Unveiling the GHRHoma syndrome: clinical insights from 100 patients with GHRHomas

Neuroendocrine neoplasms secreting the growth-hormone-releasing hormone (GHRH), referred to as GHRHomas, are extremely rare. GHRHoma syndrome is characterized by GHRHomas, acromegaly, and somatotroph hyperplasia (pituitary enlargement). A total of 100 cases with GHRHoma syndrome, reported in the literature from 1977 to 2020, were analyzed. Among these, GHRHomas was located in the lung (50 cases), pancreas (34 cases), and other sites, including the intestine, liver, thymus, adrenal/extra-adrenal organs, and lung cancer (16 cases). Approximately 85% of patients had GHRHomas in the lung and pancreas. Among all patients with lung GHRHoma (LunGHRHoma) and pancreatic GHRHoma (PanGHRHoma) syndromes, 84–89% had pituitary enlargement. LunGHRHoma syndrome displayed clinical aspects similar to PanGHRHoma syndrome in the absence of multiple endocrine neoplasia type 1 (MEN 1). These GHRHoma syndromes tended to exhibit a female predominance, malignant tumour characteristics, and recurrence or metastases (46–53%). Notably, 26–33% of these patients underwent unnecessary pituitary surgery. In contrast, PanGHRHoma syndrome with MEN 1 showed a male predominance, benign tumour characteristics, and slightly lower rates of metastases (32%). However, 47% of 19 patients underwent neurosurgery. Somatostatin (STS) analogues effectively suppressed GHRH secretion from recurrent or metastatic GHRHomas in the lung, intestine and liver. Conversely, in PanGHRHomas, an STS and its analogue only partially inhibited GHRH secretion in vivo but suppressed GHRH secretion in vitro from cultured tumour cells. This discrepancy led to the hypothesis that stromal barriers in the pancreatic tumour microenvironment may impede the binding of an STS and its analogue to its receptors. Proper diagnosis and treatment of GHRHoma syndrome require heightened awareness and multidisciplinary cooperation. Radiologists, in particular, play a crucial role in interpreting of pituitary MRI imaging, which typically reveals a diffuse or homogeneous enlargement without a focal lesion, helping to avoid unnecessary neurosurgery.