The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 2227-2230
Copyright © 2001 by The Endocrine Society
Carcinoid Syndrome, Acromegaly, and Hypoglycemia Due to an Insulin-Secreting Neuroendocrine Tumor of the Liver
J. Furrer,
A. Hättenschwiler,
P. Komminoth,
T. Pfammatter and
P. Wiesli
Department of Internal Medicine, Medical Policlinic (J.F.,
A.H., P.W.), Department of Pathology (P.K.), and Department of
Radiology (T.P.), University Hospital of Zurich, CH-8091 Zurich; and
Institute of Pathology (P.K.), Kantonsspital, CH-5404 Baden,
Switzerland
Address correspondence and requests for reprints to: Jörg Furrer, M.D., Department of Internal Medicine, Medical Policlinic, University Hospital of Zurich, CH-8091 Zurich, Switzerland.
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Abstract
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We report a patient with a hepatic neuroendocrine tumor showing an
extraordinary change of the tumor’s humoral manifestations from a
clinically documented extrapituitary acromegaly and a typical carcinoid
syndrome toward a hyperinsulinemic hypoglycemia syndrome. At the
primary manifestation of the tumor, an increased serum level of
insulin-like growth factor I due to overproduction of GHRH and an
increased urinary excretion of 5-hydroxyindoleacetic acid were found.
The clinical manifestation of the GHRH excess was an arthralgia, which
resolved completely after operative tumor debulking and normalization
of insulin-like growth factor I and GHRH serum levels. The secretion of
serotonin from the tumor resulted in a typical carcinoid syndrome
including right-sided valvular heart disease. On the later course of
the disease, the humoral manifestations of the tumor were supplemented
by the secretion of insulin, leading to recurrent severe
hyperinsulinemic hypoglycemia. The hepatic origin of hyperinsulinism
was demonstrated by selective arterial calcium stimulation. Moreover,
tumor cells revealed insulin and C-peptide immunoreactivity in the
immunohistochemical analysis. The patient died 8 yr after the initial
diagnosis of the tumor, and a carefully performed autopsy procedure
confirmed the absence of any extrahepatic tumor manifestation.
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Introduction
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CARCINOID TUMORS ("NEUROENDOCRINE
tumors" based on the WHO classification) have been reported in a wide
range of organs, but most commonly involve the gastrointestinal tract
or the respiratory system (1). Primary neuroendocrine
tumors arising from the liver are extremely rare, with only about 50
reported cases until today (2).
Cells of neuroendocrine tumors may contain membrane-bound granules with
a variety of hormones and biogenic amines, which can be secreted into
the systemic circulation. The most common encountered hormonal
secretion of carcinoid tumors is the secretion of serotonin, leading to
the well known "carcinoid syndrome." However, most of the few
reported patients with a primary hepatic carcinoid tumor were
clinically neuroendocrine inactive, and an abdominal mass was the
leading symptom in the majority of the described patients
(2).
Here, we report a patient with a hepatic neuroendocrine tumor, in which
the humoral manifestations of the tumor changed during the course of
the disease from an extrapituitary acromegaly and a typical carcinoid
syndrome toward a hyperinsulinemic hypoglycemia syndrome.
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Case Report
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A 66-yr-old woman presented in 1989 because of epigastric pain.
She had a history of kidney stones 13 yr ago and was on prednisone (5
mg daily) for 2 yr due to an arthralgia predominantly involving the
metacarpo-phalangeal and interphalangeal joints of both hands.
Furthermore, she complained of occasional flushing symptoms during the
preceding year. Routine laboratory investigations during that time were
within the normal limits (i.e. plasma glucose,
transaminases, and calcium). Ultrasonography disclosed a solid tumor in
the right hepatic lobe (7.7 x 6.4 x 6.0 cm). The tumor was
found to be hypervascular by selective hepatic angiography. A core
biopsy of the liver disclosed the presence of cells, morphologically
typical for a neuroendocrine tumor. Levels of 
-fetoprotein and
carcinoembrionic antigen were within the normal range. Further
laboratory testing exhibited an excess of insulin-like growth factor
(IGF) I (61.9 nmol/L; normal, 16–39) and GHRH (245 pmol/L; normal,
<50). Human GH was at the upper normal limit (10 mIE/L; normal,
1–10). Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA)
was markedly increased (989 µmol/24 h; normal, 10–73). Basal levels
for gastrin, substance P, neurotensin, vasoactive intestinal peptide,
and somatostatin were within the normal range. Further diagnostic
investigations for primary tumor localization in the lungs or
gastrointestinal tract were negative. In July 1989, extended right
hemihepatectomy was performed, and at the operation, multiple small
tumor nodules were found in both hepatic lobes. The intraoperative
exploration for any tumor manifestation in the pancreas or small
bowel was negative. The resected right hepatic lobe disclosed a 7
x 6 x 6-cm solid tumor and multiple satellite nodules.
Histologically, the tumor showed a neuroendocrine pattern and
immunohistochemically tumor cells exhibited immunoreactivity for
neuroendocrine markers (neuron- specific enolase, synaptophysin,
chromogranin-A) as well as for glucagon, insulin, serotonin, and the
-chain of glycoproteins in single cells or cell groups. The other
investigated markers (GH, somatostatin, pancreatic polypeptide, and
gastrin) were negative.
The complained arthralgia and flushing symptoms resolved
completely after surgical tumor debulking and normalization of IGF-I
(14 nmol/L; normal, 16–39) and GHRH levels (46 pmol/L; normal, <50).
The urinary excretion of 5-HIAA normalized postoperatively also (55
µmol/24 h; normal, 10–73). An octreotide scan using single
photon-emission computed tomography imaging was negative despite
known small tumor nodules in the left hepatic lobe. Follow-up was
uneventful until 1991, when the patient suffered again from arthralgia
and recurrent flushing symptoms. Levels of IGF-I and GHRH rose, and
increased urinary excretion of 5-HIAA (390 µmol/24 h; normal, 10–73)
indicated progression of the tumor. Therapy with daily 100 µg sc
injected octreotide promptly resolved the arthralgia and resulted in
suppression of GHRH, IGF-I, and 5-HIAA into the middle normal range.
Flushing symptoms were only complained occasionally during follow-up,
but were associated now with bronchoconstriction, palpitations, and
diarrhea. The intake of alcohol and fatty food triggered the symptoms
of the carcinoid syndrome. On the later course, the clinical signs of
right heart failure occurred and echocardiography revealed tricuspid
valve regurgitation due to plaque-like thickenings on the endocardium
of the tricuspid valve. In the following years, it was necessary to
increase the octreotide dose several times due to clinical symptoms and
increasing 5-HIAA excretion in the urine. Increasing the octreotide
doses always improved the clinical complaints (less flushing, diarrhea,
and arthralgia) and decreased the GHRH serum levels as well as the
5-HIAA excretion in the urine.
Serum calcium levels were determined several times during
follow-up and were always in the low normal range. An elevated PTH
level in the later course of the disease (189 ng/L; normal, 12–72) in
association with normal calcium level (2.2 mmol/L; normal, 2.1–2.6)
and normal albumin level was interpreted as secondary
hyperparathyroidism due to impaired renal function (creatinine, 143
µmol/L; normal, 70–105). A genetic analysis for the presence of
germ-line mutations in exons 2–10 of the MENIN gene was performed
despite negative family history for multiple endocrine neoplasia
and absence of primary hyperparathyroidism. No evidence of germ-line
mutations was found.
In November 1996, a generalized seizure in association with a
spontaneous hypoglycemia occurred under the therapy with 300 µg
octreotide daily. IGF-II and big IGF-II (10% of total IGF-II) were
within the normal range. Measurement of insulin (187 pmol/L; reference,
21–243) and C-peptide (464 pmol/L; reference, 90–400) during fasting
hypoglycemia (1.9 mmol/L venous plasma) disclosed spontaneous
hyperinsulinemic hypoglycemia. Laboratory investigations showed
additional biochemical progression of the tumor with increasing urinary
5-HIAA excretion (1597 µmol/24 h; normal, 10–73). A liver biopsy was
performed and showed infiltrates of the neuroendocrine tumor with
immunohistochemical expression of serotonin and insulin in tumor cells,
suggesting insulin secretion from the hepatic neuroendocrine tumor.
Treatment with diazoxide (100 mg daily) and prednisone (25 mg daily)
was started, but recurrent hyperinsulinemic hypoglycemia with
seizures continuously occurred. A chemotherapy regimen
consisting of streptozocin (5-day course of 1000 mg daily),
5-fluorouracil (5-day course of 1000 mg daily), and dexamethasone
(5-day course of 12 mg daily) decreased 5-HIAA excretion from 2327 to
912 µmol/24 h (normal, 10–73) and resulted in normal to diabetic
plasma glucose levels. In March 1997, 1 month after the second
chemotherapy trial was completed, severe hypoglycemia reoccurred. Even
under therapy with diazoxide (300 mg daily), prednisone (40 mg daily),
and octreotide (600 µg daily), the administration of a glucose
infusion was required to prevent hypoglycemia. Therefore, a third
chemotherapy trial was performed, resulting again in normal to diabetic
plasma glucose levels. To demonstrate the hepatic origin of
hyperinsulinism, a selective arterial calcium stimulation was
performed. A 14-fold rise in the insulin level in the hepatic vein
after calcium injection (0.025 mEq Ca2+ per kg
body weight) into the arteria hepatica propria documented definitively
the hepatic neuroendocrine tumor as the source of hyperinsulinism (Fig. 1
). Within the next few weeks, severe
hypoglycemia reoccurred. The general condition of the patient
deteriorated rapidly, and she died in May 1997.
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Figure 1. Selective arterial calcium
stimulation. Insulin levels (insulin in pmol/L, reference
21–243) in the left hepatic vein 0, 30, 60, and 120 sec after the
intra-arterial injection of calcium (0.025 mEq Ca2+ per
kg body weight) into the superior mesenteric artery (SMA), splenic
artery (SA), gastroduodenal artery (GDA), and hepatic artery (HA). A
14-fold rise in the insulin level in the hepatic vein (from 183 pmol/L
to 2530 pmol/L) 60 sec after the calcium injection into the arteria
hepatica propria indicates an insulin-secreting tumor localized in
the liver.
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Hormone assays
Serum insulin (Diagnostic Products, Los Angeles, CA)
and C-peptide (Diagnostic Products) were measured by RIA.
Serum GHRH, IGF-I, and IGF-II and its precursor big IGF-II were
measured by RIA as described elsewhere (3, 4). Urinary
excretion of 5-HIAA was measured by high-performance liquid
chromatography.
Selective arterial calcium stimulation with hepatic venous
sampling
The procedure was performed as described previously (5, 6). A sampling catheter was placed transfemorally in the
left hepatic vein close to its junction with the inferior vena cava.
The left hepatic vein was chosen because our patient had a right
hemihepatectomy. After full-standard angiography, the gastroduodenal,
splenic, proper hepatic, and superior mesenteric arteries were
catheterized. Each artery was stimulated with calcium gluconate (0.025
milliequivalents Ca2+ per kg body weight). Blood
was sampled from the left hepatic vein before ( = 0) and 30, 60, and
120 sec after the intra-arterial injection of calcium. At least 5 min
passed between each calcium injection. The hepatic artery supplies the
liver, the splenic artery supplies primarily the body and tail of the
pancreas, and the gastroduodenal and superior mesenteric arteries
supply the pancreatic head and uncinate process. A more than 2-fold
rise in insulin levels within 30–120 sec after the injection of
calcium indicates the localization of an insulin-secreting tumor in the
vascular territory of the artery stimulated.
Autoptic findings
The autopsy revealed the known multicentric neuroendocrine tumor
of the liver (Fig. 2A). Similar
immunohistochemical results were obtained as described above.
Serotonin, insulin, and C-peptide were found immunohistochemically in
tumor cells (Fig. 2, C–E). The pancreas, duodenum, and small bowel
were sectioned systematically, and careful microscopic examination
failed to demonstrate any extrahepatic tumor manifestation. The
pancreas exhibited fibrotic and atrophic exocrine pancreatic tissue
with ectatic ducts but no insulinoma or islet-cell carcinoma. The heart
disclosed the typical signs of a carcinoid heart disease, with
extensive fibrosis of the tricuspidal and pulmonary valves. The
parathyroid glands showed diffuse hyperplasia, and the pituitary gland
was normal.
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Figure 2. Pathology findings. Macroscopic view of the
liver with multiple tumor nodules (A) and hematoxylin and eosin-stained
slide of the neuroendocrine liver tumor (B, right;
x100). Positive immunostaining for serotonin (C), C-peptide (D), and
insulin (E) in the tumor tissue (C, ABC staining; D and E,
immunogold-silver staining; x200).
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Immunohistochemistry
Paraffin sections (4 µm thick) were immunostained using the
avidin-biotin-peroxidase technique with diaminobenzidine as peroxidase
substrate (Vectastain ABC-kit; Vector Laboratories, Inc., Burlingame, CA) or immunogold-silver-technique, as
described previously (7). The primary antibodies were
directed against neuron-specific enolase (BioGenex Laboratories, Inc., San Ramon, CA), chromogranin A (1:1000; Roche Molecular Biochemicals, Mannheim, Germany), synaptophysin (1:80;
DAKO Corp., Carpinteria, CA), glucagon (1:250; DAKO Corp.), insulin (BioGenex Laboratories, Inc.),
C-peptide (1:100; Immuno Nuclear Corp, Stillwater, MN), -human
chorionic gonadotropin (1:50; Seralab, Crawley Down, Sussex,
UK), GH (1:500; DAKO Corp.), somatostatin (1:300;
DAKO Corp.), pancreatic polypeptide (1:60000; Chance,
Indianapolis, IN), gastrin (1:200; DAKO Corp.),
serotonin (1:50; Seralab), and substance P (1:3000; Seralab).
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Discussion
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The liver is the most common site of metastases of neuroendocrine
tumors. Only very few cases of primary hepatic neuroendocrine tumors
have been reported until today, some of them are insufficiently
documented (2). In our patient, extensive clinical work-up
and a carefully performed autopsy failed to reveal any extrahepatic
tumor manifestation. Most of the reported primary hepatic
neuroendocrine tumors were functionally inactive, and only a few were
classified as neuroendocrine carcinoma on the basis of histological
type and clinical behavior (2). The association of a
primary hepatic neuroendocrine tumor with the change of the tumor’s
humoral manifestations from a clinically documented extrapituitary
acromegaly and a typical carcinoid syndrome toward a hyperinsulinemic
hypoglycemia syndrome is very uncommon.
Most patients with a clinical carcinoid syndrome, although not
all, have hepatic metastases of a carcinoid tumor, because the hepatic
localization increases the likelihood of vasoactive substances reaching
the systemic circulation without undergoing metabolic degradation
(1). So, the occurrence of a carcinoid syndrome in our
patient with multiple tumor nodules in the liver is not uncommon. GHRH
secretion from tumors arising outside the central nervous system is
recognized as etiology of the rare extrapituitary acromegaly. Carcinoid
tumors (the majority bronchial in origin) comprise even most of the
tumors associated with an ectopic GHRH secretion (8). When
the GH excess is documented (i.e. by elevated IGF-I levels,
as in our case), an ectopic GHRH-induced acromegaly can be diagnosed by
measurement of circulating levels of GHRH (9). GHRH is
elevated in patients with acromegaly due to GHRH secretion and is
normal or low in patients with pituitary acromegaly. Positive
immunoreactivity for GHRH in tumor cells or abnormal GH secretory
dynamics may be encountered in patients with carcinoid tumors, although
most of these patients do not exhibit the clinical features of
acromegaly, probably due to defective bioactivity of expressed GHRH
(10, 11). The clinical manifestation of GHRH-induced GH
excess in our patient was an arthralgia involving predominantly the
hands. Evidence for the hepatic neuroendocrine tumor as origin of the
GHRH excess was the clinical and biochemical response to therapy.
Surgical debulking of the tumor mass was followed by normalization of
IGF-I and GHRH serum levels and cured arthralgia completely. Recurrence
of the arthralgia during follow-up was accompanied by the recurrence of
the GHRH excess, responding both biochemically and clinically to the
therapy with octreotide.
Nonislet-cell tumors may induce hypoglycemia by several
mechanisms, including the secretion of IGF-II or its high molecular
weight precursor, among others (12, 13). Hypoglycemia due
to the secretion of insulin from nonislet-cell tumors is under debate
(14). Only some sporadic reports of insulin secretion from
nonislet-cell tumors exist, and they are usually based on the
measurement of high serum insulin concentrations in patients with
tumor-associated hypoglycemia (13). An insulin secretion
due to a concurrent islet-cell tumor cannot be excluded definitively in
most of these cases. The proof of the insulin secretion itself by
a nonislet-cell tumor is demonstrated neither with the
immunohistochemical detection of insulin in tumor cells nor with the
detection of proinsulin messenger RNA and insulin protein within the
tumor cells by in situ hybridization (15). In
our patient, it was possible to demonstrate the insulin secretion
itself from the hepatic neuroendocrine tumor by selective arterial
calcium stimulation. Due to a 14-fold rise in the insulin level in the
hepatic vein after calcium injection into the hepatic artery, the liver
tumor as origin of hyperinsulinism was confirmed definitively. In
addition, insulin and C-peptide was demonstrated in tumor cells
immunohistochemically several times. This study definitively confirms
that tumor-associated hypoglycemia due to insulin secretion from
nonislet-cell tumors is possible.
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Acknowledgments
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We thank Prof. Dr. Jürgen Zapf (University Hospital of
Zurich) for the determination of IGF-I, IGF-II, and big IGF-II; and
Charlotte Eberle (University Hospital of Zurich) for the determination
of GHRH and other peptide hormones. We also thank Dr. Seife Hailemariam
(University Hospital of Zurich), who performed the autopsy, and Miss
Parvin Saremaslani (University Hospital of Zurich), who performed the
immunohistochmemical analysis.
Received November 9, 2000.
Revised January 11, 2001.
Accepted January 24, 2001.
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Abstract
Introduction
