Early surgical intervention for patients with possible clinically silent somatotroph adenoma: a case series
Clinically silent somatotroph adenoma is characterized by elevated serum growth hormone but without the clinical symptoms of acromegaly, and it is considered rare. The natural history is not well understood, progress to symptomatic is uncertain, and treatment strategy has not been established.
The first patient was a 48-year-old-Asian woman who presented with serum growth hormone 6.99 ng/ml and insulin-like growth factor 1 of 476 ng/ml, but no characteristic features of acromegaly. Five years after initial diagnosis, she presented with acromegalic facial appearance. Transsphenoidal surgery achieved gross total removal and endocrinological remission. The second patient was a 40-year-old-Asian woman who presented with serum growth hormone 31.14 ng/ml and insulin-like growth factor 1 of 709.6 ng/ml, but no characteristic features of acromegaly. Three years after initial diagnosis, she presented with acromegalic facial appearance. Transsphenoidal surgery achieved gross total removal and endocrinological remission. The third patient was a 64-year-old-Asian woman who presented with serum growth hormone 6.0 ng/ml and insulin-like growth factor 1 of 341 ng/ml, but no characteristic features of acromegaly. Eight months after initial diagnosis, hand enlargement was detected. Transsphenoidal surgery achieved gross total removal and endocrinological remission.
Due to its potential for evolving to symptomatic disease, the risks of surgery and observation for patients with somatotroph adenoma should be carefully compared from the viewpoint of better health outcome.
KeywordsAcromegaly Clinically silent Growth hormone Somatotroph adenoma Transsphenoidal surgery
Insulin-like growth factor 1
Oral glucose tolerance test
Somatotroph adenoma is defined as a pituitary neoplasm characterized by unregulated growth hormone (GH) hypersecretion. Typical features such as acral enlargement and coarse facial features identify patients with somatotroph adenomas, leading to a diagnosis of acromegaly. Such patients present with several coexisting clinical conditions, including hypertension, cardiovascular diseases, abnormal glucose tolerance, obstructive sleep apnea, and malignant neoplasms such as colon and thyroid cancer [1, 2, 3, 4, 5, 6, 7, 8]. Without treatment, their mortality rate is high compared with the general population . Consequently, early surgical intervention is recommended.
Recently, somatotroph adenomas have been classified according to pathological GH expression and excessive serum GH levels. Adenomas with positive immunohistochemical staining for GH but no elevation of serum GH concentration are considered to be “silent” somatotroph adenoma. Similarly, “clinically silent” adenomas are defined as GH-secreting tumors with elevated serum GH concentration, but without the clinical manifestations of excess GH . This entity of clinically silent somatotroph adenoma is now recognized, but whether clinically silent adenoma will become symptomatic remains uncertain, so no treatment strategy has been established.
We treated three patients with somatotroph adenomas without signs of acromegaly despite elevated serum GH concentration. They developed acromegalic features during follow-up for small sellar tumors and later underwent surgery leading to disappearance of the tumors. We discuss the validity of early surgery for such patients. Informed consent was obtained from all individual participants included in the study.
Clinically silent somatotroph adenoma was first described in 1985 . Since then, several case reports and case series have been published [10, 12, 13], but this entity is still considered rare. Recently, one-third of somatotroph adenomas were reported as clinically silent, a relatively higher incidence rate than previously believed . However, the natural history of this entity is still unknown. Clinically silent somatotroph adenoma may be biologically active with the potential to become symptomatic . Our series illustrates the natural course of the disease and confirms this potential.
Long-term exposure to excess GH in patients with definitive acromegaly might be associated with the development and progression of comorbidities such as hypertension, diabetes mellitus, cardiovascular diseases, and certain cancers, so early diagnosis and early treatment are recommended to reduce the risk of premature death [15, 16]. However, no treatment strategy has been established for patients with clinically silent somatotroph adenoma, because the risk of clinical symptoms is uncertain. Consequently, surgery for these patients is prophylactic and is only justified if the surgical risk is lower than the risk of simple observation. Morbidity and mortality associated with surgery are decreased if the surgeon has experience of more than 200 procedures . Our institution is a high-volume center for transsphenoidal surgery. The operator (Y.O.) has performed more than 1000 procedures, and the outcomes for the three cases presented here were acceptable. For our patients, medical therapy was a considerable option. Several medicines, such as dopamine agonists or somatostatin analogues, have been advocated, and preoperative medical therapy has been considered useful to obtain enhanced extent of surgical resection and better biochemical remission [18, 19, 20, 21]. If the initial diagnostician had chosen medical therapy, our patients possibly could have avoided having acromegalic symptoms. However, the primary mode of therapy for patients with acromegaly is surgery because of better remission rate. Unfortunately, neither surgery nor medical therapy was chosen as an initial treatment for our patients because of patient-related and/or diagnostician-related reasons. To achieve better biochemical remission, surgery should be considered for these patients at the time of initial diagnosis with small sellar mass.
This case series has several limitations. First, the clinical manifestations were initially judged by neurosurgeons. An experienced endocrinologist might have detected subtle features of acromegaly. Second, this report is a three-case series and does not assess the actual rate of evolution to symptomatic disease. Moreover, surgery was performed after symptom onset, so the efficacy of early intervention was not fully addressed. Surgery is prophylactic, so the relative advantages and risks of surgery and simple observation must be considered carefully.
Although somatotroph adenomas lack the characteristic feature of acromegaly at initial diagnosis, there is a possibility of evolving into symptomatic disease. Further investigation with larger series and longer follow-up is needed.
The authors declare that they have no acknowledgements about this manuscript.
Availability of data and materials
Because this manuscript is a case report, there are no datasets which could be freely available to use supporting the conclusions of this article.
TK analyzed the patient data regarding the endocrinological outcome and was a major contributor to the writing of the manuscript. YO performed tumor removal all through the investigated period. TT initially raised the question and essential suggestion and supervised this manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The surgical policy was explained preoperatively to the patients and written informed consents were obtained. Overall study design was approved by the Ethical Committee of Kohnan Hospital 2017.
Consent for publication
Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors declare that they have no competing interests.
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- 5.Gasperi M, Martino E, Manetti L, Arosio M, Porretti S, Faglia G, Mariotti S, Colao AM, Lombardi G, Baldelli R, Camanni F, Liuzzi A, Acromegaly Study Group of the Italian Society of Endocrinology. Prevalence of thyroid diseases in patients with acromegaly: results of an Italian multi-center study. J Endocrinol Investig. 2002;25:240–5.CrossRefGoogle Scholar
- 7.Terzolo M, Reimondo G, Gasperi M, Cozzi R, Pivonello R, Vitale G, Scillitani A, Attanasio R, cecconi E, Daffara F, Gaja F, Martino E, Lombardi G, Angeli A, Colao A. Colonoscopic screening and follow-up in patients with acromegaly: a multicenter study in Italy. J Clin Endocrinol Metab. 2005;90:84–90.CrossRefGoogle Scholar
- 15.Colao A, Marzullo P, Cuocolo A, Spinelli L, Pivonello R, Bonaduce D, Salvatore M, Lombardi G. Reversal of acromegalic cardiomyopathy in young but not in middle-aged patients after 12 months of treatment with the depot long-acting somatostatin analogue octreotide. Clin Endocrinol. 2003;58:169–76.CrossRefGoogle Scholar
- 20.Carlsen SM, Lund-Johansen M, Schreiner T, Aanderud S, Johannesen O, Svartberg J, Cooper JG, Hal JK, Fougner SL, Bollerslev J, Preoperative Octreotide Treatment of Acromegaly Study Group. Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: a prospective, randomized trial. J Clin Endocrinol Metab. 2008;93:2984–90.CrossRefGoogle Scholar
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