Diagnostic Applications of Nuclear Medicine: Neuroendocrine Tumors
Neuroendocrine tumors (NETs) originate from neuroendocrine cells ubiquitously distributed throughout the body and occur mainly in the gastrointestinal and bronchopulmonary system. They are rare, are mostly sporadic, and comprise 0.66% of all neoplasia. Their incidence/prevalence is increasing based upon more sophisticated diagnostic strategies. Despite the majority being indolent, they are frequently metastatic at diagnosis. As a consequence their prognosis is often limited.
The European Neuroendocrine Tumor Society (ENETS) diagnostic and prognostic stratification criteria are based on histological typing, differentiation, grading (Ki67), and TNM staging. Although the general application of Ki67 is controversial, it remains embedded in therapeutic decision-making pending the implementation of molecular stratification systems.
Surgery is the only curative option. It is however effective in ~20% given the metastatic status of most lesions. Other therapeutic options include somatostatin analogs, interferon, “targeted” drugs, and peptide receptor radionuclide radiotherapy (PRRT).
NETs present a diagnostic and therapeutic challenge as their clinical presentation is protean, nonspecific, and late with hepatic metastases often present. Imaging plays a fundamental role in diagnosis, staging, treatment selection, and follow-up. Current modalities include morphologic techniques (CT, MRI), transabdominal ultrasound (US), and endoscopic (EUS) and intraoperative US (IOUS). Molecular imaging includes scintigraphy (111In-pentetreotide or 99mTc-HYNIC-Tyr3-octreotide), and, more recently, PET with 68Ga-labeled somatostatin analogs (SSA), 18F-DOPA and [11C]5-HTP; catecholamine metabolism is usually imaged with 123I-metaiodobenzylguanidine. [18F]FDG PET/CT has a prognostic role. A role for somatostatin receptor antagonists (better target/background ratio) as theranostics is currently proposed.
The major unmet needs are the development of more inclusive criteria for therapy monitoring, the validation of the recent PET techniques, and the integration of molecular biologic and metabolic information.
KeywordsNeuroendocrine tumors Imaging Scintigraphy PET/CT
5-Hydroxyindoleacetic acid, an end-metabolite of serotonin
5-Hydroxytriptamin, also known as serotonin
Aromatic L-amino acid decarboxylase
American Joint Committee on Cancer
Amine precursor uptake and decarboxylation
Area under the curve
Chromogranin A, a tumor-associated marker for neuroendocrine tumors
X-ray computed tomography
Circulating tumor cell
Connective tissue growth factor, also known as CCN2
2-(4-Isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)
Diffusion-weighted magnetic resonance imaging, an MR technique used to detect changes in the distribution of water molecules in selected regions
European Association of Nuclear Medicine
European Neuroendocrine Tumor Society
Gene encoding for the hypoxia-inducible factor 2-alpha (HIF-2α); the gene is also known as HIF2A
Fine needle aspiration cytology
Originated in the gastroenteropancreatic tract
Growth-hormone releasing hormone
Gastrointestinal stromal tumor
Exendin, a glucagon-like protein
High-power field in optical microscopy
Large-cell neuroendocrine carcinoma
Metastasis status according to the AJCC/UICC TNM staging system
Gene encoding for the myc-associated factor X
Multi-detector X-ray computed tomography
Multiple endocrine neoplasia
Magnetic resonance imaging
Lymph node status according to the AJCC/UICC TNM staging system
Gene encoding for neurofibromin
United States National Institutes of Health
Gene encoding for Na+/K+ ATPase
Tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)
Polymerase chain reaction
Positron emission tomography
Positron emission tomography/Computed tomograhy
Pheochromocytoma and paraganglioma
Peptide receptor radionuclide therapy
Parathyroid-hormone related protein
Response evaluation criteria in solid tumors
Proto-oncogene encoding for a receptor tyrosine kinase
Small-cell lung cancer
Gene encoding for succinate dehydrogenase B
Gene encoding for succinate dehydrogenase D
Surveillance, Epidemiology, and End Results, a tumor registry of the National Institutes of Health
Syndrome of inappropriate antidiuretic hormone secretion
Society of Nuclear Medicine and Molecular Imaging
Single-photon computed tomography
Single-photon computed tomography/Computed tomography
Somatostatin receptor scintigraphy
Standardized uptake value
Standardized uptake value at point of maximum
Tumor status according to the AJCC/UICC TNM staging system
Gene encoding for a protein that acts as a tumor suppressor
AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status), and “M” (distant metastasis status)
Gene encoding for the tuberous sclerosis factor, also known as hamartin
Thyroid stimulating hormone
Union Internationale Contre le Cancer (International Union Against Cancer)
Vasoactive intestinal peptide
Gene encoding for the vesicular monoamine transporter
A syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria
World Health Organization
Neuroendocrine tumors (NETs) represent a major diagnostic challenge since their clinical presentation is variable, nonspecific, and usually late, often when hepatic metastases are already present [1, 2]. Critical issues in diagnosis are the identification of primary tumor location and of regional and distant metastases. Plasma biomarkers, histopathology, and imaging are used to define these areas. Imaging includes radiological and nuclear medicine techniques to acquire information on tumor site, extent, and functionality. These include delineation of somatostatin receptor expression (somatostatin receptor imaging), neuroendocrine tumor metabolism (18F-DOPA), and metabolic status ([18F]FDG-PET). Histopathological examination of tumor biopsies provides further information but is limited by tumor heterogeneity and a paucity of molecular markers that accurately demarcate tumor biology. Although Ki67 is widely used, it is a monoanalyte, and controversy exists in regard to its accuracy and precise clinical application (2). Biomarkers such as plasma chromogranin A (CgA) and urinary 5-hydroxyindoleacetic acid (5-HIAA) are currently most used. They are monoanalytes; the assays are suboptimal in terms of sensitivity and specificity and do not meet the NIH performance metrics for accurate biomarkers . The recent reports of the high accuracy of the measurement of circulating mRNA neuroendocrine transcripts suggest that this strategy may facilitate early diagnosis and detection of lesions and may provide an accurate basis for prognostic determination and therapeutic recommendation [4, 5].
Imaging plays a central role in diagnosis, staging, treatment selection, and follow-up of NETs. Current diagnostic modalities include radiological techniques such as multi-detector CT (MDCT), MRI, transabdominal ultrasound (US), and endoscopic (EUS) and intraoperative US (IOUS). Nuclear medicine strategies or molecular imaging includes scintigraphy (including single photon emission computed tomography, SPECT) with 111In-pentetreotide or 99mTc-HYNIC-Tyr3-octreotide and, more recently, PET with 68Ga-labeled somatostatin analogs (SSA), 18F-DOPA, and [11C]5-HTP . Recently somatostatin receptor (SSR) antagonists have been investigated in clinical trials, based upon their better targeting properties . No modality alone is entirely effective, and the overall sensitivity and specificity of diagnostic imaging is ~80–90% [2, 7]. Regardless of imaging modalities utilized, about 50% of NETs remain with an unknown primary site . In order to optimize sensitivity and specificity, anatomic and functional techniques are generally combined [8, 9]. The development of hybrid scanners (SPECT/CT, PET/CT), whereby molecular and anatomic details are superimposed, has facilitated an increase diagnostic accuracy. Somatostatin receptor imaging (either with conventional 111In-pentetreotide scintigraphy or with 68Ga-SSA-PET/CT) is a prerequisite to evaluate the eligibility and also putative efficacy of peptide receptor radionuclide therapy (PRRT) and, to a lesser extent, systemic treatment with unlabeled somatostatin analogs.
Despite substantial advances in the fields of anatomic and functional imaging, a number of critical unmet needs remain in NET imaging. These are the development of more inclusive criteria for NET progression, the delineation of therapeutic responses that can be applied to slow-growing tumors, the validation of the more recent functional techniques (such as somatostatin receptor PET), and the integration of novel molecular genomic, biologic, and metabolic information [10, 11].
Neuroendocrine tumors (NETs) are relatively rare tumors originating from ubiquitous neuroendocrine cells distributed throughout the body. The term “neuroendocrine” relates to the hybrid morphological and biological nature of these cells, which have both endocrine secretory properties. Such cells synthesize, store, and secrete a variety of classic (circulating) hormones as well as local chemical messengers which function as neurotransmitters or neuromodulators [12, 13].
In 1907, the pathologist Siegfried Oberndorfer was the first to describe small tumors of the intestine that he referred to using the German diminutive for cancer, “Karzinoide,” thereby erroneously suggesting a benign tumor. Although he subsequently reversed this conclusion, the incorrect concept of a benign neoplasm has unfortunately remained enshrined in medical oncological dogma. In 1914, Pierre Masson suggested the endocrine origin of these tumors, and thereafter Friedrich Feyrter in 1938 introduced the concept of diffuse endocrine system. In 1966, Anthony Pearse sought to unify the origin of all neuroendocrine tumors by expanding Feyrter’s concept. He ascribed a series of common biochemical characteristics to embrace all such neoplasia using the term APUDoma (amine precursor uptake decarboxylation) and concluded all had a neural crest origin. Further studies by Bloom and Polak linked the immunohistochemical and secretory characteristics of NETs with their symptoms and formed the basis for the contemporary understanding of neuroendocrine neoplasia .
The neuroendocrine system is composed of three major compartments: (1) neurons in the central and peripheral nervous system; (2) epithelial endocrine cells (often with neuronal features), dispersed individually in the gastroenteric and respiratory tracts, thyroid, thymus, skin, breast, larynx, kidney, urinary bladder, and prostate and in some instances assembled in units, such as the pancreatic islets of Langerhans or the renal juxtaglomerular apparatus (polkissen cells); and (3) the classic endocrine organs, such as the anterior pituitary, parathyroid glands, and adrenals . Neuroendocrine cells regulate activity systemically or locally via endocrine or autocrine/paracrine mechanisms and thereby modulate metabolic, chemoreceptor, motility, and secretion functions .
Neuroendocrine cells, depending on their degree of differentiation, produce, store, and exocytose a number of bioactive agents, including gastrin; insulin; serotonin; somatostatin; glucagon; pancreatic polypeptide; VIP in gastroenteropancreatic (GEP) tract; catecholamines in the adrenal medulla; ACTH, GH, prolactin, FSH, LH, and TSH in the anterior pituitary; and PTH in parathyroid glands. The majority of these cells contain chromogranins (a constitutive secretory proteins and/or synaptophysin), which have by default become utilized as nonspecific biomarkers of the neuroendocrine cell system or its neoplasia .
The majority of neuroendocrine neoplasia (NEN) (>95%) are sporadic. Others, particularly of gastric and pancreatic origin, may be related to genetic conditions including multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis (NF1), von Hippel–Lindau (VHL) disease, tuberous sclerosis complex (TSC), or Carney’s syndrome . Overall, there are at least 13 different neuroendocrine cell types in the gastrointestinal tract (EC, ECL, gastrin, δ, etc.) and four in the pancreas (α, β, δ, PP) with individual anatomical localization and defined neuroendocrine secretory products. Germline mutations in five genes have been recognized to be responsible for familial pheochromocytomas: the von Hippel–Lindau gene (VHL), causing VHL syndrome; the RET gene, leading to multiple endocrine neoplasia (MEN) type 2; the neurofibromatosis type 1 gene (NF1), associated with von Recklinghausen’s disease; and the genes encoding the B and D subunits of mitochondrial succinate dehydrogenase (SDHB and SDHD), which are associated with familial paragangliomas and pheochromocytomas. Hereditary GEP or bronchial NET and pituitary adenomas occur in MEN type 1.
Tumors may arise from each of the neuroendocrine cell types and can exhibit a wide spectrum of clinical and pathological behavior, ranging from asymptomatic to florid (flushing/diarrhea) or from indolent (e.g., gastric type I tumor) to highly aggressive growth (e.g., glucagonomas). Their natural history varies from torpid local invasion and fibrosis in the peritoneal cavity or heart to diffuse metastatic spread, most commonly to the liver and lungs . Metastases are present overall in ~35% of all gastroenteropancreatic (GEP) NETs at presentation, ranging from <5 for type I gastric tumors to 60–80% for those originating in the small bowel and colon [2, 19].
The Rochester Epidemiology Project revealed that pheochromocytomas demonstrated an overall incidence in the white population of 0.8/100,000 cases per year over 30 years . Of note was the observation that 0.5% of subjects with hypertension and 4% of those with an incidental adrenal mass harbor a pheochromocytoma .
Sporadic forms of pheochromocytoma are diagnosed in individuals aged 40–50 years, whereas hereditary forms are diagnosed at a younger age, often before 40. Pheochromocytoma is rare in children, but, when found, it is often extra-adrenal, multifocal, and associated with hereditary syndromes.
NETs represent different pathological entities, depending on their organ and cell of origin, and have been considered as representing three categories: (a) those arising in neuroendocrine organs, such as medullary thyroid carcinomas, pancreatic endocrine tumors, pheochromocytomas, and paragangliomas; (b) those arising from dispersed neuroendocrine cells, such as bronchial or gastroenteric NETs; and (c) those arising from non-neuroendocrine organs, such as thymic carcinoids or cutaneous NETs.
WHO 2010 general neuroendocrine neoplasm categories: comparison with previous classifications
1. Well-differentiated endocrine tumor (WDET)a
1. NET G1 (carcinoid)b
2. Well-differentiated endocrine carcinoma (WDEC)a
2. NET G2b
3. Poorly differentiated endocrine carcinoma/small cell carcinoma (PDEC)
3. NEC (large cell or small cell type)b, c
4. Mixed exocrine–endocrine carcinoma (MEEC)
4. Mixed adenoneuroendocrine carcinoma (MANEC)
III Mixed forms carcinoid – adenocarcinoma
IV Pseudotumor lesions
5. Tumor-like lesions (TLL)
5. Hyperplastic and preneoplastic lesions
WHO 2010 working principles for neuroendocrine neoplasms
Neoplasm definition to embrace all grades of endocrine tumors (low, intermediate, and high grade)
Neuroendocrine connotation recommended as description of shared neural–endocrine markers
Standard definition of neuroendocrine tumor (NET) for low- to intermediate-grade neoplasms and neuroendocrine carcinoma (NEC) for high grade
NET subdivision according to grade (ICDO codes 8240/3 and 8249/3); potential malignancy formalized
NEC subdivision in LCNEC and SC-NEC (ICDO codes 8013/3 and 8041/3)
Synonyms for NET: carcinoid, well-differentiated endocrine tumor/carcinoma; for NEC: poorly differentiated endocrine carcinoma, high-grade neuroendocrine carcinoma
TNM recommended (AJCC–UICC–WHO 2010)
For carcinoids only (excluded G3 neoplasms)
Blueprint from ENETS proposals 2006–2007 for the stomach, ileum, and colon but with significant differences for the appendix and pancreas (generate data)
Diagnosis by site according to the above uniform grading and staging parameters
Minimal histopathology report recommendation
Neoplasm definition as NET or NEC
Grade definition as G1–G3
pTNM definition (when possible)
The Travis 2004 classification of bronchopulmonary neuroendocrine tumors
A tumor with carcinoid morphology and less than 2 mitoses per 2 mm2 (10 high-power field (HPF)), lacking necrosis and 0.5 cm or larger
A tumor with carcinoid morphology with 2–10 mitoses per 2 mm2 (10 HPF*) OR necrosis (often punctate)
Large-cell neuroendocrine carcinoma
A tumor with a neuroendocrine morphology (organoid nesting, palisading, rosettes, trabeculae)
High mitotic rate: 11 or greater per 2 mm2 (10 HPF), median of 70 per 2 mm2 (10 HPF)
Necrosis (often large zones)
Cytologic features of a non-small cell carcinoma (NSCLC): large cell size, low nuclear to cytoplasmic ratio, vesicular or fine chromatin, and/or frequent nucleoli. Some tumors have fine nuclear chromatin and lack nucleoli, but qualify as NSCLC because of large cell size and abundant cytoplasm
Positive immunohistochemical staining for one or more neuroendocrine markers (other than neuron-specific enolase) and/or neuroendocrine granules by electron microscopy
Small cell carcinoma
Small size (generally less than the diameter of three small resting lymphocytes)
Nuclei: finely granular nuclear chromatin, absent or faint nucleoli
High mitotic rate (11 or greater per 2 mm2 (10 HPF), median of 80 per 2 mm2 (10 HPF)
Frequent necrosis often in large zones
Proposed Grading system for bronchopulmonary neuroendocrine tumors
Mitotic count (10 HPF)a
Genetically related forms of pheochromocytoma and paraganglioma
Neurofibromatosis type 1
Café-au-lait spots, neurofibromas, axillary and inguinal freckling, Lisch nodules, osseous lesions, optic gliomas, mainly pheochromocytomas
Multiple endocrine neoplasia type 2
2A: Medullary thyroid cancer, primary hyperparathyroidism, PPGL
2B: Medullary thyroid cancer, PPGL, Marfanoid habitus, mucocutaneous neuromas, gastrointestinal ganglioneuromatosis
von Hippel–Lindau disease
Central nervous system or retinal hemangioblastomas, renal cell carcinoma, PPGL, pancreatic neuroendocrine tumors and cysts, endolymphatic sac tumors, papillary cystadenoma of the epididymis and broad ligament
1. PGL5: SDHA
2. Head and neck paraganglioma
3. PPGL, rare renal cancers, GIST
4. PPGL, rare renal cancers, GIST
5. PPGL, GIST
1. Mainly pheochromocytomas, rare renal cancers
2. Mainly PPGL
Polycythemia, PPGL, somatostatinoma
Leiomyomatosis and renal cell
Cutaneous and uterine leiomyomas, type 2 papillary renal carcinoma, rare PPGL
In addition to their hormonal profile, PPGL often exhibits neuroamine uptake mechanisms and/or specific receptors, such as cell membrane somatostatin receptors and norepinephrine transporter (vesicular monoamine transporter 1 and 2, VMAT 1 and 2), which are of critical relevance to their localization and treatment .
Clinical Symptomatology and Presentation
NETs, particularly those of GEP origin, exhibit protean symptomatology that is often overlooked. They may present with symptoms related to the inappropriate hypersecretion or paroxysmal bioactive peptide or amine. The large majority is nonfunctioning and such lesions are asymptomatic presenting late due to a mass effect (jaundice/pain). Thus, despite a sometime typical clinical scenario, such as the carcinoid syndrome, symptoms remain frequently unrecognized, and diagnosis is often tardy. Diagnostic delay is usually 5–7 years since the symptoms are considered as caused by other ubiquitous conditions (e.g., allergy, anxiety, menopause) as opposed to a tumor, or the paroxysmal nature of the symptoms leads to considerations of neurotic complaints or somatization . NET is therefore often diagnosed late when metastasis (usually hepatic) has occurred; thus, curative surgery is no longer possible. Thus, despite the fact that the tumors tend to be well differentiated and slow growing, with a minority of aggressive forms, outcome is significantly diminished by delay in diagnosis.
Gastric NETs (frequently referred to as gastric carcinoids) are typically multiple, small, and generally benign and derived from ECL cells. They are associated with hypergastrinemia and have been classified as type I, associated with atrophic gastritis, or type II, in conjunction with MEN1 and/or the Zollinger–Ellison syndrome. Type I are very rarely malignant, whereas type II in 20–30% are malignant and metastatic. Type III gastric carcinoids not associated with hypergastrinemia and present as single, usually larger lesions often associated with metastatic disease.
Duodenal NETs frequently secrete gastrin and may be associated with Zollinger–Ellison syndrome, occasionally as part of MEN1. Intestinal NETs (the so-called classic “carcinoids,” described by Oberndorfer) derive from enterochromaffin cells (EC cells). Symptoms are usually only evident after metastasis to the liver and are often paroxysmal and have been described as typical or atypical. Manifestations are protean and include cutaneous flushing, diarrhea, bronchospasm, tachycardia, and abdominal pain. Symptoms represent the overproduction and release in the systemic circulation of bioactive amines and peptides including mostly serotonin, histamine, and tachykinins. The classic carcinoid syndrome, however, is relatively uncommon (10–15%) . A not insignificant percentage of carcinoids may be discovered when nonmetastatic due to emergency surgery for acute abdominal events relating to perforation, bleeding, or obstruction . Colonic carcinoids are frequently large, nonfunctioning, and with a poor prognosis, while rectal lesions are small and rarely metastasize. Appendiceal carcinoids are usually identified early when they cause obstructive appendicitis and are mostly benign. A small percentage is malignant and metastatic usually manifesting with mucin producing diffuse peritoneal metastases and only occasionally functional .
NETs in the pancreas vary in size depending upon the time of identification and their symptomatology. Asymptomatic lesions usually present late unless identified by mass lesions obstructing the common bile duct or with bleeding and/or pain. Up to 50% have synchronous local or liver metastatic disease. Functioning pancreatic islet cell tumors may present with syndromes related to the hyperproduction of insulin, gastrin, VIP, glucagon, or somatostatin. These tumors represent markedly different clinical and pathological entities depending upon their cell of origin and symptomatology. Insulinomas are often small and benign lesions causing hypoglycemia. Pancreatic gastrinomas are less common than in the duodenum but generally malignant, causing Zollinger–Ellison syndrome and in ~25% of cases are associated with MEN1. Glucagonomas present with mild diabetes and a characteristic rash (necrolytic migratory erythema). Finally, VIPomas may produce severe diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Rarely, a group of more malignant lesions may secrete ACTH, GH-RH, PTH-RP, and somatostatin .
The majority of patients with BP-NETs have symptoms present with symptoms of cough, hemoptysis, and pneumonia (a classical triad), resulting from the lumen obstruction and ulceration of the tumor. Pathological classification predominantly divides the group into typical and atypical lesions although the criteria are sometimes difficult to ascertain. Typical carcinoids (TC) present characteristically as a central lesion, with signs and symptoms of bronchial obstruction, and exhibit a relatively benign/indolent biological behavior. Atypical carcinoids (AC) are frequently peripheral and functional. Their behavior may vary from indolent to aggressive, with lymphatic and hematogenous metastases. Less than 5% of BP-NETs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing syndrome, acromegaly, or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Large-cell neuroendocrine cancers are aggressive and rare form of NET, usually metastatic at diagnosis, causing rapid clinical deterioration. Paraneoplastic syndromes are sporadic. Small-cell lung cancers (SCLCs) are particularly aggressive and are associated with early hematogenous and lymphatic metastasis. SCLCs are extremely chemosensitive but usually relapse. Mediastinal syndrome, caused by lymph node metastases, is a relatively common clinical presentation and is often accompanied by distant metastases, typically to the brain or bones. In many instances, they are associated with paraneoplastic syndromes, particularly Cushing syndrome and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [55, 56, 57].
Chromaffin Cell NETs
Most PPGLs, except those arising from the head and neck region, are associated with catecholamine hypersecretion . The majority (80–85%) of pheochromocytomas arise from the adrenal medulla, while about 15–20% are extra-adrenal. Catecholamine-producing paragangliomas are usually located in the abdomen [45, 58]. The most frequent signs of catecholamine hypersecretion (pheochromocytoma has been described as “the great mimic”) are hypertension, tachycardia, headache, pallor, sweating, and feelings of panic or anxiety. Hyperglycemia, lactic acidosis, weight loss, nausea, fever, and flushing may also occur. Hypertension is usually paroxysmal, sometimes severe, leading to hypertensive emergencies, superimposed on a state of normal blood pressure or of hypertension. Sometimes blood pressure may be normal, when tumor load is limited or when dopamine is preferentially secreted. In rare cases of prevalent epinephrine secretion, patients may even present with hypotension .
Serum or blood hormone assays are currently used for diagnosis in conjunction with histopathology and clinical evaluation. Numerous different peptides and amines (secretory unianalytes) have been proposed as biomarkers to identify and monitor disease status of NETs. In the past, the most common markers of NETs have been chromogranins A and B, pancreatic polypeptide, pancreastatin, and NSE . The majority of biomarkers proposed for the diagnosis of these lesions have proven to exhibit a low sensitivity and specificity, are difficult to measure accurately or easily, and are therefore mostly of research use, with the exceptions of the specific peptides gastrin, insulin, VIP, and glucagon in pancreatic NETs, which proved to be of clinical utility.
Recently the development of molecular multianalyte markers (mRNA transcripts) has provided evidence that this strategy is more sensitive and specific . Transcript analysis in the blood provides >90% accuracy in the identification of NETs and the ability to define disease progression .
In the past, plasma CgA levels have been widely utilized as the default biomarker for all NETs. Although they are relatively sensitive (60–90%), their specificity is poor (10–30%). This reflects elevated levels in other NETs and other malignancies, spurious increases in individuals with impaired renal function or during administration of proton pump inhibitors . CgA has mostly been used as the default measurement to confirm diagnosis and obtain information as to tumor burden and possible location of the tumor. Its interpretation is limited however by the fact that it is a secretory product and does not represent the diverse biological activity of the tumor (proliferation, metabolic status, etc.). Circulating CgA is elevated in ~60% of individuals with GEP-NETs, most frequently in subjects with gastrinomas (100%), followed by small-bowel “carcinoid” tumors (80%) and nonfunctioning pancreatic NETs (70%) . Plasma CgA levels are considered more frequently elevated in well-differentiated tumors compared to poorly differentiated tumors of the midgut reflecting the observation that it is a secretory marker and dedifferentiated lesions rarely secrete. It has been proposed that CgA possesses some utility in predicting survival and in providing information on the efficacy of therapy; however, this is likely a surrogate of the fact that secretory capacity is inversely related to tumor differentiation . Measurement of CgA is substantially limited by a lack of standardization of assays and a relatively low sensitivity/specificity in some clinical situations. Thus, CgAs measured at different time points in the disease or using different commercial assays are not comparable or provide information that is difficult to interpret. Moreover, measurement of urinary 5-HIAA levels or plasma 5-HT levels is cumbersome, insensitive, and difficult to quantify.
If a secretory phenotype is present, the diagnosis of chromaffin cell tumors is based on syndromic presentation, which triggers the assessment of plasma and urinary catecholamines and genetic testing . Functioning chromaffin cell tumors secrete catecholamines, namely, norepinephrine, epinephrine, and dopamine. These agents are catabolized to metanephrines, which may be identifiable in high concentration in the urine. Urinary and plasma catecholamines, urinary metanephrines (normetanephrine and metanephrine), and urinary vanillylmandelic acid are usually measured for diagnosis. Currently, the plasma and 24-h urinary measurement of free metanephrines is the most sensitive method to accurately diagnose a pheochromocytoma/paraganglioma (96–100% and 92–99% sensitivity, respectively, and 87–92% and 64–72% specificity, respectively) . Due to its low sensitivity and specificity, CgA is not used in chromaffin cell tumor assessment . To avoid false-positive results, biochemical evaluation should not be performed if the patient is receiving drugs that can increase catecholamine levels. These agents include phenoxybenzamine and tricyclic antidepressants, monoaminooxidase inhibitors, calcium channel blockers, and caffeine. Biochemical evaluation of patients receiving these drugs is a major cause of false-positives. Dynamic tests, such as the clonidine test, are sometimes performed in norepinephrine-secreting tumors . Head and neck paragangliomas are rarely hormonally active.
A key unmet need in the diagnostic assessment of NETs and chromaffin tumors is the availability of a blood test for early diagnosis or surveillance. The recent demonstration of specific NEN transcripts in plasma suggests that this strategy may enable early diagnosis and detection of lesions and even provide a basis for prognostic determination and therapeutic recommendation. Recent reports indicate that measurements of neuroendocrine blood transcripts are significantly more specific and reproducible than CgA measurement .
NET transcript analysis can identify PCC/PGL in 95–100%, and expression levels correlate with lesion extent, particularly extra-adrenal. Furthermore SDH mutations were associated with decreased expression of genes involved in metabolism providing a functional dimension to the assessment. In addition proliferation-associated genes are elevated in progressive, metastatic disease; thus, measurement of circulating transcripts focusing on gene clusters has utility in identifying and differentiating disease activity in PGL/PCC tumors where other neuroendocrine biomarkers lack specificity .
Localization of GEP-NETs may be difficult since they often present as small lesions and their anatomic location is ubiquitous. EUS is mainly useful in the diagnosis and staging of small and intramural lesions of the duodenum, pancreas, stomach, and rectum and can detect up to 60% of duodenal and up to 100% of pancreatic lesions. EUS and IOUS have a detection rate of 92% for insulinomas. Although the diagnostic accuracy of US for the detection of pancreatic NETs is high, the best performance of US is for the diagnosis and follow-up of liver metastases (sensitivity and specificity are 88% and 95%, respectively) [27, 28].
GEP-NETs may metastasize systemically or locally into the bowel mesentery. Mesenteric disease can be identified on CT as a contrast-enhancing mass often containing calcifications . Angio-CT has particular utility in the identification of the involvement of vascular structures (such as mesenteric arteries) that may preclude surgical resection . However, CT and MR imaging cannot always differentiate tumors and mesenteric metastasis from intestinal structures. Lymphoma or retractile mesenteritis can also have a similar CT appearance .
Primary carcinoids of the lungs account for ~25–30% of all NETs. Most carcinoids (typical and atypical) are located close to central bronchi, although in about 16–40% (often atypical) are located in the peripheral lung. They typically show a spherical or ovoid shape with a well-defined border, but sometimes they develop along bronchi or pulmonary arteries. Punctate or diffuse calcifications are frequently observed on CT. Both typical and atypical carcinoids are usually hypervascular and demonstrate intense contrast enhancement (more than 30 HU). Atypical carcinoids are associated with hilar or mediastinal lymph node metastases. LCNEC, which is a poorly differentiated and high-grade NET, is morphologically intermediate between atypical carcinoid and SCLC. LCNEC and SCLC do not show any specific CT feature and can indistinguishable from the other common NSCLCs. However, CT plays a main role for staging and follow-up of all NETs of the lung.
Nuclear Medicine Techniques
Molecular imaging provides spectrum of information which includes somatostatin receptor status (e.g., 111In-pentetreotide scintigraphy or 68Ga-DOTA-SSA-PET/CT), metabolic activity ([18F]FDG), and specific amine metabolism (e.g. 18F-DOPA). As a result, further information regarding the biology of the lesion and the extent of disease may be generated, thus facilitating staging in molecular, metabolic, spatial, and functional dimensions.
Rationale of Nuclear Medicine Techniques
Somatostatin receptor imaging is used to obtain information as to the localization of disease and extent (staging and restaging) and to select patient for therapy with “cold” or radiolabeled somatostatin analogs [11, 90]. The rationale of somatostatin receptor imaging is the tumor cell receptor-mediated internalization of the receptor-radioanalog complex and its retention in the cytoplasm. 111In-pentetreotide or OctreoScan® represents the first approved radiopharmaceutical for NEN imaging and is the commonly used agent.
Somatostatin is a ubiquitous peptide that exists in either a 14-amino acid or a 28-amino acid form present in the hypothalamus, brainstem, gastrointestinal tract, and pancreas. SSTRs are found on cells of neuroendocrine origin as well as on activated lymphocytes. Six subtypes of SSTRs have been identified by molecular analysis (named sst1, sst2a, sst2b, sst3, sst4, and sst5), each exerting its action by inhibition of adenylyl cyclase activity. Each receptor subtype exhibits a different binding affinity for native somatostatin and for somatostatin analogs. Subtype 2 has the highest affinity (Kd 0.1–1 nM), whereas subtypes 3 and 5 are within the 10–100 nM range, and subtypes 1 and 4 exhibit a low affinity. Moreover, since SSTR2 is the most frequently expressed in NET tumors, it has proved to be the optimal target for imaging. A key advantage of somatostatin imaging efficacy is based upon the significant overexpression and hence high density of SSTRs in neuroendocrine neoplasia (80–2,000 fmol/mg protein compound) as compared to the relatively low expression within normal neuroendocrine tissue .
Currently, the majority of radiotracers used for SSTR imaging are based on octreotide, which is a long-acting analog of the human hormone, somatostatin. The presence of octreotide-binding sites (SSTRs) on tumors permits their in vivo visualization after injection of a radionuclide-labeled octreotide analog. Although 123I-[Tyr3]-octreotide was the initial imaging, radio compound utilized its relatively short effective half-life, and the high background of radioactivity within the abdomen limited its clinical application. The subsequent development of 111In-[DTPA-D-Phe1]-octreotide, or 111In-pentetreotide, which exhibited greater stability and facilitated the acquisition of enhanced imaging characteristics in the delayed images. This compound is a registered trademark of Mallinckrodt Inc. with the name of OctreoScan®. Octreotide binds with high affinity to the SSTR2 and with moderate affinity to the SSTR3 and SSTR5 receptors. Subsequently since the early 2000s, the approach to the functional imaging of NENs has been substantially advanced by the introduction of octreotide derivatives, the DOTA-peptides, labeled with the positron emitter Gallium-68. The three most commonly used analogs are DOTA-Tyr3-octreotide (DOTATOC), DOTA-Tyr3-Thr8-octreotide (DOTATATE), and DOTA-Nal3-octreotide (DOTANOC). These analogs retain an octreotide-like affinity profile and, in particular, a high affinity for SSTR2. Only DOTANOC exhibits a substantial affinity for SSTR3 .
Initially NENs were referred to as APUD (amine precursor uptake and decarboxylation) tumors because of their ability to take up amino acids and transform them into biogenic amines by means of the enzyme aromatic amino acid decarboxylase. The terminology APUDoma was first used by Ilona Szij of Budapest and subsequently adopted by A. Pearse . The amine uptake, decarboxylation characteristic remains a biological hallmark of chromaffin and neuroendocrine cells although the inelegant term for the tumors, APUDomas has over time evolved into the more commonly used acronym NETS. NET cells synthesize catecholamines in an enzymatic pathway, which initially converts the amino acid tyrosine into L-DOPA; thereafter, L-DOPA is decarboxylated to dopamine, oxidized to norepinephrine, and methylated to epinephrine, which is transported into synaptic vesicles. Reuptake of catecholamines occurs presynaptically by norepinephrine transporters present on the cell membrane . Based upon this series of biochemical events, NETs can be imaged with 18F-DOPA PET (6-L-18F-dihydroxyphenylalanine) and [11C]5-hydroxytryptophan ([11C]5-HTP), which accumulate within cells due to the high activity of the aromatic amino acid L-DOPA decarboxylase. Thus, the tracer radioiodinated metaiodobenzylguanidine (MIBG) is internalized by the cell via the norepinephrine transporter and stored in neurosecretory vesicles by a catecholamine transporter (VMAT). 18F-DOPA or 18F-dopamine PET and 123I/131I-MIBG scintigraphy are highly sensitive for detecting tumors arising from the adrenal medulla. However, they can also be taken up by non-adrenomedullary NETs and paragangliomas [92, 93].
Metaiodobenzylguanidine (MIBG) is a norepinephrine analog that concentrates within secretory granules of catecholamine-producing cells. It is structurally similar to guanethidine. MIBG, like norepinephrine, is taken up by a cell membrane based active, sodium- and energy-dependent amine uptake mechanism (uptake-1), inserted into the cell membrane of chromaffin tissues, and then transported to the intracellular storage granules by an active uptake mechanism .
Pharmaceutical compounds that reduce the sensitivity of scintigraphy (Adapted with permission from )
Mechanism of interference
Withdrawal before MIBG
Antiarrhythmics (e.g., amiodarone)
Uptake inhibition and depletion
Not easily feasible
Alpha–beta blockers (e.g., labetalol)
Uptake inhibition and depletion
Calcium channel blockers (e.g., amlodipine)
Increased uptake and retention
Alpha2 sympathomimetics (e.g., salbutamol)
Depletion of granules
Vasoconstrictor sympathomimetics (e.g., pseudoephedrine)
Uptake inhibition and depletion
Neuroleptics (e.g., haloperidol)
1–15 days (short-acting formulations)
Antihistamine (e.g., promethazine)
Opioid analgesics (e.g., tramadol)
Tricyclic antidepressants (e.g., amitriptyline)
Psychostimulants (amphetamines, cocaine)
Uptake inhibition and depletion
[18F]FDG, a glucose analog, is transported into the cell via dedicated glucose transporters and thereafter phosphorylated by the cytoplasmic enzyme, hexokinase. The resulting compound cannot be further metabolized and is trapped within the cytoplasmic space. Since many tumors, particularly those of aggressive or accelerated proliferative nature, exhibit an increased glycolytic metabolism, they overexpress glucose transporters and have abundant hexokinase. This phenomenon provides the biological basis for the use of [18F]FDG as a radiopharmaceutical to detect such tumors. The process of accelerated glycolytic metabolism is also however a common occurrence in activated inflammatory cells. Thus [18F]FDG may also accumulate at sites of inflammation and constitute a potential cause of false positivity for malignancy .
Somatostatin Receptor Scintigraphy
Preparation for the scan includes laxatives, to eliminate nonspecific activity in the bowel, and withdrawal of somatostatin analogs (short-acting analogs for at least 48 h, long-acting formulations for 4–6 weeks), although the latter point is still debated .
Assessment of images should be guided by clinical information. As a general rule, clearly outlined areas that show an isotope uptake higher than the normal liver distribution are classified as positive for receptor expression and thus considered to represent neuroendocrine malignancy. There are, however, alternative conditions that may be associated with increased somatostatin receptor expression and, hence, exhibit increased uptake. Possible sources of false positives include areas of chronic inflammation (such as radiation pneumonitis, sequelae of recent surgery), accessory spleens, gallbladder accumulation, focal stool aggregation, thyroid nodules, pulmonary granuloma, diffuse breast uptake, recent cerebrovascular infarction, arthritis, abscesses, and urine contamination .
False negatives imply the lack of visualization of NEN lesions, most commonly related to an incorrect methodology, such as low administered activity, a too rapid (or too early) scan time, the absence of SPECT images, or lesions whose dimensions fall below the resolution limit of the gamma camera. Other possible causes may be competition for receptor uptake by recent analog therapy (although this issue is debated), alteration of receptor expression by recent chemotherapy, or truly receptor-negative disease (e.g., benign insulinomas, high-grade NETs). In some cases, normal accumulation in the liver may mask isointense metastases or those with a relatively low expression of somatostatin receptor density .
Although both 131I-MIBG and 123I-MIBG are commercially available for diagnostic imaging, the former has been preferred since it is more widely available and economical. The physical characteristics of 131I-MIBG, although not optimal for scintigraphic imaging (gamma energy 364 keV, half-life 8 days), facilitate delayed studies. Alternatively, the physical properties of 123I (gamma energy 159 keV, half-life 13.3 h) provide better image quality, more favorable dosimetry, and the possibility of performing a SPECT study, rendering it the agent of choice. 123I-MIBG has, however, been approved for US usage by the Food and Drug Administration .
Thyroid blockade with nonradioactive iodide or, alternatively, potassium perchlorate is necessary to avoid thyroid uptake of free radioiodine and consequent potential damage. A solution of saturated potassium iodide (1–2 mg/kg per day) is commonly used, beginning 1 day before injection and continuing for 3–5 days.
Administered activities are 37–74 MBq (1–2 mCi) for 131I-MIBG and 370 MBq (10 mCi) for 123I-MIBG. To avoid potential bioactive adverse events, 123I- or 131I-MIBG should be administered by slow intravenous injection.
131I-MIBG scan is performed using a gamma camera equipped with a high-energy, parallel-hole collimator. Images are collected at 24 and 48 h after injection. If nonspecific activity is suspected in the kidneys or bowel, delayed images can be recorded after 72–120 h. Whole body and planar images of areas of interest are collected.
123I-MIBG scan is performed with a medium-energy, collimator. Images are collected 6 and 24 h after injection and, if needed, 48 h postinjection. Whole body and spot images are recorded. The use of 123I-MIBG allows SPECT imaging which is usually undertaken 24 h after administration. The use of hybrid SPECT/CT system further improves sensitivity . Suboptimal sensitivity can be caused by a small lesion size and and/or an extra-adrenal location. MIBG SPECT, evaluated side-by-side with contrast CT or MRI and/or hybrid imaging with SPECT/CT, provides an even more accurate anatomic localization of areas of MIBG uptake .
Physiologic accumulation of MIBG in the urinary tract or bowel can be a source of false-positive results. 123I-MIBG SPECT evaluated with contrast CT or MRI or hybrid imaging with SPECT/CT allows more accurate anatomic localization of areas of uptake . Rare causes of false-positive results such as the physiological accumulation of MIBG within the urinary tract or the bowel, which can mimic a tumor lesion, should also be considered. False negative results include lesions with dimensions below the spatial resolution of the gamma camera (~1 cm) or lesions whose uptake mechanisms have been altered by concomitant usage of drugs (Table 6).
In the last 15 years, the approach to the molecular imaging of NETs has been revolutionized by the introduction of PET with the Gallium-68 (68Ga)-labeled octreotide derivatives, DOTATOC, DOTATATE, and DOTANOC (68Ga-SSA-PET/CT) [125, 126, 127]. The overall sensitivity of 68Ga-SSA-PET/CT for NETs is >90%, while the specificity ranges from 92% to 98% [106, 128, 129]. Copper-64 (64Cu)-labeled SSA has also been evaluated for PET/CT of NETs with better imaging at later times (3–24 h p.i.) . Compared to CT scan and receptor scintigraphy, PET exhibited the greatest sensitivity (97%) compared to CT (61%) and SRS (52%) for the detection of NET lesions, especially in patients with small tumors at a nodal or bone level. PET is also able to identify small lesions in unusual locations such as the breast, uterus, prostate, ovary, and kidney [106, 131]. PET with 68Ga-DOTA-peptides is particularly useful in the early visualization of bone metastases, with a higher sensitivity, specificity, and accuracy than a CT scan. In a study of 84 patients (116 PET-positive lesions), only 84 (72.5%) were evident at conventional scintigraphy and only 58 (50%) at CT scan . Recently, a study of 51 patients, 35 of which were GEP-NETs, among other SSTR2 positive tumors, demonstrated that PET/CT with 68Ga-DOTATOC performed better than conventional somatostatin receptor scintigraphy or bone scintigraphy, resulting in a 97% sensitivity and 92% specificity .
Radiolabeled somatostatin receptor antagonists, characterized by a lack of internalization and a greater tumor uptake, were recently introduced in clinical trials due to their putative advantage of the much greater tumor-to-background ratio. Antagonists, such as 68Ga-DOTA-JR11, have provided very interesting novel information in the largely explored SSR imaging .
Alternative PET tracers include 18F-DOPA, which is a measure of neuroendocrine cell metabolism. This is a substrate utilized in the catecholamine synthesis pathway and is stored in the secretory granules . The diagnostic performance of this compound appears however to be inferior to 68Ga-DOTANOC . [11C]5-HTP, a serotonin precursor, which is the substrate for aromatic L-amino acid decarboxylase, is also utilized in research centers . 18F-DOPA PET was commonly used in the last decade, since it was the first PET modality to outperform 111In-pentetreotide scintigraphy. In a variety of GEP-NETs, it exhibited high sensitivity and specificity for small-bowel carcinoid tumors (93% and 89%, respectively) compared to 111In-pentetreotide . In a prospective cohort of 53 patients with carcinoid tumors, 18F-DOPA PET with carbidopa pretreatment demonstrated a per-patient sensitivity of 100%, detecting more lesions than conventional scintigraphy and CT scan . The enthusiasm for the use of these alternative PET techniques has however been diminished by the increased availability of 68Ga-DOTA-peptides and the demonstration of a superior sensitivity of somatostatin receptor PET with both 68Ga-DOTANOC (71 vs. 45 lesions for 18F-DOPA) and 68Ga-DOTATATE (96% vs 56% for 18F-DOPA) [135, 137]. A further limitation in their usage has been the fact that unlike somatostatin receptor imaging, these techniques do not possess a therapeutic counterpart.
[18F]FDG-PET is usually not considered a primary diagnostic tool in well-differentiated NETs, because of its low sensitivity. Its optimal application is for imaging of high G2 NETs with Ki67 >15–20% for which SRS and 68Ga-SSA-PET/CT may be less reliable . [18F]FDG-PET is generally recommended for neuroendocrine cancers (NEC) G3 tumors, although it has been reported as positive in 57% of G1 and 66% of G2 NETs . The increased glucose metabolism, expressed as standardized uptake value (SUV), can provide predictive information in terms of overall survival (OS) and progression-free survival (PFS, SUV >3) . Thus NETs that exhibit increased metabolic activity have a significantly lower disease control rate (100% vs 76%) and PFS (32 vs 20 months) after PRRT, compared to [18F]FDG-negative tumors . It has recently been proposed that [18F]FDG can be used as an independent prognostic marker by applying a three-tier metabolic grading system based on the tumor-to-background ratio of uptake . Finally, GLP1 receptor peptides for imaging of insulinomas (exendin analogs labeled with 68Ga) are under investigation in clinical trials .
[18F]FDG-PET/CT in NETs of the lungs shows variable [18F]FDG uptake according to tumor proliferation. A low [18F]FDG uptake (SUVmax < 2.5) is evident in typical (low-grade) bronchial carcinoids . Tumors of a higher grade than typical bronchial carcinoids can have high [18F]FDG uptake. Atypical carcinoids can be more metabolically active and usually appear as a small pulmonary nodule with hilar or mediastinal lymph nodes showing high SUV. LCNECs usually exhibit high [18F]FDG uptake, and PET/CT and stand-alone CT demonstrate high accuracy in prediction of the presence of hilar and mediastinal nodal involvement. However, PET/CT seems to be better than CT alone in detecting distant metastases and leading to the changes in the clinical management. An SUVmax greater than 13.7 predicts a short survival period, suggesting the use of PET/CT with [18F]FDG not only in staging but also in assessing prognosis of LCNEC . In SCLC, [18F]FDG PET is valuable for initial staging to distinguish localized vs. metastatic disease, and [18F]FDG PET/CT is also useful for prognosis, especially after treatment .
Early data addressing the combined use of [18F]FDG and 68Ga-DOTATOC appear to have clinical utility. Thus typical carcinoids, with high expression levels of SSRs, show high uptake on 68Ga-DOTATOC PET/CT imaging but low [18F]FDG uptake due to the low proliferative index. It has been proposed that increased avidity of [18F]FDG and/or decreased avidity for 68Ga-DOTATATE could identify aggressive tumors containing sites of possible dedifferentiation .
Data from a recent multi-center study of sporadic pheochromocytomas and paragangliomas indicate that PET/CT with 68Ga-DOTATATE is superior to any other imaging modality, including [18F]FDG PET/CT and CT/MRI, with a lesion-based detection rate of 97.6% versus 49.2% of [18F]FDG PET/CT, 74.8% of 18F-DOPA PET/CT, and 81.6% of CT/MRI . In a group of 30 patients with pheochromocytomas and paragangliomas at initial diagnosis or relapse, 68Ga-DOTATATE PET/CT exhibited the highest per lesion sensitivity (93% vs. 89% and 76%, compared to 18F-DOPA PET and conventional imaging). The highest sensitivity was identified in the detection of head and neck paragangliomas, especially in SDHD-related tumors . Integration of this information with circulating mRNA from tumor may add further to the precise delineation of the biological behavior of these tumors.
Somatostatin Receptor PET/CT
The serotonin precursor [11C]5-HTP is used in some investigative centers to define the metabolism of the neuroendocrine cell and is thus considered a universal imaging method for NETs. Tomographic imaging is performed after intravenous injection of 370 MBq . However, its widespread application is limited by the short half-life of 11C, which requires an on-site cyclotron.
For a detailed description of the scan methodology, reference should be made to the specific section on this subject.
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