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Original Studies |
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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 Top Abstract IntroductionCase ReportDiscussionReferences |
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Introduction |
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TopAbstractIntroductionCase ReportDiscussionReferences |
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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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TopAbstractIntroductionCase ReportDiscussionReferences |
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-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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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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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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TopAbstractIntroductionCase ReportDiscussionReferences |
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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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Received November 9, 2000.
Revised January 11, 2001.
Accepted January 24, 2001.
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References |
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This article has been cited by other articles:
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  C. D. Knox, C. D. Anderson, L. W. Lamps, R. B. Adkins, and C. W. Pinson Long-Term Survival after Resection for Primary Hepatic Carcinoid Tumor Ann. Surg. Oncol., December 1, 2003; 10(10): 1171 - 1175. [Abstract] [Full Text] [PDF]
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