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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3739-3744
Copyright © 2004 by The Endocrine Society

Malignant Gastric Ghrelinoma with Hyperghrelinemia

Apostolos V. Tsolakis, Guida M. Portela-Gomes, Mats Stridsberg, Lars Grimelius, Anders Sundin, Barbro K. Eriksson, Kjell E. Öberg and Eva T. Janson

Department of Medical Sciences, Sections of Endocrine Oncology (A.V.T., B.K.E., K.E.O., E.T.J.) and Clinical Chemistry (M.S.), Departments of Genetics and Pathology (G.M.P.-G., L.G.) and Oncology, Clinical Immunology, and Radiology (A.S.), Uppsala University Hospital, 751 85 Uppsala, Sweden; and Centre of Nutrition (G.M.P.-G.), Lisbon University, 1649-028 Lisbon, Portugal

Address all correspondence and requests for reprints to: Apostolos V. Tsolakis, Department of Medical Sciences, Clinical Research Section 2, University Hospital, 751 85 Uppsala, Sweden. E-mail: apostolos.tsolakis{at}medsci.uu.se.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
A characteristic feature of neuroendocrine tumors is production and release of peptide hormone. Ghrelin is a 28-amino acid hormone that stimulates GH release. In this paper, we describe a patient with a metastasizing gastric neuroendocrine tumor displaying intense immunoreactivity for ghrelin and extremely high circulating levels of ghrelin.

Tumor tissue biopsies from the primary tumor and one liver metastasis were examined by immunohistochemistry. Ghrelin and several other hormones and tumor markers were measured in blood. The clinical course of the patient was followed.

Tumor tissue biopsies showed immunoreactivity for cytokeratin, chromogranin A, human synaptic vesicle protein 2, synaptophysin, and ghrelin. Grossly elevated circulating levels of total ghrelin, 2100 µg/liter (reference interval < 5 µg/liter) and active ghrelin, 28 µg/liter (reference interval < 0.1 µg/liter) were found at presentation. Chromogranin A, chromogranin B, and calcitonin levels were also increased. Both total and active ghrelin increased, despite treatment, during follow-up of the patient.

We have identified and characterized a patient with a malignant gastric neuroendocrine tumor secreting ghrelin as the main hormone. This might be a new tumor entity of the stomach, and it is suggested that patients with malignant gastric neuroendocrine tumors should be investigated for ghrelin production.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GHRELIN IS A 28-amino acid peptide that was first identified in rat stomach (1). The human ghrelin is homologous to rat ghrelin apart from two amino acids. Their propeptides are both composed of 117 amino acids (1). Ghrelin-immunoreactive (IR) cells have been identified in the oxyntic glands of the human gastric mucosa. There are indications that ghrelin-IR cells in humans correspond to the P/D1 cells (2). No other hormone production has been associated with these cell types. The ghrelin-IR cells are abundant in stomach with gradually decreasing number throughout the gastrointestinal tract (1, 2, 3, 4). Expression of ghrelin has also been detected in several other tissues including the lung and endocrine cells of the pancreas, pituitary gland, hypothalamus, heart, adipose tissue, and reproductive system (1, 5, 6, 7, 8).

Ghrelin acts through the GH secretagogue receptors, which belong to the family of G protein-coupled receptors, and ghrelin strongly stimulates GH secretion (9). In agreement with the expression of GH secretagogue receptors in different organs, this natural secretagogue shows gastroenteropancreatic (10, 11, 12) and cardiovascular (13) functions. The hormone also plays a role in energy balance by enhancing appetite and food intake (14, 15). Ghrelin secretion is suppressed by somatostatin and cortistatin (16) and may induce hyperglycemia probably through a transient inhibition of insulin secretion (11, 12).

Most neuroendocrine tumors of the gastric mucosa are low-malignancy tumors developing in patients with hypergastrinemia. They are usually discovered at gastroscopy during the clinical work-up of patients with chronic atrophic gastritis with or without pernicious anemia. These tumors arise from the enterochromaffin-like cells and seldom induce any clinical symptoms (17). Apart from these benign tumors, there is also a small number of tumors that shows a more malignant course and develops metastases mainly in lymph nodes and the liver. A minority of these tumors causes an atypical carcinoid syndrome that can be linked to histamine production (18). However, most patients with malignant neuroendocrine tumors in the stomach have so called nonfunctioning tumors.

Recently tumors containing ghrelin-producing cells have been identified by immunohistochemistry or expression of mRNA for ghrelin using reverse transcriptase PCR and Northern blotting techniques (19, 20, 21, 22). However, so far only one patient with a neuroendocrine pancreatic tumor containing ghrelin expressing cells has been reported to have an elevated circulating concentration of ghrelin (22). The present patient showed grossly elevated circulating levels of ghrelin associated with a metastasizing gastric neuroendocrine tumor displaying a high frequency of ghrelin IR cells.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
A 46-yr-old Caucasian man with hypertension, diagnosed 2 yr earlier, was referred to Uppsala University Hospital because of occult gastrointestinal bleeding inducing anemia. At referral, the patient reported inconsistent diarrhea and sweating during the night for the past 3–4 months. He did not complain of any other symptoms. The patient’s body mass index (BMI) was 32 kg/m2. During workup, a gastric tumor in the corpus region was diagnosed and biopsied at gastroscopy. Liver and lymph node metastases were detected by computerized tomography (Fig. 1AGo). Somatostatin receptor scintigraphy showed an intense tracer uptake in the liver metastases as well as in the primary tumor in the stomach. Positron emission tomography with 18F-deoxyglucose as tracer also showed a strong uptake in all tumor locations (Fig. 1BGo), whereas an irregular unspecific uptake was observed when 11C-5-hydroxytryptophan was used as tracer.



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  		FIG. 1. A, Intravenously contrast-enhanced computerized tomography of the upper abdomen showing multiple liver metastases and a lymph node metastasis in the upper left part of the abdomen adjacent to the left liver lobe. B, Corresponding positron emission tomography scan with 18F-deoxyglucose showing increased tracer accumulation in the lymph node metastasis.

 
Biopsy samples from the gastric tumor and from one of the liver metastases (1.2 mm needle biopsy) were obtained before treatment and after 12 months. They were fixed in 10% buffered neutral formalin and routinely processed to paraffin. Five-micrometer sections were stained with hematoxylin-eosin or immunostained by either the streptavidin-biotin complex technique or a nonbiotin amplification detection system (Zymed Laboratories Inc., San Francisco, CA) using a fluorescein-labeled secondary antibody and a tertiary horseradish peroxidase-labeled antifluorescein antibody. Before immunostaining the sections were pretreated in a microwave oven (Philips Whirlpool, Stockholm, Sweden) for 2 x 5 min at 750 W, using, as retrieval solution, citrate buffer (pH 6.0) for ghrelin staining and Tris buffer saline (pH 8.0) for human synaptic vesicle protein 2 (SV2) and human vesicular monoamine transporter 2 (VMAT 2).

As primary antibodies for immunohistochemistry, we used mouse monoclonal antibodies to cytokeratin (M3515, DakoCytomation, Glostrup, Denmark), chromogranin A (LK2H10, Roche Molecular Biochemicals, Mannheim, Germany), SV2 (15E11, NovoCastra, Newcastle upon Tyne, UK), and serotonin (M0758, DakoCytomation). Rabbit polyclonal antibodies against synaptophysin (A0010, DakoCytomation); VMAT2 (AB1767, Chemicon International, Temecula, CA; dilution 1:400); human ghrelin (H-031–30, Phoenix Pharmaceuticals Inc., Belmont, CA; dilution 1:2400); and calcitonin, gastrin-releasing peptide, and Ki67/MIB-1 (A0576, A0429, and M7240, respectively, DakoCytomation) were also used.

Circulating hormones and tumor markers were measured in blood collected after an overnight fast before treatment was initiated (see Table 1Go) and during follow-up (see Table 2Go). The assays were performed at the routine clinical chemistry laboratory using commercial kits, except for chromogranin B, which was measured by an in-house method as previously described (23). Total and active ghrelin were measured with commercial RIA kits (Linco Research Inc., St. Louis, MO).


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  		TABLE 1. Biochemical characterization before treatment initiation

 

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  		TABLE 2. Hormonal and clinical parameters of the patient at diagnosis and during follow-up

 
The research protocol was reviewed and approved by the local ethics committee at the Uppsala University Hospital. An informed consent was obtained from the patient.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Light microscopy

The small biopsies taken before treatment, which consisted of gastric mucosa and submucosa, contained rather well-differentiated tumor cells of small to intermedium size arranged mainly in nests and in irregular trabecular patterns with varying amount of stroma. The nuclei were relatively uniform; no mitoses were seen. The tumor cells, in a biopsy from a liver metastasis taken at referral, showed a similar cellular appearance and arrangement, compared with the primary tumor.

The biopsies taken from the primary tumor area and a liver metastasis 1 yr after the initiation of the treatment revealed a similar cellular and nuclear appearance, compared with those seen at the initial biopsies, but the pattern was more solid.

Immunohistochemistry

The immunostaining pattern of the gastric tumor and in the metastasis, which were obtained before treatment, was similar. All tumor cells displayed cytokeratin immunoreactivity (data not shown). About half of the tumor cells showed chromogranin A (Fig. 2AGo) and SV2 immunoreactivity (Fig. 2B). Virtually all expressed synaptophysin (Fig. 2CGo) and ghrelin (Fig. 2Go, D and E). No tumor cells showed VMAT2 (Fig. 2FGo), serotonin, calcitonin, or gastrin-releasing peptide immunostaining (data not shown). The proliferation index (Ki67/MIB-1) was about 12% in both the primary tumor and the metastasis.



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  		FIG. 2. A, Liver metastasis immunostained for chromogranin A. The tumor cells, arranged in irregular nests, show IR cells mainly located in the periphery. Original magnification, x100. B, Liver metastasis immunostained for SV2. IR cells are seen with a distribution pattern similar to that in panel A. Original magnification, x100. C, Gastric tumor immunostained for synaptophysin. The tumor cells are arranged in an irregular trabecular pattern, showing immunoreactivity with varying intensities. Original magnification, x100. D, Gastric tumor immunostained for ghrelin. Almost all neoplastic cells display immunoreactivity. Original magnification, x200. E, Liver metastasis immunostained for ghrelin. The tumor cells arranged in an irregular trabecular pattern show immunoreactivity. The strongest immunoreactivity is seen in cellular regions facing the fibrovascular stroma. Original magnification, x100. F, Gastric tumor immunostained for VMAT2. No IR tumor cells are seen. Occasional mast cells in the stroma are VMAT2 IR. Original magnification, x100.

 
The immunostaining pattern in the biopsies, obtained 12 months after treatment initiation, was similar to the above-mentioned biopsies, apart from the presence of a tumor cell population displaying VMAT 2 immunoreactivity in both the primary tumor and the liver metastasis (data not shown). The proliferation index (Ki67/MIB-1) was about 10% in both the gastric tumor area and the metastasis.

Circulating biochemical markers

Before the initiation of the treatment, elevated circulating levels of total ghrelin, 2100 µg/liter (reference interval < 5 µg/liter) and active ghrelin, 28 µg/liter (reference interval < 0.1 µg/liter), were detected. Levels of calcitonin, 11.6 ng/liter (reference interval < 10 ng/liter); chromogranin A, 19.4 nmol/liter (reference interval < 4.0 nmol/liter); and chromogranin B, 3.1 nmol/liter (reference interval < 2.0 nmol/liter) were also elevated. Although leptin, 9.0 µg/liter (reference interval < 7.4 µg/liter), and insulin, 15.2 mU/liter (reference interval < 11 mU/liter), were slightly above the reference interval, these hormone levels were considered normal in relation to the patient’s BMI. Circulating levels of GH and IGF-I were within the normal range consistent with the absence of clinical features of acromegaly. All other hormones and tumor markers measured were within the reference interval (see Table 1Go). During follow-up, increasing concentrations of both total and active ghrelin as well as calcitonin were recorded (see Table 2Go). The two tumor markers, chromogranin A and B, also increased during follow-up (data not shown).

Clinical course

At referral the patient was in good clinical condition. Treatment was initiated with paraplatin and etoposide (see Table 2Go). However, the liver metastases progressed and the therapy was changed to taxotere and cyclophosphamide and later on, due to continuous progression and a high tracer uptake at somatostatin receptor scintigraphy, to 111In-Octreotide treatment. The patient failed to respond to all treatments used and died 15 months after the tumor was diagnosed. After 9 months, the patient developed diabetes mellitus (plasma glucose 51 mmol/liter and blood hemoglobin A1C 12.8%), which required insulin treatment. He also developed hypothyroidism with rising TSH levels combined with low T3 and free T4 (data not shown). Apart from this, he had diffuse abdominal pain and tiredness related to anemia due to gastrointestinal bleeding from the tumor. At the last follow-up, 12 months after diagnosis, the patient complained of aggravation of his diarrhea that was now on a daily and more frequent basis. At this time, the serum total ghrelin, active ghrelin, and calcitonin were highly elevated (see Table 2Go). Despite the high circulating level, immunoreactivity for calcitonin in a biopsy from the primary tumor area and one liver metastasis, taken at the 12-month visit, was negative.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first report concerning a patient with a malignant neuroendocrine tumor arising from the gastric mucosa with ghrelin immunoreactivity and concomitant markedly elevated levels of circulating total and active ghrelin. The primary tumor was localized to the corpus region of the stomach. There have been some previous reports concerning neuroendocrine tumors with ghrelin immunoreactivity. Papotti et al. (19) reported on increased ghrelin expression in the mucosa from patients with chronic atrophic gastritis. They also found ghrelin immunoreactivity in 12 of 16 patients with gastric carcinoid tumors and five of 18 with intestinal carcinoid tumors. However, they did not measure ghrelin levels in blood and could not identify any clinical symptoms of elevated growth hormone levels. Rindi et al. (20) described ghrelin expression in 25 of 37 gastric neuroendocrine tumors, six of 16 endocrine pancreatic tumors, and four of eight neuroendocrine lung tumors. A patient with a multiple endocrine neoplasia 1 syndrome and a glucagon-producing tumor in the pancreas was investigated by Iwakura et al. (21). In this case, the tumor also displayed immunoreactivity for ghrelin. They measured only circulating levels of total ghrelin, which were normal. Recently, Corbetta et al. (22) reported a patient with a malignant neuroendocrine pancreatic tumor with immunoreactivity for ghrelin and a 50-fold increase of circulating total ghrelin levels. In this case also, in accordance with our data, GH and IGF-I levels were within the normal range, and the patient had no clinical features of acromegaly.

Very high plasma levels of total and active ghrelin were detected in the patient presented. Despite this, no elevation of GH or IGF-I was observed, and the patient did not exhibit any clinical signs of acromegaly (see Table 1Go). In previous studies, short-time infusion of ghrelin induced a transient increase in GH levels (11), and it is possible that the high and constant ghrelin level, produced by secretion from the tumor, is unable to stimulate a continuous hypersecretion of GH. However, there are no long-term infusion studies that have addressed this question.

Ghrelin is known to increase appetite and enhance food intake (14). Despite an advanced malignant tumor with a large primary tumor and several liver metastases (Fig. 1Go, A and B), the patient had a BMI of 32 kg/m2 at presentation. Although the tumor failed to respond to all cytotoxic treatment used, appetite was good and the patient had a high BMI at the last follow-up 1 yr after diagnosis (see Table 2Go). The slightly increased levels of leptin could be related to the high BMI, and a secondary peripheral insulin resistance can play a role for the high insulin levels observed.

After about 9 months, the patient developed diabetes mellitus with very high blood sugar levels (plasma glucose 51 mmol/liter and blood hemoglobin A1C 12.8%). During this time he lost some weight and his BMI dropped to 27 kg/m2. He also developed hypothyroidism with rising TSH and low T3 and free T4 levels. There is no obvious reason for the development of diabetes or hypothyroidism in this patient. However, the pathophysiological role of ghrelin has to be further studied.

During the last 3 months, the patient complained of frequent diarrhea. At presentation calcitonin levels in plasma were only slightly elevated [11.6 ng/liter (reference interval < 10 ng/liter)]. However, at the last measurement, calcitonin levels increased up to 436 ng/liter, and thus, diarrhea might have been due to the high calcitonin levels. It is well known that calcitonin can result in a marked intestinal secretion of water, sodium, potassium, and chloride (24, 25, 26), which is the reason diarrhea occurs in patients with calcitonin-secreting tumors. The biopsy from the primary tumor area and one liver metastasis, taken at the same occasion that the measurement showed high circulating calcitonin level, revealed no immunoreactivity for the peptide. It is possible that the tumor was producing calcitonin in other areas than the ones that were biopsied. Another explanation might be that the tumor cells had only the capacity to synthesize and immediately secrete and not to store calcitonin. However, we cannot exclude an effect of ghrelin on calcitonin release from normal C cells.

Another factor that might contribute to the diarrhea could be the increased levels of ghrelin itself, under the concept that ghrelin stimulates gastric motility, induces fasted motor activity of the gastrointestinal tract, and can reverse gastric postoperative ileus in rat (27, 28, 29).

Compared with other well-differentiated neuroendocrine tumors, this tumor reveals a high proliferation rate, indicating a rapidly growing tumor. Positron emission tomography with 18F-deoxyglucose (Fig. 1BGo) was positive, whereas the investigation with 11C-5-hydroxytryptophan as tracer was negative, supporting a high-grade malignancy of the tumor. In previous studies, most neuroendocrine tumors containing ghrelin IR cells were regarded as low-grade malignant neoplasms. However, in most of these tumors, not all of the neoplastic cells displayed immunoreactivity for ghrelin, whereas in the present tumor, almost all tumor cells expressed this hormone (Fig. 2Go, D and E). Thus, we believe that this is the first case of a true gastric ghrelinoma in a patient without association with chronic atrophic gastritis.

In conclusion, we have characterized a patient with a malignant gastric ghrelinoma with hypersecretion of total and active ghrelin. This might represent a new neuroendocrine tumor entity of the stomach. It is proposed that patients with neuroendocrine tumors of gastric origin should be examined for ghrelin immunoreactivity in tumor cells as well as total and active ghrelin concentrations in the blood.


   Acknowledgments
 
The skillful technical assistance of Åsa Forsberg is gratefully acknowledged.


   Footnotes
 
This work was supported by the Swedish Cancer Society and Selanders and Lions Foundations for Cancer Research at the Uppsala University Hospital.

Abbreviations: BMI, Body mass index; IR, immunoreactive; SV2, synaptic vesicle protein 2; VMAT 2, vesicular monoamine transporter 2.

Received December 15, 2003.

Accepted April 26, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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A. M. Avram, C. A. Jaffe, K. V. Symons, and A. L. Barkan
Endogenous Circulating Ghrelin Does Not Mediate Growth Hormone Rhythmicity or Response to Fasting
J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2982 - 2987.
[Abstract] [Full Text] [PDF]

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M. Kojima and K. Kangawa
Ghrelin: Structure and Function
Physiol Rev, April 1, 2005; 85(2): 495 - 522.
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