Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1

doi:10.1016/S0016-5085(99)70124-1

Gastroenterology

Volume 116, Issue 2, February 1999, Pages 286-293

https://doi.org/10.1016/S0016-5085(99)70124-1 Get rights and content

Abstract

Background & Aims: Risk factors of metachronous liver metastases and death are not well known in patients with the Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1. These factors were retrospectively determined in 77 patients. Methods: Data chart review was performed. Results: Median follow-up was 102 months (range, 12–366). Surgery was performed on 48 patients, including 9 of the 10 patients with large pancreatic tumors (≥3 cm). Liver metastases developed in 4 patients (40%) with large pancreatic tumors, in 3 (4.8%) without, and in 1 of the 4 patients with pancreatic tumors of unknown size; all had previously undergone surgery. The only independent factor associated with development of liver metastases identified by multivariate analysis was large pancreatic tumors (risk ratio, 29.0; 95% confidence interval [CI], 3.2–260.7). Surgery was not selected. The probability of being free of liver metastases in the 63 patients without large pancreatic tumors was 96% (95% CI, 88–100) at 10 and 15 years. Thirteen (16.9%) patients died. The only independent factors of death selected by multivariate analysis were Zollinger–Ellison syndrome diagnosis before 1980 (risk ratio, 8.2; 95% CI, 1.7–40.6) and age at diagnosis (risk ratio/year, 1.08; 95% CI, 1.03–1.14). Conclusions: Large pancreatic tumors are predictive of the development of metachronous liver metastases, and surgery does not seem to prevent them.

GASTROENTEROLOGY 1999;116:286-293

Section snippets

Patients

In 1995, specific questionnaires were sent to GRESZE and GENEM members to collect prognostic data from the medical records of their patients with ZES and MEN-1.

To be included in the study, patients had to have ZES and MEN-1. Exclusion criteria were presence of synchronous LM at the time of ZES diagnosis, patients who died postoperatively, and patients with short follow-up (<12 months).

ZES was diagnosed based on a suggestive clinical history and histological proof of endocrine tumor and/or

Results

Data on 91 patients were collected. Twelve patients did not meet the inclusion criteria: postoperative death (n = 7, all deaths before 1984) and/or follow-up <12 months (n = 10). None of these latter patients developed LM or died (except postoperatively, n = 5) during this 12-month follow-up. Two additional patients were excluded due to lack of information concerning tumor status. Therefore, results are based on a study population of 77 patients. One center (Bichat group) included 45 patients;

Discussion

Despite limitations because of the retrospective design of the study and the long period covered, the number of patients studied and the duration of follow-up were sufficient to evaluate some major events in the medical history of patients with ZES and MEN-1, i.e., development of LM and death and also the main factors associated with these events. These factors were chosen because it was improbable that they were biased.

Acknowledgements

The authors thank Drs. S. Chaussade, J. C. Croisier, P. Goudet, H. Licht, and E. Metman for providing data on their patients.

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Sporadic nonmetastatic gastrinomas had an excellent overall survival. Recurrence is frequent and influenced by tumor size and grade. Regarding sporadic duodenal gastrinoma, duodenotomy with excision of duodenal wall tumors with lymphadenectomy could be considered a valid surgical option, in the absence of clear oncologic superiority of PD.
New therapies for patients with multiple endocrine neoplasia type 1
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In 1953, for the first time, Paul Wermer described a family presenting endocrine gland neoplasms over several generations. The transmission was autosomal dominant and the penetrance was high. Forty years later in 1997, the multiple endocrine neoplasia type 1 (MEN1) gene was sequenced, thus enabling diagnosis and early optimal treatment. Patients carrying the MEN1 gene present endocrine but also non-endocrine tumors. Parathyroid, pancreatic and pituitary impairment are the three main types of endocrine involvement. The present article details therapeutic management of hyperparathyroidism, neuroendocrine pancreatic tumors and pituitary adenomas in patients carrying the MEN1 gene. Significant therapeutic progress has in fact been made in the last few years. As concerns the parathyroid glands, screening of family members and regular monitoring of affected subjects now raise the question of early management of parathyroid lesions and optimal timing of parathyroid surgery. As concerns the duodenum-pancreas, proton-pump inhibitors are able to control gastrin-secreting syndrome, reducing mortality in MEN1 patients. Mortality in MEN1 patients is no longer mainly secondary to uncontrolled hormonal secretion but to metastatic (mainly pancreatic) disease progression. Tumor risk requires regular monitoring of morphological assessment, leading to iterative pancreatic surgery in a large number of patients. Finally, pituitary adenomas in MEN1 patients are traditionally described as aggressive, invasive and resistant to medical treatment. However, regular pituitary screening showed them to be in fact infra-centimetric and non-secreting in the majority of patients. Consequently, it is necessary to regularly monitor MEN1 patients, with regular clinical, biological and morphological work-up. Several studies showed that this regular monitoring impairs quality of life. Building a relationship of trust between patients and care provider is therefore essential. It enables the patient to be referred for psychological or psychiatric care in difficult times, providing long-term support and preventing any breakdown in continuity of care.
En 1953, Paul Wermer décrivit pour la première fois une famille présentant, sur plusieurs générations, des tumeurs de glandes endocrines. La transmission était autosomique dominante et la pénétrance était élevée. Quarante ans plus tard, en 1997, le gène de la néoplasie endocrinienne multiple de type 1 (NEM1) fut séquencé, permettant ainsi un diagnostic et une prise en charge précoce et optimisée de ces patients. Les patients porteurs d’une NEM1 présentent des atteintes des glandes endocrines, mais également des atteintes non endocrines. Les atteintes parathyroïdiennes, pancréatiques et hypophysaires sont les trois principales atteintes endocrines. Nous détaillerons dans ce texte la prise en charge thérapeutique des hyperparathyroïdies, des tumeurs neuroendocrines pancréatiques et des adénomes hypophysaires chez les patients porteurs d’une NEM1. Les avancées thérapeutiques ont en effet été importantes ces dernières années. Sur le plan parathyroïdien, le dépistage des apparentés et la surveillance régulière de sujets atteints posent désormais la question de la prise en charge précoce des lésions parathyroïdiennes et du meilleur moment pour proposer à ces patients une chirurgie parathyroïdienne. Sur le plan duodéno-pancréatique, les inhibiteurs de la pompe à protons sont capables de contrôler le syndrome sécrétoire des gastrinomes, permettant ainsi de diminuer la mortalité des patients NEM1. La majorité des décès des patients NEM1 ne sont désormais plus secondaires à une sécrétion hormonale non contrôlée mais à une évolution tumorale métastatique principalement pancréatique. Ce risque tumoral impose une surveillance régulière du bilan morphologique et conduit à des chirurgies itératives du pancréas chez un grand nombre de patients. Enfin, sur le plan hypophysaire, les adénomes sont classiquement décrits chez les patients NEM1 comme agressifs, invasifs et résistants au traitement médical. Le dépistage régulier des patients NEM1 sur le plan hypophysaire a permis de démontrer que ces adénomes hypophysaires sont, en réalité, chez la majorité des patients, infra-centimétriques et non sécrétants. Un suivi régulier des patients NEM1 est par conséquent nécessaire. Ce suivi nécessite des surveillances régulières cliniques, biologiques et morphologiques. Plusieurs études ont démontré que ces surveillances régulières altèrent la qualité de vie des patients NEM1. La construction d’une relation de confiance patient/soignant est par conséquent primordial, permettant ainsi d’orienter le patient vers une prise en charge psychologique ou psychiatrique dans les moments difficiles afin d’accompagner ces patients sur le long terme et d’éviter des ruptures de suivi.
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Citation Excerpt :
There are no randomized controlled nor controlled comparative studies that evaluated the optimal surgical procedure for MEN1-ZES with regards to biochemical cure, complications, and recurrence. Independent of the surgical procedure the reported morbidity rates range from 30% to 40% and the reported perioperative mortality is below 2%, which is in the lower range of those reported for pancreatic surgery [8,15,19,22–24,41]. The cure rates after surgery range from 0% to 100% depending on the surgical procedure (Tables 1 and 2).
About 30% of patients with MEN1 develop a Zollinger-Ellison syndrome. Meanwhile it is well established that the causative gastrinomas are almost exclusively localized in the duodenum and not in the pancreas, MEN1 gastrinomas occur multicentric and are associated with hyperplastic gastrin cell lesions and tiny gastrin-producing micro tumors in contrast to sporadic duodenal gastrinomas. Regardless of the high prevalence of early lymphatic metastases, the survival is generally good with an aggressive course of disease in only about 20% of patients. Symptoms can be controlled medically. The indication, timing, type, and extent of surgery are highly controversial and are discussed in detail in this article by a thorough and critical review of literature. More radical procedures, like partial pancreaticoduodenectomy, are weighed against less aggressive local excision of gastrinomas and the pros and cons of both approaches are discussed in terms of long-term morbidity, biochemical cure, and survival.
Prognostic value of WHO grade in pancreatic neuro-endocrine tumors in Multiple Endocrine Neoplasia type 1: Results from the DutchMEN1 Study Group
2017, Pancreatology
Citation Excerpt :
In our cohort of MEN1 patients that underwent surgery for PanNET, liver metastases did not occur in patients with PanNETs <3 cm. An association between tumor size and liver metastases, aggressive growth and survival has also been found in MEN1 patients with Zollinger-Ellison syndrome [24,28,29]. Tumors >3 cm were associated with poor prognosis.
The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown.
We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated.
Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs ≥3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors ≤2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000).
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During the last decades an increase in the incidence of neuroendocrine tumors (NETs) was observed. Gastroenteropancreatic NETs represent the majority of NETs. Compared with their epithelial counterpart they usually have a more indolent behaviour and surgical resection improves survival. Tumor diameter is one of the main parameter in the decision making process for nonfunctioning forms. Generally, small lesions can be treated conservatively whereas larger tumors should be treated with standard surgical resection and lymphadenectomy. Functioning tumors should be resected regardless the dimension of the lesion. Locally advanced and metastatic disease should be also treated with extended resections, keeping in consideration the grading, size, Ki67, and presence of extra-abdominal disease. In the case of metastases the panel of operative treatment includes resection, ablation, up to liver transplantation.
Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1
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Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder, is characterised by the occurrence of pancreatic neuroendocrine tumours (P-NETs) in association with parathyroid and pituitary tumours. P-NETs, which include gastrinomas, insulinomas, and non-functioning tumours, occur in more than 80% of MEN1 patients and account for 50% of disease-specific deaths. However, there is no consensus about the optimal methods for detecting and treating P-NETs in MEN1 patients, and extrapolations from approaches used in patients with non-familial (sporadic) P-NETs require caution because of differences, such as the younger age of onset, multi-focality of P-NETs, and concomitant presence of other tumours in MEN1 patients. Thus, the early detection of P-NETs by circulating biomarkers and imaging modalities, and their appropriate treatments by surgical approaches and/or radionuclide therapy, chemotherapy, and biotherapy pose challenges and controversies. These challenges and controversies will be reviewed and possible approaches proposed.

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^☆: Address requests for reprints to: Guillaume Cadiot, M.D., Service d'hépato-gastroentérologie, Hôpital Robert-Debré, 51092 Reims Cedex, France. Fax: (33) 3-2678-4061.

^☆☆: GRESZE is partly supported by Takeda France. Supported in part by the Institut National da la Santé et de la Recherche Medicale (INSERM), C.A.R.M. 494017.

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Alimentary TractPrognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1☆,☆☆

Abstract

Section snippets

Patients

Results

Discussion

Acknowledgements

Gastroenterology

Gastroenterol Clin North Am

Am J Surg

Am J Surg

Surgery

Gastroenterology

Gastroenterology

Clinical, anatomical, and evolutive features of patients with the Zollinger-Ellison syndrome combined with type 1 multiple endocrine neoplasia

Pancreas

The Zollinger-Ellison syndrome. A collective surgical experience

Ann Surg

Forty-year appraisal of gastrinoma. Back to the future

Ann Surg

Long-term prognosis of Zollinger-Ellison syndrome in multiple endocrine neoplasia

Surgery

Surgical treatment of the Zollinger-Ellison syndrome

World J Surg

Gastrinomas: a 42-year experience

World J Surg

Surgical pathology of gastrinoma: site, size, multicentricity, association with multiple endocrine neoplasia type 1, and malignancy

Cancer

Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma

Ann Surg

Gastrinomas (Zollinger-Ellison syndrome)

Surgical treatment of islet cell tumors with special emphasis on operative ultrasound

Front Gastrointest Res

Gastrinoma

Alimentary Tract
Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1☆,☆☆