Summary
objectives Anecdotal reports have suggested that silent corticotroph tumours behave in an aggressive fashion; however, clear comparative data with other non-functioning adenomas (NFAs) are lacking. The aims of the study were, first, to review the natural history of those non-functioning pituitary adenomas with positive immunoreactivity for ACTH and secondly, to determine whether this subgroup behave more aggressively than ACTH immunonegative NFAs by means of comparison with existing departmental data.

methods and patients Twenty-eight patients (16 men, mean age 51·3 years) who underwent transsphenoidal surgery in Oxford between 1975 and 2001 for clinically non-functioning adenomas where the subsequent immunostaining was positive for ACTH were identified from the patient database. All patients with silent corticotroph tumours who presented during this time period have been included in the analysis; three of the patients have subsequently died but none have been lost to follow-up. The mean follow-up period was 7·4 years (range 0·5–26·9 years) and the results were compared with departmental data for NFAs which were immunonegative for ACTH. None of the patients had clinical evidence of Cushing's syndrome. Tumour invasiveness was classified according to the modified Hardy criteria (Grade 1 = microadenoma (  1 cm) ± suprasellar extension, Grade 3 = local invasion with bony destruction and tumour in sphenoid/cavernous sinus and Grade 4 = central nervous sytem (CNS) spread or extracranial spread, i.e. metastatic). Tumour recurrence was defined as an increase in tumour size compared with the first postoperative scan which was used as a baseline. Visual field defects were documented in 79% of the 28 patients at presentation compared to 69% in the non-functioning population as a whole (P = 0·3). The preoperative imaging in the silent corticotroph group (13 CT, 14 MRI and one air encephalogram) revealed 68% Grade 2 and 32% Grade 3 adenomas.

results The recurrence rate in the ACTH immunopositive tumours was 32% at a mean of 5·8 years (range 1–16 years) which was not significantly different from the 33% recurrence rate previously recorded in the ACTH immunonegative tumours (P = 0·9). Two of the patients with silent corticotroph adenomas have suffered multiple recurrences; one patient has had three operations and two courses of radiotherapy for two episodes of recurrence and one patient has had four operations, two courses of radiotherapy and gamma knife therapy after three recurrences in total. In contrast, no patient with an ACTH immunonegative tumour has required more than one course of treatment for tumour regrowth.

conclusions This is the first single-centre comparative study of a series of clinically silent ACTH immunopositive tumours and has demonstrated that although they do not recur more often than ACTH immunonegative tumours, when they do regrow they show a more aggressive course. The practical implication of this is that there is no evidence for different postoperative imaging and radiotherapy protocols for ACTH immunopositive and immunonegative NFAs at initial presentation. However, if regrowth of a silent corticotroph tumour does occur then very careful monitoring is essential, after further treatment.

Non-functioning pituitary adenomas with positive immunoreactivity for ACTH behave more aggressively than ACTH immunonegative tumours but do not recur more frequently.

Silent corticotroph adenomas (SCAs) are clinically silent and non-secreting, but exhibit positive adrenocorticotropic hormone (ACTH) immunostaining. We characterized a single center cohort of SCA patients, compared the SCAs to silent gonadotroph adenomas (SGAs), identified predictors of recurrence, and reviewed and compared the cohort to previously published SCAs cases. Retrospective review of SCA and SGA surgically resected patients over 10 years and 6 years, respectively. Definitions; SCA—no clinical or biochemical evidence of Cushing’s syndrome and ACTH positive immunostaining, and SGA—steroidogenic factor (SF-1) positive immunostaining. A systematic literature search was undertaken using Pubmed and Scopus. Review revealed 814 pituitary surgeries, 39 (4.8%) were SCAs. Mean follow-up was 6.4 years (range 0.5–23.8 years). Pre-operative magnetic resonance imaging demonstrated sphenoid and/or cavernous sinus invasion in 44%, 33% were > 50% cystic, and 28% had high ACTH levels pre-operatively. Compared to SGAs (n = 70), SCAs were of similar size and invasiveness (2.5 vs. 2.9 cm, p = 0.2; 44 vs. 41%, p = 0.8, respectively), but recurrence rate was higher (36 vs. 10%, p = 0.001) and more patients received radiation therapy (18 vs. 3%, p = 0.006). Less cystic tumors (0 vs. 50%, p < 0.001) and higher pre-operative ACTH levels (54 vs. 28 pg/ml, p = 0.04) were predictors of recurrence for SCAs. This review is unique; a strict definition of SCA was used, and single center SCAs were compared with SGAs and with SCAs literature reviewed cases. We show that SCAs are aggressive and identify predictors of recurrence. Accurate initial diagnosis, close imaging and biochemical follow up are warranted.

Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review

Background Silent pituitary adenomas are a subtype of adenomas characterized by positive immunoreactivity for one or more hormones classically secreted by normal pituitary cells but without clinical expression, although in some occasions enhanced or changed secretory activity can develop over time. Silent corticotroph adenomas are the classical example of this phenomenon. Patients and Methods A series of about 500 pituitary adenomas seen over a period of 20 years were screened for modification in hormonal secretion. Biochemical and immunohistochemical data were reviewed. Results Two cases were retrieved, one silent somatotroph adenoma and one thyrotroph adenoma, both without specific clinical features or biochemical abnormalities, which presented 20 years after initial surgery with evidence of acromegaly and hyperthyroidism, respectively. While the acromegaly was controlled by a combination of somatostatin analogs and growth hormone (GH) receptor antagonist therapy, neurosurgery was necessary to manage the thyrotroph adenoma. Immunohistochemical examination demonstrated an increase in the number of thyroid stimulating hormone (TSH)-immunoreactive cells compared to the first tissue. Apparently, the mechanisms responsible for the secretory modifications are different, being a change in secretory capacity in the silent somatotroph adenoma and a quantitative change in the silent thyrotroph adenoma. Conclusions These two cases, one somatotroph and one thyrotroph adenoma, are an illustration that clinically silent pituitary adenomas may in rare circumstances evolve over time and become active, as previously demonstrated in silent corticotroph adenomas.

Modification of hormonal secretion in clinically silent pituitary adenomas

A 49-yr-old woman with a large pituitary tumor leading to visual loss and galactorrhea-amenorrhea was submitted to transcranial pituitary surgery, when a clinically nonfunctioning pituitary adenoma was partially removed. Histopathology and immunohistochemistry confirmed the diagnosis of “non-secreting atypical adenoma”.

Cushing's disease arising from a clinically nonfunctioning pituitary adenoma.

18 – Pathology of the Pituitary and Sellar Region

Silent pituitary adenomas occur in 25–40% of all clinically apparent pituitary tumours. However, the subsequent development of florid Cushing's disease in a patient with a previous non-functioning tumour is extremely rare. We describe a 47 year-old woman presenting initially with a large, invasive and recurrent, non-functioning pituitary tumour. Histopathologic study of the initial tissue did not stain for any hormones. Six years after the initial presentation, she manifested florid ACTH dependent Cushing's syndrome. A recurrent invasive pituitary macroadenoma necessitated a third transphenoidal surgery. The resected specimen, in this instance, revealed positive staining for ACTH, FSH, prolactin, and growth hormone on immunocytochemistry. An incomplete response to surgical, radiation and medical therapy necessitated a bilateral adrenalectomy to control the hypercortisolism, which resulted in remarkable clinical improvement. We also review five previous case reports from the revision literature of similar transformations from non-secreting pituitary adenomas to Cushing's disease. This subset of patients may represent yet another entity in the widening spectrum of Cushing's syndrome.

Metamorphosis of a non-functioning pituitary adenoma to Cushing's disease.

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Metamorphosis of a non-functioning pituitary adenoma to Cushing's disease.