Aggressive Pituitary Tumors

Agressive pituitary adenomas are important in clinical practice. Analysis of their molecular mechanisms and genetic underpinnings also provides important lessons relevant to the fundamental biology of pituitary neoplasia. All too often, however, the proliferative and invasive features of pituitary tumors are downplayed, and such tumors are assumed, even by endocrinologists and oncologists (who should know better), to be benign, slow to enlarge, easy to treat with drugs or transsphenoidal microsurgery, and harmful mainly in the perturbations of hormonal homeostasis that they induce. Patients, on the other hand, often fear rapid growth, metastasis, and worse. As usual, the truth lies somewhere between these two extremes. "Invasive" Does Not Necessarily Mean "Aggressive" As Blevins et al show in their systematic, thorough review of the different subtypes of pituitary tumors, invasion is a frequent event. It usually occurs at the interface with the dura of the sellar floor or medial wall of the adjacent cavernous sinus, which form the first barriers to egress from the sella turcica. The authors focus on this attribute, rather than on rapid growth, which is less common by far but more clinically significant. The most frequently cited study, by Selman et al, found microscopic invasion of the dura in 85% of patients, with a slightly lower incidence in individuals with small tumors and a slightly higher one in those with larger tumors.[1] Perhaps this number is actually an underestimate, as it comes from operative biopsies, which, practically speaking, can be done only on the portion of the sellar floor exposed at surgery, not the entire lining of the pituitary fossa. The problem in extrapolating from these data to the clinical arena is that the majority of such "invasive" tumors are histologically benign and actually quite sluggish in their growth. Even those that grossly invade the cavernous sinus and skull base, as judged by modern scanning techniques, need not enlarge quickly, do not generally invade the brain or cranial nerves, and (usually) offer no external clinical clues that predict their identity as invasive tumors. We really have no defined criteria for determining what denotes clinically significant invasion, or for predicting which tumors will grow quickly. What Constitutes a Truly Aggressive Pituitary Tumor? What, then, constitutes a truly aggressive pituitary tumor? And which tumors should be called pituitary carcinomas? Much confusion and argument are evident in the literature through the late 1980s, with the most cogent statement being that put forward over 40 years ago by Sir Geoffrey Jefferson.[2] He suggested that although rapid progression, an invasive pattern of growth, and an anaplastic histology were helpful features, metastasis should be required for the diagnosis of a pituitary carcinoma. The current consensus in the pathologic literature holds that spread by either blood (extraneurally) or cerebrospinal fluid (within the central nervous system) qualifies a pituitary tumor as a carcinoma. However, such malignant tumors may exhibit a bland histology indistinguishable from that of their benign counterparts, and may follow a variable clinical course that may allow long survival. Indeed, most "aggressive" pituitary adenomas do not metastasize: Only 100 such tumors have been reported.[3-5] This number is somewhat higher than the figure quoted by Blevins et al but still low enough to make such behavior distinctly unusual. Thus, pinning down the elusive sine qua non, the defining element of such tumors, demands something beyond the clinical criteria applied to other neoplasms. Molecular Correlates of Aggressive Pituitary Tumor Behavior In an effort to find that defining element, Blevins et al review some of the molecular correlates of