Langenbeck’s Arch Surg (2002) 386:525–533 DOI 10.1007/s00423-001-0260-z

Helmut Witzigmann Clemens Loracher Felix Geissler Theodor Wagner Andrea Tannapfel Dirk Uhlmann Karel Caca Johann Hauss John Adolf Hehl

Received: 27 April 2001 Accepted: 12 September 2001 Published online: 6 November 2001 © Springer-Verlag 2001

Dedicated to Prof. Dr. J. Witte on the occasion of his 60th birthday. H. Witzigmann (✉) · F. Geissler D. Uhlmann · J. Hauss Department of Abdominal, Transplantation and Vascular Surgery, University of Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany e-mail: [email protected] Tel.: +49-341-9717232 Fax: +49-341-9717209 C. Loracher Department of Cardiology, Central Hospital Augsburg, Germany T. Wagner Institute of Pathology, Central Hospital Augsburg, Germany A. Tannapfel Institute of Pathology, University of Leipzig, Germany J.A. Hehl Department of General and Visceral Surgery, Zentralklinikum Augsburg, Germany K. Caca Department of Medicine, University of Leipzig, Germany

O R I G I N A L A RT I C L E

Neuroendocrine tumours of the duodenum Clinical aspects, pathomorphology and therapy

Abstract Background and aims: Neuroendocrine tumours (NTs) of the duodenum are uncommon neoplasms. They represent a heterogeneous spectrum of subtypes and may be associated with von Recklinghausen’s disease type I (VRD) and multiple endocrine neoplasia type I. There are few studies concerning the biological characteristics and adequate therapy of these tumours. Patients and methods: We report on a retrospective analysis of 12 patients with NTs of the duodenum: six non-ampullary (naNTs) and six ampullary tumours (aNTs). These patients were treated between January 1992 and January 2001. Clinical and histopathological features, therapy and follow-up were evaluated retrospectively and compared with the literature. Results: All tumours were located in the first and second portions of the duodenum. Three of six aNTs presented with jaundice, and four of six naNTs were incidental findings. Two patients with naNTs showed Zollinger-Ellison syndrome and two with aNTs VRD. Of the six patients with naNTs, four were treated by local excision (two endoscopically, two surgical resection), one by Kausch-Whipple operation and in one patient the tumour was an incidental finding in the Billroth II specimen. Four of the six patients with aNTs underwent Kausch-Whipple procedure, one patient ampullectomy (gangliocytic paraganglioma) and

one patient palliative chemotherapy. The size of the naNTs were less than 0.6 cm, whereas the size of the aNTs ranged from 1.5 cm to 4 cm. Tumour size of aNTs had no correlation with depth of invasion and metastases. Metastases were found in two aNTs and none of the naNTs. Immunohistochemically tumour cells expressed somatostatin in 5 of 6 aNTs and gastrin in 1 of 6 aNTs and in two gastrinomas. There was no hospital mortality. Two patients died for reasons not related to the tumour. Tumour excision of both patients with gastrinomas was not curative. Three patients with naNTs and four with aNTs are alive without disease. One patient with palliative treatment of a metastasising aNT is alive 66 months after diagnosis. Conclusion: Nonampullary duodenal NTs differ clinically, histologically and immunohistochemically as well as with respect to the extent of resection from NTs of the ampulla of Vater. Keywords Duodenum · Neuroendocrine tumours · Pathomorphology · Recklinghausen’s disease · Therapy

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Introduction Neuroendocrine tumours (NTs) of the duodenum including those of the ampulla of Vater are rare, amounting to 1–5% of gastrointestinal endocrine tumours [1, 2, 3]. However, in a recent histopathology series duodenal tumours comprised 22% of all gastrointestinal endocrine neoplasms [4]. These tumours mostly arise in the first and second portions of the duodenum [1, 5]. Ampullary NTs (aNTs) are usually discussed together with nonampullary duodenal NTs (naNTs). They represent a heterogeneous spectrum of diseases. Little data are available concerning their clinical characteristics and the appropriate extent of resection. Apart from “typical carcinoids”, specific neoplasms among duodenal NTs according to the World Health Organization (WHO) histological classification [6] are gastrin cell and somatostatin cell tumours and gangliocytic paragangliomas [1, 5]. Very few cases of small cell neuroendocrine carcinomas, adenocarcinoids (goblet cell carcinoids) [7, 8], serotonin-producing epithelial/endocrine-cell neoplasms [5, 9] and mixed ductal-endocrine carcinomas [1, 10] have been reported, mostly as single case reports. Duodenal NTs are mainly sporadic and solitary and may be associated with von Recklinghausen’s disease type I (VRD) and multiple endocrine neoplasia (MEN) type 1. There is one case report on a patient with familial adenomatous polyposis who has recurrent NTs at the base of duodenal adenomas [11]. Zollinger-Ellison syndrome (ZES) is the most frequent clinical syndrome [5]. Reports on a history of carcinoid syndrome are extremely rare [3, 12, 13, 14]. The full somatostatinoma syndrome has been described in none of the patients with duodenal somatostatin cell tumours so far reported [5]. Clinical findings, therapy, histopathological data and follow-up of 12 patients with duodenal NTs are recorded and discussed with respect to the literature.

Patients and methods From January 1992 until January 2001, 12 patients (9 men, 3 women) with NTs of the duodenum were treated at the Department of Abdominal, Transplantation and Vascular Surgery, University of Leipzig and the Department of General and Visceral Surgery, Central Hospital Augsburg. The medical records were reviewed retrospectively to examine the clinical characteristics, histopathological features, therapeutic procedures and prognosis. Follow-up data were obtained from all 12 patients. The following macroscopic and microscopic features were evaluated: size, depth of invasion, rate of mitosis and metastatic spreading. The histological typing and clinicopathological classification used here were adapted from the WHO histological classification of tumours [5, 6, 9, 15]. Neuroendocrine differentiation was identified with the silver impregnation technique (argyrophil Grimelius) and immunostaining for neuroendocrine markers. For immunohistochemical analysis of chromogranin A, synaptophysin and neuron-specific enolase (NSE), somatostatin, gastrin, S 100 and pancreatic polypeptide,

the material was routinely fixed in 4% formaldehyde solution and embedded in paraffin. The sections were covered with normal goat serum for 20 min and then incubated with the primary antibodies: chromogranin A, (clone LK2H10, dilution 1:1, Linaris, Germany), synaptophysin (clone Sup88, dilution 1:1, BioGenex, Germany), NSE (Clone BBS/NC/VI-H14, dilution 1:300, Dako, Germany), somatostatin polyclonal (dilution 1:50, Zymed, Germany), gastrin polyclonal (dilution 1:200, Dako), S-100 polyclonal (dilution 1:50, Dako) and pancreatic polypeptide polyclonal, (dilution 1:5, Chemicon International, Germany). The slides were examined independently by A.T. and T.W., who were blinded to clinical and pathological information.

Results Clinical manifestation and diagnosis The mean age of the patients was 55.4 years (range 41–72 years). There were six ampullary and six nonampullary duodenal NTs (Table 1).

Non-ampullary NTs Recurrent duodenal and gastric ulcers led to the diagnosis of a gastrinoma (ZES) in one female patient (no. 1). The fasting serum gastrin value was 1100 pg/ml (normal value <125 pg/ml) and rose by more than 400 pg/ml after stimulation of secretion. The location of a tumour could be identified neither on the basis of imaging techniques nor of somatostatin receptor scintigraphy. In patient no. 2 with a history of peptic ulcer disease, a gastrin-cell tumour was detected in the proximal duodenum as a chance finding in a Billroth I to Billroth II conversion operation because of an anastomotic ulcer. The serum gastrin value was not determined before the operation. Both patients with gastrinoma in our series showed no clinical or biochemical signs of MEN I. However, a gene mutation analysis was not performed. In one patient (no. 3) with upper abdominal bleeding, a polyp in pars II of the duodenum outside the papilla of Vater was found to be the cause. Biopsy of this polyp revealed a gangliocytic paraganglioma. In three further patients (nos. 4, 5 and 6), NTs were diagnosed fortuitously by gastroduodenoscopy carried out for other reasons (reflux oesophagitis in one case, search for a tumour in two cases). The result of computed tomography (CT) was normal in all three patients. In patient no. 6, a residual tumour 3.5 cm in diameter that infiltrated the pancreas was found endosonographically after endoscopic tumour resection. Somatostatin receptor scintigraphy confirmed the result of endosonography in this patient with the additional suspicion of lymph-node metastases. Retrospectively, the results obtained by endosonography and scintigraphy that had crucially influenced the treatment proved to have been false positive.

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Table 1 Clinical data, treatment and follow-up of 12 patients with duodenal neuroendocrine tumours. Histologic typing is according to World Health Organization classification [6] Patient no.

Sex/age (years)

Histologic typing

Clinical manifestation

Location

Treatment

Follow-up

1

Female/45

Gastrin cell tumour

Recurrent duodenal ulcers

Duodenum, pars I

2

Male/43

Gastrin cell tumour

Duodenum, pars I

3

Male/64

4

Male/69

Gangliocytic paraganglioma Multiple carcinoids

Incidental finding in Billroth II specimen Bleeding

Surgical excision, lymph-node dissection Conversion Billroth I to Billroth II

5

Male/60

Postoperative elevated gastrin, well after 102 months Postoperative elevated gastrin, well after 92 months Well after 65 months Died after 80 months (no recurrence) Well after 8 months

6

Incidental finding

Duodenum, pars II Duodenum, pars I+II

Endoscopic excision Endoscopic excision

Carcinoid

Incidental finding

Duodenum, pars I

Male/72

Carcinoid

7

Male/75

Carcinoid

Incidental finding Jaundice, weight loss

Duodenum, pars I Ampullary

Surgical excision, lymph-node dissection Whipple

8

Male/46

Jaundice

Ampullary

Whipple

9

Female/44

Somatostatin cell tumour Somatostatin cell tumour

Bleeding

Ampullary

Whipple

10

Female/53

Somatostatin cell tumour

Jaundice

Ampullary

Chemotherapy

11

Male/53

Carcinoid

Ampullary

Whipple

12

Male/41

Gangliocytic paraganglioma

Abdominal pain Bleeding

Ampullary

Ampullectomy, lymph-node dissection

Ampullary NTs Of the six patients with aNTs, three had jaundice (nos. 7, 8 and 10), two presented with upper gastrointestinal haemorrhage (nos. 9 and 12) and abdominal pain was noted in one (no. 11). Preoperative biopsies of the ampullary tumours revealed NTs in four patients (nos. 7, 9, 10 and 12) and were misdiagnosed as well-differentiated adenocarcinomas in two patients (nos. 8 and 11). Abdominal CT showed an ampullary and/or pancreatic mass in all six patients. Two of the three patients with somatostatin cell tumours (nos. 8 and 9) suffered from a VRD. However, there were no signs of a somatostatinoma syndrome in these three patients. In one patient with VRD (no. 9) 1 year after the manifestation of the somatostatin cell tumour, a unilateral phaeochromocytoma was diagnosed.

Whipple

Well after 11 months Died after 96 months (no recurrence) Well after 85 months Phaeochromocytoma after 12 months, well after 68 months No tumour progression, alive after 66 months Well after 105 months Well after 36 months

The values of gastrin and serotonin in the serum and urinary 5-hydroxyindoleacetic acid measured preoperatively in five patients (nos. 1, 3, 4, 8 and 12) were all in the normal range with the exception of a marked increase of serum gastrin in patient no. 1. Chromogranin A in the serum, measured in patients nos. 9 and 12 only, was increased twofold in both patients. Preoperative somatostatin levels in the serum were available for none of the patients. Treatment and complications Five patients were treated by local excision (two endoscopically, three surgical resection). In patient no. 4, who was at high cardiorespiratory risk, the multiple tumours, being small (0.1 cm) and confined to the submucosa,

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Table 2 Histopathological data of neuroendocrine tumours examined. Classification according to Capella et al. [9, 15] A well-differentiated endocrine tumour, B well-differentiated endocrine carcinoma, C poorly differentiated endocrine carcinoma, HPF high-power field Patient no.

Tumour size (cm)

Depth of invasion

Mitoses/10 HPF

Metastasis

Clinicopathological classification

1 2 3 4 5 6 7 8 9 10 11 12

0.6 0.6 0.4 0.1 0.4 0.5 1.5 1.5 1.4 4 3 4

Submucosa Submucosa Submucosa Submucosa Submucosa Submucosa Muscularis propria Intestinal wall, pancreas Submucosa Intestinal wall, pancreas Intestinal wall, pancreas Muscularis propria

None None None None None None 1–2 1–2 (psammoma bodies) 1–2 (psammoma bodies) 1–2 (psammoma bodies) 1–2 None

pN0, M0 pN0, M0 pNX, M0 pNX, M0 pN0, M0 pN0, M0 pN0, M0 pN0, M0 pN1, M0 pNX, M1 (liver) pN0, M0 pN0, pM0

A A A A A A B B B B B A

Table 3 Immunohistochemical findings, silver staining (semiquantitative analysis). EC epithelial/endocrine cells, NC neural cells, NSE neuron-specific enolase, PP pancreatic polypeptide,

+ weak staining intensity, ++ moderate staining intensity, +++ strong staining intensity, Np not performed

Patient no.

Argyrophil reaction grimelieus

NSE

Chromogranin A

Synaptophysin

Gastrin

Somatostatin

S100

PP

1 2 3

++ ++ Np

4 5 6 7 8 9 10 11 12

Np + + ++ Np + + Np Np

Np ++ EC+ NC– Np + + ++ – ++ + ++ EC+ NC–

+ Np EC+ NC– + + + + – + + ++ EC+ NC–

Np ++ EC++ NC– Np – – – Np + + +++ EC++ NC–

+ ++ EC– NC– Np – – – – – – + EC– NC–

Np Np EC– NC– Np – – – +++ +++ +++ + EC++ NC–

Np Np EC– NC++ Np +/– – – Np – Np + EC– NC++

Np v EC– NC– Np – – Np – – Np + EC++ NC–

were excised endoscopically in several sessions. Endoscopic resection in patient no. 3 and ampullectomy with lymph-node dissection in patient no. 12 were considered appropriate for the two patients with gangliocytic paragangliomas despite infiltration of the muscularis propria in the latter patient due to the benign behaviour of these tumours. Likewise, local surgical resection with peripancreatic lymph-node dissection as described by Thompson et al. [16] was performed in the patient with gastrinoma (no. 1) and in a patient (no. 5) after non-curative endoscopic excision. In one patient (no. 2), a preoperative unknown gastric-cell tumour in the first portion of the duodenum was fortuitously resected in a Billroth I to Billroth II conversion operation. Four patients with aNTs (nos. 7, 8, 9 and 11) underwent Kausch-Whipple pancreatoduodenectomy (PD). In these patients, radical resection was performed due to the size of the tumours and in two patients (nos. 8 and 11) additionally because of preoperatively suspected carcinoma. Patient no. 9 with so-

matostatin cell tumour underwent right adrenalectomy 1 year after PD because of phaeochromocytoma. Patient no. 6 underwent a PD because of the results of endosonography and scintigraphy after local resection. Patient no. 10 received gemcitabine chemotherapy for inoperable somatostatin cell tumour with liver metastases. There was no hospital mortality. We observed three complications after PD, including two transient pancreatic fistulas and one bleeding. All three were controlled conservatively. Histological and immunohistochemical findings The results of histology, tumour classification and immunohistochemistry are summarised in Table 2 and Table 3. The size of the six naNTs was 0.6 cm in maximum diameter or less, and the invasion depth was confined to the submucosa. These tumours showed no mitotic activity

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and no metastases with the caveat that lymph-node status was known only in the four patients who were operated upon. No residual tumour could be found in the KauschWhipple specimen of patient no. 6 after prior endoscopic resection. In contrast to the naNTs, the six aNTs ranged in size from 1.5 cm to 4 cm. Tumour size had no correlation with depth of invasion and metastases. Of these six patients, the only tumour that was limited to the submucosa (size 1.4 cm) showed lymph-node metastases. Involvement of the muscularis propria was present in two patients (sizes 1.5 cm and 4 cm) and invasion of the pancreas was noted in three patients (sizes 1.5, 3 and 4 cm), one with hepatic metastases. All six ampullary tumours but one (no. 12, gangliocytic paraganglioma) revealed two or fewer mitoses per ten high-power fields. All three somatostatin cell tumours contained psammoma bodies. According to the classification by Capella et al. [15, 17], all NTs outside the ampulla of Vater were well-differentiated endocrine tumours. In contrast to this, five of the six tumours of the ampulla of Vater were well-differentiated endocrine carcinomas. The argyrophil reaction was assessed in seven patients only, and not all immunohistochemical markers were tested for all tumours. Grimelius’ argyrophil reaction was positive in all seven patients tested. Of the nonspecific neuroendocrine markers, NSE was positive in 9 of 10, chromogranin A in 10 of 11 and synaptophysin in 6 of 9 tumours tested. Expression of gastrin was found in the two gastrin cell tumours and in one somatostatin cell tumour in a total of 11 patients investigated. Five of six aNTs expressed somatostatin. In the three somatostatin cell tumours, somatostatin was detectable in the majority of tumour cells. There was no detection of somatostatin in two naNTs investigated. S100 was highly positive in the neural cells of both gangliocytic paragangliomas. Follow-up Complete follow-up data were obtained for all 12 patients. The mean duration of follow-up was 68 months (range 8–102 months). Two patients (nos. 4 and 7) died of causes not related to the tumours. The gastrin values of both patients with gastrin-cell tumours (nos. 1 and 2) were lower immediately after surgery but rose continuously in the further course (basal gastrin December 2000: patient no.1 563 ng/ml, no.2 1400 ng/ml). However, until now both patients have been free of symptoms under omeprazole treatment (1×40 mg Antra daily) without evidence of tumour upon imaging studies during their follow-up periods of 102 months and 92 months, respectively. Seven of the other eight patients who are still alive have been free of symptoms and have not shown any signs of recurrence at regular follow-up investigations by means of CT and endoscopy. Patient no.

8 is suffering from insulin-dependent diabetes mellitus, which developed after surgery. The female patient with metastasising somatostatin cell tumour is in a good general and nutritional state 5.5 years after diagnosis and chemotherapy and does not show any tumour progression in morphological imaging. The preoperatively elevated chromogranin A values in the serum of patient nos. 9 and 12 remained within the normal range during the entire follow-up period.

Discussion Histogenesis Neuroendocrine cells and their neoplasms originate from incompletely differentiated, mostly plurihormonal, precursor cells of (pro-) neural phenotype [18, 19]. Each of these so-called “germ layers”, including the endoderm, are able to form these progenitor cells [19, 20, 21, 22]. Under abnormal conditions, neuroendocrine precursor cells leave the epithelial lining of the gut by way of “drop out” (endophytie [23], bourgeonnement [24]) and reappear as hyperplastic endocrine cell formations in the submucosa. These micronests of endocrine cell are the starting points for the development of neuroendocrine tumours and related neoplasms [23, 24, 25]. Clinical and pathomorphological aspects Duodenal NTs are found in people older than 34 years, the incidence being higher in men [1, 12, 26]. The first and second portion of the duodenum, including the ampulla of Vater, are the most favoured locations. The second portion, especially in and around the papilla of Vater, is the preferred site of somatostatin cell tumours and gangliocytic paragangliomas [9]. These data from the literature are similar to the results of our series. All tumours in our patients but one were solitary. To the authors’ knowledge, until now only one patient with multiple duodenal NTs in the absence of MEN type I, ZES or gastritis type A has been reported [27]. The patient presented in this study showed, in contrast to our patient with multiple NTs (no. 4), hypergastrinaemia in the setting of chronic duodenitis. aNTs should be discussed separately because they differ clinically, histologically and immunohistochemically from NTs elsewhere in the duodenum. Clinically, aNTs became evident from jaundice (the leading symptom) and bleeding, whereas non-functioning NTs outside the ampulla are essentially unexpected findings during the work-up or treatment of other conditions [9, 12, 28]. In our series 3 of 6 aNTs presented with jaundice, and 4 of 6 naNTs were incidental findings. In the study by

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Kirshbom et al., the 10-year survival for duodenal NTs was 58% [13]. Prognostic features of gastrointestinal NTs comprise size, depth of invasion and mitotic rate [29]. Burke et al. have shown that spread into muscularis propria, a size greater than 2 cm and rate of mitosis are significant risk factors for metastases in duodenal NTs [30, 31]. Our findings in non-ampullary NTs (all <1 cm) agree with those of Burke et al. for small NTs. However, according to Stamm et al. [28] and Weichert et al. [32] there is no correlation between tumour size and the risk of developing metastases in duodenal NTs. Makhlouf et al. demonstrated that in aNTs tumour size had, in accordance with the findings of Hatzitheokiltos et al. [33] and Liu et al. [14], no correlation with metastatic potential, whereas in NTs outside the ampulla a size greater than 2 cm, involvement of muscularis propria and mitotic rate correlated with metastatic risk [12]. Similar to these studies, we found in our investigation that size and depth of invasion of ampullary tumours had no prognostic implications. Like all foregut NTs and in contrast to midgut NTs, duodenal tumours can show immunohistochemical evidence of multiple hormone production and partially location-related “ectopic” peptide messengers [1, 9, 12, 28]. Such hormonal contents do not necessarily contribute to determining the clinical features or the prognosis of the disease [9, 12]. In this series, most ampullary and non-ampullary duodenal NTs expressed the neuroendocrine makers NSE, chromogranin and synaptophysin. In addition, all seven tumours tested showed a positive argyrophil reaction. Similar results have been obtained by previous investigators [12, 28, 30]. There are reports of positive immunohistochemical reactions for somatostatin of 47% [30] to 75% [28] with higher rates in aNTs than naNTs [12]. Positive reactions for gastrin are found in approximately 60% [28, 30]. Makhlouf et al. [12] reported gastrin positivity in 56% of naNTs and in 0% of aNTs. In accordance with these data in our investigation, tumour cells expressed somatostatin in 5 of 6 and gastrin in 1 of 6 aNTs. In contrast to the multiple hormones identified immunohistochemically, the clinical expression of hormone overproduction by duodenal NTs is limited to the gastrinoma [5, 12, 28]. Therapy The failure to identify the precise biology of NTs confounds the development of adequate therapeutic rules. Therapeutic strategy must take into account tumour type, differentiation, tumour size, depth of invasion and site of the tumour. Furthermore, the new classification of endocrine tumours by the WHO [9, 34] into five categories (well-differentiated tumour and carcinoma, poorly differentiated carcinoma, mixed exocrine-endocrine tumour and tumour-like lesions) can help determine the extent of resection.

The results of the clinicopathological study by Burke et al., comprising 99 duodenal carcinoids, led to the following conclusion. Endoscopic treatment or local surgical excision are likely to be adequate for tumours smaller than 1 cm, provided they are limited to the submucosa and do not show evidence of metastases, especially if the patients suffer from additional cardiopulmonary conditions [31]. For tumours larger than 2 cm with or without evidence of regional lymph-node metastases PD is generally indicated. Controversy exists as to the extent of resection necessary for NTs 1–2 cm. However, when only aNTs were analysed, data indicate, corresponding to our results, that NTs involving the ampulla of Vater metastasise in half of the cases regardless of primary tumour size [12, 33]. This finding leads to the conclusion that the tumour size cannot determine the radicality of resection. Therefore, considering the relatively young age of these patients and the potentially curable disease, a more aggressive surgical procedure for aNTs should be used than with naNTs, with the exception of gangliocytic paragangliomas. This is underscored by the good long-term results in four patients with aNTs of our series treated by PD. The difficulty of diagnosis before or during operation is another problem in the management of NTs of the papilla of Vater. If there are no exact diagnoses or doubts concerning the tumour stage, surgery in two stages seems useful. Stage 1 includes tumour classification by biopsy or excision with lymph-node dissection, whereas stage 2 comprises treatment according to the findings of stage 1. Specific aspects of gastrinomas, NTs of the ampulla of Vater and gangliocytic paragangliomas are discussed as follows. Gangliocytic paraganglioma GPGs, which are mostly located in the periampullary region, can occur throughout all age groups, mainly in men. Upper gastrointestinal bleeding and upper abdominal discomfort are the leading symptoms [35]. These clinical findings are similar to those in our two patients. GPGs are usually benign despite their occasional deep invasion into the duodenal wall. Therefore, endoscopic or surgical excision of GPGs has hitherto been considered to be curative [35]. However, since several cases of regional lymph-node metastases and local recurrence have been reported, the assumption of their benign behaviour as a rule must be doubted [36, 37, 38]. Considering the little experience, we recommend lymph-node dissection for large tumours (size >2 cm) as we did in patient no. 12. NTs of the ampulla of Vater – neurofibromatosis – somatostatin cell tumours So far about 80 NTs of the ampulla of Vater have been reported [12, 33]. Similar to our patients, the tumours

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were found more often in men. The mean survival of 76 months in our patients compares well with the 5-year survival rate of 90% in the literature. Immunohistochemically, the predominant hormone is somatostatin, which can be detected in approximately 60% [33]. In our series, tumour cells expressed somatostatin in 5 of 6 ampullary NTs. In the study by Hatzitheoklitos et al., metastases to lymph nodes and/or liver are found in 45% of ampullary NTs [33]. This correlates with the finding of metastases in two of six patients in our study. Neurofibromatosis type I is evident in 7% of all duodenal NTs [31] and in 25–40% in patients with NTs located at the papilla of Vater [28, 31, 33, 39]. The neoplastic syndrome characterised by the sequence neurofibromatosis, duodenal NT and phaeochromocytoma has been described in various investigations [28, 40, 41, 42, 43, 44] and was found in one patient in our study. Duodenal NTs in patients with neurofibromatosis are almost always located within the ampullary region and are mostly pure somatostatin cell tumour [45, 46]. Furthermore, about 50% of all reported duodenal somatostatin cell tumours occur in patients with VRD [46]. This presumed association between somatostatin cell tumours and VRD is supported by our investigation showing two of three somatostatin cell tumours in patients with VRD. Duodenal somatostatin cell tumours are less aggressive than the corresponding pancreatic tumours [26, 47] and have a good prognosis even if there are lymph-node metastases [1]. In accordance with this report, all three patients are alive more than 5 years later. The therapeutic management of ampullary tumours is discussed in the section “Therapy”. Duodenal gastrinomas The extensive study by Burke et al. comprised 99 duodenal NTs reports gastrinomas in five patients [31], while in other reports ZES occurred in 8 of 21 [32], in 4 of 12

[28] and in 2 of 12 in our series. Surgical treatment is generally recommended for patients with sporadic duodenal and/or pancreatic gastrinomas [48, 49]. The management of MEN I-associated gastrinomas is still controversial due to the fact that surgery is seldom curative in the long-term follow-up [34, 49, 50]. However, it has been shown that surgery may be effective in decreasing or preventing the development of liver metastases, which are the main determinants of survival [48, 50, 51]. In the study by Bartsch et al. an aggressive surgical approach, including Whipple procedure, resulted in biochemical cure in four of five patients with MEN I-associated duodenal gastrinomas [34]. The two patients with gastrinomas of our series refused the suggested re-operation after non-curative tumour excision and resection of the proximal duodenal portion, respectively.

Conclusion Non-ampullary duodenal NTs differ clinically, histologically, immunohistochemically and with regard to therapy from NTs of the ampulla of Vater as follows: 1. naNTs are essentially incidental findings or show ZES. In contrast, the leading symptom of aNTs is jaundice. 2. In aNTs tumour size shows no correlation with depth of invasion and metastases. 3. Immunohistochemically, gastrin is mainly expressed in naNTs and somatostatin in aNTs. 4. Somatostatin cell tumours are often malignant, whereas gangliocytic paragangliomas tend to be benign. 5. For naNTs less than 1 cm local excision is the adequate treatment. With an aggressive surgical approach for aNTs (with the exception of gangliocytic paragangliomas), good long-term results are obtained.

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