Pancreatic cancer (PC) is characterized by extremely high mortality and poor prognosis. Unfortunately, compared with other malignancies, there has been little improvement in the survival rate of patients with PC in recent decades. In almost all cases, pancreatic cancer is detected in the non-resectable advanced stages because the disease is usually asymptomatic in the early stages. At the time of diagnosis 20% of patients have localized disease, approximately 30% present with regional disease, and more than 50% present with distant disease. The only cure pancreaticoduodenectomy, is available to fewer than 20% of patients. Moreover, chemotherapy and immunotherapy regimens have limited efficacy in patient with nonresectable disease . Since therapeutic choices are limited at the advanced stage, screening and early diagnostic tools are indispensable for a better prognosis. This article reviews current screening methods used in high risk patients and discusses some of the methods in development to improve early detection.
Keywords: Pancreatic Cancer; Screening; Endoscopic Ultrasound; Biomarkers; Magnetic Resonance Imaging
Although most cases of pancreatic adenocarcinomas are thought to be sporadic, up to 10% may be due to an underlying genetic predisposition. “Familial pancreatic cancer” (FPC) has been used to describe families with at least 2 first-degree relatives (FDR) with pancreatic cancer without a known genetic defect. Aggregation of pancreatic cancer in these families is due to an unidentified, autosomal dominantly inherited gene with reduced penetrance. A population-based, case control study conducted in the United States found that individuals with a first-degree relative (FDR) with pancreatic cancer had a 3.2-fold increased risk of developing pancreatic cancer  as compared to population controls. Hemminki et al.  also demonstrated 1.7-fold increased risk of pancreatic adenocarcinoma in an individual with a parent with pancreatic cancer . The risk of pancreatic cancer based upon family history can be determined using a Mendelian risk assessment tool which calculates the probability that an individual carries a deleterious mutation in a pancreatic susceptibility gene.
This cancer antigen 19-9 (CA 19-9), a sialylated Lewis blood group antigen has been the standard serum tumor marker utilized
for diagnosis, prognosis, and recurrence detection in patients with pancreatic cancer. However only 65% of patients with resectable PC have elevated serum CA19-9 levels [and elevated level of CA19-9 has been observed in other gastrointestinal malignancies, such as gastric cancer and colorectal cancer, and in various benign conditions, including chronic pancreatitis and acute cholangitis Therefore, recent efforts have been focused on improving the diagnostic efficacy of CA19-9 by combining it with a panel of markers.
CEA is the second most common serum biomarker used in clinical practice for pancreatic cancer diagnosis. It has sensitivity of 54% and a specificity of 79% for discriminating between malignant and benign conditions . However, CEA is less accurate than CA 19-9 for malignant pancreatic cancer diagnosis.
Recently, new-onset diabetes has been recognized as an early manifestation of pancreatic cancer, which could aid the diagnosis of asymptomatic patients with pancreatic cancer. Identification of new-onset diabetes could lead to diagnosis at an early resectable stage, as early as 18 to 24 months . However, several studies have shown either no association or mild increased risk for pancreatic cancer in patients with long-standing diabetes. In one of the studies approximately 1% of diabetes subjects aged ≥50
years will be diagnosed with pancreatic cancer within 3 years of
first meeting criteria for diabetes.
It is generally known that the smaller the tumor size and
the earlier the clinical stage, the better the prognosis. Small
pancreatic cancer is defined as a tumor smaller than 2 cm
with or without invasion to the peripancreatic vasculature or
metastasis. Contrast-enhanced helical CT has facilitated the
detection and staging of pancreatic cancer and is accepted as
one of the most effective imaging techniques for the diagnosis of
pancreatic cancer. The main early signs detected in the CT scans
are pancreatic ductal dilation and CT has a threshold for lesion
detection of 0.3 to 0.5 cm.
Gangi and colleagues conducted a study, 2 radiologists
blindly interpreted 62 CT scans performed before a pancreatic
cancer clinical diagnosis was made, and both radiologists
agreed that suspicious findings were present in 50% of CT
scans performed within 18 months prior to pancreatic cancer
diagnosis and only in 7% of CT scans performed more than
18 months .Maximal pancreatic enhancement and optimal
enhancement of peripancreatic vessels is essential for the
detection of pancreatic carcinoma. Pancreatic-phase imaging
(40–70 s after infusion of IV contrast material at 3 ml s–1) is
important for the detection of pancreatic tumor and evaluation
of peripancreatic vasculature involvement. Lu et al.  explained
that, compared with hepatic-phase imaging, pancreatic-phase
acquisition provides significantly better pancreatic, arterial and
portal venous enhancement with improved tumor–pancreatic
MRI with MRCP allows more successful tumor detection
at an early stage than multi-detector CT. However, small or
non-contour-deforming pancreatic adenocarcinomas may
lack classic imaging features and thus may not be detected on
conventional MRI . The use of functional imaging methods
such as diffusion-weighted imaging may allow earlier detection
of pancreatic adenocarcinoma .
Pancreatic cancer is usually hypointense in T1-weighted
images compared to the pancreatic parenchyma. A study
comparing MRI with CT scans showed no significant differences,
with similar sensitivities of 84% and 86%, respectively. MRCP
imaging is superior to CT scans or MRI in distinguishing
inflammatory, nonmalignant pancreatic masses from pancreatic
Endoscopic method that is clinically used for pancreatic
cancer screening is EUS, commonly performed in combination
with cross-sectional imaging modalities such as MRI. The
diagnostic yield of EUS ranges from 10% to 50%. Brentnall and
colleagues prospectively studied 14 patients who had 2 or more
family members in more than 2 generations with a history of
pancreatic cancer. Patients were assessed with EUS, ERCP, CEA,
and CA 19-9. Seven of 14 patients had abnormal, findings on EUS
and ERCP. These 7 patients underwent pancreatic resections,
which showed evidence of intraductal dysplasia in all specimens
. Rulyak  and colleagues studied 35 patients from 13
familial pancreatic cancer. EUS was the initial test followed by
ERCP in cases of symptomatic individuals. Twelve of 35 patients
had abnormalities on both EUS and ERCP and underwent
pancreatectomy, with histology showing pancreatic dysplasia on
all 12 cases. Follow-up of the 35 patients varied from 1 to 48
months, and none had pancreatic cancer at follow-up .
Plectin-1 is a high molecular weight–protein normally
expressed in several tissues, including skin, muscle, and brain,
required in the maintenance of mechanical integrity and
viscoelasticity properties of tissues. Studies have demonstrated
that plectin-1, which is normally expressed in the cytoplasm, is
overexpressed in the cell membrane of PDAC cells compared to
normal pancreatic ductal cells .
Glypican-1 is a cell membrane proteoglycan, implicated in
the control of cellular growth and differentiation and is also
expressed in breast and pancreatic cancer–derived exosomes.
Melo and colleagues analyzed 56 patients with pancreatic cancer,
6 with pancreatitis, and 20 healthy donors and demonstrated
that exosomes from pancreatic cancer patients express higher
levels of glypican-1 than healthy subjects. Gypican-1 circulating
exosomes correlate with tumor burden and could be used to
assess prognosis and pancreatic cancer recurrence .
Urinary metabolomics studies offer an opportunity to
identify tumor-associated perturbations of cellular metabolism
reflecting changes that occur in the tumor micro- and
macroenvironment. Such is the case with 3 proteins recently
reported to be useful as pancreatic cancer biomarkers: REG1A,
TFF1, and LYVE1 . The 3 markers have been found to be
increased in urine samples from patients with pancreatic cancer
compared with healthy controls.
Pancreatic cancers are commonly hypoattenuating
while Kim and colleagues have found that 27% of pancreatic
adenocarcinomas smaller than 2 cm were isoattenuating by
(MDCT), which results in lesions potentially being missed.
In comparison with a weighted-average 120-kVp data set,
generation of pure 80-kVp data at dual-source dual-energy
MDCT improves differentiation of attenuation values between
malignant tumors of the pancreas and normal pancreas.
The single-source, dual-energy system utilizes a single
radiograph beam source that switches energy between 80 and
140 kVp, offers the ability to detect hypovascular pancreatic
cancers at lower viewing energy levels, diminishing the number
of isoattenuating early-stage tumors . This technique can also
be performed with a dual-source system with two independent
x-ray tubes .
Fusion imaging studies have demonstrated an improved
quality of differentiation of pancreatic cancer from benign
lesions. MRI provides useful structural and functional tumor
information. Positron emission tomography (PET), is an effective
predictor of staging and prognosis in cancer patients . A
study has demonstrated that hybrid PET-MRI is significantly
more accurate (96.6%) than PET-CT (86.6%) in terms of
performing a diagnosis of pancreatic cancer. PET-MRI fusion also
offers information such as involvement of the main pancreatic
duct or collateral veins, peripancreatic anatomic borders,
and superior mesenteric artery or celiac artery, which are
important predictive factors for respectability. PET/MR imaging,
which provides anatomic information, as well as PET and DW
imaging, can be useful in the detection and characterization of
lymph nodes  which is an important factor in the accurate
prediction of a patient’s prognosis (30).
Endoscopic methods may help provide better screening
yield for pancreatic cancer, because of the information about
precursor lesions or prediction of which precursor lesions
are likely to behave in an aggressive manner. Some of these
techniques are briefly described below.
This relatively new technique, based on the detection
of signals from microbubbles in vessels, can visualize both
parenchymal perfusion and microvasculature in the pancreas for
the neoplastic solid components as hyper enhanced lesions .
Elastography is a relatively new technique applied to
EUS imaging to distinguish different tissues based on their
elastic properties. Cancerous tissue is known to be stiffer than
corresponding healthy tissue .
Combining EUS guided fine-needle aspiration cytopathology
analysis with KRAS mutation assay and Detection of TP53
mutations in secretin-stimulated pancreatic juice increased the
sensitivity and accuracy of cytopathology .
Needle-based confocal laser endomicroscopy (nCLE) is
a newly developed endomicroscopic technique that enables
imaging of the mucosal layer at a subcellular level of resolution.
In pancreatic cancer, nCLE can detect vascular leakage with
irregular vessels and leakage of fluorescein into the tumor .
The periampullary duodenal mucosa has genetic and
environmental sharing with of the pancreas . Based on
this Mutual and colleagues conducted a case-control study to
evaluate low-coherence–enhanced backscattering spectroscopy
to predict the probability of pancreatic cancer by analyzing the
While the early diagnosis of pancreatic cancer remains
challenging, improvements in diagnostic technology and
methodologies will hopefully translate into improved outcomes.
Screening of high-risk individuals using EUS and/or MRI is
recommended and shows promise in early detection. Several
potential novel biomarkers and imaging techniques are under
evaluation for detecting premalignant and early malignant
changes in the pancreas. Further advancement and progress in
these techniques will help in identifying precursor lesions while
they are still resectable.