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Sporadic versus hereditary gastrinomas of the duodenum and pancreas:
distinct clinico-pathological and epidemiological features.World
J Gastroenterol. 2006 Sep 14;12(34):5440-6.
Gastrinomas are
defined as gastrin secreting tumors that are associated with Zollinger-Ellison
syndrome (ZES). ZES is characterized by elevated fasting gastrin serum
levels, positive secretin stimulation test and clinical symptoms such
as recurrent peptic ulcer disease, gastroesophageal reflux disease and
occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas
are distinguished from hereditary gastrinomas, which are associated
with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general,
duodenal gastrinomas are small and solitary if they are sporadic and
multiple as well as hereditary. The sporadic gastrinomas occur in the
duodenum or in the pancreas while the hereditary gastrinomas almost
all occur in the duodenum. Our series of 77 sporadic duodenal
neuroendocrine tumors (NETs) includes 18 patients (23.4%) with
gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected
from the NET archives of the departments of pathology in Zurich,
Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from
sporadic pancreatic gastrinomas and ZES. These NETs have to be
distinguished from tumors with immunohistochemical positivity for
gastrin but without evidence of ZES. An additional 19 patients
suffered from MEN1 and ZES. These patients showed exclusively duodenal
gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic
and MEN1-associated duodenal gastrinomas is better than that of
pancreatic gastrinomas, since they progress slowly to liver
metastasis. In summary, sporadic and MEN1-associated gastrinomas in
the duodenum and pancreas show different clinico-pathological and
genetic features. The incidence of sporadic duodenal gastrin-producing
tumors is increasing, possibly due to optimized diagnostic procedures.
In contrast, pancreatic MEN1-associated gastrinomas seem to be
extremely rare. A considerable subset of tumors with
immunohistochemical expression of gastrin but without evidence of ZES
should be designated as functionally inactive NETs expressing gastrin,
but not as gastrinomas.
Increased
islet beta cell replication adjacent to intrapancreatic gastrinomas in
humans. Diabetologia.
2006 Nov;49(11):2689-96.
AIMS/HYPOTHESIS:
Type 1 and type 2 diabetes are characterised by a beta cell deficit.
Islet hyperplasia has been described in patients with Zollinger-Ellison
syndrome secondary to gastrin-producing tumours (gastrinomas), and
gastrin therapy has increased beta cell mass in rodents and human
islets in vitro. In the present studies we addressed the following
questions: (1) In pancreas specimens from gastrinoma cases, is the
fractional beta cell area increased? (2) If so, is this restricted to
tumour-adjacent islets or also present in tumour-distant islets? (3)
Is new beta cell formation (beta cell replication and islet neogenesis)
increased and beta cell apoptosis decreased in pancreas specimens from
gastrinoma cases? METHODS: Pancreas was obtained at surgery from four
patients with Zollinger-Ellison syndrome caused by pancreatic
gastrinomas and 15 control subjects at autopsy. RESULTS: Islet
fractional beta cell area (p<0.001), islet size (p<0.001) and beta
cell replication (Ki67 staining) (p<0.05) were increased in islets
adjacent to the tumours, but not in tumour-distant pancreas, compared
with control subjects. We did not observe any differences in beta cell
apoptosis or in the number of insulin-positive cells in ducts either
adjacent to or distant from the tumour. CONCLUSIONS/INTERPRETATION:
One or more factors released by human gastrinomas increase beta cell
replication in islets immediately adjacent to the tumour, but not in
tumour-distant islets. While these findings demonstrate that adult
human beta cells can be driven into the cell cycle, they caution
against the therapeutic usefulness of gastrin, since islets located >1
cm away from the gastrinomas did not exhibit changes in beta cell
turnover, despite markedly elevated systemic gastrin levels sufficient
to cause severe gastrointestinal symptoms.
Gastrinomas:
advances in diagnosis and management.
Neuro endocrinology.
2004;80 Suppl 1:23-7.
Gastrinomas
causing Zollinger-Ellison syndrome (ZES) are the most common
functional, malignant pancreatic endocrine tumors. In this paper, the
diagnosis and treatment of these tumors are reviewed, incorporating
recent advances in each area. Furthermore, recent advances in their
pathology, molecular pathogenesis, and aspects of their localization
using somatostatin receptor scintigraphy, as well as their treatment
are discussed. Recent data from our NIH prospective studies on
patients with ZES are included to illustrate many of these points.
Expression of the
calcium-sensing receptor in gastrinomas.J
Clin Endocrinol Metab. 2000 Nov;85(11):4131-7.
Extracellular
calcium levels are able to influence the secretion of gastrin by
gastrinomas and possibly affect the growth pattern. The molecular
mechanisms of these functions are not known. The purpose of the
present study was to investigate the presence of the calcium-sensing
receptor (CaR) in 10 gastrinomas and determine the extent of
expression in the tumors. The amounts of CaR messenger ribonucleic
acid in eight tumors were determined by quantitative RT-PCR. Protein
expression was analyzed by Western blot and immunohistochemistry using
a monoclonal antibody (ADD). CaR messenger ribonucleic acid was
detected in all gastrinomas with levels ranging from 0.04-3.16 times
the amount of beta-actin transcripts. The Western blot showed a major
immunoreactive band at 250 kDa and a minor at 140 kDa, corresponding
to the receptor dimer and monomer, respectively. Immunohistochemistry
demonstrated variable membranous staining in all gastrinomas and
normal pancreatic islets. No staining was observed in the normal
liver, lymph node, or exocrine pancreas. We conclude that the CaR is
present in all gastrinomas, with expression varying by 80-fold. It
probably contributes to the calcium-stimulated gastrin release by
gastrinomas. Whether the density of the CaR is a determining factor of
the magnitude of this gastrin release or plays a role in regulating
the growth pattern of the gastrinoma, as it does in other cells,
remains unclear at present.
Pathologic aspects of gastrinomas in patients with Zollinger-Ellison
syndrome with and without multiple endocrine neoplasia type I.World
J Surg. 1993 Jul-Aug;17(4):481-8.
During the three
decades since the recognition of the Zollinger-Ellison syndrome (ZES),
major progress has been made in the diagnosis and treatment of this
disease. However, the many failed operations in patients with ZES, the
existence of primary lymph node gastrinomas, and the surgical approach
of patients with ZES and multiple endocrine neoplasia type I (MEN-I)
have remained controversial issues. In this review, our experience
with the pathology of immunocytochemically identified gastrinomas in
44 patients with ZES is presented and related to the relevant
literature. (1) Gastrinomas occur frequently in the duodenum (> 40%)
and are commonly small (< 1 cm). They can therefore easily be missed
at surgical exploration; lymph node metastases from such occult
gastrinomas may be mistaken for primary tumors. (2) Most pancreatic
gastrinomas reside in the head of the gland and have a diameter of 1
to 3 cm. (3) Gastrinomas associated with MEN-I are predominantly of
duodenal origin and frequently multicentric; sporadic gastrinomas are
single and more often pancreatic. Because MEN-I associated pancreatic
tumors seldom contain gastrin, ZES in MEN-I patients is almost never
cured by resection of the pancreatic tumors. (4) The metastatic
potential of most small duodenal gastrinomas seems to be restricted to
the regional lymph nodes.
Surgical pathology of gastrinoma. Site, size, multicentricity,
association with multiple endocrine neoplasia type 1, and malignancy.Cancer.
1991 Sep 15;68(6):1329-34.
Specimens from
the pancreas and duodenum of 26 patients with sporadic Zollinger-Ellison
syndrome (ZES) and 18 patients with multiple endocrine neoplasia type
1 (MEN-1) and hypergastrinemia (17 with ZES) were screened
immunocytochemically for gastrinomas. Location, size, multicentricity,
and malignancy of the gastrinomas were evaluated. The MEN-1 patients
had gastrinomas in the duodenum (nine of 18), pancreas (one of 18),
and periduodenal lymph nodes (two of 18). No gastrinoma was identified
in six patients. Most duodenal gastrinomas were multiple (five of
nine) and smaller than 0.6 cm (six of nine). Lymph node metastases
were present in eight of 12 patients. All 26 patients with sporadic
ZES had a solitary gastrinoma; 14 were found in the pancreas and had a
diameter greater than 2 cm. Ten patients had a duodenal gastrinoma,
two with a diameter less than 0.6 cm. In two patients, only
periduodenal "lymph node gastrinomas" were detected. Eighteen of the
sporadic gastrinomas were malignant. These results suggest that
duodenal location and multicentricity of gastrinomas are associated
with the MEN-1 syndrome, and solitary gastrinomas, either in the
pancreas or the duodenum, are predominantly seen in sporadic ZES.
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