Natural course of small, asymptomatic neuroendocrine pancreatic tumours in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study

in Endocrine-Related Cancer
View More View Less
  • 1 1Division of Endocrinology and Diabetology,
  • | 2 2Department of Surgery, Philipp’s University, D-35033 Marburg, Germany
  • | 3 3Departments of Radiology and
  • | 4 4Nuclear Medicine, Philipp’s University, Marburg, Germany,
  • | 5 5I M Sechenov Moscow Medical Academy, Moscow, Russia

Contributor Notes

Free access

Endoscopic ultrasound (EUS) enables detection and localization of pancreatic neuroendocrine tumours. Even small tumours down to a diameter of 1–2 mm can be visualized. Since such small tumours usually cannot be detected by computed tomography (ct), magnetic resonance imaging (mri) and somatostatin receptor scintigraphy (srs), and experience with EUS imaging is limited, there is no clear evidence for clinical management in multiple endocrine neoplasia type 1 (MEN1). Knowledge about the natural course of growth and metastatic distribution is mandatory to come to appropriate clinical decisions and guidelines. This prospective study was aimed to assess the natural course of small (<15 mm) neuroendocrine pancreatic tumours without clinical symptoms due to endocrine activity or mechanical problems and without clear indication for surgical therapy in MEN1 by EUS.

A total of 82 asymptomatic tumours <15 mm (5.9 ± 3.2 mm diameter at baseline) in 20 patients with MEN1-disease (8 female/12 male, 43 ± 13 years) were studied over a period of 20 ± 12 months (33.8 patient years, 106.7 tumour years) by EUS. Change in largest diameter of each tumour and annual tumour incidence rate in the patients’ cohort were calculated.

Increase of largest tumour diameter was found to be 1.3 ± 3.2% per month, annual tumour incidence rate 0.62 new tumours per patient year. In one patient, rapid progressive pancreatic manifestation of MEN1 was observed. There was no evidence in ct and/or srs and/or mri for metastatic disease in all patients. Only 4/84 (4.8%) pancreatic tumours could be visualized by computed tomography, 5/79 (6.3%) by somatostatin receptor imaging and 4/39 (10.3%) by magnetic resonance imaging.

Small asymptomatic neuroendocrine pancreatic tumours in MEN1 usually seem to grow slowly. Annual tumour incidence rate is low. However, faster growing tumours and patients with rapidly progressive disease can be observed. Risk for obvious metastatic disease from asymptomatic neuroendocrine pancreatic tumours <15 mm in MEN1 seems to be low.

Abstract

Endoscopic ultrasound (EUS) enables detection and localization of pancreatic neuroendocrine tumours. Even small tumours down to a diameter of 1–2 mm can be visualized. Since such small tumours usually cannot be detected by computed tomography (ct), magnetic resonance imaging (mri) and somatostatin receptor scintigraphy (srs), and experience with EUS imaging is limited, there is no clear evidence for clinical management in multiple endocrine neoplasia type 1 (MEN1). Knowledge about the natural course of growth and metastatic distribution is mandatory to come to appropriate clinical decisions and guidelines. This prospective study was aimed to assess the natural course of small (<15 mm) neuroendocrine pancreatic tumours without clinical symptoms due to endocrine activity or mechanical problems and without clear indication for surgical therapy in MEN1 by EUS.

A total of 82 asymptomatic tumours <15 mm (5.9 ± 3.2 mm diameter at baseline) in 20 patients with MEN1-disease (8 female/12 male, 43 ± 13 years) were studied over a period of 20 ± 12 months (33.8 patient years, 106.7 tumour years) by EUS. Change in largest diameter of each tumour and annual tumour incidence rate in the patients’ cohort were calculated.

Increase of largest tumour diameter was found to be 1.3 ± 3.2% per month, annual tumour incidence rate 0.62 new tumours per patient year. In one patient, rapid progressive pancreatic manifestation of MEN1 was observed. There was no evidence in ct and/or srs and/or mri for metastatic disease in all patients. Only 4/84 (4.8%) pancreatic tumours could be visualized by computed tomography, 5/79 (6.3%) by somatostatin receptor imaging and 4/39 (10.3%) by magnetic resonance imaging.

Small asymptomatic neuroendocrine pancreatic tumours in MEN1 usually seem to grow slowly. Annual tumour incidence rate is low. However, faster growing tumours and patients with rapidly progressive disease can be observed. Risk for obvious metastatic disease from asymptomatic neuroendocrine pancreatic tumours <15 mm in MEN1 seems to be low.

Introduction

Endoscopic ultrasound (EUS) performed via the stomach and the duodenum is an established diagnostic approach in pancreatic diseases. In gastroenterology, it is mainly used for detection and staging of pancreatic adenocarcinomas, inflammatory diseases and their sequelae (Lees 1986, Yasuda et al. 1988, Grimm et al. 1990, Rösch et al. 1990, Zuccaro & Sivak 1992, Nattermann & Dancygier 1993, Nattermann et al. 1993, Wiersema et al. 1993, Devière et al. 1994, Müller et al. 1994, Dancygier 1995, Nattermann et al. 1995, Wiersema & Wiersema 1995).

In addition, EUS enables to visualize small neuroendocrine tumours down to a diameter of 1–2 mm can be visualized (Kann et al. 2001, 2003, Wamsteker et al. 2003, Hellman et al. 2005, Thomas-Marques et al. 2006). Therefore, its use in endocrinology for imaging of the endocrine pancreas and also the adrenal glands is becoming more frequent (Kann et al. 1998a, 1998b, 1999, 2000, 2004, Kann 2005). However, compared with pancreatic adenocarcinomas, neuroendocrine tumours of the pancreas are rare. Only small series or single cases have been published (Bolondi et al. 1990, Lightdale et al. 1991, Zimmer et al. 1994, Meyenberger et al. 1995, Scheffold et al. 1995, Kann et al. 2001, 2003).

Occurrence of neuroendocrine gastroenteropancreatic tumours is a feature of MEN1-disease, reports on their prevalence usually refer to surgery (Carty et al. 1998) and histopathological studies (Le Bodic et al. 1996). Recommended imaging procedures are abdominal sonography, ct, mri and srs (Chanson et al. 1997, Owen et al. 2001). However, very small tumours cannot be detected by these means.

Detection of small pancreatic tumours in MEN1-patients by EUS imaging (Langer et al. 2004) raises new questions. Experiences with EUS in MEN1 are limited. Thus, there is no knowledge on clinical relevance and no clear evidence for clinical management of small neuroendocrine pancreatic tumours only detected by EUS, however negative by ct, mri and srs.

Knowledge about natural course of growth, proliferation and metastatic distribution is mandatory to come to appropriate clinical decisions and guidelines (Mignon 2000).

This study was aimed to assess the natural course by EUS imaging of small (<15 mm) neuroendocrine pancreatic tumours without clinical symptoms due to endocrine activity or mechanical problems such as obstruction of biliary and/or pancreatic ducts, and no clear indication for surgical therapy to provide information on the clinical relevance of these small tumours. Besides change in tumour diameter, annual incidence rate of neuroendocrine pancreatic tumours as detected by EUS should be calculated in these patients. Further, risk for obvious metastatic disease should be considered.

The purpose of this study was thus to provide information about the spontaneous follow-up of small neuroendocrine pancreatic tumours in MEN1. Knowing this, it can be possible to distinguish patients with the ‘usual course’ from patients with rapid progressive disease.

This study was approved by the local ethical committee and conducted as a prospective study. From two patients (patients no. 1 and 2) also results from EUS examinations performed before starting the prospective study were included, since these examinations were performed according to the same protocol by the same examiner. Informed consent was obtained from each patient.

Materials and methods

Twenty patients with MEN1-disease (8 female/12 male, 43 ± 13 years: patient characteristics given in Tables 1 and 2) with a total of 84 asymptomatic, endocrine inactive tumours <15 mm in largest diameter in were studied. In total, this analysis refers to 33.8 patient years and 106.7 tumour years respectively.

In 61 of these tumours, change in largest tumour diameter could be calculated since at least two EUS ultrasound examinations were performed, and these tumours could clearly be reidentified during follow-up. Ten of these 61 tumours were newly detected during follow-up, not at the first examination, however included into the calculation of growth velocity since they were measured at least twice.

Concerning the remaining 23 tumours, six were newly detected in follow-up and only examined once, one additional tumour was detected once and could not clearly be reidentified at the following examinations. Thus, in these tumours calculation of change in largest tumour diameter was not possible. One patient (patient no. 18) with rapidly progressive disease could not be included into the calculation of growth velocity. At the time of inclusion into the study, he had two tumours, after 12 months, four tumours were found, and after 29 months, a total of nine pancreatic tumours were detected. It was not possible to discriminate clearly between newly detected and formerly described tumours. Two tumours in patient no. 11 were excluded from analysis since they were larger than 15 mm (20.2 mm/20.5 mm). This patient was treated by surgery after 5 months of follow-up. This is the only patient where the tumours were confirmed by histology to be neuroendocrine tumours in this study yet.

The mean observation time of patients was 20 ± 12 months (range 5–45 months, median observation time 20 months). The mean observation time of the tumours that were taken to calculate growth velocity (n = 61) was 19 ± 12 months (range 5–45 months, median observation time 20 months).

EUS was performed by one single experienced investigator (phk) using a Pentax FG 32 UA endosonoscope with a longitudinal 7.5 MHz sector array in combination with a Hitachi EUB 525 ultrasound computer. Premedication was performed with 30 mg pentazocine, 10–30 mg diazepam and 0.25–0.5 mg atropine. Examination time was approximately 45 min.

Neuroendocrine pancreatic tumours were defined by EUS imaging according to the recently published criteria obtained from patients where the EUS findings were confirmed by postoperative histology (Kann et al. 2001, 2003). In summary, neuroendocrine pancreatic tumours usually appear hypoechoic compared with normal pancreatic tissue or, more rarely, isoechoic with a small hypoechoic bordering (halo).

EUS imaging was performed at least twice, up to eight (mean ± s.d., 3.2 ± 1.5) times, time interval between the EUS examination – by study protocol to be performed every 6 months – was 9.8 ± 5.1 months. This deviation from the study protocol was due to the retrospective inclusion of examinations in patients no. 1 and 2 and also due to clinical and logistic needs and problems. Patients from all regions in Germany were included in this study.

Referring to RECIST criteria (Therasse et al. 2000) and a recent study confirming reliability of this approach for EUS imaging (Kann et al. 2006), largest diameter of each tumour that could be detected was determined by EUS at baseline and in follow-up. The slope of the regression line (change from baseline (%)/time (months)) of each single tumour referring to all measurements available for each particular tumour was taken as change in largest tumour diameter.

Annual tumour incidence rate was calculated as cumulative number of newly detected tumours in all patients divided by the cumulative observation period of all patients included in this study.

Besides in one patient (patient no. 11, mentioned above), all the tumours investigated in this study were not yet confirmed by histology. Even if the diagnosis of MEN1-disease makes in very likely to consider pancreatic lesions as described above as neuroendocrine tumours, it cannot completely be ruled out that also different pancreatic processes might have been detected by EUS imaging in these patients (Kann et al. 2003).

In all patients, EUS findings were compared with ct (systematically performed in every patient) and/or srs and/or mri (as available) not only concerning the pancreas, but also whether there might be evidence for metastatic disease in the abdomen, especially in the liver (systematic EUS imaging of the liver was not performed in this study).

Therapeutic means that might influence tumour behaviour such as somatostatine analogues, α-interferon, radioligand therapy, irradiation, embolization and cytostatic therapy were defined exclusion criteria.

Results

At the time of first detection, mean tumour size was 5.9 ± 3.2 mm (range 1.5–14.5 mm, n = 73; patient no.18 –who developed seven new tumour during a period of 29 months – was excluded from this analysis since the time of first detection could not clearly be defined as explained above; two tumours larger than 15 mm [patient no. 11] were also not included in this calculation).

Change in largest tumour diameter was found to be 1.3 ± 3.2% per month and ranged from −7.8 to +10.6% per month (n = 61; Fig. 1).

Annual tumour incidence rate was calculated 0.62 new tumours/patient year (n = 20 patients; this calculation included patient no. 18).

The large majority of the tumours analysed in this study was not detected by any other imaging procedure:

ct: 4/84 (4.8%) detected

srs:5/79 (6.3%) detected

mri:4/39 (10.3%) detected

In all the patients, there was no evidence for metastatic disease by ct and/or srs and/or mri during the study.

One patient (no. 18, already mentioned above with the increasing number of pancreatic tumours from 2 to 9 over a period of 29 months) had previous resection of a gastrinoma in the duodenal wall and of one solitary metastasis in the liver (detected by ct, mri, srs; confirmed by histology; 2.5 cm in diameter in liver segment 4) before the start of the study.

Discussion

In general, neuroendocrine tumours of the pancreas are rare. If they cause typical symptoms, such as recurring and multiple peptic ulcers, severe diarrhoea or fasting hypoglycaemia due to endocrine activity, there is a clear indication for surgical treatment (Kann et al. 2001).

Large clinically hormone inactive neuroendocrine pancreatic tumours may cause abdominal discomfort, pain, symptoms of intestinal and biliary obstruction, nausea and other unspecific epigastric symptoms and thus be a target of surgical intervention, also to come to an histological diagnosis (Onaitis et al. 2003).

There is a very low probability for incidental detection of small, endocrine inactive, asymptomatic neuroendocrine tumours of the pancreas in the general population since EUS imaging of the pancreas is not used in a widespread matter, and these tumours usually do not seem to be detectable by other methods of imaging. If a small pancreatic tumour is detected incidentally, this – if operability and resectability is given – will usually be considered as an indication for surgery since the most probable histological correlate for such a pancreatic tumour will be an adenocarcinoma, and the patient might benefit from early surgical treatment.

The situation is completely different in patients with known MEN1-disease. They have a very large a priori probability for neuroendocrine pancreatic tumours. Each pancreatic lesion detected in these patients is much more likely to be a neuroendocrine tumour than anything else. Neuroendocrine pancreatic and duodenal tumours are an important factor determining mortality in these patients. These tumours may be clinically insignificant with a benign course, others however are very malignant (Bartsch et al. 2000, Lairmore et al. 2000). Such malignant neuorendocrine pancreatic tumours occur in about 30% of patients (Bartsch et al. 2000, Dotzenrath et al. 2001).

Management of neuroendocrine pancreatic and duodenal tumours in MEN1 is discussed controversially. Aggressive surgical treatment may prevent metastatic disease and can be performed by preserving apparently healthy parts of the pancreas (Thompson 1998, Bartsch et al. 2000, Azimuddin & Chamberlain 2001). On the other hand, sequelae of pancreatic surgery have to be considered. Besides complications closely related to the surgical procedure, increased morbidity and mortality due to possibly occurring diabetes mellitus have to be taken into account.

In the future, surgical strategy may be adapted to certain mutations in the MEN1-gene which seem to determine benign or malignant courses (Bartsch et al. 2000).

Gastrinomas and insulinomas are the most frequent hormone active pancreatic and duodenal tumours in MEN1-disease (Thompson 1995). Surgery is considered a curative therapeutic option: it enables control of symptoms and prevents tumours growth and metastases in potentially malignant tumours (Thompson 1995, 1998, Jordan 1999, Azimuddin & Chamberlain 2001).

Management of asymptomatic pancreatic tumours is being discussed. Very aggressive surgical strategies, i.e. removing everything that has been detected, have been suggested (Akerstrom et al. 2002). A possible malignant course which seems to be correlated to tumour size is the most relevant problem (Sato et al. 2000). Early detection of small hormone inactive tumours in MEN1 is not yet very frequent (Plöckinger & Wiedenmann 2002).

Ct, srs, percutaneous sonography and angiography are established imaging procedures (Meko & Norton 1994). However, tumours <1 cm are rarely detected (Weinel et al. 1994, Skogseid & Öberg 1995). Intraoperative sonography and palpation have a better sensitivity, lesions <0.3 mm may even be missed (Skogseid & Öberg 1995).

EUS as a harmless procedure improves non-surgical pancreatic imaging and enables to detect and localize symptomatic neuroendocrine pancreatic tumours better and earlier and may be helpful in planning therapeutical strategy (Bansal et al. 1999, Kann et al. 2001, 2003, 2006, Wamsteker et al. 2003, Hellman et al. 2005, McLean & Fairclough 2005, Thomas-Marques et al. 2006). It also has been introduced into the diagnostic repertoire in MEN1-disease, however also raising new and specific questions.

We are now able to find more and smaller tumours in MEN1-patients that formerly were undetectable in vivo. Since knowledge about natural course of growth, proliferation and metastatic distribution of small neuroendocrine pancreatic tumours in MEN1-disease is fragmentary, change in largest tumour diameter and metastatic behaviour of such lesions was assessed in this study. Furthermore, annual tumour incidence rate was assessed in affected patients.

Our results indicate that small asymptomatic neuroendocrine pancreatic tumours in MEN1 usually seem to grow slowly. In average, doubling of tumour diameter can be expected after 5–10 years. However, patients with rapidly progressive disease, i.e. with faster growing tumours and high annual tumour incidence rate can be observed. Spontaneous decrease of tumour size may occur by nature, however can also be a result of variation of repeated measuring, which is of course higher in small than in large tumours.

No metastatic disease was found in our cohort during the study period. Thus, risk for metastatic disease from slowly growing, asymptomatic, endocrine inactive pancreatic tumours <15 mm may be considered low. However, it has to be taken into account that criteria for metastatic disease were suspicious lesions in ct and/or srs and/or mri. These methods were unable to detect the primary pancreatic lesions in our cohort in almost all cases. Systematic hepatic imaging by EUS has not been established yet. It needs to be stated in this context that the imaging techniques used in this study are unable to detect or exclude micrometastases.

In conclusion, the data obtained from this study referring to 33.8 patient years and 106.7 tumour years can be taken as an information on the natural course of small, asymptomatic, neuroendocrine pancreatic tumours in MEN1-disease. Usually they grow slowly and there is no obvious evidence for a high tendency to be metastatic. However, exceptions showing different biological behaviour (in this study patient no. 18) can be observed and need to be considered.

These data may justify a conservative approach in the typical situation: no symptoms, tumour(s) <15 mm, missing or slow growth velocity as assessed by repeated competent EUS imaging. Based on our data, ‘usual or slow progression’ may be defined as mean increase of largest tumour diameter(s) of about 15% per year and detection of maximally one new neuroendocrine pancreatic tumour every 2 years by EUS. In such patients with ‘usually’ or ‘slowly’ progressing asymptomatic small neuroendocrine pancreatic tumours associated to MEN1-disease, besides aggressive surgical treatment, also an assessment of follow-up and a later decision about surgical seem to be possible. However, this has to be discussed extensively with the patient.

Table 1

clinical characteristics of 20 patient with MEN1-disease

f, female; m, male; y, yes; n, no; n/d, not done.
Patient number1234567891011121314151617181920
Gender/agef/42m/36m/21m/69m/54f/51m/55m/60f/29m/51f/33f/54f/24m/49m/38m/27f/37m/53m/38f/41
Pituitary tumournynyynnnnnnynnynynnn
Primary hyperparathyroidismyyyyyyyyyynyyyyyyyyn
Neuroendocrine pancreatic tumor(s) confirmed by previous pancreatic surgeryynynnyyynyynnnynyynn
Genetical diagnosis MEN1ynynyyyynyyyyyyyynyy
Number of pancreatic tumours detected by endosonography (first examination)22416452216352221213
Number of pancreatic tumours detected by endosonography (last examination)4241114102217352252935
Observation period (months)3173734302936686520910142036293122
Number of pancreatic tumours detected by ct (last examination)02000001000010000000
Number of pancreatic tumours detected by srs (last examination)00n/dn/d0010001010100100
Number of pancreatic tumours detected by mri (last examination)0000n/dn/d1n/dn/d2n/d0n/dn/dn/d0n/d1n/dn/d
Table 2

genetical diagnosis of 20 patient with MEN1-disease

Patient numberMutation
1c.155-3TCC > TTC missense
2No mutation detected
367 Ins AGCCC
4No mutation detected
5E116X
6427 Del 6 bp 1390 (GTCCCA)
7Q554X
8splice Intron 4 C894 G → A
9No mutation detected
10466 14 bp Del
11c.894-9G > A splice-site
12E116X
13K119X
14514 Ins C
15C488G → stop
16E116X
17K120X
18No mutation detected
19L168P
20L168P
Figure 1
Figure 1

Follow-up of the largest diameter of 61 small asymptomatic neuroendocrine pancreatic tumours in MEN1 obtained by EUS imaging (data of one patient with rapid progressive disease and where due to a relevant increase in the number of pancreatic tumours reidentification of each particular tumour was not possible during follow-up are not displayed in this figure).

Citation: Endocrine-Related Cancer Endocr Relat Cancer 13, 4; 10.1677/erc.1.01220

This study was supported by the Foundation for Innovation of Rhineland-Palatinate, Mainz/Germany and Novartis Pharma GmbH, Nuremberg/Germany. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

References

  • Akerstrom G, Hessman O & Skogseid B 2002 Timing and extent of surgery in symptomatic and asymptomatic neuroendocrine tumors of the pancreas in MEN 1. Langenbecks Archives of Surgery 386 558–569.

    • Search Google Scholar
    • Export Citation
  • Azimuddin K & Chamberlain RS 2001 The surgical management of pancreatic neuroendocrine tumors. Surgical Oncology Clinics of North America 81 511–525.

    • Search Google Scholar
    • Export Citation
  • Bansal R, Tierney W, Carpenter S, Thompson N & Scheiman JM 1999 Cost effectiveness of EUS for preoperative localization of pancreatic endocrine tumors. Gastrointestinal Endoscopy 49 19–25.

    • Search Google Scholar
    • Export Citation
  • Bartsch DK, Langer P, Wild A, Schilling T, Celik I, Rothmund M & Nies C 2000 Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance? Surgery 128 958–966.

    • Search Google Scholar
    • Export Citation
  • Bolondi L, Li Bassi S, Gaiani S, Campione O, Marrano D & Barbara L 1990 Diagnosis of islet cell tumor by means of endoscopic ultrasonography. Journal of Clinical Gastroenterology 12 212–218.

    • Search Google Scholar
    • Export Citation
  • Carty SE, Helm AK, Amico JA, Clarke MR, Foley TP, Watson CG & Mulvihill JJ 1998 The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 124 1106–1113.

    • Search Google Scholar
    • Export Citation
  • Chanson P, Cadiot G & Murat A 1997 Management of patients and subjects at risk for multiple endocrine neoplasia type 1: MEN 1. Hormone Research 47 211–220.

    • Search Google Scholar
    • Export Citation
  • Dancygier H 1995 Endoscopic ultrasonography in chronic pancreatitis. Gastrointestinal Endoscopy Clinics of North America 5 1052–1057.

  • Devière J, Finet L, Dunham F & Cremer M 1994 Endoscopic ultrasonography in chronic pancreatitis. Endoscopy 26 808–809.

  • Dotzenrath C, Goretzki PE, Cupisti K, Yang Q, Simon D & Roher HD 2001 Malignant endocrine tumors in patients with MEN 1 disease. Surgery 129 91–95.

    • Search Google Scholar
    • Export Citation
  • Grimm H, Mayendo A & Soehendra N 1990 Endoluminal ultrasound for the diagnosis and staging of pancreatic cancer. Baillieres of Clinical Gastroenterology 4 869–888.

    • Search Google Scholar
    • Export Citation
  • Hellman P, Hennings J, Akerstrom G & Skogseid B 2005 Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1. British Journal of Surgery 92 1508–1512.

    • Search Google Scholar
    • Export Citation
  • Jordan PH, Jr 1999 A personal experience with pancreatic and duodenal neuroendocrine tumors. Journal of the American College of Surgery 189 470–482.

    • Search Google Scholar
    • Export Citation
  • Kann PH 2005 Endosonographic imaging of the adrenals. Endoscopy 37 244–253.

  • Kann P, Bittinger F, Hengstermann C, Engelbach M & Beyer J 1998a Endosonographische Darstellung der Nebennieren: Eine neue Methode. Ultraschall in der Medizin 19 4–9.

    • Search Google Scholar
    • Export Citation
  • Kann P, Hengstermann C, Heussel CP, Bittinger F, Engelbach M & Beyer J 1998b Endosonography of the adrenal glands: normal size – pathological findings. Experimental and Clinical Endocrinology and Diabetes 106 123–129.

    • Search Google Scholar
    • Export Citation
  • Kann P, Heintz A, Bittinger F, Herber S, Kunt T & Beyer J 1999 Endosonographie bei kleinen Nebennierenraumfor-derungen: Morphologischer Nachweis der mikro- und makronodulären Nebennierenrindenhyperplasie in vivo als Ursache einer autonomen Sekretion von Steroidhormonen. Tumordiagnostik und Therapie 20 135–143.

    • Search Google Scholar
    • Export Citation
  • Kann P, Heintz A, Bittinger F, Kessler S, Forst T, Weis A & Beyer J 2000 Bildgebende Diagnostik der Nebennieren: neue Aspekte durch die Einführung der Endosonographie. Minimal Invasive Chirurgie 9 58–61.

    • Search Google Scholar
    • Export Citation
  • Kann P, Bittinger F, Engelbach M, Bohner S, Weis A & Beyer J 2001 Endosonography of insulin-secreting and clinically non-functioning neuroendocrine tumors of the pancreas: criteria for benignancy and malignancy. European Journal of Medical Research 6 385–390.

    • Search Google Scholar
    • Export Citation
  • Kann PH, Wirkus B, Keth A & Goitom K 2003 Pitfalls in endosonographic imaging of suspected insulinomas: pancreatic nodules of unknown dignity. European Journal of Endocrinology 148 531–534.

    • Search Google Scholar
    • Export Citation
  • Kann PH, Wirkus B, Behr T, Klose K-J & Meyer S 2004 Endosonographic imaging of benign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 89 1694–1697.

    • Search Google Scholar
    • Export Citation
  • Kann PH, Kann B, Fassbender WJ, Forst T, Bartsch DK, Langer P 2006 Small neuroendocrine pancreatic tumors in multiple endocrine neoplasia type 1 (MEN1): least significant change of tumor diameter as determined by endoscopic ultrasound (EUS) imaging. Experimental and Clinical Endocrinology and Diabetes 114 361–365.

    • Search Google Scholar
    • Export Citation
  • Lairmore TC, Chen VY, DeBenedetti MK, Gillanders WE, Norton JA & Doherty GM 2000 Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Annals of Surgery 231 909–918.

    • Search Google Scholar
    • Export Citation
  • Langer P, Kann PH, Fendrich V, Richter G, Diehl S, Rothmund M & Bartsch DK 2004 Prospective evaluation of imaging procedures for the detection of pancreaticoduodenal endocrine tumors (PETs) in patients with multiple endocrine neoplasia type 1 (MEN1). World Journal of Surgery 28 1317–1322.

    • Search Google Scholar
    • Export Citation
  • Le Bodic MF, Heymann MF, Lecomte M, Berger N, Berger F, Louvel A, De Micco C, Patey M, De Mascarel A, Burtin F et al.1996 Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. American Journal of Surgical Pathology 20 1378–1384.

    • Search Google Scholar
    • Export Citation
  • Lees WR 1986 Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scandinavian Journal of Gastroenterology 123 123–129.

    • Search Google Scholar
    • Export Citation
  • Lightdale CJ, Botet JF, Woodruff JM & Brennan MF 1991 Localization of endocrine tumors of the pancreas with endoscopic ultrasonography. Cancer 68 1815–1820.

    • Search Google Scholar
    • Export Citation
  • McLean AM & Fairclough PD 2005 Endoscopic ultrasound in the localisation of pancreatic islet cell tumours. Best Practice and Research Clinical Endocrinoly and Metabolism 19 177–193.

    • Search Google Scholar
    • Export Citation
  • Meko JB & Norton JA 1994 Endocrine tumors of the pancreas. Current Opinions in Genetics and Surgery 1994 186–194.

  • Meyenberger C, Bertschinger P, Zala GF & Marincek B 1995 Endosonography in diagnosis of insulinoma. Ultraschall in der Medizin 16 224–227.

    • Search Google Scholar
    • Export Citation
  • Mignon M 2000 Natural history of neuroendocrine enter-opancreatic tumors. Digestion 62 51–58.

  • Müller MF, Meyerberger C, Bertschinger P, Schaer R & Marincek B 1994 Pancreatic tumors: evaluation with endoscopic US, CT, and MR imaging. Radiology 190 745–751.

    • Search Google Scholar
    • Export Citation
  • Nattermann C & Dancygier H 1993 Endosonographie bei Tumoren des Pankreas und der Gallenwege. Leber Magen Darm 1 13–23.

  • Nattermann C, Goldschmidt AJW & Dancygier H 1993 Endosonography in chronic pancreatitis – a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy 25 565–570.

    • Search Google Scholar
    • Export Citation
  • Nattermann C, Goldschmidt AJW & Dancygier H 1995 Endosonographie in der Dignitätsbeurteilung von Pankreastumoren. Deutsche Medizinische Wochenschrift 120 1571–1576.

    • Search Google Scholar
    • Export Citation
  • Onaitis M, White R & Tyler D 2003 Carcinoid tumors of the gastrointestinal tract. A review and the Duke University institutional overview. Minerva Chirurgica 58 1–8.

    • Search Google Scholar
    • Export Citation
  • Owen NJ, Sohaib SA, Peppercorn PD, Monson JP, Grossman AB, Besser GM & Reznek RH 2001 MRI of pancreatic neuroendocrine tumors. British Journal of Radiology 74 968–973.

    • Search Google Scholar
    • Export Citation
  • Plöckinger U & Wiedenmann B 2002 Neuroendocrine tumors of the gastro-entero-pancreatic system: the role of early diagnosis, genetic testing and preventive surgery. Digestive Diseases 20 49–60.

    • Search Google Scholar
    • Export Citation
  • Rösch T, Lorenz R, Braig C, Feuerbach S, Siewert JR & Classen M 1990 Endosonographische Diagnostik bei Pankreastumoren. Deutsche Medizinische Wochenschrift 115 1339–1347.

    • Search Google Scholar
    • Export Citation
  • Sato M, Kihara M, Nishitani A, Murao K, Kobayashi S, Miyauchi A & Takahara J 2000 Large and asymptomatic pancreatic islet cell tumor in a patient with multiple endocrine neoplasia type 1. Endocrine 13 263–266.

    • Search Google Scholar
    • Export Citation
  • Scheffold N, Arnold R & Cyran J 1995 Metastasierendes Pankreas-Vipom. Deutsche Medizinische Wochenschrift 129 1463–1466.

  • Skogseid B & Oberg K 1995 Experience with multiple endocrine neoplasia type 1 screening. Journal of Internal Medicine 238 255–261.

  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al.2000 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 92 205–216.

    • Search Google Scholar
    • Export Citation
  • Thomas-Marques L, Murat A, Delemer B, Penfornis A, Cardot-Bauters C, Baudin E, Niccoli-Sire P, Levoir D, Choplin Hdu B, Chabre O et al.2006 Groupe des tumeurs endocrines (GTE) Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. American Journal of Gastroenterology 101 266–273.

    • Search Google Scholar
    • Export Citation
  • Thompson NW 1995 The surgical management of hyperparathyroidism and endocrine disease of the pancreas in the multiple endocrine neoplasia type 1 patient. Journal of Internal Medicine 238 269–280.

    • Search Google Scholar
    • Export Citation
  • Thompson NW 1998 Management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1. Surgical Oncology Clinics of North America 7 881–891.

    • Search Google Scholar
    • Export Citation
  • Wamsteker EJ, Gauger PG, Thompson NW & Scheiman JM 2003 EUS detection of pancreatic endocrine tumors in asymptomatic patients with type 1 multiple endocrine neoplasia. Gastrointestinal Endoscopy 58 531–535.

    • Search Google Scholar
    • Export Citation
  • Weinel RJ, Kisker O, Joseph K, Welcke U, Zaraca F & Rothmund M 1994 Somatostatin receptor scintigraphy in preoperative diagnosis of the site of endocrine gastrointestinal tumors. Chirurg 65 849–855.

    • Search Google Scholar
    • Export Citation
  • Wiersema MJ & Wiersema LM 1995 Endosonography of the pancreas: normal variation versus changes of early chronic pancreatitis. Gastrointestinal Endoscopy Clinics of North America 5 487–496.

    • Search Google Scholar
    • Export Citation
  • Wiersema MJ, Hawes H, Lehmann GA, Kochmann ML, Sherman S & Kopecky KK 1993 Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 25 555–564.

    • Search Google Scholar
    • Export Citation
  • Yasuda K, Mukai H, Fujimoto S, Nakajiama M & Kawai K 1988 The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointestinal Endoscopy 134 1–8.

    • Search Google Scholar
    • Export Citation
  • Zimmer T, Ziegler K, Liehr RM, Stolzel U, Riecken EO & Wiedenmann B 1994 Endosonography of neuroendocrine tumors of the stomach, duodenum, and pancreas. Annals of the New York Academy of Sciences 733 425–436.

    • Search Google Scholar
    • Export Citation
  • Zuccaro G, Jr & Sivak MV, Jr 1992 Endoscopic ultrasonography in the diagnosis of chronic pancreatitis. Endoscopy 24 347–349.

 

Society for Endocrinology logo

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 40 40 4
PDF Downloads 33 33 10
  • View in gallery

    Follow-up of the largest diameter of 61 small asymptomatic neuroendocrine pancreatic tumours in MEN1 obtained by EUS imaging (data of one patient with rapid progressive disease and where due to a relevant increase in the number of pancreatic tumours reidentification of each particular tumour was not possible during follow-up are not displayed in this figure).

  • Akerstrom G, Hessman O & Skogseid B 2002 Timing and extent of surgery in symptomatic and asymptomatic neuroendocrine tumors of the pancreas in MEN 1. Langenbecks Archives of Surgery 386 558–569.

    • Search Google Scholar
    • Export Citation
  • Azimuddin K & Chamberlain RS 2001 The surgical management of pancreatic neuroendocrine tumors. Surgical Oncology Clinics of North America 81 511–525.

    • Search Google Scholar
    • Export Citation
  • Bansal R, Tierney W, Carpenter S, Thompson N & Scheiman JM 1999 Cost effectiveness of EUS for preoperative localization of pancreatic endocrine tumors. Gastrointestinal Endoscopy 49 19–25.

    • Search Google Scholar
    • Export Citation
  • Bartsch DK, Langer P, Wild A, Schilling T, Celik I, Rothmund M & Nies C 2000 Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance? Surgery 128 958–966.

    • Search Google Scholar
    • Export Citation
  • Bolondi L, Li Bassi S, Gaiani S, Campione O, Marrano D & Barbara L 1990 Diagnosis of islet cell tumor by means of endoscopic ultrasonography. Journal of Clinical Gastroenterology 12 212–218.

    • Search Google Scholar
    • Export Citation
  • Carty SE, Helm AK, Amico JA, Clarke MR, Foley TP, Watson CG & Mulvihill JJ 1998 The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 124 1106–1113.

    • Search Google Scholar
    • Export Citation
  • Chanson P, Cadiot G & Murat A 1997 Management of patients and subjects at risk for multiple endocrine neoplasia type 1: MEN 1. Hormone Research 47 211–220.

    • Search Google Scholar
    • Export Citation
  • Dancygier H 1995 Endoscopic ultrasonography in chronic pancreatitis. Gastrointestinal Endoscopy Clinics of North America 5 1052–1057.

  • Devière J, Finet L, Dunham F & Cremer M 1994 Endoscopic ultrasonography in chronic pancreatitis. Endoscopy 26 808–809.

  • Dotzenrath C, Goretzki PE, Cupisti K, Yang Q, Simon D & Roher HD 2001 Malignant endocrine tumors in patients with MEN 1 disease. Surgery 129 91–95.

    • Search Google Scholar
    • Export Citation
  • Grimm H, Mayendo A & Soehendra N 1990 Endoluminal ultrasound for the diagnosis and staging of pancreatic cancer. Baillieres of Clinical Gastroenterology 4 869–888.

    • Search Google Scholar
    • Export Citation
  • Hellman P, Hennings J, Akerstrom G & Skogseid B 2005 Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1. British Journal of Surgery 92 1508–1512.

    • Search Google Scholar
    • Export Citation
  • Jordan PH, Jr 1999 A personal experience with pancreatic and duodenal neuroendocrine tumors. Journal of the American College of Surgery 189 470–482.

    • Search Google Scholar
    • Export Citation
  • Kann PH 2005 Endosonographic imaging of the adrenals. Endoscopy 37 244–253.

  • Kann P, Bittinger F, Hengstermann C, Engelbach M & Beyer J 1998a Endosonographische Darstellung der Nebennieren: Eine neue Methode. Ultraschall in der Medizin 19 4–9.

    • Search Google Scholar
    • Export Citation
  • Kann P, Hengstermann C, Heussel CP, Bittinger F, Engelbach M & Beyer J 1998b Endosonography of the adrenal glands: normal size – pathological findings. Experimental and Clinical Endocrinology and Diabetes 106 123–129.

    • Search Google Scholar
    • Export Citation
  • Kann P, Heintz A, Bittinger F, Herber S, Kunt T & Beyer J 1999 Endosonographie bei kleinen Nebennierenraumfor-derungen: Morphologischer Nachweis der mikro- und makronodulären Nebennierenrindenhyperplasie in vivo als Ursache einer autonomen Sekretion von Steroidhormonen. Tumordiagnostik und Therapie 20 135–143.

    • Search Google Scholar
    • Export Citation
  • Kann P, Heintz A, Bittinger F, Kessler S, Forst T, Weis A & Beyer J 2000 Bildgebende Diagnostik der Nebennieren: neue Aspekte durch die Einführung der Endosonographie. Minimal Invasive Chirurgie 9 58–61.

    • Search Google Scholar
    • Export Citation
  • Kann P, Bittinger F, Engelbach M, Bohner S, Weis A & Beyer J 2001 Endosonography of insulin-secreting and clinically non-functioning neuroendocrine tumors of the pancreas: criteria for benignancy and malignancy. European Journal of Medical Research 6 385–390.

    • Search Google Scholar
    • Export Citation
  • Kann PH, Wirkus B, Keth A & Goitom K 2003 Pitfalls in endosonographic imaging of suspected insulinomas: pancreatic nodules of unknown dignity. European Journal of Endocrinology 148 531–534.

    • Search Google Scholar
    • Export Citation
  • Kann PH, Wirkus B, Behr T, Klose K-J & Meyer S 2004 Endosonographic imaging of benign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 89 1694–1697.

    • Search Google Scholar
    • Export Citation
  • Kann PH, Kann B, Fassbender WJ, Forst T, Bartsch DK, Langer P 2006 Small neuroendocrine pancreatic tumors in multiple endocrine neoplasia type 1 (MEN1): least significant change of tumor diameter as determined by endoscopic ultrasound (EUS) imaging. Experimental and Clinical Endocrinology and Diabetes 114 361–365.

    • Search Google Scholar
    • Export Citation
  • Lairmore TC, Chen VY, DeBenedetti MK, Gillanders WE, Norton JA & Doherty GM 2000 Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Annals of Surgery 231 909–918.

    • Search Google Scholar
    • Export Citation
  • Langer P, Kann PH, Fendrich V, Richter G, Diehl S, Rothmund M & Bartsch DK 2004 Prospective evaluation of imaging procedures for the detection of pancreaticoduodenal endocrine tumors (PETs) in patients with multiple endocrine neoplasia type 1 (MEN1). World Journal of Surgery 28 1317–1322.

    • Search Google Scholar
    • Export Citation
  • Le Bodic MF, Heymann MF, Lecomte M, Berger N, Berger F, Louvel A, De Micco C, Patey M, De Mascarel A, Burtin F et al.1996 Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. American Journal of Surgical Pathology 20 1378–1384.

    • Search Google Scholar
    • Export Citation
  • Lees WR 1986 Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scandinavian Journal of Gastroenterology 123 123–129.

    • Search Google Scholar
    • Export Citation
  • Lightdale CJ, Botet JF, Woodruff JM & Brennan MF 1991 Localization of endocrine tumors of the pancreas with endoscopic ultrasonography. Cancer 68 1815–1820.

    • Search Google Scholar
    • Export Citation
  • McLean AM & Fairclough PD 2005 Endoscopic ultrasound in the localisation of pancreatic islet cell tumours. Best Practice and Research Clinical Endocrinoly and Metabolism 19 177–193.

    • Search Google Scholar
    • Export Citation
  • Meko JB & Norton JA 1994 Endocrine tumors of the pancreas. Current Opinions in Genetics and Surgery 1994 186–194.

  • Meyenberger C, Bertschinger P, Zala GF & Marincek B 1995 Endosonography in diagnosis of insulinoma. Ultraschall in der Medizin 16 224–227.

    • Search Google Scholar
    • Export Citation
  • Mignon M 2000 Natural history of neuroendocrine enter-opancreatic tumors. Digestion 62 51–58.

  • Müller MF, Meyerberger C, Bertschinger P, Schaer R & Marincek B 1994 Pancreatic tumors: evaluation with endoscopic US, CT, and MR imaging. Radiology 190 745–751.

    • Search Google Scholar
    • Export Citation
  • Nattermann C & Dancygier H 1993 Endosonographie bei Tumoren des Pankreas und der Gallenwege. Leber Magen Darm 1 13–23.

  • Nattermann C, Goldschmidt AJW & Dancygier H 1993 Endosonography in chronic pancreatitis – a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy 25 565–570.

    • Search Google Scholar
    • Export Citation
  • Nattermann C, Goldschmidt AJW & Dancygier H 1995 Endosonographie in der Dignitätsbeurteilung von Pankreastumoren. Deutsche Medizinische Wochenschrift 120 1571–1576.

    • Search Google Scholar
    • Export Citation
  • Onaitis M, White R & Tyler D 2003 Carcinoid tumors of the gastrointestinal tract. A review and the Duke University institutional overview. Minerva Chirurgica 58 1–8.

    • Search Google Scholar
    • Export Citation
  • Owen NJ, Sohaib SA, Peppercorn PD, Monson JP, Grossman AB, Besser GM & Reznek RH 2001 MRI of pancreatic neuroendocrine tumors. British Journal of Radiology 74 968–973.

    • Search Google Scholar
    • Export Citation
  • Plöckinger U & Wiedenmann B 2002 Neuroendocrine tumors of the gastro-entero-pancreatic system: the role of early diagnosis, genetic testing and preventive surgery. Digestive Diseases 20 49–60.

    • Search Google Scholar
    • Export Citation
  • Rösch T, Lorenz R, Braig C, Feuerbach S, Siewert JR & Classen M 1990 Endosonographische Diagnostik bei Pankreastumoren. Deutsche Medizinische Wochenschrift 115 1339–1347.

    • Search Google Scholar
    • Export Citation
  • Sato M, Kihara M, Nishitani A, Murao K, Kobayashi S, Miyauchi A & Takahara J 2000 Large and asymptomatic pancreatic islet cell tumor in a patient with multiple endocrine neoplasia type 1. Endocrine 13 263–266.

    • Search Google Scholar
    • Export Citation
  • Scheffold N, Arnold R & Cyran J 1995 Metastasierendes Pankreas-Vipom. Deutsche Medizinische Wochenschrift 129 1463–1466.

  • Skogseid B & Oberg K 1995 Experience with multiple endocrine neoplasia type 1 screening. Journal of Internal Medicine 238 255–261.

  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al.2000 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 92 205–216.

    • Search Google Scholar
    • Export Citation
  • Thomas-Marques L, Murat A, Delemer B, Penfornis A, Cardot-Bauters C, Baudin E, Niccoli-Sire P, Levoir D, Choplin Hdu B, Chabre O et al.2006 Groupe des tumeurs endocrines (GTE) Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. American Journal of Gastroenterology 101 266–273.

    • Search Google Scholar
    • Export Citation
  • Thompson NW 1995 The surgical management of hyperparathyroidism and endocrine disease of the pancreas in the multiple endocrine neoplasia type 1 patient. Journal of Internal Medicine 238 269–280.

    • Search Google Scholar
    • Export Citation
  • Thompson NW 1998 Management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1. Surgical Oncology Clinics of North America 7 881–891.

    • Search Google Scholar
    • Export Citation
  • Wamsteker EJ, Gauger PG, Thompson NW & Scheiman JM 2003 EUS detection of pancreatic endocrine tumors in asymptomatic patients with type 1 multiple endocrine neoplasia. Gastrointestinal Endoscopy 58 531–535.

    • Search Google Scholar
    • Export Citation
  • Weinel RJ, Kisker O, Joseph K, Welcke U, Zaraca F & Rothmund M 1994 Somatostatin receptor scintigraphy in preoperative diagnosis of the site of endocrine gastrointestinal tumors. Chirurg 65 849–855.

    • Search Google Scholar
    • Export Citation
  • Wiersema MJ & Wiersema LM 1995 Endosonography of the pancreas: normal variation versus changes of early chronic pancreatitis. Gastrointestinal Endoscopy Clinics of North America 5 487–496.

    • Search Google Scholar
    • Export Citation
  • Wiersema MJ, Hawes H, Lehmann GA, Kochmann ML, Sherman S & Kopecky KK 1993 Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 25 555–564.

    • Search Google Scholar
    • Export Citation
  • Yasuda K, Mukai H, Fujimoto S, Nakajiama M & Kawai K 1988 The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointestinal Endoscopy 134 1–8.

    • Search Google Scholar
    • Export Citation
  • Zimmer T, Ziegler K, Liehr RM, Stolzel U, Riecken EO & Wiedenmann B 1994 Endosonography of neuroendocrine tumors of the stomach, duodenum, and pancreas. Annals of the New York Academy of Sciences 733 425–436.

    • Search Google Scholar
    • Export Citation
  • Zuccaro G, Jr & Sivak MV, Jr 1992 Endoscopic ultrasonography in the diagnosis of chronic pancreatitis. Endoscopy 24 347–349.