Acromegaly is a disease of disproportionate skeletal, tissue, and organ growth. Though the incidence of acromegaly is only 5 cases per million, untreated patients face a 10 year reduction in life expectancy and doubling of standardized mortality rates due to cardiovascular, cerebrovascular, metabolic, and respiratory comorbidities (87
Silent acromegaly can be considered as either as a clinical NFA which is immunopositive for GH on surgical specimen or as biochemical acromegaly without clinical stigmata. Rather than typing silent acromegaly as a distinct entity, there may be a continuous spectrum from clinically functioning, sparsely granulated adenomas to silent somatotroph adenomas with elevated GH levels and abnormal dynamics to SSAs with normal GH levels and dynamics.
In the earliest reports of silent acromegaly, 3 patients were described without clinical stigmata of acromegaly but with elevated IGF-1 and nonsuppressed GH levels on OGTT were found on IHC to have GH positive tumors. Tumor tissue exhibited high GH levels as measured by gel chromotography. However, EM did not classify the adenomas as typical somatotroph adenomas (89
). Three other patients presented with no clinical features of acromegaly and normal to slightly elevated random GH levels. While one adenoma was immunonegative for GH, the other 2 tumors were positive for GH with EM showing features consistent with sparsely granulated somatotroph adenomas. Cultured tumors released GH into the medium and appropriately responded to stimulatory and inhibitory substances. GH mRNA was detected in all 3 adenomas by in situ hybridization (30
In a cohort of 17 silent somatotroph adenomas, one group had mildly elevated GH (n=4) and the second group had GH levels below 5 mcg/L (n=13). Immunocytochemistry confirmed tumoral GH secretion in all adenomas while five cases had intratumoral GH elevations, in vitro
culture, and/or ISH. In the 1st
group, the tumors were small, well differentiated somatotroph adenomas and were felt to be an early presentation of acromegaly while in group 2, the tumors were larger and more poorly differentiated, thereby secreting lower GH (90
In patients with silent acromegaly who presented with normal preoperative IGF-1 but nonsuppressed GH levels on OGTT, these adenomas were GH positive on IHC with EM features similar to sparsely granulated somatotroph adenomas. Additionally, these adenomas had positive signal for GH mRNA as assessed by in situ hybridization. Reverse hemolytic plaque assay confirmed that fewer cells secreted GH and produced less GH compared to clinically active somatotroph adenomas. Postoperatively, GH dynamics normalized. Though no correlation was found between adenoma type and serum GH and IGF-1 levels or signs/symptoms of acromegaly, the amount of GH secretion per tumor volume was lower in sparsely granulated subtypes (91
1.1% of 620 pituitary adenomas met the following criteria for silent somatotroph adenomas as defined by a preoperative clinical presentation of nonfunctioning adenoma with either (a) positive staining for GH on pathologic specimen, (b) positive GH mRNA by in situ hybridization but negative GH immunostaining, or (c) somatotroph morphology on electron microscopy. Clinical symptoms included headache and visual disturbances, and all patients had macroadenomas with suprasellar extension. Serum GH was mildly elevated in 2/7 cases while normal in the remainder. IGF-1 levels were normal in 3/7 that were measured, and 3 patients had hyperprolactinemia. Morphological features of SSAs demonstrated that these were chromophobic adenomas with some nuclear atypia, occasional mitotic figures, Ki-67 <1%, and no p53. Immunopositivity for GH was <25% compared to the acromegaly cases. GH mRNA was detected on ISH in all SSAs, with higher signal in densely granulated compared to sparsely granulated types. Five of seven SSAs recurred after resection. The group concluded that SSAs presented at younger ages with larger, more invasive adenomas than classic acromegaly and tend to recur more often (92
In a retrospective review of 100 consecutive cases, 24 somatotroph adenomas were subclassified as classic somatotroph adenomas (n=11) (clinical and biochemical acromegaly with GH positive adenomas), subtle acromegaly (n=4) (mild clinical symptoms, elevated IGF-1, and GH positivity), clinically silent acromegaly (n=8) (no acromegaly features, elevated IGF-1, and GH positive staining), and silent somatotroph adenoma (n=1) (no features, normal IGF-1 but GH positive staining). There was an even distribution of gender and age in clinically silent somatotrophs. All adenomas were macroadenomas and expressed GH in variable patterns on IHC. One adenoma was densely granulated and the others either sparsely or intermediate granulated. The silent somatotroph adenoma was intermediately granulated. All 8 patients showed a decrease in serum IGF-1 levels after resection of the adenomas, or on treatment with somatostatin analogues (93
Despite normal preoperative GH dynamics, some patients with silent acromegaly manifest abnormal GH dynamics after surgery. Two patients with GH positive tumors had normal IGF-1 levels pre-operatively possibly due to oral contraceptive use. After surgery, persistent biochemically active disease was unmasked (94
Clinical presentation of silent acromegaly is similar to nonfunctioning adenomas. However, as up to 40% of somatotroph adenomas may co-secrete PRL, patients may indeed present with symptoms secondary to hyperprolactinemia. In a series of 17 somatotroph adenomas without acromegaly features, 13 presented with amenorrhea and/or galactorrhea associated with elevated PRL levels (90
In 3 silent somatotroph adenomas, 2/3 of premenopausal females presented with amenorrhea and mild hyperprolactinemia, normal IGF-1 levels, and normal GH suppression on OGTT. The resected adenomas were chromophobic, acidophilic, and immunopositive for PRL and GH. In situ hybridization confirmed positive signal for GH mRNA, PRL mRNA, and Pit-1 mRNA. These patients were also noted to have paradoxical rises in serum GH on TRH and GnRH provocation tests. Postoperatively, these paradoxical responses resolved and menses resumed (95
Knowledge of positive GH immunostaining of silent somatotroph adenomas may change management of persistent disease after surgery by providing options to treat these patients with somatostatin analogues and/or dopamine agonists.
- Clinically silent functioning adenomas may present with hyperfunctioning endocrine profiles even in asymptomatic patients
- Preoperative testing of pituitary incidentalomas should include measurement of PRL and IGF-1 levels
- Comprehensive immunostaining of silent adenomas for cell-specific markers may help guide medical management after surgical resection
- Further studies on postoperative clinical course of silent adenomas
- Trials are needed to determine if silent functioning adenomas respond to medical therapies similarly to their functioning counterparts
Silent functioning adenomas are relatively common. They are diagnosed as clinically nonfunctioning adenomas on preoperative assessment. Often they present as pituitary incidentalomas. Some patients may manifest with mild hypersecretion on biochemical testing despite the lack of symptoms. Pathologic examination of resected tissue confirms the diagnosis of silent functioning adenomas and determines the final classification of these tumors as silent subtype 3, prolactinomas, gonadotroph adenomas, silent corticotroph adenomas, or silent somatotroph adenomas. Each class of silent adenomas has a unique diagnostic and ultrastructural profile, reflective of the cell of origin (). Knowledge of the subtypes may help determine postoperative surveillance as some of these adenomas exhibit more aggressive growth. Medical therapy used in functioning counterparts may be a potential avenue of treatment for silent adenomas, though this approach has yet to be studied in future trials.
Features of silent pituitary adenomas