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Clinical and genetic changes in a case of a Cushing's carcinoma

Silent corticotroph adenomas present as clinically nonfunctioning pituitary tumours which show positive immunoreactivity to ACTH. Occasionally, these tumours subsequently become clinically active with the development of Cushing’s disease. Bates and co-workers (1995) present a case report of a patient who presented initially with a large invasive clinically non-functioning pituitary adenoma. The tumour was removed, but recurred 2 years later. Further surgery, followed by radiotherapy, was carried out after which the patient developed GH, gonadotrophin and TSH deficiency. Unusually, the patient did not have concomitant ACTH deficiency, and 4 years later he developed Cushing’s disease. Further debulking of the tumour was required but 6 months later MRI scan demonstrated massive tumour recurrence with the development of meningeal deposits. Despite further radiotherapy to the primary tumour and metastases, the patient died. The tumour and meningeal metastases immunostained for ACTH and retrospective immunostaining of tumour tissue at presentation was also positive for ACTH, confirming the diagnosis of a silent corticotroph adenoma. The questions that arise are first, what triggered the change in tumour function from a biologically inactive to an active corticotroph adenoma and secondly, what triggered the change in tumour behaviour from an apparently benign but aggressive pituitary adenoma to a carcinoma? Although the authors do not give any histological details of tumour morphology at the different stages of the disease, the tumour does appear to have undergone a change in growth characteristics, becoming progressively more aggressive and ultimately metastasizing. This is an uncommon but well recognized scenario both in corticotroph adenomas and also in other types of pituitary tumours. Multiple oncogenic mutations of autosomal dominant oncogenes, and, with later tumour development, loss of heterozygosity (LOH) of tumour suppressor genes, is now a well recognized occurrence in thyroid neoplasia (Fagin, 1992). It is possible that similar additive genetic changes occur with the development of pituitary tumours and with subsequent changes in their growth characteristics. At present, however, we have little understanding of the oncogenic mechanisms occurring in pituitary neoplasia. The best characterized genetic change in pituitary tumours is the gsp oncogene, which occurs in 35-40% of somatotroph adenomas (Landis et al., 1990). There have been few reports of multiple presumed oncogenic mutations in pituitary tumours. Thakker et ul. (1993) have described a non-MEN-I somatotrophinoma which harboured both a gsp mutation and LOH at the MEN-I locus, llq13. Williamson et al. (1994) have recently described two large, invasive, clinically non-functioning pituitary adenomas which both demonstrated what at first sight appear to be paradoxical gsp and gip mutations. Bystrom et ul. (1990) have described an aggressive corticotroph adenoma with multiple allelic deletions, and a previous report from Clayton’s group has described the presence of multiple allelic deletions in two other pituitary tumours, one of which was a recurrent acidophil stem cell tumour (Boggdd et ui. 1994). Analysis of the tumour in this case report demonstrated LOH at lp, 3p, 10q26 and 22q12. All these deletions were present in the tumour tissue at initial presentation and in the metastases. Interestingly, there was no LOH for Rb, which has been shown to be present in some pituitary carcinomas. Similarly, LOH for p53 was absent, but the authors did describe cytoplasmic staining for p53 in tumour tissue 2 years after initial presentation. This was the only demonstrable event which preceded the change of tumour phenotype from a clinically non-functioning to a functioning ACTH secreting tumour. The cytoplasmic staining of p53 has been thought to indicate the presence of abnormal mutant p53 protein, although Levy et al. (1994) have recently reported that five pituitary adenomas demonstrating immunocytochemical staining for p53 did not have mutations in exons 7 and 8, where the majority of genetic changes are known to occur. The significance of this finding is therefore unclear. The fact that multiple allelic deletions were found to be present in the tumour tissue at initial presentation does not, as the authors rightly point out, exclude the possibility of a stepwise progression in genetic mutations during tumour development up to the point of presentation, at which time the tumour was already an aggressive invasive macroadenoma. What is the significance of these allelic deletions? Are they merely epiphenomena associated with cellular dedifferentiation, or are they true oncogenic mutations, releasing the cells from as yet unidentified tumour suppressor gene control?