Академический Документы
Профессиональный Документы
Культура Документы
Pancreatic cancer is the fourth leading cause of cancer deaths, being responsible for 7% of all
cancer-related deaths in both men and women. Approximately 75% of all pancreatic
carcinomas occur within the head or neck of the pancreas, 15-20% occur in the body of the
pancreas, and 5-10% occur in the tail. See the image below.
Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm
resected from the pancreatic body and tail. Although the tumor was considered to have been
fully resected and had not spread to any nodes, the patient died of recurrent cancer within 1
year.
View Media Gallery
Signs and symptoms
The initial symptoms of pancreatic cancer are often quite nonspecific and subtle in onset.
Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise,
nausea, fatigue, and midepigastric or back pain.
Patients with pancreatic cancer may present with the following signs and symptoms:
Significant weight loss: Characteristic feature of pancreatic cancer
Midepigastric pain: Common symptom of pancreatic cancer, sometimes with radiation
of the pain to the midback or lower-back region
Often, unrelenting pain: Nighttime pain often a predominant complaint
Onset of diabetes mellitus within the previous year
Painless obstructive jaundice: Most characteristic sign of cancer of head of the pancreas
Pruritus: Often the patient's most distressing symptom
Depression
Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis: May be the
first presentation
Palpable gallbladder (ie, Courvoisier sign)
Developing, advanced intra-abdominal disease: Presence of ascites, a palpable
abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein
obstruction
Advanced disease: Paraumbilical subcutaneous metastases (or Sister Mary Joseph
nodule or nodules)
Possible presence of palpable metastatic mass in the rectal pouch (Blumer shelf)
Possible presence of palpable metastatic cervical nodes: Nodes may be palpable behind
the medial end of the left clavicle (Virchow node) and other areas in the cervical region
See Clinical Presentation for more detail.
Diagnosis
Pancreatic cancer is notoriously difficult to diagnose in its early stages. [93]
Testing
The laboratory findings in patients with pancreatic cancer are usually nonspecific. Patients
with advanced pancreatic cancers and weight loss may have general laboratory evidence of
malnutrition (eg, low serum albumin or cholesterol level).
Potentially useful tests in patients with suspected pancreatic cancer include the following:
CBC count
Hepatobiliary tests: Patients with obstructive jaundice show significant elevations in
bilirubin (conjugated and total), ALP, GGT, and, to a lesser extent, AST and ALT
Serum amylase and/or lipase levels: Elevated in less than 50% of patients with
resectable pancreatic cancers and in only 25% of patients with unresectable tumors
Tumor markers such as CA 19-9 antigen and CEA: 75-85% have elevated CA 19-9
levels; 40-45% have elevated CEA levels
Imaging studies
Imaging studies that aid in the diagnosis of pancreatic cancer include the following:
CT scanning
Transcutaneous ultrasonography
Endoscopic ultrasonography
Magnetic resonance imaging
Endoscopic retrograde cholangiopancreatography
Positron emission tomography scanning
See Workup for more detail.
See also Pancreatic Adenocarcinoma Imaging: What You Need to Know, a Critical Images
slideshow, to help identify which imaging studies to use to identify and evaluate this disease.
Management
Surgery is the primary mode of treatment for pancreatic cancer. However, an important role
exists for chemotherapy and/or radiation therapy.
Surgical options
Curative resection options include the following:
Pancreaticoduodenectomy (Whipple Procedure), with/without sparing of the pylorus
Total pancreatectomy
Distal pancreatectomy
Chemotherapy
Antineoplastic agents and combinations of agents used in managing pancreatic carcinoma
include the following:
Gemcitabine monotherapy: For symptomatic patients with metastatic or locally
advanced unresectable disease with poor performance status [1]
GTX regimen (gemcitabine, docetaxel and capecitabine) [1]
Gemcitabine and albumin-bound paclitaxel [1]
FOLFIRINOX (LV5-FU [leucovorin/5-fluorouracil] plus oxaliplatin plus irinotecan):
National Comprehensive Cancer Network recommends as first-line treatment for
patients with metastatic or locally advanced unresectable disease with good
performance status [1, 2]
Paclitaxel protein bound 125 mg/m2 plus gemcitabine 1000 mg/m2 IV over 30-40 min
on Days 1, 8, and 15 of each 28-day cycle [3, 4]
5-FU
Erlotinib plus gemcitabine
Capecitabine monotherapy or capecitabine plus erlotinib: May provide second-line
therapy benefit in patient's refractory to gemcitabine [5]
Adjuvant therapy with gemcitabine is accepted as standard therapy for surgically resected
pancreatic cancer. [6]
Neoadjuvant therapy
The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a
source of controversy. The rationale for using neoadjuvant therapy includes the assertions
that (1) pancreatic cancer is a systemic disease and should be treated systemically from the
start, (2) patients will be able to tolerate the toxic effects of chemotherapy more readily
before undergoing major pancreatic resection than after, and (3) the tumor will shrink with
neoadjuvant therapy, and the resection will be less cumbersome, leading to an improved
overall survival.
Palliative Therapy
Palliative therapy may be administered for the following conditions associated with
pancreatic cancer:
Pain: Pain relief is crucial for patients not undergoing resection for pancreatic cancer;
narcotic analgesics should be used early and in adequate dosages
Jaundice: Obstructive jaundice warrants palliation if the patient has pruritus or right
upper quadrant pain or has developed cholangitis
Duodenal obstruction secondary to pancreatic carcinoma: Can be palliated operatively
with a gastrojejunostomy or an endoscopic procedure
See Treatment and Medication for more detail.
Background
Although pancreatic cancer accounts for only about 3% of all cancers in the United States, it
is the fourth leading cause of cancer deaths in both men and women, being responsible for
7% of all cancer-related deaths. The average lifetime risk of developing pancreatic cancer is
about 1 in 67. [7] (See Epidemiology.)
Pancreatic cancer is notoriously difficult to diagnose in its early stages. At the time of
diagnosis, 52% of all patients have distant disease and 26% have regional spread. The relative
1-year survival rate for pancreatic cancer is only 28%, and the overall 5-year survival is
7%. [8] (See Prognosis and Workup.)
Types of pancreatic cancer
Of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of
tumors of the exocrine pancreas are benign. (See Etiology and Histologic Findings.)
Less common histologic appearances of exocrine pancreatic cancers include giant cell
carcinoma, adenosquamous carcinoma, microglandular adenocarcinoma, mucinous
carcinoma, cystadenocarcinoma, papillary cystic carcinoma, acinar cystadenocarcinoma, and
acinar cell cystadenocarcinoma. Very rarely, primary connective tissue cancers of the
pancreas can occur. The most common of these is primary pancreatic lymphoma.
An adenocarcinoma of the pancreas is seen below. (See Histologic Findings.)
Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm
resected from the pancreatic body and tail. Although the tumor was considered to have been
fully resected and had not spread to any nodes, the patient died of recurrent cancer within 1
year.
Pathophysiology
Typically, pancreatic cancer first metastasizes to regional lymph nodes, then to the liver and,
less commonly, to the lungs. It can also directly invade surrounding visceral organs such as
the duodenum, stomach, and colon, or it can metastasize to any surface in the abdominal
cavity via peritoneal spread. Ascites may result, and this has an ominous prognosis.
Pancreatic cancer may spread to the skin as painful nodular metastases. Metastasis to bone is
uncommon.
Pancreatic cancer rarely spreads to the brain, but it can produce meningeal carcinomatosis.
Etiology
Pancreatic cancers can arise from the exocrine and endocrine portions of the pancreas, but
95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells,
connective tissue, and lymphatic tissue. Approximately 75% of all pancreatic carcinomas
occur within the head or neck of the pancreas, 15-20% occur in the body of the pancreas, and
5-10% occur in the tail.
Tobacco smoking is the most common recognized risk factors for pancreatic cancer. Others
include obesity, high alcohol consumption, history of pancreatitis and diabetes, family history
of pancreatic cancer, and possibly selected dietary factors. [94] Only 5-10% are hereditary in
nature. [9]
Because excess risk for pancreatic cancer is greater in patients recently diagnosed with
diabetes mellitus, it has been suggested that diabetes may be at least in part a consequence or
an early manifestation of pancreatic cancer. However, the International Pancreatic Cancer
Case-Control Consortium reported that a 30% excess risk for pancreatic cancer persists for
more than 2 decades after diabetes diagnosis, which supports the hypothesis that diabetes has
a causal role in pancreatic cancer. [37]
Less than 5% of all pancreatic cancers are related to underlying chronic pancreatitis. Alcohol
consumption does not appear to be an independent risk factor for pancreatic cancer unless it
is associated with chronic pancreatitis.
The risk factors for pancreatic cancer are discussed in more detail below.
Smoking
Smoking is the most common environmental risk factor for pancreatic carcinoma. Estimates
indicate that smoking accounts for up to 30% of cases of pancreatic cancer.
People who smoke have at least a 2-fold greater risk for pancreatic cancer than do
nonsmokers. Current smokers with over a 40 pack-year history of smoking may have up to a
5-fold risk greater risk for the disease. Smokeless tobacco also increases the risk of pancreatic
cancer.
It takes 5-10 years of discontinued smoking to reduce the increased risk of smoking to
approximately that of nonsmokers.
Obesity and dietary factors
In a number of studies, obesity, especially central, has been associated with a higher
incidence of pancreatic cancer. For example, Li et al found that being overweight or obese
during early adulthood was associated with a greater risk of pancreatic cancer and a younger
age of disease onset, while obesity at an older age was associated with lower overall
survival. [10] Several other studies have supported a link between early obesity and the risk of
pancreatic cancer. [11, 12]
The incidence of pancreatic cancer is lower in persons with a diet rich in fresh fruits and
vegetables. Fruits and vegetables rich in folate and lycopenes (such as tomatoes) may be
especially good at reducing the risk of pancreatic cancer. [13, 14]
Consumption of red meat, especially of the processed kinds, is associated with a higher risk
of pancreatic cancer. Poultry and dairy product consumption does not increase the risk of this
disease. [15]
Despite early reports to the contrary, coffee consumption is not associated with an increased
risk of pancreatic cancer. [16]
Diabetes mellitus
Numerous studies have examined the relative risk of pancreatic cancer in persons with
diabetes mellitus. A systematic review of 30 studies concluded that patients with diabetes
mellitus of at least 5-years' duration have a 2-fold increased risk of developing pancreatic
carcinoma. Pancreatic cancer may follow 18-36 months after a diagnosis of diabetes mellitus
in elderly patients with no family history of diabetes mellitus.
The National Comprehensive Cancer Network (NCCN) acknowledges long-standing
diabetes mellitus as a risk factor for pancreatic cancer. The NCCN also notes an association
between sudden onset of type II diabetes mellitus in an adult older than 50 years and a new
diagnosis of pancreatic cancer, although in those cases the diabetes is thought to be caused by
the cancer. [1]
Chronic pancreatitis
Long-standing, chronic pancreatitis is a substantial risk factor for the development of
pancreatic cancer. A multicenter study of more than 2000 patients with chronic pancreatitis
showed a 26-fold increase in the risk of developing pancreatic cancer. This risk increased
linearly with time, with 4% of patients who had chronic pancreatitis for 20 years' duration
developing pancreatic cancer. [17]
The risk of pancreatic cancer is even higher in patients with hereditary pancreatitis. The mean
age of development of pancreatic cancer in these patients is approximately 57 years. The
relative risk of pancreatic cancer in hereditary pancreatitis is increased more than 50-fold, and
the cumulative risk rate of pancreatic cancer by age 70 years is 40%.
This cumulative risk increases to 75% in persons whose family has a paternal inheritance
pattern. [18]
Chronic pancreatitis from alcohol consumption is also associated a much higher incidence
and an earlier age of onset of pancreatic carcinoma. [19]
Genetic factors
Approximately 5-10% of patients with pancreatic carcinoma have some genetic
predisposition to developing the disease. [20]
The molecular genetics of pancreatic adenocarcinoma have been well studied. [21,22, 23] Of
these tumors, 80-95% have mutations in the KRAS2 gene; 85-98% have mutations, deletions,
or hypermethylation in the CDKN2 gene; 50% have mutations in p53; and about 55% have
homozygous deletions or mutations in Smad4. Some of these mutations can also be found in
high-risk precursors of pancreatic cancer. For example, in chronic pancreatitis, 30% of
patients have detectable mutations in p16 and 10% have K-ras mutations.
Families with BRCA-2 mutations, which are associated with a high risk of breast cancer, also
have an excess of pancreatic cancer. [24]
Assaying pancreatic juice for the genetic mutations associated with pancreatic
adenocarcinoma is invasive, but it may be useful for the early diagnosis of the
disease. [25] However, this approach is problematic, because genetic mutations in the
pancreatic juice may be found in patients with inflammatory pancreatic disease.
Certain precursor lesions have been associated with pancreatic tumors arising from the ductal
epithelium of the pancreas. The main morphologic form associated with ductal
adenocarcinoma of the pancreas is pancreatic intraepithelial neoplasia (PIN). These lesions
arise from specific genetic mutations and cellular alterations that contribute to the
development of invasive ductal adenocarcinoma. [26]
The initial alterations appear to be related to KRAS2 gene mutations and telomere shortening.
Thereafter, p16/CDKN2A is inactivated. Finally, the inactivation of TP53 and MAD4/DPC4
occur. These mutations have been correlated with increasing development of dysplasia and
thus with the development of ductal carcinoma of the exocrine pancreas.
Based on more recent data from sequencing of human tumors, pancreatic cancer is a
genetically complex and heterogeneous disease. [27] This is confounded by considerable
variability in terms of the genetic malformations and pathways involved between individual
tumors. In addition, the long time from early to clinically manifested disease (21.2 y on
average) allows for an accumulation of complex genetic changes, which probably explains
the fact that it is often resistant to chemotherapy and radiation therapy. [28, 29]
The inherited disorders that increase the risk of pancreatic cancer include hereditary
pancreatitis, multiple endocrine neoplasia (MEN), hereditary nonpolyposis rectal
cancer (HNPCC), familial adenomatous polyposis (FAP) and Gardner syndrome, familial
atypical multiple mole melanoma (FAMMM) syndrome, von Hippel-Lindau
syndrome (VHL), and germline mutations in the BRCA1 and BRCA2 genes.
Hereditary pancreatitis has been associated with a 40% cumulative risk of developing
pancreatic cancer at 40%. [18] MEN-1 and VHL are other genetic syndromes associated with
pancreatic endocrine tumor development.
Patients with MEN-1 develop symptomatic pancreatic endocrine tumors about 50% of the
time, and these pancreatic tumors are noted to be the leading cause of disease-specific
mortality. [30] Von Hippel-Lindau syndrome has been associated with malignancy in 17% of
masses found in the pancreas in people with this syndrome. [31]
Syndromes associated with an increased risk of the development of colon cancer, such as
HNPCC and FAP (and Gardner syndrome), have also shown an increased correlation with
existence of pancreatic cancer, but the statistics have not been impressive.
In a cohort study of 1391 patients with FAP, only 4 developed pancreatic adenocarcinoma.
No statistics are available to show the incidence of pancreatic cancer in patients with
HNPCC. [32]
FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to
22-fold and the incidence in sporadic cases to be 98%. [33]
The above disorders have specific genetic abnormalities associated with the noted increased
risk of pancreatic cancer. Pancreatic cancer in hereditary pancreatitis is associated with a
mutation in the PRSS1 gene. Pancreatic cancer appearing in FAP and HNPCC has been
associated with a mutation in the APC gene and MSH2 and MLH1 genes respectively.
FAMMM and pancreatic cancer has been associated with a mutation in CDKN2A. Endocrine
tumors of the pancreas associated with VHL are thought to develop by way of the
inactivation of the VHL tumor suppressor gene.[20]
Germline mutations in BRCA1 and BRCA2 have been shown to moderately increase the risk
of developing pancreatic cancer by 2.3- to 3.6-fold, but BRCA2 has been associated more
commonly with pancreatic cancer, at an incidence of 7%. [20]
Race-related factors
Black males in the United States have the highest incidence rate of pancreatic cancer. [34] (See
Epidemiology, below.) The reasons for the higher incidence of pancreatic cancer in African
Americans are unclear. Certainly, differences in risk factors for pancreatic cancer, such as
dietary habits, obesity, and the frequency of cigarette smoking, are recognized among
different population groups and may contribute to the higher incidence of this disease among
blacks.
However, Arnold et al found that excess pancreatic cancer in blacks cannot be attributed to
currently known risk factors, suggesting that as-yet undetermined factors play a role in the
disease process. [35] One possibility is a difference in the underlying frequency of predisposing
genetic mutations for pancreatic cancer.
Epidemiology
Incidence in the United States
The American Cancer Society estimates that in the United States in 2017, about 53,670 new
cases of pancreatic cancer (27,970 in men and 25,700 in women) will be diagnosed. [7] In
whites, the overall incidence rate of pancreatic cancer increased by about 1% per year from
2004 to 2013, but in blacks the rate remained stable. [8]
International incidence
Worldwide, pancreatic cancer ranks 13th in incidence but 8th as a cause of cancer death. [36]
Most other countries have incidence rates of 8-12 cases per 100,000 persons per year. In
some areas of the world, pancreatic cancer is quite infrequent; for example, the incidence in
India is less than 2 cases per 100,000 persons per year.
Race predilection
The highest incidence rate of pancreatic cancer is 16.2 cases per 100,000 persons per year, in
black males in the United States. [34] The incidence for black females in the United States was
12.4 cases per 100,000 persons per year from 2001 to 2005.
For white males in the United States from 2001 to 2005, the incidence was 12.1 cases per
100,000 persons per year, and for white females, the incidence was 9.1 cases per 100,000
persons per year. [34]
Native Hawaiian males and men of Korean, Czech, Latvian, and New Zealand Maori
ancestry also have high incidence rates: 11 cases per 100,000 persons per year.
Age predilection
In the absence of predisposing conditions, such as familial pancreatic cancer and chronic
pancreatitis, pancreatic cancer is unusual in persons younger than 45 years. After age 50
years, the frequency of pancreatic cancer increases linearly.
The median age at diagnosis is 69 years in whites and 65 years in blacks; some single-
institution data reported from large cancer centers suggest that the median age at diagnosis in
both sexes has fallen to 63 years of age.
Mortality
Although pancreatic cancer constitutes only about 3% of all cancers in the United States, it is
the fourth leading cause of cancer deaths in both men and women, being responsible for 7%
of all cancer-related deaths. [7] The death rate from the disease rose from 5 per 100,000
population in 1930 to more than 10 per 100,000 in 2003. The American Cancer Society
estimates that in the United States in 2014, about 39,590 people (20,170 men and 19,420
women) will die of pancreatic cancer.[8]
Prognosis
Pancreatic carcinoma is unfortunately usually a fatal disease. The collective median survival
time for all patients is 4-6 months.
The relative 1-year survival rate for patients with pancreatic cancer is only 28%, and the
overall 5-year survival rate is 7%, having increased from the 3% rate as calculated between
1975 and 1977. [8] (However, patients with neuroendocrine and cystic neoplasms of the
pancreas, such as mucinous cystadenocarcinomas or intraductal papillary mucinous
neoplasms [IPMN], have much better survival rates than do patients with pancreatic
adenocarcinoma.)
A 5-year survival in pancreatic cancer is no guarantee of cure; patients who survive for 5
years after successful surgery may still die of recurrent disease years after the 5-year survival
point. The occasional patient with metastatic disease or locally advanced disease who
survives beyond 2-3 years may die of complications of local spread, such as bleeding
esophageal varices.
In patients able to undergo a successful curative resection (about 20% of patients), median
survival time ranges from 12-19 months, and the 5-year survival rate is 15-20%. The best
predictors of long-term survival after surgery are a tumor diameter of less than 3 cm, no
nodal involvement, negative resection margins, and diploid tumor deoxyribonucleic acid
(DNA) content.
The median survival for patients who undergo successful resection (only 20% of patients) is
approximately 12-19 months, with a 5-year survival rate of 15-20%.
Patient Education
Smoking is the most significant reversible risk factor for pancreatic cancer.
Alcohol consumption does not increase the risk of pancreatic cancer unless it leads to chronic
pancreatitis. A multicenter study of more than 2000 patients with chronic pancreatitis showed
a 26-fold increase in the risk of developing pancreatic cancer.[17]
For patient education information, see the Liver, Gallbladder, and Pancreas Centerand Cancer
and Tumors Center, as well as Pancreatitis and Pancreatic Cancer.
History
The early clinical diagnosis of pancreatic cancer is fraught with difficulty. Unfortunately, the
initial symptoms of the disease are often quite nonspecific and subtle in onset. Consequently,
these symptoms can be easily attributed to other processes unless the physician has a high
index of suspicion for the possibility of underlying pancreatic carcinoma.
Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise,
nausea, fatigue, and midepigastric or back pain.
Significant weight loss is a characteristic feature of pancreatic cancer.
Midepigastric pain is a common symptom of pancreatic cancer, with radiation of the pain to
the midback or lower-back region sometimes occurring. Radiation of the pain to the back is
worrisome, as it indicates retroperitoneal invasion of the splanchnic nerve plexus by the
tumor.
Often, the pain is unrelenting in nature, with nighttime pain often being a predominant
complaint. Some patients may note increased discomfort after eating. The pain may be worse
when the patient is lying flat.
Weight loss may be related to cancer-associated anorexia and/or subclinical malabsorption
from pancreatic exocrine insufficiency caused by pancreatic duct obstruction by the cancer.
Patients with malabsorption usually complain about diarrhea and malodorous, greasy stools.
Nausea and early satiety from gastric outlet obstruction and delayed gastric emptying from
the tumor may also contribute to weight loss.
The onset of diabetes mellitus within the previous year is sometimes associated with
pancreatic carcinoma. Even so, only about 1% of cases of new-onset diabetes mellitus in
adults are related to occult pancreatic cancer. [37] Nevertheless, pancreatic cancer should be at
least thought of in a patient older than 70 years with a new diagnosis of diabetes and without
any other diabetic risk factors.
The most characteristic sign of pancreatic carcinoma of the head of the pancreas is painless
obstructive jaundice. Patients with this sign may come to medical attention before their tumor
grows large enough to cause abdominal pain. These patients usually notice a darkening of
their urine and lightening of their stools before they or their families notice the change in skin
pigmentation.
Physicians can usually recognize clinical jaundice when the total bilirubin reaches 2.5-3
mg%. Patients and their families do not usually notice clinical jaundice until the total
bilirubin reaches 6-8 mg%. Urine darkening, stool changes, and pruritus are often noticed by
patients before clinical jaundice.
Pruritus may accompany and often precedes clinical obstructive jaundice. Pruritus can often
be the patient's most distressing symptom.
Depression is reported to be more common in patients with pancreatic cancer than in patients
with other abdominal tumors. In some patients, depression may be the most prominent
presenting symptom. This may in part be secondary to the high frequency of delayed
diagnosis with this disease. In addition, although patients may not communicate it to their
families, they are often aware that a serious illness of some kind is occurring in them.
A study by Turaga et al determined that male patients with pancreatic adenocarcinoma have a
risk of suicide that is almost 11 times higher than the remainder of the population. [38] Patients
who undergo surgery are more likely to commit suicide, specifically in the early
postoperative period.
Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis also occur with
higher frequency in patients with pancreatic cancer and may be the first presentation.
Marantic endocarditis may develop in pancreatic cancer, occasionally being confused with
subacute bacterial endocarditis.
Physical Examination
Pain is the most common presenting symptom in patients with pancreatic cancer. As
previously mentioned, the pain typically takes the form of mild to moderate midepigastric
tenderness. In some cases, radiation of the pain to the midback or lower-back region occurs.
Such radiation is worrisome, as it indicates retroperitoneal invasion of the splanchnic nerve
plexus by the tumor.
However, at the time of initial presentation, about one third of patients may not have pain,
one third have moderate pain, and one third have severe pain. All patients experience pain at
some point in their clinical course.
Patients with clinical jaundice may also have a palpable gallbladder (ie, Courvoisier sign) and
may have skin excoriations from unrelenting pruritus.
Patients presenting with or developing advanced intra-abdominal disease may have ascites, a
palpable abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal
vein obstruction.
Subcutaneous metastases (referred to as a Sister Mary Joseph nodule or nodules) in the
paraumbilical area signify advanced disease.
A metastatic mass in the rectal pouch may be palpable on rectal examination (Blumer's shelf).
A metastatic node may be palpable behind the medial end of the left clavicle (Virchow's
node). However, other nodes in the cervical area may also be involved. Indeed, prior to the
advent of computed tomography (CT) scanners to assess intra-abdominal disease, pancreatic
cancer accounted for some 25% of adenocarcinomas of the cervical nodes, primary site
unknown.
Diagnostic Considerations
Pancreatic cancer is notoriously difficult to diagnose in its early stages, when it is a protean
disease that can be difficult to distinguish from other, much more common disorders. For
example, the National Comprehensive Cancer Network (NCCN) recommends that clinicians
consider pancreatic cancer in patients with diabetes who have unusual symptoms such as
continuous weight loss and abdominal problems. [1]
Many patients have sought care for symptoms for weeks or months before receiving a
definitive diagnosis of pancreatic cancer; in the past, fewer than a third of patients were
diagnosed within 2 months of the onset of their symptoms. However, the availability of CT
scanning has shortened that interval. Even so, at the time of diagnosis, 52% of all patients
with pancreatic cancer have distant disease and 26% have regional spread.
In addition to the differentials listed in the next section, diseases that can mimic the
symptoms of pancreatic cancer include the following:
Abdominal aortic aneurysm
Ampullary carcinoma
Intestinal ischemia
Gastric lymphoma
Pancreatic lymphoma
Hepatocellular carcinoma (hepatoma)
Bile duct strictures
Bile duct tumors
Neoplasms of the endocrine pancreas
Differential Diagnoses
Acute Pancreatitis
Cholangitis
Cholecystitis
Choledochal Cysts
Chronic Pancreatitis
Gallstones (Cholelithiasis)
Gastric Cancer
Peptic Ulcer Disease
Approach Considerations
The laboratory findings in patients with pancreatic cancer are usually nonspecific. However,
a number of continually evolving imaging modalities are available to help diagnose
pancreatic carcinoma in patients in whom the disease is suggested clinically. These
include the following:
Computed tomography (CT)
Transcutaneous ultrasonography (TUS)
Endoscopic ultrasonography (EUS)
Magnetic resonance imaging (MRI)
Endoscopic retrograde cholangiopancreatography (ERCP)
Positron emission tomography (PET)
Which of these modalities is used at a particular institution may depend largely on the local
availability of and expertise with the procedure, as well as local cancer protocols. Additional
considerations in the choice of diagnostic modality include the following:
Accuracy for providing staging information
Allowance for simultaneous collection of tissue samples for cytologic or histologic
confirmation of the diagnosis
Capacity to facilitate therapeutic procedures, such as biliary stent placement or celiac
neurolysis
The most difficult clinical situation in which to diagnose pancreatic carcinoma is in the
patient with underlying chronic pancreatitis. In such cases, all of the above imaging studies
may show abnormalities that may not help to differentiate between pancreatic carcinoma and
chronic pancreatitis. Even tumor markers can be elevated in patients with chronic
pancreatitis. In these patients, one must often combine multiple imaging modalities, close
clinical follow-up, serial imaging studies, and, occasionally, empiric resection, to diagnose an
underlying pancreatic carcinoma.
Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information
on this topic.
Laboratory Findings
The laboratory findings in patients with pancreatic cancer are usually nonspecific. As with
many chronic diseases, a mild normochromic anemia may be present.
Thrombocytosis is also sometimes observed in patients with cancer.
Patients presenting with obstructive jaundice show significant elevations in bilirubin
(conjugated and total), alkaline phosphatase, gamma-glutamyl transpeptidase, and to a lesser
extent, aspartate aminotransferase and alanine aminotransferase.
Serum amylase and/or lipase levels are elevated in less than half of patients with resectable
pancreatic cancers and are elevated in only one quarter of patients with unresectable tumors.
However, about 5% of patients with pancreatic cancer present initially with acute
pancreatitis, in which case amylase and lipase would be uniformly elevated. Thus, pancreatic
cancer should be in the differential diagnosis of an elderly patient presenting for the first time
with acute pancreatitis without any known precipitating factors.
Liver metastases alone are not associated with clinical jaundice but may result in relatively
low-grade elevations of serum alkaline phosphatase and transaminase levels.
Patients with advanced pancreatic cancers and weight loss may also have general laboratory
evidence of malnutrition (eg, low serum albumin or cholesterol level).
Tumor Markers
Carbohydrate antigen 19-9
The CA 19-9 antigen is a sialylated oligosaccharide that is most commonly found on
circulating mucins in cancer patients. [39] It is also normally present within the cells of the
biliary tract and can be elevated in acute or chronic biliary disease. Some 5-10% of patients
lack the enzyme necessary to produce CA 19-9; in these patients with low or absent titer of
CA 19-9, monitoring disease with this tumor marker will not be possible.
The reference range of CA 19-9 is less than 33-37 U/mL in most laboratories. Of patients
with pancreatic carcinoma, 75-85% have elevated CA 19-9 levels. In the absence of biliary
obstruction, intrinsic liver disease, or benign pancreatic disease, a CA 19-9 value of greater
than 100 U/mL is highly specific for malignancy, usually pancreatic.
Evaluation of CA 19-9 levels has been used as an adjunct to imaging studies for helping to
determine the resectability potential of pancreatic carcinoma. Fewer than 4% of patients with
a CA 19-9 level of more than 300 U/mL have been found to have resectable tumors.
Unfortunately, CA 19-9 is least sensitive for small, early stage pancreatic carcinomas and
thus has not proven to be effective for the early detection of pancreatic cancer or as a
screening tool. [39]
An elevated CA 19-9 level is found in 0.2% of an asymptomatic population older than 40
years. Of these elevations, 80% are false-positive results. If only symptomatic patients are
studied, 4.3% have elevated CA 19-9 levels. Two thirds of these results are false positive.
Although no standardized role has been set for CA 19-9 in the diagnosis of pancreatic
carcinoma, it has growing importance in the staging and follow-up of patients with this
disease. Patients presenting with low levels of CA 19-9 (< 100 IU) are unlikely to have occult
metastatic disease and therefore may not need a staging laparoscopy prior to resection if other
imaging shows no advanced disease.
Additionally, during surgical, chemotherapeutic, and/or radiotherapeutic treatment for
pancreatic cancer, a falling CA 19-9 seems to be a useful surrogate finding for clinical
response to the therapy. If biliary obstruction is not present, a rising CA 19-9 suggests
progressive disease.
Preoperative CA 19-9 levels may be of prognostic value, with high levels indicating poorer
outcome and less chance of resectability. [40, 41] Preoperative values above 50 U/mL have been
shown to be associated with higher chances of recurrence.
Carcinoembryonic antigen
Carcinoembryonic antigen (CEA) is a high–molecular weight glycoprotein found normally in
fetal tissues. It has commonly been used as a tumor marker in other gastrointestinal
malignancies.
The reference range is less than or equal to 2.5 mg/mL.
Only 40-45% of patients with pancreatic carcinoma have elevated CEA levels.
Because benign and malignant conditions other than pancreatic cancer can lead to elevated
CEA levels, CEA is not a sensitive or specific marker for pancreatic cancer.
Research
Many other tumor markers have been studied in pancreatic cancer, but none has yet been
shown to have general clinical utility in this disorder. As with all cancers, there is growing
interest in molecular diagnosis using powerful techniques, such as gene expression
microarrays and proteomics. These novel tests are adding to our understanding of the basic
defects causing pancreatic neoplasms and pathobiology. However, these are still research
tools at present.
Computed Tomography
Because of its ubiquitous availability and its ability to image the whole abdomen and pelvis,
abdominal CT scanning continues to be the mainstay of initial diagnostic modalities used for
assessing patients suspected to have pancreatic carcinoma. (See the images below.)
Guidelines Summary
Guidelines Contributor: Lewis J Rose, MD Clinical Associate Professor of Medical
Oncology, Division of Regional Cancer Care, Kimmel Cancer Center, Thomas Jefferson
University Hospital; Consulting Staff, LRCRZ Associates
Screening
Guidelines on pancreatic cancer screening have been issued by the following organizations:
U.S. Preventive Services Task Force (USPSTF)
American Academy of Family Physicians (AAFP)
International Cancer of the Pancreas Screening (CAPS) Consortium
The USPSTF found no evidence that screening for pancreatic cancer is effective in reducing
mortality and recommends against routine screening in asymptomatic adults using abdominal
palpation, ultrasonography, or serologic markers. [86] The AAFP guidelines concur with the
USPSTF recommendation. [87]
The USPSTF did not review the effectiveness of screening individuals at high risk for
pancreatic cancer.
In 2012, the International CAPS Consortium, a panel of 49 multidisciplinary experts, released
consensus guidelines for pancreatic cancer screening. While also recommending against
routine screening in the general population, the members recommended screening with
endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI)/magnetic resonance
cholangiopancreatography (MRCP) for the following high-risk groups [88] :
Individuals with two or more blood relatives, and at least one first-degree relative, with
pancreatic cancer
Carriers of p16, PALB2, or BRCA2 mutations with a first-degree relative with
pancreatic cancer
All individuals with Peutz-Jeghers syndrome
Individuals with Lynch syndrome and a first-degree relative with pancreatic cancer
(In practice, however, many carriers of p16, PALB2, or BRCA2 mutations opt for screening
even if they do not have a relative with the disease.)
The panel agreed that to be considered successful, screening should detect and lead to
treatment of T1N0M0 margin-negative pancreatic cancer and high-grade dysplastic precursor
lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm).
However, the group did not reach consensus on the optimal management of detected lesions,
the age to begin screening, or screening intervals.
Use of Tumor Markers in Pancreatic Cancer
In its 2006 update, the American Society of Clinical Oncology (ASCO) expanded the scope
of the guidelines for use of tumor markers in gastrointestinal cancer to include CA 19-9 as a
marker for pancreatic cancer. The recommendations for evaluation of CA 19-9 levels are as
follows [39] :
CA 19-9 is least sensitive for small, early-stage pancreatic carcinomas and thus is not
effective for the early detection of pancreatic cancer or as a screening tool
Use of CA 19-9 levels alone is not recommended for use in determining operability
Rising levels of CA 19-9 postoperatively may predict recurrent disease, but
confirmation with imaging studies and/or biopsy is required.
CA 19-9 can be measured at the start of treatment for locally advanced metastatic
disease and every 1-3 months during active treatment; elevation of levels in serial
determinations may be an indication of progressive disease, but confirmation with other
studies is required
5-10% of patients lack the enzyme necessary to produce CA 19-9; in these patients with
low or absent titer of CA 19-9, monitoring disease with this tumor marker will not be
possible
Both the European Society of Medical Oncology (ESMO) and the National Comprehensive
Cancer Network (NCCN) guidelines for diagnosis and treatment of pancreatic cancer
recommend the measurement of serum CA 19-9 levels after surgery and before adjuvant
therapy to guide treatment and follow up. [56, 1]
Diabetes Mellitus as Risk Factor
The NCCN guideline for pancreatic adenocarcinoma acknowledges long-standing diabetes
mellitus as a risk factor for pancreatic cancer. The guideline also notes an association
between sudden onset of type 2 diabetes mellitus in an adult older than 50 years and a new
diagnosis of pancreatic cancer. NCCN guidelines states that clinicians should consider
pancreatic cancer in patients with diabetes who have unusual symptoms such as continuous
weight loss and abdominal problems.[1]
Diagnosis
The European Society of Medical Oncology (ESMO) recommendations for diagnosis of
pancreatic cancer include the following [56] :
Abdominal ultrasound for the initial examination
Endoscopic ultrasound (EUS), contrast-enhanced multi-detector computed tomography
(MD-CT) and MRI combined with magnetic resonance cholangiopancreatography
(MRCP) for additional evaluation
Endoscopic retrograde cholangiopancreatography (ERCP) only to relieve bile duct
obstruction
ERCP and biliary stenting should be performed only if surgery is not possible
Positron emission tomography (PET) is not recommended for diagnosis
Biopsy is recommended only when imaging results of a pancreatic lesion are
ambiguous; EUS-guided biopsy is preferred and percutaneous sampling should be
avoided
Metastatic lesions can be biopsied percutaneously under ultrasound or CT guidance or
during EUS
The NCCN guidelines recommend that diagnostic management involve multidisciplinary
consultation and be done at a high-volume center with appropriate high-quality imaging that
includes specialized pancreatic CT or MRI. Additional recommendations include the
following [1] :
Patients should undergo triphasic multidetector CT with thin-slice, cross-sectional
imaging; the difference in contrast enhancement is highest during the second phase, so a
triphasic approach enables a clear distinction between a hypodense lesion and the rest of
the pancreas.
Contrast MRI is acceptable when CT is not possible, but MRI has not been shown to be
more effective or accurate in diagnosing and staging pancreatic cancer; however, MRI
can be a useful adjunct in diagnosing high-risk patients.
PET/CT is not a substitute for high-quality contrast-enhanced CT, but may be
considered after CT to detect small metastatic deposits.
If no mass is evident in the pancreas on CT protocol imaging, EUS is recommended
before other evaluation options.
EUS-guided fine-needle aspiration (FNA) offers better safety and lower risk of
peritoneal seeding than CT-guided FNA
The NCCN recommends staging laparoscopy in patients who meet any of the following
criteria [1] :
CA 19-9 level >150 U/mL
Low-volume ascites
Tumor in the body of the pancreas
Borderline resectable tumor
Tumor size >3 cm
Common bile duct lymphadenopathy
The NCCN guidelines aside, staging laparoscopy may not be absolutely necessary in a patient
with a borderline resectable tumor, if the treatment team plans to use neoadjuvant
chemotherapy to shrink the tumor before resection.
Localized Disease Management
Defining Resectability Status
The National Comprehensive Cancer Network (NCCN) has adopted criteria for defining
resectability status, which the European Society of Medical Oncology (ESMO) also
recommends. For tumors to be considered localized and clearly resectable, they must
demonstrate the following [1] :
No distant metastases
No evidence of superior mesenteric vein (SMV) or portal vein (PV) distortion
Clear fat planes around the celiac axis, hepatic artery and superior mesenteric artery
(SMA)
Borderline resectable tumors include the following:
No distant metastases Involvement of the SMV or PV with distortion or narrowing or
occlusion of the vein with vessel proximal and distal, allowing for resection and
replacement
Gastroduodenal artery encasement up to the hepatic artery, without extension to the
celiac axis.
Tumor abutment to the SMA <180° of the circumference of the vessel wall.
The American Society of Clinical Oncology (ASCO) recommends primary surgical resection
of the primary tumor and regional lymph nodes for all patients meeting the following
criteria [89] :
No clinical evidence for metastatic disease
Performance status and comorbidity profile that can withstand major abdominal surgery
No radiographic interface between primary tumor and mesenteric vasculature
CA 19-9 level suggestive of localized disease
Treatment
In 2016, the American Society of Clinical Oncology released guidelines for the treatment of
potentially curable pancreatic cancer which included the following key recommendations [89] :
After histopathologic confirmation of the diagnosis, a multiphase CT scan of the
abdomen and pelvis using a pancreatic protocol or MRI should be performed to gauge
the anatomic relations of the tumor to other internal structures and to evaluate patients
for the presence of intra-abdominal metastases.
Supplemental studies may include endoscopic ultrasound, diagnostic laparoscopy, or
both.
Performance status, symptom burden, and comorbidity profile should be carefully
evaluated at baseline, and the goals of care should be shaped by patient preferences
before arriving at a multidisciplinary treatment plan.
Patients should be informed about any relevant clinical trials for experimental or
palliative care.
Preoperative therapy is recommended for patients who meet any of the following criteria [89] :
Radiographic findings are suspicious but not diagnostic for extrapancreatic disease
Poor performance status or comorbidities not conducive to major abdominal surgery if
it is thought that their status might be reversed after treatment
A radiographic interface between the primary tumor and mesenteric vasculaturea
radiographic interface that does not meet appropriate criteria for primary resection
CA 19-9 level (in absence of jaundice) suggestive of disseminated disease
After preoperative treatment, patients should be restaged before making plans for surgery.
Post-operative recommendations include the following [89] :
In the absence of medical or surgical contraindications, patients who did not receive
preoperative therapy should be offered 6 months of adjuvant chemotherapy with either
gemcitabine or fluorouracil plus folinic acid initiated within 8 weeks of surgical
resection.
Patients who have not received preoperative therapy and who have microscopically
positive margins or node-positive disease after 4 to 6 months of adjuvant chemotherapy
should be offered adjuvant chemoradiation.
For patients who underwent peroperative therapy, although evidence supporting the
duration of post-operative therapy is weak, the panel recommends that patients receive a
total of 6 months of adjuvant therapy, including time spent on the preoperative regimen.
Adjuvant combination chemotherapy regimens are not recommended outside of a
clinical trial.
Patients should receive ongoing supportive care for symptom burden that may result
from the operation and (preoperative and/or adjuvant) chemotherapy
Patients who have completed treatment and have no evidence of disease should be
monitored for recovery of treatment-related toxicities and recurrence. Visits may be
offered at 3- to 6-month intervals but the role of serial cross-sectional imaging, the
extent to which surveillance intervals should be prolonged over time, and the duration
of recommended surveillance are all undefined
The European Society of Medical Oncology (ESMO) recommendations for treatment of
pancreatic cancer include the following [56] :
Radical surgery is the only curative treatment and is mainly suitable for patients with
stage I and some patients with stage II
In elderly patients (>75 years old), comorbidity can be a reason to abstain from
resection; the risk of perioperative mortality in patients undergoing pancreatic resection
can be estimated using a surgical outcomes analysis and research (SOAR)
pancreatectomy score
ESMO recommendations for treatment of resectable disease are as follows [56] :
Pancreatoduodenectomy (Whipple procedure) is the treatment of choice for tumors of
the pancreatic head
For tumors in the body or tail of the pancreas, distal pancreatectomy, including the
resection of the body and the tail of the pancreas and the spleen, is usually performed
No evidence exists that extended lymphadenectomy is beneficial; standard
lymphadenectomy should involve the removal of ≥15 lymph nodes to allow adequate
pathologic staging
Postoperative gemcitabine or 5-fluorouracil (5-FU) chemotherapy is recommended
No chemoradiation should be given to patients after surgery except in clinical trials
For patients with borderline resectable lesions, ESMO recommends participation in clinical
trials wherever possible. Otherwise, preoperativechemotherapy (gemcitabine or
FOLFIRINOX) followed by chemoradiation and then surgery appears to be the best option.
NCCN treatment guidelines concur that resection is the only potentially curative treatment for
pancreatic cancer, but note that 80% of patients present with incurably advanced disease. Key
recommendations for treatment of localized disease include the following [1] :
Decisions about treatment and resectability should involve input from a
multidisciplinary group of specialists.
Selection of patients for surgery should be based on the probability of cure, as
determined by resection margins; other factors include comorbidities, overall
performance status, and age.
Postoperative adjuvant therapy improves outcomes but no definite standard has been
set. Options for patients who did not receive preoperative neoadjuvant therapy include
clinical trials (preferred), chemotherapy, or chemoradiation. When chemotherapy alone
is chosen, gemcitabine is preferred over 5-FU/leucovorin; capecitabine should only be
considered when other options are contraindicated.
For patients who received neoadjuvant therapy, post-operative therapy options are
dependant on response to neoadjuvant therapy and other clinical considerations.
Like ESMO, NCCN recommends considering preoperative neoadjuvant thereapy for patients
with borderline resectable tumors. However, no form of neoadjuvant therapy in pancreatic
carcinoma should be regarded as standard; this remains an area for clinical trial study. [1]