Introduction: Ectopic secretion of GHRH is a rare cause of acromegaly. However, its recognition is clinically important because different therapeutic approaches are required. Case Presentation: We present a challenging case of acromegaly secondary to ectopic GHRH secretion from pancreatic neuroendocrine tumor in a 52-year-old female. The patient is treated with different modalities which include pegvisomant in an attempt to control the stimulated GH-axis considering the limited data about its use in treatment of ectopic acromegaly. Conclusion: GHRH-secreting tumor is a rare cause of acromegaly. Surgical resection of the tumor is the therapy of choice whenever possible. However, further studies are warranted for unresectable tumor or resistant cases.
A 52-year-old woman presented initially in May 2007 with a 2.5 cm firm non-tender nodule over her right triceps area and significant weight loss over 1 year. Medical history included left breast cancer for which she had undergone mastectomy followed by chemotherapy at age of 34. She had no evidence of disease since then. Excisional biopsy of the right arm lesion and further diagnostic work-up revealed metastatic well differentiated neuroendocrine carcinoma originating from a large (10 × 6 cm) pancreatic tail mass. An octreotide scan was negative. She received 7 cycles of chemotherapy (carboplatin and gemcitabine) followed by palliative radiotherapy for spinal propagation of her retroperitoneal tumor. Several months later, radiological imaging showed stable disease.
On January 2009, she was admitted because of heart failure secondary to cardiomyopathy. Coarse facial features noticed this admission prompted a work-up for acromegaly. This diagnosis was confirmed on the basis of elevated serum insulin-like growth factor 1 (IGF-I) 77 nmol/L (reference range, 10 - 29.4 nmol/L) and growth hormone (GH) of 14.4 ug/L (reference range, 0.03 - 4.00 ug/L) that failed to be suppressed during oral glucose tolerance test. A normal sellar MRI prompted the requisition of serum Growth Hormone-Releasing Hormone (GHRH) which was indeed elevated at 185 pg/ml (reference range, 5 - 18 pg/ml) strongly favoring ectopic acromegaly syndrome. The remaining pituitary function normal included a serum prolactin of 5.6 mcg/L (reference range, 3.3 - 26.7 mcg/L).
She started on octreotide LAR monthly injections. Everolimus 10 mg daily was added for a short period as she developed a skin reaction that forced to stop it. During this period, she had fine needle aspiration cytology (FNAC) from right firm thyroid nodule that was measured as 1.5 cm and reported as possible medullary thyroid cancer (MTC). Calcitonin level was ˂2 ng/L (reference range 0 - 10 ng/L). She underwent right hemithyroidectomy and neck dissection. The final pathology was metastatic well differentiated pancreatic neuroendocrine carcinoma rather than MTC. As the tumor was invading the recurrent laryngeal nerve on the opposite side, it was decided that no further surgery would be offered for the neck lesions. Also, she was discovered to have left superior parathyroid adenoma which has been resected. Multiple Endocrine Neoplasia (MEN) screening revealed one high parathyroid hormone (PTH) reading of 10.68 pmol/L (reference range, 1.60 - 6.90 pmol/L) in face of normal serum calcium concentration.
The pancreatic tumor, which had initially been considered unresectable at another center, was reassessed by our surgical team. It was decided that good tumor debulking could be achieved. She underwent elective surgery in August 2010 involving distal pancreatectomy and splenectomy, partial liver resection, cholecystectomy and perinephric tumor excision. Post-surgically IGF-I concentrations fell to around 40 - 45 nmol/L, which were still about 30% above the upper limit of normal. Therefore octreotide LAR was resumed. Post-surgical CT imaging showed no residual pancreatic tumor, however progression of liver involvement was reported. Her clinical complaints of hot flushes, diarrhea and spinal cord compression symptoms became significant at this point. Therefore, sunitinib 37.5 mg daily was added to the monthly 60 mg of octreotide. Three months later, the radiological imaging showed massive metastatic lesions in the liver, bone, lungs and new lesion in right breast which were confirmed pathologically to have the same nature of the other tumors foci. Six cycles of chemotherapy (dacarbazine and 5-fluorouracil) also did not halt her disease progression at this point although clinically she seemed better.
In an effort to suppress the IGF-I production, pegvisomant 10 mg daily was added to octreotide for a period of 6 months. Shortly after initiating pegvisomant, her IGF-I had been completely normalized (from 67.1 to 15.2 nmol/L). Unfortunately she had a pelvis fracture in October 2012 at the site of a bone metastasis and was admitted to another hospital. The oncology considered that at this point all her treatment was probably futile and in agreement with the patient, all but essential medications were discontinued. She was then transferred to a hospice. At this point we lost further contact with the patient.
Ectopic secretion of Growth Hormone Releasing Hormone (GHRH) accounts for <1% of acromegaly cases [
The clinical features of ectopic GHRH-secreting tumors causing acromegaly are indistinguishable from those caused by GH-secreting pituitary adenomas. However, symptoms due to the underlying neoplasm or cosecretion of other substances by the tumor might be suggestive of an ectopic origin. GHRH-omas in the pancreas are often single, large tumors arising from the tail of pancreas which might explain the late discovery. One third of patients have liver metastases at diagnosis [
Regardless of the cause, GH and IGF-I are invariably elevated and GH levels fail to suppress after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing pituitary acromegalic patients from those harboring extrapituitary tumors. The diagnosis is usually established by presence of an elevated plasma GH levels accompanied by elevated plasma GHRH levels. Imaging of the sellar region is necessary to verify the presence and size of a pituitary lesion even if the diagnosis of ectopic GHRH secretion has been established. Different radiological tools can be used to localize the GHRH-secreting tumor such as chest CT scan, trans-abdominal or endoscopic ultrasound, abdominal CT scan and MRI. Octreotide scan can provide additional tool as these tumors very often express subtype 2 and 5 of the somatostatin receptors. However, despite the high sensitivity of octreotide scan in diagnosing of NET, tumor differentiation significantly impact the octreotide uptake [
Important clues to the presence of a GHRH producing acromegaly are absence of a pituitary tumor on imaging [
Despite the fact that the initial isolation of GHRH was from pancreatic islet cell tumors from patients with ectopic acromegaly [
The secretion of both GH and ectopic GHRH has been shown to be pulsatile [
Treatment of ectopic acromegaly involves surgical resection of the tumor whenever possible. Long-acting somatostatin analogs are generally successful in the initial management of patients with GHRH-omas. The long acting somatostatin analogs may be able to control the ectopic hormonal secretion and tumor growth. The efficacy of somatostatin analogs depends on the pattern of somatostatin receptor (SSTR) expression in the tumor. For this reason there is usually a better response in pituitary adenomas causing acromegaly where the GH secreting pituitary adenomas express mainly SSTR2 and 5, while SSTR1 is expressed mainly in mixed GH-prolactin adenomas [
The standard chemotherapy regimens that target GHRH producing tumors are generally unsuccessful in controlling the activated GH axis [
GHRH secreting tumor is a rare cause of acromegaly. However, its recognition is clinically important because more different therapeutic approaches are needed than GH secreting pituitary adenoma. Surgical resection of the tumor is the therapy of choice whenever possible. Pegvisomant seems promising for resistant cases in an attempt to control the GH-axis. However, further studies are warranted. Finally, the experimental results of GHRH antagonists should provide motivation to continue developing new antagonistic analogs of GHRH and explore their potential benefit in human cancers.