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Diagnostic Applications of Nuclear Medicine: Neuroendocrine Tumors

  • Lisa BodeiEmail author
  • Mark Kidd
  • Laura Gilardi
  • Duccio Volterrani
  • Giovanni Paganelli
  • Chiara M. Grana
  • Irvin M. Modlin
Living reference work entry

Abstract

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.

Keywords

Neuroendocrine tumors Imaging Scintigraphy PET/CT 

Glossary

[11C]5-HTTP

[11C]5-Hydroxytryptophan

18F-DOPA

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

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

5-HIAA

5-Hydroxyindoleacetic acid, an end-metabolite of serotonin

5-HT

5-Hydroxytriptamin, also known as serotonin

AADC

Aromatic L-amino acid decarboxylase

AC

Atypical carcinoid

ACTH

Adrenocorticotropin hormone

AJCC

American Joint Committee on Cancer

APUD

Amine precursor uptake and decarboxylation

AUC

Area under the curve

BP

Bronchopulmonary

CEUS

Contrast-enhanced ultrasonography

CgA

Chromogranin A, a tumor-associated marker for neuroendocrine tumors

CT

X-ray computed tomography

CTC

Circulating tumor cell

CTGF

Connective tissue growth factor, also known as CCN2

DOTA

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)

DOTANOC

DOTA-Nal3-octreotide

DOTATATE

DOTA-Tyr3-Thr8-octreotide

DOTATOC

DOTA-Tyr3-octreotide

DTPA

Diethylenetriaminepentaacetic acid

DWI

Diffusion-weighted magnetic resonance imaging, an MR technique used to detect changes in the distribution of water molecules in selected regions

EANM

European Association of Nuclear Medicine

EC

Enterochromaffin

ECL

Enterochromaffin-like

EDDA

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

ENETS

European Neuroendocrine Tumor Society

EPAS1

Gene encoding for the hypoxia-inducible factor 2-alpha (HIF-2α); the gene is also known as HIF2A

EUS

Endoscopic ultrasonography

FNAC

Fine needle aspiration cytology

FSH

Follicle-stimulating hormone

GEP

Originated in the gastroenteropancreatic tract

GH-RH

Growth-hormone releasing hormone

GH

Growth hormone

GIST

Gastrointestinal stromal tumor

GLP

Exendin, a glucagon-like protein

HPF

High-power field in optical microscopy

HYNIC

Hydrazidonicotinic acid/Hydrazinonicotinamide

IOUS

Intraoperative ultrasonography

LCNEC

Large-cell neuroendocrine carcinoma

LH

Luteinizing hormone

M

Metastasis status according to the AJCC/UICC TNM staging system

MAX

Gene encoding for the myc-associated factor X

MDCT

Multi-detector X-ray computed tomography

MEN

Multiple endocrine neoplasia

MIBG

meta-Iodobenzylguanidine

MRI

Magnetic resonance imaging

N

Lymph node status according to the AJCC/UICC TNM staging system

NE

Neuroendocrine

NEN

Neuroendocrine neoplasia

NET

Neuroendocrine tumor

NF1

Gene encoding for neurofibromin

NIH

United States National Institutes of Health

NKA

Gene encoding for Na+/K+ ATPase

NSE

Neuron-specific enolase

OS

Overall survival

p53

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)

PCC

Pheochromocytoma

PCR

Polymerase chain reaction

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomograhy

PFS

Progression-free survival

PGL

Paraganglioma

PPGL

Pheochromocytoma and paraganglioma

PRRT

Peptide receptor radionuclide therapy

PTH-RP

Parathyroid-hormone related protein

PTH

Parathyroid hormone

qPCR

Quantitative PCR

RECIST

Response evaluation criteria in solid tumors

RET

Proto-oncogene encoding for a receptor tyrosine kinase

SCLC

Small-cell lung cancer

SDHB

Gene encoding for succinate dehydrogenase B

SDHD

Gene encoding for succinate dehydrogenase D

SEER

Surveillance, Epidemiology, and End Results, a tumor registry of the National Institutes of Health

SIADH

Syndrome of inappropriate antidiuretic hormone secretion

SNMMI

Society of Nuclear Medicine and Molecular Imaging

SPECT

Single-photon computed tomography

SPECT/CT

Single-photon computed tomography/Computed tomography

SRS

Somatostatin receptor scintigraphy

SSA

Somatostatin analog

SSTR

Somatostatin receptor

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

TC

Typical carcinoid

TMEM127

Gene encoding for a protein that acts as a tumor suppressor

TNM

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

TSC

Gene encoding for the tuberous sclerosis factor, also known as hamartin

TSH

Thyroid stimulating hormone

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

VHL

von Hippel-Lindau

VIP

Vasoactive intestinal peptide

VMAT

Gene encoding for the vesicular monoamine transporter

WDHA

A syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria

WHO

World Health Organization

Introduction

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 [3]. 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 [2]. Recently somatostatin receptor (SSR) antagonists have been investigated in clinical trials, based upon their better targeting properties [6]. 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 [2]. 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

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 [14].

Biomorphology

  1. (a)

    NE cells

    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 [15]. Neuroendocrine cells regulate activity systemically or locally via endocrine or autocrine/paracrine mechanisms and thereby modulate metabolic, chemoreceptor, motility, and secretion functions [16].

    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 [17].

     
  2. (b)

    Neoplastic spectrum

    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 [18]. 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 [2]. 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].

     

Incidence

The Surveillance, Epidemiology, and End Results (SEER) database, containing 48,195 NENs from 1973 to 2006 [20], indicates that NETs constitute 0.66% of all malignancies in the United States and the incidence is increasing at a rate of 3–10% per year depending on the subtype (Fig. 1). Thus in 2004 NETs comprised 1.25% of all malignancies, as compared to 0.75% in 1994 [19, 20]. This increment is related to the technical progress of more sensitive diagnostic tools and to an increased awareness among clinicians and pathologists [2, 21]. However, the greater frequency (1.22%) of NETs in a large autopsy series indicates that they are predominantly underdiagnosed [22]. It also suggests that there is a significant percentage that may have no clinical consequences during the lifetime of an individual. According to SEER, the most frequent site is the gastrointestinal tract (66%) followed by the bronchopulmonary system (25%). Other less frequent locations are the ovaries, testes, hepatobiliary, and pancreas (Fig. 2) [23].
Fig. 1

Incidence of neuroendocrine neoplasms by anatomical location in the US population between 1973 and 2007

Fig. 2

Distribution of neuroendocrine tumors (n = 49,012) in the Surveillance, Epidemiology, and End Results (SEER) tumor registry database from 1973 to 2007, according to anatomical site and tumor type: total NETs (top left), gastroenteropancreatic (GEP)-NETs (bottom left), and pancreatic NETs (bottom right). Non-GEP-NETs are predominantly located in the respiratory system (∼70 % are bronchopulmonary NETs; top right)

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 [24]. Of note was the observation that 0.5% of subjects with hypertension and 4% of those with an incidental adrenal mass harbor a pheochromocytoma [25].

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.

Histopathological Classification

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.

NETs can be functioning or nonfunctioning, depending on the presence of a clinical symptomatology syndrome due to hypersecretion of bioactive amines or peptides. The 1963 classification of GEP-NETs, based on their embryologic origin (foregut, midgut, or hindgut) by Williams and Sandler [26], is used, though of minimal value, and has mostly been supplanted by the World Health Organization (WHO) classification system. The latter has defined these tumors based upon a number of morphological criteria including their degree of differentiation and site of origin [27]. The initial (2004) iteration identified well-differentiated neuroendocrine tumors (benign behavior or uncertain malignant potential), well-differentiated neuroendocrine carcinomas (low-grade malignancy), or poorly differentiated (small or large cell) neuroendocrine carcinomas of high-grade malignancy. The term “carcinoid” was reserved for “well-differentiated” tumors. Size, angioinvasion, proliferative activity, histologic differentiation, metastases, and hormonal activity (association with clinical syndromes or diseases) were included in the classification scheme. Histochemical indicators of prognosis include the degree of expression of the proliferation protein Ki-67 and the p53 tumor suppressor protein [28, 29]. ENETS and later WHO in 2010 further refined this classification to include the Ki-67 scoring index and the TNM classification system (Table 1) [30, 31]. The grading proposal stratifies tumors in G1, G2, and G3 and is based on the premise that all NETs are intrinsically malignant (Table 2) [32, 33]. The tumor grading, histopathology type and staging, reflects on the potential metastatic spread and, therefore, influences the choice of therapeutic options (surgery, biotherapy, and chemotherapy) [34]. Although the function of Ki-67 remains poorly characterized [35] and concerns remain regarding heterogeneity of expression and measurement techniques, it is used as a surrogate marker of proliferation [36]. In order to assure an optimal treatment of GEP-NETs, a standardized diagnostic procedure is required. The ENETS society has proposed diagnostic and prognostic stratification criteria, based on histological typing, differentiation, grading, and TNM staging. Immunostaining for the neuroendocrine markers synaptophysin and chromogranin and for the proliferation marker Ki67/MIB1 is considered mandatory, while immunostaining for hormones, receptors, and other markers is optional [34]. The recent development and introduction of a minimal data set for pathologists will add consistency and uniformity to the evaluation and classification of GEP-NENs [37].
Table 1

WHO 2010 general neuroendocrine neoplasm categories: comparison with previous classifications

WHO 1980

WHO 2000

WHO 2010

I Carcinoid

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

II Mucocarcinoid

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

From Bosman et al. [151], with permission

aThe difference between WDET and WDEC was defined according to staging features in the WHO 2000 classification. G2 NET does not necessarily translate into WDEC of the WHO 2000 classification

bDefinition in parentheses for the International Classification of Diseases for Oncology (ICDO) coding

c“NET G3” has been used for this category but is not advised since NETs are by definition well differentiated

Table 2

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)

From Bosman et al. [151], with permission

This classification applies easily to GEP-NETs, while bronchopulmonary (BP) and thymic NETs are still classified according to a proposal by Travis (Table 3). Travis recognized low-grade NETs – typical and atypical carcinoids – and high-grade NETs, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). The most prevalent high-grade NET, accounting for 89% of cases according to the SEER database of National Cancer Institute, is SCLC [38, 39, 40].
Table 3

The Travis 2004 classification of bronchopulmonary neuroendocrine tumors

Typical carcinoid

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

Atypical carcinoid

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)

Scant cytoplasm

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

From Travis et al. [152], with permission

A recent proposal of a three-tier grading system for BP-NETs has been published. It is based upon that currently utilized for GEP tumors and includes Ki67 index (with specific cut-offs) in addition to mitotic count and necrosis (Table 4) [41]. However, the utility of this new classification using Ki67 in BP-NETs requires prospective confirmation [42].
Table 4

Proposed Grading system for bronchopulmonary neuroendocrine tumors

Grade

Mitotic count (10 HPF)a

Ki67 (%)b

Necrosis (%)c

G1

2

<4

No

G2

>2–47

4–<25

<10

G3

>47

≥25

>10

From Rindi et al. grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer. 2013, with permission

a10 HPF, ten high-power field=2 mm2, to be assessed in at least 50 fields at 40× in areas of highest mitotic density

bKi67%: MIB antibody, as percentage of 500–2,000 cells counted in areas of highest nuclear labeling

cNecrosis as % of sample: focal, presence of <10% of sample, diffuse, more than 10% of sample

Pheochromocytomas and paragangliomas (PPGL) derive from sympathetic chromaffin tissue in the adrenal medulla and from the extra-adrenal paraganglial system of the thorax and abdomen. The frequency malignant propensity of chromaffin tumors, pheochromocytomas, and paragangliomas reflects the genetic background. Over 50% of PPGL can be attributed to genetic alterations [43]. These most frequently involve germline mutations of VHL or SDH genes (Table 5). The 2004 WHO classification recognized the common origin of PPGL from neuroectoderm and divided them into pheochromocytomas and paragangliomas, arising, respectively, in the adrenals or the extra-adrenal sympathetic tissue. Pheochromocytomas are usually considered as malignant only in the presence of metastases. These usually are found with decreasing frequency in the liver, lymph nodes, lung, and bone, either at diagnosis or during follow-up. This group has been colloquially defined by the so-called 10% rule, namely, 10% bilateral, 10% extra-adrenal, 10% familial, and 10% malignant [44]. Histopathological scoring criteria utilizing the presence of diffuse cellular growth, high cellularity, monotony, tumor cell spindling, atypical mitotic figures, high mitotic count, etc. failed to accurately assess the malignant potential due to inter- and intra-observer variation [45]. Malignant pheochromocytomas account for about 10% of all pheochromocytomas and are associated with capsular invasion and large tumor size (>5 cm in size and >80 g in weight) [46]. Genetically five autosomal dominant disorders are recognized: the paraganglioma (PGL) syndromes types 1–5 are characterized by a familial predisposition to PGLs, pheochromocytomas (PCCs), renal cell cancers, gastrointestinal stromal tumors and, rarely, pituitary adenomas. The different syndromes are based on five different/separate mutations of the SDH gene (SDHD=PGL1, SDHAF2=PGL2, SDHC=PGL3, SDHB=PGL4, and SDHA=PGL5) [47]. Malignant pheochromocytomas are evident in individuals with MEN2, > 90% of those in VHL disease, and ~90% of those in NF1 [48]. Malignant paragangliomas have a higher prevalence, 15–35% when associated with the SDHB gene mutations [49, 50, 51].
Table 5

Genetically related forms of pheochromocytoma and paraganglioma

Gene

Disease

Features

NF1

Neurofibromatosis type 1

Café-au-lait spots, neurofibromas, axillary and inguinal freckling, Lisch nodules, osseous lesions, optic gliomas, mainly pheochromocytomas

RET

Multiple endocrine neoplasia type 2

2A: Medullary thyroid cancer, primary hyperparathyroidism, PPGL

2B: Medullary thyroid cancer, PPGL, Marfanoid habitus, mucocutaneous neuromas, gastrointestinal ganglioneuromatosis

VHL

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

PGL1: SDHD

Hereditary paragangliomas

1. PGL5: SDHA

PGL2: SDHAF2

2. Head and neck paraganglioma

PGL3: SDHC

3. PPGL, rare renal cancers, GIST

PGL4: SDHB

4. PPGL, rare renal cancers, GIST

PGL5: SDHA

5. PPGL, GIST

1. TMEM127

Familial pheochromocytomas

1. Mainly pheochromocytomas, rare renal cancers

2. MAX

2. Mainly PPGL

EPAS1

Polycythemia paraganglioma

Polycythemia, PPGL, somatostatinoma

FH

Leiomyomatosis and renal cell

Cutaneous and uterine leiomyomas, type 2 papillary renal carcinoma, rare PPGL

GIST: gastrointestinal stromal tumors (Adapted from Favier et al. [43] with permission)

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 [52].

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 [2]. 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.

Gastroenteropancreatic NETs

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%) [22]. 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 [53]. 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 [54].

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 [2].

Bronchopulmonary NETs

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 [58]. 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 [58].

Biochemical Profile

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 [59]. 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 [4]. Transcript analysis in the blood provides >90% accuracy in the identification of NETs and the ability to define disease progression [60].

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 [61]. 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%) [62]. 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 [4]. 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.

A recent Delphic consensus unanimously established that common biomarkers used for GEP-NETs are inadequate for BP-NETs and concluded that mRNA transcript analysis (NETest) was provided a greater opportunity for clinical utility [63]. The multianalyte-derived NET gene signature encompasses the expression of 51 genes, measured by qPCR that are assessed by four different prediction algorithms scaled to a disease/tumor activity (0–100%) score [64] using expression that specifically capture the hallmarks of neoplasia [65]. The expression of 51 NET marker genes includes analysis of clusters of biologically relevant genes that constitute the different “omes” (proliferome, metabolome, secretome, epigenome, and pluromes) [64] which define the NET “fingerprint.” This can be used to provide direct information about the tumor, its pathophysiology, and its state of evolution from stability to progression [66]. The test has a sensitivity and specificity of greater than 90% and significantly outperforms CgA measurement in every assessable parameter [67]. Clinically, gene expression is decreased following surgery and can be used to identify residual/recurrent disease [68]; it can also effectively monitor treatment protocols, e.g., somatostatin analog therapy [69, 70], and can predict disease progression Fig. 3 [71].
Fig. 3

Utility of biomarkers and imaging techniques in NET management. (a) The utility of current NET biomarkers and imaging based on published use and performance metrics. Overall clinical utility can be estimated by referencing the arrow (red) to the x any axes of metrics and utility. miRNA assessment (orange) has no rigorous utility or metrics available. CTC measurement (yellow) exhibits moderate metrics but has not been validated in NETs. Substance P, NSE, pancreatic polypeptide, NKA, pancreastatin, CTGF, and brain natriuretic peptide (green) all display variable performance metrics. Their overall utility is weak. Biomarkers including urinary 5-HIAA and CgA have moderate utility, but their metrics are highly variable. NET transcript analysis (red) exhibits high level metrics, and early clinical studies support its clinical utility. Imaging data derived from CT scan, MRI, somatostatin receptor scintigraphy, [18F]FDG, and 68Ga-SSA-PET/CT (blue) are included for comparison with current biomarkers. All imaging techniques have high utility, but the metrics exhibit a wide range from [18F]FDG to 68Ga-PET. BNP brain natriuretic peptide, Ga-PET 68Ga-SSA-PET/CT, PP pancreatic polypeptide, Pro-GRP progastrin-releasing peptide, SRS somatostatin receptor scintigraphy, u5-HIAA urinary 5-HIAA. (b) Receiver operating characteristic curves for peripheral blood NET transcript analysis {polymerase chain reaction (PCR)} (red) compared to chromogranin A (CgA) (blue) for GEP-NETs. The NET transcript analysis area under the curve (AUC) was significantly more effective (AUC = 0.98, p < 0.0001) than CgA (AUC = 0.64, p < 0.002). In the efficacy analysis of NET, transcript analysis demonstrated that it was significantly more accurate than CgA (p < 0.0001)

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 [43]. 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) [72]. Due to its low sensitivity and specificity, CgA is not used in chromaffin cell tumor assessment [73]. 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 [74]. 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 [5].

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 [75].

Techniques

Radiological Techniques

Transabdominal ultrasonography (US) is usually the first examination to identify the location of the tumor. It is also used for needle guidance in case of fine needle aspiration cytology (FNAC) or core biopsy. To improve sensitivity, contrast-enhanced US (CEUS), endoscopic US (EUS), and intraoperative US (IOUS) are also used. Contrast-enhanced multi-detector CT (MDCT) and MRI are considered the fundamental methods for localizing the primary tumor and delineating its local extent, staging the locoregional and distant metastases, and restaging the patients after therapy [53]. Three-phase scans are performed to best delineate hypervascular and hypovascular lesions. Since NETs are typically hypervascular, CT and MRI are performed early after the bolus of contrast is injected (arterial phase) (Fig. 4). The sensitivity for pancreatic NETs ranges from 69% to 94% for CT and 74–94% for MRI and is >80% for EUS coupled with biopsy [53, 76, 77, 78, 79, 80]. The sensitivity for locating a primary small intestine NET is >90% for CT enteroclysis and 86–94% for MRI [81, 82, 83]. Although tumor arterial enhancement is homogeneous in small NETs, heterogeneous enhancement is more common in lesions larger than 3 cm. However, the degree, uniformity, and timing of enhancement can be highly variable, and other lesions, such as intrapancreatic accessory spleen, can be commonly mistaken for a NET. Vascular heterogeneity itself is considered to be a sign of malignancy since malignant lesions often have heterogeneous vascular structure, perfusion, and vascular permeability [84, 85].
Fig. 4

Patient with a liver metastasis from an ileal neuroendocrine tumor. Upper images show SPECT/CT images demonstrating uptake of 111In-pentetreotide within a liver metastasis. The bottom left image shows the metastasis with a typical contrast enhancement on CT during the arterial phase. The lesion enhancement decreases during the venous phase when compared to the liver parenchyma (bottom right image)

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 [86]. Angio-CT has particular utility in the identification of the involvement of vascular structures (such as mesenteric arteries) that may preclude surgical resection [87]. 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 [88].

The liver is the commonest site of NET metastases. The metastatic lesions are typically hypervascular, and most can be detected on CT or MR images acquired during the hepatic arterial phase. However, liver metastases may be hypovascular (Fig. 5). Moreover, larger metastases may show heterogeneous enhancement due to central necrosis. For liver metastases, MRI fast spin echo has a high sensitivity, while a single-shot sequence allows optimal distinction between hypervascular metastases from hemangiomas. Contrast-enhanced CT and MR imaging can also disclose occasional metastases to other intra-abdominal organs. Metastases to bone are easily missed on CT. Although MR imaging has a sensitivity of nearly 100%, the appearance of lesions may be identical to that of bone metastases from other primary tumors. Contrast-enhanced CT, MR imaging, and US are routinely used for monitoring lesions. Finally, video capsule and double-balloon enteroscopy can identify otherwise undetectable small intestine tumors [10].
Fig. 5

Patient with a pancreatic NET and multiple liver metastases that result positive at SRS but negative at the three-phase contrast-enhanced CT

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.

CT and MRI are sensitive and specific for detecting adrenal pheochromocytomas (77–98% for CT and 95–100% for MRI). However, MRI and CT have a lower sensitivity (sensitivity of CT is 29%) for extra-adrenal lesions or metastases from malignant pheochromocytomas [46, 89]. In this setting, specificity may be decreased since other tumors of neurogenic origin or mesodermal origin may resemble paragangliomas in both distribution and appearance [25] (Figs. 6 and 7).
Fig. 6

Patient with an abdominal paraganglioma. The left images (from top to bottom) of a three-phase contrast-enhanced CT disclose a paraganglioma located in front of the left renal vein showing the typical contrast enhancement during the arterial phase (top). In the middle, MRI images show the same lesion hyperintense on T2-weighted image (top) and on DWI (bottom). The right images of a SPECT/CT study show the high uptake of 111In-pentetreotide within the paraganglioma

Fig. 7

CT shows a lesion with contrast enhancement during the arterial phase along the left ureter suggesting a diagnosis of paraganglioma. Subsequent SRS and 123I-MIBG scintigraphy were negative. After surgery, the lesion resulted to be a neurinoma at histopathology

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 [91].

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 [91].

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 [13]. 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 [13]. 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 [94].

There are numerous drugs that reduce the sensitivity of the scintigraphy and frequently result in false negatives; this occurs through interference with the uptake, intracellular transport, granule storage, or the retention of MIBG [95]. To ensure optimal imaging, these pharmaceuticals should be temporarily withdrawn before the examination, for a time period of approximately five times longer their respective half-lives before imaging [58] (Table 6).
Table 6

Pharmaceutical compounds that reduce the sensitivity of scintigraphy (Adapted with permission from [96])

Drugs

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

3 days

Calcium channel blockers (e.g., amlodipine)

Increased uptake and retention

1–2 days

Alpha2 sympathomimetics (e.g., salbutamol)

Depletion of granules

1 day

Vasoconstrictor sympathomimetics (e.g., pseudoephedrine)

Uptake inhibition and depletion

1–2 days

Neuroleptics (e.g., haloperidol)

Uptake inhibition

1–15 days (short-acting formulations)

Antihistamine (e.g., promethazine)

Uptake inhibition

1 day

Opioid analgesics (e.g., tramadol)

Uptake inhibition

1 day

Tricyclic antidepressants (e.g., amitriptyline)

Uptake inhibition

2–8 days

Psychostimulants (amphetamines, cocaine)

Uptake inhibition and depletion

1–5 days

[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 [97].

Scintigraphy

Somatostatin Receptor Scintigraphy
Clinical Application
The radiolabeled somatostatin analog 111In-pentetreotide (or 111In-DTPA-D-Phe1-octreotide or OctreoScan®) is the commonly used agent for somatostatin receptor scintigraphy (SRS) [98, 99, 100, 101], although the 99mTc-labeled peptide 99mTc-EDDA-HYNIC-octreotide (Tektrotyd®) is used in several European countries [102]. The sensitivity of 111In-pentetreotide scintigraphy has been well documented in the 1990s as >75% for gastroenteropancreatic (GEP-NETs) and bronchial tumors (BP-NETs, compared to other imaging modalities available (CT/MRI) [103]. Information from OctreoScan® images modified the therapeutic strategy in ~53% of cases by accurately staging NETs and especially by detection of metastatic disease [104, 105]. Currently, however the OctreoScan technique is regarded as suboptimal, with sensitivities <60%, compared with state-of-the-art morphological imaging (CT and MRI) [106]. Although MRI is considered to have the highest sensitivity for liver metastases, SRS is the most accurate imaging modality for “one-shot” detection of liver and extrahepatic metastases in patients with GEP-NETs [107] (Fig. 8). OctreoScan® is also utilized to monitor treatment efficacy. Changes in functional volume at scintigraphy are considered more useful than CT and RECIST (Response Evaluation Criteria in Solid Tumors) in monitoring tumor response after treatment and correlate well with later clinical response [108] (Fig. 9).
Fig. 8

SRS with 111In-pentetreotide. On the left (a, b), a whole body scan shows a patient with an intestinal lesion, abdominal lymph nodes, and multiple lung metastases. On the right (c, d), a patient with liver metastases

Fig. 9

SRS with 111In-pentetreotide. Peritoneal relapse of a GEP-NET

In BP-NETs, molecular imaging can help differentiate the etiology of bronchial masses [109]. Since most of thoracic NETs express somatostatin receptors, especially subtypes 2 and 5 (Fig. 10), 111In-pentetreotide scintigraphy can detect most bronchial carcinoids >1 cm in diameter, including those associated with ectopic GH-RH secretion [110]. SRS is also helpful for radioguided surgery, allowing evaluation of the tumor bed after resection to detect any residual radioisotope uptake that might reflect the presence of residual tumor [111]. Since SSTRs are expressed on inflammatory cells, some degree of caution in the misinterpretation of early postsurgical changes should be considered.
Fig. 10

Typical bronchial carcinoid. SRS with 111In-pentetreotide shows an intense uptake of the tracer within a mass in the medium lobe

Technique

The radiopharmaceutical should be prepared in accordance with the manufacturer’s instructions and quality control performed with a calibrated ionization chamber. Radiochemical purity should be checked with thin-layer chromatography prior to patient administration. The amount of peptide injected in this preparation is 10 μg. To preserve diagnostic sensitivity, the recommended injected activity should be ~200 MBq (5.4 mCi). Lower activities can only be administered if acquisition parameters are adjusted accordingly [112]. At least two different sets of planar and/or whole body images should be acquired to facilitate the interpretation of the exam. Commonly adopted protocols include scans at 4 and 24 h or, optimally, 24 and 48 h postinjection and three-dimensional SPECT at 4, 24, and optionally at 48 h postinjection. Currently, the extensive use of SPECT/CT has reduced the need for the 4 and 48 h examinations, due to the increased specificity [100] (Fig. 11). Later images can also be acquired in case of equivocal findings. A gamma camera equipped with a medium-energy, parallel-hole collimator, with the window set for 20% on 111In photopeaks (172 and 245 keV) should be used to acquire planar images, either spot or whole body. To achieve an acceptable sensitivity, planar images should be acquired for 10–15 min/image, using a 512 × 512 word matrix or 256 × 256 word matrix, whole body images into a 1,024 × 512 word matrix or 1,024 × 256 word matrix for a minimum of 30 min, corresponding to a maximum scanning speed of 3 cm/min. For precise details of the detailed scanning protocol, the SNMMI (Society of Nuclear Medicine and Molecular Imaging) or the EANM (European Association of Nuclear Medicine) procedure guidelines for 111In-pentetreotide scintigraphy should be consulted [112].
Fig. 11

SPECT/CT shows uptake of 111In-pentetreotide within a NET of the ileum

After injection, plasma clearance is rapid, followed by a progressive accumulation in tissues. Elimination occurs mainly via the kidneys and, to a lesser extent, the hepatobiliary system. Physiologic areas of uptake are the spleen, the liver, and the kidneys. Normal scans also show variable uptake in the pituitary, thyroid, urinary bladder, and bowel [112]. The visualization of the kidneys is mainly due to filtration and proximal tubular reabsorption of the radiopeptide, while the uptake to the spleen, pituitary, and thyroid is receptor mediated (Fig. 12).
Fig. 12

Normal distribution of 111In-pentetreotide, anterior (a) and posterior (b) whole body images, 24 h p.i., with physiological visualization of the liver (L), kidneys (K), and spleen (S) and of the activity eliminated in the urinary bladder (B) and the intestine (I)

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 [112].

Interpretation

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 [90].

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 [101].

Metaiodobenzylguanidine

Clinical Application
Functional imaging with 123I-MIBG is still the first choice among nuclear medicine methods available for chromaffin tumors although recent data suggest a superiority of 68Ga-DOTA-SSA-PET/CT in pheochromocytomas and paragangliomas [113, 114, 115, 116, 117]. 123I-MIBG has been used (labeled with 131I or since 1980, with 123I) for the specific imaging of tumors that originate from the neural crest (chromaffin tumors and NETs). Apart from its diagnostic utility, 131I-MIBG has also been used (since 1984) for the therapy of chromaffin tumors and NETs [118]. In adrenal pheochromocytomas, 123I-MIBG scintigraphy has sensitivity and specificity of 90% and 95%, respectively. Moreover, the combined sensitivity of catecholamine measurements and 123I- MIBG scan approached 100% [119]. Thus a whole body scan 123I-MIBG is particularly helpful in the preoperative identification of multiple primary lesions (relatively frequent in norepinephrine-secreting pheochromocytomas) or metastases from malignant tumors (Fig. 13). 123I-MIBG is of especial utility in the detection of recurrences since the radiotracer accumulates specifically within the tumor and is not affected by postsurgical or post-radiotherapy structural changes (Fig. 14). In extra-adrenal tumors, 123I-MIBG imaging has a lower sensitivity (58%) than adrenal lesions (90–95%) [120]. Unlike abdominal and thoracic paragangliomas, 123I-MIBG imaging has limited sensitivity for the detection of paragangliomas of the head and neck region (17–42%) [121].
Fig. 13

123I-MIBG whole body scintigraphy. Multiple foci of tracer uptake indicating the presence of diffused bone metastases from a malignant pheochromocytoma

Fig. 14

Recurrence of adrenal pheochromocytoma. 123I-MIBG SPECT/CT demonstrates a large lesion close to the site of the previous left adrenal resection. Patient history shows a laparoscopic surgery complicated by intense hemorrhage within the pheochromocytoma, producing the tumor seeding into the whole abdominal cavity (multiple other lesion are clearly shown in the MIP image on the right)

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 [122].

Technique

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 [123]. 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 [120].

Interpretation
Normal findings, with either 123I- or 131I-MIBG, are the visualization of the lacrimal and salivary glands, heart, lungs, liver, spleen, urinary bladder, and, to some extent, bowel. Normal adrenal medulla is frequently visible with 123I-MIBG but rarely with 131I-MIBG. Any area of uptake located outside of these sites should be regarded as suspicious for malignancy (Fig. 15).
Fig. 15

123I-MIBG scintigraphy. The tracer uptake within a large tumor with central necrosis confirms the diagnosis of pheochromocytoma

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 [124]. 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).

PET/CT

Clinical Application

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.) [130]. 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 [106]. 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 [132].

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 [133].

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 [134]. The diagnostic performance of this compound appears however to be inferior to 68Ga-DOTANOC [135]. [11C]5-HTP, a serotonin precursor, which is the substrate for aromatic L-amino acid decarboxylase, is also utilized in research centers [92]. 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 [136]. 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 [93]. 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 [138]. [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 [139]. 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) [140]. 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 [139]. 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 [141]. Finally, GLP1 receptor peptides for imaging of insulinomas (exendin analogs labeled with 68Ga) are under investigation in clinical trials [142].

In bronchopulmonary NETs, 68Ga-DOTA-SSA-PET/CT has surpassed OctreoScan in the assessment of small-volume disease, as well as mediastinal lymph node involvement and distant metastases (Fig. 16) [143].
Fig. 16

68Ga-DOTATOC maximum intensity projection, CT, and PET images (a, b, and c, respectively) of a small typical bronchial carcinoid of the right upper lobe

[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 [144]. 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 [145]. 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 [146].

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 [144].

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 [117]. 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 [147]. 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
Clinical Application
Somatostatin analogs labeled with 68Ga (produced by a generator, therefore not requiring an in-house cyclotron) offer the advantage of both higher spatial resolution (about 4–5 mm) and signal-to-noise ratio as well as easier image quantification than SPECT (Fig. 17). Despite differences in receptor affinity, a clear clinical superiority of one of the three available compounds over the others has not been unambiguously demonstrated. A comparison of 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in the same patients yielded comparable diagnostic accuracy for the two radiopeptides, with a potential advantage for 68Ga-DOTATOC in the number of detected lesions and the higher SUV [148]. However, a recent comparison of 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT imaging in the same patients with NETs showed higher SUV values and superiority of 68Ga-DOTATATE on a lesion basis and a comparable diagnostic accuracy on a patient basis [149]. The inconclusive results on this issue may reflect the particular receptor configuration of the individual tumors. These novel radiopharmaceuticals are currently in use only as components of research projects, since none have yet been registered for use in routine clinical practice. The compound 68Ga-DOTATATE was recently (2016) approved by FDA. It is of note that PET/CT with 68Ga-DOTA-peptides offers several advantages over the conventional scintigraphic technique. These include: the synthesis of the radiopeptide from the 68Ge/68Ga generator eluate is simple and economical and can also be undertaken in centers without an on-site cyclotron, the imaging can be performed as a single day procedure, the activity in a given region of interest can be semi-quantified as SUV, and the spatial resolution of the method is higher and allows an excellent quality of the images with the detection of small lesions <10 mm. A further potential advantage is the possibility of labeling the same peptide used for radionuclide therapy (whether DOTATOC, DOTATATE, or DOTANOC).
Fig. 17

Comparison between SRS with 111In-pentetreotide and PET with 68Ga-DOTANOC. The higher spatial resolution and signal-to-noise ratio of PET allow the identification of two small liver metastases which were not visualized by SRS

Technique
The recommended injected activity to obtain diagnostic quality images ranges from 100 to 300 MBq, depending on the tomographic characteristics and body weight. To avoid possible clinico-pharmacologic effects, the amount of the injected peptide should not exceed 50 μg [150]. The clearance of 68Ga-DOTA-peptides from the blood is rapid. Arterial activity elimination is bi-exponential, and no radioactive metabolites are detected in serum and urine in the first 4 h. Maximal tumor activity accumulation is reached at 70 ± 20 min postinjection. Excretion occurs almost exclusively via the kidneys. The PET/CT acquisition begins 45–60 min after the intravenous administration of the radiopeptide, by means of a dedicated PET/CT scanner as a whole body image, preferably in a 3D mode. For a detailed description of the scanning protocol and image reconstruction, reference should be made to the EANM procedure guidelines for 68Ga-DOTA-peptides [150]. The use of contrast media may further enhance detection. However, in standard usage, unenhanced PET/CT is considered sufficient. As for conventional scintigraphy, the normal findings include the visualization of the liver, the spleen, the pituitary, the thyroid, the kidneys, as well as the adrenal glands, salivary glands, the stomach wall, and the intestines (Fig. 18). Preparation is the same as for 111In-pentetreotide.
Fig. 18

Normal distribution of 68Ga-DOTATOC (MIP, maximum intensity projection image) with physiological visualization of the pituitary (P), thyroid (T), liver (L), adrenals (A), kidneys (K), spleen (S), pancreatic head (PH) and of the elimination of the activity in the urinary bladder (B) and the intestine (I)

Interpretation
The clinical interpretation of these images is easier than with single photon tomography, due to the better spatial resolution and the CT co-registration (Figs. 19 and 20). Criteria for defining areas of uptake as consistent with NET disease are the same as for 111In-pentetreotide. In PET imaging, however, the head of the pancreas, in particular the uncinate process, may exhibit a variable physiologic uptake of 68Ga-DOTA-peptides, related to the great concentration of pancreatic polypeptide cells [150]. This may represent a potential source of false-positive results that should not be ignored, since the pancreas and the duodenum are frequent sites of neuroendocrine malignancies. Other common non-NET-related sources of somatostatin receptor-mediated uptake (e.g., accessory spleens, sites of inflammation with lymphoid infiltrate, recent surgery, or urinary contamination) should be taken into consideration in the interpretation of the images (Fig. 21a–c).
Fig. 19

68Ga-DOTATOC (left) and [18F]FDG (right) PET/CT appearance of atypical bronchial carcinoid (black arrows). 68Ga-DOTATOC maximum intensity projection image shows some bone metastases, while [18F]FDG PET/CT detected only the one at the right femur (red arrows)

Fig. 20

Unknown primary NET with multiple liver lesions. 68Ga-DOTATOC PET detected the primary tumor in the pancreatic tail (red arrow in a) and concomitant paracaval lymph nodes and bone metastases (blue arrows in a)

Fig. 21

Common non-NET-related findings at 68Ga-DOTATOC PET/CT. (A) Common non-NET-related thoracic findings: Fused 68Ga-DOTATOC PET/CT images of left breast fibroadenoma (a), breast physiologic radiotracer uptake (d), residual thymus (b and c), and hiatal hernia (e and f). (B) Common non-NET-related inguino-pelvic findings: fused 68Ga-DOTATOC PET/CT images of physiologic radiotracer uptake in uterus and prostate (a and c, respectively), in uterus fibromatosis (b) and in reactive bilateral inguinal lymph nodes (d). (C) Common non-NET-related skeletal findings: 68Ga-DOTATOC uptake in vertebral hemangioma (axial fused PET/CT, axial CT, and sagittal CT images a, b, and c, respectively), osteophyte (axial fused PET/CT and axial CT images d and e, respectively) and degenerative changes at L3–L4 passage (sagittal fused PET/CT image f)

18F-DOPA

NETs can be imaged with 18F-DOPA PET/CT (Fig. 22). Oral co-administration of carbidopa, a peripheral inhibitor of AADC normally used in the treatment of Parkinson’s disease, is routinely performed during 18F-DOPA imaging to reduce the background activity, particularly in the pancreas, and to increase the tumor uptake and, ultimately, sensitivity [93]. Whole body imaging is initiated 30–90 min after injection of at least 100 MBq. Normal findings include the visualization of the kidneys, ureter, and bladder, with variable uptake in the gallbladder; intermediate uptake may be noted in the corpus striatum, myocardium, and liver and low uptake in the small intestine and muscles. There is also evidence of minimal uptake in the normal adrenal medulla [134].
Fig. 22

18F-DOPA PET/CT in a patient affected by diffuse bone, lymph node, liver, and soft tissue metastases from a small bowel NEN (Courtesy of Prof. S. Fanti, University of Bologna)

[11C]5-HTP

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 [92]. However, its widespread application is limited by the short half-life of 11C, which requires an on-site cyclotron.

[18F]FDG

For a detailed description of the scan methodology, reference should be made to the specific section on this subject.

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Lisa Bodei
    • 2
    Email author
  • Mark Kidd
    • 3
  • Laura Gilardi
    • 1
  • Duccio Volterrani
    • 4
  • Giovanni Paganelli
    • 5
  • Chiara M. Grana
    • 1
  • Irvin M. Modlin
    • 3
    • 6
  1. 1.Division of Nuclear MedicineEuropean Institute of OncologyMilanItaly
  2. 2.Molecular Imaging and Therapy ServiceMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Wren LaboratoriesBranfordUSA
  4. 4.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly
  5. 5.Nuclear Medicine and Radiometabolic UnitsIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCSMeldolaItaly
  6. 6.Department of SurgeryYale School of MedicineNew HavenUSA

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