A Case of Cushing’s Disease Caused by Pituitary Adenoma Producing Adrenocorticotropic Hormone and Growth Hormone Concomitantly: Aberrant Expression of Transcription Factors NeuroD1 and Pit-1 as a Proposed Mechanism

Abstract

A 53-year-old Japanese woman was diagnosed with Cushing's disease caused by a adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma on the basis of clinical an imaging data. The surgically resected tumor tissue was investigated histopathologically using immunohistochemical analysis of pituitary hormones. Our study revealed that the adenoma expressed not only ACTH but growth hormone (GH) in the tumor cells. Furthermore, immunohistochemical double staining showed that some adenoma cells were positive for both ACTH and GH. In situ hybridization for GH mRNA revealed that the adenoma cells produced GH as opposed to simply storing it. Although many pituitary adenomas produce multiple pituitary hormones, pituitary adenoma producing both ACTH and GH in the same adenoma cells, such as seen in this case, is extremely rare. To elucidate the molecular mechanism involved, we investigated the expression of transcription factors NeuroD1 and Pit-1 and found that both transcription factors were expressed in many tumor cells. This case report describes a very rare case of pituitary adenoma that produced both ACTH and GH. We propose a hitherto undescribed translineage expression of transcription factors as the basic mechanism of this unique functional differentiation.

A somatotropin-producing pituitary adenoma with an isolated adrenocorticotropin-producing pituitary adenoma in a female patient with acromegaly, subclinical Cushing’s disease and a left adrenal tumor

“…A conjunction of two pituitary tumors may imply common genetic and molecular mechanisms of tumorigenesis. Tahara et al reported that pituitary transcription factors such as NeuroD1 and Pit-1 were aberrantly expressed in pituitary adenomas secreting ACTH and GH concomitantly [9]. The expression patterns of pituitary transcriptional factors may reveal the origin and development of tumor cells, and future studies should examine this possibility.…”

“…Although several combinations of hormonally-functioning double pituitary adenomas have been reported [4][5][6][7][15][16][17][18][19][20][21][22][23][24][25][26][27][28], the coexistence of acromegaly and pituitary Cushing's disease is rare [3,[8][9][10][11] (Table 4). Although our case resembles previous cases in terms of the immunohistochemical staining pattern, ours differs in the lack of Cushingoid features (i.e.…”

A Case of Acromegaly Associated with Subclinical Cushing's Disease

“…Since either immunohistochemical study using double staining, electron microscopic study, or clonal analysis was not performed in this case, it remains unknown whether GH, PRL, and ACTH are synthesized in the same or different cells, and whether the tumor cells are monoclonal or polyclonal. It has been reported that two transcription factors, NeuroD1 and Pit-1, are aberrantly co-expressed in the same pituitary tumor cells with ACTH and GH production, respectively [9], suggesting their potential roles in the differentiation into ACTH-and GH-producing cells. Thus, such translineage co-expression of transcription factors (NeuroD1, Pit-1) may be responsible for the multihormone synthesis as in the present case.…”

ACTH response to desmopressin in a patient with acromegaly; Expression of corticotropin-releasing factor, urocortins and vasopressin V1b receptor in GH-producing pituitary adenoma

“…Therefore, it might be considered that GH and CRF family neuropeptides were produced concomitantly from the same cells although the double stains for GH and CRF family peptides were not examined. Tahara et al reported a case in which ACTH and GH were concomitantly produced from the pituitary adenoma [24]. They showed the aberrant expression of transcription factors NeuroD1 and Pit-1 by in situ hybridization, and proposed it for the concomitant production of ACTH and GH.…”