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


    Introduction
 Top
 Introduction
 Differential diagnosis
 Follow-up course
 Discussion
 Note Added in Proof
 References
 
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 1Go) 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. 1AGo]. 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. 2AGo) 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 2Go). Somatostatin receptor scintigraphy with [111In-DTPAo]octreotide showed major, but heterogeneous, uptake by the hepatic tumor without evidence of other tumor sites (Fig. 3Go). 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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Table 1. Biochemistry at diagnosis and during follow-up

 


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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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Figure 3. In vivo [111In-DTPAo]octreotide scan showing major uptake at the hepatic tumor site.

 
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 2Go). The patients’ visual fields were normal, but pituitary enlargement with chiasmatic compression was present on MRI of the sella (Fig. 4AGo).



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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.

 

    Differential diagnosis
 Top
 Introduction
 Differential diagnosis
 Follow-up course
 Discussion
 Note Added in Proof
 References
 
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.


    Follow-up course
 Top
 Introduction
 Differential diagnosis
 Follow-up course
 Discussion
 Note Added in Proof
 References
 
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. 3Go). 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. 5Go).



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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.

 
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 6–7 h after the injection, reflected by the wide variation of GH levels obtained during a 24-h profile (Table 3Go). 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. 6Go). 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 3Go).


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Table 3. Hormonal characteristics during follow-up and treatment with somatostatin analogs

 


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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.

 
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 4Go and Fig. 4Go, A and B). Moreover, liver tests normalized, and the hepatic tumor volume decreased markedly. The liver became palpable only 2–3 cm below the right costal margin, and the volume measured by MRI was reduced by 70% (Table 4Go and Fig. 1Go, A and B).


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Table 4. Tumor features at diagnosis and during follow-up and treatment with somatostatin analogs

 

    Discussion
 Top
 Introduction
 Differential diagnosis
 Follow-up course
 Discussion
 Note Added in Proof
 References
 
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 300–145,000 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 5Go). 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.


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Table 5. GHRH-producing tumors treated by somatostatin analogs: review of the literature

 
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 40–90%, and IGF-I decreased by 47–75%, accompanied by GHRH reductions of 54–70% 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.


    Note Added in Proof
 Top
 Introduction
 Differential diagnosis
 Follow-up course
 Discussion
 Note Added in Proof
 References
 
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).


    Acknowledgments
 
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.


    References
 Top
 Introduction
 Differential diagnosis
 Follow-up course
 Discussion
 Note Added in Proof
 References
 

  1. Faglia G, Arosio M, Bazzoni N. 1992 Ectopic acromegaly. Endocrinol Metab Clin North Am. 21:575.[Medline]
  2. Ezzat S, Asa SL, Stefaneanu L, et al. 1994 Somatotroph hyperplasia without pituitary adenoma associated with a long standing growth hormone-releasing hormone-producing bronchial carcinoid. J Clin Endocrinol Metab. 78:555–560.[Abstract]
  3. Bertherat J, Turpin G, Rauch C, Li JY, Epelbaum J, Sassolas G, Schaison G. 1994 Presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic growth hormone-releasing hormone- and {alpha}-subunit-secreting tumors from acromegalic patients responsive to octreotide. J Clin Endocrinol Metab. 79:1457–1464.[Abstract]
  4. Lefebvre S, De Paepe L, Abs R, Rahier J, Selvais P, Maiter D. 1995 Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion. Eur J Endocrinol. 133:320–324.[Medline]
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