Diagnostic Applications of Nuclear Medicine: Pancreatic Cancer
Pancreatic cancer can be assessed through a variety of imaging techniques including endoscopic ultrasonography (EUS), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP).
These imaging modalities are often effective in the evaluation of pancreatic cancers although sometimes they require the use of radiopharmaceuticals with positron and single-photon emission CT (PET and SPECT) imaging techniques. In this chapter the role of nuclear medicine with various radiolabeled compounds and the rationale for their use in endocrine and nonendocrine pancreatic tumors are discussed.
KeywordsPancreatic cancer Neuroendocrine tumor Gastroenteropancreatic tumor SPECT/CT PET/CT Somatostatin receptor scintigraphy Somatostatin analogues 111In-pentetreotide [18F]FDG 123I-MIBG 131I-MIBG 18F-DOPA 68Ga-DOTA-peptides Peptide radioreceptor therapy
Neuroendocrine tumor producing adrenocorticopic hormone
American Joint Committee on Cancer
Breast cancer type 1 susceptibility protein
Breast cancer type 2 susceptibility protein
- CA 19-9
Carbohydrate antigen 19-9
Neuroendocrine tumor producing corticotropin-releasing hormone
X-ray computed tomography
European Neuroendocrine Tumor Society
Endoscopic retrograde cholangiopancreatography
Multiple mole melanoma syndrome
Granulocyte colony-stimulating factor
Gastro-entero-pancreatic neuroendocrine tumor
Neuroendocrine tumor producing growth hormone-releasing hormone
Glucagon-like peptide 1 receptor
Gross tumor volume
Human equilibrative nucleoside transporter-1
Intraductal papillary mucinous neoplasm
Multi-detector row computed tomography
Maximum intensity projection
Magnetic resonance cholangiopancreatography
Magnetic resonance imaging
Medullary thyroid carcinoma
Mammalian target of rapamycin
National Comprehensive Cancer Network
Pancreatic intraepithelial neoplasia
Positron emission tomography
Positron emission tomography/computed tomography
Integrated positron emission tomography/magnetic resonance system
Pancreatic neuroendocrine neoplasm
Pancreatic neuroendocrine tumors
Peptide receptor radionuclide therapy
Surgery achieving negative microscopic resection margins
Surgery achieving microscopic positive resection margins
Surgery achieving residual macroscopic disease
Single-photon emission computed tomography
Single-photon emission computed tomography/computed tomography
Somatostatin receptor scintigraphy
Standardized uptake value
AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status) and “M” (distant metastasis status)
Union Internationale Contre le Cancer (International Union Against Cancer)
Vasoactive intestinal peptide
World Health Organization
Epidemiology of the Tumor
Unfortunately, at the time of diagnosis, over 80% of all pancreatic tumors are unresectable .
Tumor detection at an earlier stage and development of effective therapies are the mainstay for reducing cancer death rate, even if the lack of a valid screening tool in terms of cost-efficacy makes this challenge difficult.
Environmental Factors and Genetic Predisposition
Less than 20% of familial pancreatic cancers can be attributed to a genetic syndrome , including hereditary cancer syndromes (like Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, hereditary breast-ovarian cancer associated with BRCA1 and BRCA2 mutations, hereditary nonpolyposis colorectal carcinoma, and familial adenomatous polyposis) and syndromes related to inherited pancreatitis. Subjects presenting known familial adenomatous polyposis, BRCA1, or BRCA2 mutations have less than 5% increased relative risk  in comparison to the general population, while the risk in familial atypical multiple mole melanoma syndrome (FAMM) or Peutz-Jeghers is much greater . The number of affected first-degree relatives and environmental factors can affect this genetic predisposition: some families with pancreatic cancer affecting at least two first-degree relatives and no association with genetic syndrome are currently defined as a “familial” pancreatic cancer kindred .
Hereditary pancreatitis and cystic fibrosis represent other syndromes that lead to an increased risk of pancreatic cancer. The remaining 80% of cases with an inherited predisposition remain under the generic term of familial pancreatic cancer with unclear genes identification.
Other epidemiological risk factors for pancreatic cancer include smoking , age (the risk increases with the age with a peak between 60 and 80 years) , race/ethnicity (more common in the African American population in comparison to the white population, probably as a result of socioeconomic factors and cigarette smoking) , gender (slightly more common in men than in women), chronic pancreatitis , long-standing diabetes (long-standing DM is a modest risk factor for pancreatic cancer; conversely, new adult-onset diabetes mellitus can be a manifestation of pancreatic cancer ), partial gastrectomy , dietary risk factors (high meat intake, fried foods, nitrosamines) , and ABO blood groups (subjects with non-O-type blood are at modestly increased risk) .
Clinical Manifestations and Diagnosis
In the natural history of PC, symptoms at the time of diagnosis predict early death because symptoms are related to an advanced stage of disease: PC is diagnosed a median of 2 months after onset of symptoms, and death usually occurs 4–6 months following diagnosis. Delay in diagnosis is not uncommon due to nonspecific symptoms.
PC is considered a tumor with high propensity for metastatic dissemination so much that most patients with a history of resected PC subsequently die of metastatic disease .
To suspect PC on physical examination is a challenge for clinicians due to its retroperitoneal location. Disease-related symptoms depend on tumor location within the pancreas and on the degree of pancreatic involvement. First symptoms to appear include painless jaundice (in case of bile duct obstruction) and weight loss.
In advanced, metastatic disease, palpable lymph nodes, hepatomegaly, splenomegaly, ascites and peripheral edema (portal vein obstruction), palpable gallbladder (Courvoisier’s sign), left supraclavicular lymphadenopathy (Virchow’s node), or an abdominal mass might be appreciated .
Unfortunately, even laboratory findings in pancreatic cancer are nonspecific: raised liver enzymes and abnormalities in vitamin K-dependent clotting factors are related to biliary obstruction and malabsorption of fat-soluble vitamins, while impaired glucose tolerance or frank diabetes could be secondary to pancreatic duct obstruction and pancreatic atrophy (in as many as 70% of patients) .
Carbohydrate antigen 19-9 (CA 19-9) is the most commonly used serological marker in pancreatic cancer. Although it has a sensitivity of 80%, specificity is low (67.5%) because serum levels increase in many benign and malignant gastrointestinal conditions. For this reason, routine use as a diagnostic tool is not recommended, even if sequential evaluations may correlate with tumor growth. The presence of a normal CA 19-9, however, does not exclude recurrence [22, 23, 24].
Recent studies identified several promising biomarkers from saliva, stool, blood, and pancreatic juice, but their clinical utility must be validated .
Currently, available pancreatic imaging has a key-role in the characterization of pancreatic focal lesions, initial staging, surgical and therapeutic planning, and assessment of the treatment response using various imaging modalities, including ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and endoscopic ultrasonography (EUS) [25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35].
Multi-detector row computed tomography (MDCT) has a major role in the diagnosis and staging of pancreatic malignancies. MDCT of the pancreas is favorably complemented by EUS, which is more sensitive for the early detection of lesions, and allows relatively easy access to the pancreas for tissue diagnosis using fine-needle aspiration (FNA), as well as providing further important information for use in tumor staging . MRI with magnetic resonance cholangiopancreatography (MRCP) and PET scanning can also contribute as secondary imaging modalities under selected circumstances, namely, when CT and EUS are not diagnostic.
List of pancreatic neoplasms which occur frequently
Epithelial neoplasms with multiple directions of differentiation
Epithelial neoplasms of uncertain direction of differentiation
Miscellaneous epithelial neoplasms
Serous cystic neoplasms
Microadenoma (<0.5 cm)
Mixed acinar-endocrine carcinoma
Microcystic serous cystadenoma
Macrocystic serous cystadenoma
Solid serous adenoma
von Hippel-Lindau-associated serous cystic neoplasm
Mucinous cystic neoplasms
Well-differentiated pancreatic endocrine neoplasm
Mixed acinar-ductal carcinoma
With low-grade dysplasia
With moderate dysplasia
With high-grade dysplasia (carcinoma in situ)
With an associated invasive carcinoma
Poorly differentiated endocrine carcinoma
Mixed ductal-endocrine carcinoma
Epidermoid cyst in intrapancreatic heterotopic spleen
Intraductal papillary mucinous neoplasms
Small cell carcinoma
With low-grade dysplasia
With moderate dysplasia
Large cell endocrine carcinoma
With high-grade dysplasia (carcinoma in situ)
With an associated invasive carcinoma
Intraductal oncocytic papillary neoplasm
Intraductal tubular neoplasms
With low-grade dysplasia
With high-grade dysplasia (carcinoma in situ)
With an associated invasive carcinoma
Pancreatic intraepithelial neoplasia (PanIN)
Well-differentiated pancreatic endocrine neoplasm
Mixed acinar-ductal carcinoma
PanIN-1A and PanIN-1B
Invasive ductal adenocarcinoma
Colloid (mucinous noncystic) adenocarcinoma
Signet ring cell carcinoma
Undifferentiated carcinoma with osteoclast-like giant cells
Acinar cell neoplasms
Acinar cell cystadenoma
Acinar cell carcinoma
Acinar cell cystadenocarcinoma
A particular group is represented by pancreatic neuroendocrine neoplasms (pNEN) which originate from neuroendocrine cells of the pancreas and account for less than 3% of all malignancies of the pancreas (increasing annual incidence in a range of 0.32–0.43/100,000) [38, 39, 40].
For the most part, they are sporadic but they can also be part of rare hereditary syndromes like multiple endocrine neoplasia type 1 (with hyperparathyroidism and adenomas of the pituitary gland), von Hippel-Lindau syndrome, and tuberous sclerosis.
Clinical syndromes depending on the specific hormonal hypersecretion
Tumor subtype/associated syndrome
Chromogranin A, pancreatic polypeptide, a-/β-human chorionic gonadotropin, calcitonin
Diarrhea, flush, bronchial obstruction
Vasoactive intestinal peptide
Necrolytic migratory erythema, diabetes mellitus
Diabetes mellitus, steatorrhea, cholelithiasis
Growth hormone-releasing hormone
Corticotropin-releasing hormone, adrenocorticotropic hormone
Nonfunctioning NETs may not present with clinical symptoms until they produce tumor mass effects at a late stage of tumor growth, so they are often diagnosed because of nonspecific abdominal symptoms or weight loss that leads the physician to make a referral for CT scanning of the abdomen.
All pancreatic neuroendocrine tumors <2.0 cm in largest dimension with no evident local invasion or angioinvasion and no regional lymphatic or distant metastases are classified as “benign.” Tumors confined to the pancreas and without metastases are said to be “uncertain” if the tumor size is >2.0 cm or local invasion has occurred (or both). Tumors with extended invasion of peripancreatic tissue or regional or distant tumor spread are classified as “malignant.” These tumors can have heterogeneous microscopic findings, and immunohistochemical staining with markers (such as chromogranin A, synaptophysin, and neuron-specific enolase) can usually confirm the neuroendocrine origin .
Staging, Prognostic Classification, and Common Therapies
TNM of the pancreatic ductal adenocarcinoma (From AJCC, 7th Edition)
Primary tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ
Tumor limited to the pancreas, 2 cm or less in greatest dimension
Tumor limited to the pancreas, more than 2 cm in greatest dimension
Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery
Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)
Regional lymph nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Regional lymph node metastasis
Distant metastasis (M)
No distant metastasis
Staging of the pancreatic adenocarcinoma based on TNM classification
AJCC staging for pancreatic cancer
T stage includes: TX (primary tumor cannot be assessed), T0 (no evidence of primary tumor), Tis (carcinoma in situ, PanIN 3), T1 (tumor limited to the pancreas and no larger than 2 cm in greatest dimension), T2 (tumor limited to the pancreas but larger than 2 cm in greatest dimension), T3 (tumor extends beyond the pancreas but it doesn’t involve the celiac axis or the superior mesenteric artery), and T4 (tumor extends beyond the pancreas and involves the celiac axis or the superior mesenteric artery).
N stage includes N0 (no regional lymph node metastasis) and N1 (presence of regional lymph node metastasis); the M stage includes M0 (absence of distant metastasis) and M1 (presence of distant metastasis).
The survival rate of patients with any stage of pancreatic exocrine cancer is poor. Clinical trials are appropriate alternatives for treatment of patients with any stage of disease and should be considered prior to selecting palliative approaches. Surgical resection remains the primary modality when feasible because it can lead to long-term survival and provides effective palliation [50, 51, 52].
Overall survival in pancreatic adenocarcinoma
Median survival (Mo)
Surgical staging criteria based on the MD Anderson criteria and NCCN guidelines
Abutment, ≤180° involvement of circumference of the vessel; encasement, >180° involvement of circumference of the vessel
Superior mesenteric artery
Superior mesenteric vein/portal vein
Abutment; involvement of hepatic artery without expansion to celiac (NCCN)
Abutment/short segment encasement with option for reconstruction
Short segment occlusion with option for reconstruction
Encasement; abutment for pancreatic ductal adenocarcinoma of the head (NCCN)
Encasement and no option for reconstruction
Occluded and no option for reconstruction
According to these, localized pancreatic ductal adenocarcinomas are separated into three categories based on the relationship to the major visceral vessels as well as the prospect of achieving an upfront or initial complete resection.
The resectable tumors are usually removed with R0 resection (negative microscopic resection margins); the borderline resectable ones are usually resected with R1 resection margins (microscopic positive resection margins), and locally advanced tumors will most likely achieve R2 resection margins (residual macroscopic disease). Resection margins refer to the surgical or transected resection margins and comprise the transected pancreatic neck, the uncinate margin, the duodenum, and the bile duct .
Radical pancreatic surgery includes the Whipple procedure (pancreaticoduodenal resection for the head and uncinate process masses) and distal pancreatectomy for tumors of the body and tail of the pancreas. To obtain negative margins of the surgical specimen, total pancreatectomy could be necessary (with or without splenectomy) [62, 63].
Patients with locally advanced or metastatic disease are not suitable for surgery, and a single therapy with gemcitabine is generally regarded as first-line therapy even if numerous patients do not respond due to chemoresistance . The variation in chemoresistance between individuals is partly related to the human equilibrative nucleoside transporter-1 (hENT-1) responsible for the intracellular uptake of gemcitabine .
Few combinations of gemcitabine with other cytotoxic agents have yet provided any significantly prolonged overall survival rates with more toxic effects compared with gemcitabine as monotherapy [66, 67].
The use of capecitabine and erlotinib in patients with gemcitabine refractory first-line treatment of advanced pancreatic cancer is associated with modest improvements in overall survival .
Pain-relieving procedures such as celiac or intrapleural block and palliative biliary bypass or stent placement must be considered.
Radiologists commonly use language in reports that could lead inexperienced clinicians to falsely assume a pancreatic ductal adenocarcinoma as unresectable ; for this reason, a multidisciplinary approach or surgical consultation in the evaluation of all patients with localized tumors is important.
Less than 20% of patients with pancreatic ductal adenocarcinoma are candidates for resection, and the majority of patients who undergo resection will still recur .
This is most likely due to occult metastases that had already occurred at the time of diagnosis although patients presented with clinical stage I or II.
At the moment, there are no effective screening tests to detect pancreatic ductal adenocarcinoma at a curable stage, and ongoing studies focus on innovative molecular markers in serum and gastrointestinal secretions that could lead to early detection. The staging system based on regional and distant disease spread seems relatively crude: some patients without lymph node spread have rapid recurrence after resection, while many with lymph node spread have long-term survival . It appears likely that genomic, transcriptomic, proteomic, and metabolomic signatures associated with a more aggressive biology will emerge and these will complement or replace the current staging system.
Pancreatic neuroendocrine neoplasms are classified based on histopathology according to the World Health Organization (WHO) classification (2010) , and an important part of this classification is the tumor grading (proliferative activity evaluated by Ki-67 index or by counting mitoses) that correlates with prognosis .
Neuroendocrine tumors with a proliferation index <2% usually show a slow growth, while neuroendocrine carcinomas with a proliferation index >20% usually have an aggressive behavior . Also the size of the tumor affects the likelihood of metastasis: primary tumors of <2 cm only rarely metastasize. When possible, surgical resection of primary tumors with radical intent is recommended and that is the mainstay of therapy in insulinoma. If the primary tumor is a G1/2 pNET, surgical approaches also include metastases. Systemic treatment can be used for palliative care or as neoadjuvant approach to reduce tumor size before surgical treatment. For symptom control, functional tumors are primarily treated with somatostatin analogues (SSA) with the exception of gastrinomas that can be treated using proton-pump inhibitors alone for long periods. In insulinomas diazoxide is used to inhibit the release of insulin from the pancreas.
Antiproliferative SSA-based treatment can be used in functional and nonfunctional pNET with a proliferation index <10% ; streptozotocin-based chemotherapy is recommended according to the guidelines of the European Neuroendocrine Tumor Society (ENETS) in patients with progressive disease.
In patients with progressive disease while on chemotherapy, targeted therapies are used such as the multi-targeted receptor tyrosine kinase inhibitor sunitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus. Other treatment options are peptide receptor radionuclide therapy (PRRT) and other kinds of chemotherapy like temozolomide . Diagnostic imaging, beside clinical assessment, has a major role in therapeutic decision in this setting of multidisciplinary treatment options.
Diagnostic Imaging and Role of Nuclear Medicine
Early detection of pancreatic cancer is pivotal to improve the patient’s survival rate. The standard imaging technique for the initial evaluation of pancreatic cancer is contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP). Endoscopic ultrasound (EUS) allows further local staging and allows histologic confirmation by means of EUS-guided biopsy or fine-needle aspiration on the detected lesion. Although CT currently has a major role in the evaluation of pancreatic cancer, MRI with MRCP allows better detection of tumors at an earlier stage through a comprehensive analysis of the morphological changes of the pancreatic parenchyma and ductal system. The diagnosis could be improved using positron emission tomography techniques (PET/CT) in selected scenarios where CT and EUS are equivocal. It is essential for clinicians to understand the advantages and disadvantages of each imaging modality in order to select the correct imaging workup and pursue optimal treatment .
Fluorine-18 fluorodeoxyglucose-based positron emission tomography ([18F]FDG PET) imaging allows the assessment of in vivo tissue metabolism and defines malignant tumors as hypermetabolic lesions hence lesions with an increased tracer uptake. The rationale for its use is based on the increased expression of membrane glucose transporters subsequent to an enhanced anaerobial glycolytic activity in cancer cells, which leads to a higher glucose demand. [18F]FDG is carried into the cell by glucose transporters, as the normal glucose to be rapidly phosphorylated in a biochemical form that causes its virtual trapping into the cell.
The CT component of [18F]FDG PET/CT can be either a noncontrast CT (for anatomical localization of the abnormalities seen on PET and further attenuation correction of PET images) or a contrast-enhanced CT (a true diagnostic adjunct to PET) [33, 35].
Integrated PET and MR (PET/MR) scanners have recently become available. As MR has the inherent strength of superior soft-tissue contrast resolution, multiplanar imaging acquisition, and functional imaging capability, such as that seen in DCE-MR, DWI, MR spectroscopy, or elastography, PET/MR may exhibit superior diagnostic performance compared with PET/CT .
Since [18F]FDG mimics glucose metabolism, there is physiologially a diffuse accumulation of this tracer in tissues such as the brain and liver. [18F]FDG uptake in both normal tissues and tumor is influenced by a variety of patient-related factors like blood glucose levels, diabetes, recent meals, administration of granulocyte colony-stimulating factor (G-CSF), etc. For this reason, a proper prescan protocol is essential for diagnostic accuracy and reproducibility, including fasting for at least 6 h prior to the study, administering a dose of [18F]FDG based on the patients height and weight in an optimal blood glucose range (usually <200 mg/dL), voiding prior to the study to avoid mistaking [18F]FDG in the urine for pathologic uptake, minimizing patient motion prior to the study to reduce [18F]FDG uptake in the muscles and misregistration during the acquisition phase, and maintaining moderate room temperatures to avoid uptake in brown fat [33, 35, 79].
Primary Lesion Detection and Characterization
PET alone is not considered a first-line examination to identify a primary pancreatic malignancy although some studies reported a relatively high sensitivity for pancreatic cancer (84–95%) [80, 81, 82, 83].
Despite some intensely [18F]FDG-avid tumors, pancreatic cancers do not usually show high [18F]FDG uptake, with a mean SUV of only 6.7 as described in a study by Izhuishi et al. This value is only slightly higher than the mean SUV of the pancreas itself (2.0) . Another limitation of PET is the identification of lesions <1 cm in size, and for this reason, MDCT remains the primary diagnostic modality for identifying a suspected pancreatic malignancy with a sensitivity approaching 97% and with a rapid exam execution, wide availability, and diagnostic accuracy. In most cases, MRI or endoscopic ultrasound is a better second-line modality than PET or PET/CT, such as in cases with a dilated pancreatic duct on MDCT without a discrete identifiable mass or an equivocal lesion on CT .
On the other hand, an important role for PET or PET/CT in primary diagnosis of a pancreatic mass is the differentiation of a pancreatic cancer from a focal chronic pancreatitis: Van Kouwen et al. described that 87% of chronic pancreatitis did not have any [18F]FDG uptake while 24/26 patients with pancreatic cancer had focal uptake . There is also evidence that PET may have a role in distinguishing pancreatic cancer from autoimmune pancreatitis: Lee et al. suggested that autoimmune pancreatitis showed diffuse uptake throughout the gland in more than 50% of cases (without focality contrarily to what happens in pancreatic cancer) and tended to be associated with abnormal uptake in the salivary glands and kidneys . An advantage of using [18F]FDG PET has been observed in the characterization of pancreatic cystic lesions with a sufficient amount of [18F]FDG-avid tumor cells [87, 88, 89].
Sperti et al.  studied the usefulness of [18F]FDG PET in differentiating malignant from benign pancreatic cysts in 50 patients concluding that [18F]FDG PET was more accurate than CT (94% vs. 80% respectively).
Intraductal papillary mucinous neoplasms (IPMNs), are tumors characterized by the intraductal proliferation of neoplastic mucinous cells in the main pancreatic duct or in major branches, represent a diagnostic challenge: an accurate differentiation between IPMN with low-grade or moderate-grade dysplasia and malignant lesions (IPMN with high-grade dysplasia and invasive carcinoma) is essential to an appropriate treatment planning , and in this scenario PET/CT seems to be useful [92, 93].
Pancreatic Cancer Staging
It should be emphasized that PET without a diagnostic contrast-enhanced CT is highly limited for staging, and a study by Imai et al. found that PET was as insensitive as CT for nodal metastases to the para-aortic chain (most likely due to PET’s lack of sensitivity for lesions <1 cm) . Furthermore, the role of PET in assessing local tumor spread and vascular involvement remains uncertain because the [18F]FDG uptake within the primary mass can confound the assessment of the vascular margins where a degree of intrinsic [18F]FDG blood activity is also present. For this reason, at the time, the resolution of PET is not considered sufficient to determine the vessels involvement, therefore the tumor resectability.
Therapy Response Evaluation
In patients who are judged to be borderline resectable and are recommended to undergo neoadjuvant therapy, a baseline PET scan and CA 19-9 would allow the assessment of tumor metabolic response during therapy .
It is desirable to determine an appropriate time interval between end of treatment and time of posttherapy PET scan. Whereas oncologic therapies are expected to decrease the tumor metabolism, a treatment-induced inflammatory reaction can increase [18F]FDG uptake. It has been demonstrated that also nonirradiated organs could show this inflammatory reaction probably via a cytokine interaction, and total [18F]FDG uptake could fluctuate for more than 1 month .
However, perhaps because of its poor prognosis and short follow-up, there are no data on the right time interval between therapy and the PET study; therefore, we use the timing applied to other malignancies such as the head and neck (3 months from radiotherapy).
[18F]FDG PET/CT may predict survival by distinguishing between responders and nonresponders in order to plan the best treatment strategy [104, 105] and may be useful in differentiating recurrent disease from postsurgical/radiotherapy changes, especially if there is an increase in tumor marker levels with negative or equivocal conventional imaging findings [87, 109].
Several studies have shown a correlation between higher metabolic activity of pancreatic carcinoma and poorer prognosis thus providing prognostic information .
Suspect of Relapse
An elevated CA 19-9 has a positive predictive value for pancreatobiliary malignancy of only 69%. This means that over 30% of those with an elevated CA 19-9 may have another tumor originating in another organ, or they may have no tumor at all. False-positive results have been associated with other pancreatobiliary disorders such as gallstones, pancreatitis, inflammatory bowel disease, other liver disorders, pulmonary diseases such as pneumonia, and hydronephrosis .
Radiotherapy (RT) Planning
A well-established treatment option for patients with locally advanced pancreatic cancer is concurrent chemoradiotherapy, but, despite significant improvements in diagnostic imaging, chemotherapy, and radiotherapy, the outcome remains poor [112, 113].
The accurate definition of target volumes and administration of appropriate radiation doses to these volumes represent a reasonable way to reduce local disease.
According to literature, the accuracy of target volume delineation, sometimes difficult with the use of conventional imaging alone (low accuracy on N and M staging), might be improved beyond the CT-based delineation by integrating PET and CT data. This integration allows an enlargement of the gross tumor volume (GTV) in 35.7% of cases due to detection of additional CT occult lymph node metastases and/or primary tumor extensions defined on the co-registered [18F]FDG PET/CT with no evidence of increased toxicity .
Regarding resectable pancreatic cancer, in several surgical series, the outcome is proven to be affected by tumor size, status of resection margins, invasion of vascular and/or adjacent structures, degree of differentiation, performance status, CA 19-9, and C-reactive protein levels . A few series indicate prognostic factors in locally advanced pancreatic cancer. A study by Parlak et al.  conducted on patients with locally advanced pancreatic cancer investigated the potential prognostic value of the GTV delineated by co-registered contrast-enhanced CT and [18F]FDG PET/CT-based RT on their outcome. This study suggests [18F]FDG PET/CT-defined GTV may have a role in predicting outcome (in terms of overall survival, local regional progression free survival and progression free survival).
However, further evaluation in prospective clinical trials will be required to assess the real impact of change management induced by PET/CT on the overall survival of unresectable patients.
[18F]FDG PET/CT-Guided Biopsy
PET/CT-guided biopsy combines the well-established value of anatomical information from CT with PET metabolic characterization  also in view of the fact that a lesion can present [18F]FDG uptake with no anatomical alterations.
When deciding on therapy, [18F][18F]FDG PET/CT-positive results should be confirmed by histology when possible: PET/CT-guided biopsy is feasible with reduced invasiveness, lower costs, and complication rate compared with surgical methods  and may optimize the diagnostic yield of image-guided interventions.
Ultrasound, computed tomography, magnetic resonance, and nuclear medicine imaging play an important role also in the detection of clinically suspected or diagnosed pancreatic neuroendocrine tumors for staging.
Single photon and positron emitting radionuclides can be combined with various ligands (functionally active part) including somatostatin analogues . Overexpression of subtypes of somatostatin receptors (SSTRs) in well- to moderately differentiated pNEN allows their in vivo characterization using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) while for high-grade (more aggressive) pNEN, [18F]FDG is preferred [124, 125].
The diagnosis of insulinomas poses a problem with somatostatin receptor analogues, and other tracers have been suggested as alternatives including 18F-DOPA and GLP-1 (exendin labeled with either 111In or 68Ga) . The major advantages of nuclear medicine imaging are the high sensitivity in detecting the primary tumor and metastases in unusual locations (whole body imaging), the high specificity in case of SSTR-positive lesions, and the assessment of SSTR positivity for therapeutic purposes. In order to add additional morphological informations, SPECT and PET should be combined with CT or MR imaging . According to the ENETS guidelines, when initial SSTRs imaging is positive, patients should undergo SSTRs imaging for staging every 18–24 months .
Somatostatin Receptor Scintigraphy
Somatostatin is a peptide secreted by endocrine D cells in the gastrointestinal (GI) tract and pancreas, and it inhibits the release of endocrine and exocrine factors in the GI system itself .
Most GEP-NET cells have a high expression of high-affinity somatostatin receptors which are further classified into five subtypes (SSTR1, SSTR2, SSTR3, SSTR4, SSTR5) [129, 130]. More than 80% of GEP-NET express the subtype SSTR2 that binds the commercially available somatostatin analogues (SSAs) and the radiolabeled SSAs [129, 131].
111In-DTPA-pentetreotide (Octreoscan®) is used for somatostatin receptor scintigraphy (SRS) : it preferentially binds to SSTR2 with lower affinity to SSTR5 and SSTR3 [129, 133, 134]. Planar and single-photon emission computed tomography (SPECT) images are generally obtained 24 and 48 h after injection of this radiopharmaceutical. SRS has an overall sensitivity for well-differentiated GEP-NET of more than 80% and plays an important role in localization of primary GEP-NETs, their metastases and in monitoring treatment responses. SRS with 111In-DTPA-pentetreotide can predict the clinical efficacy of current commercially available SSAs, and it is a useful tool to select patients for PRRT utilizing beta-radiation-emitting SSAs [135, 136, 137, 138]. Physiological uptake of radiolabeled SSAs is shown in the pituitary gland, thyroid, kidneys, liver, and spleen . False-positive results can derive from the presence of accessory spleen, infections, adrenal medullary tumors, and sometimes a specific uptake in the uncinate process of the pancreas . The sensitivity is lower for small lesions (diameter <1 cm) due to insufficient tumor to background uptake ratio for nonmetastasized insulinomas due to low expression of SSTR2 [132, 140], and for NETs with high Ki-67 index .
Other radiolabeled SSAs (some still under investigation or already been used in few centers) are those labeled with 99mTc including 99mTc-depreotide (high affinity for SSTR2, SSTR3, and SSTR5)  and 99mTc-vapreotide (high affinity for SSTR2 and SSTR5 and low affinity for SSTR3 and SSTR4 ).
Metaiodobenzylguanidine (MIBG) Scintigraphy
Radioiodinated MIBG, 123I-MIBG (or 131I-MIBG), is a guanethidine analogue with structural features similar to norepinephrine that at low concentrations is transported across the plasma membrane and accumulated in catecholamine-storing granules . 123I-MIBG (or 131I-MIBG) scintigraphy has a lower sensitivity than SRS for the imaging of NETs of the gastrointestinal tract (sensitivity about 50%) and pancreas (sensitivity <10%), but in patients with metastatic and inoperable GEP-NETs, high uptake on MIBG scintigraphy suggests a role for palliative treatment with 131I-MIBG [147, 148, 149, 150].
False-positive 123I-MIBG scintigraphy is possible in adrenocortical adenoma, adrenocortical carcinoma, angiomyolipoma, and gastrointestinal stromal tumors .
Gastrin Receptor Scintigraphy
A high percentage of medullary thyroid carcinomas (MTCs) express the cholecystokinin 2 (CCK2) receptor, and many CCK2 receptor-binding radiopeptides have been developed for scintigraphy (111In-DOTA-CCK, 99mTc-demogastrin, 111In-DOTA-MG11), whereas for PET/CT imaging, 68Ga-DOTA-minigastrin is used [152, 153, 154]. As GEP-NETs also express CCK2 receptors, this imaging modality was tested also in a variety of GEP-NETS (overall tumor detection reached 74% for 68Ga-DOTA-minigastrin PET) .
Glucagon-Like Peptide 1 Receptor Imaging
Pancreatic beta-cells mainly express the glucagon-like peptide 1 receptor (GLP1R), and for this reason, it represents a target for imaging of insulinomas even if malignant insulinomas (unlike benign insulinomas) often lack GLP1R . In many studies, GLP1R scintigraphy using 111In-DOTA-exendin-4 successfully detected benign insulinomas, and this radiopharmaceutical is applied for the intraoperative localization of these benign tumors [155, 156, 157, 158, 159].
(Lys40(Ahx-HYNIC-99mTc/EDDA)NH2)-exendin-4 is another radiopeptide used for targeting the GLP1R and has been studied in medullary thyroid carcinomas (MTCs) and benign insulinomas [160, 161] .Ga-DOTA-exendin-3 is a promising tracer to visualize insulinomas on PET imaging .
Vasoactive Intestinal Peptide Receptor Scintigraphy
123I-labeled vasoactive intestinal peptide (VIP) receptor scintigraphy generally shows lower sensitivity compared to SRS in GEP-NET localization, and for this reason, it is generally not recommended for the diagnostic workup of GEP-NETs [163, 164, 165].
PET/CT Using 68Ga-DOTA-Labeled SSAs
There are new 68Ga-DOTA-labeled SSAs for PET imaging that include 68Ga-DOTAVAP and 68Ga-DOTALAN .
High [18F]FDG uptake is generally associated with more aggressive (poorly differentiated) GEP-NETs; thus, the use of this radiotracer can have an additional value in grade 3 neuroendocrine carcinomas (especially when SRS is negative) [123, 132, 170, 171].
[18F]FDG PET has been used to predict the GEP-NET and lung-NET responses to PRRT with 177Lu-octreotate: if [18F]FDG PET after PRRT was negative, no tumor progression was found at follow-up. Patients with both a grade 2 NET and a positive [18F]FDG PET finding showed a worse disease course after PRRT with subsequent changes in their therapeutic approach .
The use of fluorine-18-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET/CT is based on co-secretion of dopamine and hormones or peptides by GEP-NET cells. In these cells, L-DOPA is converted by the enzyme L-DOPA decarboxylase to dopamine.
In comparison with SRS and [11C]5-hydroxy-L-tryptophan ([11C]5-HTP) PET and 18F-DOPA PET showed the highest sensitivity (98%) for the detection of NETs of the gastrointestinal tract but not for those of the pancreas [132, 173].
[11C]5-HTP is a radiolabeled precursor in the synthesis of serotonin. The short half-life of the 11C radiolabel and the complex synthesis limits the clinical use and the availability of [11C]5-HTP PET. Compared with CT, SRS, and 18F-DOPA PET, [11C]5-HTP PET showed the highest sensitivity (96%) for the detection of pancreatic NETs [132, 173, 174, 175, 176], and it is particularly useful for detecting small pancreatic NETs and early recurrences.
Future Directions and Ongoing Studies
New tracers such as [11C]thymidine or the thymidine analogue 3’-18F-fluoro-3’-deoxythymidine (18F-FLT) could be a potential alternative to [18F]FDG in prognosticating and characterizing pancreatic cancer: some studies have demonstrated that the quantification of the nuclear antigen Ki-67, a proliferation indicator, enables reliable differentiation between benign and malignant pancreatic tumors ; therefore, compounds that indicate proliferative activity, such as 18F-FLT , should be more suitable for differentiating between malignancy and inflammatory processes than nonspecific metabolic markers such as [18F]FDG .
It is apparent that PET techniques will gradually replace SPECT. New somatostatin receptors radioligands are being developed for clinical imaging, not only are somatostatin receptor agonists being studied but also receptor antagonists . Other peptide receptors might be interesting target for receptor imaging like gastrin-releasing peptide or bombesin receptors [181, 182, 183].
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