Introduction

The pituitary gland is an extremely well-defined structure that occupies a central place both anatomically and physiologically in the chain of neuroendocrine command from the hypothalamus and higher brain centers to the peripheral endocrine organs. Isolated as it is from ultraviolet radiation and from direct contact with ingested and inhaled irritants and carcinogens, it is remarkable that occult pituitary adenomas can be disclosed by imaging and histologic studies in as many as 11% of people at autopsy (7) (Fig. 1). Overt pituitary adenoma formation presenting with symptoms and signs of space occupation, hypopituitarism, and/or one of the classic syndromes of hormone excess is fortunately relatively rare, and true pituitary carcinoma characterized by metastatic spread has been described fewer than 100 times (2).

From: Management of Pituitary Tumors: The Clinician's Practical Guide, Second Edition Edited by: M. P. Powell, S. L. Lightman, and E. R. Laws, Jr. © Humana Press Inc., Totowa, NJ

Fig. 1. Coronal MRI reconstructions, 3 mm apart, through the pituitary of a patient with an incidentally discovered, nonfunctional microadenoma.

Much of the literature that addresses the pathogenesis of pituitary adenomas centers on an examination of whether they are likely to arise after the acquisition of an intrinsic pituitary defect, such as chromosomal instability or point mutation, or whether an inappropriate quantity, combination, or pattern of exposure to growth factors from the hypothalamus or elsewhere acting on one or more genetically normal pituitary cells is to blame.

This chapter summarizes current understanding of the pathogenesis of pituitary adenomas. Its brevity is consistent with the fundamental reality that the pathogenesis of pituitary adenomas remains almost entirely obscure. The molecular defects that have been identified do not have the consistency, strength, and biologic plausibility to necessarily be pathogenic, and many of the mechanisms suggested are difficult to verify experimentally because of profound differences between the behavior of spontaneous pituitary adenomas in humans, which tend to have low levels of mitotic activity and in animal models, which tend to have relatively high levels.

ARE PITUITARY ADENOMAS TUMORS?

Currently, pituitary adenomas are a group of related conditions that require a combination of congenital or acquired intracellular abnormalities acting together with a permissive extrapituitary microenvironment to bring about the distinct pathologic processes of tumor induction and subsequent propagation. The temptation is to assume that pituitary adenomas are "true tumors"; in other words, the mechanisms responsible for neoplasia in most other organ systems are responsible for pituitary adenomas. For those who believe this scenario, if pituitary adenomas behave in an atypically benign fashion, the responsible mechanisms merely differ quantitatively rather than qualitatively from those seen in rapidly progressive malignancies.

An alternative opinion might be that in many cases pituitary adenomas are developmentally and behaviorally little different from, for example, thyroid nodules; however, by being more confined anatomically and by having a broader synthetic portfolio at the time of their departure into malignancy, pituitary adenomas appear as true tumors and require treatment as such. The distinction between the latter mechanism, which might be likened to "exuberant normality," and the former mechanism, "benign malignancy," is important because the molecular miscreants are likely to lurk in quite different places.

One of the most useful guides to help evaluate the legitimacy of the various pathogenic mechanisms is to consider how they correspond with the observed behavior ofpituitary adenomas. Clearly, if activation of a new powerful oncogene is adduced (3), studies investigating why a tumor harboring such a mutation should behave in such a benign fashion must immediately follow.

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