Lisa Bodei • Mark Kidd • Irvin M. Modlin • Giovanni Paganelli
Neuroendocrine tumors were first described in 1907 by Oberndorfer1 (1876–1944) as small tumors of the intestine that he referred to using the German diminutive for cancer, Karzinoide, and thereby mistakenly implying a benign tumor. It is now apparent that this class of tumors, neuroendocrine tumors, exhibit a wide range of malignancy, are ubiquitous, are rapidly increasing in incidence, and have a greater prevalence in the gut than all other neoplasia except colon cancer.2 They have, in the past, been considered rare and were overall little understood as scientific and clinical attention and research resources were mostly focused on adenocarcinoma. As a consequence of limited clinical awareness, diagnosis was usually made late in the course of the disease when metastatic disease was already evident.3
The recent recognition that the incidence of the disease is rapidly increasing and that its prevalence as a gastrointestinal cancer was only exceeded by that of colon cancer has resulted in significant clinical and scientific focus on the problem.4 It is now evident that they behave much as do other cancers, cause severe alterations in quality of life (QoL) because of their bioactive secretory products, and can be effectively treated if appropriately managed with the wide array of diagnostic and therapeutic strategies that have been developed to support such patients.5
In contradistinction to the notion that they are benign and indolent, they often exhibit a poor prognosis because of widespread metastatic disease and a low QoL caused by disabling symptoms. A key issue in limiting clinical advances in this disease has been the paucity of information about the cells of origin and the biology of the tumors.3 More recently, scientific advances have yielded considerable information which has allowed introduction of sensitive techniques for detection of these tumors.6 In addition, a better delineation of the molecular mechanisms of the tumors has facilitated the development of effective therapeutic agents including somatostatin analogs, interferon, targeted drugs (mTOR kinase inhibitors, antityrosine kinase agents), and peptide receptor radionuclide radiotherapy (PRRT).7 Although diagnostic modalities such as somatostatin receptor scintigraphy (SRS), positron emission tomography (PET), and the combination of nuclear imaging techniques with anatomical imaging are useful in accurate and early diagnosis, a critical issue is the absence of a peripheral blood or genetic marker to identify early disease or predict and recognize micrometastasis.8 Apart from early diagnosis, delineation of the mechanistic and biologic basis of neuroendocrine tumor biology is necessary to develop a rational and effective therapeutic approach using targeted agents. Increased knowledge about cell biology and genetic characteristics, therefore, is the key to the evolution of therapy.
At this time, nuclear medicine strategies have become key elements in the diagnostic strategy to identify tumor location and extent of metastatic disease as well as providing information as to the metabolic activity of the tumor (Fig. 20.1).
Similarly, the development of appropriate nuclear medicine therapeutic strategies to control and eradicate metastatic disease as well as ameliorate symptoms has become an important component of the advancing therapeutic strategy to manage this disease.
MOLECULAR AND CELLULAR BIOLOGY
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), or “carcinoid” as they are often labeled, are now known as neuroendocrine neoplasms (NENs) and are derived from neuroendocrine cells in the pancreas and gastrointestinal tract which themselves are derived from local tissue-specific stem cells, probably through a committed precursor cell.9
The mechanisms leading to tumorigenesis are largely unknown but the majority of lesions (>95%) are sporadic. Others, notably some gastric and pancreatic types, are related to genetic defects such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis (NF-1) von Hippel–Lindau (VHL), or tuberous sclerosis (TSC).10 Overall, there are at least 13 different neuroendocrine cell types in the gastrointestinal tract and four in the pancreas with distinct anatomical localization and secretory products (Table 20.1).
Some of these are localized to a single organ (e.g., the gastric enterochromaffin-like [ECL] cell) and others are distributed throughout the GI tract (e.g., the enterochromaffin [EC] cell). Although diverse in location, neuroendocrine cells share a number of common features including (1) lineage derivation (largely neurogenin 3-expressing secretory progenitor cells); (2) production of specific proteins (e.g., chromogranin A [CgA]) involved in secretory granule formation, maturation, and exocytosis11; (3) transport (vesicular monoamine transporters—VMAT1, VMAT2)12; (4) amine synthesis through specific rate-limiting enzymes (histamine and histidine decarboxylase in gastric ECL cells or serotonin and tryptophan hydroxylase—Tph1—in EC cells), and amine uptake and decarboxylation (APUD)13; (5) electron-dense secretory granules (readily visible by electron microscopy)14; (6) Calcium and ERK1/2 signaling pathways for secretion15; (7) MAPK pathways for growth factor (e.g., gastrin/TGF) mediated proliferation16; and (8) inhibitory receptors that can be targeted, for example, somatostatin receptors (SRs).17,18
The majority of these cell types can transform into tumors which, based on the cell of origin, exhibit a wide spectrum of clinical behavior that ranges from indolent (e.g., gastric type I tumor or insulinomas) to highly aggressive (e.g., glucagonomas and colon NENs3) (Table 20.2).
FIGURE 20.1. Key figures in the discovery of radionuclides and the pathobiologic elucidation of gastroenteropancreatic neuroendocrine tumors. The central background motif represents element 71, described by Georges Urbain (upper center) of France and Carl Auer von Welsbach of Austria (lower center) almost simultaneously in 1907. The element originally called cassiopium by Welsbach was in fact an impurity of ytterbium (discovered in Ytterby, Sweden) and nationalistically named lutetium (after the Lutetii tribe, founders of Paris) by Urbain, given his precedence in the original description. Oberndorfer (top right) identified a series of diminutive small bowel tumors as “Karzinoide” as opposed to Karzinoma (cancer) in 1907. Feyrter (bottom right) described a linking system—the diffuse neuroendocrine system that characterizes the different cell types which he proposed as the source of the tumors. This was further expanded into the amine uptake and decarboxylation classification by Pearse (top left) based upon his delineation of their common cytochemical characteristics. Bloom (bottom left) provided a clinical understanding of the pathologic nature (top) of the tumors and linked their immunocytochemical characteristics (bottom) with their secretory characteristics and symptoms.
GASTROINTESTINAL AND PANCREATIC NEUROENDOCRINE CELL TYPES AND SECRETORY PRODUCTS
Their natural history varies from local invasion and fibrosis in the peritoneal cavity to metastatic spread, most commonly to the liver and lungs. Their biologic characteristics (local invasion, fibrosis, and metastatic potential) vary considerably depending on anatomical site, neuroendocrine cell(s) of origin, and secretory products. However, despite their diversity in tissue origin and biologic behavior, GEP-NENs share many common features including pathologically definable growth patterns, secretion of bioactive products (most commonly serotonin or peptides such as insulin, gastrin, and glucagons), and expression of neuroendocrine markers including CgA.
NEUROENDOCRINE NEOPLASM CLASSIFICATION SYSTEMS
The 1963 classification of GEP-NENs based on their putative embryologic origin (foregut, midgut, or hindgut) by Williams and Sandler,19 although still in use, has largely been superseded by the World Health Organization (WHO) classification system which has defined these tumors by degree of differentiation and the tumor site of origin.20 In this schema, tumors are described as well-differentiated neuroendocrine tumors (benign behavior or uncertain malignant potential), well-differentiated neuroendocrine carcinomas (low-grade malignancy), or poorly differentiated (usually small cell) neuroendocrine carcinomas of high-grade malignancy. The term “carcinoid” applies to tumors classified as “well differentiated.” Size, angioinvasion, proliferative activity, histologic differentiation, metastases, and hormonal activity (association with clinical syndromes or diseases) are also taken into consideration. Histochemical indicators of prognosis include the degree of expression of the proliferation protein Ki-67 and the p53 tumor suppressor protein.21,22 Metastases are present overall in ∼35% of all GEP-NENs at presentation23 but may be as high as 60% to 80% for tumors that originate in the small bowel and colon. By contrast, gastric tumors very rarely metastasize <10%.3
CHARACTERIZATION AND CLINICAL PRESENTATION OF GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS
The European Neuroendocrine Tumor Society (ENETS) group and the Neuroendocrine Tumor Summit Consensus of 2009 have proposed to further refine this classification to include the Ki-67 scoring index and a TNM classification system (Table 20.3).24,25
Historically, Ki-67 was incidentally identified as an antibody that bound a nuclear antigen associated with proliferation in Hodgkin and Reed–Sternberg cells. This measurement of its detection (the Ki-67 index [proportion of cells positively stained by the antibody]) was used in the assessment of Hodgkin lymphoma.26 Although discovered 30 years ago, the function of Ki-67 remains unclear27; there is, however, evidence that it regulates ribosomal expression rather than directly contributing to cell cycle progression.28 Nevertheless, its expression has been noted in cells in all phases of mitosis26 and despite reservations as to its efficacy, it is used as a surrogate marker of proliferation. Although controversy exists as to the utility of the Ki-67 and its general application, it is embedded in therapeutic decision making.29 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.29
CLASSIFICATION OF NEUROENDOCRINE NEOPLASMS
FIGURE 20.2. Incidence of neuroendocrine neoplasms by anatomical location in the US population between 1973 and 2005.
EPIDEMIOLOGY OF NEUROENDOCRINE NEOPLASMS
The Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2006), containing 48,195 NENs,30 demonstrates that in the United States, NENs comprise 0.66% of all malignancies and the incidence is increasing at a rate of 3% to 10% per year depending on the subtype (Fig. 20.2).
NENs comprised 1.25% of all malignancies in 2004 compared to only 0.75% of all malignancies in 1994.23,30 Much of this increase probably reflects the introduction of more sensitive diagnostic tools (topographic and immunohistochemical) as well as an overall increased awareness among clinicians and pathologists.31,32 The frequency (1.22%) of NENs in a large autopsy series also indicates that they have previously been underdiagnosed.33 In the United States, NENs occur most frequently in the gastrointestinal tract (66%) with the second most common location in the bronchopulmonary system (25%), followed by considerably less frequent locations such as the ovaries, testes, hepatobiliary, and pancreas (Fig. 20.3).34
In SEER (1993 to 2006), African Americans exhibited a high overall incidence of 6.5/100,000 compared to 4.4/100,000 among caucasians. Rectal NENs were the most common lesion (1.65/100,000, 27%) among African Americans, followed by small intestinal (1.42/100,000, 21%) and bronchopulmonary (1.20/100,000, 18%) lesions. Taking gender and ethnicity into consideration, the highest incidence rates were small intestinal (1.83/100,000) and rectal NENs (1.81/100,000) in black males followed by bronchopulmonary NENs (BPNs) (1.51/100,000) in white females. Despite the relative rarity of the disease (∼1% of all tumors), the prevalence of GEP-NENs is substantial given the often indolent nature of the disease process.35
CLINICAL PRESENTATION OF NEUROENDOCRINE NEOPLASMS
GEP-NENs may present a considerable diagnostic and therapeutic challenge as their clinical presentation is protean, nonspecific, and usually late when hepatic metastases are already evident. Symptomatology is referable to either local tumor mass effects (pain, bleeding, or biliary duct obstruction), local (pain from adhesions and obstruction) or distant fibrotic events (pulmonary and right-sided cardiac), or the biologic consequences of the secretion of bioactive amines or peptides (Fig. 20.4).
Diagnostic delay is usually 5 to 7 years because the symptoms are considered as caused by other conditions as opposed to a tumor. The fact that they are not persistent but episodic further hinders the diagnosis because their paroxysmal nature often results in the incorrect assumption of an allergy or an unreliable patient. Thus, the diarrhea is considered as response to a food or irritable bowel disease, whereas the sweating and flushing as anxiety, menopause, or thyroid abnormalities. Tachycardia or anxiety is misdiagnosed as a neurotic issue and bronchospasm as allergy or asthma. The classical carcinoid syndrome is relatively uncommon (10% to 15%), typically consisting of diarrhea, cutaneous flushing, bronchospasm, and right-sided heart failure.33
BPNs represent a spectrum of tumors (benign to malignant) arising from respiratory neuroendocrine cells. They comprise ∼20% of all lung cancers and 25% of all NENs.36 BPNs present with cough, hemoptysis, and obstructive pneumonia but this varies depending on the site, size, and growth pattern. A substantial number is identified serendipitously on chest radiology. Less than 5% of BPNs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing, acromegaly, or SIADH. They are usually divided into four subgroups: Typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The TC group generally behaves in a benign/indolent fashion, whereas the atypical tumors can range from indolent to highly aggressive. SCLC is the most common variant, whereas LCNEC is rare. The only curative treatment for BPNs is surgical resection. The slow-growing TC exhibits a fairly good prognosis (5-year survival, ∼88%,), whereas this is 50% for AC and 15% to 57% for the highly malignant LCNEC and SCLC (<5%), respectively.36
FIGURE 20.3. Distribution of 49,012 neuroendocrine neoplasms (NENs) from the Surveillance, Epidemiology, and End Results (SEER) 1973 to 2007 tumor registry database. Pie charts reflect the distribution of NENs by anatomical site and tumor type. Total NEN distribution (top left), gastroenteropancreatic (GEP)-NEN distribution (bottom left), and pancreatic NEN distribution (bottom right). Non–GEP-NENs are predominantly located in the respiratory system (bronchopulmonary NENs ∼70%, top right ).
FIGURE 20.4. The inner circle represents symptoms associated with the classical “carcinoid” disease. The outer circle represents common misdiagnoses based on incorrect interpretation of the symptoms. GI, gastrointestinal.
DIAGNOSTIC STRATEGIES IN NEUROENDOCRINE NEOPLASMS
A history of flushing, sweating, diarrhea, or bronchospasm whose precise etiology cannot be satisfactorily demonstrated within 3 months should give cause for consideration of the diagnosis especially in someone older than 30 years (Fig. 20.5). Similarly, the association with intermittent abdominal pain, gastrointestinal bleeding, or concomitant cardiac issues should arouse suspicion.
A 24-hour measurement of urinary 5-hydroxyindole-3-acetic acid (5-HIAA) can be undertaken to detect serotonin (5-HT) producing lesions. This is a somewhat useful laboratory marker but is cumbersome in terms of collection and the onerous dietary restrictions necessary to avoid false-positive diagnoses. It has 88% specificity for serotonin-producing GEP-NENs although tryptophan/serotonin-rich foods (bananas, avocados, plums, eggplants, tomatoes, plantains, pineapples, and walnuts) can provide false elevations and several drugs (antihypertensive agents) can result in increased or decreased 5-HIAA levels. Higher concentrations of urinary 5-HIAA are consistent with a worse prognosis, whereas persistently low levels suggest a more favorable survival in disseminated disease.
FIGURE 20.5. Current diagnostic algorithm for gastrointestinal neuroendocrine neoplasms (NENs). CT, computed tomography; echo, echocardiography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; 5-HIAA, 5-hydroxyindole-3-acetic acid; MRI, magnetic resonance imaging; PET, positron emission tomography; SRI, somatostatin receptor imaging; VIP, vasoactive intestinal peptide.
Blood Peptide and Amine Measurement
A wide variety of peptides and amines have been proposed as biomarkers to identify NEN disease. These include histamine, gastrin, vasoactive intestinal peptide (VIP), glucagon, bradykinin, substance P, neurotensin, neuron-specific enolase, pancreastatin, human chorionic gonadotropin (hCG), neuropeptide K, neuropeptide L, pancreatic polypeptide, and 5-HT. 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. Exceptions to this are the PNENs in which measurement of the peptides gastrin, insulin, VIP, and glucagon have been of clinical utility.
Levels of the general GEP-NEN marker, plasma CgA, are sensitive (>90%) but nonspecific (elevated in other types of NENs, by impaired kidney function and during proton pump medication).37 Currently, CgA measurements are used to confirm diagnosis and gain insight as to tumor burden and possible location of the tumor. Circulating CgA is elevated in the majority of patients with GEP-NENs and is most frequently increased in subjects with gastrinomas (100%), followed by “carcinoid” tumors (80%), and nonfunctioning PNENs (70%).38 NonGEP-NENs including pheochromocytomas (90%) and medullary thyroid carcinomas (50%) also express elevated levels.39 Some studies have noted an association between CgA concentrations and tumor location and it has been proposed that plasma CgA levels are more frequently elevated in well-differentiated tumors compared to poorly differentiated tumors of the midgut. CgA has also been suggested to have some utility in predicting survival40 as well as providing insight into the efficacy of therapy. However, measurement of CgA is substantially limited by a lack of standardization of assays and a relatively low sensitivity 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.
Overall, individual markers like urinary 5-HIAA levels or plasma 5-HT levels are cumbersome, insensitive, and difficult to quantify whereas the most commonly used, CgA levels, varies between laboratories and can be nonspecifically elevated (Fig. 20.6).
Blood Transcript Analysis
A key unmet need therefore 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.8 Recent reports indicate that measurement of neuroendocrine blood transcripts is significantly more specific and reproducible than CgA measurement (Fig. 20.7).41
FIGURE 20.6. Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) biomarkers. Chromogranin A (CgA) is the most widely used biomarker for GEP-NENs, but many others have been used and some in particular have utility in identifying neoplasms with specificities that range from high to intermediate. Thus, specific tumor types can be identified using, for example, serotonin (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) for enterochromaffin cell tumors (small bowel NENs), gastrin for a gastrinoma, or glucagon for a glucagonoma. A variety of putative biomarkers (left) of variable clinical utility that are occasionally used include adrenomedullin, neurokinin, and bradykinin. ANP/BNP, atrial natriuretic peptide and brain/ventricular natriuretic peptide; GHRH, gonadotropin hormone-releasing hormone; hCG, human chorionic gonadotropin; NSE, neuron-specific enolase; PYY, peptide YY.
FIGURE 20.7. Receiver operating characteristic curves for a polymerase chain reaction (PCR)-based peripheral blood fingerprint compared to chromogranin A (CgA) for the correct identification of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). The areas under the curve (AUC) were significant in two validation sets—1 (AUC = 0.98, p < 0.0001) and 2 (AUC = 0.95, p < 0.0001) compared to CgA (AUC = 0.64, p < 0.002). Direct comparisons of the PCR fingerprint with CgA identified performed significantly better (p < 0.0001).
Once the biochemical diagnosis of a NEN has been made, it is necessary to identify the primary site, define the extent of the locoregional disease, and assess metastatic spread before determining therapeutic strategy. Topographic localization using endoscopy/ultrasound, capsule endoscopy, CT, MRI, SRS, and whole-body PET are all variously effective depending upon equipment availability and user skill. No modality alone is entirely secure and overall, these exhibit a sensitivity and specificity of ∼80% to 90%.42 These techniques are dealt with in detail later in this chapter. Of particular relevance to nuclear medicine imaging, however, are modalities that utilize the SR or a variety of metabolic or amine precursors that are unambiguously related to neuroendocrine tumor cells. More specifically these include SRs and precursors of serotonin and dopamine.
Somatostatin Receptor Expression as Target for Imaging
Neuroendocrine cells express a range of SRs. Five SR subtypes (1 to 5) have been identified in human tissues, and 70% to 90% of GEP-NENs express multiple subtypes with a predominance of subtypes 2 and 5.43 It appears that most tumors originating from tissues that are physiologically regulated by somatostatin express a high density of SR.44 Diverse neoplasia, apart from GEP-NENs and BPNs, therefore also express SR including pituitary tumors, meningiomas, medulloblastomas, medullary thyroid carcinomas, adenocarcinomas of the breast, ovary, and colon.44 By contrast, poorly differentiated or undifferentiated tumors express SR less often and at a lower density than well-differentiated (less malignant) neoplasia. In general, SR subtypes 2 and 5 are expressed in high density on most GEP-NENs.45,46 Receptor expression is thus a useful target to either detect or treat these lesions using radiolabeled somatostatin analogs, such as 111In-DTPA-octreotide.
Amine Precursor Imaging
A principal function of neuroendocrine cells is to regulate physiologic functions through paracrine stimulation which is achieved by the production of a large variety of bioactive agents, for example, 5-HT or catecholamines. The production of these aminergic hormones is accomplished via APUD, features that were initially identified by the biochemist, Pearse13 (1916–2003) in 1966. This capability to synthesize bioactive products is retained following neoplastic transformation and has allowed for the development of isotopic imaging techniques with amine precursors such as 5-HTP and L-dihydroxyphenylalanine (L-DOPA) which can be internalized into tumor cells and are then incorporated in the synthesis of peptide hormones like 5-HT and dopamine.47,48 By way of example, both tryptophan and 5-hydroxytryptophan (5-HTP) enter the cell using L-type amino acid transporters (LATs). Thereafter, a decarboxylation step to 5-HT occurs through the enzyme aromatic amino acid decarboxylase (AADC) and the resulting end product (in this case 5-HT) is transported into storage vesicles through VMATs from which they can be released into the extracellular environment. Although the exact uptake mechanism and intracellular fate of these amines and their metabolites are not precisely understood, it appears that increased LAT activity plays a role in supporting a high precursor turnover because of an increased metabolic pathway, for example, 5-HT, or at least increased AADC activity in NENs. Using this feature of the cell, PET for example, using the 11C-labeled serotonin-precursor, 5-HTP, has been shown to be a sensitive modality for imaging.49
Despite the introduction of novel treatments including PRRT and enzyme inhibitors (tyrosine kinase inhibitors), primary surgical resection of the tumor and regional lymph nodes remains the only curative treatment available for GEP-NENs (Fig. 20.8).
This approach, however, is usually only possible in ∼20% because of the delay in diagnosis and the presence of metastatic disease at the time of the initial procedure. Small, solitary noninvasive (endosonographically proven) lesions in the stomach, duodenum, and rectum may be treated with endoscopic local resection.50,51 Somatostatin analogs usually induce biochemical stabilization or effective biochemical response (∼85%) and manage clinical symptoms (∼80%) in patients with SR-positive tumors. More recently, the PROMID and Radiant 001 studies have indicated a positive effect of both octreotide alone and the combination of octreotide and an mTOR kinase inhibitor on tumor progression and survival.52,53 By way of example, in the latter study, the activity of the oral inhibitor of mTOR, everolimus (RAD001) in combination with octreotide LAR was investigated in 60 patients with advanced low- to intermediate-grade NENs.35 There were 13 (22%) with partial responses, 42 (70%) with stable disease, and 5 (8%) patients with progressive disease. The positive data represent increases in progression-free survival as opposed to an increase in life expectancy. Similar clinical data exist for an alternative agent Sutent, a receptor protein-tyrosine kinase inhibitor that inhibits the actions of vascular endothelial growth factor (VEGF) and is an angiogenesis inhibitor.54 A diverse array of single- or multiagent chemotherapeutic regimes have also been examined. Invariably, they exhibit little, short-lasting, or no effect on NEN response and, in most circumstances, the associated adverse events usually exceed the efficacy of the agents.55 Novel agents, including inhibitors of the tyrosine kinase receptor family c-kit, platelet-derived growth factor receptors (PDGF-R) α and β and epidermal growth factor receptor (EGFR) have shown modest (∼10% tumor response rate) results.56,57
Unfortunately, most patients have multiple, bilateral liver metastases at diagnosis, and ∼5% to 10% metastases are available for “complete” resection.58 Liver transplantation may be an option in highly selected patients59 but for the majority, ablative techniques including hepatic arterial embolization or radio frequency ablation are effective in decreasing tumor load and reduce symptoms and prolong survival with a 5-year survival of up to 50%.60 The strategy of reducing liver tumor bulk to 10% followed by therapy with a somatostatin analog in conjunction with a pharmacotherapeutic strategy warrants consideration. In this respect, the field of radionuclide therapy via a targeting agent such as a somatostatin molecule has considerable potential given the initial early encouraging data.61
FIGURE 20.8. Potential therapeutic algorithm for metastatic neuroendocrine neoplasms. 5-FU, 5-fluorouracil; CgA, chromogranin A; chemo, chemotherapy; CT, computed tomography; embo, embolization; MRI, magnetic resonance imaging; PET, positron emission tomography; PRRT, peptide receptor radionuclide therapy; RF, radiofrequency; STZ, streptozotocin.
The 5-year survival rate for GEP-NEN disease between 1973 and 2005 ranged from 56.2% for colon NENs to 87.6% for rectal NENs. Disappointingly, the overall 5-year survival has not improved appreciably over this time period.62 The 5-year survival is highly dependent on tumor stage and grade and ranges from only 4.5% in undifferentiated NENs with distant spread to 83.4% in localized, well-differentiated tumors.
ROLE OF DIAGNOSTIC IMAGING
The localization of a NEN and the assessment of the extent of disease are two critical requirements to ensure optimal patient management. As a consequence, every effort should be undertaken to ensure accuracy and thereby facilitate the interface of the diagnostic and therapeutic components necessary for disease staging and application of the appropriate therapeutic modalities.
The aims of diagnostic imaging embrace a number of interrelated areas but primarily, this is used to localize the tumor lesion and define its relation to adjacent structures as well as to evaluate the extent of disease at both locoregional and distant levels (staging). Thereafter, attention should be directed to reassessment of the tumor burden (restaging) and to guide the selection or stratification of patients for a specific therapy or sequence of therapies. The different therapeutic strategies may include either one or more combinations of surgery, locally directed ablative therapies, bioactive agents (somatostatin analogs/interferon), chemotherapy, and/or molecular targeted agents or PRRT.
Diagnostic strategies that are available include morphologic modalities such as CT, MRI, transabdominal ultrasound (US), endoscopic (EUS) and intraoperative US (IOUS), and selective angiography with or without hormonal sampling. Nuclear medicine imaging consists of 111In-pentetreotide (OctreoScan), 123I-MIBG, or, more recently, PET with 68Ga-labeled octreotides, 18F-DOPA, and 11C-5-hydroxytryptophan (11C-5-HTP).3
Usually, a sequence including more than one examination is needed to obtain information on the site and extent of disease, which represent the two most pertinent clinical issues. In this regard, a combination of anatomic and functional techniques is routinely performed to optimize sensitivity and specificity thereby maximizing the acquisition of clinically relevant information.63,64
From a strictly technical point of view, imaging findings of NENs, whether using morphologic or functional modalities, are not necessarily indicative of tumor differentiation as lesions with different grading may show common features.65
Imaging features are also not directly indicative of the secretory status of the tumor. This aspect descends from the recent reconsideration of the common biology of NENs, irrespective of their clinically evident functionality.66
However, the biologic and growth characteristics of a specific tumor may be reflected in the appearance of the corresponding lesions at imaging. Functional, hormonally active tumors tend to be diagnosed earlier, because of the recognition of a related clinical syndrome. Nevertheless, even in the event of the recognition of a functional syndrome, the detection of a primary tumor may be difficult, because of its small size. In general, nonfunctional tumors are detected later unless they obstruct the common bile duct or pancreatic duct and present with jaundice or pancreatitis. Thus, nonfunctioning tumors may grow to represent larger lesions, and despite being asymptomatic, may have associated liver metastases at diagnosis.
In the past, despite all diagnostic efforts, in as many as 50% of patients in some series, the primary neoplasm may remain undetected.3 The recent availability of more sophisticated diagnostic methodology has, however, substantially decreased this number.
Many imaging modalities have been advocated, especially for GEP-NENs, which have lesions that often may be small and difficult to locate. Studies directly aimed at a rigorous comparison of the various methods are limited and have been hindered by the constant evolution of the available techniques at the time of the analysis.67 Table 20.4 reports a detailed description of morphologic and functional imaging techniques in NENs, and the suggested sequence for localization, staging, restaging, and therapy selection. Where applicable, the impact on patient management is reported.
MORPHOLOGIC AND FUNCTIONAL TECHNIQUES FOR THE DIAGNOSIS OF NEUROENDOCRINE NEOPLASMS
Morphologic imaging generally refers to radiologic modalities such as US techniques, CT, and MRI. Transabdominal US is often the first technique utilized to study a patient with a GEP-NEN. Its value is limited by the fact that it is an operator-dependent technique capable of producing a wide variation of sensitivity and specificity. Therefore, in the vast majority of individuals with GEP-NENs, conventional imaging with contrast-enhanced CT and MRI are the principal methods used for the detection of primary tumors, the delineation of the extent of metastatic disease, and as the modalities to assess therapeutic response.
Contemporary CT utilizes multidetector CT (MDCT) scanners whereas MRI is undertaken with scanners exhibiting a field strength of at least 1.5 T. Sequences should be evaluated with fat suppression, to increase tissue contrast. The more recent development of liver-specific contrast agents has significantly improved the detection of liver and lymph node metastases.91 Both CT and MRI should be performed as multiphasic studies.72
Because neuroendocrine lesions and their metastases are usually hypervascular, they enhance after contrast medium injection on CT and MRI. The degree, uniformity, and timing of enhancement may vary, although vascular heterogeneity is generally considered a sign of malignancy, because of the related variety of vasculature, perfusion, and permeability.92,93
Among the morphologic modalities, US generally yields a poor sensitivity in localizing NENs. However, improved techniques, including contrast-enhanced US, EUS, or IOUS have allowed for an increase in sensitivity.
Usually, primary NEN lesions appear as low echogenic masses. Liver metastases may appear as either hypo- or hyperechogenic, generally with hypervascular aspects of contrast enhancement.72 US is the method of choice when there is a need to perform a biopsy of liver metastases.
Upper gastrointestinal endoscopy can detect lesions up to the ligament of Treitz, whereas colonoscopy can reveal colorectal lesions and can visualize the terminal ileum. Flexible fiberoptic bronchoscopy is the method of choice to detect a bronchial NEN, which tend to present as central lesions. In some instances, endoscopic maneuvers allow cytologic or histologic sampling and may, even in certain circumstances, allow a resection of the primary lesion to be undertaken.34
Although conventional, morphologic imaging is useful in the initial localization of the primary tumor and in the characterization of its architectural relationship with the surrounding structures, functional techniques provide added information in establishing the receptor status (somatostatin, e.g., OctreoScan), metabolic activity (glucose, e.g., 18FDG-PET), and specific amine or peptide regulatory profile (e.g., 5-HTP). In addition, they may provide further details in respect to the extent of disease and thereby facilitate more accurate staging and precise therapy.
Nuclear medicine imaging is able to detect both the expression and function of identifiable targets within a lesion. In most circumstances NENs present two targets, SRs and the neuroamine uptake system that can be utilized for imaging and therapy. In addition, in aggressive forms of the disease, the presence of accelerated glucose consumption can be traced via the glucose transporters. Conversely, the absence of accelerated glucose metabolism may also be used to predict low-activity disease.94
Radiolabeled somatostatin analogs have been successfully used for imaging of NENs since the early 1990s and their introduction represented a significant advance in the management of NEN disease. Somatostatin is a biologically active peptide present in the hypothalamus, brainstem, gastrointestinal tract, and pancreas that exists in either a 14-amino acid or a 28-amino acid isoform. SRs are ubiquitously expressed throughout the body and on circulating white cells but their presence on cells of neuroendocrine origin is of special relevance in the identification of NENs. The receptor profile consists of five G-protein–coupled somatostatin subtypes (sst1 to 5), all of which have been cloned and characterized. All five receptors bind with high affinity to native somatostatin, whereas its principal synthetic analog, octreotide, binds with very high affinity to subtype 2 (sst2), showing moderate affinity for sst5 and intermediate affinity for sst3. Sst2 is the most frequently overexpressed receptor in NENs, and, therefore represents the optimal target for imaging, enabling primary and metastatic masses to be localized by scintigraphy. Furthermore, there is some evidence of a correlation between SR expression and prognosis, because patients with NENs that exhibit a positive scan profile usually have a better response to treatment with analogs.84
In nuclear medicine imaging, octreotide derivatives are used for SR imaging. 123I-labeled octreotide (123I-[Tyr3]-octreotide) was the first radiolabeled analog used for the in vivo visualization of lesions overexpressing sst2 receptors. However, its relatively short effective half-life and the high background of radioactivity within the abdomen were drawbacks that limited its clinical application. 111In-[DTPA-D-Phe1]-octreotide, or 111In-pentetreotide (OctreoScan), was subsequently developed and because of its stability in plasma, as well as its more favorable imaging characteristics in delayed images, has became the agent of diagnostic choice.95
Other radiolabeled somatostatin analogs that have been utilized in clinical studies include the 99mTc-labeled depreotide (P829) (currently commercially available for lung cancer studies) and 99mTc-EDDA/HYNIC-octreotide (99mTc-N-α-[6-hydrazinonicotinoyl]-octreotide), and 111In-DOTA-lanreotide (MAURITIUS).96–98 Tc-labeled octreotide derivatives, such as 99mTc-EDDA/HYNIC-octreotide, or alternative somatostatin analogs, for example, 111In-labeled lanreotide have failed to supplant 111In-pentetreotide because no overt advantage over the conventional, commercially available technique has been demonstrated.
In addition to the biologic propensity to overexpress SRs, NENs possess the chemical capacity of decarboxylation; amino acids acquired by the cells can thus be transformed into biogenic amines. This unique biochemical property was recognized in the original denomination as APUD tumors. Certain types of neuroendocrine cells can, in addition, synthesize catecholamines in an enzymatic pathway by converting the amino acid tyrosine into L-DOPA (L-dihydroxyphenylalanine). L-DOPA is subsequently decarboxylated to dopamine, oxidized to norepinephrine (NE), and methylated to produce epinephrine, which is transported into synaptic vesicles. NE transporters present on the cell membrane are then capable of presynaptic catecholamine reuptake. As a consequence of these biochemical features, NENs can be imaged by either 18F-DOPA PET, which accumulates within cells because of the high activity of the aromatic amino acid L-DOPA decarboxylase, or by metaiodobenzylguanidine (MIBG). The latter strategy relies upon MIBG uptake by the cell via the NE transporter and accumulation in neurosecretory vesicles by means of the vesicular catecholamine transporter. In this technique, expression of transporters and the neurosecretory vesicles for catecholamine are the basis of imaging. Usually, 18F-DOPA or 18F-Dopamine PET and MIBG scintigraphy are highly effective in the detection of chromaffin tumors, but the isotopes can also be taken up by nonchromaffin NENs.99
Similarly, SR imaging, which is predominantly of value in the identification of GEP-NENs or bronchial NENs, may also be used for imaging chromaffin tumors, which also express SR in a very high percentage of cases.100
The specific aims of functional imaging of NENs are the localization of the disease, the staging, and the characterization of tumor lesions (as to their somatostatin expression, neuroamine uptake mechanism, specific neuroendocrine metabolism, or glucose consumption). In addition, these techniques are of considerable value in the restaging disease after therapy (as to the presence of tumor residues, relapse, or progression), and guiding therapy selection (in particular “cold” and radiolabeled somatostatin analogs) based upon the identification of a target, for example, SR.
Somatostatin Receptor Scintigraphy
The rationale of SR imaging is the 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.
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. The recommended injected activity, to obtain a high quality examination in terms of sensitivity, should be ∼200 MBq (5.4 mCi). However, lower activities can be administered if acquisition parameters are adjusted accordingly.101 At least two different sets of planar and/or whole-body images should be acquired to facilitate the interpretation of the examination. Commonly adopted protocols include scans at 4 and 24 hours or, optimally, 24 and 48 hours post injection. Later images can also be advantageously acquired should the earlier images provide equivocal clinical information. A γ-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 increase sensitivity it is mandatory to acquire 3D reconstructed SPECT images, preferably after 24 hours to increase sensitivity.80 The concentration of the radiopharmaceutical increases significantly after the first hours and it is evident that the coregistration of SPECT/CT images, by means of hybrid devices that combine SPECT and multislice CT, increases the specificity of the study, by improving the anatomical localization of the areas of uptake and therefore reducing equivocal findings.102 Laxatives are also recommended to eliminate nonspecific activity in the bowel. To achieve an acceptable sensitivity, it is mandatory to acquire images with sufficient counts per view. To obtain this, planar images should be acquired for 10 to 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 minutes, corresponding to a maximum scanning speed of 3 cm/min. For precise details of the detailed scanning protocol, the Society of Nuclear Medicine (SNM) or the European Association of Nuclear Medicine (EANM) procedure guidelines for 111In-pentetreotide scintigraphy should be consulted.101,103
After injection, there is a rapid plasma clearance and a progressive accumulation in tissues. The kidneys are the principal route of elimination, followed by the hepatobiliary system.86 A normal scan clearly depicts the spleen, the liver, and the kidneys, together with a variable visualization of the pituitary, thyroid, urinary bladder, and bowel. The visualization of the kidneys is mainly because of the proximal tubular reabsorption of the radiopeptide, whereas the uptake to the spleen, pituitary, and thyroid is receptor mediated. Figure 20.9 demonstrates an example of a normal distribution.
FIGURE 20.9. Normal distribution of 111In-pentetreotide, anterior (left) and posterior (right) whole-body images, 24 hours post injection with physiologic visualization of liver (L), kidneys (K), spleen (S), and of the activity eliminated in the intestine (I) and urinary bladder (B).
Images should be interpreted based upon the integration of clinical information. Nevertheless, as a general rule, clearly outlined areas that show an isotope uptake higher than the normal liver (below, if outside the 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 SR expression and hence, exhibit increased uptake.
In the evaluation of a scan, it is therefore important to consider possible sources of a false-positive, namely nonNEN SR-positive lesions or accumulations of isotope that represent other disease states or scan irregularities. These may generically be divided into abnormal sites of isotope accumulation, areas of inflammation, or other tumors. As such, false positives may 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, a recent cerebrovascular accident, arthritis, abscesses, and urine contamination.104 Figure 20.10 shows a positive OctreoScan in a patient affected by a pancreatic NEN (A) and a false-positive result related to postactinic chronic inflammatory modifications in a patient affected by bronchial NEN (B).
In the interpretation of scans, it should be considered that prolonged therapy with “cold” somatostatin analogs may reduce the physiologic uptake to the spleen and the liver.
As opposed to false positives, the issue of false negatives is worthy of clinical consideration. This reflects the lack of visualization of NEN lesions and is most commonly ascribed to incorrect methodology. This may be a consequence of too low a dose of administered activity, too rapid (or too early) scan time, the absence of SPECT images, or lesions whose dimensions fall below the resolution limit of the γ-camera. Other possible causes may be competition for receptor uptake by recent analog therapy, alteration of receptor expression by recent chemotherapy, or receptor-negative disease. The latter may especially occur in benign insulinomas (malignant insulinomas are usually positive) or in dedifferentiated, highly aggressive malignant NEN disease. In some cases, normal accumulation in the liver may mask isointense metastases or those with a relatively low expression of SR density.81
The issue of the possible competition by unlabeled somatostatin analogs on the uptake of the radiolabeled counterpart has long been debated and remains unresolved.101 The lack of predictable behavior of these neoplasms during therapy may be ascribed to the variable sensitivity that different types of NENs exhibit to the effect of chronic exposure to somatostatin analogs on intracellular receptor trafficking and membrane redisplay.105 However, to minimize any diminution in scan sensitivity, it is considered prudent to withdraw short-acting analogs for at least 48 hours, long-acting formulations for 4 to 6 weeks, and to otherwise undertake scintigraphy just prior to the next administration.106
SRS is commonly used to select patients for therapy with “cold” and radiolabeled somatostatin analogs.73
The sensitivity of 111In-pentetreotide scan has been well documented.68,79–81,84,95 Given the heterogeneity of NENs, they may be categorized into high sensitivity tumors (detection rate >75%), such as pituitary tumors, GEP-NENs, paragangliomas, SCLC, and intermediate sensitivity tumors (detection rate ranging between 40% and 75%), such as insulinomas, medullary thyroid carcinomas, and pheochromocytomas.73
Somatostatin Receptor PET
The goal of an optimal protocol of 111In-pentetreotide scan is to be able to ensure good image quality and to provide useful clinical information. Nevertheless, since the beginning of 2000, the approach to the functional imaging of NENs has been revolutionized 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 (DOTA-TOC), DOTA-Tyr3-octreotate (DOTA-TATE), and DOTA-1-Nal3-octreotide (DOTA-NOC). These analogs retain an octreotide-like affinity profile and, in particular, a high affinity for sst2. Only DOTA-NOC exhibits a substantial affinity for sst3.107 Despite these differences in receptor affinity, a clear superiority of one compound over the others has not been unambiguously demonstrated in clinical practice. A comparison of 68Ga-DOTA-TOC versus 68Ga-DOTA-TATE PET/CT in the same patients, yielded comparable diagnostic accuracy for the two radiopeptides, with a potential advantage for 68Ga-DOTA-TOC in the number of detected lesions and the higher SUV.108 However, a recent comparison of 68Ga-DOTA-TATE and 68Ga-DOTA-NOC PET/CT imaging in the same patients with NENs, showed higher SUV values and superiority of 68Ga-DOTA-TATE on a lesion basis, and a comparable diagnostic accuracy on a patient basis.109 The inconclusive results on this issue as reported in the literature possibly reflect the particular receptor configuration of the individual tumors.
FIGURE 20.10. Pancreatic neuroendocrine neoplasm (NEN) visualized by 111In-pentetreotide scintigraphy. Planar abdominal imaging, 24 hours post injection (A) depicts the primary tumor in the pancreatic head (solid arrow), clearly visible in the corresponding computed tomography (CT) slice (B, dashed arrow). Bronchial NEN with previous radiotherapy. A typical nonspecific, postactinic bilateral symmetrical image (dotted arrows) is visible on the anterior (C) and posterior (D) images collected 24 hours post injection. The corresponding CT scan (E) shows bilateral diffuse ground glass opacities related to the previous external irradiation.
Currently, these novel radiopharmaceuticals are in use only as components of research projects, because none have yet been registered for use in routine clinical practice. It is of note that PET/CT with 68Ga-DOTA-peptides offers several advantages over the conventional scintigraphic technique: 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 semiquantified 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. Another advantage is the possibility of labeling the same peptide used for radionuclide therapy (whether DOTA-TOC, DOTA-TATE, or DOTA-NOC).110,111
As a result, PET/CT with 68Ga-DOTA-peptides represents a major advance in the management of NEN patients and is increasingly being utilized in specialized centers given its greater accuracy over conventional scintigraphic imaging.112 The acceptance of the increased accuracy obtained with 68Ga-DOTA-peptides in NENs is further substantiated by the rapid increase in the number of recent publications detailing their clinical use (an in-house PubMED search identified 228 publications relating to 68Ga-DOTA; 51 in 2012, and 54 in the first 9 months of 2012).110
The recommended activity to obtain good image quality ranges from 100 to 300 MBq, depending on the tomographic characteristics and body weight. To avoid possible clinicopharmacologic effects, the amount of the injected peptide should not exceed 50 μg.113
The clearance of 68Ga-DOTA-peptides from the blood is rapid. Arterial activity elimination is biexponential and no radioactive metabolites are detected in serum and urine in the first 4 hours. Maximal tumor activity accumulation is reached at 70 ± 20 minutes post injection. Excretion occurs almost exclusively via the kidneys.114
The PET/CT acquisition begins 45 to 60 minutes 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.113
As in the case of conventional scintigraphy, the normal findings at receptor-based PET include the visualization of the liver, the spleen, the pituitary, the thyroid, the kidneys, as well as the adrenal glands, the salivary glands, the stomach wall, and the intestines. Figure 20.11 demonstrates an example of normal distribution.
The clinical interpretation of the images is easier than SRS because of the better spatial resolution and the CT coregistration. As with 111In-pentetreotide, besides normal findings, clearly defined areas that show an uptake higher than that of the normal liver are considered as positive for receptor expression, and thus consistent with the presence of a NEN lesion.
When using receptor-based PET, the pancreas requires somewhat different consideration as it may exhibit a variable uptake of 68Ga-DOTA-peptides. Although SRs are located preferentially in the endocrine component of the pancreas, uptake at the pancreatic head has been documented. This may represent a potential source of false-positive results that should not be ignored. Because the pancreas and the duodenum are frequent sites of neuroendocrine malignancies, it is important to differentiate pathologic from physiologic accumulation of the radiopeptide. In a series of 245 patients undergoing PET/CT with 68Ga-DOTA-NOC, nonspecific uptake to the head of the pancreas with a focal and diffuse pattern was identified in 23% and 8% of patients, respectively.115 It has recently been demonstrated that this focal uptake is most likely to be the result of a nonspecific phenomenon if the SUV is low and similar to the liver, with a threshold value of the average head-to-liver SUV ratio around 1. The precise clinical significance of the uptake in this location is still unclear, although misalignment of PET and CT data, caused by different breathing phases, is a common cause.116
FIGURE 20.11. Normal distribution of 68Ga-DOTA-TOC (maximum intensity projection image) with physiologic visualization of the pituitary (P), thyroid (T), liver (L), adrenals (A), kidneys (K), spleen (S), pancreatic head (PH), and of the activity eliminated in the intestine (I) and urinary bladder (B).
False-positive results occur as with conventional somatostatin imaging and can be because of the presence of accessory spleens, sites of inflammation with lymphoid infiltrate, or urinary contamination. Figure 20.12 shows a positive 68Ga scan in a patient with a pancreatic NEN (A); (B) shows an example of nonspecific accumulation to the head of the pancreas.
As noted for scintigraphy, therapy with “cold” somatostatin analogs may interfere with the uptake of 68Ga-DOTA-peptides, although there is no consensus on this issue. In a recent series of 105 patients, 35 of whom had received chronic therapy with LAR octreotide at various intervals between the injection and the PET examination, treatment with somatostatin analogs did not significantly alter the tumor uptake, in comparison to binding levels in the normal spleen and liver.117 Nevertheless, given the pharmacokinetics of the long-acting release formulations, this subject requires further exploration in larger series of patients studied at homogeneous intervals between the analog injection and the PET.118
Although the sensitivity of 68Ga-DOTA-TOC PET/CT for NENs is high, it has been proposed that the use of contrast media may further enhance detection; in standard usage, unenhanced PET/CT is considered sufficient.119
Evaluation of the performance of 68Ga-DOTA-TOC PET has been undertaken in a large series of 84 patients with NENs of various origin and compared to CT scan and receptor scintigraphy. PET exhibited the greatest sensitivity (97%) compared to CT (61%) and SRS (52%) for the detection of NEN lesions, especially in patients with small tumors at a nodal or bone level. PET was also able to identify small lesions in unusual locations such as the breast, uterus, prostate, ovary, and kidney.71,120
PET/CT with 68Ga-DOTA-peptides is used to select patients for therapy with “cold” and radiolabeled somatostatin analogs.
FIGURE 20.12. A:68Ga-DOTA-TOC PET/CT in a patient with a pancreatic neuroendocrine tumor (1, MIP, maximum intensity projection image) with visualization of the primary (solid arrow) and liver metastases (dotted arrow). These lesions are more clearly depicted in the correspondent transaxial fused slices (2, liver metastasis in the liver dome; 3, primary tumor). B: An example of focal non specific uptake to the head of the pancreas (solid arrows) at PET/CT with 68Ga-DOTA-TOC. The MIP image (4) shows an area of focal uptake that has no anatomical reference on the correspondent fused transaxial slice (5). Moreover, the uptake is similar to the one of the normal liver.
PHARMACEUTICAL COMPOUNDS THAT REDUCE THE SENSITIVITY OF SCINTIGRAPHY
The ligand 6-L-18F-dihydroxyphenylalanine (18F-DOPA) is a substrate for the LAT and is utilized in the catecholamine synthesis pathway where it is subsequently decarboxylated by the AADC. The resulting decarboxylated 18F-dopamine is transported by the monoamine transporters and stored in the secretory granules, where the radioactivity remains trapped. The enzyme, AAAD, constitutes a hallmark of neuroendocrine cells, namely APUD, and is generally upregulated in chromaffin tumors as well as in many NENs.121,122
Oral coadministration of carbidopa, a peripheral inhibitor of AADC normally used in the treatment of Parkinson disease, is routinely performed during 18F-DOPA imaging to reduce the background activity, particularly in the pancreas, and to increase the tumor uptake.123
Whole-body imaging begins 30 to 90 minutes 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 in the corpus striatum, myocardium, liver, and low uptake in the small intestine and muscles. There is also evidence of minimal uptake in the normal adrenal medulla.121
11C-5-HTP is a serotonin precursor, which is the substrate for DOPA decarboxylase.49 11C can be incorporated without changing the biologic properties of the molecule and 11C-5-HTP is therefore able to define the metabolism of the neuroendocrine cell, and is thus considered a universal imaging method for NEN detection. Tomographic imaging is performed after intravenous injection of 370 MBq.124 Despite this obvious application in diagnosis, its short half-life and the need for an on-site cyclotron have relegated the synthesis and clinical utility of 11C-labeled 5-HTP in NEN disease to specialized centers.
MIBG is an NE analog that concentrates within secretory granules of catecholamine-producing cells. It is structurally similar to guanethidine. The agent has been in use either labeled with 131I or, later, with 123I, since 1980 for the specific imaging of tumors that originate from the neural crest (chromaffin tumors and NENs).125 Apart from its diagnostic utility131I-MIBG has also been used (since 1984) in the therapy of chromaffin tumors and NENs.126
MIBG, like NE, is taken up by an 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.127
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.128To 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 (Table 20.5).129,130
Although 131I-MIBG and 123I-MIBG are commercially available for diagnostic imaging, the former has been preferred because it is more widely available and economical. The physical characteristics of 131I-MIBG, although not optimal for scintigraphic imaging (γ-energy 364 keV, half-life 8 days), facilitates delayed studies.131 Alternatively, the physical properties of 123I (γ-energy 159 keV, half-life 13.3 hours) provide better image quality, more favorable dosimetry, and the possibility of performing a SPECT study, rendering it the agent of choice.132,133 123I-MIBG has, however, recently been approved for US usage by the Food and Drug Administration.134
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 to 2 mg/kg/day) is commonly used, beginning 1 day before injection and continuing for 3 to 5 days.
Administered activities are 37 to 74 MBq (1 to 2 mCi) for 131I-MIBG and 370 MBq (10 mCi) for 123I-MIBG. To avoid potential hormonal side effects, 123I- or 131I-MIBG, should be administered by slow intravenous injection.
131I-MIBG scan is performed using a γ-camera equipped with a high-energy, parallel-hole collimator. Images are collected at 24 and 48 hours after injection. If nonspecific activity is suspected in the kidneys or bowel, delayed images can be recorded after 72 to 120 hours. Whole-body and planar images of areas of interest are collected.
123I-MIBG scan is performed with a low-energy, high-resolution collimator. Images are collected 6 and 24 hours after injection and, if needed, 48 hours post injection. Whole-body and spot images are recorded. The use of 123I-MIBG allows SPECT imaging which is usually undertaken 24 hours after administration. The use of hybrid SPECT/CT system further improves sensitivity.133 Suboptimal sensitivity can be caused by a small lesion size and/or an extra-adrenal location.135 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.136
Normal findings, with either 123I- or 131I-MIBG, are the visualization of salivary glands, heart, lungs, liver, spleen, bladder and, to some extent, the 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. Figure 20.13 provides an example of normal distribution (A) and a metastatic pheochromocytoma (B).
FIGURE 20.13. A: Normal distribution of 131I-MIBG, 6 hours after injection (S, salivary glands; Lu, lungs; H, heart; Li, liver; K, kidneys; B, bladder.) (Courtesy of Dr. A. Chiti, Istituto Clinico Humanitas, Rozzano, Milan, Italy). B:Patient affected by a right adrenal pheochromocytoma. An area of intense 131I-MIBG uptake (solid arrows) is visible in the whole-body (left) and fused SPECT-CT (right) images. (Courtesy of Dr. P. Erba, University of Pisa, Pisa, Italy.)
Rare causes of false-positive results such as the physiologic accumulation of MIBG within the urinary tract or the bowel, which can mimic a tumor lesion, should also be considered. False-negative results may occur if the lesion is of small dimension or in lesions whose uptake mechanisms have been altered by concomitant usage of drugs (Table 20.5).
18F-FDG, a glucose analog, is transported into the cell via dedicated glucose transporters where it is subsequently phosphorylated by the cytoplasmic enzyme, hexokinase. The resulting compound cannot be further metabolized and is thus trapped within the cytoplasm. Because many tumors, particularly those of aggressive or accelerated proliferative nature, exhibit an increased glycolytic metabolism, they overexpress glucose transporters and hexokinase. This provides the biologic basis for the use of 18F-FDG as a radiopharmaceutical to detect such tumors. The process of accelerated glycolytic metabolism is, in addition, a phenomenon that is common to activated inflammatory cells and 18F-FDG may accumulate at sites of inflammation which constitutes a potential cause of false positivity for malignancy.
For a detailed description of the scan methodology, reference should be made to the specific section on this subject.
Currently, 18F-FDG PET has widespread use in oncology, particularly in staging, assessing the response to treatment and in planning external-beam radiotherapy.137
The reported sensitivity of 18F-FDG PET in NENs, however, is generally low. A recent prospective study in 96 patients showed a sensitivity of only 58%. As a result, 18F-FDG PET has always been regarded as a secondary modality in neuroendocrine oncology, particularly apt for the identification of undifferentiated (aggressive/high) tumors, especially in the lung, or when the SRS is negative.138
Recently, however, the utility of this modality has been reconsidered as a predictor of tumor assessment. Thus, in a prospective study of 38 patients with GEP or bronchial NENs, 18F-FDG PET positivity was noted to be an independent predictor (irrespective of grading, based on Ki-67 index) of the progression-free survival at multivariate analysis.94 Thereafter, a second study in a larger cohort of 98 patients prospectively enrolled after surgery and scheduled for various therapies, demonstrated that between 18F-FDG uptake, Ki-67, CgA, and liver metastases, the only parameter that correlated with prognosis was positivity at 18F-FDG PET. Of particular note was the observation that univariate analysis indicated that an SUVmax >9 and a high Ki-67 index were significant predictors of overall survival, whereas multivariate analysis showed that an SUVmax >3 was the only predictor of progression-free survival.78 Although additional concordant reports are emerging in the literature, these observations need confirmation in larger series.
The use of 18F-FDG PET has been re-evaluated in chromaffin tumors given the observations of a study of 216 patients which reported a high sensitivity for metastatic forms (82.5%). In the same study it was noted that the uptake was higher in succinate dehydrogenase (SDH) and VHL-related tumors.139
GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS
Pancreatic NENs typically are highly vascularized and enhance during the arterial and venous phases on CT. Heterogeneous enhancement may occur in lesions of larger dimension which are often associated with necrosis, therefore, representing an indirect sign of tumor aggression.140
The localization of a small tumor, like an insulinoma, may be difficult and modern multiplanar CT examinations are recommended to improve the visualization of the pancreas.141
The diagnosis of a gastrinoma suggests a localization most commonly in the duodenum or the pancreas. These lesions can also be multifocal, especially in MEN type 1. Metastatic spread may occur to lymph nodes in the peripancreatic area, often referred to as the “gastrinoma triangle.”
Pancreatic lesions appear as hypointense on fat-suppressed T1-weighted sequences, hyperintense on fat-suppressed T2-weighted sequences, and hyperintense on diffusion images.65 These lesions markedly enhance after gadolinium injection, resulting in hypointense to isointense, when compared to the surrounding parenchyma.142
Despite the variability in presentation, clinically silent tumors generally have larger dimensions and may have metastatized when identified. The image features are similar to functioning lesions, namely an iso/hypodense aspect on basal CT images, which show contrast enhancement in arterial and portal venous phases, as well as a hypointense appearance in T1 images, hyperintense in T2 phase, which show enhancement after gadolinium.
An overview of 11 studies in 343 patients with pancreatic NENs reported CT to have a mean sensitivity and detection rate of 73%, with 96% specificity. Mean sensitivity and specificity for MRI are 93% and 88% for pancreatic NENs. Transabdominal US per se has a poor detection rate in pancreatic lesions (mean 39%). A collation of six studies noted that this modality has largely been superseded by EUS (90%) and IOUS (92%).72
In a separate assessment, EUS was considered able to detect 45% to 60% of duodenal lesions and 90% to 100% of pancreatic lesions.3 It has been reported that the combination of MDCT and EUS may reach 100% sensitivity in the localization of a primary pancreatic lesion.143
On CT scans, small bowel NENs usually appear as a contrast-enhancing spiculated mass, sometimes containing calcifications, surrounded by lines of desmoplastic reactions.144 Angio-TC may be useful to assess the involvement of vessels, such as the superior mesenteric vasculature or the portal venous system.
The MRI appearance of these lesions is isointense to muscle in T1-weighted sequences and hyper/isointense in T2-weighted images. Usually, they enhance on fat-suppressed T1 images.
The efficacy of endoluminal diagnostic studies such as enteroscopy, contrast intestinal radiography, and videocapsule endoscopy is suboptimal given the difficulty in adequately accessing the small bowel.34 Most of the small bowel is not directly accessible, and videocapsule endoscopy or the more invasive double balloon enteroscopy is the only technique that can study this area, although their sensitivity is not high.34 CT enteroclysis has a clearly inferior sensitivity and specificity to videocapsule enteroscopy (50% and 25% versus 38% and 100%, respectively for the two methods).145
Endoluminal lesions, such as gastric (especially types 1 and 2), duodenal, rectal and colonic NENs, are better diagnosed by endoscopy. The role of radiologic imaging, in these cases, is mainly directed at staging the disease by providing anatomic evidence of the locoregional and distant involvement.
Colonic and rectal NENs are generally diagnosed with endoscopy and a CT scan is used to assess the regional and distant metastases. In rectal NENs, MRI may also be used to evaluate the invasion of the rectal wall and adjacent structures although EUS is also an effective modality in delineating transmural disease and perirectal lymph node involvement.72
The most common site of NEN metastasis is hepatic and such lesions are often like the primary, hypervascular. They appear as hypodense masses on CT, with rich enhancement during the arterial phase, and revert to hypodense during the portal phase.146 Larger metastases, enclosing areas of necrosis, may appear as heterogeneously enhanced.
Likewise, on MRI study, liver metastases show enhancement after gadolinium. Hepatic arterial phase and fast spin-echo T2-weighted sequences are the most sensitive method.147 Overall, MRI is considered to provide a higher sensitivity than CT.
An analysis of four studies of hepatic metastases in 135 patients, reported 82% sensitivity and 92% specificity for CT, and 82% and 95% for MRI. Data on the sensitivity of US for the detection of liver metastases are scarce but overall are lower than CT/MRI. A study on 17 patients with 69 liver metastases reported a sensitivity of 68% for unenhanced US, rising to 99% after contrast medium.148 The clinical utility of US is most effective in providing guidance when undertaking a biopsy.72
In the two decades since its introduction, the use of SRS in GEP-NENs has become widespread. As illustrated below, considerable data have accumulated indicating a sensitivity of 75% to 100% in localizing the primary tumor and, at the same time, assessing the extent of disease.149 Studies have demonstrated a higher accuracy compared to conventional imaging such as CT/MRI.149,150
SRS has a central role in the tumor localization in the presence of clinical syndromes, such as Zollinger–Ellison, where it represents the single most sensitive method for imaging either primary or metastatic liver lesions.68 The European Multicenter Trial concluded that the sensitivity of SRS in locating glucagonomas was 100%, VIPomas 88%, and gastrinomas 73%, whereas the diagnostic sensitivity was 43% for insulinomas.69 Somatostatin scintigraphy is thus considered to play a secondary role in localizing insulinomas, which generally have a low expression of sst2, although a variable proportion of benign and malignant insulinomas may show uptake.151,152 The nuclear medicine study of most utility in the diagnosis of insulinoma is 111In-GLP-I because both benign and malignant insulinomas express the glucagon 1–like peptide.153
In functioning tumors, receptor scintigraphic techniques may also allow the localization of the primary tumor in anomalous sites, such as a gastrinoma of the cardiac septum, or in areas that may be difficult to explore, such as the retroperitoneal or posterior mediastinal region.154
The diagnostic accuracy of 111In-pentetreotide scintigraphy in nonfunctioning tumors is not much different to secreting tumors, as the SR-mediated internalization of the radiopeptide is independent of the secretory activity of the cell. However, in the absence of a clinical syndrome that might initiate earlier imaging, nonfunctional tumors may be larger when identified. In this case, nuclear medicine techniques may have a secondary role in locating the primary tumor, compared to conventional imaging.
In a study of 131 patients with GEP-NENs comprising a subgroup of 26 nonfunctional pancreatic lesions, the sensitivity of SR imaging was 79%.79
Other series have demonstrated a sensitivity in locating noninsulinoma pancreatic NENs ranging from 75% to 100%.70,79,80,155
The sensitivity of 111In-pentetreotide in detecting small bowel NENs is high, and in some centers has been reported to reach 100% although it is generally somewhat less.81,82,149
In an initial study of more than 1,000 patients, 52 of which had carcinoids, SRS localized the primary tumor in 86% of patients.95 In a study in 131 patients, 87 of which were carcinoids (mainly intestinal), the sensitivity for primary tumor localization was 54%.79
In a group of 12 patients with positive scan referred for the search of a primary, SPECT/CT improved the localization of the primary tumor in only three of the patients.80
In the evaluation of liver metastases, present in 40 of 64 patients with GEP-NENs studied with CT, MRI, and 111In-pentetreotide, planar and tomographic receptor imaging exhibited the lowest sensitivity (204 lesions), compared to arterial phase–enhanced CT (325 lesions), and arterial phase–enhanced T1-weighted MRI (394 lesions). The median size of metastases was the only factor significantly associated with the sensitivity of scintigraphy for the detection of liver metastases.156
The principal limitation of SRS resides in the typical low spatial resolution of the γ-camera. In recent times, the introduction of novel somatostatin analogs labeled with positron emitters such as 68Ga has altered the diagnostic approach to NENs. Numerous studies have demonstrated a high tumor to nontumor contrast and a higher sensitivity of PET/CT with 68Ga-DOTA-peptides compared to conventional imaging and scintigraphy.110 Although not all studies rigorously compared the PET technique with an adequate scintigraphic protocol, it seems probable that PET with 68Ga-DOTA-peptides will replace conventional receptor imaging in the future.6,157 In the initial published study with 68Ga-DOTA-TOC, the sensitivity of PET in a group of eight NEN patients, six of which were GEPs, was 100% as opposed to 85% for conventional scintigraphy.114
The use of 68Ga-DOTA-NOC in a group of 84 patients (62 GEPs) demonstrated 97% sensitivity, compared to 61% and 52% for conventional imaging and scintigraphy, respectively.71
PET/CT with 68Ga-DOTA-TATE produced a positive interpretation in 87% of 47 patients with a radiologic or biochemical suspicion of NENs, mainly GEPs 79%, when conventional receptor imaging was ambiguous. No false positive was identified.158
In a series of 59 patients with an unknown primary studied in an attempt to locate the primary tumor, 68Ga-DOTA-NOC was successful in 35 (32 of which were GEP-NENs), with an overall detection rate of 59%.159
When seeking to establish the location of a NEN, receptor PET should not be performed as the initial technique in patients with a suspicion of a NEN based only on increased blood markers, like CgA, or clinical symptoms. 68Ga-DOTA-NOC is more frequently positive when conventional imaging or when clinical and biochemical findings suggest a NEN.85
Unless specifically investigated, skeletal metastases are easily missed on CT. PET with 68Ga-DOTA-peptides is 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%) bone metastases were evident at conventional scintigraphy and only 58 (50%) at CT scan.71 Recently, in a study of 51 patients, 35 of which were GEP-NENs, demonstrated that PET/CT with 68Ga-DOTA-TOC performed better than conventional SRS or bone scintigraphy, resulting in 97% sensitivity and 92% specificity.160 Figure 20.14 reports examples of localization and staging with 68Ga-DOTA-TOC of a duodenal gastrinoma in the MEN1 syndrome (A); (B) shows an example of restaging with 68Ga-DOTA-TOC of a patient with a pancreatic NEN who had undergone receptor radionuclide therapy with 177Lu-DOTA-TATE (A to C).
FIGURE 20.14. A: Example of localization of a duodenal gastrinoma in multiple endocrine neoplasia type 1 with 68Ga-DOTA-TOC PET/CT after a positive secretin test. A magnetic resonance image (2) is silent, while both maximum intensity projection (MIP) (1) and transaxial fused images (3) show the duodenal lesion (dashed arrows) with peripancreatic lymph nodes (solid arrows). In this case the PET examination serves also as a staging technique. B: Example of restaging with 68Ga-DOTA-TOC PET/CT in a patient affected by multiple bone marrow metastases from a pancreatic neuroendocrine tumor (1 and 2, fused sagittal and MIP images, respectively, at basal evaluation), undergone peptide receptor radionuclide radiotherapy with 177Lu-DOTA-TATE (25 GBq). Follow-up 68Ga-DOTA-TOC PET/CT performed after the end of treatment shows a complete response (3 and 4, fused sagittal and MIP images, respectively).
FIGURE 20.15. 18F-DOPA PET/CT in a patient affected by diffuse bone, lymph node, liver, and soft tissue metastases from a small bowel neuroendocrine tumor. (Courtesy of Professor S. Fanti, University of Bologna, Bologna, Italy.)
Alternative modalities of imaging GEP-NENs include 18F-DOPA and 11C-HTP. 18F-DOPA PET was popular in the past decade, because it was the first PET modality to outperform 111In-pentetreotide scintigraphy. It has a high sensitivity and accuracy for carcinoid tumors (93% and 89%, respectively) compared to the performance of 111In-pentetreotide in a variety of GEP-NENs.48
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.47
PET/CT with 11C-HTP has been proposed as a universal imaging method for the detection of NENs. Compared to conventional receptor imaging and CT, 11C-HTP was able to detect more lesions than scintigraphy and CT in 58% of 42 patients with NENs, mainly of GEP origin. Moreover, in 84% (16 of 19 patients), 11C-HTP could visualize the primary tumor, as opposed to 47% and 42% for somatostatin imaging and CT, respectively.49
The sensitivity of radiolabeled serotonin and catecholamine precursors was studied in a group of 47 patients with GEP-NENs (24 carcinoids and 23 pancreatic NENs) and compared to conventional morphologic and functional imaging. In all carcinoid patients, the two PET techniques had a higher sensitivity than receptor scintigraphy (100%, 96%, and 86%, respectively). Moreover, PET with 11C-5-HTP was superior to 18F-DOPA PET in pancreatic NENs (67% versus 41%), whereas 18F-DOPA PET is the optimal imaging modality for staging in carcinoid patients (87%). The sensitivity was further increased by CT fusion (87% to 98% in carcinoids for 18F-DOPA and 67% to 96% in pancreatic NENs for 11C-5-HTP).83 Figure 20.15 illustrates an example of 18F-DOPA PET/CT.
The enthusiasm for these alternative PET techniques has been somewhat diminished by the increased availability of 68Ga-DOTA-peptides and the demonstration of a better performance of SR PET. By way of illustration, in a group of 13 patients affected mainly by GEP-NENs, 68Ga-DOTA-NOC identified more lesions than 18F-DOPA (71 compared to 45), especially in the liver, lung, and lymph nodes. It was also of advantage, because, unlike 18F-DOPA, it facilitated selection for therapy with “cold” or radiolabeled somatostatin analogs.161 Similar results were obtained with 68Ga-DOTA-TATE in a group of 25 patients with NENs mainly of GEP origin. SR PET yielded a clearly superior sensitivity compared to 18F-DOPA (96% versus 56%, respectively).
At this time, it may be concluded that PET with alternative tracers can be regarded as a viable second investigative modality when SR imaging is negative, particularly in NENs associated with high plasma serotonin values.162
BRONCHIAL NEUROENDOCRINE NEOPLASMS
Conventional Radiologic Imaging
Primary NENs of the lungs represent ∼25% of all NENs and are the second most common presentation, after GEP, among well-differentiated forms.163 In general, they are divided in an archaic fashion into typical (mostly benign) and atypical. The latter usually exhibit malignant behavior but the criteria for differentiating between atypical and typical are sometimes difficult to determine.164 Most BPNs are located close to central bronchi, although ∼40% of cases are located in the peripheral lung.165 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 BPNs are usually hypervascular and demonstrate intense contrast enhancement (more than 30 HU).87 Atypical BPNs are associated with hilar or mediastinal lymph node metastases.166LCNEC, which is a poorly differentiated and high-grade NEN, is a morphologic entity that is between the “atypical” BPN and SCLC. LCNEC and SCLC do not show any specific CT feature and are similar to other, more common non small cell lung carcinomas (NSCLCs). However, CT plays a role in staging and follow-up for all BPNs.
CT is the modality of choice for bronchial NENs, although MRI can be undertaken, especially if iodinated contrast medium cannot be used. At MRI, lesions can appear as hypointense or isointense in T1-weighted images.87 MRI is more sensitive than CT scan for the detection of liver metastases.147
FIGURE 20.16. Example of PET/CT with 68Ga-DOTA-TOC in a patient affected by a bronchial neuroendocrine tumor (arrows) with liver and skeletal metastases; A: Maximun intensity projection image; B:correspondent fused transaxial slice.
Molecular imaging can help differentiate the etiology of bronchial masses.167 SR imaging combined with CT or MRI is used for staging, restaging, and treatment monitoring, thus optimizing management strategy.87 Figure 20.16reports an example of 68Ga-DOTA-TOC in a patient with a bronchial NEN.
Because most thoracic NENs exhibit SRs, especially sst2 and sst5, 111In-pentetreotide scintigraphy is useful to detect most bronchial NENs >1 cm in diameter, including those associated with ectopic ACTH or GHRH secretion.168,169 SRS is also helpful for radioguided surgery, allowing evaluation of the tumor bed after resection to detect any residual radioisotope uptake that corresponds to the presence of residual tumor.170 PET/CT with 68Ga-DOTA-peptides has the highest sensitivity in the detection of mediastinal lymph node involvement and distant metastases.88
PET/CT with 18F-FDG in lung NENs exhibits variable uptake, depending upon the tumor proliferation (grade). A low 18F-FDG uptake (SUVmax <2.5) is usual in bronchial NENs.89 Tumors of a higher grade than typical bronchial NENs can have high 18F-FDG uptake. Atypical BPNs can be more metabolically active and usually appear as a small pulmonary nodule associated with hilar or mediastinal lymph nodes, and exhibit high SUV values. The more dedifferentiated forms, such as LCNECs, usually have a high 18F-FDG uptake and PET/CT as well as CT alone, have a high accuracy in predicting the presence of hilar and mediastinal nodal involvement. However, PET/CT seems to be better than CT alone in detecting distant metastases and thus altering clinical management. An SUVmax greater than 13.7 has been suggested as predictive of a short survival period suggesting the use of PET/CT with 18F-FDG not only in staging but also as a prognostic tool in LCNEC.171 In SCLC, 18F-FDG PET is valuable for initial staging, to distinguish localized from metastatic disease. It has been reported that 18F-FDG PET/CT is also useful for prognostic prediction after treatment.172
Initial data examining the combined use of 18F-FDG and 68Ga-DOTA-TOC are encouraging. Typical BPNs, rich in SRs, exhibit high uptake on 68Ga DOTA-TOC PET/CT imaging, but low 18F-FDG uptake because of the low proliferative index. An increased avidity of 18F-FDG and/or decreased avidity for 68Ga-DOTA-TATE might therefore be useful to identify aggressive tumors containing foci of possible dedifferentiation.90
Pheochromocytomas and paragangliomas derive from sympathetic chromaffin tissue in the adrenal medulla and from the extra-adrenal paraganglial system of the thorax and abdomen. The majority of these tumors, except for those arising from the head and neck region, are associated with catecholamine hypersecretion.129 Imaging is usually initiated after the biochemical demonstration of these tumors, with the aim of locating the primary tumor (or the primary lesions associated with hereditary neoplasia) or detecting metastases in malignant diseases.173 CT and MRI are sensitive and specific for detecting adrenal pheochromocytomas (77% to 98% for CT and 95% to 100% for MRI) and provide useful information for the surgical intervention. MRI is usually the preferred modality in children and young adults. However, MRI and CT have a lower sensitivity (29% for CT) for extra-adrenal lesions or metastases from malignant pheochromocytomas.174 When metastases are suspected, particularly in large lesions over 5 to 6 cm, functional techniques exploring the whole body may help in staging the patient.173 In extra-adrenal lesions, the specificity may be decreased, because other tumors of neurogenic or mesodermal origin may resemble paragangliomas in both distribution and appearance. MRI is the technique of choice for head and neck paragangliomas.175,176
Functional imaging with 123I-MIBG, is the primary choice as a nuclear medicine diagnostic.132,177,178 MIBG scintigraphy is frequently used to confirm if the disclosed adrenal mass is actually a pheochromocytoma. MIBG has a sensitivity and specificity of 90% and 95%, respectively. Overall, the combined sensitivity of catecholamine measurements and an 123I-MIBG scan is close to 100%.179 A whole-body MIBG scan is particularly helpful in the preoperative identification of multiple primary lesions (relatively frequent in NE secreting pheochromocytomas) or metastases from malignant tumors. Functional MIBG studies are also able to detect recurrences because the radiotracer accumulates specifically within the tumor and is not affected by postsurgical or postradiotherapy changes.
Initial studies using 131I-MIBG reported 77% to 90% sensitivity in detecting pheochromocytomas, with a specificity of 95% to 100%.99 Because 123I yields a superior image quality compared to 131I, subsequent studies confirmed that 123I-MIBG exhibited a better performance for pheochromocytoma detection with 83% to 100% sensitivity.180
Several factors such as drug administration can decrease the sensitivity of MIBG scintigraphy, these are based on interference with MIBG uptake, and thus produce false-negative results. In addition, false-negative scans may occur because of small lesion size, or extra-adrenal location. MIBG imaging has a sensitivity of 58% for extra-adrenal tumors compared to 85% for adrenal pheochromocytomas.135
A sensitivity of only 65% is reported in familial forms associated with succinate dehydrogenase B (SDHB) mutations.181
MIBG imaging is not very useful in the detection of paragangliomas (17% to 42%) located in the craniocervical area. Although paragangliomas of the abdomen and thorax can be functionally active (catecholamine secreting), head and neck paragangliomas are rarely hormonally active. Such lesions were, in the past, referred to as glomus tumors and although of chromaffin cell origin, actually consist of a local regulatory cell system as opposed to the endocrine functionality of adrenal lesions.182,183
In those settings where scintigraphic results could be affected by a lack of sensitivity of MIBG (size and site of the lesions, extra-adrenal, familial, and malignant pheochromocytomas) other radiopharmaceuticals should be considered as diagnostic adjuncts.
SRs are overexpressed in chromaffin tumors and SR imaging is therefore of use. The sensitivity of SRS is inferior to MIBG for the detection of benign adrenal pheochromocytomas because small lesions can be obscured by gastrointestinal activity and renal excretion.184 However, 111In-pentetreotide has been reported as more sensitive than 123I-MIBG in the detection of malignant pheochromocytoma and metastatic lesions.185 SR imaging is more effective than MIBG in the localization of head and neck paragangliomas, with a higher sensitivity (93% versus 44%) and image quality.182
Catecholamine-based PETs with 18F-fluorodopamine, 18F-fluorodopa, 18F-fluorodeoxyglucose, or 11C-hydroxyephedrine are alternative functional imaging methods to 123I-MIBG or can be used as additional procedures if 123I-MIBG scanning is negative. The reported sensitivities are 18F-dopamine (76%), 18F-DOPA (45%), 18F-FDG (74%), and 123I-MIBG (57%).99,186 18F-FDG, the only PET imaging compound that is widely available, is not recommended for initial diagnostic localization, because it is nonspecific for pheochromocytoma and sensitivity is restricted, although it can offer important prognostic information.139
Recent reports suggest that 68Ga-DOTA-TATE PET/CT SR imaging has a higher sensitivity than 123I-MIBG in patients with chromaffin tumors (pheochromocytomas and paragangliomas).187
Despite the low number of published studies, there is evidence that 68Ga-labeled-peptides are promising agents for the diagnosis and management of pheochromocytomas, as well as for the selection of patients for radionuclide therapy with radiolabeled somatostatin analogs.188
Overall, it has been demonstrated that nuclear medicine tracers of proven utility in studying pheochromocytomas are 123I-MIBG, 11C-hydroxyephedrine, 18F-dopamine, and 18F-DOPA, with sensitivities ranging from 90% to 100%. 18F-FDG was found to be of moderate utility, with a sensitivity of 72%. 111In-pentretreotide can be of selected utility, particularly in metastatic forms.
In paragangliomas, 18F-dopamine, 18F-DOPA, and SR imaging are the modalities of proven utility, whereas 123I-MIBG appears of moderate utility, with 71% sensitivity.189
Impact of Functional Techniques on Patient Management
It has become apparent in numerous studies that patient management is significantly altered by the use of both functional and morphologic imaging. The impact of each diagnostic modality on therapeutic strategy is more critical than its diagnostic performance alone. In a group of 186 NEN patients, partly studied with radiologic techniques as a first approach and partly studied with 111In-pentetreotide, it was demonstrated that the influence of morphologic or functional imaging on therapy management was equivalent. The authors concluded that a combination of both morphologic and functional imaging represented the optimal management strategy.63
Prior to 2000 and the advent of last generation radiologic techniques, the impact of SRS on altering GEP-NENs management strategy, ranged from 21% to 53% in a variety of studies.70,74,75,79,84
More recently, with the introduction of newer radiologic techniques, it has become evident that conventional imaging, MRI in primis, followed by CT scan have the greatest sensitivity for the detection of liver metastases.156 The principal limitation of conventional receptor scintigraphy is low spatial resolution.
In most patients, however, the detection of an increased number of metastases, for example, in the liver, does not translate into a modification of the therapeutic approach. Nevertheless, the demonstration of unsuspected metastatic deposits, local recurrence, the identification of the primary tumor or the demonstration of the absence of SRs in the lesions can alter therapeutic strategy. Of note therefore is a recent report indicating that PET/CT with 68Ga-DOTA-NOC was able to modify the stage or the therapy in more than 50% of 90 patients with NENs (62 GEP-NEN primary). Alterations included initiation or continuation of therapy with “cold” or radiolabeled somatostatin analogs, an indication for exclusion from surgery or to stop somatostatin analog use.76 In a separate study, the clinical impact of PET/CT with 68Ga-DOTA-TOC compared to standard imaging was evaluated in 52 patients. PET/CT detected several more lesions compared to standard radiologic imaging and was able to modify the treatment decision in almost 60% of patients, through a change in surgical or nonsurgical strategy.77 A third study with 68Ga-DOTA-TATE PET/CT of 51 patients (37 GEP-NENs), identified more lesions than conventional receptor scintigraphy (168 versus 27 of the 226 identified with cross-sectional imaging, namely 74% versus 12%), resulting in a management change in 36 patients (71%).158
CLINICAL UTILITY OF EACH NUCLEAR IMAGING TECHNIQUE IN NEUROENDOCRINE NEOPLASMS
ADVANTAGES AND LIMITATIONS OF NUCLEAR MEDICINE TECHNIQUES IN NEUROENDOCRINE NEOPLASMS
It may therefore be inferred that SR imaging, particularly PET/CT with 68Ga-DOTA-peptides, can be regarded as an axiomatic or fundamental procedure to define management strategy. Table 20.6 illustrates the clinical utility of each nuclear imaging technique in NENs.
A further advantage of PET is that the SUVmax expression of uptake, represents a prognostic tool because it is higher in well-differentiated NENs with elevated sst2 expression which are therefore predicted to be more responsive to “cold” and radiolabeled somatostatin analogs.190 Table 20.7 illustrates advantages and limitations of nuclear medicine techniques in NENs.
A further prognostic advantage of 68Ga-DOTA-TATE PET regards therapy with radiolabeled somatostatin analogs because an early reduction of SUV correlates with a response to radioreceptor therapy with somatostatin analogs.191
Apart from clinical issues, there is a need to consider the cost/benefit ratio of different diagnostic strategies. Previous data from the 1990s had noted that combining appropriate modalities into rational algorithms, for example, 111In-pentetreotide and abdomen CT scan for gastrinomas, resulted in an optimal cost-effectiveness ratio in terms of tumor localization, effect on patient management, and financial costs. It was concluded that the relatively high cost of the scintigraphic procedure was largely outweighed by the invaluable information obtained.192
A more recent cost comparison analysis of 111In-pentetreotide scintigraphy and 68Ga-DOTA-TOC PET/CT for staging GEP-NENs indicated lower costs for the PET procedure. This analysis considered the cost of the materials and personnel, as well as the cost reduction associated with the considerable reduction of additional examinations.193 Nevertheless, the need to establish a GMP certified laboratory and the fact that, to date, no commercial group has marketing authorization for 68Ge/68Ga generators as medicinal product somewhat increases the complexity of the precise fiscal evaluation.111,194
RADIONUCLIDE THERAPY OF NEUROENDOCRINE NEOPLASMS
Peptide Receptor Radionuclide Therapy
In the past two decades a new approach to the treatment of unresectable or metastasized NENs based on specific receptor targeting with radionuclides has gained acceptance in clinical practice in many European centers. PRRT consists of the systemic administration of a synthetic somatostatin analog, radiolabeled with a suitable β-emitting radionuclide. The compound is able to irradiate tumors and their metastases via the internalization through SRs overexpressed on the cell membrane. As a result, the radiopharmaceutical is concentrated in the tumor cell, where sensitive molecules, such as DNA, can be targeted. 111In-pentetreotide was the initial therapeutic agent utilized based upon the emission of Auger and conversion electrons by 111In in close proximity to the cell nucleus. A multicenter trial demonstrated some clinical benefit although partial remissions were rare.195
Further investigations led to the development and usage of radiopharmaceuticals labeled with higher-energy and longer-range β-emitters, such as Yttrium-90 (Emax 2.27 MeV, Rmax 11 mm, half-life 64 hours) and Lutetium-177 (Emax 0.49 MeV, Rmax 2 mm, half-life 6.7 days). Subsequently 90Y-DOTA-Tyr3-octreotide or 90Y-DOTA-TOC or 90Y-octreotide (with an octreotide-like pattern of affinity), was developed based upon its favorable chemical profile. This agent has since been used in a number of clinical trials.196,197 Thereafter, a newer analog, DOTA-TATE, with a six- to nine-fold higher affinity for sst2, was synthesized. The 177Lu-labeled form, 177Lu-DOTA-Tyr3-octreotate or 177Lu-DOTA-TATE or 177Lu-octreotate, is currently one of the most clinically used radiopharmaceuticals.198
It is now widely accepted and demonstrated by dosimetric studies that PRRT with either 90Y-octreotide or 177Lu-octreotate delivers radiation doses adequate to achieve significant tumor responses.199
Patients who are candidates to receive PRRT with radiolabeled somatostatin analogs are those with lesions that significantly overexpress SRs, namely with an adequate uptake (at least equal to that of normal liver) at OctreoScan or PET with 68Ga-DOTA-peptides. This strategy is critical, as it enables the delivery of high doses to the tumor, whereas sparing the normal tissues.
FIGURE 20.17. Example of objective response to peptide receptor radionuclide therapy (PRRT) with 90Y-DOTA-TOC in a patient affected by liver metastases from a resected ileal neuroendroine tumor. Basal OctreoScan imaging shows the biggest liver lesions (solid arrows; A, planar anterior image; B, transaxial SPECT slice), whereas computed tomography (C [CT]) shows another small lesion in the seventh segment. Follow-up imaging after the end of PRRT shows a partial reduction of the disease, both from a functional (dashed arrows on planar [D] and transaxial [E] SPECT images) and morphologic (F [CT ]) point of view.
PRRT is typically fractionated in multiple cycles. The maximum cumulative administrable activity depends on the irradiation of the kidneys, which are the dose-limiting organs. The absorbed dose threshold is conventionally set at 25 to 27 Gy, or, optimally, at ∼40 Gy (for a biologic effective dose [BED]).200
To reduce the renal dose, patients are coinfused with an intravenous infusion of positively charged amino acids, such as lysine or arginine. This measure reduces the renal dose by competitive inhibition of the proximal tubular reabsorption of the radiopeptides via the COAL (cystine, orthinine, arginine, lysine) transporter mechanism.201
In more than 15 years of academic phase I/II trials, despite the lack of homogeneity among studies, PRRT has proved to be efficient and consistent in efficacy and has, ultimately, demonstrated an impact on survival.73
The radiopeptide most commonly utilized in the first 8 to 10 years of experience was 90Y-octreotide. All the published results derive from different phase I/II studies and represent a heterogeneous group in terms of inclusion criteria and treatment schemes. As a consequence, a direct comparison is virtually impossible at this time. Nevertheless, even with these limitations, objective responses (Fig. 20.17) are registered in 6% to 37% of patients (Table 20.8).
A recent study of the role of 90Y-octreotide in 90 patients with metastatic midgut “carcinoids,” demonstrated that symptomatic responses had an impact on survival, because progression-free survival was significantly longer in those who had a durable diarrhea improvement.207
More recently, objective morphologic and symptomatic responses in 1,109 patients, (821 GEP-NENs), treated with 90Y-octreotide were demonstrated to have an impact on survival. The best predictor of survival was the tumor uptake at baseline.208
CLINICAL RESULTS OF PEPTIDE RECEPTOR RADIONUCLIDE THERAPY IN GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS
FIGURE 20.18. Example of objective response to peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-TATE. A: Basal anterior scan, 24 hours post injection in a patient affected by liver (solid arrows) and skin (dotted arow) metastases from a pancreatic NET (dashed arrow). B: Posttherapy scan at the last PRRT cycle, which demonstrates the almost complete disappearance of liver metastases (solid arrows), and persistence of faint uptake at the head of the pancreas (dashed arrow). The skin metastasis is no longer visible. C and D: The PET/CT with 68Ga-DOTA-TOC performed 6 months after the end of treatments (C, maximum intensity projection image) confirms the disappearance of liver metastases and the persistence of a small lesion located at the head of the pancreas (dashed arrows) (D, fused transaxial slice).
Since its introduction in 2000, 177Lu-octreotate, has gained popularity, because of its higher affinity for sst2, its easier manageability, and the ability to undertake synchronous imaging.
In a series of 310 GEP-NENs treated with 177Lu-octreotate, PRRT proved to be oncologically active (lesion shrinkage) and it is likely to have an impact on survival parameters. A median overall survival >48 months was observed in responding patients, with a median progression-free survival of 33 months. A direct comparison with the literature obtained from similar patients showed a 40- to 72-month survival benefit. Although these data are not the result of a rigorous randomized trial, the substantial difference in survival is probably as a consequence of the PRRT. These data compare favorably to other treatments, such as chemotherapy, in terms of the cost/benefit and tolerability point of view.61
In a prospective study on 51 patients treated with 177Lu-octreotate, in a subpopulation of 39 patients in progression at enrolment, it was noted that stabilization and objective responses shared the same survival probability, thus indicating that stabilization may be regarded as a form of response (Fig. 20.18).210
PRRT is generally well tolerated. Acute side effects, such as nausea or fatigue, are usually mild and self-limiting. From a hematologic point of view, severe (WHO grade 3 or 4) toxicity occurs in <13% of cases after 90Y-octreotide and in 9.5% after 177Lu-octreotate.73,211
Chronic and permanent effects on kidneys and bone marrow are generally mild if the necessary precautions, such as coinfusion of positively charged amino acids and fractionation of the cumulative activity, are undertaken.212 With advances in expertise and knowledge about PRRT, cases of severe, end-stage, renal damage are currently very rare.73 Studies have demonstrated that a higher and more persistent decline in creatinine clearance and the subsequent development of renal toxicity were risk factors for delayed renal toxicity, particularly in long-standing and poorly controlled diabetics and hypertensives (with a lower renal BED threshold of about 28 Gy).213
It is apparent that 177Lu-octreotate significantly improved the global health/QoL and a variety of symptom scales, particularly fatigue, insomnia, pain, as well as emotional, and social functional roles, in patients with metastatic GEP-NENs. The effect was more frequent in individuals with tumor regression, but surprisingly, was also evident in those with progressive disease.214 In a series of 265 patients, no significant deterioration of QoL was observed in asymptomatic patients treated with 177Lu-octreotate. On the contrary an improvement was evident, in those treated in suboptimal clinical conditions.215
Treatment of malignant pheochromocytomas and paragangliomas is complex and can be difficult. Surgery is the only curative treatment but in the event of unresectable or residual malignant disease, the use of 131I-MIBG has been advocated since the mid-80s. 131I is a β- and γ-emitter that can be used both for diagnosis and therapy. The γ-emission component is of diagnostic value whereas the high kinetic energy of the β-electrons provides a viable strategy for radionuclide therapy. The high sensitivity and specificity of MIBG for the detection of primary and secondary tumor sites has facilitated the use of the 131I-labeled compound for the treatment of malignant tumors of neuroectodermal origin.216
Initial studies with 131I-MIBG were undertaken in 1984 in patients with malignant pheochromocytomas.126 Given the success of this therapeutic modality, numerous patients with malignant chromaffin tumors have since been treated with a variety of clinical protocols (single and cumulative).217 Overall, the interpretation of MIBG studies has been hampered by the lack of homogeneity in terms of the therapeutic scheme and by the generally low number of patients studied. Nevertheless, the clinical results in advanced disease treated with 131I-MIBG (Europe and the United States) have demonstrated that it is possible to provide a significant symptomatic response. Thus, diminution of catecholamine hypersecretion, consequent blood pressure control, and substantial pain control have proved to be viable outcomes of therapy. Although tumor responses are mainly stabilization or partial responses, complete responses are rarely evident (Table 20.9).218
RESPONSE TO 131I-MIBG IN THE MAIN STUDIES ON PATIENTS WITH MALIGNANT CHROMAFFIN TUMORS
More recently, a comprehensive review of 116 patients with malignant pheochromocytomas treated with 131I-MIBG demonstrated that symptomatic improvement could be obtained in 76% of patients, hormonal responses in 45%, and tumor responses, mainly partial, in 30%. Usually, responses are more frequent in patients with limited disease and soft tissue metastases.225 Experience related to metastatic paragangliomas treated with 131I-MIBG are more limited; the observed results, however, appear similar.218 Tumor control is an important parameter in terms of the determination of survival parameters. Thus, patients with stabilization and objective responses 6 months after the completion of treatment exhibit a longer time to progression, compared to those not responding to 131I-MIBG (14.5 versus 4.5 months).226 Although it has been reported that survival is prolonged in patients receiving higher cumulative activities (>500 mCi),227 these observations need to be confirmed in controlled studies. Moreover, the possible additional efficacy of treatment combinations with myeloablative chemotherapy require further investigation.129 Figure 20.19 illustrates an example of response to 131I-MIBG.
131I-MIBG has been used also for the treatment of nonchromaffin NENs (e.g., GEP-NENs). Objective response rates, not surprisingly, are low (10% to 15%) and complete responses are rare. On the other hand, symptomatic responses are frequent (∼65%) and have a positive impact on survival.228 In more recent times, the role of 131I-MIBG in the management of NENs has decreased as a result of the emerging efficacy of PRRT. This reflects the clinical advantages that have accrued based upon the higher uptake and efficacy of radiolabeled octreotides.229,230 In the event of renal impairment or when PRRT is not available or not feasible (e.g., sst-negative lesions) 131I-MIBG may represent a viable alternative strategy in the treatment of NENs.228
Individuals most likely to benefit from 131I-MIBG are those with a significant uptake (at least 1% of the injected dose) at diagnostic imaging with either 123I-MIBG or 131I-MIBG scans. This level is consistent with adequate irradiation of tumor lesions, whereas sparing normal tissues. The bone marrow is the dose-limiting organ for 131I-MIBG therapy.224 Thyroid blockade with potassium iodide preparations from at least 1 day before to 15 days after the therapy is mandatory to avoid unnecessary radiation exposure of the thyroid and, consequently, hypothyroidism.231 Observed hematologic toxicity is usually mild, and mainly consists of a transient leucopenia and thrombocytopenia. Severe myelosuppression is extremely rare and generally occurs when high-dose regimens are applied.217
Occasionally, malignant pheochromocytomas and paragangliomas may show an elevated uptake at OctreoScan and no uptake at MIBG. In such cases, therapy with radiolabeled octreotides may be used and sporadic successes have been reported.43
NENs are ubiquitous and exhibit a wide range of malignancy. Their incidence is rapidly increasing and their prevalence in the gut exceeds that of all other neoplasia except colon cancer. Recent scientific advances in understanding the biology of these diseases have yielded considerable novel information. This has allowed for the introduction of sensitive techniques for the detection of these tumors, as well as the development of effective management approaches.
The different therapeutic strategies include surgery, locally directed ablative therapies, bioactive agents (somatostatin analogs/interferon), chemotherapy, molecular targeted agents, and PRRT.
FIGURE 20.19. Example of objective response to 131I-MIBG in a patient with diffuse peritoneal metastases by a malignant pheochromocytoma. The arrows indicate the largest metastatic deposits (A, basal scan, anterior view; B,basal scan, fused SPECT/CT images). Collected after the last cycle (C, anterior view) shows the reduction of intensity and extension of uptake as the therapeutic response. (Courtesy of Dr. P. Erba, University of Pisa, Pisa, Italy.)
Diagnostic imaging allows localization of the tumor lesion, definition of its relationship to adjacent structures, and evaluation of the extent of disease at both locoregional and distant levels (staging). In addition, it allows the reassessment of the tumor burden (restaging) and thereby guides the identification of patients for a specific therapy or sequence of therapies. It has become apparent from numerous studies that patient management is significantly altered by the use of both functional and morphologic imaging. In the last decade, nuclear medicine strategies have become key diagnostic elements in the precise delineation of tumor location and metastatic disease as well as providing information regarding the metabolic activity of the tumor. Currently, SR imaging, particularly PET/CT with 68Ga-DOTA-peptides, can be regarded as a fundamental procedure in determining the optimal management strategy for an individual patient. The utility of this technique is of primary importance in tumor localization, staging, and restaging. Furthermore, its application in selecting specific tumors for therapy is unique. In this respect, the combination of SR imaging and a metabolic assessment by 18FDG PET, has utility in providing prognostic parameters that may guide the clinician in their assessment of the patient.
The development of nuclear medicine therapeutic strategies, such as PRRT with radiolabeled somatostatin analogs, to control and eradicate metastatic disease as well as ameliorate symptoms, has become an important component of the advancement of therapeutic strategy in the management of NENs.
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