The occurrence of multiple adenomas of the
endocrine system was first reported at the turn of this century.
This
condition is infrequent, has a familial distribution, and is characterized by adenomatosis of the pituitary, parathyroids, and pancreas (MEN type I).
It is frequently associated with the Zollinger-Ellison
syndrome, in which case gastrin-secreting islet cell tumors are usual.
The syndrome reflects the functional state of the neoplastic glands
and may be quite complex.
Such adverse conditions as acromegaly, pituitary dwarfism, hypogonadism, hyperparathyroidism, and the carcinoid syndrome have been described either alone or in various combinations.
Multiple endocrine neoplasia with peptic ulceration is inherited as an autosomal dominant gene with a high level of penetrance.
Since abnormal
growth of different tissues is the major common feature of this condition, the gene abnormality has been described as pleiotropic.
The syndrome has
been documented in various ethnic groups, including Italian, Swiss, Mexican, and Puerto Rican families.
A variant of the multiple endocrine neoplasia
syndrome - Sipple’s syndrome, or MEN type II—consists
of multiple tumours of the adrenal
medulla (pheochromocytomas),
medullary carcinomas of the thyroid (calcitonin-secreting tumors), and
parathyroid hyperplasia or adenoma.
In this condition the pancreas is
normal and hypergastrinemia and peptic ulceration are absent.
A
variant of Sipple’s syndrome presents with mucocutaneous neuromas of
the eyelids, lips, tongue, bronchus, intestines, and urinary bladder.
Zollinger-Ellison Syndrome (Gastrinoma):
Zollinger-Ellison
syndrome comprises a triad of recalcitrant peptic ulcer disease,
gastric hypersecretion, and an endocrine cell tumor elaborating gastrin.
Lesions:
Sixty percent of
gastrinomas are malignant, with spread to lymph nodes and metastasis;
40% are benign.
Gastrinomas are most common in the pancreas, but 10 to
15% arise in the duodenum.
The histologic and ultrastructural features
are similar to normal intestinal and gastic G cells.
Peptic ulcers are in the usual sites
in the stomach or duodenal in 75% of cases. Abnormally located ulcers in the stomach or first and second portion of duodenum
occur in 25%.
The stomach shows hyperplasia of parietal
cells.
Clinical features:
Features include
striking gastric hypersecretion with intractable ulcers and severe
diarrhea, with fluid and electrolyte imbalance and malabsorption.
Surgical removal is extraordinarily difficult, with recurrence of
symptoms postsurgically common.
Tumours in
Zollinger-Ellison Syndrome:
Before the
advent of immunocytochemistry it was thought that the great
majority of gastrinomas occurred in the pancreas.
The paradox
remained, however, the gastrin secreting G cells are not found in
the normal pancreas but are present in the gastric antral and
duodenal mucosa.
Re-analysis
by immunocytochemistry of older pancreatic resections done for
Zollinger-Ellison syndrome (ZES) showed that some of the tumours
thought to be gastrinomas contained no gastrin.
The
explanation for this probably lies in the fact that approximately 40% of
patients with ZES have Multiple Endocrine Neoplasia Type 1 Syndrome
(MES-1).
Equally, 40% to 60% of patients with MEN-1 have ZES.
It has now
been shown that the great majority of gastrinomas in patients with
MEN-1 are to be found in the duodenum.
Here they are
usually small, often multiple and can easily be missed at
surgery unless specifically
sought.
By contrast, gastrinomas in patients with ZES who do not have
MEN-1(sporadic ZES) are usually solitary and over half are to be found
in the pancreas. Forty per cent are, however, still present in the
duodenum.
Majority of
the duodenal tumors metastasize to regional pancreatic lymph nodes,
but inspite of this, 10-year survivals of up to 85% have been
reported.
Compared to
duodenal gastrinomas, pancreatic gastrinomas are more
frequently large and likely to cause widespread liver metastases.
Patients with
metastatic gastrinoma to the liver have a 5 year survival rate of less
than 20% .
Thus pancreatic gastrinomas tend to behave as
neuroendocrine carcinomas producing an ectopic hormone, while duodenal
gastrinomas, which do not produce an ectopic hormone, are less
likely to be aggressive having a course which has been likened to that of
papillary carcinoma of the thyroid.
The great
majority of patients with MES-1 have pancreatic tumours which are usually
multiple - in some cases hundreds of microscopic lesions are
present.
A large
variety of tumours can be found. Glucagonomas
are most frequent, followed by insulinoma and PPomas.
As described
above gastrin immunostaining is rare.
Diagnostic and therapeutic strategies in Zollinger-Ellison syndrome
associated with multiple endocrine neoplasia type I (MEN-I):
experience of the Zollinger-Ellison Syndrome Research Group: Bichat
1958-1999.Bull
Acad Natl Med. 2003;187(7):1249-58;
About 25% of
patients with ZES have MEN 1. Except diarrhoea, less frequent in
patients with ZES-MEN 1 than in sporadic ZES, and specific MEN
1-related signs, clinical characteristics are similar in both ZES
types. Acid output and gastrin levels are also similar whether in the
basal state or after secretin stimulation. Primary hyperparathyroidism
(PHPT) exists in the majority of ZES-MEN 1 patients, 30% have
pituitary adenoma (prolactinomas for half), 30% adrenal involvement,
25 to 30% have EC-Lomas; bronchial and thymic carcinoids have probably
been underevaluated. Gastrinomas are multiple predominantly located in
the duodenal wall, but also in the pancreas in association with
clinically silent endocrine tumors. The spread of the disease:
metastases to the liver (LM), mediastinum, bones, is evaluated at best
by Octreoscan. Endoscopic ultrasonography evaluates the number, size
and anatomical characteristics of gastrinomas. Patients without LM
have an excellent prognosis. Surgery never cures ZES, but is necessary
in case of associated life-threatening condition such as insulinoma
and has been advocated to prevent LM development in patients with
large pancreatic tumor(s). However although, indeed, the size of the
tumor, when located in the pancreas > 3 cm, favours metachronous LM
occurrence, surgery, in our experience, has not been able to prevent
LM development. Hepatic malignancies remain however the most
pejorative prognostic determinant for survival and raise the most
difficult therapeutic challenge. Surgery is the best option whenever
feasible; specific chemotherapy and chemo-embolisation have not
conclusively achieved definite successes. Long-term octreotide
treatment, however, has been shown recently to obtain tumour
stabilisation. Internal irradiation with 90 Ytrium-labelled octreotide
is a new promising option, presently under evaluation (Novartis
European trial). Preliminary results are promising.
Type I multiple endocrine neoplasia--Wermer syndrome.Schweiz
Rundsch Med Prax. 1989 Aug
29;78(35):935-40.
Multiple
endocrine neoplastic diseases are genetically determined conditions
with particular organ patterns for endocrine tumors. In Type I or
Wermer's syndrome the endocrine pancreas, anterior pituitary and
parathyroids are involved, insulinoma being the most frequent
pancreatic tumor. To facilitate diagnosis, a prolonged oral glucose
tolerance test, a fasting test and determination of the
glucose-insulin ratio are recommended. Localisation is sought by
computer tomography and angiography. A gastrinoma is excluded on the
basis of normal gastrin levels in serum and by means of the secretin-provocation-test.
Pituitary tumors can be classified more closely with prolactin levels
and releasing-hormone tests (LH-RH and TRH). Prolactinoma is the most
frequent pituitary tumor and amenable to bromocryptin treatment. If
Wermer's syndrome is suspected, primary hyperparathyroidism has to be
excluded on the basis of calcium and parathormone levels. Chief cell
hyperplasia or multiple adenomas are frequent. Surgical resection is
necessary.
The pathology
of insulinoma and gastrinoma. The location, size, multicentricity,
association with multiple endocrine type-I neoplasms and malignancy.Dtsch
Med Wochenschr. 1990 Sep
14;115(37):1386-91.
The pathology
of insulinoma and gastrinoma was studied in 81 patients (31 men, 50
women, mean age 48.4 years) suffering from persistent
hyperinsulinaemic hypoglycaemia, and in 44 patients (28 men, 16 women,
mean age 48.5 years) with Zollinger-Ellison syndrome. Insulinomas were
seen in the pancreas of all patients with persistent hyperinsulinaemic
hypoglycaemia. In 70 of the 81 patients the insulinoma was solitary,
whereas six patients had multiple insulinomas. In five patients with
multiple endocrine neoplasia type I, multiple endocrine tumours of the
pancreas were visible, only one of them in each case being an
insulinoma. 75% of all insulinomas were less than 2 cm in size and 15%
were malignant. 18 of the 44 Zollinger-Ellison syndrome patients also
had multiple endocrine neoplasia type I. Nine of these patients
presented with duodenal gastrinomas which were often multiple and
smaller than 0.5 cm. The gastrinoma was located in the pancreas of one
of the patients with multiple endocrine neoplasia, in two patients in
lymph nodes, and no gastrinoma was identified in the specimens from
six patients. 33% of the duodenal gastrinomas had metastasised.
Solitary gastrinomas were found in all 26 patients with sporadic
Zollinger-Ellison syndrome, 14 being located in the pancreas (diameter
over 2 cm in eight cases) and ten in the duodenum (diameter less than
1 cm in seven cases). 16 of these gastrinomas were malignant.
