REVIEW
`
`Neuroendocrine tumours
`
`Endocrine-Related Cancer (2004) 11 1–18
`
`M T Barakat, K Meeran and S R Bloom
`
`Department of Metabolic Medicine, Division of Investigative Science, Imperial College London at Hammersmith
`Campus, Du Cane Road, London W12 ONN, UK
`
`(Requests for offprints should be addressed to S R Bloom; Email: s.bloom@imperial.ac.uk)
`
`Abstract
`
`carcinoid,
`for example,
`Neuroendocrine tumours are a heterogeneous group including,
`gastroenteropancreatic neuroendocrine tumours, pituitary tumours, medullary carcinoma of
`the
`thyroid and phaeochromocytomas. They have attracted much attention in recent years, both because
`they are relatively easy to palliate and because they have indicated the chronic effect of the particular
`hormone elevated. As neuroendocrine phenotypes became better understood,
`the definition of
`neuroendocrine cells changed and is now accepted as referring to cells with neurotransmitter,
`neuromodulator or neuropeptide hormone production, dense-core secretory granules, and the
`absence of axons and synapses. Neuroendocrine markers, particularly chromogranin A, are invaluable
`diagnostically. Study of several neuroendocrine tumours has revealed a genetic etiology, and
`techniques such as genetic screening have allowed risk stratification and prevention of morbidity in
`patients carrying the particular mutation. Pharmacological
`therapy for these often slow-growing
`tumours, e.g. with somatostatin analogues, has dramatically improved symptom control, and
`radiolabelled somatostatin analogues offer targeted therapy for metastatic or inoperable disease. In
`this review, the diagnosis and management of patients with carcinoid, gut neuroendocrine tumours,
`multiple endocrine neoplasia types 1 and 2, and isolated phaeochromocytoma are evaluated.
`
`Endocrine-Related Cancer (2004) 11 1–18
`
`Introduction and definition
`
`The definition of a neuroendocrine cell has changed over
`the last few years as our understanding and experimental
`techniques have advanced. In 1969, Pearse proposed the
`APUD (amine precursor uptake and decarboxylation)
`classification to describe cells producing polypeptide
`hormones and biogenic amines identical to those found
`in neurons (Pearse 1968, 1969). These cells would make up
`the tightly coordinated diffuse neuroendocrine system,
`present either in endocrine organs or dispersed through-
`out the body (Polak & Bloom 1979). The gastroentero-
`pancreatic system alone provides the richest source of
`regulatory peptides outside the brain (Polak & Bloom
`1986a). Indicating a unified origin to these cells, it was
`originally thought that they all derived from neuroecto-
`derm, but increasingly this was found not to be the case
`for all neuroendocrine cells (Le Douarin 1988). The
`following criteria are now generally accepted as defining
`neuroendocrine cells (Langley 1994): the production of a
`neurotransmitter, neuromodulator or neuropeptide hor-
`mone; the presence of dense-core secretory granules from
`which the hormones are released by exocytosis in response
`
`to an external stimulus; and the absence of axons and
`synapses. In practical
`terms, molecular markers are
`invaluable in defining neuroendocrine cells, and in
`particular chromogranin A (Winkler & Fischer-Colbrie
`1992, Taupenot et al. 2003). More recently, the subtilase
`proprotein convertases (SPC), particularly SPC2 and
`SPC3, have been added to the list of useful markers
`(Bergeron et al. 2000). With the discovery of neuroendo-
`crine phenotypes developing in cells such as immunocytes
`and certain neoplastic cells such as small cell carcinomas,
`it has recently been proposed that activation of specific
`genetic switches leading to neuroendocrine phenotypes
`should also be included in the definition (Day & Salzet
`2002).
`Neuroendocrine tumours are therefore a very hetero-
`geneous group arising from these neuroendocrine cells,
`and include carcinoid, non-carcinoid gastroenteropan-
`creatic tumours (such as insulinoma, gastrinoma and
`VIPoma
`(VIP,
`vasoactive
`intestinal
`polypeptide)),
`catecholamine-secreting tumours (phaeochromocytomas,
`paragangliomas, ganglioneuromas, ganglioneuroblasto-
`mas, sympathoblastoma, neuroblastoma), medullary car-
`cinoma of the thyroid, chromophobe pituitary tumours,
`
`Endocrine-Related Cancer (2004) 11 1–18
`1351-0088/04/011–1 # 2004 Society for Endocrinology Printed in Great Britain
`
`Online version via http://www.endocrinology.org
`
`Ex. 1072-0001
`
`

`

`Barakat et al.: Neuroendocrine tumours
`
`lung cancer and Merkel cell tumours. The
`small cell
`World Health Organization’s definition of neuroendo-
`crine tumours is ‘morphofunctional’ and is primarily
`based on microscopic characteristics, but incorporates
`immunohistological data (with such markers as the
`chromogranins, synaptophysin and non-specific enolase),
`special stains (e.g. silver), in addition to immunohisto-
`chemical stains for specific hormones which result in
`endocrine hyperfunction syndromes (Solcia et al. 2000).
`For the purposes of this review, the following topics are
`covered in the vast field of neuroendocrine tumours:
`etiology, general markers and the specific syndromes
`related to a limited subset of neuroendocrine tumours,
`namely
`carcinoid and other
`gastroenteropancreatic
`neuroendocrine tumours, multiple endocrine neoplasia
`types 1 and 2, and phaeochromocytoma.
`
`Etiology
`
`The genetic predisposition to certain neuroendocrine
`tumours has generated much interest, particularly with
`advanced techniques facilitating the identification of
`mutated genes. Similarly, with analysis of gene expression
`microarray profiles and multivariate analysis of complex
`traits (Phillips & Belknap 2002), important information
`can be used to prognosticate and risk stratify patients. A
`plethora of genes are known to be involved in neuroendo-
`crine tumorigenesis, including MEN1, RET, VHL, TSC1
`and TSC2 (Calender 2000), with mutations in MEN1
`remaining the most common form of genetic predisposi-
`tion to neuroendocrine tumours. Despite the lack of direct
`evidence, it is likely that neuroendocrine tumorigenesis is
`similar to that of the well-studied colorectal carcinoma
`model of a series of multiple genetic alterations leading to
`activation of oncogenes and/or inactivation of tumour
`suppressor genes and failure of apoptosis (Fearon &
`Vogelstein 1990, Shannon & Iacopetta 2001). Intrigu-
`ingly,
`the exact
`sequence of events
`is crucial
`for
`determining the phenotype, as demonstrated by the effect
`of early loss of Lkb1 in protection against transformation
`in Peutz-Jeghers syndrome (Bardeesy et al. 2002).
`In multiple endocrine neoplasia type 1 (MEN1),
`germline inactivating mutations in the tumour suppressor
`MEN1 gene (chromosome 11q13; Larsson et al. 1988) are
`found in 95% of patients. Somatic mutations of MEN1
`are also found in sporadic cases: 21% of parathyroid
`adenomas, 33% of gastrinomas, 17% of insulinoma, 36%
`of bronchial carcinoid, and 50–70% of sporadic thymic
`and duodenal carcinoid (Jakobovitz et al. 1996, Lubensky
`et al. 1996, Emmert-Buck et al. 1997, Marx et al. 1998,
`1999). The absence of detectable mutations in MEN1 may
`reflect deficiencies of current technology, or that the
`inactivation process is via non-mutation mechanisms such
`
`as methylation in the CpG-rich 50-region of MEN1.
`Indeed, such hypermethylation is found in the VHL
`promoter in von Hippel Lindau (Herman et al. 1994,
`Prowse et al. 1997).
`In keeping with Knudson’s model (Knudson 1971,
`Pannett & Thakker 2001), a two-hit process is required for
`MEN1 tumorigenesis (Larsson et al. 1988, Thakker et al.
`1989, Bystrom et al. 1990). Familial and somatic MEN1
`mutations differ in terms of the former usually presenting
`with tumour expression at an earlier age, multiple organs
`affected, and multiple tumours in one organ (Marx et al.
`1999). Although many mutations have been found in
`MEN1,
`there seems to be poor genotype–phenotype
`correlation (Kouvaraki et al. 2002). The majority of
`patients with familial MEN1 will develop non-functioning
`pancreatic tumours, while 40% will develop gastrinoma,
`10% insulinoma and 2% other functioning pancreatic
`tumours, such as glucagonoma, VIPoma and somatosta-
`tinoma (Marx et al. 1999).
`Based on Fearon and Vogelstein’s (1990) genetic
`model for colorectal tumorigenesis, Fig. 1 illustrates the
`possible pathways from induction to metastases for
`neuroendocrine
`tumours
`(Calender 2000),
`including
`MEN1, MEN2 and phaeochromocytoma.
`
`General markers for neuroendocrine
`tumours
`
`The group of neuroendocrine tumours can be character-
`ized both by general and specific markers, the most
`strikingly consistent general markers being the chromo-
`granins. Other general staining markers include pancrea-
`tic polypeptide, neuron-specific enolase (NSE), peptide
`histidine-methionine and human chorionic gonadotro-
`phin subunits (Tapia et al. 1981, Hamid et al. 1986,
`Yiangou et al. 1987). Chromogranin A (CgA), a secretory
`granule, is located alongside specific hormones in large
`dense-core vesicles of neuronal and neuroendocrine cells.
`Chromogranin B (CgB) is also widely distributed in
`neuroendocrine cells, although CgA seems to be more
`widespread (Winkler & Fischer-Colbrie 1992). Staining
`for
`the
`chromogranins
`in different neuroendocrine
`tumours
`is
`summarized in Table 1 (adapted from
`Taupenot et al. 2003), where CgA seems ubiquitous with
`the exception of the CgB-staining pituitary lactotrophs
`and some pancreatic beta-cell tumours.
`In one study, plasma CgA was elevated in 94% of
`endocrine pancreatic tumours, and pancreatic polypeptide
`in 74% (Eriksson et al. 1990). Elevated CgA levels were
`even more frequent (99%) in malignant carcinoid and
`gastroenteropancreatic tumours (99%) (Stridsberg et al.
`1995), with the highest levels seen in metastatic carcinoid
`(particularly midgut). Plasma CgB (and its 74-amino-acid
`
`2
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`
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`

`

`INITIATION
`
`TRANSFORMATION
`PROLIFERATION
`
`Acetylation
`Methylation
`TGF-α
`
`MALIGNANT EVOLUTION
`
`deficiency in
`MMR
`(mismatch
`repair)
`
`METASTASIS
`
`Normal
`neuroendocrine
`cells
`
`Hyperplastic
`cells
`
`Dysplastic cells
`
`Well differentiated
`tumour
`
`Moderately
`differentiated tumour
`
`Poorly differentiated
`tumour
`
`Metastasis
`
`Endocrine-Related Cancer (2004) 11 1–18
`
`Inactivation of MEN1 (1st hit) VHL, NF1, TSC1, TSC2,
`?3q, ?1q
`
`
`Activation of RET (MEN-2)
`
`Growth factors:
`? NGF, TGF , bFGF, VEGF
`MEN1 (2nd hit)
`
`activation of oncogenes
`e.g. c-myc, K-ras
`
`Large LOHs
`3p-, 1p-, 18q-, 17p-, 8p-
`Loss of tumour suppressors e.g. PTEN
`Loss of apoptosis gene(s)
`Chromosomal instability
`
`Loss of adhesion (CD44, NCAMs)
`Oncogene activation
`?VEGF induction
`? ineffective nm23 (MEN1)
`
`Figure 1 Process of tumorigenesis from initiation to metastatic cancer in neuroendocrine tumours. Based on Calender (2000) and
`Fearon and Vogelstein (1990). Genes: MEN1, multiple endocrine neoplasia type 1; VHL, von Hippel Lindau; NF1, neurofibromatosis
`type 1; TSC1 and TSC2, tuberous sclerosis genes 1 and 2; PTEN, tumour suppressor gene PTEN (‘phosphatase and tensin
`homolog, deleted on chromosome 10’). NGF, nerve growth factor; TGF, transforming growth factor; bFGF, basic fibroblast growth
`factor; VEGF, vasculoendothelial growth factor; NCAM, neural cell adhesion molecule; nm23, tumour metastasis suppressor nm23
`(in MEN1); LOH, loss of heterozygosity.
`
`fragment termed GAWK) is usually a better marker for
`benign insulin-producing tumours (Sekiya et al. 1989,
`Yasuda et al. 1993). Finally, multiple hormones may be
`secreted by some tumours (Wood et al. 1983), and up to
`62% have elevated gastrin despite only 30% presenting
`with peptic ulcer disease.
`
`Although these two categories differ in specific histology
`and location, there are many diagnostic and therapeutic
`similarities between them, and these will be covered in the
`sections below. In general, neuroendocrine tumours are
`slow-growing. The classification into benign and malignant
`depends on various features summarized in Table 2 (Rindi
`et al. 1998).
`
`Specific syndromes
`
`Carcinoid and other gut neuroendocrine
`tumours
`
`Over the last few years, a new classification of neuroendo-
`crine gastroenteropancreatic tumours (GEPs) has been
`developed based on clinicopathologic features (Capella et
`al. 1994, Kloppel & Heitz 1994, Rindi et al. 1998). Tumours
`are termed functioning neuroendocrine tumours according
`to their leading clinical and endocrine profile, while those
`without plasma hormone elevation and lacking endocrine
`symptoms are labelled non-functioning neuroendocrine
`tumours (Taheri & Meeran 2002). In excess of 50% of
`neuroendocrine tumours are of the ’carcinoid’ type, with
`the remainder being mostly pancreatic and including
`insulinomas, gastrinomas, VIPomas and glucagonomas.
`
`Carcinoid
`Mostly derived from serotonin-producing enterochrom-
`affin (EC, or Kulchitsky’s) cells, these tumours termed
`’carcinoid’ have a wide clinical spectrum of presentation
`and symptomatology (McStay & Caplin 2002). Indeed, it
`is felt by some that the term should be made archaic
`because of this wide spectrum (Gilligan et al. 1995). Fewer
`than 10% of patients with carcinoid suffer from the
`classical carcinoid syndrome of flushing, hypotension,
`diarrhoea, wheezing and heart disease. These symptoms
`seem to be related directly to serotonin levels (elevated in
`93–94% of 600 patients with carcinoid syndrome),
`although serotonin can still be elevated in asymptomatic
`individuals (elevated in 25–30% of 7000 asymptomatic
`patients) (Vinik 2001). High serotonin levels seem to
`predict the development of carcinoid heart disease (Moller
`
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`
`3
`
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`
`

`

`Barakat et al.: Neuroendocrine tumours
`
`Table 1 Detection of granins in neuroendocrine tumours. Adapted from Taupenot et al. (2003).
`
`Chromogranin A
`
`Chromogranin B
`
`Secretogranin III
`
`Carcinoid
`Gastrinoma
`Glucagonoma
`Insulinoma
`PPoma
`Somatostatinoma
`VIPoma
`Non-functioning islet cell carcinoma
`
`Corticotrophinoma
`Gonadotrophinoma
`Somatotrophinoma
`Thyrotrophinoma
`Prolactinoma
`Non-functioning pituitary adenoma
`
`Phaeochromocytoma
`
`Parathyroid adenoma
`
`Ganglioneuroblastoma
`Ganglioneuroma
`Neuroblastoma
`Medulloblastoma
`Paraganglioma
`
`Medullary thyroid carcinoma
`
`Prostate tumour with neuroendocrine differentiation
`Breast tumour with neuroendocrine differentiation
`
`ND, not detected.
`
`+
`+
`+
`+
`+
`+
`+
`+
`
`+
`+
`+
`+
`
`+
`
`+
`
`+
`
`+
`+
`+
`+
`+
`
`+
`
`+
`+
`
`+
`+
`+
`+
`ND
`ND
`ND
`ND
`
`+
`+
`+
`+
`+
`+
`
`+
`
`+
`
`ND
`ND
`+
`ND
`+
`
`+
`
`+
`+
`
`+
`ND
`+
`+
`ND
`ND
`ND
`ND
`
`+
`+
`+
`+
`+
`+
`
`+
`
`+
`
`ND
`+
`+
`ND
`+
`
`+
`
`+
`+
`
`et al. 2003). Other carcinoid tumours deriving from the
`gastric histamine-secreting enterochromaffin-like (ECL)
`cells produce an ‘atypical’ carcinoid syndrome. These
`tumours, which have low serotonin levels, frequently
`secrete the serotonin precursor 5-hydroxytryptophan (5-
`HTP). This produces the ‘atypical’ symptoms seen in
`foregut carcinoids with more intense and protracted
`purplish flushing; the limbs as well as the upper trunk
`are often affected and frequently result in telangiectasia
`(Snow et al. 1955, Sandler & Snow 1958, Vinik 2001).
`From the most recent and largest US epidemiology
`series (using the 1992–1999 cohort), the age-adjusted
`incidence of carcinoid tumours varies between 2.47 and
`4.48 per 100 000 population, with the rates being highest
`
`Table 2 The proposed classification into benign, uncertain and
`malignant gastroenteropancreatic tumours (Rindi et al. 1998).
`
`Tumour characteristic
`
`Size of tumour (cm)
`Local spread
`Vascular invasion
`Nuclear atypia
`Gross invasion
`Metastases
`
`Benign
`2
`No
`No
`No
`No
`No
`
`Uncertain Malignant
`
`> 2
`Yes
`Yes
`Yes
`No
`No
`
`> 2
`Yes
`Yes
`Yes
`Yes
`Yes
`
`in black males, then black females, then white Americans
`(Modlin et al. 2003). In this series,
`the population-
`corrected male-to-female ratio for all carcinoid sites was
`0.86, and the average age at diagnosis for all carcinoids
`was 61.4 years (compared with 63.9 years for non-
`carcinoid tumours). Table 3 summarizes the frequency
`of carcinoid at different sites (most occurring in the gut at
`67.5%, then the lung at 25.3%), with the associated 5-year
`survivals. Predisposition to metastatic spread depends on
`location and size (Lauffer et al. 1999, Modlin et al. 2003).
`In addition to the general markers mentioned above,
`the specific markers for carcinoid include urinary 5HIAA,
`neuropeptide K, substance P and other tachykinins.
`Urinary 5-hydroxyindole acetic acid (5HIAA) and neu-
`ropeptide K show high sensitivity in midgut carcinoid,
`with less diagnostic usefulness in foregut and hindgut
`carcinoid (Janson et al. 1997). If a diagnosis of carcinoid is
`suspected with normal baseline urinary testing,
`the
`pentagastrin test with measurements of plasma tachykinins
`is helpful (Norheim et al. 1986).
`
`Non-carcinoid gastroenteropancreatic
`neuroendocrine tumours
`Most of the non-carcinoid gastroenteropancreatic neuro-
`endocrine tumours arise in the pancreas. Making up less
`
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`

`

`Table 3 Carcinoid tumours – relation between site, metastatic potential and 5-year survival. Data from the 1992–1999 cohort
`(Modlin et al. 2003).
`
`Endocrine-Related Cancer (2004) 11 1–18
`
`% of all
`carcinoids
`
`Regional
`metastases
`(%)
`
`Distant
`metastases
`(%)
`
`5-year
`survival with
`no metastases
`(%)
`
`5-year
`survival with
`regional metastases
`(%)
`
`5-year
`survival with
`distant metastases
`(%)
`
`25.3
`
`28.2
`2.4
`7.6
`18.5
`5.9
`1.4
`
`5.2
`
`35.9
`28.9
`25.8
`2.2
`3.1
`5.2
`
`0.5
`
`22.4
`9.9
`29.5
`1.7
`6.5
`0.5
`
`81.1
`
`59.9
`80.8
`76
`90.8
`69.1
`90.9
`
`76.7
`
`72.8
`88.1
`71.6
`48.9
`N/A
`N/A
`
`25.6
`
`50
`9.6
`30
`32.3
`21.2
`28.3
`
`Site
`
`Lung
`Small
`intestine
`Appendix
`Colon
`Rectum
`Stomach
`Ovary
`
`N/A, not available.
`
`than half of all neuroendocrine tumours and only 1–2%
`of all pancreatic tumours, pancreatic neuroendocrine
`tumours (PET) form an important group with a better
`prognosis than non-neuroendocrine tumours. Deriving
`from the diffuse neuroendocrine system of the gut (Polak
`& Bloom 1986a), PETs were formerly classified as
`APUDomas (tumours of the amine precursor uptake
`and decarboxylation system), and can secrete a vast
`number of hormones depending on the cell of origin.
`Physiologically,
`these hormones are involved in an
`intricate network of autocrine, paracrine, endocrine and
`neurotransmitter communication.
`Although the annual incidence of PETs is approxi-
`mately 3.5 to 4 per million population, post-mortem data
`suggests a much higher incidence. Indeed they have been
`detected in 0.3% to 1.6% of unselected autopsies in which
`only a few sections of pancreas were examined, and in up
`to 10% of autopsies in which the whole pancreas was
`systematically inspected (Kimura et al. 1991).
`Depending on whether secreted hormone is detectable
`and associated symptoms are present, gastroenteropan-
`creatic neuroendocrine tumours (GEPs) can be divided
`into ‘functioning’ and ‘non-functioning’ tumours. The
`‘functioning’ tumours may secrete several peptides, only
`some of which may produce symptoms. Similarly, a
`tumour which originally secreted one peptide may de-
`differentiate to co-secrete other peptides. Typically, these
`tumours are slow-growing, and often morbidity is from
`the secreted hormone (or hormones) rather than tumour
`bulk. The presence of a specific endocrine hyperfunction
`syndrome seems to be as important as purely pathological
`features for predicting tumour behaviour (Kloppel &
`Heitz 1988, Solcia et al. 1990) (see Table 4 taken from
`data from Aldridge & Williamson 1993, Arnold et al.
`2000, Schindl et al. 2000, Jensen 2001, Taheri et al. 2001).
`In the case of ‘non-functioning tumours’, it is accepted
`that there may be secreted, but as yet undetectable,
`peptides. These non-functioning tumours tend to be more
`
`aggressive and often present after metastasizing with
`symptoms of tumour bulk (Legaspi & Brennan 1988).
`The following are specific markers for functioning
`non-carcinoid GEPs: fasting hormones such as gastrin,
`glucagon, pancreatic polypeptide, somatostatin, neuro-
`tensin, and vasoactive intestinal polypeptide (VIP), and
`random parathyroid hormone-related peptide
`levels
`(PTHrP) (with simultaneous calcium and parathyroid
`hormone (PTH) measurements). In the case of gastrin, the
`patient has to be off proton pump inhibitors for at least
`two weeks and off H2-blockers for at least three days.
`Caution, however, is required if the clinical likelihood of
`gastrinoma is high, since there is a high risk of peptic ulcer
`perforation when medical therapy is stopped for the
`gastrin test. Even on proton pump inhibitors, very high
`gastrin levels (> 500 pg/ml or > 250 pmol/l) are indicative
`of gastrinoma, and repeat testing off therapy should not
`be recommended (Ashrafian et al. 2002). Differential
`diagnoses, which include atrophic gastritis, hypercalcae-
`mia and renal impairment, may be excluded by measuring
`basal acid output: spontaneous basal acid outputs of 20 to
`25 mmol/h are almost diagnostic and > 10 mmol/h
`suggestive. If the test results are equivocal, the secretin
`test is helpful: a rise of gastrin (instead of the normal fall)
`in response to intravenous secretin of greater than 200 pg/
`ml
`(100 pmol/l) has a sensitivity of 80–85% for
`gastrinoma (McGuigan & Wolfe 1980, Frucht et al. 1989).
`The dynamic test for the diagnosis of an insulinoma is
`a three-day fast, allowing unlimited non-caloric fluids
`(Service 1995, Service & Natt 2000). Elevated plasma
`insulin and C-peptide levels are diagnostic in the presence
`of hypoglycaemia (glucose below 2.2 mmol/l (40 mg/dl)),
`and this is achieved by 48 h of the fast in > 95% of
`insulinomas (Friesen 1987). If no hypoglycaemia is
`achieved by the end of the fast, the sensitivity can be
`further increased by exercising the patient for 15 min. The
`fast is terminated after the exercise period, or prior to this
`if hypoglycaemia is achieved, with simultaneous plasma
`
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`
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`

`Barakat et al.: Neuroendocrine tumours
`
`Hypoglycaemia
`Weight gain
`Abdominal pain
`Diarrhoea
`Peptic ulceration
`Secretory diarrhoea
`Hypokalaemia
`Achlorhydria
`Metabolic acidosis
`Flushing
`Necrolytic migratory erythema
`Diabetes
`Cachexia
`Thromboembolic disease
`Pain
`Weight loss
`Diarrhoea
`Steatorrhoea
`Diabetes
`Gallstones
`Weight loss
`Classical carcinoid
`Flushing
`Diarrhoea
`Wheeze
`Cardiac fibrosis
`Pellagra dermatosis
`Cushing’s syndrome
`Pigmentation
`Hypercalcaemia
`Nephrolithiasis
`Nephrocalcinosis
`Osteoporosis
`Diarrhoea, flushing
`Acromegaly
`
`Symtoms of tumour bulk
`Weight loss
`
`Glucagonoma
`
`1–2
`
`Pancreas 100%
`
`1–20
`
`> 70
`
`PPoma
`
`<1
`
`Pancreas 100%
`
`Somatostatinoma
`
`<1
`
`Pancreas 55%
`Duodenum + jejunum 44%
`
`Carcinoid
`
`<1 mostly extrapancreatic
`
`Midgut 75–87%
`Foregut 2–33%
`Hindgut 1–8%
`Unknown 2–15%
`
`18–44
`
`45
`
`> 60
`
`> 50
`
`Rare
`
`90
`
`Corticotrophinoma
`CRFoma
`PTHrPoma
`
`<1
`
`<1
`
`Calcitoninoma
`Somatotrophinoma
`
`<1
`
`‘‘Non-functioning’’
`
`<1
`
`Pancreas 4–14% (of all ectopic ACTH)
`
`Rare
`
`Pancreas
`
`Pancreas
`Pancreas 30%
`Lung 54%
`Jejunum 7%
`Pancreas + gastrointestinal tract
`
`Rare
`
`16
`16
`
`18–44
`
`> 99
`
`> 99
`
`> 80
`50
`
`> 80
`
`PPoma, pancreatic polypeptide secreting tumour; CRF, corticotrophin releasing factor.
`
`www.endocrinology.org
`
`6
`
`Table 4 Tumour syndromes of gastrointestinal neuroendocrine tumours (NET). Adapted from Aldridge & Williamson (1993), Arnold et al. (2000), Jensen (2001), Schindl et al.
`(2000) and Taheri et al. (2001). The percentage with MEN1 of each tumour is independent of family history.
`
`Tumour
`
`Insulinoma
`
`Gastrinoma
`
`Frequency of pancreatic
`neuroendocrine tumours (%)
`
`70–75
`
`20–25
`
`VIPoma
`
`3–5
`
`Tumour location
`
`Pancreas > 99%
`
`Duodenum 70%
`Pancreas 25%
`
`Pancreas 90%
`
`% with MEN1
`
`Malignancy (%)
`
`Clinical syndrome
`
`4–5
`
`20–25
`
`6
`
`<10
`
`> 50
`
`> 50
`
`Ex. 1072-0006
`
`

`

`Endocrine-Related Cancer (2004) 11 1–18
`
`Table 5 Imaging modalities for gastroenteropancreatic neuroendocrine tumours.
`
`Somatostatin- receptor- scintigraphy
`
`CT
`
`Endoscopic ultrasound of pancreatic neuroendocrine
`tumours
`
`Visceral angiography
`
`Sensitivity 90% (excluding insulinoma)
`Specificity 80% (excluding insulinoma)
`Sensitivity 10–50% for insulinoma
`
`Useful preoperatively for localizing tumours, but difficulty detecting
`tumours <1 cm
`Sensitivity of 29% in one study for detecting pancreatic insulinoma
`compared with endoscopic ultrasound
`
`Sensitivity 80–90%
`Most sensitive for detecting insulinomas (94%)
`Smallest lesion detectable 5 mm in pancreatic head
`Lower sensitivities for extrapancreatic tumours (50%)
`
`Helpful for subcentimetre tumours, where a tumour blush is seen
`Futhermore, can be combined with calcium stimulation in
`individual pancreatic arteries with venous sampling from the hepatic
`vein (see text for details)
`
`MRI
`
`In general no more helpful than CT
`
`Positron emission tomography with 11C-serotonin
`precursor 5-HTP instead of 18F-deoxyglucose
`
`Selective uptake in carcinoid with high resolution allowing liver
`and lymph node lesion detection
`
`Intraoperative ultrasound for pancreatic tumours
`
`Additional invaluable information for the surgeon operating on the
`delicate pancreas
`
`Intraoperative gamma probes with somatostatin
`analogue (111InDTPA-D-Phe1)-pentetreotide tracer
`
`Recently introduced, allows detection of lesions <5 mm and
`identified 57% more lesions than the ‘‘palpating finger’’
`
`MIBG for gastroenteropancreatic neuroendocrine tumours
`
`Very few gastroenteropancreatic tumours take up MIBG, since
`they derive from endoderm and not neuroectoderm
`
`and urine samples for sulphonylurea analysis, which must
`be shown to be negative for the diagnosis of insulinoma
`(Todd & Bloom 2002). Finally, the reader needs to be
`aware of the various insulin assays: the competitive and
`increasingly used two-site noncompetitive immunoassays.
`The main problems relate to the variable specificity, with
`some detecting proinsulin, the interference from insulin-
`degrading enzymes
`in haemolysed samples and the
`presence of anti-insulin antibodies (Sapin 2003)
`
`Radiological localization of carcinoid and other gut
`neuroendocrine tumours
`The Delphi consensus has recently been published for
`standardizing the diagnostic imaging of neuroendocrine
`(Ricke et al. 2001). Somatostatin receptor
`tumours
`scintigraphy (SRS)
`forms
`the mainstay of
`imaging
`techniques, with a sensitivity of up to 90% and specificity
`of 80% (Krenning et al. 1993, Lebtahi et al. 1997,
`Termanini et al. 1997, Kwekkeboom & Krenning 2002),
`although only 10 to 50% of insulinomas are SRS-positive
`(Modlin & Tang 1997, Warner & O’dorisio 2002). Table 5
`summarizes the different modalities and their usefulness,
`including computed tomography (CT), endoscopic ultra-
`sonography (EUS) (Lightdale et al. 1991, Glover et al.
`1992, Palazzo et al. 1992, Rosch et al. 1992, de Kerviler et
`al. 1994, Thompson et al. 1994, Ruszniewski et al. 1995,
`Zimmer et al. 2000), positron emission tomography
`
`(Eriksson et al. 2000, 2002, Warner & O’dorisio 2002),
`intraoperative ultrasound and intraoperative gamma
`probes with the tracer (111)In DTPA-D-Phe1-pentetreo-
`tide (Adams & Baum 2000). Given that GEPs derive from
`endoderm and not catecholamine-producing neuroecto-
`derm, there is little place for 131I-metaiodobenzyl-guani-
`dine (MIBG) in GEP imaging (European Neuroendocrine
`Tumour Network (ENET) 2000).
`With pancreatic tumours, the surgeon requires as much
`information regarding location as possible. Selective
`angiography with secretagogue injection into the main
`pancreatic arteries allows biochemical
`in addition to
`angiographic localization. In this procedure, the main
`pancreatic arteries (gastroduodenal, superior mesenteric,
`inferior pancreaticoduodenal and splenic) are cannulated
`separately and examined for a tumour blush. A secretago-
`gue (calcium has taken the place of secretin; Turner et al.
`2002) is injected into each of these arteries individually, and
`venous samples are collected from the hepatic vein for
`biochemical analysis of
`the suspected hypersecreted
`hormone (e.g. gastrin or insulin). In the presence of a
`tumour, the hormone levels double after 30 s, whereas the
`normal effect is a reduction in levels (Doppman et al. 1990,
`1991, Fedorak et al. 1993, Goldstone et al. 1996, O’Shea et
`al. 1996). The tremendous advantage of this technique is
`that it allows biochemical localization of the tumour (e.g. a
`very small
`insulinoma) even if the radiology appears
`
`www.endocrinology.org
`
`7
`
`Ex. 1072-0007
`
`

`

`Barakat et al.: Neuroendocrine tumours
`
`Table 6 The specific medical treatments for some neuroendocrine tumour syndromes.
`
`Hypersecretion syndrome
`
`Medical therapy
`
`Carcinoid
`
`Insulinoma
`
`Gastrinoma
`
`Glucagonoma
`
`VIPoma
`
`Somatostatinoma
`
`PTHrPoma
`
`Somatostatin analogue for SRS positive carcinoid
`Interferon- for SRS negative carcinoid
`Histamine antagonists (H1 and H2)
`Cyproheptadine, nicotinamide
`
`Frequent slow-release complex carbohydrate intake
`Guar gum
`Diazoxide
`Intravenous dextrose if period of fasting
`Somatostatin analogue if SRS positive (usually malignant)
`
`High dose proton pump inhibitor (life-long in patients with MEN1, since high recurrence
`rate with surgery)
`
`High dose somatostatin analogue
`Anticoagulation since associated with thrombophilia
`Insulin for diabetes mellitus
`
`High dose somatostatin analogue
`Aggressive intravenous rehydration in acute attack of diarrhoea
`Potassium + bicarbonate in acute attacks
`
`Pancreatic enzyme supplementation
`Insulin for diabetes mellitus
`
`High dose somatostatin analogue
`Intravenous rehydration
`Bisphosphonates for often life-threatening hypercalcaemia
`Somatostatin analogue
`
`Non-functioning
`
`Somatostatin analogue if SRS scan positive and progressive disease
`
`normal. Furthermore, with MEN1, different tumours may
`co-exist, and this technique will help to distinguish them
`biochemically. Finally, and perhaps the procedure’s great-
`est advantage is that it allows the detection of liver
`metastases, since the hepatic artery is always cannulated
`at the end of the procedure and a rise in hormone levels
`detectable in the hepatic vein after calcium injection into
`the hepatic artery is diagnostic of liver metastases.
`
`Medical treatment
`Until curative surgical treatment is performed, or if
`surgery is not indicated, medical treatment has to be
`initiated for symptom control. Table 6 summarizes the
`medical
`treatments
`for
`the various hypersecretion
`syndromes. The greatest impact for control of symptoms
`has been afforded by the somatostatin analogues in
`SRS-scan positive tumours, and it
`is known that
`somatostatin immunoreactivity is often found in neuro-
`endocrine tumours (Polak & Bloom 1986b). There are
`five somatostatin receptors (sstr1–5), but
`the longer-
`acting
`analogues,
`lanreotide
`and octreotide, bind
`preferentially to sstr2 and to a lesser extent to sstr5
`(Patel & Srikant 1994, Reisine & Bell 1995, de Herder &
`Lamberts 2002). The effectiveness of these analogues at
`reducing hormone production and tumour stabilization
`(Arnold et al. 1996, di Bartolomeo et al. 1996, Eriksson
`
`et al. 1997, Faiss et al. 1999) has been attributed to the
`sstr2 receptor (Patel & Srikant 1994, Buscail et al. 1995,
`Reisine & Bell 1995, Wulbrand et al. 1998). Given the
`low sensitivity of SRS imaging for insulinomas, it is not
`surprising that only 50% of insulinomas express sstr2
`(Wulbrand et al. 1998), and it therefore follows that
`long-acting somatostatin analogues benefit only those
`with
`sstr2-positive
`tumours.
`In
`‘non-functioning’
`tumours, somatostatin analogues are beneficial where
`the SRS scan is positive and there is evidence of tumour
`progression or high mitotic rate (European Neuroendo-
`crine Tumour Network (ENET) 2000). An exciting
`prospect
`in this field is
`the development of new
`somatostatin analogues that have differing specificities
`to the various somatostatin receptors,
`improving their
`therapeutic effectiveness
`in tumours
`that
`lack,
`for
`instance, sstr2. Until these are available, for progressive
`SRS-negative (i.e. sstr2/5 negative) carcinoid tumours,
`interferon-alpha should be the treatment of choice.
`
`Interferon-alpha and chemotherapy for gut
`neuroendocrine tumours
`Interferon-alpha has been used in the treatment of
`carcinoid for some time (Oberg et al. 1983) to control
`hormone secretion, symptoms and tumour growth. Many
`trials looking at its effectiveness in malignant and mostly
`
`8
`
`www.endocrinology.org
`
`Ex. 1072-0008
`
`

`

`Endocrine-Related Cancer (2004) 11 1–18
`
`Table 7 Non-medical treatment options for gastroenteropancreatic neuroendocrine tumours.
`
`Non-medical treatment
`
`Effectiveness
`
`Curative surgery
`Resection of primary
`Resection of resectable liver metastases
`Liver transplantation
`Hepatic arterial embolization
`
`Chemotherapy with hepatic arterial occlusion
`
`Hepatic chemoembolization
`
`Hepatic radioembolization
`
`Hepatic cryosurgery
`
`Palliative surgery
`
`Radio-labelled somatostatin analogues
`
`Best option if feasible
`Often pancreatic insulinomas can be enucleated easily
`70–80% 4–5 year survival with curative surgery
`In highly selected cases can improve survival
`Most effective for liver metastases from functioning neuroendocrine tumours
`producing symptoms. Significant reduction in symptoms (40–90%)
`Difficult to com