GHRH secretion from a pancreatic neuroendocrine tumor causing gigantism in a patient with MEN1

Summary A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare. Learning points It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1). Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis. Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.

MON-294 T2 MRI Signal Analysis of The Pituitary Gland Is Efficient in the Diagnosis of Acromegaly Due to GHRH Ectopic Secretion

Less than 1% of cases of acromegaly are secondary to ectopic secretion of Growth Hormone Releasing Hormone (GHRH), usually from a neuroendocrine tumor. Symptoms of ectopic acromegaly did not differ from classical acromegaly from pituitary origin. GH and IGF 1 values are in the same range. GHRH measurement only could make the correct diagnosis but is not routinely proposed in acromegaly. MRI of the pituitary gland is considered not very effective in ectopic acromegaly. In the literature (1), different patterns are described: pituitary enlargement (46%), adenoma (30%), empty sella (2%) or normal (20%). But T2MRI signal of the pituitary is never mentioned nor illustrated. Finally, in about 30 % of published cases, pituitary surgery, of course inefficient, was performed. These data enhance the poor contribution of imaging studies in the published cases of ectopic acromegaly. We have been able to obtain and read MRIs and particularly T2WI of 27 acromegalic patients- 20 female, 7 male- due to GHRH hypersecretion from a neuroendocrine tumor –principally bronchial carcinoid and pancreatic NET- which have been published or not. Remarquably, T2 sequences were available in only 27/61 cases we have collected. In all these 27 cases but two, the T2 signal was clearly hypointense if compared with the brain cortex, as it has been described in densely granulomated somatotropinomas (2). In one case with T2 hyperintensity, the pituitary mass presented the same imaging characters as multiple brain metastases from a bronchial carcinoïd. In one case, T2 signal was isointense. In 3 cases, tiny millimetric T2 hyperintense images were disseminated within pituitary hyperplasia. In several cases where pituitary MRI was considered as normal, correlation of the patient’age with pituitary size could make suspect an enlarged gland. In a case labeled empty sella, T2MRI signal of the pituitary remnant was hypointense. When coupling T2 and T1 gadolinium enhanced sequences, no pituitary adenoma was visualized and normal pituitary tissue was never identified along with pituitary hyperplasia. In conclusion, T2 MRI hypointense signal of the pituitary gland is a better hallmark than pituitary hyperplasia for the diagnosis of acromegaly due to GHRH ectopic secretion. Analysis of T2 MR signal in these cases is essential to avoid unnecessary interventions to the pituitary. References 1 Ghazi A Endocrine 2013 2 Potorac J Endocr Relat Cancer 2015

Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour

Summary A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH) and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient’s acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed. Learning points: Ectopic acromegaly is rare, accounting for less than 1% of all cases of acromegaly. Ectopic acromegaly is almost always due to extra-pituitary GHRH secretion, mainly from neuroendocrine tumours of pancreatic or bronchial origin. Differentiating between acromegaly of pituitary origin and ectopic acromegaly can cause diagnostic challenges due to similarities in clinical presentation and biochemistry. Serum GHRH can be a useful diagnostic tool to diagnose ectopic acromegaly. Pituitary imaging is crucial to differentiate between a pituitary adenoma and pituitary hyperplasia, which is a common finding in ectopic acromegaly. Diagnosing ectopic acromegaly is pivotal to avoid unnecessary interventions to the pituitary and preserve normal pituitary function.