Are the silent corticotroph adenomas a new category of ACTH-producing tumours?

Abstract

A minority of corticotroph adenomas are not related to Cushing's disease so that they have been defined “silent corticotropinomas“. Silent ACTH adenomas present with symptoms of mass effect, they are often haemorrhagic and show more aggressive behaviour than the conventional pituitary adenomas. Likely deriving for the POMC cells of the pars intermedia, silent corticotroph adenomas have been considered a separate entity within the spectrum of ACTH-producing adenohypophysial tumours. We studied 20 patients with non-functioning ACTH adenoma operated over the period January 1992– April 2003 at the Bellaria Hospital, Bologna, Italy. All had normal free urinary 24 hr cortisol level. Nine were female. Their age ranged from 34 to 77 years (mean, 52 years). Despite normal urinary cortisol, serum ACTH was markedly elevated in two patients (42 and 89.6 pmol/L, respectively; normal, 2–11) and slightly increased in 3. Radiologically, all lesions were macroadenoma and 12 were invasive. Cystic component was present in 5. Pathological examination revealed 8 adenomas type I, 3 of which were Crooke's cell adenomas, and 12 lesions of type II. One tumour was atypical in that it showed mitoses, MIB-1 labelling index higher that 3% and p53 nuclear over-expression. Pseudopapillary architecture due to poor cell-to-cell cohesion predominated in the majority of lesions. After a follow-up ranging from 12 to 136 months (mean, 54 months), three patients experience local recurrence but none died of disease. Silent corticotroph adenomas were compared with Cushing's related adenomas, particularly with the 13 macroadenomas operated in the same period. In these latter lesions, symptoms of mass effect were less common than in the silent tumours. Percentage of invasion was similar in the two groups whereas cystic change was more common in silent corticotropinomas. Persistence/recurrence rate was as high as noted in the silent adenoma groups. Pseudopapillary pattern was also a common finding on Cushing-related macroadenomas. Finally, we studied 5 silent corticotroph carcinomas. Patient's age ranged from 26 to 58 years. They had normal serum and free urinary cortisol as well as normal serum ACTH. All tumours were invasive macroadenoma. Histologically, 3 primary tumours were indistinguishable from conventional silent ACTH adenomas and 2 had features of atypical adenoma. All patients experienced local recurrence and, after a follow-up ranging form 2 to 23 years, all had metastases, 3 outside the central nervous system. Four patients died of disseminated disease and 1 of myocardial infarction. No patient developed Cushing's disease. Many of their clinicopathological features were similar to those of previously reported Cushing's disease related carcinomas. Our results suggested that some clinical and pathological features of silent corticotroph adenomas and carcinomas overlap with those of Cushing-related lesions. Therefore, silent adenomas are more likely part of the continuum of ACTH-producing tumours than a separate entity.