The pituitary in gigantism

To compare the pituitary pathology of gigantism to that of acromegaly, 19 surgically resected lesions were studied from 10 males and 9 females, ages 13-49 (mean, 19 yr) with excessive height (≥95th percentile), onset of disease prior to puberty, elevated growth hormone (GH) levels despite glucose suppression, and a pathologically confirmed GH-producing pituitary mass. One patient had MEN-I. The lesions included 18 adenomas and 1 case of pure hyperplasia. The median, mean, and range of serum GH and prolactin (PRL) levels were 64, 235, 5-1000 ng/mL and 47, 146, 29-770 ng/mL, respectively. Of the 8 adenoma specimens accompanied by nontumoral pituitary (i.e., tissue wherein the presence of hyperplasia was assessable), 3 (37%) demonstrated both. Of the 18 tumors, 78% were macroadenomas and 22% were grossly invasive; their immunophenotypes included GH (5%), GH and PRL (19%), and GH-PRL and a glycoprotein hormone, usually TSH and/or α-subunit (76%). Of the 10 adenoma-containing lesions subject to electron microscopy (EM), 2 consisted of GH cells alone; 2 of mammosomatotroph (MS) cells alone; 1 of GH and MS cells; 1 of GH and PRL cells; 2 of GH, PRL, and MS cells; 1 of GH, PRL, and glycoprotein cells; and 1 was a subtype 3 adenoma. Ultrastructurally, GH cells and/or MS cells predominated in these lesions. Immuno-EM of one GH and PRL cell and of one GH-PRL-MS tumor showed GH and PRL to be present not only in single cells but within the same granules. Nine of 12 adenoma-associated lesions subject to combined in situ hybridization (ISH) and immunostaining showed double labeling for PRL (or GH) mRNA and for GH (or PRL), respectively, features indicating MS differentiation. In the 4 lesions exhibiting hyperplasia, either alone (1) or in association with adenoma (3), EM showed MS cells in 3, and immuno-EM as well as combined immunohistochemistry and ISH showed double labeling for GH and PRL in both of the 2 cases studied. In summary, although in terms of their tinctorial characteristics and tumor size, the lesions of giants resemble those of acromegalics, those of the former are less often invasive and glycoprotein hormone containing, and more often contain ultrastructurally distinctive MS cells. The high frequency of adenoma with hyperplasia (37%) and the occurrence of hyperplasia alone (6%) is of particular notice since this finding is rare in patients with acromegaly. Hyperplasia is, however, seen in ectopic GH-releasing hormone production and the McCune-Albright syndrome. We conclude that the presence of MS is not rare in the pituitary lesions of patients with gigantism. Their presence may be a reflection of either hypothalamic dysfunction or of an intrinsic abnormality of pituitary cells.