Chapter 15 15Neuroendocrine Gastro-Entero-Pancreatic (GEP ... · a Zollinger-Ellison syndrome in...

Chapter 15

15 Neuroendocrine Gastro-Entero-Pancreatic (GEP) TumorsR. Arnold, R. Göke, M. Wied, Th. Behr

fuse endocrine cell system scattered within the mucosaof the gastrointestinal tract and the pancreatic duct sys-tem cannot be excluded. At least in vertebrates, the isletsof Langerhans arise within an independent islet organwhich melts together with the exocrine pancreas duringontogenesis. The blurredness of the term “carcinoid”results from its histological features which are almostidentical with those of endocrine pancreatic tumors.Therefore, even pathologists frequently use the term “car-cinoid” to describe an endocrine pancreatic tumor. Toavoid the dilemma, the term “carcinoid” should be usedonly for well-differentiated endocrine tumors of the gutand the term “malignant carcinoid” to designate the cor-responding well differentiated endocrine carcinoma [1].If a “carcinoid” is associated with a clinical syndrome asa Zollinger-Ellison syndrome in the case of a gastrin-producing endocrine tumor of the duodenum, the re-spective “carcinoid” should better be called gastrinoma.

The term “neuroendocrine” reflects the origin of theendocrine cells of the gastrointestinal tract fom the em-bryonic neural crest. They have been designated as “Hel-les Zellenorgan” by F. Feyrter. The acronym “APUDoma”(amine precursor uptake and decarboxylation) describesthe potency of endocrine tumors to synthesize in addi-tion to hormones biogenic amines as serotonin andother peptides characteristic to cells originating fromthe neural crest first described by A.E.G. Pearse.

Endocrine tumors of the gastrointestinal tract areepithelial tumors and differ histologically from neuronaltumors as neuroblastomas, pheochromocytomas andparagangliomas which also arise from the diffuse neu-roendocrine system and are, therefore, of neural crestorigin.

Amphicrine and mixed endocrine-exocrine tumorswill not be discussed within this survey since their prog-nosis and biological features are determined by the exo-crine cell department with a predominantly unfavourableprognosis.

Summary

Neuroendocrine gastro-entero-pancreatic (GEP) tumorsare rare but present with variable, sometimes dramaticclinical syndromes. The majority of these tumors is non-functioning and most functioning and non-functioningtumors are malignant. This chapter describes the vari-ous clinical entities, has a special focus on histopathol-ogy of these tumors as a reliable source for prognosisand summarizes current state and new trends in diagno-sis and treatment of these tumors. The management ofneuroendocrine GEP-tumors needs a multidisciplinaryapproach. Therefore, diagnostic and therapeutic aspectsof this chapter recognize the important contributions ofsurgery, pathology, radiology, nuclear medicine and gas-trointestinal endocrinology.

Definition

Several terms for endocrine tumors of the gastrointesti-nal tract are currently applied to describe the same path-ological entity: “carcinoid”, “neuroendocrine tumor”,“neuroendocrine carcinoma”, “APUDoma”, “gastro-en-tero-pancreatic (GEP) tumor”, “islet cell tumor” (in caseof pancreatic origin). The term “carcinoid” was intro-duced by S. Oberndorfer in 1907 to distinguish carci-noids as less rapidly growing and well-differentiatedepithelial tumors of the small intestine from the moreaggressively growing adenocarcinoma of the gut and,thus, recognizing the decisive difference to carcinomaswhich is the very slow growth of most endocrine tumorsand which is frequently associated with an uncompromi-zed life quality. Strictly speaking is the term “carcinoid”reserved for endocrine tumors of the gastrointestinaltract (Table 2) and not for those of the pancreas (Table 1).Endocrine pancreatic tumors are assumed to arise fromislets of Langerhans although their origin from the dif-

15 Neuroendocrine Gastro-Entero-Pancreatic (GEP) Tumors196

Table 1Classification and leading symptoms of the most frequent endocrine tumors of the gastrointestinal tract

Name (Syndrome) Leading Symptoms Responsible Other Malignancy Localization Extra-pancrea-

Hormone Hormones (%) of primary tic Localization

in the Tumor

Insulinoma Hypoglycaemia Insulin Glucagon, PP 5–10 Pancreas very rare

Gastrinoma Peptic Ulcers, Diarrhea, Gastrin Insulin, PP, Glucagon, ACTH, >90 Pancreas Duodenum, Stomach,

(Zollinger-Ellison Reflux Disease Somatostatin, Chromogranin A Mesenterium

syndrome)

Carcinoid syndrome Flush, Diarrhoea, Bronchial Serotonin Tachykinins, Prostaglandins, 100 Ileum Pancreas (rare)

Obstruction Chromogranin A

VIPoma (Verner- Intractable Diarrhea, VIP, PHI PP, Glucagon, Somatostatin, 75 Pancreas

Morrison syndrome), Hypokalemia Chromogranin A

Pancreatic Cholera

Glucagonoma Erythema necrolyticans Glucagon PP, Insulin, Somatostatin, 50 Pancreas Rare

migrans, Diabetes Chromogranin A

Somatostatinoma Diabetes, Steatorrhea, Somatostatin PP, Insulin, Calcitonin 50 Pancreas Duodenum

Gallstones

GHRHoma Acromegaly GHRH Somatostatin, Gastrin, Insulin, 100 Pancreas Lung

Chromogranin A

CRHoma, ACTHoma Cushing’s syndrome CRH Gastrin, PP, Chromogranin A >90 Pancreas Lung

ACTH Adreno-corticotrophic hormone; CRH Corticotropin releasing hormone; GHRH Growth hormone releasing hormone; PHI Peptidehistidine isoleucine; PP Pancreatic peptide; VIP Vasoactive intestinal polypeptide.

Table 2Characteristics of extra-pancreatic endocrine gastrointestinal tumors (“carcinoids”)

Localization % of all carcinoids Peptides and hormones Functional activity Endocrine cell type Malignancy

Esophagus 0.04 Chromogranin A rarely Grimelius positive, >50%

NSE positive

Stomach 2–3 Chromogranin A (histamine,gastrin), very rarely ECL-cells, rarely highly variable

Ghrelin, VMAT-2 EC-cells, rarely G-cells

Duodenum and 22 5-HT, gastrin, somatostatin, PP, Zollinger-Ellison syn- EC-cells, G-cells, 50%

proximal jejunum calcitonin, ACTH drome or functional somatostatin-cells

inactive

Distal jejunum 23–28 Chromogranin A, serotonin, mostly inactive; carcinoid EC-cells >50% in tumors

and ileum substance P, tachykinins, others syndrome in 5–7% larger then 1 cm

Appendix 19 Serotonin, GLP-1,GlP-2, PP/PYY mostly inactive; carcinoid EC-cells, L-cells risk factor size >2 cm

syndrome extremely rare and invasion of me-

soappendix

Cecum 8 Serotonin carcinoid syndrome in 5% EC-cells > 50%

Ascending Colon 8 GLP-1,GLP-2 PP/PYY L-cells

Rectosigmoid 20 Serotonin, no EC-cells 15% depends on tu-

Rectum 20 GLP-1,GLP-2 PP/PYY L-Cells mor size and invasion

197Classification

Classification

Endocrine GEP tumors can be subdivided according totheir origin into those originating from the foregut (eso-phagus, stomach, duodenum, proximal jejunum, pan-creas), midgut (distal jejunum, ileum, appendix, cecum,right-sided colon) and hindgut (left-sided colon andrectum). This classification is based on the embryologicassignment of the different parts of the gut. Vary rarelyendocrine tumors of the same histology can arise in theovary, extrahepatic bile ducts, the liver, the kidney, testis,spleen, breast and larynx and other organs as the bron-cial system and thymus.

Clinically more relevant is a classification accordingto the functional activity of endocrine GEP tumors. Mostbenign and malignant endocrine GEP tumors are func-tionally inactive and patients commonly present withabdominal pain, weight loss, obstructive jaundice andintestinal obstruction depending on the localization andsize of the tumor. Noteworthy, many tumors are asymp-tomatic even in the presence of metastases and are dis-covered incidentally during routine imaging procedures.

Survival of patients with GEP tumors is even in themetastatic state much more favourable than in patientswith other malignancys and depends on the site of theprimary tumor and the extent of metastatic spread. Ofpancreatic endocrine tumors the best prognosis is asso-

ciated with insulinomas which are in more that 95% ofpatients solitary and benign. In contrast, most of theother pancreatic entities are malignant (see Table 1).

As shown in Tables 1 and 2 the majority of function-ally active endocrine tumors arise within the pancreas(see Table 1) whereas functionally active tumors withinthe gastrointestinal tract can cause the Zollinger-Ellisonsyndrome if originating from the duodenum or causea Carcinoid syndrome due to a metastatic tumor of theileum.

Endocrine GEP tumors may be benign or malignant.The majority of endocrine pancreatic tumors are malig-nant and present with metastases mostly to the liver (seeTable 1). The malignancy rate of endocrine tumors with-in the gastrointestinal tract is highly variable and mostlydepending on the size of the carcinoid.

Endocrine GEP tumors can arise sporadic or as partof the Multiple Endocrine Neoplasia (MEN) syndromes(Table 3). MEN-I syndrome is an autosomal dominantlyinherited disorder characterized by the synchronous ormetachronous occurrence of tumors in multiple endo-crine organs, predominantly the pancreas, parathyroid,pituitary and duodenum. The genetic locus was ascribedto a segment of the long arm of chromosome 11, wherethe menin gene – a tumor suppressor gene – is locatedwhich is in MEN-I syndrome mutated [2, 3]. MEN-Isyndrome is present in 20% of patients with gastrinoma

Table 3MEN syndromes

Syndrome Affected organ Alterations

MEN-1 (Wermer’s syndrome) Parathyroid gland Hyperplasia, multiple adenomas

Pancreas Islet cell tumors (insulinoma, gastrinoma, VIPoma,

glucagonoma)

Pituitary (anterior) Adenoma (prolactin, ACTH, STH, GH, non-funtioning)

MEN-2A (Sipple’s syndrome) Thyroid gland C-cell hyperplasia, medullary thyroid carcinoma

Adrenal medulla Phaeochromocytoma

Parathyroid gland Hyperplasia, multiple adenomas

MEN-2B Thyroid gland C-cell hyperplasia, medullary thyroid carcinoma

Adrenal medulla Phaeochromocytoma

Mucosa Neuromas

Other abnormalities:

Marfanoid habitus,

Megacolon


[4], 4% of patients with insulinoma [5] and 13–17% ofpatients with glucagonoma [6]. However, in MEN-Isyndrome most endocrine pancreatic tumors are non-functional containing mostly pancreatic polypeptideor glucagon [5].

Epidemiology

Endocrine GEP tumors are rare events. The exact inci-dence and prevalence of these tumors is difficult to as-certain because many are asymptomatic. From autopsystudies an annual incidence of 8.4 gastrointestinal endo-crine tumors (carcinoids) per 100.000 people has been

calculated [7, 8] (Table 4). 90% of these tumors were in-cidental autopsy findings. For endocrine pancreatic tu-mors an annual incidence of 0,1–0,4 tumors per 100.000has been reported. [8]. Table 4 summarizes the publish-ed annual incidence rates for the most common gastro-intestinal (carcinoids) and pancreatic endocrine tumors.Endocrine tumors originating in the midgut encompassby far the majority of all endocrine tumors followed bythe pancreatic endocrine tumors.

Almost all endocrine tumors originating within thehindgut are asymptomatic and do not create symptomsas a consequence of hormone overproduction. The rea-son for that is unknown since many of these tumorscontain peptides and hormones which are also pro-

Table 4Epidemiological data of endocrine GEP tumors

Localization Incidence cases Remarks Mean age [years] (range)

per 100.000 people (% of all gastro-

per year intestinal carcinoids)

Stomach 0.002–0.1 (11–14%) 50–60

type I: 74% 63 [15–88]

type II: 6% 50 [28–67]

type III: 13% 55 [41–61]

poorly differentiated: 6%

Duodenum (22%) 59 [30–90]

Gastrin-producing: 62%

Somatostatin-producing: 21%

Gangliocytic pasaganglioma: 9%

Undefined tumors: 5,6%

Proximal Jejunum (1%)

Distal Jejunum/Ileum 0.28–0.89 (28%) 60–70

[30–99]

Appendix (19%) more frequent in females 32–45

[6–80]

Colon 0.07–0.21 (right-sided colon: 8%) 58

(left-sided colon: 20%)

Rectum 0.14–0.76 60

Pancreas

all 0.01 – 0.3

Insulinoma 0.1–0.2 47 [8–82]

Gastrinoma 0.05–0.15 [33–53]

VIPoma 0.005–0.02

Glucagonoma 0.001–0.01

199Histopathology

duced in tumors responsible for the carcinoid syndrome.The same is true for most gastric carcinoids and carci-noids arising in the distal ileum. Even in metastatic tu-mors a hormone mediated symptomatology is mostlyabsent. Of the endocrine pancreatic tumors almost 50%are functionally inactive as well [8]. The incidence ratesof the functionally active tumors with insulinoma as themost frequent tumor are listed in table 4.

According to an analysis of 8305 cases of carcinoidtumors identified by the “Surveillance, Epidemiology,and End Results” (SEER) program of the American Na-tional Cancer Institute (NCI) from 1973 to 1991 and byan earlier NCI program 5-year survival of patients was50.4% [7]. The presence of regional and distant metas-tases reduced survival rate to 21,8%. If survival rates arecalculated separately for tumors arising in the foregut,midgut and hindgut 5-year survival rates were 44.5%,61% and 72% respectively [7]. Most favourable survivalhave appendiceal carcinoids with 85.9%. Surveillancerates for endocrine GEP tumors of specific localizationswill be discussed in more detail later in this chapter.

Etiology

The etiology of endocrine GEP tumors is unknown. It iscomprehensible to assume that they originate from cellsor rather precursor cells of the diffuse neuroendocrinecell system. Endocrine tumor cells display certain cyto-chemical properties with endocrine cells scattered with-in the mucosa of the gastrointestinal tract and with theconstituents of the islets of Langerhans as the expres-sion of neuron-specific enolase, synaptophysin and cho-mogranin A and C [1, 16]. Chromogranins are acidicglycoproteins present in almost all endocrine and neu-ronal tissues. They are released into the circulation andcan serve as tumor markers since they are found in morethan 90% of patients with endocrine GEP tumors. Al-though endocrine pancreatic tumors are also called“islet cell tumors” it is unproven that pancreatic insuli-nomas, gastrinomas, VIPomas etc. originate from theislets of Langerhans. In favour of this assumptionare findings in experimental settings which clearly de-monstrate that insulinomas in rats can under definedconditions arise from islets. However, some endocrinepancreatic tumors produce hormones and peptides asgastrin or VIP which are not synthesized from islet cells

after birth. Therefore, it is conceivable to assume thatislet tumors originate from endocrine pancreatic multi-potent precursor cells which are constituants of the pan-creatic duct epithelium [13].

General Pathophysiology

The key event occurring in functionally active endo-crine GEP tumor cells is the loss of capacity to storetheir hormonal product as insulin in insulinomas, gas-trin in gastrinomas etc. within the tumor cell. Therefore,inappropriately released hormones and peptides not re-sponding to the physiological feadback inhibition areresponsible for the clinical manifestation of the disease.According to the concept of an impaired storage capac-ity of tumor cells, it has been shown, that insulinomacells contain less insulin than normal β-cells, and themean total insulin content of insulinomas was evenlower than the mean insulin content of the whole pan-creas of the respective patient [14]. Very similar is thegastrin content of the majority of gastrinomas lowercompared to the gastrin content of the whole antral mu-cosa which contains more gastrin-producing cells thanthe tumor [15].

Histopathology

Most endocrine GEP tumors display a solid, trabecularor glandular arrangement of well-different (Fig. 1a–c)[1, 16]. However, not in every case these features permitrecognition of the endocrine nature of the tumor. Inthese tumors special staining methods as silver methodsor immunohistochemical staines for general endocrinemarkers as chromogranins (Fig. 1e), synaptophysin orneuron-specific enolase are needed for tumor identifi-cation [1, 16]. To characterize the tumor cell further withregard to their hormone/peptide production specificantibodies against polypeptide hormones are needed toidentify a tumor cell as insulin-, gastrin-, glucagon- orother hormones producing cell (Fig 2a, b) [16]. Endo-crine tumors with predominant insulin production canbe classified as insulinoma, those with predominantglucagon- or gastrin production as glucagonoma orgastrinoma. This does not indicate that a tumor whichhistologically has been diagnosed as insulinoma or glu-


Figure 1a–fHistopathological patterns in pancreatic endocrine tumors. a trabecular pattern; PAS staining; b glandular pattern; PAS staining; c solidpattern; PAS staining; d poorly differentiated neuroendocrine tumor; PAS staining; e staining with the endocrine marker chromogranin A;f staining with an antibody against the proliferation marker Ki-6

cagonoma acts as a functionally active endocrine tumorresponsible for hypoglycemic attacks in the case of aninsulinoma or giving rise to the typical symptoms of aglucagonoma syndrome. Functional activity or inactiv-

ity cannot be deducted from histology. Correspondinglyand most characteristicly, many endocrine tumors aspart of the MEN-I syndrome are functionally inactive[18].

201Histopathology

Most endocrine tumors are composed of more thanone cell type. An endocrine pancreatic tumor with pre-dominant insulin-producing cells can contain additionalsomatostatin- or glucagon- or pancreatic polypeptide-producing cells [15]. This feature is independent on thefunctional status of the tumor and can be observedin functionally active and inactive tumor [15]. It is un-clear, why in the presence of multiple hormones withina single endocrine tumor only one or no clinical syn-drome occurs. Nevertheless, in few patients, a secondclinical syndrome can be present initially or developlater. This occurs preferably in patients with metastaticendocrine pancreatic tumors or in patients with MEN-Isyndrome and multiple endocrine pancreatic tumors[4]. According to own observations which are in accor-dance with reports from the literature the combinationof ectopic ACTH-producing and gastrin-producing pan-creatic tumors giving rise to a combination of Cushing’ssyndrome and Zollinger-Ellison syndrome is frequent,although the condition itself with two functionally ac-tive tumors is a rare event.

Since most endocrine tumors are well-differentia-ted, their mitotic index visualized by the Ki67 labelling(Fig. 1f) index [9] is low which is in accordance withtheir slow growth behaviour. Therefore, it is difficult topredict the biological behaviour of well-differentiatedtumors using classical histopathological malignancy cri-teria as cellular or structural atypia, necrosis, mitoticactivity or microscopic invasion. A panel of internatio-nal pathologists has, therefore, proposed to classify

benign and malignant endocrine tumors into the cat-egories listed in table 5 [1]. The basis for distinguishinga well-differentiated endocrine tumor from a well-dif-ferentiated endocrine carcinoma is the presence of me-tastases and/or evidence for local invasion. Benign orlow risk endocrine tumors are distinguished from tu-mors with greater risk of malignancy on the basis of acombination or features such as tumor size, local exten-sion, angioinvasion, cellular atypia, proliferative activityand the expression of hormones regularly found in thespecific organ (“eutopic” hormone production) or theexpression of “ectopic” hormonal products (as ACTH inan endocrine pancreatic tumor).

Poorly differentiated small cell carcinoma (Fig. 1d)is for experienced pathologists easy to distinguish fromwell-differentiated endocrine tumors on the basis of cel-lular atypia, the presence of markedly hyperchromaticnuclei, a high nuclear/cytoplasmic ratio, focal necrosisand high mitotic activity. To classify such an indiffe-rentiated tumor as endocrine, tumors must react for

Table 5General endocrine tumor categories

1 Well-differentiated endocrine tumor

2 Well-differentiated endocrine carcinoma

3 Poorly differentiated endocrine (small cell) carcinoma

4 Mixed exocrine-endocrine tumor

5 Tumor-like lesions

Figure 2a,bDemonstration of several hormones present within the same endocrine Pancreatic tumor. a immunohistological staining for insulin;b immunohistological staining for gastrin


cytosolic neuroendocrine markers as synaptophysinand neuron-specific enolase [1]. However, these tumorsare frequently negative for markers of endocrine gran-ules as chromogranin and for specific hormonal prod-ucts.

Additional histopathologic characteristics and tumorclassifications will be discussed later when specific tu-mors are described in more detail.

Molecular Pathogenesis

Sporadic GEP Tumors

In sporadic pancreatic endocrine tumors (PETs) anallelic deletion of the tumor-suppressor gene MEN-Ilocated on chromosome 11q13 has been found very fre-quently [3, 17]. However, the mutational frequency ofMEN-I is different in functional and non-functionalPETs: 30% of functional but only 8% of non-functionalPETs showed mutations of the MEN-I gene [17, 18]. Fur-thermore, there are differences within the group of func-tional PETs: Alterations in MEN-I have been foundin 54% (15/28) of gastrinomas, 50% (4/8) of VIPomas,2/3 glucagonomas, 1/1 somatostatinoma but only in 7%(4/54) of insulinomas [17]. While such findings supportthe relevance of MEN-I for the pathogenesis of endo-crine neoplasms, it is important to note that the in-cidence of MEN-I alteration is obviously tumor-typerelated and found more frequently in gastrinomas andnon functional PETs than in insulinomas. Other fre-quent genetic abberations found in 25–50% of PETs ana-lyzed are chromosomal deletions on 3p, 3q, 6q, 10q, 11q,11p, 16p, 20q, 21q, 22q, Xq and Y. In up to 25% of PETsgains on chromosomes 5q, 7q, 7p, 9q, 12q, 17p and 20qwere found.

The p53 tumor suppressor gene located on chromo-some 17p13 encodes a nuclear protein which is involvedin multiple cellular processes like cell cycle, DNA repair,replication, transcription, apoptosis and cell differentia-tion. p53 alterations are detectable in almost all cancersbut are extremely rare in PETs. However, increased p53protein concentrations were found in malignant insuli-nomas most likely due to inactivating mutations result-ing in an increased stability or posttranslational eventsleading to overexpression [19].

The p16 (INK4a, MTS1) gene located on chromo-some 9p21 encodes a protein that binds to cyclin-depen-dent kinase 4 inhibiting its interaction with cyclin. p16alterations do not play a role in non-functional PETs andinsulinomas. Since p16 was found abnormal in 42% of 8gastrinomas analyzed [20] it might play a role in gastri-noma tumorigenesis. However, further studies are nec-essary to confirm this assumption.

DPC4/Smad4 is a tumor suppressor gene located onchromosome 18q21 encoding a protein which is involvedin the TGF-β signaling pathway. Previous data suggestedthat Smad4 mutations seem to be common in non-func-tional PETs [21]. However, based on a more recent studyit is unlikely that Smad4 plays a role in tumorigenesis ofendocrine tumors.

Of the oncogenes c-myc, c-fos, K-ras and c-erbB-2only K-ras was found to be overexpressed in PETs. How-ever, only 10 of 90 PETs analyzed in the literature show-ed a ras mutation indicating that this is a rare eventin these tumors. Most PETs with ras mutations were ma-lignant insulinomas suggesting that alterations of rasmight play a role in the pathogenesis of these tumors.

Recent data indicate that losses of sex chromosomesare common in PETs and are associated with presence ofmetastases, local invasion and poor survival.

Up to date the pathogenesis of neuroendocrine tu-mors of the gastrointestinal tract is not well character-ized. Allelic loss of the MEN-I gene located on chromo-some 11q13 was identified in type II ECL cell tumorsand carcinoids of the jejunum and ileum. In type I ECLcell tumors abnormal RegIalpha gene was observed. Inpoorly differentiated neuroendocrine neoplasms allelicloss of p53 located on chromosome 17p13 were found in4 of 9 cases suggesting a role for p53 in the developmentof these aggressive tumors.

Multiple Endocrine Neoplasia-Type 1

Multiple endocrine neoplasia-type 1 (MEN-I; Wermer’ssyndrome) is characterized by a combined occurrenceof primary hyperparathyroidism, pancreatic endocrinetumors and pituitary adenomas [5]. The development ofadditional tumors in other endocrine or non-endocrinetissues indicates that the protein menin encoded by theMEN-I gene might have a function in a wide variety oftissues. Most MEN-I patients (90%) exhibit primary hy-

203Molecular Pathogenesis

perparathyroidism. Pancreatic endocrine tumors occurin ~60% and are usually benign and non-functional [5].The most common functional tumors are insulinomasand gastrinomas. The prevalence of pituitary adenomasis between 15–50%. A recent large study including 324MEN-I patients showed pituitary adenomas in 42% ofthe cases which were larger in size and more aggressivethan without MEN-I.

MEN-I is an autosomal dominant inherited syn-drome and is related to mutations of the MEN-I genelocated on chromosome 11q13 [2, 3]. The tumorigenesisof MEN-I is supposingly a process according to the twohit model by Knudson (Fig. 3). Patients inherit a muta-ted MEN-I gene and later aquire another mutation in thewild-type allel (loss of heterozygosity) in vulnerableendocrine tissue. This results in a loss of the tumor sup-pressor function of the MEN-I gene. The MEN-I genecontains 10 exons encoding the protein menin consitingof 610 amino acids [2]. Two transcripts have been iden-tified which are most likely due alternative splicing.

A 2.9 kb transcript was detected in all tissues while a4.2 kb transcript was found in pancreas, stomach andthymus only [2]. Menin contains two nuclear localiza-tion sites and is predominantly a nuclear protein. How-ever, during cell cycle menin was shown to shuttle fromnucleus to cytoplasm.

In Ras-transformed NIH3T3 cells overexpression ofmenin resulted in decreased proliferation, suppressionof clonogenicity in soft agar and inhibition of tumorgrowth in mice. Menin directly interacts with JunD, atranscriptional factor of the AP-1 complex, via three JunDinteracting domains and inhibits JunD activation oftranscription [22]. However, since JunD inhibits growthof Ras-transformed NIH3T3 cells the repressive effect ofmenin should result in enhanced growth. This indicatesthat the mechanism of action of menin is more complexthan we know today and probably involves other genesand proteins. This assumption is supported by a recentobservation that menin interacts with NF-κB proteinsand inhibits NF-κB-mediated transactivation).

Figure 3Tumorigenesis in MEN-1 according to the two hit model described by Knudson. Patients show a germline mutation of the MEN-1 gene. Laterthey acquire another mutation in the wild-type allele resulting in an loss of suppressor function of the gene


Up to date more than 400 mutations of the MEN-Igene have been identified. Most mutations were uniquebut some occurred twice or more in unrelated families(107, 110–112). Of 262 mutations observed in MEN-I pa-tients between 1997 and 1999 approximately 22% arenonsense mutations, 48% frameshift deletions and in-sertions, 8% inframe deletions and insertions, 5% do-nor-splice site mutations and 17% missense mutations.The majority of mutations result in an inactivation ofthe MEN-I gene. There is no genotype-phenotype corre-lation in MEN-I. However, most patients with agressivephenotypes show truncating mutations.

Multiple Endocrine Neoplasia-Type 2

The term multiple endocrine neoplasia-type 2 (MEN-2)describes the combined occurrence of inherited formsof medullary thyroid carcinoma (MTC) with othermalignomas. In MEN-2A (Sipple’s syndrome) MTC iscombined with pheochromocytoma and primary hyper-parathyreoidism. MEN-2B (Gorlin’s syndrome) is char-acterized by the occurrence of MTC, pheochromocy-toma, neurinomas of the gastrointestinal tract and amarfanoid habitus [23].

Men-2 is caused by germline mutations of the RETgene located on chromosome 10q11–2 encoding a trans-membrane tyrosine kinase receptor with cadherin-likeand cystein-rich extracellular domains and a tyrosinekinase intarcellular domain [23]. RET genomic size is60 kb and the gene contains 21 exons. GDNF (glia cellline-derived neurotrophic factor), neurturin, arteminand persephrin act as RET protein ligands inducinghomodimerization through the cystein-rich region re-sulting in an activation of the tyrosine kinase domainand the Ras-MAP-kinase pathway. 95% of MEN-2A pa-tients show mutations of the cystein-rich extracellulardomain. The most common mutation affects codon 634(Cys→Arg/Tyr/Gly). Missense mutations have also beenidentified in codons 609–611, 618 and 620. Approxi-mately 98% of MEN-2B patients exhibit mutations inthe intracellular tyrosine kinase domain (codon 918;Met→Thr). While mutations in the cystein-rich regionresult in the formation of constitutive active RET di-mers, mutations in the intracellular tyrosine kinase do-main lead to a switch to an abnormal signalling pathway.

Germline RET mutations were observed in approxi-mately 100% of men-2 families. Therefore, genetic analy-sis of RET is advisable to identify young asymptomaticgene carriers and perform prophylactic thyroidectomy.

Other Inherited Syndromes Associated with GEP Tumors

In a recent report 12% of 158 patients with von Hippel-Lindau (VHL) syndrome had neuroendocrine tumors[24]. These patients showed no symptoms due to hor-monal hypersecretion suggesting that the endocrinetumors were non-functioning. The VHL syndrome iscaused by a germline mutation of the VHL gene which islocated on chromosome 3p35–36 coding for a 213-aa pro-tein. The VHL gene product is a component of an Skp1-Cdc53-F-box-like ubiquitin-ligase complex targeting theα-subunits of the hypoxia-inducible factor heterodi-meric transcription factor for polyubiquitylation andproteasomal degradation. Somatostatinomas have beendescribed in patients with von Recklinghausen‘s neuro-fibromatosis. Neurofibromatosis is caused by alterationsof the NF1 gene located on chromosome 17q11.2 codingfor neurofibromin which is a 2485-aa protein.

Growth Characteristics and Metastatic Spreadand Secondary Non-Endocrine Malignancies

As recognized as early as in 1907 by S. Oberndorfer whointroduced the term “carcinoid”, endocrine GEP tumorsgrow slowly even in the metastatic state compared toadenocarcinomas of the gastrointestinal tract. However,the spontaneous tumor growth varies from one patientto another. Some tumors remain unchanged in size formonths or even years without therapy, others grow slow-ly independent of any antiproliferative measures andstill others exhibit exploding growth. The latter tumorsare poorly differentiated and mostly small cell carcino-mas. Even spontaneous tumor regression without anytreatment has been reported in well-differentiated tu-mors. A schematic presentation, how malignant GEPtumors can grow is shown in fig. 4.

Unfortunately the use of proliferative markers andimmunostaining of tumors for oncoproteins, tumor sup-pressor genes, and adhesion molecules gave contradic-

205Growth Characteristics and Metastatic Spread and Secondary Non-Endocrine Malignancies

tory results. One study was performed in gastrointestinalcarcinoid tumors and indicated that expression of p53,cyclin D1, Rb, bcl-2 and Ki-67 does not correlate withmalignant behaviour, whereas p21 overexpression did.Others concluded from studies in bronchial carcinoidtumors and in gastrointestinal carcinoid tumors thathigh expression of ki-67, a tumor size >3 cm and a highmitotic index (in the case of ECL cell tumors of the sto-mach) is malignancy predictive. Possibly, these findingsare dependent on the site of the primary tumor since incarcinoid tumors of the duodenum and ampulla of vateran aggressive behaviour of the tumor was not associatedwith higher proliferative indices as proliferating cell nu-clear antigen (PCNA), Ki-67 and p21.

Malignant GEP tumors can spread in almost all or-gans: lymphnodes, peritoneal spread, liver, spleen, kid-ney, lung, skin, brain and bones. Table 6 is an example ofthe metastatic spread of patients with malignant gastri-noma and patients with carcinoid syndrome observedin the institution of the authors.

It is noteworthy that patients with malignant en-docrine GEP tumors tend to synchronous and meta-chronous non-endocrine malignancies. In a 20-yearretrospective study of 150 patients with gastrointestinal

Table 6Metastatic spread in different endocrine GEP tumors (own data,values in percent)

Site Non-functioning Carcinoid Gastrinoma

tumor syndrome

Lymph nodes 64 76 54

Liver 61 88 57

Bones 13 17 11

Lung 9 14 7

CNS 2 0 4

Peritoneal 17 23 4

Other 28 24 4

Figure 4Schematic presentation how endocrine GEP tumors can grow. Some tumors grow so slowly that they do not meet the 25% increase accord-ing to the accepted NIH criteria of tumor progression even after 18 months (1). Tumor (2) displays an intermediate tumor growth. Tumor(3) grows very rapidly corresponding to its histology of a small cell neuroendocrine carcinoma. Tumor (4) decreased spontaneously in size,remained constant for 2 years and started to grow after 24 months of observation without any treatment


carcinoids followed up for a median of 66 months 22%developed synchronous non-carcinoid tumors and 10%metachronous tumors. In another retrospective study on69 patients with gastrointestinal carcinoid tumors 42%hat synchronous and 4% metachronous tumors. Themost common site for the secondary primary malig-nancy was the gastrointestinal tract with carcinoma ofthe colon and rectum. Patients with colorectal carcinoidshave, in addition, an increased risk for cancer in thecolon, ano-rectum, small bowel, esophagus, stomach,lung, urinary tract and prostate.

Staging of Endocrine GEP Tumors

Staging of tumors is a useful and essential tool in on-cology to define tumor size, invasion and infiltrationinto adjacent tissues and metastatic spread into regionallymph nodes, liver and other organs. This is importantfor further management using surgical, radiotherapeu-tic and chemotherapeutic approaches. For this, TNMclassification has been elaborated for specific tumor en-tities as published by the AICC Cancer Staging Manualand UICC. No corresponding TNM classifications existfor endocrine GEP tumors and their malignant variantsbecause management of endocrine tumors depends evenin metastatic tumors primarily on growth behaviour(see Fig. 4) and functional activity. Insulinomas must beremoved because they produce life-threatening symp-toms independent on the size of the tumor which maybe too small to be visualised by available imaging tech-niques. Metastatic insulinomas have to be partially re-sected if possible to reduce tumor burden and, thus, tofacilitate control of hypoglycemic symptoms. In patientswith very slowly growing metastatic GEP tumors the be-neficial effect of many therapeutic measures is unsettled.The same applies for non-functioning small endocrinepancreatic tumors in patients with MEN-I syndrome forwhom resection has not been shown to influence pa-tient’s outcome.

In an attempt to classify endocrine GEP tumors nothaving metastasized at diagnosis a panel of pathologistshas recently proposed a classification of endocrine GEPtumors and assigned the tumors according to the cat-egories summarised in table 5 [1]. The basis of distin-guishing well differentiated endocrine carcinomas fromother well differentiated endocrine tumors was usuallythe presence of metastases and/or evidence of local in-

vasion. Benign or low risk endocrine tumors were dis-tinguished from tumors with greater risk of malignancyon the basis of a combination of features such as tumorsize and site, local extension, angioinvasion, cellular aty-pia and proliferative activity. Differentiation of poorlydifferentiated endocrine small cell carcinoma from well-differentiated endocrine tumors was performed by con-ventional histological characteristic featurs includinghigh-grade cellular atypia, markedly hyperchromaticnuclei, focal necrosis and high proliferation.

In tables 7–11 these major principles have been trans-ferred to endocrine tumors arising in different organs ofthe GI tract as the pancreas (Table 7), stomach (Table 8),the duodenum and upper jejunum (Table 9), the ileum,cecum, colon and rectum (Table 10) and the appendix(Table 11).

Clinical Entities: Symptomsand Laboratory Findings

Insulinoma

Epidemiology

Around 40% of endocrine pancreatic tumors are insuli-nomas. Based on a review of 224 insulinoma patientsover a 60-year period the medium age was 47 (range8–82) years and 41% of patients were male [25]. Theyearly incidence is 0,5 to 4 per one million populationand 5,8% had malignant insulinoma [25]. In 7,6% of pa-tients the insulinoma was part of the MEN-I syndrome[4, 25]. Almost all insulinomas are situated in or close tothe pancreas. 1–3% of insulinomas have been reported toarise in the duodenum, ileum and lung [26]. Insulino-mas are evenly distributed within the pancreas [26].Based on a study in 1067 cases most insulinomas aresmall: 5% smaller then 0.5 cm, 34% were 0.5 to 1 cm, 53%1 to 5 cm and only 8% larger then 5 cm in size. With theexception of the rare malignant insulinomas prognosisof patients with a benign insulinoma and curative resec-tion is excellent. For definition of “benign” insulinomasee Table 7.

207Clinical Entities: Symptoms and Laboratory Findings

Table 11Clinicopathological staging of endocrine tumors of the appendix.(Mod. according to [1])

1 Well-differentiated endocrine tumor – carcinoid, benign beha-

viour, nonfunctioning, confined to appendiceal wall, nonangio-

invasive, ≤2 cm in size

1.1.1 Serotonin-producing tumor

1.1.2 Enteroglucagon-producing tumor – uncertain behaviour, nonfunc-

tioning, confined to subserosa, >2 cm in size, or angioinvasive

tumor

2 Well-differentiated endocrine carcinoma – malignant carcinoid

2.1 Low grade malignant, invading the mesoappendix or beyond, and/

or with metastasis

2.2 Serotonin-producing carcinoid with or without carcinoid syndrome

3 Mixed exocrine-endocrine carcinoma

3.1 Low grade malignant – goblet-cell carcinoid

Table 10Clinicopathological staging of endocrine tumors of the ileum,cecum, colon and rectum. (Mod. according to [1])

1 Well-differentiated tumor – carcinoid

1.1 Benign behaviour: confined to mucosa-submucosa, nonangio-

invasive, ≤1 (small int.) or ≤2 cm (large int.) in size

1.2 Uncertain behaviour: nonfunctioning, confined to mucosa-sub-

mucosa, >1 cm (small int.) or >2 cm (large int.) in size, or angio-

invasive

2 Well-differentiated endocrine carcinoma – malignant carcinoid,

low grade malignant, deeply invasive (muscularis propria or

beyond), or with metastases

3 Poorly differentiated endocrine carcinoma – small cell carcinoma,

high grade malignant

4 Mixed exocrine-endocrine carcinoma – moderate to high grade

malignant

Table 9Clinicopathological staging of endocrine tumors of the duodenumand upper jejunum. (Mod. according to [1])

1 Well-differentiated endocrine tumor – carcinoid

1.1 Benign behaviour: nonfunctioning, confined to mucosa-submu-

cosa, ≤1 cm in size, nonangioinvasive

1.1.1 Gastrin-producing tumour (proximal duodenum)

1.1.2 Serotonin-producing tumor

1.1.3 Gangliocytic paraganglioma, any size and extension (ampullary

region)

1.2 Uncertain behaviour: confined to mucosa-submucosa >1 cm in

size or angioinvasive

1.2.1 Gastrin-producing tumor, functioning (Zollinger-Ellison syndrome)

or nonfunctioning, sporadic, or MEN-1-associated

1.2.2 Somatostatin-producing tumor (ampullary region) with or with-

out Recklinghausen disease

1.2.3 Serotonin-producing tumor, nonfunctioning

2 Well-differentiated endocrine carcinoma – malignant carcinoid

2.1 Low grade malignant. extending beyond submucosa or with

metastasis

2.2 Gastrin-producing carcinoma, functioning (Zollinger-Ellison syn-

drome) or nonfunctioning, sporadic, or MEN-1-associated

2.3 Somatostatin-producing carcinoma (ampullary region) with or

without Recklinghausen disease

2.4 Serotonin-producing carcinoid, nonfunctioning or functioning

(any size or extension) with carcinoid syndrome

2.5 Malignant gangliocytic paraganglioma

3 Poorly differentiated endocrine carcinoma – small cell carcinoma

4 High grade malignant (ampullary region)

Table 7Clinicopathological staging of endocrine tumors of the pancreas.(Mod. according to [1])

1 Well-differentiated endocrine tumor

1.1 Benign behaviour: confined to the pancreas, nonangioinvasive,

<2 cm in size*, ≤2 mitoses and ≤2% Ki67 positive cells/10HPF

1.2 Uncertain behaviour: confined to the pancreas ≥2 cm in size, >2

mitoses, >2% Ki67 cells/10 HPF, or angioinvasive

2 Well-differentiated endocrine carcinoma

2.1 Low grade malignant with gross local invasion and/or metastases

3 Poorly differentiated endocrine carcinoma – small cell carcinoma,

high grade malignant

*<2 cm in size implies close to 100% probability of benign be-haviour, >3 cm corresponds to 90% probability of malignancy.Functioning, associated with pertinent clinical syndrome of en-docrine hyperfunction; nonfunctioning, not associated with per-tinent clinical syndrome, irrespective of hormone detection inblood or tumor tissue.

Table 8Clinicopathological staging of endocrine tumors of the stomach.(Mod. according to [1])

1 Well-differentiated endocrine tumor – carcinoid

1.1 ECL-cell carcinoid

1.1.1 ECL-cell carcinoid type I associated with type A gastritis

1.1.2 ECL-cell carcinoid type II associated with Zollinger-Ellison syndrome

1.1.3 Sporadic ECL-cell carcinoid

1.2 ECL-cell carcinoid

1.3 G-cell carcinoid

2 Small cell carcinoma – poorly differentiated endocrine tumor

3 Tumor like lesions: Hyperplasia, Dysplasia


Table 12Clinical symptoms in patients with insulinoma

Symptoms of neurohypoglycemia Symptoms of adrenergic cate-

cholaminergic response

Diplopia Anxiety

Blurred vision Sweating

Confusion Tremulousness

Abnormal behaviour Hunger

Weakness Nausea

Amnesia Fatique

Aphasia Tremor

Transient motor defects Palpitation

Dizziness

Speech difficulty

Headache

Seizure

Memory loss

Lethargy

Disorientation

Mental change

Convulsion

Coma

Obesity

Pathophysiology

Insulinoma cells fail to respond adequately to low bloodglucose levels. This is indicative of a defective negativefeedback which maintains euglycemia in healthy sub-jects. In addition, the storage capacity of insulinomacells is impaired, resulting in an inappropriate insulinrelease [14].

Symptoms

Insulinoma symptoms are the consequence of neuro-hypoglycemia and superimposed by symptoms whichare the consequence of adrenergic counter regulation assweating, tremulousness, palpitation (Table 12). As a rule,the frequently nonspecific symptoms are associated withfasting and occur more often after muscular exerciseand during late night or early morning and when a mealis delayed. Whipple’s triad is highly suggestive of an in-sulinoma and comprises of hypoglycemic symptoms,a parallel demonstration of low blood glucose levelsless then 50 mg/dl (2.8 mmmol/l) and improvement of

symptoms after administration of glucose [12, 25, 26].There is often a long-lasting delay between onset of cli-nical signs and diagnosis, because symptoms listed intable 12 are unspecific and do not appear in a clear se-quence. The mean duration of symptoms prior to diag-nosis varies between 15 months and more then 3 years[12, 25]. Each patient displays his/her own pattern ofsymptoms which differ from patient to patient. Sinceregular food intake prevents the occurrence of symp-toms, patients are used to eat regularly and often gainweight. If misinterpreted, severe and longer lastinghypoglycemia can progress to seizure and permanentbrain damage. Some insulinoma patients are diagnosedonly in psychiatric hospitals, having been admitted withmisdiagnosed symptoms.

Differential Diagnosis

In addition to insulinoma hypoglycemia can have sev-eral causes which are summarised in table 13. Factitioushypoglycemia secondary to self-administration of insu-

Table 13Other causes of hypoglycemia

Insulin or insulin-like- Factitious hypoglycemia (153)

mediated Tumor associated hypoglycemia (151, 152)

insulin autoantibodies (154)

Transient hypoglycemia of infancy

Nesidioblastosis

Postprandial (reactive) Previous gastric surgery (Billroth I and II gas-

hypoglycemia trectomy)

Idiopathic

Food stimulated Ethanol

Unripe kakee fruit (159)

Hormone deficiency Addison’s disease

Growth hormone deficiency

Hypothyroidism

Hepatic diseases End-stage liver failure

Glycogen storage disease

Glycogen synthetase deficiencies

Fructose-1,6-disphosphate deficiency

Metabolic diseases Severe malnutrition

Sepsis

Drugs Sufonylureas (155)

Quinine (156)

Disopyramide (157)

Haloperidol (158)


lin or oral intake of hypoglycemic agents should beconsidered if an insulinoma cannot be ascertained bydiagnostic measures. In the author’s institution the fol-lowing conditions are mostly the cause of hypoglycemicepisodes if an insulinoma could be excluded: postpran-dial hypoglycemia (late dumping syndrome) even in theabsence of gastric resection (Billroth I and II resection)due to rapid gastric emptying; mesenchymal tumors,such as fibrosarcoma, liposarcoma, rhabdomyosarcoma,hemangiopericytoma, mesothelioma, leiomyosarcoma,IGF-II-producing tumors; endstage of liver cirrhosis.

Diagnosis

Biochemical testing. The gold standard for the diagnosisof an insulinoma is the “72 h fast” test. About 75% ofinsulinoma patients will develop symptoms and bloodglucose levels of <40 mg/dl (2.2 mmol/l) within the first

24 h of the fast (Fig. 5), 90% within 48 h, and 100% with-in 72 h. The test should be performed using a standar-dised protocol as follows:1. begin the test immediately after the last meal (break-

fast); insert a capped intervenous cannula;2. allow intake of calorie-free fluid ad lib (water);3. encourage physical activity (walking);4. analyze plasma glucose, insulin and C-peptide in the

same specimen every 6 h until blood glucose dropsto <60 mg/dl; then increase sampling to every 1–2 h;

5. terminate the test when the patient develops symp-toms of hypoglycemia and glucose is <40 mg/dl.If the patient is asymptomatic, prolong the test untilsuggestive symptoms appear; sample always bloodglucose, insulin and C-peptide at the end of thetest;

6. when symptoms arise, give 10% glucose intrave-nously or orally until the patient is asymptomatic.

Fig. 5a,bBlood glucose, insulin and C-peptide levels during a 40 h fast, suggesting an insulin producing tumor since insulin and C-peptide levels re-mained inadequately elevated despite low blood glucose levels (a). In b insulin and C-peptide levels dropped down to very low levels duringa 72 hour fast

a b


The pathophysiologic background of the prolonged fasttest is that steadily decreasing blood glucose levels sig-nal to the normal b-cell of the islets of Langerhans toturn down insulin and C-peptide levels which decreaseto either not measurable or very low levels. In insuli-noma patients insulin and C-peptide are inadequatelysuppressed despite even lower blood glucose levels thenobserved in healthy controls (see Fig. 5). Importantly,plasma insulin in insulinoma patients go rarely beyondlevels normally found in the fasted and fed state of nor-mal subjects; however, they are inappropriately high forthe prevailing blood glucose concentration. Therefore,plasma insulin and C-peptide levels must always beassessed in relation to the corresponding blood glucoselevels. Some authors have advised to calculate a ratio ofinsulin to glucose because borderline low levels of insu-lin have been reported in some patients with proveninsulinoma in association with hypoglycemia. However,also these ratios do not reliably differentiate betweeninsulinoma patients and healthy subjects since there isnot in every subject a linear correlation of insulin andglucose levels. Normal subjects rarely exceed a ratioof plasma insulin (in µU/ml) to glucose (in mg/dl) of 0.3which is based on the observation that insulin levels arein normals less than 6 µU/ml when blood glucose levelsdecrease to less than 40 mg/dl. For example: if plasmainsulin measures 8 µU/ml and blood glucose is 40 µg/dl,than the ration is 8: 40=0.2. However, neither this ratioor an amended variation of such a ratio do reliablydiscriminate between insulinoma patients and healthysubjects because there is not in every patient a clear lin-earity between plasma insulin and glucose levels.

Some experts recommend estimation of proinsulinin insulinoma patients which is elevated in most insuli-noma patients to more than 20% of the total plasmainsulin levels. Indeed, some insulinomas produce andsecrete predominately proinsulin.

In previous literature, various stimulatory and sup-pressive tests have been recommended because they arebelieved to facilitate the diagnosis of an insulinoma asC-peptide suppression test, tolbutamide test, glucagontest, calcium infusion test, euglycaemic clamp procedureand others. These tests are neither specific nor sensitiveand due to the possibly harmful side effects of prolong-ed hypoglycemia in case of the tolbutamide and calciuminfusion not favoured in the more recent literature.

To exclude other causes of hypoglycemia as facti-tious hypoglycemia or postprandial hypoglycemia mea-surement of plasma sulfonylurea should be performedto exclude surreptitious use of these drugs and an oralglucose load with estimation of blood glucose and insu-lin levels in 30 minutes intervals for 3 h should be con-sidered if reactive hypoglycemia is considered.

Localization. Imaging studies to localize an insulinomashould only be performed once the diagnosis of an in-sulinoma is highly suggestive by biochemical testing.Experienced surgeons claim that the most sensitivelocalization instrument is the finger of the skilled sur-geon during intraoperative abdominal exploration andrecommend no preoperative localization procedures.Indeed, almost all insulinomas are situated in the pan-creas and only 1–3% found ectopically. On the otherside, there is no localization procedure available with an100% detection rate. At the institution of the authors,50 patients with biochemically proven insulinoma hadundergone operative exploration within the last 10 yearsand all insulinomas have been identified at the first op-eration (R. Rothmund, personal communication). Theseresults have been confirmed by some but not all authors.The latter claim that 10–27% of insulinomas remainedundetected and advocated, therefore, the need for pre-operative localization procedures.

The most accurate and sensitive imaging procedureto localize and to stage (see table 7) an insulinoma isendoscopic ultrasound (EUS) which localizes an insuli-noma in up to 85% and thus being superior to otherimaging studies as CT, MRT, conventional ultrasoundand arteriography (Fig. 6a). Of course, detection rate ismostly dependent on the experience of the investigatorand expert investigators will detect tumors less than0.4 cm in diameter. In such institutions EUS will be the

Figure 6a–fLocalization of endocrine GEP tumors by various imaging tech-niques. a Endoscopic ultrasound showing a small (11 mm) pancre-atic insulinoma; b CT imaging of desmoplastic reaction in a patientwith carcinoid syndrome due to an ileum carcinoid; c OctreoScanshowing wide metastatic spread in a patient with a non-functioningendocrine pancreatic tumor; d MRT imaging of liver metastases ina patient with non-functioning endocrine pancreatic tumor; e MRTimaging of two brain metastases in a patient with malignant gastri-noma; f endoscopic demonstration of a rectal carcinoid. Notice theyellow colour �


a

b

c

d

e

f


primary and exclusive diagnostic modality for tumorimaging. Sensitivity of other imaging procedures aresummarised in table 14. Angiography was for manyyears the preferential method in localising insulinomasdue to the characteristic high blood supply of the tumor.In earlier reports successful tumor localization of up to90% has been described whereas more recent data indi-cated a sensitivity of only 30–50%. The method is inva-sive, expensive and requires considerable experience indata interpretation. Therefore, both computed tomogra-phy (CT) with rapid-sequence spiral CT, with oral andintravenous contrast enhancement and magnetic reso-nance imaging (MRI) with the use of dynamic gadoli-nium enhancement and fat suppression have replacedangiography in many centers that prefer an exact pre-operative tumor localization. Somatostatin receptorszintigraphy which recognizes high numbers of soma-tostatin receptors present on most endocrine GEP tu-mors detects, in contrast to other GEP tumors, only 50%of insulinomas due to the inconsistant frequency of so-matostatin receptor subtype 2 on insulinomas. There-fore, negative somatostatin receptor scintigraphy doesnot exclude the presence of an insulinoma.

Treatment. The primary treatment option in patientswith a biochemically proven insulinoma is surgery. Oncethe tumor is localized pre- and intraoperatively sur-geons will decide whether the tumor can be enucleatedor whether proximal or distal pancreatic resection is theperferred method. Total pancreatectomy or “blind” dis-tal resection should be avoided if the insulinoma cannotbe identified intraoperatively. In this case laparotomyshould be terminated and tumor localization repeated.Surgery is also indicated in metastatic insulinoma sinceoperative tumor debulking has been shown to providelong-lasting symptomatic improvement. Symptomatic

antisecretory therapy is indicated in the pre-operativephase and in metastatic disease. To prevent hypoglyce-mic events regular intake of carbohydrates in requiredand a light carbohydrate meal in the late evening isimportant. If diet does not prevent hypoglycemia, oraladministration of diazoxide and subcutaneous long-act-ing somatostatin analogues are the therapeutic priciplesof choice to prevent hypoglycemia whereas β-blockingagents, glucocorticoids, calcium-channel blockers andphenytoin have been used earlier but with limited thera-peutic effects.

Diazoxide is a non-diuretic benzothiadizine that in-hibits the release of insulin from the secretory granulesof normal β-cells and of insulinoma cells. Unfortunately,not all insulinoma patients respond to diazoxide but itshould be tried with starting dosages of 25 µg b.i.d. andthe dose can be escalated up to 200 µg t.i.d. Side effectsincluding cardiac arrhythmia, cardiomyopathy, bonemarrow depression, sodium retention and peripheraledema should be noticed and can force to discontinuetherapy.

Also long-acting somatostatin analogues (Fig. 7) asoctreotide and lanreotide suppress insulin secretion.They have been first introduced for the treatment is dis-abling acromegaly and later for functionally active en-docrine GEP tumors to supress hormone secretion [27].Octreotide, lanreotide and octreotide LAR are modifica-tions of the naturally occuring somatostatin (Fig. 7).Lanreotide and octreotide-LAR bound to polylactid-glycolide microspheres permit sustained release allow-ing single subcutaneous injections of lancreotide every2 weeks and of octreotide-LAR every 4 weeks. Soma-tostatin and its analogs act through a family of at least 5receptors (sstr 1–5). Most encocrine GEP tumors expresssstr 2, whereas the other 4 sstr are less frequently or notexpressed (179). Unfortunately, long acting somatostatinanalogs are effective in only 50% of insulinoma patientssince sstr 2 is only expressed in 50% of insulimas. There-fore, the hypoglycemia preventing effect of somatostatinanalogs is unpredictable. Importantly, somatostatinanalogs can even aggravate hypoglycemic symptomsbecause they suppress also the counter regulatory hor-mone glucagon. Therefore, insulinoma patients mustbe monitored carefully if somatostatin analogs are con-sidered to prevent hypglycemia. Treatment should bestarted with 50 µg short-acting octreotide b.i.d. and in-creased to 200 µg t.i.d. according to the patients re-

Table 14Sensitivity of imaging studies in the detection of endocrine GEPtumors

SRS [%] CT [%] MRI [%] EUS [%]

Gut tumors 72–96% 33% n.d. -

Pancreatic tumors 58–100% 25–38% 24–71% 58–86%

Insulinoma 12–50% 29% 13% 81–94%


sponse. If they respond adequately to the short lastingsomatostatin formulations, the longer lasting octreo-tide-LAR and lanreotide-LAR which have to be admin-istered only every 2 weeks (lanreotide-LAR) or every 28days (octreotide LAR) can be offered.

In patients with malignant and metastatic insuli-noma several therapeutic options have to be consideredincluding palliative surgery, embolisation of liver metas-tases and chemotherapy with streptozotocin combina-tions (for further details see “General aspect of manage-ment” under “Medical treatment of symptoms”)

Persistent Neonatal Hyperinsulinemic Hypoglycemia (PNHH).Persistent neonatal hyperinsulinemic hypoglycemia wasearlier called “nesidioblastosis” and originally describedby Laidlow in 1938 [28]. He called cells which originatedfrom the pancreatic ductal epithelium nesidioblasts,their proliferation nesidioblastosis and the resulting

tumor nesidioblastoma. Today, the term “nesidioblasto-sis” is substituted by the term “persistent neonatal hy-perinsulinemic hypoglycemia (PNHH). This entity ischaracterized by the occurrence of hyperinsulinemichypoglycemia in the absence of an endocrine pancreatictumor. As in insulinomas hypoglycemia occurs in thefasting state and insulin secretion is not adequately sup-pressed. The disease affects newborn children within thefirst 6 months of life and only very rarely adults [28]. Theterm nesidioblastosis is misleading since it implies gen-eral islet cell hyperplasia which does not exist. The pan-creas of the newborn enfant has physiologically muchmore and smaller islets of Langerhans compared to thesituation in later life. The morphological abnormalitiesof the endocrine pancreas that underly PNHH are het-erogeneous and encompass small endocrine tumors(insulinoma), unifocal or multifocal adenomatosis char-acterized by local and excessive proliferation of islet

Figure 7Structure and characteristics of native somatostatin and its long-acting analogues octreotide and lanreotide


cells, hyperplasia of islets of Langerhans and frequentlyeven no recognizable pathomorphological abnormali-ties [28]. In the latter situation, a functional defect of thepancreatic β-cells is assumed to cause unrestrained in-sulin release. PNHH occurs in a sporadic and a familialautosomal recessive form [28]. In the familial variant ofPNHH a genetic defect has been identified on the shortarm of chromosome 11p14–15.1. The respective genecodes for the sulfonylurea receptor which is mutated inthe familial form of PNHH. This mutation results inabnormal insulin secretion and altered sensitivity ofthe β-cell to glucose. The genetic defect responsible forthe sporadic form of PNHH is also identified. A recentreport suggests a dysfunction in the adenosine triphos-phate-sensitive potassium channel present in the plasmamembrane of pancreatic β-cells [29].

Clinically, the respective infants present with non-specific symptoms resulting from neuroglucopenia. Me-dical management includes continuous glucose infusionvia a central venous catheter, diazoxide and long-act-ing somatostatin analogs. Recently, it has been demon-strated that calcium channel blocking agents can beused with efficacy and safety to control hypoglycemia inPNHH. However, definitive cure requires in most pa-tients subtotal pancreatectomy.

Adult onset PNHH is very rare and requires the samemultimodal therapeutic approach as in the infantileform.

Gastrinoma

Epidemiology and Prognosis

Gastrinomas are as insulinomas very rare tumors. Theyearly incidence is 0,5 to 3 per one million population[4, 8]. The mean age at diagnosis is 50 years. Unlikeinsulinomas, the majority of gastrinomas is malignant.Gastrinomas are in 30–50% part of the MEN-1 syndrome[8]. In a recent study with 151 patients with surgicallyremoved non-metastasised gastrinoma, of whom 128were part of MEN-1 syndrome, it has been shown that34% of patients with sporadic gastrinoma but none ofpatients with MEN-1 syndrome were disease free after 10years [30]. This demonstrates that in sporadic gastri-noma definitive cure can be achieved in a substantialproportion by surgery. In contrast, patients with gastri-noma as part of MEN-1 syndrome have either multiplegastrinoma or have metastatic disease at operation.

Whereas insulinomas are almost exclusively locatedin the pancreas and are not located in a special part ofthe pancreas, the vast majority of gastrinomas occur inthe “gastrinoma triangle”. This region is defined by thejunction of the neck and body of the pancreas, the junc-tion of the second and third part of the duodenum andthe confluence of the cystic and common bile duct. 50%of gastrinomas are located in the duodenum. Very rarely,gastrinomas arise in the antrum, omentum, liver, lymphnode or elsewhere [8]. In MEN-1 gastrinomas are morefrequently located in the duodenum where they aremostly very small and multifocal. Sporadic gastrinomas,in contrast, occur more frequently in the pancreas. Themalignant potential of sporadic gastrinomas and thosearising in patients with MEN-1 syndrome is not uniform.Recent studies indicate that approximately one fourth ofpatients with sporadic gastrinomas persue an aggressivegrowth pattern, with a 10-year survival of 30%, whereasin the remaining 75% of patients gastrinomas displaya less aggressive growth pattern with a 10 year survivalof 95% [30]. Similarly, in patients with metastatic gastri-nomas to the liver aggressive growth was demonstratedonly in a minority of patients whereas the majority dis-played indolent growth [30]. Tumor related deaths occuralmost entirely in the aggressive growth group. Accord-ing to a recent investigation in patients with gastrinomaand MEN-1 syndrome growth behaviour is also not uni-form. 23% of patients with gastrinoma and MEN-1 syn-drome developed liver metastases and 14% had anaggressively growing gastrinoma. Aggressive growth ofthe primary gastrinoma but not of liver metastasesgrowing less aggressively was associated with decreasedsurvival [30]. High serum gastrin levels, a primary tu-mor size of >3 cm and the presence of bone and livermetastases were associated with an aggressive gastri-noma growth [30].

Pathophysiology

The pathophysiological events occurring in patients withZollinger-Ellison syndrome are summarized in Fig. 8.Hypergastrinemia as the result of unrestrained hor-mone release from the tumor displays two effects: sti-mulation of gastrid acid secretion from the parietal celland stimulation of parietal and ECL-cells both located inthe oxyntic mucosa of the proximal stomach. The conse-quences of gastric acid hypersecretion are summarizedin Fig. 8. All patients with gastrinoma develop diffuse,


linear and micronodular ECL-cell hyperplasia but gas-tric carcinoids arise almost exclusively in patients withMEN-1 syndrome. This indicates that a genetic traitmust be present together with the trophic action of highserum gastrin levels.

Symptoms

Clinical presentation of patients with Zollinger-Ellisonsyndrome has changed considerably in the last twodecades mainly due to the availability of potent anti-secretory drugs. Before the discovery of H

2-blockers and

proton pump inhibitors patients presented with severerelapsing peptic ulcer disease and its sequelae: life-threatening bleeding and perforation. Patients died fromcomplications and not from the tumor itself. This hasdramatically changed. Most patients with gastrinomapresent today with severe and medically resistant refluxdisease requiring higher than standard dosages of PPIs.More then 90% of gastrinoma patients suffer from epi-gastric discomfort and peptic ulcer disease. Most ulcersare situated in the duodenal bulb or the distal stomach,whereas ulcers located in atypical sites (distal to the

duodenal bulb, jejunum) are the exception. 30% of gas-trinoma patients have helicobacter pylori infection, buteradication has virtually no influence on peptic ulcerrelapse rate. 5–10% of patients do not have peptic ulcerdisease and present with secretory diarrhea (Fig. 8). Pa-tients report on watery stools arising during late nightand early morning with some improvement after intakeof meals. Secretory diarrhea is present in more than50% of gastrinoma patients. A history of nephrolithiasisand the presence of hypercalcemia are suspicious forhyperparathyroidism as part of MEN-1 syndrome. Theassociation between Zollinger-Ellison syndrome andCushing’s syndrome due to ectopic ACTH production bythe endocrine pancreas tumor is rare and patient’s sur-vival depends mainly on the control of hypercorticism(see later).


Differential diagnosis of Zollinger- Ellison syndromeencompass few states of relapsing ulcer disease, hyper-gastrinemia and gastric acid hypersecretion. AntralG-cell hyperfunction is are rare event and results, ac-

Figure 8Pathophysiology of Zollinger-Ellison syndrome


cording to recent reports, from H. pylori infection. Inthese patients H. pylori inhibits antral somatostatinrelease much more powerfully then in other H. pyloriinfected individuals and leads to hypergastrinemia be-cause antral gastrin producing G- and somatostatin-producing D-cells are situated in close vicinity. Afterfood intake serum gastrin increases in patients with an-tral G-cell hyperfunction to much higher levels then inpatients with normogastrinemic ulcer disease. Cure ofinfection prevents further peptic ulcer relapse and fast-ing and postprandial hypergastrinaemia normalize.

The “excluded antrum syndrome” is currently ex-tremely rare and was more frequent in earlier decadeswhen patients with peptic ulcer disease have been sub-jected to distal gastric resection (Billroth II). In this con-dition, a small part of the distal antrum adjacent to theduodenal bulb was inadvertently left on the blind loop.Hypergastrinemia results from the neutral environmentof this part of antral mucosa and produces acid hyperse-cretion with the consequence of relapsing ulcer diseasein the remaining stomach or around the gastro-jejunalanastomosis.

Diagnosis

Biochemical Testing. The triad: “excessive gastric acidhypersecretion, intractable peptic ulcer disease and thepresence of a non-insulin-producing pancreatic endo-crine tumor” was recognized as entity in 1955 by Zollin-ger and Ellison. Biochemically, diagnosis of a Zollinger-Ellison syndrome is based on the simultaneous presenceof elevated serum gastrin levels and low intragastric pH.Elevated serum gastrin levels alone do not prove a gas-trinoma since it can be found in several conditionsmostly as consequence of reduced or absent gastric acid.Examples are the intake of PPIs, the presence of chronicatrophic gastritis (type A gastritis) and severe H. pylori

associated chronic gastritis (Table 15). Therefore, diag-nosis of Zollinger-Ellison syndrome is easily made if el-evated serum gastrin levels combined with gastric acidhypersecretion exists. Since most patients with Zollin-ger-Ellison syndrome are under long-term PPIs, treat-ment should be stopped and shorter lasting H

2-blockers

offered. Ten days after discontinuation of PPI-treatmentbasal acid secretion and serum gastrin should be stud-ied after 12 hours withdrawal of H

2-blockers. A serum

gastrin level of greater 500 pg/ml in the absence of con-ditions summarized in table 14 but in the presence ofelevated basal acid output (BAO) are highly suggestiveof Zollinger-Ellison syndrome. BAO is generally above10 mEq/hr in an intact stomach and above 5 mEq/hr inpatients after Billroth I and II resection. If serum gastrinlevels are in the upper normal range or only moderatelyelevated Zollinger-Ellison syndrome can be confirmedby a secretin provocative test. After intravenous rapidinjection of 2 U/kg secretin, serum gastrin rises “pa-radoxically” within 15 minutes by more then 50% or200 pg/ml in patients with Zollinger-Ellison syndrome.Blood for gastrin measurement should be taken at times– 5 min and immediately before secretin and after 2, 5, 15and 30 minutes post secretin. The mechanism of gastrinincrease after secretin is not completely understood.There are no other conditions with gastrin increase aftersecretin. In contrast, hypergastrinemia due to chronicatrophic gastritis or “excluded antrum” declines aftersecretin (Fig. 9). The sensitivity of the secretin test is be-low 100% since in some gastrinoma patients no or onlysmall increases of serum gastrin occur.

Localization. During the past decade significant advancesin the localization of endocrine GEP tumors could beachieved. Imaging studies in patients with gastrinomaare focused on the detection of the primary (pancreas,duodenum, elsewhere) and to the presence of metasta-ses. As other malignant endocrine tumors malignantgastrinomas tend to metastasize into lymph nodes, liver,bones and other sites as skin and brain. Somatostatinreceptor szintigraphy using 111indium-labelled octreotide(OctreoScan) has changed the imaging strategies ofgastrinomas and other endocrine pancreatic tumorssince somatostatin subtype 2 (sst

2) receptors have been

demonstrated in approximately 90% of gastrinomas us-ing in vitro autoradiography. It could be shown thatOctreoScan has a sensitivity of 71–75% and a specificityof up to 82% (see Fig. 7c). According to a recent report in

Table 15Differential diagnosis of hypergastrinemia

With gastric acid hypersecretion With hypo- or achlorhydria

Antral G-cell hyperfunction Typ-A gastritis

Massiv resection of small bowel Renal insufficiency

“excluded antrum” Prolonged acid-suppressive

medication


which OctreoScan was compared with conventional im-aging procedures in 80 gastrinoma patients, OctreoScanwas the most sensitive modality for detection of primaryand metastatic gastrinoma. However, size of the primarygastrinoma was an important factor and tumors smallerthen 0.5 cm could not be visualized. According to thisstudy 33% of primaries, especially small duodenal gas-trinomas that could be detected later intraoperatively,were missed by OctreoScan [8]. Somatostatin receptorszintigraphy and MRI were the most sensitive imagingprocedures to detect bone metastases and OctreoScanwas the only method to distinguish small liver metas-tases from small hemangiomas. Therefore, OctreoScanis presently the imaging procedure of choice to localizethe primary and to define the extent of metastatic spread.As in insulinomas endoscopic ultrasound is highly accu-rate in the localization of small pancreatic and duodenalgastrinomas whereas contrast medium enhanced CTand MRT have been shown to have sensitivities of ap-proximately 80–85% [32].

The most important questions which have to be an-swered are:� Is the biochemically and clinically highly suggestive

gastrinoma sporadic or part of the MEN-1 syndrome?� Is the gastrinoma malignant and has spread to lymph

nodes, to the liver and elsewhere?� What is the potential benefit of surgical interven-

tion?

If the size of a gastrinoma is greater then 2 cm in case ofa pancreatic tumor (see Table 7) and greater then 1 cm incase of a duodenal tumor (see Table 9) malignant be-haviour is likely and the effect of surgical interventionwith respect to cure the disease uncertain. In patientswith MEN-1 syndrome frequently more then only 1 en-docrine pancreatic tumor can be visualized. In this con-dition it is almost impossible to identify the tumorwhich is responsible for the Zollinger-Ellison syndrome.

For practical reasons one should always start withOctreoScan. If the primary as well as metastatic spreadhave been detected by OctreoScan the findings shouldbe further confirmed by contrast-medium enhanced CTor MRT (see Fig. 7e). If a solitary gastrinoma, no pri-mary and no metastases are found by OctreoScan andupper abdominal CT and/or MRT careful upper gastro-duodenoscopy should be performed to confirm the pre-sence of a duodenal primary. Endoscopic ultrasoundshould complete endoscopy. In case of a solitary primary

and if no primary and no metastases exist laparotomy isindicated to localize and to remove the primary tumorwithin the “gastrinoma triangle”.

Treatment. The sequelae of gastric acid hypersecretion asreflux disease, peptic ulceration and watery diarrhea canbe effectively controlled by proton pump inhibitors (PPI).They have completely substituted surgical procedures astotal gastrectomy and vagotomy. They are superior to allavailable histamin-H

2-blockers. For all currently avail-

able PPIs a comparable therapeutic efficacy and safetyhas been demonstrated. However, the exact dosage nec-essary for symptomatic control and for inhibition ofgastric acid secretion has to be determined for every in-dividual patient. The dosage can range from normal and3–4 times elevated dosages. One should start with theregular PPI dose bid (2×20 mg Omeprazole; 2×30 mgLanzoprazole; 2×40 mg Pantoprazole; 2×40 mg Rabe-prazole etc.) and increase the dosage until patients are

Figure 9a–dSerum gastrin levels after secretin injection in patients with aZollinger-Ellison syndrome; b antral G-cell hyperfunction; c patientwith “excluded antrum”; d patients with regular duodenal ulcer dis-ease


symptom-free and BAO decreased to less then 5 mEq/hrin patients with intact stomach. BAO should be studiedprior to the next scheduled dose. If BAO is around0 mEq/hr PPI dosage should be reduced if desired.

There is no place for long-acting somatostatin ana-logs which have to be administered subcutaneously andwhich do not control acid secretion as reliably as PPIs.

In case of a sporadic non-metastasized gastrinoma,surgical removal should always be desired [31]. In pa-tients with a gastrinoma as part of MEN-1 syndromeavailable data do not indicate whether removal of theprimary has an survival advantage for the patient. In ad-dition it is difficult to define which of several pancreatictumors is the tumor responsible for the Zollinger-Ellisonsyndrome. Therefore, laparotomy in Zollinger-Ellisonsyndrome and MEN-1 syndrome is a controversial issue.

For management of metastatic disease see under“General aspect of management”.

Glucagonoma

Definition, Epidemiology and Prognosis

Glucagonomas are endocrine pancreatic tumors thatcontain predominantly glucagon. However, only some ofthese tumors secrete excessive amounts of glucagon intothe circulation and cause the glucagonoma syndrome.The latter tumors are malignant, sized 5 cm in diameterand even larger, frequently solitary but they can spreadto the liver, lymphnodes, bone and other sites. Most glu-cagonomas, especially small tumors found in most pa-tients with MEN-1 syndrome are non-functioning andnot associated with a clinical syndrome. Their malig-nant potential is small.

All glucagonomas whether functionally inactive oractive encompass less then 1% of all endocrine tumorsof the GEP system. Whereas functionally inactive smalland benign glucagonomas are found not only in patientswith MEN-1 syndrome but even by chance at autopsy theglucagonoma syndrome is rare if compared withinsulinoma and gastrinoma.

The prognosis of small functionally inactive gluca-gonomas is likely favourable whereas in the malignantvariant as cause of the glucagonoma syndrome progno-sis depends on the aggressiveness of tumor growth andthe response to antiproliferative measures.

Pathophysiology

Elevated glucagon levels have metabolic consequenceswhich explain some but not all clinical features in pa-tients with glucagonoma syndrome. Weight loss resultsfrom the catabolic effects of glucagon and from a re-cently described anorectic substance found in animalswith transplantable glucagonoma. Glucagon stimulatesglycogenolysis and gluconeogenesis leading to impairedglucose tolerance and diabetes mellitus as found in mostPatients with glucagonoma syndrome. Since exogenousadministration of glucagon decreases erythropoiesis inanimals anemia which is frequently observed in thesepatients can be attributed to glucagon hypersecretion.However, the role of hyperglucagonemia in the patho-genesis of thromboembolic complications includingpulmonary embolism is poorly understood. The necro-lytic migratory erythema (Fig. 10) is believed to be re-lated to hypoaminoacidemia present in most but not allpatients and not the consequence of hyperglucagon-emia. Skin lesions disappear despite high glucagonlevels if plasma amino acid levels normalize. They aresimilar to those observed in patients with zink defi-ciency and zink suplementation has been shown toimprove skin lesions in some patients as well. Accordingto the authors experience skin lesions can disappearafter resection of the primary without normalizationof hyperglycagonemia and hypoaminoacidemia due tometastases to the liver suggesting a still undetected sub-stance released by the tumor as cause of the necrolyticmigratory erythema.

Symptoms

Main symptoms in patients with glucagonoma syn-drome are skin lesions, diabetes mellitus, weight lossand anorexia present in up to 90% of patients with glu-cagonoma syndrome. Less frequently normochromicand normocytic anemia, venous thrombosis and pul-monary embolism occur. Diarrhea and steathorhea arepresent in 14% of patients. Their etiology is unclear. Rareclinical features include, in addition, psychiatric distur-bances including depression and complex neurologicsymptoms with dementia and optic atrophy, possiblerelated to protein hypercatabolism that can recover aftertreatment with long-acting somatostatin analogs.


The necrolytic migratory erythema is one of themost impressive clinical symptoms in patients with glu-cagonoma syndrome. Skin lesions involve the lower ab-domen, groin perineum, face, armpits (Fig. 10) and distalextremities. They start with an erythematous lesionwhich becomes papular. The erythema spreads periph-erally and becomes raised with superficial central blis-tering. Lesions begin to heal in the center with a raisederythematous ring. Healing is followed by hyperpig-mentation. The sequence of skin manifestations take1–2 weeks while new lesions appear elsewhere. Skin le-sions frequently precede the diagnosis of the syndromefor many years and are misdiagnosed as acrodermatitisenteropathica, psoriasis, contact dermatitis and otherskin disorders.

Diagnosis

Diagnosis is based on the presence of a mostly largepancreatic tumor with and without metastases to theliver or elsewhere, clinical symptoms described in detailin “Symptoms” and the demonstration of high plasmaglucagon levels. Total plasma aminoacids should be de-termined and support the diagnosis if they are markedly

decreased. In most patients the pancreatic tumor canbe visualized by conventional US. Fine-needle biopsyproves the endocrine nature of the tumor. Somatostatinreceptor szintigraphy, CT and MRT imaging are helpfulin evaluating tumor burden outside the pancreas [32].

Treatment

Surgical removal of the primary and of resectable livermetastases should always be considered because tumordebulking has been shown to have a favourable effect onclinical symptoms including skin lesions.

Medically, long-acting somatostatin analogs havebeen shown to be currently the medical principle ofchoice in the control of skin lesions, to improve symp-toms as weight loss, anemia and diarrhea. Most studiesrecommend 200–600 µg per day or 10–20 mg octreo-tide-LAR every 28 days. Unfortunately, long-acting so-matostatin analogs are not effective in up to 50% ofpatients. In these individuals debulking operation, em-bolization of liver metastases and chemotherapy withstreptozotocin combinations or dacarbazine should beconsidered. For details see “General aspect of manage-ment”.

Figure 10Necrolytic migratory erythemain two patients with glucagonomasyndrome


Verner-Morrison Syndrome (VIPoma)

Epidemiology and Prognosis

An endocrine tumor mostly located within the pancreasand responsible for a syndrome characterized by ex-treme watery diarrhea, hypochlohydria and hypokale-mia was first discribed by Priest and Alexander in 1957and by Verner and Morrison in 1958. Alternative acro-nyms are “Verner-Morrison syndrome”, “VIPoma” (dueto the hormone vasoactive intestinal polypeptide re-sponsible for the diarrhea), “WDHH (watery diarrhea,hypokalemia, hypochlorhydria) syndrome” and “Pan-creatic Cholera”. In adults VIPomas are mostly locatedin the pancreas and rarely outside the pancreas in theretroperitoneum, liver, small intestine and bronchial sys-tem. In children, a ganglioneuroma or an ganglioneuro-blastoma can cause a VIPoma syndrome. Most VIPomasare malignant and have metastasized to the liver at diag-nosis. VIPomas are as glucagonomas, somatostatinomasand endocrine pancreatic tumors with ectopic hormoneproduction very rare. Prognosis of this malignant tumorwas prior to the availability of long-acting somatostatinanalogues unfavourable and patients died from the con-sequences of excessive watery diarrhea as dehydratationand pulmonary embolism. Presently, prognosis dependson the aggressiveness of tumor growth which differsbetween VIPomas and their responsiveness to chemo-therapy.

Pathophysiology

Although VIPomas produce frequently several hor-mones as Peptide Histidine-Methionine-28 (PHM-27),secretin, pancreatic polypeptide and prostaglandines,vasoactive intestinal polypeptide (VIP) which is eleva-ted in all patients with Verner-Morrison syndrome is thecause of watery diarrhea and electrolyte disturbances.VIP induces massive small intestinal net secretion ofwater and ions, especially potassium with an inconsis-tent effect on water absorption in the colon. If VIP is in-fused intravenously in healthy individuals in amountsreflecting circulating VIP-levels in patients with Verner-Morrison syndrome, subjects develop massive secretorydiarrhea, hypokalemia and hypochloremic metabolicacidosis. VIP reduces water and sodium absorption

from the colon and induces potassium secretion, thusexplaining hypokalemia which may induce secondaryhypoaldosteronism. In addition, VIP inhibits gastricacid secretion. Fluid secretion from the small intestine isattributed to activation of adenylate cyclase and cyclicadenosine monophosphate in intestinal cells. Some pa-tients develop hypercalcemia which is attributed to thestimulation of bone osteolytic activity by VIP.

Symptoms

Patients with Verner-Morrison syndrome present withexcessive watery diarrhea up to 5–10 L per day. Chronicdiarrhea is a constant feature in 50% of patients butmay be intermittent in others. Diarrhea decreases onlyslightly during fasting or exclusive parenteral nutritionproving its secretory nature. Untreated diarrhea leads todehydration, weight loss, hypkalemia and hypomagnes-emia resulting in paresthesia, muscle weakness and car-diac arrhythmia. Before the availability of long-actingsomatostatin analogs patients died from the consequen-ces of dehydration and electrolyte loss as cardiac ar-rhythmia and pulmonary embolism. 25% of patientsreport flushing episodes.


Secretory diarrhea of other origin as diarrhea in pa-tients with Zollinger-Ellison syndrome, carcinoid syn-drome, medullary carcinoma of the thyroid is mostlyless pronounced compared to diarrhea in VIPomapatients. A stool volume of less then 700 ml per dayexcludes a VIPoma and is suggestive for other causesof secretory diarrhea. The most important differentialdiagnosis is laxative abuse and Münchhausen’s syn-drome. Repeatedly normal VIP-levels should inducesearch for laxatives in stool and urine.

Diagnosis

The combination of excessive watery diarrhea, hypo-kalemia and elevated plasma VIP-levels together witha pancreatic mass visualized by conventional US or CT/MRT imaging are highly suggestive for a VIPoma. Theendocrine nature of the tumor can be ascertained byfine needle biopsy.


Treatment

Surgical intervention should always be considered ifthe primary is resectable and liver metastases could beremoved with tenable risk for the patients. Medicaltherapy and patient’s prognosis have been dramaticallychanged through the currently available long-acting so-matostatin analogs. They substituted a number of drugstried earlier to control diarrhea as loperamide, pred-nisone, clonidine, phenothiazines, indomethacin, lithi-um and others. Octreotide is in most patients effectiveand doses of 200–600 µg per day in two to three singleinjections are recommended. If the short lasting formu-lations are effective, long-acting depot formulationsas octreotide-LAR 20 mg every 28 days can be offered.Unfortunately, some patients escape from treatmentwith long-acting somatostatin analogs after an initiallonger lasting response. The mechanisms behind tachy-phylaxis and/or desensitisation are not completely un-derstood. Treatment should be terminated and startedagain after few weeks.

Somatostatinoma

Epidemilogy and Prognosis

Somatostatinoma is an endocrine tumor containing so-matostatin as shown by immunihistology and ariseseither in the pancreas or in the duodenum where it is lo-cated close to the ampulla vateri. Most duodenal soma-tostatinomas are solitary and small (<1,5 cm) whereaspancreatic somatostatinomas tend to be larger. Malig-nancy rate in large tumors is 50–90% and metastases toliver, lymph nodes and bones have been described. Ac-cording to table 9 duodenal somatostatinomas tend tometastasize if they are larger then 2 cm.

Approximately 90% of these tumors are functionallyinactive and only 10% are cause of the somatostatinomasyndrome. Non-functional somatostatinomas located inthe region of ampulla vateri are associated with vonRecklingshausen’ s disease. Small pancreatic somatosta-tinomas of the pancreas can be part of MEN-1 syndrome.Prognosis of somatostatinomas seems to be favourablein small, non-metastasized tumors. In larger tumors itdepends on the aggressiveness of tumor growth.

Pathophysiology

Somatostatin inhibits the release of gastrointestinal hor-mones as CCK and gastrin, inhibits basal and simulatedgastric acid secretion and stimulated pancreatic secre-tion and inhibits the absorption of food constituentsfrom the intestine. Through inhibition of CCK releasesomatostatin inhibits gallbladder emptying. Inhibitionof pancreatic secretion is believed to cause diarrhea andsteatorrhea in the somatostatinoma syndrome. Sincesomatostatin inhibits insulin release impaired glucosetolerance is a frequent finding in patients with somato-statinoma syndrome.

Symptoms

Leading symptoms in patients with somatostatinomasyndrome are cholecystolithiasis, diabetes mellitus, diar-rhea and steatorrhea, hypochlorhydria and as a conse-quence of a tumor situated close to the ampulla vateriobstructive jaundice. However, the reported symptomsare rarely present in all patients with somatostatinomasyndrome. Other symptoms are epigastric pain, weightloss and nausea.

Since symptoms in patients with somatostatinomasyndrome can arise although in other conditions ascholecystolithiasis, diabetes mellitus and diarrhea andsteatorrhea some authors question the existence of thisentity.

Treatment

Medical treatment should be directed to correct symp-toms associated with cholecystolthiasis, diabetes melli-tus and diarrhea. Few observations suggest that diarrheaand diabetes mellitus can improve by exogenous soma-tostatin. But this suggestion is clearly experimental. Sur-gery should considered to be reduce tumor burden.

Tumors with Ectopic Hormone Production

Epidemiology, Classification and Prognosis

Most benign and malignant endocrine GEP tumors pro-duce more then one hormone within the same tumor.Insulinomas contain next to insulin frequently somato-


statin-producing and glucagon-producing cells, gastri-nomas additional pancreatic-polypeptide-, insulin- andsomatostatin-producing cells (see Fig. 2). As a rule theadditional hormones are not released into the circula-tion and do not produce hormone-mediated symptoms.In patients with MEN-1 syndrome, however, two clinicalsyndromes from two independent pancreatic or onepancreatic and one duodenal endocrine tumor can arise,mostly the combination of a gastrin-producing tumorsituated in the duodenal bulb with the clinical symp-toms of Zollinger-Ellison syndrome and a pancreaticfunctionally active insulinoma. In the latter conditionadditional endocrine pancreatic tumors exist, mostlyglucagonomas and somatostatinomas which are func-tionally inactive.

Apart from tumors producing multiple hormonesregularly synthetized in the normal islets of Langerhansof adults (insulin, glucagon, pancreatic polypeptide,somatostatin) or during fetal life (gastrin) (eutopic hor-mone production) endocrine pancreatic tumors canproduce hormones uncommon for the endocrine pan-creas (ectopic hormone production) as growth hormone-releasing factor (GRF), ACTH or corticotropin-releasingfactor (CRF) and parathyroid hormone-related peptide(PTH-RP) or an unknown hypercalcemic substence mi-micking the action of PTH. These tumors are mostlymalignant and very rare. In addition, few patients withneurotensin-producing tumors have been described. Tu-mor prognosis depends on the aggressiveness of tumorgrowth and the success of antiproliferative measures.

Clinical Symptoms, Pathophysiology and Diagnosis

GRFoma. The association of acromegaly with endocrinebronchial, intestinal and pancreatic tumors is rare andapproximately 150 patients with this syndrome havebeen described. Pancreatic GRFomas are mostly largebut multiple GRFomas have also been reported. Theyare part of MEN-1 syndrome. Different from pituitaryadenoma GRFomas arise 3 times more frequent in fe-males then in males. They can be associated with otherendocrine syndromes as gastrinoma, insulinoma, Cush-ing’s syndrome and pheochromocytoma. In 30–40%metastatic disease which spreads mostly to the liver ispresent.

Clinically, patients present with characteristic signsindistinguishable from pituitary derived acromegalywith elevated GH and IGF-1 levels. If GRFomas are asso-

ciated with other endocrine functionally active tumors,symptoms of acromegaly could be blurred by hypogly-cemia resulting from an insulinoma etc.

Treatment includes surgical resection of the primaryand debulking procedures and, medically, the suppres-sion GRF levels by long-acting somatostatin analogs.

ACTH-Producing Tumors. According to a recent report fromthe Mayo Clinic in 106 patients ectopic ACTH or CRFproduction results in 25% from bronchial carcinoids,16% from malignant islet cell tumors, 16% from medul-lary thyroid carcinoma, 11% from small cell carcinomaof the lung, 7% from disseminated neuroendocrine tu-mors with unknown primary source, 5% from thymiccarcinoids and 3% from pheochromocytoma. Whereasin MEN-1 syndrome Cushing’s disease results from apituitary adenoma ectopic ACTH-production in thecase of an islet cell tumor has been found mostly in spo-radic gastrinomas. In the latter condition the gastri-noma is metastatic and the prognosis poor.

In a recent prospective study Cushing’s syndrome inpatients with Zollinger-Ellison syndrome due to a soli-tary malignant gastrinoma was an independent pre-dictor for poor survival. Patients with ectopic ACTHsyndrome differ from those with pituitary adenoma be-cause they present with muscle waisting and weight losswhich is more frequently observed then the classicfeatures of Cusing’s syndrome.

Possibly, symptom differences in patients with ec-topic and eutopic ACTH-production result from a differ-ent processing of pro-piomelanocortin with the releaseof high amounts of ACTH precursors and less intactACTH in the circulation in patients with ectopic hor-mone production. However, symptoms may overlapthose seen in pituitary dependent Cushing’s disease.Ectopic ACTH-producing endocrine tumors are moreresistant to chemotherapy and the severe hyper-cortisolism is responsible for a high rate of life-threaten-ing complications.

Treatment is frequently difficult since only few tu-mors respond to long-acting somatostatin analogs. Ifketoconazoles, animogluthetimide or mifepristone donot control hypercortisolism and curative or palliativeresection of the primary tumor and its metastases is notpossible, patients are likely to benefit from bilateraladrenalectomy. For additional antiproliferative mea-sures see “general aspects of management” (below).


PTH-RP-Producing Tumors. Few endocrine pancreatic tu-mors present with hypercalcemia and secret parathyroidhormone-related peptide (PTH-RP) or not identifiedhypercalcemic substances mimicking the action PTH.According to a recent review of 19 patients common fea-tures were hypercalcemia, normal or low PTH levelsassociated with extremely vascular, large and usuallymalignant tumors (17 of 18) displaing positive stains forPTH-RP. Some patients respond favourably to long-act-ing somatostatin analogs and to streptozotocin combi-nations if tumor resection is not possible.

Nonfunctioning Endocrine Pancreatic Tumors


Nonfunctioning endocrine pancreatic tumors can besubdivided into benign and small tumors as part of theMEN-1 syndrome and large, malignant tumors whichmostly spread into lymph nodes, liver, bones, and else-where. The latter can or cannot secret hormonal prod-ucts into the circulation. Pancreatic polypeptide orneurotensin are released by some tumors but do notproduce a clinical syndrome. Other functionally inactivetumors do not secret any products with hormonal activ-ity. However, they release chromogranin A, a constituentof the secretory machinery of endocrine cells. Exactincidence rates for malignant non-functioning tumorsare missing but according to own experiences they areat least as frequent as all functionally active endocrinepancreatic tumor together. By histology and immuno-histology functioning PETs cannot be distinguishedfrom nonfunctioning tumors.

Clinically, tumors and their metastases are eitherfound incidentally at routine abdominal check-up, bythe patient itself who realizes the presence of an upperabdominal mass or by obstructive jaundice due to apancreatic head tumor. Most patients report no or onlylittle upper abdominal discomfort and few present withmore severe abdominal pain and weight loss. Frequently,tumors are misdiagnosed as endocrine pancreatic carci-nomas but the unrestricted life quality of patients andhypervascular lesions identified by imaging procedureslead the correct diagnosis. Other patients present duringroutine US investigations with cystic liver lesions mis-diagnosed as benign liver cysts. Prognosis of patientswith non-functioning malignant tumors depends onthe aggressiveness of tumor growth which can vary

considerably from exploding tumor growth to long in-tervals of stable disease even in the absence of any treat-ment.

Diagnosis

The correct diagnosis requires histology which canmostly be obtained by ultrasound or CT-guided fine-needle biopsy. If the endocrine nature of the primarytumor or of its metastases is ascertained, OctreoScanshould be performed to identify tumor load and the pre-sence of distant metastases as in bones. If the primary isnot identified within the pancreas upper and lower en-doscopy and careful CT/MRT examinations of the chestshould be performed to localize the primary within thefore-, mid- and hindgut (Fig. 6d). Because tumors do notproduce a hormone-mediated syndrome, expensive hor-mone analyses are not helpful and should be avoided.However, chromogranine A should be estimated whichis elevated in most metastatic tumors and serves as tu-mor marker. Some tumors produce, in addition, pancre-atic polypeptide which serves as tumor marker as well.

Treatment

Treatment should follow the principles of other endo-crine pancreatic malignancies. If resectable, non-meta-static primaries should be removed either by Whipple’sprocedure or partial pancreatectomy. In metastatic disea-ses several antiproliferative measures are available whichare summarized under “general aspect of management”.

Endocrine Tumors of the Stomach and Gut

Gastric Carcinoids

Epidemiology, Classification. Endocrine tumors of the sto-mach are nonfunctioning. As shown in table 8 there are4 types of tumors:� ECL-cell carcinoids;� EC-cell carcinoids;� Gastrin-cell tumors;� poorly differentiated or small cell endocrine carci-

nomas [9, 10].

With the exception of the latter tumor most endocrinetumors of the stomach are well differentiated. Gastriccarcinoids have been reported to occur with an inci-


dence of 0,002–0,1 per 100.000 population per year andaccount for 11–41% of all gastrointestinal carcinoidsfrom the esophagus to the rectum. The most frequentendocrine tumors of the stomach are gastric ECL-cellcarcinoids representing 74% of gastric endocrine tu-mors and occuring more frequently in females. Themean age of detection is 63 years. Small cell undifferen-tiated carcinomas represent 6% of endocrine tumors ofthe stomach. EC-cell and Gastrin-cell carcinoids are ex-tremely rare.

ECL-Cell Carcinoids. Clinical and histopathological aspectsand prognosis: ECL-cell carcinoids can be subdividedinto three entities:� type I ECL-cell carcinoids are associated with type

A-gastritis (autoimmune chronic atrophic gastritis)present in the oxyntic and fundic part of the gastricmucosa. Due to the loss of parietal cells type I ECL-cell carcinoids are always associated with achlorhy-dria and – as a consequence of achlorhydria – withmassive hypergastrinemia of antral origin achievinglevels comparable to that observed in Zollinger-Elli-son syndrome. Carcinoids in type A-gastritis are us-ually small and multiple.

� type II ECL-cell carcinoids arise in patients with hy-pergastrinemia due to a Zollinger-Ellison syndrome,mostly as part of MEN-1 syndrome. In contrast totype I carcinoids oxyntic mucosa is hyperplastic dueto the trophic action of gastrin but without any atro-phic changes.

� type III (sporadic) ECL-cell carcinoids are neitherassociated with type- A atrophic gastritis althoughgastritis is present nor with hypergastrinemia. Theyarise in areas without ECL-cell hyperplasia which isa prerequisite for the formation of type-I and type-IIECL-cell carcinoids. Clinically, type III tumors pre-sent with relatively large (1–3 cm) tumors that areusually aggressive with local invasion and the forma-tion of metastases to adjacent lymphnodes and theliver. They are mostly non-functioning but can bethe source of gastric hemorrhage and obstruction. Inrare cases they can be associated with an atypicalcarcinoid syndrome with red long-lasting flushingepisodes but without diarrhea. These tumors secretehistamine and 5-hydroxytryptophane.

ECL-cell carcinoids arise from ECL-cells that are physi-ologically present in the oxyntic and fundic mucosa andcontain histamine which stimulates gastric acid secre-tion via specific receptors on the parietal cells. They canproliferate by two mechanisms: both chronic atrophicgastritis and the trophic action of hypergastrinemia leadto ECL-cell hyperplasia which can further proliferate totype I ECL-cell carcinoids. Histologically ECL-cell hy-perplasia consists of linear, diffuse, micronodular andadenomatoid ECL-cell hyperplasia (Fig. 11). The nextstep in tumor formation is dysplasia with enlarging andfusing micronodules, microinvasion and newly formedstroma. Nodules greater than 0.5 mm and invading intosubmucosa are called carcinoids. Smaller and multiple

Figure 11Histology of ECL-cell hyperplasia


nodules together with linear and diffuse ECL-cell hyper-plasia a constituents of microcarcinoidosis. All theseevents are found in type A chronic atrophic gastritis andthe ultimate step is the formation of type I carcinoids.

An identical spectrum of ECL-cell growth fromECL-cell hyperplasia to carcinoid formation is present ingastrinoma patients as part of MEN-1 syndrome. In con-trast, sporadic gastrinoma patients develop ECL-cellhyperplasia but likely not ECL-cell carcinoids. This indi-cates the importance of a genetic trait (MEN-1) essentialfor the formation of type II carcinoids or the presence ofsevere atrophic gastritis as prerequisit for type I carci-noid formation through the trophic action of hyper-gastrinemia present in both.

Prognosis of type I and II ECL-cell carcinoids is ex-cellent and favourable prognostic factors are: tumorsconfined to mucosa and submucosa, size <1 cm, low mi-totic activity (Ki-67) and lack of angioinvasiveness. Incontrast, angioinvasion, a size >1 cm, invasion of muscu-laris propria and beyond and high mitotic activity indi-cate a more aggressive behaviour. Metastatic spread intolymph nodes and to the liver is rare (5% rsp. 2.5% intype-I carcinoids) and slightly greater in type-II carci-noids.

Treatment: ECL-cell carcinoids (type I) in type-Achronic atrophic gastritis are mostly small and shouldbe endoscopically excised. Yearly controls are recom-mended for further surveillance. If carcinoids are largerthan 1 cm endoscopic US should estimate whether ornot invasion of muscularis propria is present. In case ofinvasion local surgical excision is recommended. Noagreement exists between experts whether or not antr-ectomy should be offered to remove the gastrin sourceas the trophic principle responsible for carcinoid forma-tion.

Type II ECL-cell carcinoids should be handled astype I tumors but patients‘ prognosis depends mostly onthe aggressiveness of underlying Zollinger-Ellison andMEN-I syndrome.

Type III ECL-cell tumors (sporadic carcinoids) shouldbe removed according to the principles for non-endo-crine gastric adenocarcinomas. No proven strategy ex-ists if metastatic spread occurred. Tumors are mostlyinsensitive to available chemotherapeutic strategies.

EC-Cell Carcinoid. EC-cell carcinoids are very rare and al-ways malignant. They present with rapid growth and arefunctionally inactive.

Gastrin-Cell Tumor. These very rare tumors are mostly welldifferentiated and small. They are found incidentally atendoscopy as small muscosal/submucosal nodules. Theycan and can’t present with Zollinger-Ellison syndrome.

Small Cell Carcinoma (Poorly Differentiated Endocrine Neo-plasm). These very rare tumors display exploding tumorgrowth similar to small cell carcinomas of the lung andof other origin.

Endocrine Tumors of the Duodenumand Proximal Jejunum


Duodenal carcinoids account to 22% of all gastrointes-tinal carcinoids (see Table 9). In contrast, jejunal car-cinoids are very rare. Most endocrine tumors of theduodenum are gastrinomas which in 7–21% are part ofMEN-1 syndrome. Not all gastrinomas are cause for aZollinger-Ellison syndrome and present as non-func-tional tumors. Gastrinomas can arise at multiple sites(15%) and are mostly small (<1 cm). Non-functioninggastrinomas have a more favourable prognosis as tu-mors associated with Zollinger-Ellison syndrome thathave a higher incidence of metastases. However, com-pared to pancreatic gastrinomas duodenal gastrinomashave significantly less frequent metastases to the liver(5% versus 52%). Ten years survival of patients withduodenal gastrinoma is significantly better then thoseof pancreatic origin (59% versus 9%).

Somatostatinomas account for 21% of endocrinetumors in the upper small intestine and are located at,or very close to, the ampulla of vater. They are larger asgastrinomas (>2 cm) and can cause obstructive jaun-dice, pancreatitis and intestinal obstruction. Histolo-gically, tumors contain characteristic concentrically la-minated psammoma bodies. They are mostly malignant,with local invasion into surrounding tissues (sphincterof Oddi, head of the pancreas) and spread into paraduo-denal lymph nodes and to the liver. Duodenal somato-statinomas are mostly non-functioning and geneticallyassociated with neurofibromatosis von Recklinghausen.

Gangliocytic paragangliomas are very rare eventscharacterized by an admixture of three cell types: spin-dle cells, epithelial cells and ganglionic cells. The spindlecells are neural in nature. They are usually benign butcan be larger then 2 cm in size.


Treatment

Duodenal gastrinomas should be surgically removed ei-ther by local excision or Whipple’s procedure. In cased ofmetastatic spread surgery should be avoided. The placeof radical surgery in patients with duodenal and/or pan-creatic endocrine tumors as part of MEN-1 syndrome iscontroversial even between experienced surgeons. So-matostatinomas and gangliocytic paragangliomas shouldbe resected if possible. In case of metastatic spread, see“General aspect of management” under “Control of tu-mor growth in malignant and metastatic tumors”.

Endocrine Tumors of the Distal Small Intestine(Jejunum, Ileum)


The incidence of carcinoids arising in the distal smallbowel has been reported to be 0,28–0,89 per 100.000population and year. Most gastrointestinal carcinoidsare localized in this area (see Table 10). Carcinoids ofthis site have been observed in equal proportion inmales and females with and age peak in the 6th and 7th

decade. Histologically, tumors are EC (enterochromaf-fine)- cell carcinoids containing serotonin. A minority ofcarcinoids consists of glucagon-like peptides- or pancre-atic polypeptide- and peptide YY producing cells. EC-cell carcinoids can be multiple and are in 15% associatedwith other malignancies as gastrointestinal adenocarci-noma, breast cancer and others. The majority of tumorsis located in the distal ileum close to the ileocecal valve.Only 5–7% of EC-cell carcinoids are functionally activeand cause of the carcinoid syndrome. The primary ismostly situated in the ileum. Despite most EC-cell car-cinoids are functionally inactive patients present withintermittent lower abdominal cramps due to incompleteintestinal obstruction and desmoplastic reaction of themesenterium. Occasionally, small ileal carcinoids areincidentally detected during routine colonoscopy.

Prognosis of carcinoids arising in the distal jejunumand ileum is generally unfavourable if compared to thatfor duodenal, gastric (ECL-cell carcinoids) and rectalcarcinoids since endocrine tumors arising in the distalsmall intestine frequently lead to metastases. 10 yearsurvival is approximately 43% and more favourable ifthe primary tumor is removed and liver metastases ab-sent. Therefore, patients with even small ileal carcinoids

found incidentally during routine colonoscopy shouldbe recommended right-sided hemicolectomy since me-tastatic spread into regional lymph nodes occurs earlyand is independent on the size of the primary.

Pathophysiology and Symptoms

Non-Functioning EC-Cell Tumors. Even tumors less than 1 cm,confined to the mucosa and submucosa discovered inci-dentally during colonoscopy and intubation of the ter-minal ileum are frequently malignant with metastaticspread to regional lymph nodes (see Table 10). They pre-sent very rarely with gastrointestinal bleeding.

Tumors measuring >1 cm in diameter are mostlymalignant with metastases to the regional lymph nodesand later to the liver, bone and elsewhere. Patients fre-quently report on intermittent abdominal discomfortexisting sometimes for years. Later, complaints worsenand diagnosis will be made if intermittent intestinalobstruction occurs. The latter is assigned to the roleof growth factors secreted by the tumor cell as PDGF,TGFα, bFGF and others which stimulate neighburing fi-broblasts which lead to new stroma formation and laterto the typical desmoplastic reaction of the mesenterium.The consequence is angulation of the bowel with subse-quent obstruction. Since also vasculature is affected bythe stroma formation, ischemia develops in the involvedsegment and surgeons find the respective bowel dark-blue. Gastrointestinal bleeding is also in larger EC-celltumors rare. Desmoplastic reaction can easily be de-tected by high-resolution MRT.

Functioning EC-Cell Tumors and Carcinoid Syndrome. EC-celltumors responsible for the carcinoid syndrome do notdifferent histologically from non-functioning tumors.However, carcinoid syndrome apperars only in patientswith metastases to the liver. The symptoms are the con-sequence of unrestrained release of hormones and othermediators [11]. Flushing is present in up to 94% of pa-tients and is characterized by red to purple discolorationof face, neck and upper chest. Duration of episodes ismostly short (few minutes) but can continue for hours.Frequently, patients themselves do not notice flushingand their attention will be drawn by others. Occasionally,flushing is associated with unpleasant sensations of lacri-mation, warmth, facial and conjunctival edema. The hor-monal mediator of flushing has not been identified withcertainty. The elevation of blood serotonin during flush-


ing does not prove its causal relationship. In addition,serotonin antagonist as methysergide and odansetonehave only little effect. A more likely mediator are tachyki-nins as substance P and related peptides as neurokinins.

Serotonin is synthesized and secreted from carcinoidtumor cells. It arises from the amino acid tryptophanwhich is hydroxylated to 5-hydroxytryptophan and de-carboxilated to 5-hydroxytryptamin (serotonin). Throughseveral enzymes as monoamine oxidase and aldehydedehydrogenase sterotonin is converted to 5-hydroxy-indolacetic acid (5-HIAA) and excreted into urine.

Diarrhea with watery bowel movements is a com-mon symptom and present in up to 85% of patients. It ispossibly related to serotonin production but other me-diators as prostaglandins have been suggested to con-tribute to diarrhea as well. Diarrhea responds better toserotonin antagonists then flushing.

The most important consequence of long-standingcarcinoid syndrome is carcinoid heart disease, presentin 45–77% of patients. Heart disease threatens patientswith carcinoid syndrome at least by the same extentthen the tumor itself and patients can die from carcinoidheart disease despite tumor growth is well controlled.Carcinoid heart disease involves mostly tricuspidic valve,pulmonary valve and rarely mitral and aortic valve. Themediator responsible for carcinoid heart disease is un-known. Several studies suggest the concept that seroto-nin is involved by reporting higher serotinin levels inplasma and 5-HIAA levels in urine in patients with com-pared to those without heart involvement. However,anorectic factors as well are discussed to be involved.Typically, the affected valves are thickened, shortenedand retracted by fibrous transformation leading to tri-cuspid and pulmonary valve insufficiency which can beeasly visualized by two-dimensional echocardiography.

Additional symptoms in carcinoid syndrome en-compass bronchoconstriction, Pellegra-like skin changesand abdominal pain. The latter can result from diffuseliver enlargement or desmoplastic mesenterial reaction(see Fig. 7b). Pellegra-like skin reactions are the conse-quence of niacin deficiency which is due to the forma-tion of serotonin from 5-hydroxytryptophan.

Carcinoid crisis is a rare exacerbation in patientswith carcinoid syndrome mostly arising during anesthe-sia or surgery if patients are not under continuous so-matostatin treatment. Flushing, hyper- and hypotension,severe bronchospasm and cardiac arrhythmias are themain features and subsequent death is not uncommon.

Diagnosis

In non-functional tumors, incidental detection of anileal carcinoid during colonoscopy and in case of in-testinal obstruction surgery uncovers the responsiblecarcinoid, which, in the latter situation, has mostly me-tastasized into regional lymphnodes. Non-functioningliver metastases from an ileal carcinoid are frequentlydetected by US during routine check-up. Most sensitivemeasures to estimate total tumor burden are OctreoScan, CT and MRT. Biochemically, chromogranin A ser-ves as most reliable tumor marker. Diagnosis of carci-noid syndrome is based on the demonstration of high5-HIAA levels in the urine and elevated plasma seroto-nin and chromogranin A levels in the presence of livermetastases from an neuroendocrine tumor. CT, MRTand OctreoScan define total tumor burden and mostlythe site of the primary. All patients deserve careful car-diologic diagnosis with two-dimensional echocardio-graphy to prove or disprove cardiac involvement.


Some patients with non-functional ileal carcinoids de-velop diarrhea after right-sided hemicolectomy. Theyare later misdiagnosed as having carcinoid syndromeand somatostatin treatment will be started to preventdiarrhea. However, somatostatin treatment can evenworsen diarrhea which is not hormone mediated but theconsequence of bile acid loss into colon or bacterialovergrowth.

Treatment

Surgery is the treatment of choice to remove the primaryand its local metastases reponsible for the desmoplasticreaction and subsequent abdominal pain. Surgery shouldfurther be considered in case of few and large liver me-tastases. In addition, right-sided hemicolectomy shouldbe offered to patients with small ileal carcinoids detect-ed incidentally during routine colonoscopy. Symptomcontrol in patients with carcinoid syndrome was diffi-cult before the availability of long-acting somatostatinanalogs which are currently the principle or first choiceto control flushing and diarrhea. They are indispensablein the treatment and prevention of bronchial obstruc-tion and carcinoid crisis. They have, therefore, to beadministered perioperatively and during laparotomy.


Their effects on carcinoid heart disease and its progres-sion have not yet been demonstrated. Octreotide shouldbe started at doses of 2–3×50 µg, but higher doses up to3×500 µg may be necessary in some patients. If effective,LAR formulations should be offered (Octreotide-LAR20 mg every 28 days). Long-acting somatostatin analogsare safe. One of the most frequent side effects is the for-mation of gall stones since somatostatin inhibits therelease of CCK and by this mechanism gallbladder con-traction. In few patients, somatostatin analogs inducediarrhea which can be as severe as diarrhea restultingfrom carcinoid syndrome. In these patients and thosewith tachyphylaxis to long-acting somatostatin analogsdiarrhea should be controlled by serotonin receptorblockade. 5-HT

1 (methysergide)-, 5-HT

1+2 (cyprohepta-

dine)-, 5-HT2 (ketanserin)- and 5-HT

3 (ondansetron)-re-

ceptor antagonists have been recommended. But they donot completely stop diarrhea. To substitute niacin defi-ciency, patients should be offered niacin orally. Cardiacfailure should be treated by conventional pharmacologictherapy.

Endocrine Tumors of the Appendix

Incidence rates of appendiceal carcinoids account for0.075 new cases per 100.000 population and year. 19% ofall gastrointestinal carcinoids have been reported to belocalized in the appendix. Mean age of presentation is32–43 years and females are more frequently affected.

Appendiceal carcinoids are mostly detected inciden-tally during appendectomy or described by pathologistsin the resected appendix. They are mostly situated in thedistal third of the appendix. By obstructing the lumenthey can produce appendicitis. Clinicopathologic stagingis summarized in Table 11. Most appendiceal carcinoidsare well-differentiated tumors consisting of EC-cells butsome contain glucagon-like peptides and PP/PYY-pro-ducing cells.

Most patients with appendiceal carcinoids have afavourable prognosis. Several well conducted studiesdemonstrate that carcinoids of less then 2 cm size con-fined to the appendiceal wall and not angioinvasive arecompletely cured by appendectomy. Invasion of the me-soappendix, a size >2 cm and angioinvasion carry anuncertain malignant potential and right sided hemico-letomy should, therefore, be performed as in patientswith metastatic spread into regional lymph nodes. Also

location of a carcinoid at the base of the appendix withinvolvement of the cecum has a more unfavourableprognosis requiring right sided hemicolectomy.

Goblet cell carcinoids are more aggressive tumorsand should be treated by right sided hemicolectomysince these carcinoids frequently invade the wall of theappendix.

Endocrine Tumors of the Colon and Rectum

With an incidence of up to 0.21 cases per 100.000 popu-lation per year hindgut carcinoids (left sided colon, rec-tosigmoid) are less frequent then midgut carcinoids (seeFig. 7f) (jejunum, ileum, appendix). They account for20% of all gastrointestinal carcinoids. Within the hind-gut most carcinoids are situated in the rectum (54%).Average age for colonic carcinoids is 66 years and forrectal carcinoids 58 years. Histologically, colonic carci-noids consist of EC-cells or L-cells (glucagon-like pep-tides and PP/PYY-producing carcinoids) and rectal car-cinoids mainly of L-cells. Most colonic carcinoids arefound in the right colon with an average size of 4,9 cm.Rectal carcinoids represent as submucosal nodules oryellow polypoid lesions situated mostly 4 cm proximalthe dentate line. Mostly, they are less then 1 cm in diam-eter and only in 13% greater then 2 cm (see Table 10).Carcinoids of the colon/rectum are generally non-func-tioning and present with abdominal pain due to bowelobstruction, bleeding or are detected incidentally duringscreening colonoscopy or in case of carcinoids >2 cmwith liver metastases. Very few colonic carcinoids areassociated with a carcinoid syndrome. Few hindgut car-cinoids are poorly differentiated and aggressively grow-ing. Their prognosis is poor. Carcinoids >2 cm have ahigher malignancy rate with metastases mostly to theliver.

Established malignancy criteria of rectal carcinoidsare a size >2 cm, invasion of the muscularis propria,DNA aneuploidy and the presence of 2 mitosis and moreper 10 high power microscopic fields (magnification:×400). The prognosis is in general more favourable thenthe prognosis of patients with carcinoids situated in thejejunum and ileum.

229General Aspect of Management

General Aspect of Management

Surgery

Surgery and endoscopic resection is the only availablecurative treatment and should always be considered.Solitary tumors (insulinomas, gastrinomas, gastrointes-tinal carcinoids) should be resected by laparotomy orendoscopy. Surgical management in patients with meta-static spread is not very well defined but should be animportant treatment module of a multidisciplinary ap-proach. Single and few liver metastases are exepted ex-amples for palliative surgery. Many patients with slowlygrowing metastatic GEP tumors whether functionallyactive as some malignant insulinoma or functionallyinactive have a benefit from this approach. Not wellestablished is the place of surgery in patients with mul-tiple, non-functioning endocrine pancreatic tumor aspart of MEN-1 syndrome.

Liver transplantation should be considered in pa-tients with resected primary tumorbut metastases onlyto the liver as shown by Octreoscan and other sensitiveimaging methods and unresponsive to established me-dical and interventional treatment. However, reoccur-rence of metastases in the transplanted liver has beenobserved as well as newly formed extra-hepatic meta-stases. Nevertheless, some patients have a significantbenefitfrom liver transplantation with prolonged sur-vival and quality of life.

Medical Treatment of Symptoms

The respective pharmaceutical principles have been indetail discussed elsewhere in this chapter.

Control of Tumor Growth in Malignantand Metastatic Tumors

Non-surgical control of tumor growth includes biothera-py with long-acting somatostatin analogues and α-inter-feron, systemic chemotherapy, ablative methods includ-ing chemoembolizaton, thermo- and alcohol treatmentof liver lesions and tumor targeted radiotherapy.

Every therapeutic modality should recognize thatwell-differentiated endocrine GEP tumors are mostlyslow growing and often exhibit phases of stable diseaseor such a slow growth that a significant increase in tu-

mor size can only be substantiated with CT- or MRIscans performed in 6–12 months intervals. Therefore,non-surgical treatment options should not be consid-ered in patients with stable disease and uncompromisedlife quality. Such patients should be offered regularcontrol visits in 6 months intervals and treatment onlyoffered in case of significant tumor growth (>20–25%increase in 3–6 months). Therefore, patients with newly-diagnosed metastatic disease from well-differentiatedendocrine GEP-tumors and low mitotic activity shouldnot be offered a specific treatment immediately.

Long Acting Somatostatin Analogs

Evidence for antiproliferative properties of somatostatinand its analogs derives from in vitro and in vivo studies.As discussed earlier, currently available somatostatinanalogues bind preferentially to sst2 and sst5 receptorswhich mediate antimitogenic, antiproliferative and anti-apoptotic signals. Besides these receptor-dependenteffects, somatostatin controls cell growth via receptor-independent effects. These include endocrine effectswith inhibition of the release of circulating or paracrinetumor growth promoting factors, vascular antiangio-genetic effects and effects on the immune system.

Anecdotal reports of tumor regression in patientswith metastatic endocrine tumors of the GI tract and ofstable disease over a period of 4 years in two patientswith carcinoid syndrome due to malignant metastaticneuroendocrine tumors of the lung are consistent withthe above mentioned experimental data.

A retrospective report of the National Institute ofHealth on 96 patients with metastatic endocrine tumorsshowed a partial tumor response in 13%, stable diseasein 63% and tumor progression in only 24%. However,partial tumor response was a very rare event in prospec-tive studies and disease stabilization occurred in 36–70%of patients. However, even stable disease was short-last-ing for a minimum of 2 months and a maximum of 60months. In one study, patients were classified into thosewith rapidly-progressing tumors (increase >50% in 3months) and slowly progressing tumors (increase >50%in 3 months). Inhibition of tumor growth occurred pre-dominantly in slow-growing tumors [27]. All trials wereuncontrolled. Regarding the unpredictable course of thedisease and the moderate response to treatment for arelatively short period of time, it cannot be excluded that


the phases of stable disease and even partial responseobserved in a few patients reflect the natural course ofthe disease. Since long-term treatment with somatosta-tin analogs is expensive, placebo-controlled studies arenow necessary to prove or to disprove the antiprolife-rative potency of long-acting somatostatin analogs inpatients with metastatic endocrine GEP-tumors. Unre-solved issues include the therapeutic dose, the equipo-tency of octreotide and lanreotide versus the longeracting release formulations and the treatment effect withregard to prolongation of live.

α-Interferon

Interferons affect tumor growth by blocking the cellcycle during the G

0-G

1 phase with prolongation of the

S-phase. Experimental data suggest that α-interferoninduce apoptosis and that tumor cells are replaced by fi-brotic tissue. α-interferon, in addition, induces increasedexpression of class I antigens on the tumor cell surfacewhich renders cells as targets for cytotoxic T-lympho-cytes.

Several studies in metastatic endocrine GEP-tumorsdemonstrate both a symptomatic effect with improve-ment of flushing and diarrhea in patients with carcinoidsyndrome, a concomitant decrease of biochemical mar-kers and a stabilization of tumor growth in 20–40%and a reduction in tumor size in 12–20% of patients. Asshown for long-acting somatostatin analogues, these ef-fects are transient (6–20 months). Side effects of α-inter-feron treatment have a much greater impact on patientswell-being and include flu-like symptoms, weight loss,fatigue, anemia, leukopenia, thrombocytopenia, autoim-mune manifestations and psychiatric disturbances.

Combination Treatment with Octreotideand α-Interferon

In a prospective trial inhibition of tumor growth wasobserved in 67% of 21 patients with metastatic endo-crine tumors of the GI-tract who were unresponsive toprior octreotide monotheraphy. Responders to com-bined treatment had a significant survival benefit. How-ever, these data could not be confirmed by a prospectivetwo arm study, comparing octreotide versus octreotideplus α-interferon in 105 patients performed by the au-

thors of this chapter demonstrating the need for well-controlled and prospective trials in well-defined sub-groups of patients with endocrine GEP-tumors.

Chemotherapy

Several chemotherapeutic agents have been used as sin-gle agents and as combinations in metastatic endocrineGEP tumors. The respective original data demonstatethat chemotherapy is indicated only in patients withwell-differentiated endocrine carcinomas of pancreaticorigin and in rapidly growing undifferentiated and smallcell endocrine carcinomas [8]. According to a 20 yearsold prospective study from the Eastern Cooperative On-cology Group (ECOG) which enrolled 125 patients withhistologically proven unresectable islet-cell carcinomasstreptozotocin plus doxorubicin was found superior tostreptozotocin plus 5-fluouracil (5-FU) and to chlorozo-tocin. Tumor regression occurred in 69% of patientstreated with streptozotocin plus doxorubicin and in 45%of patients treated with the combination of streptozo-tocin and 5-FU. Median duration of regression was 18months for the doxorubicin combination and 14 monthsfor the 5-FU combination. These beneficial effects influ-enced also survival. These favourable effects of tumorgrowth are contrasted by toxic reactions to treatment asnausea, vomiting, alopecia, hematologic and kidney tox-icity. Heart failure has been observed in patients receiv-ing the doxorubicin regimen and a cumulative dose of400–500 mg/m2 should, therefore, not be exceeded. Inthe institution of the authors patients are treated withthe streptozotocin/doxorubicin combination. In case ofresponse, treatment is changed to streptozotocin plus5-FU if the limiting doxorubicin dose is reached. Thedosages are summarized in table 16. Unfortunately it isimpossible to identify patients responding to this treat-ment and patients not responding. In the latter situationone should try dacarbacine (150 mg/m2) as short infu-sion and repeat it every 28 days. At least 3 courses oftreatment should be performed to prove or disprovesuccess.

Importantly, streptozotocin combinations and da-carbacine are only effective in tumors of pancreatic ori-gin. There is no established chemotherapy for malignantcarcinoids of the stomach, small and large intestine. Inpatients with exploding undifferentiated tumors the fol-


lowing chemotherapeutic strategy should be offered:130 mg/m2 and day etoposide for 3 days plus 45 mg/m2

and day cisplatin on days 2 and 3. Each agent is given by24 hours infusion and cycles repeated every 6 weeks.These tumors may originate from the pancreas, stom-ach, small and large bowel and most patients with theserare undiffentiated tumors will respond at least for 2 to3 cycles. Drug toxicity is a significant problem of theseformulations requiring dosage reduction or cessation oftreatment in some patients.

Ablative Measures

Ablative measures include transarterial chemoemboli-zation and radio-frequency tissue or alcohol ablation.Transarterial chemoembolization [8] is based on theconcept that arterial blood supply of metastases (viahepatic artery) from endocrine GEP tumors is more in-tense then that of other malignancies except primaryhepatocellular carcinoma and that local ischemia in-duces cell necrosis. Unproven is the concept that thecombination of desarterialization vial embolization andlocal cytotoxic chemotherapy increases response rates.Embolization is performed by selective injection of amixture of iodinized oil plus doxorubicin followed byinjection of gelatine sponge particles. Response rateswith a decrease of symptoms in patients with carcinoidsyndrome of 68–100%, decreases of hormone levelsin 80% and a decrease in size of liver metastases in37–100% of patients have been described by several in-stitutions. Mean duration of response is approximately24 months. In the own institution it has been shown thatpatients with a tumor burden >75% of the liver have notbenefit from chemoembolization. Increased survival hasbeen observed in patients with a tumor burden <50%and an accumulation of lipiodol in more then 50% of thetumor mass. Side effects include abdominal pain, nau-sea, vomiting and fever. Fatal complications are infectionand sepsis and hepatic failure.

Radiofrequency treatment [33] is a novel advice todestroy liver metastases and can be performed percuta-neously and intraoperatively using a cooled-tip needlyapplying 50 to 90 watts over 10–12 minutes under ultra-sound control. This experimental procedure as well asablation by injection of alcohol can be considered incase of few and small liver metastases.

Radioligand Therapy

Tumor-targeted metabolic endo-radiotherapy usingspecific receptor ligands such as octreotide or lanreotidecoupled to beta-emitting radionuclides is of special in-terest in endocrine malignancies since biotherapy isonly effective in slow growing tumors and systemic che-motherapy in a subpopulation of patients with pancre-atic tumors. Almost no treatment modality has beenshown to affect bone metastases. Whereas radioiodina-ted somatostatin analogues usually show target-to-back-ground ratios not high enough for therapeutic appli-cations, which is mainly due to their lipophilicity andrapid intracellular degradability, radiometal-labelledanalogues display excellent biodistribution properties.To bind radioisotopes such as 111Indium, 90Yttrium and177Lutetium tightly to somatostatin analogs, mono- andbifunctional chelators have been developed consisting ofpolyaminopolycarboxylic acids or their macrocyclic de-rivatives such as DTPA, TTHA, DFO, DOTA or TETA. Toreach biofunctionality, aliphatic side chain, thiorurona-tobenzyl,-, acetamidobenzyl- or succinylbenzyl linkersconnect the chelators with octreotide and related pep-tides. 111In-labelled [DTPA]-octreotide has been shownto display an appropriate biodistribution profile in man.

Table 16Chemotherapeutic protocols for well differentiated metastatic isletcell carcinoms

Streptozotocin plus 5-fluorouracil 500 mg/m2 streptozotocin/day as

intravenous injection for 5 consecu-

tive days; plus

400 mg/m2 5-fluorouracil/day as


tive days, repeated every 6 weeks

Streptozotocin plus doxorubcin 500 mg/m2 streptozotocin/day as


tive days; plus

50 mg/m2 doxorubicin as intrave-

nous injection on days 1 and 22; re-

peated every 6 weeks

Maximal dose of doxorubicin: 4500 mg/m2. Reduced dosages ofevery drug in case of severe nausea, vomiting, stomatitis, diar-rhea, leukopenia, thrombozytopenia. Reduced dosages of strepto-zotocin in case of elevated creatinine or proteinuria and dis-continuation if abnormalities persist.


Although generally regarded as mainly diagnostic, 111-In-dium emits Auger and conversion electrons, which dis-play a tissue penetration of 0.02–10 µm and 200–500 µmrespectively, and which can be used therapeutically.More therapeutic experience has been gained with 90Ytt-rium, which is a classical β-particle emitter. To avoid dis-sociation of 90Yttrium with a maximum path length of9 mm from the chelated somatostatin analog, a stable[DOTA0, Tyr3]-octreotide complex has been developed.Replacement of phenylalanine at the 3-position of oct-reotide by tyrosine has been shown to even increase theaffinity of this compound for the sst2 receptors. Theeffect of endo-radiotherapy depends on binding to thesst2 receptor and requires internalization of the radio-ligand. Therefore, a sufficient number of sst2 bindingsites and rapid internalization are prerequisits for suc-cessful therapy. The principal efficacy of somatostatinreceptor-mediated radiotherapy has been demonstratedin animal models. Recently, several studies including alimited number of patients with malignant endocrinetumors have been published, suggesting that radio-therapy with 111In- and 90-Y-labelled octreotide analogs isable to control symptoms in patients with functionallyactive endocrine tumors and to inhibit or even signifi-cantly decrease tumor load. Whether or not [177Lu-DOTA,Typ3]-Octreotate with a tissue penetration of 2 mm issuperior to 111Indium and 90Yttrium labelled octreotidein the treatment of endocrine GEP tumors is currentlyunder investigation.

How Should we Proceed in Patients with MetastaticNeuroendocrine GEP-Tumors?

Despite the availability of several antiproliferative strat-egies that can be offered to patients with metastaticdisease, current recommendations how to start withnon-surgical modalities are controversial and not sup-ported by prospective and controlled studies. Therefore,therapeutic strategies for a single patient are based fre-quently on personal experiences of expert centers andvary, therefore, from center to center. To harmonize the-rapeutic ways of proceeding European experts in thefield have founded the Eureopean Network for the Studyof Endocrine GEP Tumors (ENET) to define the place ofcurrently available and future diagnostic and therapeu-tic principles. According to the experiences of the au-thors of this chapter the following recommendationscan be applied to patients with metastatic GEP tumors:

1. Surgery with curative resection of the primary in theabsence of metastatic spread and tumor debulkingin metastatic disease should be intended where everpossible.

2. Antiproliferative strategies should consider the growthcharacteristics and biology of a given tumor. Do nottreat non-growing metastases which are stable by CTfor 6 months and longer! It is questionable whetherthese patients have any benefit from anti-prolifera-tive measures. Consider surgery or local ablativemeasures (radiofrequence ablation) in these patients.

3. In the case of moderately rapid progression chemo-therapy should be offered in patients with tumors ofpancreatic origin (streptozotocin combinations, da-carbacine). Chemotherapy should not be offered topatients with well-differentiated non-functional orfunctional tumors arising from the intestine (fromstomach to rectum).

4. Offer chemotherapy (etoposid + cisplatin) in explo-ding tumors as small cell and undifferentiated neu-roendocrine carcinomas.

5. Offer local irradiation in case of pain in patients withbone metastases since bone metastases do not re-spond to chemotherapy and biotherapy.

6. Offer octreotide to patients with well-differentiatedslowly growing neuroendocrine tumors. In case offurther growth add α-interferon.

7. Consider chemoembolization primarily in patientswith liver metastases due to mid- and hindgut tu-mors since this group of patients does not respondto chemotherapy.

8. Consider radioligand therapy only within controlledand prospective studies since it is unsettled whetherthis modality should be offered to patients as first-line treatment or to patients unresponsive to othertherapeutic alternatives.

References

1. Solcia E, Klöppel G, Sobin H (2000) WHO: Histological typing of endo-crine tumours. Springer: Berlin-New York

2. Chandrasekharappa SC, Guru SC, Manickam O et al. (1997) Positionalcloning of the gene for multiple endocrine neoplasia type I. Science 276:404–407

3. Debelenko, LV, Zhuang Z, Emmert-Buck MR et al. (1997) Allelic deletionson chromosome 11q13 in multiple endocrine neoplasia type 1-associatedand sporadic gastrinomas and pancreatic endocrine tumors. Cancer Res57: 2238–2243

4. Jensen RT, Gardner JD (1993) Gastrinoma In Go VLW, DiMagno EP,Gardner JD et al. (eds): The Pancreas: Biology, Pathobiology, and Disease,2nd ed. New York, Raven Press


5. Metz DC, Jensen RT, Bale AE et al. (1994) Multiple endocrine neoplasiatype 1: Clinical features and management. In Bilezekian JP, Levine MA,Marcus R (eds): The Parathyroids. New York, Raven

6. Soga J, Yakuwa Y (1998) Glucagonomas/diabetico-dermatogenic syn-drome (DDS): A statistical evaluation of 407 reported cases. J Hepato-biliary Pancreat Sur 5(3):312–319

7. Modlin IM, Sandor A (1997) An analysis of 8305 cases of carcinoidtumors. Cancer 79:813–829

8. Jensen RT and Norton JA (2002). Pancreatic Endocrine Tumors. InFeldman M, Friedman LS, Sleisenger MH (eds.): Gastrointestinal andLiver Disease. Vol 1, 7th ed. Philadelphia, WB Saunders, p 988–1018

9. Rindi G, Azzoni C, La-Rosa S et al. (1999) ECL cell tumor and poorlydifferech GD, Brandi ML, Friedman E. Allelic loss on chromosome 11 inhereditary and sporadic tumors related to familial multiple endocrineneoplasia tyntiated endocrine carcinoma of the stomach: prognosticevaluation by pathological analysis. Gastroenterology 116:532–542

10. Solcia E, Capella C, Sessa F et al. (1986) Gastric carcinoids and relatedendocrine growths. Digestion 35 [Suppl 1]: 3–22

11. Vinik Al, McLeod MK, Fig LM et al (1989) Clinical features, diagnosis, andlocalization of carcinoid tumors and their management. GastroenterolClin North Am 18:865–896

12. Service FJ, Mc Mahon MM, O’Brion PC (1991) Functioning insulinoma– incidence, recurrence, and long-term survival of patients: a 60 yearstudy. Mayo Clinic Proc 66:711–719

13. W. Creutzfeldt (1975) Pancreatic endocrine tumors: the riddle of theirorigin and hormone secretion. Isr J Med Sci 11:762–776

14. Creutzfeldt W, Arnold R, Creutzfeldt C et al. (1973) Biochemical andmorphological investigations of 30 human insulinomas. Diabetologia9:217–231

15. Creutzfeldt W, Arnold R, Creutzfeldt C et al. (1975) Pathomorphologic,biochemical and diagnostic aspects of gastrinomas (Zollinger-Ellisonsyndrome). Hum Pathol 6:47–76

16. Capella C, Heitz Ph U, Hofler H et al. (1994) Revised classification ofneuroendocrine tumors of the lung, pancreas and gut. Digestion 55(suppl.3):11–23

17. Zhuang Z, Vortmeyer AO, Pack S et al. (1997). Somatic mutations of theMEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas.Cancer Research 57:4682–4686

18. Hessmann O, Lindberg D, Skogseid B et al. (1998). Mutation of the mul-tiple endocrine neoplasia type 1 gene in nonfamilial, malignant tumorsof the endocrine pancres. Cancer Research 58:377–379

19. La Rosa S, Sessa F, Capella C et al. (1996). Prognostic criteria in non-func-tioning pancreatic endocrine tumours. Virchow Archiv: An InternationalJournal of Pathology 429:323–333

20. Muscarella P, Melvin WS, Fisher WE et al. (1998). Genetic alterations ingastrinomas and nonfunctioning pancreatic neuroendocrine tumors: ananalysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Re-search 58:237–240

21. Bartsch D, Hahn SA, Danichevski KD et at. (1999). Mutations of theDPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene 18:2367–2371

22. Agarwal SK, Guru SC, Heppner C et al. (1999). Menin interacts with theAP1 transcription factor JunD and represses JunD-activated transcrip-tion. Cell 96:143–152

23. Mulligan LM, Kwok JB, Healey CS et al. (1993). Germ-line mutationsof the RET proto-oncogene in mulitiple endocrine neoplasia type 2A.Nature 363:458–460

24. Hammel PR, Vilgrain V, Terris B et al. (2000). Pancreatic involvement invon Hippel-Lindau disease. The Groupe Francophone d’Etude de laMaladie de von Hippel-Lindau. Gastroenterology 115:1087–1095

25. Service FJ, McMahon MM, O’Brien PC et al (1991) Functioning insuli-noma – incidence, recurrence, and long-term survival of patients: a60-year study. Mayo Clinic Proceedings 66:711–719

26. Rothmund M, Angelini L, Brunt LM et al. (1990) Surgery for benigninsulinoma: An international review. World J Surg 14:393–398

27. Arnold R, Wied M, Behr TH (2002). Somatostatin analogues in the treat-ment of endocrine tumours of the gastrointestinal tract. Expert OpinPharmacother 3:643–650

28. Arnold R, Frank M, Bülchmann G (1998). Insulinoma and persistent neo-natal hyperinsulinemic hypoglycemia (nesidioblastosis). In Beger HG,Warshaw AL, Buechler MW et al. (eds.): The pancres, Volume 2, BlackwellScience p 1187–1202

29. Someya T, Miki T, Sugihara S et al. (2000). Characterization of genes en-coding the pancreatic beta-cell ATP-sensitive K+ channel in persistenthyperinsulinemic hypoglycemia of infancy in Japanese patients. Endcr J47(6):715–722

30. Fibril F, Venzon DJ, Ojeaburu JV et al. (2001). Prospective Study of theNatural History of Gastrinoma in Patients with MEN-1: Definition of anAggressive and a Nonaggressive Form. The Journal of Clinical Endocri-nology & Metabolism, 86(11):5282–5293

31. Norton JA, Fraker DL, Alexander HR et al. (1999). Surgery to cure theZollinger-Ellison syndrome. N Engl J Med 341(9):635–644

32. Debray MP, Geoffroy O, Laissy JP et al. (2001). Imaging appearances ofmetastases from neuroendocrine tumours of the pancreas. Br J Radiol74(887):1065–1070

33. Wessels FJ, Schell SR (2001). Radiofrequency ablation treatment of refrac-tory carcinoid hepatic metastases. J Surg Res 95(1):8–12

Chapter 15 15Neuroendocrine Gastro-Entero-Pancreatic (GEP ... · a Zollinger-Ellison syndrome in...

Documents

Transcript of Chapter 15 15Neuroendocrine Gastro-Entero-Pancreatic (GEP ... · a Zollinger-Ellison syndrome in...