Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0610
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 4776-4780
Copyright © 2006 by The Endocrine Society
Acromegaly and Somatotroph Hyperplasia with Adenomatous Transformation Due to Pituitary Metastasis of a Growth Hormone-Releasing Hormone-Secreting Pulmonary Endocrine Carcinoma
Christian Nasr,
Alexander Mason,
Marc Mayberg,
Susan M. Staugaitis and
Sylvia L. Asa
Departments of Endocrinology and Metabolism (C.N.), Neurological Surgery (A.M.), and Neurosciences and Anatomic Pathology (S.M.S.), Cleveland Clinic, Cleveland, Ohio 44195; Seattle Neuroscience Institute (M.M.), Seattle, Washington 98122; and Department of Laboratory Medicine and Pathobiology (S.L.A.), University of Toronto, Toronto, Ontario, Canada M5G 2M9
Address all correspondence and requests for reprints to: Dr. Christian Nasr, Staff, Department of Endocrinology and Metabolism, The Cleveland Clinic Foundation, A53, 9500 Euclid Avenue, Cleveland, Ohio 44195. E-mail: nasrc{at}ccf.org.
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Abstract
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Context: GHRH excess from extracranial endocrine tumors is known to cause somatotroph hyperplasia and acromegaly. Hypothalamic gangliocytomas producing GHRH are also known to be associated with pituitary adenomas causing acromegaly.
Objectives: The objective of this study was to describe a case of acromegaly due to a pulmonary GHRH-secreting endocrine carcinoma with metastasis to the pituitary gland and to look at the peculiar histological features of this case.
Subject: The patient was a 44-yr-old woman who was diagnosed with a biopsy-proven metastatic pulmonary endocrine tumor during pregnancy. After delivery, she underwent radiation and chemotherapy for pulmonary and skeletal metastases. Her disease was clinically stable for 7 yr until she developed bitemporal hemianopia. She had symptoms and signs of acromegaly.
Methods: Imaging, biochemical, and histological studies were performed.
Results: Magnetic resonance imaging (MRI) of the brain confirmed the presence of a 2.6-cm lesion within the sella turcica extending above the sella and compressing the optic chiasm. Endocrine studies showed elevated serum levels of GH, prolactin, 
-subunit of glycoprotein hormones, IGF-I, chromogranin A, and GHRH. The patient underwent uneventful transsphenoidal resection of the sellar tumor. Postoperatively, she noted an improvement in symptoms of acromegaly. Histological examination confirmed metastatic endocrine carcinoma to the pituitary, and immunohistochemistry localized GHRH to the tumor cells. The adjacent pituitary exhibited somatotroph hyperplasia with abundant reactivity for GH and -subunit. In addition, there was focal neoplastic transformation to a sparsely granulated somatotroph phenotype with fibrous bodies.
Conclusion: This is the first report of a GHRH-producing endocrine tumor metastasizing to the pituitary and causing local hyperstimulation with somatotroph hyperplasia and adenomatous transformation.
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Introduction
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PITUITARY ADENOMAS ARE nonmetastasizing neoplasms composed of adenohypophyseal cells that show a wide spectrum of biological behavior from hormonally inactive incidentally discovered microadenomas to symptomatic lesions with hormonal and proliferative activity that can affect distant organ systems, invade locally, and ultimately be lethal (1). The adenohypophysis is controlled locally and distantly by a wide variety of hormonal mediators and is therefore under constant hormonal control. A causative association between GHRH hyperstimulation and pituitary somatotroph adenoma formation has been suggested by the occurrence of hypothalamic gangliocytomas associated with pituitary somatotroph adenomas (2, 3). Animal studies have also shown that prolonged stimulation of somatotrophs by GHRH can cause hyperplasia and adenomatous change (4). However, human patients with ectopic GHRH excess resulting in acromegaly and sellar enlargement usually develop hyperplasia (5) that is thought to be reversible (6). The current hypothesis is that hormonal stimulation results in increased cell proliferation that may predispose to additional genetic events that can cause transformation to neoplasia (7). The coexistence of hypothalamic and pituitary tumors has been suggested to indicate either transdifferentiation or a common transforming event affecting two tissues in proximity (2). We report an unusual case of metastatic GHRH-secreting endocrine carcinoma to the pituitary that raises new questions about the pathophysiology of the pituitary hyperplasia-neoplasia sequence.
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Patient and Methods
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Case reports
The institutional review board waived the need for review and approval of this case report. The patient was a 44-yr-old woman who presented in April 1996 with a lesion on her scalp during the last 2 wk of her pregnancy. A biopsy of that lesion showed neuroendocrine cells (Fig. 1
). On further work-up, a chest radiograph showed a lobulated 3-cm right hilar soft tissue mass. A closed biopsy of that mass showed neuroendocrine cells with mild cytologic atypia and two to four mitoses per 10 high-power fields, consistent with an atypical endocrine tumor. In October 1997, a 99m technetium methylene diphosphonate showed abnormal increased uptake in the coccyx, right iliac wing, and posterior aspect of the right ninth and 10th ribs consistent with metastatic lesions. Computerized tomography (CT) of the chest showed a 2.5-cm right infrahilar mass. There were multiple small noncalcified nodules in the periphery of both lower lobes as well as diffuse sclerotic metastases in the thoracic spine. In October 1998, she underwent fractionated x-irradiation to the infrahilar region of the right lung because of obstructive pneumonia. She also received a 15-month treatment with sc octreotide, iv 5-fluorouracil, and cyclophosphamide through September 1997. Subsequent periodic follow-up testing showed no change in the size and appearance of the metastatic lesions. In 1999, a repeat CT of the chest showed an increase in the size of the right hilar mass as well as an increase in the number and size of the spinal metastases. The bone scan showed more prominent uptake within the previously noted lesions in the right lower ribs, left upper ribs, and sternum. In December 2002, CT of the chest showed sclerotic bony lesions throughout the chest with progression compared with the previous exams. There were also several expansile rib lesions.
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FIG. 1. A, The primary tumor is an infiltrative carcinoma composed of nests and cords of epithelial cells. The lesion infiltrates into surrounding muscle and connective tissue. B, The tumor cells are strongly positive for chromogranin, proving that this is an endocrine carcinoma.
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In April 2003, she was noted to have bitemporal hemianopia on a routine eye exam. Magnetic resonance imaging (MRI) showed a 2.6-cm mass centered in the sella turcica and extending into the suprasellar cistern, surrounding the pituitary stalk and compressing the inferior aspect of the optic chiasm. On the T1-weighted sequences, the mass showed mixed signal intensity with low signal intensity seen in its center. The corresponding area on T2-weighted sequences revealed increased signal intensity. After administration of iv gadolinium, the lesion demonstrated inhomogeneous enhancement. There was no involvement of the cavernous sinuses by the mass; however, there was remodeling of the floor of the sella (Fig. 2).
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FIG. 2. Precontrast coronal T1-weighted MRI at the level of the sella showing the pituitary tumor extending upwards and compressing the optic chiasm.
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The patient had normal menstrual periods until a few months after delivery and then developed amenorrhea. Her FSH was elevated in the postmenopausal range, and it was believed that she developed ovarian failure secondary to the chemotherapy. She did not complain of galactorrhea. Her ring and shoe sizes increased shortly after her pregnancy. Her husband had noted that she was snoring and that her tongue had gotten bigger, although she did not have any change in facial features. She denied flushing or dyspnea, but she was having intermittent watery stools once or twice a month. Baseline laboratory studies showed the following: 17.4 µg/dl morning serum cortisol, 57 (5–50) pg/ml ACTH, 430 ng/ml (6–39) chromogranin A, 31 µU/ml FSH, 67.6 (0–3) ng/ml GH, 93 ng/ml -subunit (normal < 1), 2.44 (0.4–5.5) µU/ml TSH, 8.2 (5–11) µg/dl T4, 1.22 T4 uptake, 6.7 (6–11) µg/dl free T4, 3.6 pg/ml (1.8–4.6) free T3, 96 (1–17.4) ng/ml prolactin, 688 (90–360) ng/ml IGF-I, and 207 (0–10) mg/24 h 5-HIAA. Serum GHRH was 822 pg/ml (Quest Diagnostics, San Juan Capistrano, CA; normal < 50 pg/ml). We performed a 2-h oral glucose tolerance test after giving 75 g oral glucose, and the serum GH values increased progressively from 115 ng/ml at baseline to 154 ng/ml at 2 h. Fasting glucose was 113 mg/dl, peak glucose was 231 mg/dl at 30 min, and the 2-h glucose was 122 mg/dl. An echocardiogram showed normal heart valves.
In June 2003, she underwent transsphenoidal excision of the pituitary tumor. At surgery, the tumor appeared to be invading the cavernous sinus, and the margin between the tumor and the adjacent gland was poorly defined. Within a couple of weeks of the surgery, she felt that her hands were smaller, and her shoes were looser. On examination, her visual fields improved. Her energy level improved, and she stopped snoring. One month after the surgery, laboratory values were: 400 ng/ml IGF-I, 19.2 ng/ml prolactin, 197 ng/ml -subunit, and 14.8 ng/ml GH. In August 2003, she had an Indium-111 octreotide scan of the whole body that revealed numerous areas of abnormal tracer uptake involving the skull, chest, abdomen, pelvis, and bony parts of upper extremities (Fig. 3). In September 2003, she had intensity-modulated radiation therapy to the sellar area. Periodic staging of the patient’s metastatic lesions continued to show stability. Her biochemical profile did not change dramatically during follow-up.
Histology
Histological examination confirmed the presence of two distinct lesions in the pituitary mass. One component was a metastatic endocrine carcinoma with nesting and trabecular architecture and moderate cytologic atypia. This lesion contained immunoreactivity for synaptophysin, chromogranin, and GHRH (Fig. 4). The adjacent pituitary exhibited somatotroph hyperplasia with intact but dilated acini on reticulin stain (Fig. 5) and abundant reactivity for GH and -subunit (Fig. 5). In addition, there was focal neoplastic transformation with complete reticulin breakdown and transformation to a sparsely granulated somatotroph phenotype with fibrous bodies (Fig. 6). The presence of reticulin breakdown and fibrous bodies that are not found in the mature nontumorous adenohypophysis confirmed the presence of neoplastic transformation in this gland. Staining for different molecules showed variable positivity for p27, negative staining for p53, and 13% positivity for MIB. This profile is typical of pituitary adenoma (or hyperplasia), and there was no difference in staining patterns between the hyperplasia and adenoma components.
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FIG. 4. a, The adenohypophysis (A) contains a metastatic carcinoma (M) that resembles the primary lung lesion. b, The metastatic tumor is an endocrine carcinoma that contains immunoreactive GHRH.
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FIG. 5. A, The pituitary exhibits hyperplasia with expansion of acini but an intact reticulin pattern. B, The cells in the hyperplastic area are predominantly densely granulated somatotrophs that stain strongly for GH as well as -subunit (data not shown).
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FIG. 6. A, In areas, the adenohypophysis shows total breakdown of the reticulin fiber network indicating adenomatous transformation. B, The adenoma cells are occasionally binucleate and show variable GH immunoreactivity, with many exhibiting only scant GH immunopositivity. C, In these areas, there is a change in the keratin staining pattern as well, from the perinuclear pattern of the densely granulated hyperplastic cells to the conspicuous juxtanuclear globular pattern of fibrous bodies.
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Results and Discussion
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Manifestations of acromegaly are due to elevated serum levels of GH and IGF-I. The vast majority of patients with acromegaly have a GH-secreting pituitary adenoma (8). However, it is now estimated that ectopic GHRH-secreting tumors account for approximately 1% of all cases of acromegaly (9). Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms that originate from endocrine glands such as the pituitary, the parathyroids, and the adrenal glands, as well as endocrine cells within the thyroid, thymus, pancreas, and digestive and respiratory tracts. Most NETs grow slowly and retain the ability to differentiate, but occasionally, some may show very aggressive behavior. Well-differentiated NETs can secrete amines and peptides and cause clinical syndromes (10). The sites most often affected by NETs are the gastrointestinal tract (about 65%) followed by the bronchopulmonary tract (about 25%). In about 10% of cases, the primary tumor site remains unknown (11). In 45% of NETs, metastases are evident at the time of diagnosis (12). Pulmonary NETs account for approximately 1–2% of primary lung tumors and have been described as typical carcinoid tumor, atypical carcinoid tumor, large-cell neuroendocrine carcinoma, and small-cell lung cancer. However, well-differentiated NETs (so-called carcinoid tumors) can metastasize to regional lymph nodes or to the liver, bones, and brain, and the terminology carcinoid, implying a carcinoma-like process or a mimic of carcinoma, is actually a misnomer because the metastatic lesions are indeed carcinomas. The pulmonary lesions are usually located centrally close to the hilum and are associated with symptoms suggestive of a mass effect but may be peripheral and may manifest primarily with clinical syndromes secondary to hormone secretion, including hormones that are not typical of the tissue of origin, such as ACTH (12). Serum -subunit values were extremely elevated in our patient, and this has been described in NETs. Some pituitary tumors can secrete small amounts of -subunit of gonadotropins, but the serum levels in those cases are only mildly increased (12, 13).
GHRH immunoreactivity is detectable in about 25% of NETs (14); however, acromegaly in these patients is uncommon (8). Reports of cases of NETs associated with acromegaly emerged in the 1960s. It was later reported that removal of bronchial NETs resulted in remission of active disease in acromegalic patients, and it was proposed that the tumors contained GH-releasing activity (15). Indeed, the isolation and characterization of GHRH was elusive in the hypothalamus and was only successful when NETs associated with ectopic acromegaly were used to obtain large amounts of hormone (16, 17). Since the initial reports, more than 50 cases of acromegaly attributable to ectopic GHRH-secreting tumors have been described in the literature; of those, pulmonary NETs are the most common and account for 66% of the total (5, 18). Failure to down-regulate GH secretion during prolonged GHRH stimulation points to a role for GHRH in maintaining persistent GH hypersecretion. Sustained exposure to GHRH may also stimulate a rise in prolactin secretion. In fact, hyperprolactinemia is found more frequently in patients with the ectopic GHRH syndrome than in those with classic acromegaly (15). This may be attributed to stimulation of mammosomatotrophs, as seen in a mouse model of GHRH excess (4).
Hypothalamic tumors composed of ganglion cells, known as hamartomas, choristomas, gliomas, and gangliocytomas, may produce GHRH, and such lesions have been associated with somatotroph hyperplasia or even pituitary GH cell adenoma with acromegaly (2, 3). The first report suggesting a close relationship of hormonal stimulation and hyperplasia was a case report of a hypothalamic hamartoma associated with a GH adenoma within the pituitary. It was postulated that the development of the adenoma was due to GHRH from the neurosecretory hypothalamic lesion (2). This hypothesis was later confirmed in a series of six patients with hypothalamic gangliocytomas associated with the production of GHRH, suggesting that the GHRH stimulation was the mechanism responsible for GH overproduction and clinical acromegaly with somatotroph adenoma in five of the six patients and hyperplasia in the remaining one (3). In subsequent studies, transgenic mice overexpressing GHRH diffusely under the control of a metallothionein promoter with gigantism and hyperplasia of pituitary somatotrophs ultimately developed pituitary adenomas, thus proving that prolonged stimulation of somatotrophs can cause neoplastic transformation (4). GHRH directly stimulates GH gene expression and also induces somatotroph mitotic activity. However, similar models have indicated that sustained hormonal stimulation or loss of inhibition induces hyperplasia, and only after prolonged exposure, a subpopulation of hyperplastic cells can undergo neoplastic transformation, consistent with predisposition of the proliferative cell population to additional genetic events that can cause transformation to neoplasia (7).
Another possibility is that the same cells may produce GHRH and GH, and it has been suggested that hypothalamic gangliocytomas represent transdifferentiation of somatotrophs (2, 3). There is evidence that the same cells can produce both substances. Akira et al. (19) described a case of acromegaly due to a pituitary adenoma associated with very high serum level of GHRH that normalized after successful resection of the adenoma. GHRH production and GHRH gene expression were confirmed in the adenoma. Immunohistochemical staining revealed colocalization of GH and GHRH in single adenoma cells, and the authors suggested an autocrine or paracrine regulation of GH production by endogenous GHRH from the adenoma cells with a possible role of locally generated GHRH in the progression of somatotroph adenomas (19). This hypothesis was also shown by Thapar et al. (20), who identified GHRH expression in somatotroph adenomas and levels of GHRH expression correlating with clinical features of aggressive behavior.
Unlike the situation where two adjacent neoplasms have been identified in the sellar region, patients with ectopic GHRH have had evidence of pituitary hyperplasia (5). Ramsay et al. (6) described a case of multiple endocrine neoplasia type 1 in which ectopic GHRH production by two pancreatic tumors resulted in acromegaly and sellar enlargement. After partial pancreatectomy, sellar size decreased significantly, and the stigmata of acromegaly improved, thus demonstrating reversible sellar enlargement due to ectopic GHRH and indicating that GHRH excess causes hyperplasia rather than frank adenomatous transformation (6). In another case, there was evidence of a paradoxical response of somatotrophs to TRH, suggesting altered hormonal responsiveness of the hyperplastic cells (21); however, there has been no proof of neoplastic transformation due to the persistent GHRH stimulation. This represents the first report of a GHRH-producing NET associated with somatotroph hyperplasia and adenomatous transformation. It is interesting to speculate that the neoplastic transformation of hyperplastic somatotrophs was attributable to the local metastasis that resulted in extremely high local levels of GHRH. This occurrence suggests that the same mechanism may be implicated as in the case of GHRH-secreting gangliocytomas where local endocrine as well as paracrine action may compound the effects of chronic GHRH excess.
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Conclusion
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This is the first report of a GHRH-producing endocrine tumor metastasizing to the pituitary and causing local hyperstimulation with somatotroph hyperplasia and adenomatous transformation. In contrast to other situations of ectopic GHRH excess, the local effects of hyperstimulation seem to be important in the neoplastic process, analogous to those seen in patients with hypothalamic gangliocytomas producing GHRH. Numerous factors have been shown to govern the development and function of the pituitary gland and associated hyperplastic and adenomatous changes. Studies in this field are challenging because of the relative rarity of this pathologic process; however, further concentration in the area of molecular and biological signaling pathways may help improve the understanding of this complex neoplastic process.
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Footnotes
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C.N., A.M., M.M., S.M.S., and S.L.A. have nothing to declare.
First Published Online September 12, 2006
Abbreviations: CT, Computerized tomography; NET, neuroendocrine tumor.
Received March 21, 2006.
Accepted August 31, 2006.
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References
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Abstract
Introduction
