ENETS Guidelines
`
` Neuroendocrinology 2004;80:394–424
` DOI: 10.1159/000085237
`
` Published online: April 18, 2005
`
` Guidelines for the Diagnosis and
`Treatment of Neuroendocrine
`Gastrointestinal Tumours
`
` A Consensus Statement on Behalf of the European Neuroendocrine
`Tumour Society (ENETS)
`
` U. Plöckinger a G. Rindi b R. Arnold c B. Eriksson d E.P. Krenning e
`W.W. de Herder f A. Goede g M. Caplin g K. Öberg h J.C. Reubi i O. Nilsson j
`G. Delle Fave k P. Ruszniewski l H. Ahlman m B. Wiedenmann a
`
` a
` Department of Hepatology and Gastroenterology, Interdisciplinary Center for Metabolism, Endocrinology, and
`
`Diabetes, Charité-Universitätsmedizin Berlin, Berlin , Germany; b
` Department of Pathology, University of Parma,
` Section for Endocrine Parma , Italy; c Department of Gastroenterology, Philipps-Universität, Marburg , Germany; d
`
`
`Oncology, Department of Medical Sciences, University Hospital, Uppsala , Sweden; e
` Department of Nuclear
`Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands; f
` Department of Internal Medicine,
`
`
`Erasmus University Medical Center, Rotterdam , The Netherlands; g Royal Free Hospital, London , UK; h Uppsala
`University, Department of Endocrine Oncology, Uppsala , Sweden; i
` University of Bern, Institute of Pathology,
` Ospedale S. Andrea, Bern , Switzerland; j Sahlgrenska sjukhuset, Department of Pathology, Gothenburg , Sweden; k
`
`
`Department of Gastroenterology, Rome , Italy; l
` Hôpital Beaujon, Department of Gastroenterology, Clichy , France,
`and m
` Department of Surgery, Gothenburg University, Gothenburg, Sweden
`
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` Key Words
` Neuroendocrine tumour ⴢ Diagnosis ⴢ Histopathology ⴢ
`Surgery ⴢ Cytoreductive surgery ⴢ Biotherapy ⴢ
`Chemotherapy ⴢ Radioreceptor therapy
`
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` © 2004 S. Karger AG, Basel
` 0028–3835/04/0806–0394$21.00/0
`
`Fax +41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
` Accessible online at:
` www.karger.com/nen
`
` Ursula Plöckinger
` Department of Hepatology and Gastroenterology, Interdisciplinary Center for Metabolism,
` Endocrinology and Diabetes, Charité-Universitätsmedizin Berlin
` Campus Virchow-Klinikum, Augustenburger Platz 1, D–13353 Berlin (Germany)
` Tel. +49 30 450 553 552, Fax +49 30 450 7553 552, E-Mail ursula.ploeckinger@charite.de
`
`ARGENTUM
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` Introduction
` G. Rindi
`
`
` The endocrine tumours of the gastrointestinal tract
`have been attracting the attention of clinicians since their
`very fi rst identifi cation, which paralleled the identifi ca-
`tion of gut endocrine cells.
` The history of enteroendocrine cells and derived tu-
`mours begins with the early development of histology and
`histochemistry, dating back to the end of the 19th cen-
`tury. Unusual cells of gastric [1] and intestinal mucosa
` [2–4] attracted the attention of scientists and, due to their
`chromium salt affi nity [4] , were named enterochromaffi n
`cells [5] . Cells with similar properties were observed in
`other sites of the body [6] and were suggested to be part
`of a complex system exerting a local, ‘paracrine’, action
`via production and secretion of peptides or amines [7] .
`This concept was further revived and supported in the
`1960s by the identifi cation in some of these cells of the
`property of taking up amine precursors which are then
`transformed into amines by intracellular decarboxylation
` [8] .
` At the same time, a non-conventional, epithelial slow-
`growing tumour was identifi ed and defi ned as ‘karzinoide’
`(carcinoid, i.e. carcinoma-like) by Öberendorfer [9] . Some
`of these tumours were then shown to display argentaffi n
`properties [10] , thus establishing a relationship with en-
`terochromaffi n cells [11] .
` As many as 15 highly specialized epithelial cells of en-
`dodermal origin compose the diffuse endocrine system
`(DES) of the gut [12] and are considered the source of gut
`carcinoids and of tumours of the endocrine pancreas.
` Gut DES cells and derived tumours express several
`antigens shared with nerve elements, usually defi ned as
`‘neuroendocrine markers’ [13] . This phenomenon pro-
`vides reason for the term ‘neuroendocrine’ which is wide-
`ly used to connote DES cells and their tumours. The neu-
`roendocrine markers comprise neuron-specifi c enolase
`(NSE) and protein gene product 9.5 (PGP 9.5) [14, 15]
`located in the cytosol, the chromogranins (A, B and C or
`secretogranin) associated with electron-dense granules
` [16, 17] and synaptophysin within small synaptic-like
`vesicles [18, 19] .
` The remarkable heterogeneity of the endocrine cells of
`the gut [20] compose the complexity of derived tumours.
`Besides neuroendocrine markers, multiple hormones are
`in fact produced and, in some instances, also released in
`the bloodstream to determine a hyperfunctional syn-
`drome.
`
` Many attempts have been made in the past few de-
`cades to uniformly classify, diagnose and treat gut endo-
`crine tumours. Unfortunately, because of their rarity, no
`structured practice for diagnosis and therapy has been
`developed, despite increasing knowledge and awareness
`of the subject. The recent introduction of a more struc-
`tured classifi cation of tumours of the diffuse endocrine
`system by the World Health Organisation [21] inspired
`an effort to develop common diagnostic and treatment
`guidelines within Europe. As members of the European
`Neuroendocrine Tumour Society (ENETS), a group of
`clinicians became involved in the study of neuroendo-
`crine tumours and in the treatment of affected patients.
`The following papers are the result of this common effort
`and represent an organized attempt to give evidence-
`based information on this subject.
`
` References
` 1 Heidenhain R: Untersuchungen über den Bau der Labdrüsen. Ark Mik-
`rosk Anat 1870; 6: 368–406.
` 2 Nicolas A: Recherches sur l’épithélium de l’intestine grêle. Int Mschr Anat
`Physiol 1891; 8: 1–8.
` 3 Kultschitzky N: Zur Frage über den Bau des Darmcanals. Arch Mikrosk
`Anat 1897; 49: 7–35.
` 4 Schmidt JE: Beiträge zur normalen und pathologischen Histologie einiger
`Zellarten der Schleimhaut des menschlichen Darm-Kanals. Arch Mikrosk
`Anat 1905; 66: 12–40.
` 5 Ciaccio C: Sur une nouvelle espèce cellulaire dans les glandes de Lieber-
`kühn. CR Soc Biol (Paris) 1906; 60: 76–77.
` 6 Feyrter F: Über diffuse endokrine epitheliale Organe. Leipzig Zentr Inn
`Mediz 1938; 29: 545–571.
` 7 Feyrter F: Über die peripheren endokrinen (parakrinen) Drüsen des Men-
`schen. Wien, Maudrich, 1953.
` 8 Pearse AGE: Common cytochemical properties of cells producing poly-
`peptide hormones, with particular reference to calcitonin and C-cells. Vet
`Rec 1966; 79: 303–313.
` 9 Öberendorfer S: Karzinoide Tumoren des Dünndarms. Frankf Z Pathol
`1907; 1: 426–432.
` 10 Gosset A, Masson P: Tumeurs endocrine de l’appendice. Presse Médicale
`1914; 25: 237.
` 11 Masson P: Carcinoid (argentaffi n-cell tumours) and nerve hyperplasia of
`the appendicular mucosa. Am J Pathol 1928; 4: 181–212.
` 12 Solcia E, Capella C, Fiocca R, Sessa F, LaRosa S, Rindi G: Disorders of
`the endocrine system; in Ming SC, Goldman H (eds): Pathology of the
`Gastrointestinal Tract. Philadelphia, Williams & Wilkins, 1998, pp 295–
`322.
` 13 Bishop AE, Power RF, Polak JM: Markers for neuroendocrine differen-
`tiation. Pathol Res Pract 1988; 183: 119–128.
` 14 Bishop AE, Polak JM, Facer P, Ferri GL, Marangos PJP, Pearse AGE:
`Neuron specifi c enolase: A common marker for the endocrine cells and
`innervation of the gut and pancreas. Gastroenterology 1982; 83: 902–915.
` 15 Rode J, Dhillon AP, Doran JF, Jackson P, Thompson RJ: PGP 9.5, a new
`marker for human neuroendocrine tumours. Histopathology 1985; 9: 147–
`158.
` 16 Lloyd RV, Wilson BS: Specifi c endocrine tissue marker defi ned by a mono-
`clonal antibody. Science 1983; 222: 628–630.
` 17 Rindi G, Buffa R, Sessa F, Tortora O, Solcia E: Chromogranin A, B and
`C immunoreactivities of mammalian endocrine cells. Distribution, dis-
`tinction from costored hormones/prohormones and relationship with the
`argyrophil component of secretory granules. Histochemistry 1986; 85: 19–
`28.
`
` Management of Neuroendocrine
`Gastrointestinal Tumours
`
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` 18 Jahn R, Schiebler W, Ouimet C, Greengard P: A 38,000-dalton membrane
`protein (p38) present in synaptic vesicles. Proc Natl Acad Sci USA 1985;
` 82: 4137–4141.
` 19 Wiedenmann B, Franke WW, Kuhn C, Moll R, Gould VE: Synaptophysin:
`A marker protein for neuroendocrine cells and neoplasms. Proc Natl Acad
`Sci USA 1986; 83: 3500–3504.
` 20 Rehfeld JF: The new biology of gastrointestinal hormones. Physiol Rev
`1998; 78: 1087–1108.
` 21 Solcia E, Klöppel G, Sobin LH: Histological Typing of Endocrine Tu-
`mours. New York, Springer, 2000.
`
`include hypoglycaemia, VIPoma, and glucagonoma syn-
`drome. Most tumours are initially non-functioning. Ge-
`netic screening for MEN-1 should be offered to family
`members. Those with genetic lesions should be followed
`annually for detection of parathyroid disease, pituitary,
`pancreatic and other tumours [1–4] .
`
`
`
`
`
` Management of Endocrine Foregut
`Tumours
` B. Eriksson
`
`
`
` I. Introduction
`
` Endocrine foregut tumours include tumours originat-
`ing in the stomach, duodenum, pancreas, lung and thy-
`mus. For practical reasons, lung and thymic tumours are
`not included in these recommendations.
` From a clinical viewpoint, endocrine foregut tumours
`can be divided into functioning tumours, associated with
`hormonal symptoms and non-functioning tumours, not
`associated with any hormonal symptoms. Most endo-
`crine tumours are well-differentiated, non-functioning,
`and slowly growing. Some tumours are poorly differenti-
`ated small cell endocrine carcinomas that are rapidly
`growing and have a poor prognosis. The possibility of the
`endocrine tumour being part of a familiar, genetic dis-
`ease, i.e. multiple endocrine neoplasia type 1 (MEN-1),
`should be excluded.
` Comments: MEN-1 is associated with hyperparathy-
`roid hyperplasia/hyperparathyroidism, pancreatic endo-
`crine tumours, pituitary adenomas, thymic, gastric and
`bronchial carcinoids, adrenocortical hyperplasia, and
`also skin fi bromas/lipomas. The mean age of clinical di-
`agnosis has been reported to be around 30 years; how-
`ever, in screened families it is about 15 years. The exact
`incidence is not known, but a prevalence of 0.2 has been
`reported; MEN-1 is probably underdiagnosed [1] . A spe-
`cifi c deletion on chromosome 11q13 is the genetic back-
`ground of the disease. The gene encodes a protein called
`menin, which acts as a tumour suppressor [2, 3] .
` The most common clinical syndrome associated with
`MEN-1 and pancreatic or duodenal endocrine tumours
`is the Zollinger-Ellison syndrome (ZES). Other syndromes
`
` Endocrine Tumours of the Stomach
`
` Epidemiology
` The yearly age-adjusted incidence of gastric neuroen-
`docrine tumours has been reported to be around 0.2 per
`100,000 population [5] . The tumours are probably under-
`diagnosed.
`
` Clinicopathological Staging
` As in other sites of the gastrointestinal tract, neuroen-
`docrine tumours of the stomach are categorized into well-
`or poorly differentiated tumours [6, 7] .
` Well-differentiated tumours are the majority. Besides
`the extremely rare gastrin-producing (G), somatostatin-
`producing (D), or serotonin-producing (EC) cell tumours,
`most well-differentiated tumours are mainly, but not ex-
`clusively, composed of enterochromaffi n-like (ECL) cells
`and are most frequently located in the acidopeptic mu-
`cosa. They are also called ECL-cell carcinoids or ECLo-
`mas and three subtypes of well-differentiated ECL cell
`tumours are recognised [6, 7] .
` Type 1 is the most common NE neoplasm in the whole
`stomach with a relative incidence of 70–85%, and is fre-
`quently small, polypoid, often multiple and usually be-
`nign (WHO group 1). It is secondary to hypergastrinae-
`mia, related to atrophic gastritis (also includes microcar-
`cinoidosis) and is always associated with ECL-cell
`hyperplasia.
` Type 2 is a rare tumour associated with primary hy-
`pergastrinaemia as a manifestation of ZES as part of
`MEN-1. Type 2 tumours appear mostly as multiple be-
`nign polyps (WHO group 1), and are only in exceptional
`cases metastatic (WHO group 2, endocrine carcinoma).
` Type 3 is the second most common NE gastric tumour
`with a relative incidence of 13–20%; it appears sporadi-
`cally without predisposing factors either local (atrophic
`gastritis) or genetic (MEN-1: ZES). It is usually solitary
`and belongs to WHO group 2: Ki-67 1 2%, 1 2 cm in di-
`ameter and infi ltrative growth with metastases both to
`regional lymph nodes and the liver. Less than 5% of these
`tumours can cause the so-called ‘atypical carcinoid syn-
`drome’ due to histamine production.
`
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` Poorly differentiated tumours are highly malignant
`and belong to WHO group 3, i.e. poorly differentiated,
`small-cell, endocrine carcinomas (PDEC). They are rela-
`tively rare and account for ! 5% of endocrine tumours.
`They are probably underestimated since they may resem-
`ble undifferentiated carcinomas. A positive staining for
`synaptophysin may be the only indicator of endocrine
`differentiation.
`
` Prognosis/Survival
` Type 1 occurs most often in women, with no tumour-
`related death at an overall mean follow-up of 53 months
` [8] . Among type 2 tumours there was 1 tumour-related
`death (49 months after diagnosis) and an overall mean
`survival of 84 months. In the same series, type 3 tumours
`had a mean survival of 28 months and poorly differenti-
`ated only 7 months.
`
` Clinical Presentation
` Small gastric carcinoids rarely give rise to symptoms
`and are diagnosed incidentally or in patients with perni-
`cious anaemia [9] . Larger carcinoids may bleed. Occa-
`sionally, patients may complain of fl ush and present the
`‘atypical carcinoid syndrome’. The ‘atypical carcinoid
`syndrome’ includes severe generalized fl ushing, swelling,
`lacrimation, asthma and diarrhoea, caused by histamine
`production from a gastric endocrine tumour type 3.
`
` Diagnostic Procedures
` 1. Tumour Imaging
` Gastroscopy/endoscopic ultrasonography (EUS), ab-
`dominal ultrasound, contrast-enhanced CT or MRT of
`the abdomen and octreotide scintigraphy.
` Comments: Gastroscopy with multiple biopsies from
`tumour and non-tumour tissue is essential for histopath-
`ological diagnosis to distinguish between the different
`types of gastric tumours and also indicating the size and
`location of the primary tumour. It is also important to
`exclude infection with Helicobacter pylori . CT/MRT and
`octreotide scintigraphy are important for staging of the
`disease in type 3 and poorly differentiated tumours.
`
` 2. Biochemical Diagnosis [9]
` Chromogranin A, gastrin, histamine metabolites in
`urine (with appropriate diet). It is also important to de-
`termine the presence of parietal cell antibodies. MEN-1
`should be excluded by determining ionized calcium, PTH
`and possibly also pituitary hormones.
` Comments: Chromogranin A is the most sensitive
`marker for detection of gastric endocrine tumours (not in
`
`type 1 and 2). Measurement of gastrin will reveal atrophic
`gastritis and secondary hypergastrinaemia. If the patients
`present with fl ush in association with a gastric endocrine
`tumour (type 3), measurement of urinary histamine me-
`tabolites is recommended (elevated in 33% of type 1 and
`80% of type 3 gastric carcinoids). MEN-1 should be con-
`fi rmed in gastric endocrine tumours type 2.
`
` 3. Histopathology
` Haematoxylin and eosin, chromogranin, synaptophy-
`sin, Ki-67.
` Comments: If the diagnosis of a well- or poorly differ-
`entiated endocrine tumour is established by routine his-
`topathology including the staining for chromogranin A
`and synaptophysin, additional staining for Ki-67 should
`always be performed to demonstrate the proliferative ca-
`pacity of the tumour. High Ki-67 ( 1 15–20%) indicates
`poor prognosis.
`
` Endoscopic and Surgical Therapy [10]
` 1.1. Curative Therapy
` Type 1 and 2 tumours (atrophic gastritis or MEN-1).
` Polyps ! 1 cm in size: surveillance once per year; 1–6
`polyps and 1 1 cm in size, endoscopic resection after EUS
`and surveillance; 1 6 polyps and 1 1 cm in size, extension
`to muscularis and/or repeated recurrences: alternatively
`surgical resection or antrectomy (reduces gastrin stimula-
`tion from antral G-cells).
` Malignant development or recurrence despite local
`surgical resection: partial or total gastrectomy with lymph
`node dissection.
` Type 3 and poorly differentiated tumours: partial or
`total gastrectomy with lymph node dissection as recom-
`mended for adenocarcinomas.
`
` Cytoreductive Therapy (Type 3 and Poorly
`Differentiated Tumours)
` There are very few reports on the results with liver
`embolization (not recommended in histamine-produc-
`ing tumours) and radiofrequency (RF) ablation in gastric
`endocrine tumours.
`
` Medical Therapy
` 1. Biotherapy
` 1.1. Somatostatin analogues: In the case of multiple
`ECLomas with atrophic gastritis or ZES/MEN-1, soma-
`tostatin analogues have been shown to induce regression
`of gastric tumours, type 1 and 2 [11] . This scheme, how-
`ever, is not recom mended.
`
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`Gastrointestinal Tumours
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` 1.2. Interferon: Can be tried in disseminated type 2
`and 3 tumours. Experience is limited [9] .
`
` 2. Systemic Chemotherapy
` Chemotherapy should only be used in metastatic dis-
`ease (mainly type 3 and poorly differentiated tumours).
`The combination of streptozotocin (STZ) plus 5-fl uoro-
`uracil (5-FU)/doxorubicin is recommended in less aggres-
`sive tumours and cisplatin/carboplatin plus etoposide in
`poorly differentiated tumours. There are few reports in
`the literature and experience is limited.
`
` Endocrine Tumours of the Duodenum
`
` Epidemiology
` The age-adjusted annual incidence is ! 0.1 per 100,000
`individuals [5] .
`
` Clinicopathological Staging
` According to WHO indications, tumours of the duo-
`denum and upper jejunum are classifi ed together [12] .
` Well-differentiated tumours – carcinoids – are the
`majority. Most of them are mainly, but not exclusively,
`composed of gastrin-producing (G), somatostatin-pro-
`ducing (D) or serotonin-producing (EC) cells. They may
`be either benign and of uncertain behaviour (WHO
`group 1), or low-grade malignant (WHO group 2, carci-
`noma). G-cell tumours are preferentially located in the
`proximal duodenum when non-functioning. When func-
`tioning (gastrinomas) may be found at any site in the
`duodenum and jejunum and are usually multiple when
`associated with MEN-1. D-cell tumours are usually non-
`functioning and may be associated with neurofi broma-
`tosis (Recklinghausen’s disease). Serotonin cell tumours
`are rare. Gangliocytic paragangliomas are observed in
`the ampullary region, are usually benign and only excep-
`tionally low-grade malignant with metastases composed
`of the epithelial component only. Poorly differentiated
`carcinomas belonging to WHO group 3 (small-cell, poor-
`ly differentiated endocrine carcinomas) are relatively
`rare, highly malignant carcinomas of the ampullary re-
`gion.
`
` Prognosis/Survival
` Five-year survival rate for localized disease is 66%,
`regional disease 28%, distant metastases 17%, and all
`stages 51% [5] .
`
` Clinical Presentation
` The majority of patients presenting with dyspepsia are
`diagnosed with duodenal ulcer. In an occasional patient
`anaemia may be a result of bleeding. Most patients are
`diagnosed incidentally.
`
` Diagnostic Procedures
` 1. Tumour Imaging
` Endoscopy, EUS, contrast-enhanced CT or MRT of
`the abdomen, octreotide scintigraphy.
` Comments: Endoscopy with biopsy is essential for his-
`topathological diagnosis to distinguish between the dif-
`ferent types of duodenal tumours also indicating the size
`and location of the primary tumour. CT/MRT and oc-
`treotide scintigraphy are important for staging.
`
` 2. Biochemical Diagnosis
` Chromogranin A, further determination according to
`the clinical picture: gastrin, calcitonin, somatostatin, uri-
`nary 5-HIAA twice (24 h) with appropriate diet.
` Comments: Chromogranin A is the most reliable tu-
`mour marker in endocrine duodenal tumours. The levels
`of other tumour markers will vary depending on the type
`of tumour. Patients with suspected Recklinghausen’s dis-
`ease or ZES secondary to MEN-1 should have an extend-
`ed biochemical work-up.
`
` 3. Histopathology
` Haematoxylin and eosin, chromogranin A, synapto-
`physin, S-100 (gangliocytic paragangliomas only), Ki-67,
`gastrin, somatostatin, serotonin or other hormones, if re-
`quired by the clinical setting.
` Comments: The diagnosis of an endocrine tumour
`should be demonstrated by routine histopathology in-
`cluding stainings for chromogranin A and synaptophysin.
`The staining for specifi c hormones will help to establish
`the type of duodenal tumour and the determination of
`Ki-67 the proliferation rate.
`
` Surgical Therapy
` 2.1. Curative Surgical Therapy
` Small duodenal tumours may be locally resected by
`endoscopy or surgery. Patients with larger tumours should
`undergo pancreatico-duodenal resection (Whipple’s pro-
`cedure). Tumours located in the distal duodenum should
`be removed by duodenal resection.
`
` 2.2. Palliative Surgery
` Similarly as in other types of endocrine tumours, de-
`bulking of liver metastases should be considered.
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` Cytoreductive Therapy
` Research on cytoreductive therapy in endocrine duo-
`denal tumours is sparse but should be performed in ac-
`cordance with principles applied in other endocrine gas-
`trointestinal tumours. Ablative therapy may be consid-
`ered.
`
` Medical Therapy
` 1. Biotherapy
` 1.1. Somatostatin analogues: somatostatin analogues
`can be used in patients with hormonal symptoms. Expe-
`rience is limited.
` 1.2. Interferon: Interferon can be attempted in pa-
`tients with disseminated disease. However, experience is
`limited.
`
` 2. Systemic Chemotherapy
` Chemotherapy should only be used in metastatic dis-
`ease (depending on tumour proliferation). The combina-
`tion of STZ and 5-FU/doxorubicin is recommended in
`tumours with low to moderate proliferation and cisplatin/
`carboplatin plus etoposide in poorly differentiated tu-
`mours.
` In gastrin-producing tumours, proton pump inhibitors
`should be used to control acid-related symptoms.
`
` Endocrine Tumours of the Pancreas
`
` Epidemiology
` The incidence of clinically detected tumours has been
`reported to be 4–12 per million inhabitants, which is
`much lower than what is reported from autopsy series
`(about 1%) [5, 13] .
`
` Clinicopathological Staging [12, 14, 15]
` Well-differentiated tumours are the large majority of
`which the two largest fractions are insulinomas (about
`40% of cases) and non-functioning tumours (30–35%).
`When confi ned to the pancreas, non-angioinvasive, ! 2 cm
`in size, with ! 2 mitoses per 10 high-power fi eld and ! 2%
`Ki-67 proliferation index these tumours are classifi ed as
`of benign behaviour (WHO group 1) and, with the notable
`exception of insulinomas, are non-functioning.
` Tumours confi ned to the pancreas but 1 2 cm in size,
`with angioinvasion and/or perineural space invasion, or
` 1 2 cm in size, 1 2 mitoses per 20 high-power fi eld or
` 1 2% Ki-67 proliferation index, either non-functioning or
`functioning (gastrinoma, insulinoma, glucagonoma, so-
`mastatinoma or with ectopic syndromes, such as Cush-
`
`ing, hyperkalaemia or acromegaly) still belong to the
`WHO group 1 but are classifi ed as tumours with uncer-
`tain behaviour. The presence of unquestionable signs of
`malignancy like metastases or invasion of nearby struc-
`tures identifi es low-grade malignant carcinomas (WHO
`group 2).
` Poorly differentiated, small-cell carcinomas are rare
`high-grade malignant carcinomas (WHO group 3), pre-
`senting with distant metastases, and display solid struc-
`ture with necrosis, high mitotic/Ki-67 proliferation index
`and frequent hyperexpression/accumulation of p53.
`
` Prognosis/Survival
` The 5-year survival rate was reported to be 60–100%
`for localized disease, 40% for regional disease, 29% for
`distant metastases, and 80% for all stages [5, 13] . In a pub-
`lication from 1993 [16] , the 5-year survival rate for ad-
`vanced EPT approached 60 months from diagnosis.
`
` Clinical Presentation
` Endocrine pancreatic tumours are classifi ed according
`to clinical symptoms into functioning and non-function-
`ing tumours. The non-functioning tumours [17] , i.e. the
`hormonally silent tumours, constitute the largest group,
`about 50%. Next in incidence are the insulinomas [18,
`19] and gastrinomas [20, 21] , constituting about 25 and
`15%, respectively. VIPomas [22, 23] , glucagonomas [24,
`25] , somatostatinomas [26, 27] constitute the remaining
`15%. Patients with malignant tumours may present with
`mixed syndromes, or the tumours may change clinically
`over time (for details, see references).
` Endocrine pancreatic tumours can occur at any age
`with an equal sex distribution. About 15–30% of patients
`have MEN-1. In MEN-1 patients, multiple tumours occur
`syn- or metachronously [1] . MEN-1 pancreatic tumours
`are usually non-functioning in early ages and then after
`the age of 40 may turn into gastrinomas or other function-
`ing tumours. In von Hippel-Lindau’s disease the endo-
`crine pancreatic tumours are usually non-functioning.
`
` Diagnostic Procedures
` 1. Tumour Imaging
` Ultrasonography, EUS, contrast-enhanced CT or
`MRT of the abdomen, MR-angiography for surgical deci-
`sion-making, octreotide scintigraphy.
`
` Comments
` EUS combined with biopsies in experienced hands is
`the most sensitive method to detect pancreatico-duode-
`nal tumours [28] . US, CT and MRI can also be used to
`
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`Gastrointestinal Tumours
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`detect the primary tumours and metastases [29] . Octreo-
`tide scintigraphy is a routine investigation for both pri-
`mary tumours and metastases [30, 31] . However, smaller
`tumours, especially insulinomas, can be diffi cult to visu-
`alize with this method and intraoperative ultrasonogra-
`phy is still the most sensitive method [32] .
` According to Gibril and Jensen [31] , US can detect
`9%, CT 31%, MRI 30%, angiography 28%, and octreotide
`scintigraphy 58% of possible primary gastrinomas. The
`sensitivities for detection of histopathologically proven
`liver metastases with the different methods are the fol-
`lowing: US 46%, CT 42%, MRI 71%, angiography 62%,
`and octreotide scintigraphy 92%, respectively. (For detec-
`tion of intra- and extrahepatic lesions: US 19%, CT 38%,
`MRI 45%, angiography 40%, and octreotide scintigraphy
`70%.) In conclusion, octreotide scintigraphy has a sensi-
`tivity that exceeds the combination of the others. PET
`with 5-HTP or L -dopa can be an option for detection of
`small tumours [33] .
`
` 2. Biochemistry
` Chromogranin A, insulin, C-peptide, pro-insulin, gas-
`trin, VIP, glucagon, calcitonin, somatostatin.
`
` Comments
` Chromogranin A is a general tumour marker, which is
`increased in almost all different types of endocrine pancre-
`atic tumours [13] . Another general tumour marker is PP,
`which can be elevated in non-functioning tumours but also
`in functioning tumours. For each tumour type, character-
`istic clinical symptoms should lead to measurement of spe-
`cifi c markers such as gastrin, insulin, VIP, glucagon, and
`somatostatin [13] . To establish the diagnosis of insulinoma
`a 12- to 72-hour fast is recommended; a glucagon test may
`also be informative [18, 19] . For the diagnosis of gastri-
`noma, measurement of basal and maximal gastric acid out-
`put is recommended to exclude secondary hypergastrinae-
`mia [20, 34] . A secretin test may support the diagnosis.
`Determination of pituitary hormones, ionized calcium
`and PTH is included in MEN-1 screening [35] . For early
`detection of pancreatic involvement in MEN-1, a meal
`stimulation test with measurements of PP and gastrin can
`be performed. For genetic testing, see Introduction.
`
` 3. Histopathology [14, 36, 37]
` Haematoxylin and eosin, chromogranin A, synapto-
`physin, specifi c hormones (insulin, gastrin, etc.), Ki-67.
`
` Comments
` See previous chapter.
`
` Surgical Therapy
` 1.1. Curative Surgical Therapy of Primary Tumours
` The indications for surgery depend on clinical symp-
`toms, tumour size and location, malignancy and meta-
`static spread. There is a general consensus that curative
`surgery should be aimed for also in metastatic disease,
`including ‘localized’ metastatic disease to the liver [10] .
`Preoperative procedures should include exploration of
`the whole abdominal cavity, intraoperative ultrasonogra-
`phy of pancreas and liver, and transillumination of the
`duodenum in ZES [10, 38–40] . The type of surgical pro-
`cedure depends on the location of the tumour: pancre-
`atico-duodenal resection (Whipple’s operation), distal
`pancreatic resection, tumour enucleation, enucleation in
`combination with resection. If malignancy is suspected,
`lymph node dissection is mandatory.
`
` Comments
` Since the vast majority of insulinomas are benign,
`patients with insulinomas can undergo surgery. Most
`patients are cured by enucleation or pancreatic resec-
`tion. Similarly, surgery is the only treatment that can
`cure gastrinomas. With the knowledge, that most gastri-
`nomas are localized in the pancreatic head or duode-
`num, radical operation may be feasible (Whipple’s pro-
`cedure and lymph node dissection). In the other tumour
`types, radical surgery is the only treatment for cure, al-
`though it is rarely possible at the time of diagnosis [10,
`38–40] .
` The indications for surgery in MEN-1 patients are
`more controversial, since these patients have tumours in
`other endocrine organs and multiple tumours syn- and/or
`metachronously in the pancreatico-duodenal area. These
`patients are very rarely cured for their pancreatico-duo-
`denal tumour by surgery. Surgery is advocated to avoid
`later development of malignancy (tumours 1 2 cm) in
`both functioning and non-functioning cases [41] . Tu-
`mours in the head of the pancreas should be enucleated
`if possible, distal pancreatic resection for caudally-locat-
`ed tumours and duodenotomy for diagnosis and resection
`of duodenal gastrinoma.
`
` 1.2. Curative Surgery of Liver Metastases [42]
` Resection of liver metastases should always be consid-
`ered both in functioning and non-functioning tumours,
`since progression of tumour disease can be delayed. Com-
`plete resection should be aimed for. The type of surgery
`depends on the location of the metastases. The following
`procedures can be chosen: enucleation, one or more seg-
`mental resections, hemihepatectomy or extended hemi-
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`hepatectomy. Intraoperative ultrasonography should be
`performed for detection of all liver metastases.
`
` Comments
` Metastatic disease should be confi ned to the liver. Sur-
`gery should be undertaken only if 90% of the tumour’s
`mass can be successfully removed. Liver surgery can be
`done concomitantly with surgery of the primary tumour
`or on a separate occasion. Specifi c anaesthesiological pro-
`cedures and perioperative somatostatin analogue infu-
`sion are indicated to avoid hormonal crises. If feasible,
`cholecystectomy should be performed synchronously, to
`prevent gallstone formation during future somatostatin
`analogue therapy or complications after liver emboliza-
`tion.
`
`travenous infusion of somatostatin analogues is indicat-
`ed. Forced diuresis to prevent hepatorenal syndrome is
`recommended.
`
` 2. Radiofrequen