Distinct clonal composition of primary and metastatic adrencorticotrophic hormone-producing pituitary carcinoma

The pathogenetic mechanisms underlying pituitary tumorigenesis are largely unknown. Previous reports have suggested that aggressive pituitary adenomas and/or carcinomas may be associated with genetic alterations that are dist inct from those responsible for the more common and less aggressive pituita ry adenomas. Here, we describe the clonal composition of a pituitary carcin oma, its recurrence and its metastasis. The samples studied were from a 48- year-old woman who presented with recurrent Cushing's syndrome. During the 8-year course of her disease, she had an ACTH-producing pituitary carcinoma requiring two transsphenoidal procedures and resection of a metastatic cer vical lymph node. Her disease remained active despite surgical resection, e xternal beam irradiation and medical treatment with ketoconazole. Ultimatel y, bilateral adrenalectomy was performed to control the hypercortisolism. M orphological and immunohistochemical studies revealed that the primary and recurrent pituitary tumours and the metastatic lesion were an endocrine tum our with ACTH and growth hormone immunoreactivity. Primary, recurrent and m etastatic tumour DNAs were analysed for X-chromosome inactivation and loss of heterozygosity (LOH) at several microsatellite loci on chromosomes 9,10, 11, 13 and 22. All three lesions were monoclonal in composition as suggest ed by the pattern of X chromosome inactivation of the PGK-1 allele. Moreove r, the primary, recurrent and metastatic lesions demonstrated LOH at the mi crosatellite allelic markers PYGM and D10S217. In contrast, however, the me tastatic lesion showed a loss-to-retention pattern at two distinct loci (IF NA and D22S156) compared to the primary and recurrent pituitary tumours. Th ese findings, while consistent with a clonal composition of the primary and metastatic pituitary lesions, show each clone to be distinct. This is the first description of a metastatic pituitary carcinoma with a distinct clona l composition from its primary source.