Hormonal and Volumetric Long Term Control of a Growth Hormone-Releasing Hormone-Producing Carcinoid Tumor
A. Van den Bruel,
J. Fevery,
J. Van Dorpe,
L. Hofland and
R. Bouillon
Laboratory and Clinic of Experimental Medicine and Endocrinology
(A.V.d.B., R.B.), the Department of Internal Medicine, Hepatology
(J.F.), and the Department of Pathology (J.V.D.), Universitaire
Ziekenhuizen, Gasthuisberg, B-3000 Leuven, Belgium; and the Department
of Internal Medicine III, Erasmus University (L.H.), Rotterdam, The
Netherlands
Address all correspondence and requests for reprints to: Dr. R. Bouillon, Laboratory for Experimental Medicine and Endocrinology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: roger.bouillon{at}med.kuleuven.ac.be
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Introduction
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A 25-yr-old female was referred for symptoms of
acromegaly. Two months before admission she mentioned profuse sweating
and complained of severe headache. Seven years earlier a large
neuroendocrine tumor in the liver was detected. At that time she
presented with secondary amenorrhea of 2-yr duration accompanied by
fatigue, perspiration, diarrhea, weight loss, and disturbed liver tests
(Table 1
) and a large tumor in the right
liver lobe palpable 10 cm below the right lower costal margin [23
x 18 x 25 cm by magnetic resonance imaging (MRI); Fig. 1A
]. During laparatomy a highly vascular
tumor was found invading the left liver lobe. Abdominal exploration did
not reveal other tumor foci. The tumor biopsy showed characteristics of
a neuroendocrine tumor (Fig. 2A
) with
positive chromogranin and neuron-specific enolase staining. Serum
pancreatic polypeptide (PP), chromogranin, serotonin, and urinary
5-hydroxyindole acetic acid (5-HIAA) were markedly elevated. Urinary
catecholamines (dopamine and norepinephrine) as well as its degradation
products (homovanillic acid and vanillylmandelic acid) were elevated as
well (Table 2
). Somatostatin receptor
scintigraphy with
[111In-DTPAo]octreotide showed
major, but heterogeneous, uptake by the hepatic tumor without evidence
of other tumor sites (Fig. 3
). The search
for a primary tumor site, especially in the pancreas, was negative
after investigation by computed tomography scan, MRI,
endoultrasonography, and somatostatin receptor scintigraphy. The
hepatic tumor was considered unresectable by its size and site;
chemoembolization (with cisplatinum/lipiodol) was performed in 1992 and
1994 for relief of mass symptoms. Tumor volume was considered unchanged
in July 1996.

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Figure 1. The hepatic tumor before (A) and after 15
months (B) of treatment with somatostatin (SS) analogs. A marked volume
reduction (by 70%) was observed.
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Figure 2. The neuroendocrine tumor consists of
anastomosing nests and cords supported by a fibrovascular stroma. Tumor
cells have a moderate amount of lightly eosinophilic granular
cytoplasma. There is only minimal nuclear atypia. Hematoxylin and eosin
staining; original magnification, x110 (A). The lesion shows focal
positivity for GHRH. Immunoperoxidase; original magnification, x125
(B).
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Table 2. Hormonal characteristics at baseline (at diagnosis
of the neuroendocrine tumor in 1992, at diagnosis of acromegaly in
1996)
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At the time of referral in 1996, soft tissue enlargement, an enlarged
tongue, and prominence of the jaw pointed to the diagnosis of
acromegaly, confirmed by the markedly elevated GH and insulin-like
growth factor I (IGF-I) levels. Retrospective determination of the GH
and IGF-I in samples collected at the time of the initial diagnosis
showed comparable high values (Table 2
). The patients visual fields
were normal, but pituitary enlargement with chiasmatic compression was
present on MRI of the sella (Fig. 4A
).

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Figure 4. Pituitary before (A) and after 15 months (B)
of treatment with somatostatin analogs. A significant reduction of
pituitary height was observed.
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Differential diagnosis
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The differential diagnosis at this time (1996) included conditions
that would cause a combination of a carcinoid tumor along with symptoms
of GH excess. Acromegaly is usually caused by a pituitary GH-secreting
adenoma and can be associated with a carcinoid tumor in the case of
multiple endocrine neoplasia type 1 (MEN 1). Serum calcium and PRL
levels were normal in the patient. Her family history was also negative
for endocrine neoplasia. DNA analysis showed no mutations in the coding
region of the MEN 1 gene. The suspicion of MEN type 1 could therefore
not be confirmed. GHRH-producing tumors may rarely induce excess GH
secretion and thus cause the ectopic acromegaly syndrome. Tumors
causing this syndrome include carcinoids localized in the lung or
gastrointestinal tract and islet cell tumors.
The clinical course of our patient at the presentation in 1996 was
compatible with a hepatic carcinoid secreting GHRH and ectopic
acromegaly. This syndrome was reviewed in 1992 by Faglia, who reported
39 cases fulfilling this definition (1). In the meantime 12 additional
cases have been reported (2, 3, 4, 5, 6, 7), making a total of 51 cases. The
majority of such patients have symptoms related to the ectopic tumor
mass and its production of other peptides at the time they present with
symptoms related to excess GH secretion.
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Follow-up course
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Serum samples were sent for determination of GHRH levels, which
were elevated at 101 and 212 pg/mL (<50 pg/mL; RIA, Nichols Institute Diagnostics, Quest Diagnostics, Inc., San
Juan Capistrano, CA). These values should be interpreted with caution,
as the samples exceeded stability upon arrival at the laboratory. A
third sample drawn in May 1998 (after a temporary 2-week withdrawal of
therapy) showed a GHRH level of 1045 pg/mL. GHRH levels in ectopic
acromegaly are above 1 ng/mL in the majority of cases. Paraffin
sections of the tumor tissue obtained in 1992 were stained for GHRH and
GH. GHRH immunostaining was positive in 15% of the tumor cells;
staining for GH was negative. The diagnosis of a GHRH-secreting
carcinoid tumor causing ectopic acromegaly was thus confirmed.
Treatment with somatostatin analogs was initiated because of the
positive in vivo
[111In-DTPAo]octreotide scan
showing marked uptake at the hepatic tumor site (Fig. 3
). The presence
of somatostatin receptors in the tumor was confirmed by the
somatostatin receptor autoradiography technique, using
[125I-Tyr3]octreotide (8). A very high
density of somatostatin receptors could be demonstrated (Fig. 5
).

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Figure 5. Photomicrograph of the results of
somatostatin receptor autoradiography of the GHRH producing tumor
using [125I-Tyr3]octreotide. A,
Hematoxylin-eosin-stained section; B, autoradiogram showing total
binding of [125I-Tyr3]octreotide; C,
autoradiogram showing displacement of
[125I-Tyr3]octreotide binding by excess (1
µmol/L) unlabeled octreotide. Bar, 1 mm.
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Excessive sweating and headache promptly disappeared after institution
of therapy with octreotide. Serum GH concentrations were acutely
lowered by octreotide (100 µg, sc), but IGF-I levels were not
normalized after 3 months of therapy with octreotide (100 µg, three
times daily), probably due to a rebound rise of GH 67 h after the
injection, reflected by the wide variation of GH levels obtained during
a 24-h profile (Table 3
). Therefore,
therapy with long acting lanreotide (30 mg, once every 10 days) was
instituted. As GH, IGF-I, chromogranin, and serum PP decreased
substantially but were not normalized after 9 months of treatment, the
therapy was switched from lanreotide to octreotide (500 µg daily) by
continuous sc infusion (CSI). After 9 months of this therapeutic
regimen we interrupted the treatment for 2 weeks and evaluated a
dose-response curve to determine whether a higher dose of octreotide
could further ameliorate the GH excess. Indeed, octreotide lowered GH,
IGF-I, and GHRH levels in a dose-dependent way (Fig. 6
). Finally, normal or near-normal GH,
IGF-I, chromogranin, and PP levels were reached with octreotide (1000
µg daily) by CSI, whereas GHRH remained elevated. Serotonin and
urinary 5-HIAA normalized during treatment. Urinary norepinephrine and
vanillylmandelic acid normalized, whereas urinary DOPA and homovanillic
acid remained elevated (Table 3
).

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Figure 6. Dose-response effect of octreotide; GHRH,
GH, and IGF-I at baseline and after 500 and 1000 µg octreotide by CSI
for the preceding 14 days. The dashed line represents
the upper limit of normal values.
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This biochemical control was accompanied by stable or even decreased
clinical signs of acromegaly and a reduction of the pituitary mass, as
pituitary height decreased by 58% (Table 4
and Fig. 4
, A and B). Moreover, liver
tests normalized, and the hepatic tumor volume decreased markedly. The
liver became palpable only 23 cm below the right costal margin, and
the volume measured by MRI was reduced by 70% (Table 4
and Fig. 1
, A
and B).
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Discussion
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Twenty-five years ago the first case of a bronchial carcinoid
tumor suspected to secrete a substance with GHRH activity and causing
acromegaly was described. The patient was cured by resection of the
carcinoid tumor. Since then, the syndrome of ectopic GHRH-induced
acromegaly remains a rare disorder, as only 51 cases have been reported
to date (1, 2, 3, 4, 5, 6, 7). The most frequent tumors causing this syndrome are
carcinoids (66%), usually localized in the lung (79%) or
gastrointestinal tract (8%); in 28% of the cases islet cell tumors
are responsible. The present case represents the third patient with a
carcinoid tumor of unknown primary site causing GHRH-induced
acromegaly. Carcinoids as well as islet cell tumors express a broad
variety of hormones. In 7 of 14 pancreatic GHRH tumors the secretion of
other hormones was documented: insulin (4 patients), gastrin (3
patients), somatostatin (2 patients), glucagon (1 patient), and PP (1
patient). Elevated urinary 5-HIAA and/or circulating serotonin were
observed in 7 of 34 carcinoid tumors, increased ACTH production
in 3 patients, and elevated urinary dopamine levels in one case. Serum
chromogranin (measured infrequently) was increased in 1 case. In our
patient we describe elevated chromogranin, PP, serotonin, urinary
5-HIAA, urinary dopamine, and norepinephrine. Evidence of
hyperparathyroidism or familial disease suggestive of MEN 1 syndrome
was reported in 9 cases, but in our patient there was no evidence of
MEN 1.
Most tumors causing GHRH-induced acromegaly are large, as in our
patient. Pituitaries from patients with GHRH-induced acromegaly show a
morphological continuum from typical hyperplasia to adenomas; in our
patient MRI suggests pituitary hyperplasia, although there is no
histological proof.
The clinical features of ectopic acromegaly are those of patients with
classical acromegaly in addition to the manifestations attributable to
the primary tumor. The latter include mass symptoms for large tumors,
as in our case. Symptoms due to other cosecreted hormones or to the
associated hyperparathyroidism in MEN 1 have been reported in other
cases.
The strong suspicion of the carcinoid tumor causing ectopic
GHRH-induced acromegaly was confirmed in our case by the following. 1)
An elevated GHRH level of 1045 pg/mL was found (normal, <50 pg/mL,
compared to levels of 300145,000 pg/mL in other cases of GHRH-induced
acromegaly). The slightly elevated values for GHRH in 1996 and 1997
have to be interpreted with caution, as these samples exceeded
stability upon arrival at Quest Nichols. 2) There was positive
immunohistochemical detection of GHRH in the biopsy of the hepatic
tumor. The strongest proof would consist of cure of acromegaly by
resection of the carcinoid, but this could not be obtained because the
hepatic localization is presumably a metastatic site and was by its
size unresectable.
Visualization with in vivo octreotide scintigraphy indicated
substantial concentrations of somatostatin receptors in the hepatic
tumor as previously reported in the culprit tumors of four patients
with GHRH-induced acromegaly (5, 6, 7, 9). The absence of positive uptake
in the pituitary could be a problem of sensitivity of the scanning, the
high tumor burden, and uptake at the hepatic tumor site.
A very high density of somatostatin receptors in the liver tumor could
be confirmed by somatostatin receptor autoradiography. This case
therefore adds to the two cases reported by Bertherat, who documented
the presence of somatostatin receptors negatively coupled to adenylate
cyclase in ectopic GHRH-secreting tumors from acromegalic patients
responsive to octreotide (3).
Twenty years after the first description of a therapeutic trial with
somatostatin in two patients with a carcinoid tumor and acromegaly
(10), we can now evaluate the long term (22 months) use of somatostatin
analogs in our patient compared to its use (3 months to 3 yr) in 14
patients with GHRH-induced acromegaly in the literature (Table 5
). As one third of the patients with
GHRH-induced acromegaly presented with widespread or metastatic
disease, surgical cure of the culprit tumor is not possible, and
octreotide treatment is the current treatment option.
An excellent biochemical response, with GH levels becoming normal or
near normal and IGF in the normal range, was documented in 5 of 14
patients. GHRH in these patients decreased by 64% (11, 12, 13, 14, 18). An
intermediate response, with clinical improvement of acromegalic
features and a major reduction in GH and IGF-I levels, has been
described in 7 patients. GH decreased by 4090%, and IGF-I decreased
by 4775%, accompanied by GHRH reductions of 5470% from baseline
(4, 6, 7, 15, 16, 17). Treatment failure was described in 2 of 14 patients
(2, 3). Our patient showed an intermediate biochemical response during
treatment with lanreotide and octreotide (500 µg daily) by CSI. An
excellent response, however, during treatment with octreotide (1000
µg daily) by CSI was observed. We thus confirmed a dose-response
effect with regard to octreotide (12, 13, 14) and superiority of a
continuous infusion therapy compared to intermittent sc injection, as
had been observed by Wilson (13) and Lefebvre (4). The lack of a
parallel decline in GH and GHRH levels after treatment with
somatostatin analogs could be explained as a consequence of the action
of the somatostatin analog not only at the hepatic tumor site, but also
at the pituitary level.
The evolution of the pituitary volume was evaluated in five patients in
the literature. It decreased in three patients with a biochemical
response to octreotide treatment (4, 12, 13) and remained unchanged in
two patients, of whom one responded (7) and the other failed to respond
biochemically (2) to treatment with octreotide. We observed a clear
decrease in pituitary size (pituitary height decreased by 58%).
The volume of the primary tumor was unchanged in patients with
treatment failures and in the majority of patients with intermediate or
even excellent biochemical responses. In two patients with an
intermediate biochemical response there was even progression of tumor
volume, with evidence of new metastases during treatment (4, 15). In
one patient with excellent biochemical response von Werder described
some evidence of tumor shrinkage of a hepatic metastasis (18), although
clear evidence of tumor shrinkage was demonstrated in only one patient
in the literature (12). In our patient, the hepatic tumor, considered
to be a huge metastasis, showed a clear decrease (70%) in size as
measured by MRI. Along with the volumetric decrease we demonstrated a
clear decrease in chromogranin, serotonin, urinary 5-HIAA, and PP.
In conclusion, a new case of acromegaly due to a GHRH-secreting
neuroendocrine liver tumor is described, and the results of treatment
with somatostatin analogs are compared with those from previously
reported cases. Distinctive from previous reports, an excellent control
of GH excess was accompanied by a significant reduction of the tumor
volume. The clear tumor shrinkage during treatment might be due to the
high density of somatostatin receptors, as revealed by in
vitro and in vivo studies, and/or by the continuous
infusion therapy.
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Note Added in Proof
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During the preceding 12 months, treatment with octreotide has
been continued. Hormonal and volumetric control is now obtained for a
long-term period of 34 months, one of the longest treatment terms
reported in cases of GHRH-secreting tumors (July 1999).
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Acknowledgments
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We thank W. Heyns, T. Peeters, J. Billen, and K. Desmet for the
hormonal assays; Pharmacia & Upjohn, Inc. for the GHRH
antibodies, Ipsen for the compassionate use of Lanreotide, and Novartis
for the compassionate use of high doses of Sandostatine. We thank Mrs.
L. Janssens and C. Lauwers for excellent secretarial assistance and
nursing assistance, respectively.
Received January 14, 1999.
Revised June 4, 1999.
Accepted June 17, 1999.
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-subunit-secreting tumors from
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