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Diagnostic Applications of Nuclear Medicine: Pancreatic Cancer

  • Elena TabacchiEmail author
  • Cristina Nanni
  • Irene Bossert
  • Anna Margherita Maffione
  • Stefano Fanti
Living reference work entry

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Abstract

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.

Keywords

Pancreatic 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 

Glossary

[18F]FDG

2-deoxy-2-[18F]fluoro-D-glucose

[18F]FDOPA

L-3,4-Dihydroxy-6-[18F]fluorophenylalanine

18F-DOPA

2-18F-Fluoro-L-3,4-dihydroxyphenylalanine

11C-5-HTP

11C-5-Hydroxy-L-tryptophan

18F-FLT

3’-18F-fluoro-3’-deoxythymidine

123I-MIBG

meta-[123I]iodobenzylguanidine

131I-MIBG

meta-[131I]iodobenzylguanidine

ACTHoma

Neuroendocrine tumor producing adrenocorticopic hormone

AJCC

American Joint Committee on Cancer

BRCA1

Breast cancer type 1 susceptibility protein

BRCA2

Breast cancer type 2 susceptibility protein

CA 19-9

Carbohydrate antigen 19-9

CCK2

Cholecystokinin 2

CRHoma

Neuroendocrine tumor producing corticotropin-releasing hormone

CT

X-ray computed tomography

DM

Diabetes mellitus

DOPA

Dihydroxyphenylalanine

DOTA

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

DTPA

Diethylenetriaminepentaacetic acid

EDDA

Ethylenediamine-N,N'-bis(2-hydroxyphenyl)acetic acid

ENETS

European Neuroendocrine Tumor Society

ERCP

Endoscopic retrograde cholangiopancreatography

EUS

Endoscopic ultrasonography

FAMM

Multiple mole melanoma syndrome

FNA

Fine-needle aspiration

G-CSF

Granulocyte colony-stimulating factor

GEP-NET

Gastro-entero-pancreatic neuroendocrine tumor

GHRHoma

Neuroendocrine tumor producing growth hormone-releasing hormone

GI

Gastrointestinal

GLP-1

Exendin

GLP1R

Glucagon-like peptide 1 receptor

GTV

Gross tumor volume

hENT-1

Human equilibrative nucleoside transporter-1

HPF

High-power field

HYNIC

Hydrazidonicotinic acid/hydrazinonicotinamide

IPMN

Intraductal papillary mucinous neoplasm

LAN

Lanreotide

MDCT

Multi-detector row computed tomography

MIBG

Metaiodobenzylguanidine

MIP

Maximum intensity projection

MRCP

Magnetic resonance cholangiopancreatography

MRI

Magnetic resonance imaging

MTC

Medullary thyroid carcinoma

mTOR

Mammalian target of rapamycin

NCCN

National Comprehensive Cancer Network

NEC

Neuroendocrine carcinoma

NET

Neuroendocrine tumor

NOC

1-Nal3-octreotide

PanIN

Pancreatic intraepithelial neoplasia

PC

Pancreatic cancer

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PET/MR

Integrated positron emission tomography/magnetic resonance system

pNEN

Pancreatic neuroendocrine neoplasm

pNET

Pancreatic neuroendocrine tumors

PRRT

Peptide receptor radionuclide therapy

R0

Surgery achieving negative microscopic resection margins

R1

Surgery achieving microscopic positive resection margins

R2

Surgery achieving residual macroscopic disease

RT

Radiation therapy

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/computed tomography

SR

Somatostatin receptor

SRS

Somatostatin receptor scintigraphy

SSA

Somatostatin analogues

SSTR

Somatostatin receptors

SUV

Standardized uptake value

TATE

Octeotate

TNM

AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status) and “M” (distant metastasis status)

TOC

Octreotide

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

VAP

Vapreotide

VIP

Vasoactive intestinal peptide

WHO

World Health Organization

Epidemiology of the Tumor

Pancreatic cancer (PC) is one of the five most lethal malignancies in the world [1], with an incidence rate equaling that of its mortality rate [2, 3, 4].

Its overall 5-year survival rate is 6%. Even after potentially curative surgery, survival rate does not increase significantly, with a 5-year survival rate raging from 10% to 25% [5, 6, 7, 8, 9, 10].

Unfortunately, at the time of diagnosis, over 80% of all pancreatic tumors are unresectable [3].

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 [11], 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 [12] in comparison to the general population, while the risk in familial atypical multiple mole melanoma syndrome (FAMM) or Peutz-Jeghers is much greater [13]. 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 [14].

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 [15], age (the risk increases with the age with a peak between 60 and 80 years) [1], 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) [1], gender (slightly more common in men than in women), chronic pancreatitis [16], 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 [17]), partial gastrectomy [1], dietary risk factors (high meat intake, fried foods, nitrosamines) [1], and ABO blood groups (subjects with non-O-type blood are at modestly increased risk) [18].

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 [19].

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 [20].

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) [21].

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 [19].

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 [36]. 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.

Pancreatic epithelial neoplasms show a wide range of pathologic features: some of the entities are very uncommon or are regarded as variants of other entities from which they do not differ significantly in terms of treatment or prognosis. Thus, the wide and complex classification can be summarized into a shorter list of neoplasms which occur more frequently (Table 1) [37].
Table 1

List of pancreatic neoplasms which occur frequently

Exocrine neoplasms

Endocrine neoplasms

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

Solid-pseudopapillary neoplasm

Teratoma

 Microcystic serous cystadenoma

 Macrocystic serous cystadenoma

 Solid serous adenoma

 von Hippel-Lindau-associated serous cystic neoplasm

 Serous cystadenocarcinoma

Mucinous cystic neoplasms

Well-differentiated pancreatic endocrine neoplasm

Mixed acinar-ductal carcinoma

 

Lymphoepitelial cyst

 With low-grade dysplasia

 With moderate dysplasia

 With high-grade dysplasia (carcinoma in situ)

 With an associated invasive carcinoma

Intraductal neoplasms

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

 PanIN-2

 PanIN-3

Invasive ductal adenocarcinoma

 

Pancreatoblastoma

  

 Tubular adenocarcinoma

 Adenosquamous carcinoma

 Colloid (mucinous noncystic) adenocarcinoma

 Hepatoid carcinoma

 Medullary carcinoma

 Signet ring cell carcinoma

 Undifferentiated carcinoma

Anaplastic carcinoma

Sarcomatoid carcinoma

Carcinosarcoma

 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.

Pancreatic neuroendocrine neoplasms can be divided into functional and nonfunctional tumors. Functional tumors represent 10–55% of all pNEN with clinical syndromes depending on the specific hormonal hypersecretion [41, 42] (Table 2) and are most represented by insulinomas and gastrinomas. Carcinoid syndrome presenting with flush and/or diarrhea is only rarely seen (<5%) [41, 42, 43, 44].
Table 2

Clinical syndromes depending on the specific hormonal hypersecretion

Tumor subtype/associated syndrome

Secretion products

Symptoms

Nonfunctional

Chromogranin A, pancreatic polypeptide, a-/β-human chorionic gonadotropin, calcitonin

Unspecific

Carcinoid syndrome

Serotonin

Diarrhea, flush, bronchial obstruction

Insulinoma

Insulin, proinsulin

Hypoglycemia

Gastrinoma/Zollinger-Ellison syndrome

Gastrin

Ulcerations, diarrhea

VIPoma

Vasoactive intestinal peptide

Diarrhea, hypokalemia

Glucagonoma

Glucagon

Necrolytic migratory erythema, diabetes mellitus

Somatostatinoma

Somatostatin

Diabetes mellitus, steatorrhea, cholelithiasis

GHRHoma

Growth hormone-releasing hormone

Acromegaly

CRHoma, ACTHoma

Corticotropin-releasing hormone, adrenocorticotropic hormone

Cushing’s syndrome

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.

Metastases are already present at the time of diagnosis in 60–70% of patients with the exception of insulinomas that are benign in 90% of the cases [45, 46, 47, 48].

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 [41].

Staging, Prognostic Classification, and Common Therapies

The staging system for pancreatic ductal adenocarcinoma is based on the AJCC/UICC TNM Staging System, 7th Edition (Tables 3 and 4) [49] which considers primary tumor extent (T stage), regional lymph node involvement (N stage), and presence of distant metastasis (M stage).
Table 3

TNM of the pancreatic ductal adenocarcinoma (From AJCC, 7th Edition)

Primary tumor (T)

Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor limited to the pancreas, 2 cm or less in greatest dimension

T2

Tumor limited to the pancreas, more than 2 cm in greatest dimension

T3

Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery

T4

Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

Regional lymph nodes (N)

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasis

Table 4

Staging of the pancreatic adenocarcinoma based on TNM classification

AJCC staging for pancreatic cancer

Stage

T

N

M

Stage 0

Tis

N0

M0

Stage IA

T1

N0

M0

Stage IB

T2

N0

M0

Stage IIA

T3

N0

M0

Stage IIB

T1

N1

M0

T2

N1

M0

T3

N1

M0

Stage III

T4

Any N

M0

Stage IV

Any T

Any N

M1

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].

Treatment guidelines of pancreatic ductal adenocarcinoma differ according to the stage: stage II cancers are generally treated by surgery and adjuvant chemotherapy (with or without adjuvant radiation therapy); stage III disease is treated by chemotherapy with or without adjuvant radiation therapy; stage IV is controlled with a chemotherapy-only approach (Table 4). TNM staging correlates with overall survival as shown in Table 5 [53].
Table 5

Overall survival in pancreatic adenocarcinoma

Median survival (Mo)

Stage

All patients

Non-resected

Resected

IA

10.0

6.8

24.1

IB

9.1

6.1

20.6

IIA

8.1

6.2

15.4

IIB

9.7

6.7

12.7

III

7.7

7.2

10.6

IV

2.5

2.5

4.5

Total

4.4

3.5

12.6

Adapted from Bilimoria et al. [53].

Some important prognostic factors are the histological grade (poorly differentiated cancers have the worst overall survival compared to well- or moderately differentiated pancreatic ductal adenocarcinoma) [54, 55]. Also, features such as stromal content and lymphovascular invasion are associated with a poorer outcome [56, 57]. Despite the prognostic importance of TNM staging, the selection of patient candidates for resection is made through the use of a “surgical staging” defined by Varadhachary et al. from the MD Anderson Cancer Center and slightly modified by the National Comprehensive Cancer Network (NCCN) (Table 6) [58, 59, 60].
Table 6

Surgical staging

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

Stage

Superior mesenteric artery

Celiac axis

Hepatic artery

Superior mesenteric vein/portal vein

Resectable

No abutment

No abutment

No abutment

No distortion

Borderline resectable

Abutment

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

Locally advanced

Encasement

Encasement; abutment for pancreatic ductal adenocarcinoma of the head (NCCN)

Encasement and no option for reconstruction

Occluded and no option for reconstruction

Adapted from surgical staging guidelines proposed by Varadhachary et al. [59]; Evans et al. [60] and NCCN guidelines

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 [61].

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 [64]. 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 [65].

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].

Some patients have palliation of symptoms when treated by chemotherapy with gemcitabine or 5-fluorouracil [68, 69, 70].

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 [71].

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 [72]; 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 [56].

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 [73]. 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) [74], 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 [75].

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 [45]. 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% [76]; 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 [46]. 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 [77].

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 [78].

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) [80]. 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 [84].

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 [85]. 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 [86]. 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. [90] 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 [91], and in this scenario PET/CT seems to be useful [92, 93].

Pancreatic Cancer Staging

PET/CT can be a valid tool in staging patients with localized lesions on CT that are at high risk for metastatic disease, including patients with locally advanced disease, borderline resectable tumors, or a severe increase of CA 19-9 [58]. PET/CT does not currently add much staging information in most patients with resectable disease [94, 95] (Fig. 1).
Fig. 1

Staging [18F]FDG PET/CT. Red flags: pancreatic findings, pancreatic adenocarcinoma. (a) PET/CT, transaxial; (b) PET, transaxial; (c) CT, transaxial; (d) PET/CT, coronal; (e) MIP

False-negative PET results can be observed in hyperglycemic patients or in subcentimeter lesions, whereas false-positive PET results can occur in some inflammatory states like pancreatitis (Fig. 2), infection of a pseudocyst, or local inflammation due to the placement of a biliary stent and the resulting accumulation of leukocytes with high metabolic activity [96, 97, 98]. Some studies including a meta-analysis in 2001 by Gambhir et al., a study by Zafra et al., and another one by Topkan et al. found that PET/CT changed management of patients with pancreatic adenocarcinoma respectively in 36%, 34%, and 36.6% of the studied populations [99, 100, 101, 102]. Despite these results, a study by Izuishi et al. conducted in 2010 on 65 patients with pancreatic cancer found that 61.5% of patients had metastatic disease to the liver that was already confirmed on CT: hence PET did not change a single patient’s staging. However, in the same study, PET detected a considerable number of nodal and bone metastases not found on CT. Nonetheless in these patients, already judged inoperable due to vascular involvement or liver metastases, PET/CT did not change management [80]. Another study by Lytras et al. found no real benefit from PET compared to CT in identifying either liver metastases or peritoneal carcinomatosis [98]. Although literature remains equivocal on whether PET truly changes patient outcomes and management, the majority of available data suggest that PET identifies some metastases not detected on CT. Thus PET/CT has become an accepted part of the imaging algorithm for patients with a new diagnosis of pancreatic cancer.
Fig. 2

False-positive [18F]FDG PET/CT. Red flags: pancreatic findings, chronic pancreatitis. (a) PET/CT, transaxial; (b) PET, transaxial; (c) CT, transaxial; (d) PET/CT, coronal; (e) MIP

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) [103]. 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

The identification of early responders to chemotherapy is important to avoid unnecessary toxicity in patients who will not respond (Fig. 3). Sometimes the metabolic response is not accompanied by changes in tumor size after chemoradiation therapy [104], and morphological response assessment by conventional imaging can be inaccurate (e.g., presence of fibrosis induced by treatments). In this scenario we can assume that the [18F]FDG PET study can assess treatment response earlier and better compared with conventional imaging [105, 106].
Fig. 3

Restaging [18F]FDG PET/CT after 3 months from the end of radiotherapy in the same patient whose staging scan is represented in Fig. 1. Red flags: residual pancreatic cancer. (a) PET/CT, transaxial; (b) PET, transaxial; (c) CT, transaxial; (d) PET/CT, coronal; (e) MIP

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 [107].

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 [108].

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].

Prognostic Significance

Several studies have shown a correlation between higher metabolic activity of pancreatic carcinoma and poorer prognosis thus providing prognostic information [87].

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 [110].

In this setting, when CA 19-9 is rising despite negative conventional imaging, [18F]FDG PET could have a role in detecting sites of undetected recurrence, such as the local, liver, peritoneal dissemination, lung, distant lymph nodes metastasis (Fig. 4). [18F]FDG PET could also exclude the presence of recurrence in cases of indeterminate findings by other imaging modalities [111].
Fig. 4

(a) [18F]FDG PET/CT in a patient with a history of pancreaticoduodenectomy and a suspect of relapse. Red flags: recurrence, pancreatic findings. A PET/CT, transaxial; B PET, transaxial; C CT, transaxial; D PET/CT, coronal; E MIP. (b) Yellow flags: bone recurrence. F I, PET/CT, transaxial; G L, PET, transaxial; H M, CT, transaxial

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 [114].

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 [115]. A few series indicate prognostic factors in locally advanced pancreatic cancer. A study by Parlak et al. [116] 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 [117] also in view of the fact that a lesion can present [18F]FDG uptake with no anatomical alterations.

Malignant lesions can be heterogeneous and [18F]FDG PET/CT is able to guide biopsy to the area of highest [18F]FDG uptake [117, 118] (Fig. 5). The first studies on [18F]FDG PET/CT-guided biopsy were published in 2008 by O’Sullivan et al. on musculoskeletal lesions [119] and subsequently other studies including that from Cerci et al. [120] in 2012 and Purandare et al. [121] in 2013 confirmed the value of PET/CT in guiding biopsy procedures.
Fig. 5

[18F]FDG PET/CT-guided biopsy. Red flags: pancreatic findings, site of biopsy. A1 A2, PET/CT, transaxial; C1 C2, CT, transaxial; E MIP (Images kindly provided by Juliano Cerci (Clinica Quanta, Curitiba, Brazil))

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 [122] and may optimize the diagnostic yield of image-guided interventions.

Neuroendocrine Tumors

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 [123]. 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) [126]. 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 [127]. According to the ENETS guidelines, when initial SSTRs imaging is positive, patients should undergo SSTRs imaging for staging every 18–24 months [46].

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 [128].

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) [132]: 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 [139]. 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 [132]. 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 [123].

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) [141] and 99mTc-vapreotide (high affinity for SSTR2 and SSTR5 and low affinity for SSTR3 and SSTR4 [142]).

111In-DOTA-lanreotide, 99mTc-HYNIC-TOC, and 99mTc-HYNIC-TATE are similar, in terms of SSTR affinity profile and results, to 111In-pentetreotide [143, 144, 145].

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 [146]. 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 [151].

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) [153].

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 [155]. 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] [68].Ga-DOTA-exendin-3 is a promising tracer to visualize insulinomas on PET imaging [162].

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

68Ga-DOTA-labeled SSAs (DOTANOC, DOTATATE, and DOTATOC) are used for the diagnostic workup of GEP-NETs (they allow for imaging 1–3 h within i.v. injection) and differ in their affinity spectrum toward the different SSTRs [132, 166, 167, 168, 169]. 68Ga-DOTATATE has high affinity for SSTR2, 68Ga-DOTATOC for STTR2 and SSTR5, and 68Ga-DOTANOC for SSTR2, SSTR3, and SSTR5 [132, 166, 167, 168, 169] (Figs. 6 and 7). PET/CT with 68Ga-DOTANOC, 68Ga-DOTATATE, or 68Ga-DOTATOC shows higher sensitivity for GEP-NET lesions in comparison with SRS SPECT-CT (more than 90%) due to better spatial resolution and SSTR binding affinity [132, 166, 167, 168, 169].
Fig. 6

Staging 68Ga-DOTANOC PET/CT. Red flags: pancreatic findings. (a) PET/CT, transaxial; (b) PET, transaxial; (c) CT, transaxial; (d) PET/CT, coronal; (e) MIP

Fig. 7

68Ga-DOTANOC PET/CT to assess response to treatment after 2 months of therapy with somatostatin in the same patient as in Fig. 6. Red flags: pancreatic findings. (a) PET/CT, transaxial; (b) PET, transaxial; (c) CT, transaxial; (d) PET/CT, coronal; (e) MIP

There are new 68Ga-DOTA-labeled SSAs for PET imaging that include 68Ga-DOTAVAP and 68Ga-DOTALAN [142].

[18F]FDG PET/CT

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 [172].

18F-DOPA PET/CT

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

[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 [177]; therefore, compounds that indicate proliferative activity, such as 18F-FLT [178], should be more suitable for differentiating between malignancy and inflammatory processes than nonspecific metabolic markers such as [18F]FDG [179].

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 [180]. Other peptide receptors might be interesting target for receptor imaging like gastrin-releasing peptide or bombesin receptors [181, 182, 183].

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Elena Tabacchi
    • 1
    Email author
  • Cristina Nanni
    • 1
  • Irene Bossert
    • 1
    • 3
  • Anna Margherita Maffione
    • 2
  • Stefano Fanti
    • 1
  1. 1.Nuclear Medicine Unit“S. Orsola-Malpighi” University HospitalBolognaItaly
  2. 2.Nuclear Medicine UnitOspedale Santa Maria della MisericordiaRovigoItaly
  3. 3.Nuclear Medicine Service“Fondazione Salvatore Maugeri” IRCCSPaviaItaly

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