ABSTRACT
Introduction: Acromegaly and gigantism entail increased morbidity and mortality if left untreated, due to the systemic effects of chronic GH and IGF-1 excess. Guidelines for the diagnosis and treatment of patients with GH excess are well established; however, the presentation, clinical behavior and response to treatment greatly vary among patients. Numerous markers of disease behavior are routinely used in medical practice, but additional biomarkers have been recently identified as a result of basic and clinical research studies.
Areas covered: This review focuses on genetic, molecular and genomic features of patients with GH excess that have recently been linked to disease progression and response to treatment. A PubMed search was conducted to identify markers of disease behavior in acromegaly and gigantism. Markers already considered as part of routine studies in clinical care guidelines were excluded. Literature search was expanded for each marker identified. Novel markers not included or only partially covered in previously published reviews on the subject were prioritized.
Expert opinion: Recognizing the most relevant markers of disease behavior may help the medical team tailoring the strategies for approaching each case of acromegaly and gigantism. This customized plan should make the evaluation, treatment and follow up process more efficient, greatly improving the patients’ outcomes.
Article highlights
An appropriate treatment of patients with acromegaly and gigantism greatly prevents complications derived from IGF-1 excess and normalizes the mortality rate of these patients to that of the general population.
The disease course and the response to standard therapeutic approaches varies among patients with GH excess, and the medical teams should acknowledge the existence of markers of disease behavior for tailoring the clinical approach and treatment in each patient.
A careful clinical history and examination are essential in every case and might be able to identify individuals with disease-associated congenital genetic defects.
The existence of a germline genetic defect cannot be ruled out solely by a negative family history, due to the possibility of low disease penetrance or de novo genetic defects.
Clinical features at the physical examination or a personal or familial history of associated neoplasms that would be indicative of a specific genetic syndrome, should be taken into consideration.
Unless there is a high level of suspicion for a specific condition, next-generation sequencing-based techniques and/or copy number variation analysis are preferred over single-gene screening.
Low molecular weight cytokeratin immunostaining, available in most centers, differentiates between densely granulated and sparsely granulated somatotropinomas. Sparsely granulated adenomas require special attention because they are diagnosed in younger patients, are larger and more invasive, and have a poor response to surgery and first-generation SSAs.
A high immunoreactivity to SST2 is usually a good predictor of a favorable response to SSAs. In addition, proteins involved in the post-receptor effects of SSAs, such as ZAC1 and AIP, can also contribute to predict the therapeutic response.
Somatic activating mutations of the GNAS gene constitute the only well characterized recurrent mutation so far identified in somatotropinomas. Tumors harboring this genetic defect are smaller, respond better to the treatment with first-generation SSAs, and are more often of the densely granulated subtype.
Recurrent chromosome losses in somatotropinomas have recently been identified, although their frequency is still uncertain. In general, tumors negative for GNAS mutations display more features of genomic instability, compared with GNAS mutation positive tumors.
Most of the markers reviewed here are not yet widely available, but currently the patients and their treating physicians can access such tests by means of research studies.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.