement, liver metastases, and peritoneal spread. The
sensitivity of helical CT for the detection of pancreatic cancer
ranges from 85% to 95%; however, this is highly dependent
on tumor size. Dual-phase CT helps to determine surgical
resectability through assessment of invasion of major vessels.
Although CT is the best imaging test for metastatic
disease, it may underestimate hepatic and lymph node
involvement because small nodes may contain cancer
and diminutive hepatic lesions may be missed.

Magnetic resonance imaging (MRI) with gadolinium
enhancement compares favorably with CT in the
assessment of local tumor extent, relationship to
vascular structures, lymph node involvement, and distant
metastases. MRI may improve differentiation of a
pancreatic cancer from chronic pancreatitis in
evaluating a pancreatic head mass, and offers
simultaneous assessment of the pancreatic and
bile ducts by heavily T2-weighted imaging
(MR-cholangiopancreatography).
(See Disease Management chapter, Chronic Pancreatitis).

Endoscopic ultrasound (EUS) is an accurate test for
diagnosing and staging pancreatic ductal cancer.
Several studies have demonstrated increased sensitivity
and specificity of EUS compared with conventional,
single-phase CT for the detection and local staging
of pancreatic cancer. However, more recent studies
have shown similar test characteristics for EUS
compared with dual-phase CT. The AGA guidelines
suggest that EUS has the greatest role in the
detection of small tumors missed by CT.

EUS may offer a better assessment of local blood-vessel
involvement, and allows fine needle aspiration (FNA) of tumor
and lymph nodes. Disadvantages include increased
invasiveness, operator dependence, lack of widespread
availability, and inability to detect distant metastasis.

The role of endoscopic retrograde cholangiopancreatography
(ERCP) in the diagnosis of pancreatic disease has diminished
in recent years as a result of improved noninvasive and
less-risky imaging techniques. ERCP is most useful for
detecting small tumors not visualized by CT, palliating
unresectable tumors causing biliary obstruction, and
ruling out differential causes of pain or jaundice
(ie, bile duct stones, chronic pancreatitis, intraductal papillary
mucinous tumor, or ampullary cancer). ERCP has a >90%
sensitivity for the diagnosis of pancreatic cancer. Diagnostic
features detectable on ERCP include an irregular, solitary
pancreatic duct stenosis >1 cm long, an abrupt cutoff of
the main pancreatic duct, or an obstruction of both
pancreatic and bile ducts (double-duct sign) . Importantly,
none of these findings is specific for pancreatic cancer
as they may also be observed in chronic pancreatitis.
Brush cytology from the pancreatic duct has fair
sensitivity (about 70%) but excellent specificity
for the diagnosis of adenocarcinoma.

Tumor markers are valuable adjunctive tests in the
diagnosis of gastrointestinal cancers. A CA19-9
concentration >70 U/mL has a sensitivity of 70%
and specificity of 87% for pancreatic cancer. CA19-9
may also be significantly elevated in benign
conditions such as choledocholithiasis and cholangitis.
In the absence of a mass, elevated CA19-9 and other
tumor markers are difficult to interpret, and tests for
those markers should not be routinely ordered. Elevated
of islet amyloid polypeptide have been found in
pancreatic cancer compared with controls, and may
hold promise in the early detection of pancreatic
cancer. Specific genetic mutations of the K-ras
oncogene, c-erb B-12 oncogene, and p16 tumor
suppressor genes have also been described in pancreatic
cancer and may have a future role in screening high-risk
individuals.

Biopsy of a pancreatic mass or metastasis may be
obtained percutaneously under CT guidance or by
EUS with FNA. EUS/FNA has been shown to be
relatively safe and offers improved sensitivity for small
tumors in close proximity to vascular structures.
Biopsy is indicated in unresectable disease to confirm
the diagnosis and aid in decision-making regarding
chemotherapy and radiation therapy. The use of biopsy
in presumed resectable disease is more controversial.
Critics of routine biopsy argue that the theoretical risk
of peritoneal seeding and inherent risks of the biopsy
procedure (hemorrhage, perforation) outweigh the
low potential benefit. Proponents of routine biopsy
cite the rare possibility of detecting a chemosensitive
tumor (lymphoma) and the desire of many patients to
know their diagnosis before major surgery. The AGA
guidelines recommend FNA only for patients with
unresectable lesions; however, individual circumstances
may dictate otherwise.

All the current imaging tests may underestimate tumor,
nodal, and metastatic staging. Staging laparoscopy with
or without laparoscopic ultrasound improves accuracy
through detection of small hepatic or peritoneal
metastases, widespread sampling of regional lymph
nodes, and direct visualization of the primary tumor
and its relationship to peripancreatic vessels. The AGA
guidelines recommend staging laparoscopy if there
is a high likelihood of unresectability that has not been
confirmed by imaging tests. See for a suggested
diagnostic algorithm for pancreatic cancer incorporating
the AGA guidelines.

THERAPY

The only potentially curative therapy for pancreatic cancer
is surgical resection. Pancreatic cancer is resectable if the
tumor is confined to the pancreas without: (1)
encasement of adjacent surrounding major vessels
(superior mesenteric artery or vein, portosplenic
confluence, celiac trunk or aorta); (2) extensive
peripancreatic lymph node involvement; or (3)
distant metastases. Unfortunately, because of late
presentation and delay in diagnosis, only 20%
of patients present with resectable disease. The
long-term prognosis is poor even among those who
undergo resection and have tumor-free margins
(5-year survival after resection, 10% to 25%);
however, outcomes may be improving with the
advent of superior diagnostic and surgical techniques.
the only chance of cure is through resection,
all patients with potentially resectable lesions by
CT criteria should be referred for surgical consultation
in a high-volume center. The AGA guidelines state,
"the bias is toward interpretation of imaging test results
as indicating resectable tumors because an aggressive
surgical approach is safe in experienced hands."

The standard operation for adenocarcinoma in the pancreatic
head or uncinate process is the pancreaticoduodenectomy,
or "Whipple operation." The Whipple operation involves
resection of the pancreatic head, duodenum, common
bile duct, distal stomach, and gallbladder.
Reconstruction involves pancreaticojejunostomy,
hepatoicojejunostomy, and gastrojejunostomy. This
extensive surgery is best performed in a high-volume
center to minimize the risk of perioperative complications.
Although the perioperative mortality in high-volume
centers is <2%,>

The AGA guidelines stress the importance of cardiac,
pulmonary, and nutritional optimization before pancreatic
surgery. Although frequently performed, routine preoperative
endoscopic biliary decompression is not beneficial and
may actually worsen outcomes. The AGA guidelines
recommend preoperative biliary stenting for jaundiced
patients in whom surgery will be delayed for several weeks
or in patients with unresectable tumors.

Although chemo- and radiotherapy are not curative, they
may offer some clinical benefits, including shrinkage
of the primary tumor, improvement of symptoms, and
prolongation of survival. These modalities have been
studied in locally metastatic disease, advanced disease,
and as surgical adjuvant therapies. The AGA guidelines state:
"all patients with unresectable locoregional or metastatic
pancreatic cancer should be considered for inclusion into
investigational trials."

Single-agent gemcitabine is often administered in
patients with advanced, metastatic pancreatic cancer.
Studies with gemcitabine have demonstrated a significant
clinical response (decreased pain, increased functional
status) even in the absence of a measurable tumor
response. The AGA guidelines state that gemcitabine is
an option for treatment of all patients with poor performance
status and/or pain or for management of metastatic disease.
Patients with locally advanced cancer may be considered
for combined 5-fluorouracil-based chemotherapy and external
beam radiation. The combination of these modalities has
been shown to improve median survival by several months
compared with radiation therapy alone. The benefit of
chemotherapy and radiation as therapies adjuvant to surgical
resection is not yet settled. The AGA guidelines state that
5-fluorouracil-based adjuvant chemotherapy should be considered
after surgical resection. Patients who undergo surgical resection
may also be encouraged to enter therapeutic trials of adjuvant therapy.

The palliation of symptoms is arguably the most important
goal in patients with locally advanced and metastatic disease.
Patients with pancreatic cancer may develop debilitating
symptoms of pain (neural plexus invasion), jaundice
(biliary obstruction), or vomiting (gastric outlet obstruction).
Pain can usually be managed with escalating doses of
narcotic agents. In spite of their benefits, narcotics may
produce constipation and depressed mental status.
Celiac nerve blocks (CT- or EUS-guided) or thorascopic
splanchnicectomy may offer significant pain control
and decrease narcotic requirements. Diarrhea and
weight loss from maldigestion may be palliated through
the use of pancreatic enzymes (30,000 IU or 90,000 US
Pharmacopeia units lipase per meal). Enzymes are best
dosed as follows: one third of the dose at onset of meal,
one third during meal, and one third at the end of meal.

Surgical biliary bypass is the optimal management
of biliary obstruction; however, many patients do not
undergo this procedure because of increased surgical risk.
Patients with high surgical risk may receive percutaneous
or endoscopic stenting of the bile duct. Metal stents offer
more prolonged patency; however, they cannot be removed
and should be reserved for patients with severely
advanced disease. Endoscopic plastic stents should be
changed every 3 months to minimize the risk of cholangitis.

Gastric outlet obstruction develops in 10% to 15% of
patients and may be managed by surgical gastrojejunostomy
or endoscopic stenting. Not all vomiting arises from outlet
obstruction; many patients have impaired gastric motility as a
result of the local invasion of nerve fibers.

PANCREATIC
NEUROENDOCRINE TUMORS

Also known as islet-cell tumors, neuroendocrine tumors
(NETs) are rare tumors (incidence rate, 5 cases per million
person years) that arise from endocrine cells within or near the
pancreas . The National Comprehensive Cancer Network (NCCN)
has practice guidelines for diagnosis and management of the
different types of NETs.NETs may occur sporadically or as part
of the multiple endocrine neoplasia type 1. Most primary NETs
arise within the "gastrinoma triangle," composed of the joining
of the cystic and common hepatic ducts, the joining of the
second and third portions of the duodenum, and the border of the
body and tail of the pancreas. Although a subset of NETs is
nonfunctional, most secrete hormones leading to a variety
of clinical syndromes. Patients with insulinoma present
with symptomatic hypoglycemia from hyperinsulinemia.
Gastrinomas produce recalcitrant peptic ulcer disease
resulting from hypergastrinemia (Zollinger-Ellison syndrome).
Less commonly encountered NETs include glucagonoma,
VIPoma (secreting vasoactive intestinal polypeptide),
somatostatinoma, and PPoma (secreting pancreatic
polypeptide). Carcinoid tumors are also NETs; however,
they are rarely found in the pancreas. Most NETs are
listed in the differential diagnosis for secretory diarrhea,
although the yield of testing in this setting is extremely low.
NETs may be suspected based on symptoms related to the
secretory product.

Nonfunctional tumors are occasionally detected on imaging
tests done for other indications or for abdominal pain in patients
with significant tumor growth. They are most often
indolent but may demonstrate malignant behavior, including
metastases. The prognosis for nonfunctional tumors may be
poorer than that of functional tumors because of a delay in
diagnosis.

When a NET is suspected based on laboratory testing,
imaging tests are important to locate the primary tumor
and determine the presence of metastases. NETs may be
difficult to localize with available imaging tests. Both
contrast-enhanced CT and MRI may be employed as
initial tests; however, they have a low yield for small
tumors. EUS is a more sensitive test for detecting
small pancreatic neuroendocrine tumors, and allows
simultaneous FNA for tissue diagnosis. Disadvantages
of EUS include increased invasiveness, inability to
consistently visualize the pancreatic tail, and lack
of widespread availability. Functional tests may be helpful
in localizing NETs not detected on standard imaging tests.
Nuclear imaging after administration of radiolabeled
octreotide can aid in location of most neuroendocrine
tumors. Insulinomas are not well visualized with octreotide
scans because they do not possess high concentrations
of somatostatin receptors.

NETs confined to the pancreas should be surgically
resected, either through enucleation or more extensive
resection of the head (Whipple procedure), body, or tail
of the pancreas. Before resection, symptoms of hormonal
excess must be treated and controlled. Treatment
measures for hormonal excess syndromes are summarized in .
Patients with metastatic disease can be managed medically
with octreotide, chemotherapy (streptazocin), or radiographic
embolization of the primary tumor and metastases. Debulking
of primary and metastatic disease may also be considered
patients with debilitating symptoms related to tumor secretory
products. A general management approach to pancreatic
NETs is shown in . More detailed recommendations
for diagnosis and treatment of specific types of NETs are
found on the NCCN website.

PANCREATIC CYSTIC NEOPLASMS

Up to 90% of pancreatic cysts are inflammatory pseudocysts
arising from acute or chronic pancreatitis. Other types of
pancreatic cysts include simple cysts and cystic

neoplasms. Cystic neoplasms are reported to account for <1%>

The primary aim of diagnosis is to differentiate benign
(pseudocysts, serous tumors) from malignant
(mucinous tumors, IPMNs) cysts. Small (<1>

Via: http://www.clevelandclinicmeded.com

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