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Goals of Therapy
Acromegaly is a severe disease with increased rates of morbidity and mortality if not treated appropriately. Epidemiological studies estimate the excess mortality rate as approximately 2-fold, attributed primarily to cardiovascular, cerebrovascular, and respiratory disease. A potential confounding mortality factor in patients appears to be the presence of hypopituitarism, mainly adrenocorticotropic hormone deficiency. Adverse mortality outcomes have been linked to both GH and IGF-I levels.
Earlier studies suggested that GH levels < 10 ng/ml, and later ≤ 5 ng/ml, were adequate for control. Based on newer data, these values are now associated with mortality rates above those in the normal population. Growth hormone concentrations < 2.5, < 2, or < 1 ng/ml are associated with mortality rates comparable with those in the normal population. Five epidemiological studies investigated IGF-I as a predictor of increased mortality, although not everyone agrees that IGF-I is predictive of death. Swearingen et al., in 1998, were the first to suggest that a normal IGF-I level in patients with acromegaly predicted a normal expected mortality rate.
A comprehensive treatment strategy should alleviate pituitary tumor effects, normalize GH and IGF-I hypersecretion, improve associated comorbidities, and reverse the increase in mortality risk, all while preserving normal pituitary function (Table 1).
Surgery remains the first treatment of choice for patients with acromegaly, given 2 caveats: the need for an experienced surgeon and the tumor's appearance on MR imaging. In the hands of an inexperienced surgeon, the results of surgery can be quite disappointing. If an experienced surgeon is not available, medical therapy can be offered to the patient as first-line therapy. If the tumor has invaded the cavernous sinus or for other reasons is not completely resectable, medical therapy can be offered as a first-line treatment or in addition to surgery.
Surgical treatment also offers a significant advantage: a final pathological diagnosis. The pathological distinction between different types of GH-secreting tumors can impact the response to therapy as well as prognosis making; therefore, accurate pathological classification is important. Growth hormone–producing tumors range from well-demarcated slowly growing microadenomas to large, more rapidly growing macroadenomas. They vary in morphology and can be separated into several different types: tumors that secrete only 1 GH (monohormonal somatotroph adenomas), tumors that secrete GH and prolactin (bihormonal mammosomatotroph adenomas), and silent GH-secreting adenomas (express GH in the tumor without GH hypersecretion or acromegaly). Monohormonal somatotroph adenomas represent the majority of these lesions (90%) and can be further classified as densely granulated or sparsely granulated. Densely granulated tumors are composed of well-differentiated somatotrophs with positive staining for GH when using an immunoperoxidase technique and an electron microscope appearance similar to nontumoral cells. They have a better prognosis overall with slower growth rates, are easier to remove, and recur less frequently after surgery. Sparsely granulated tumors consist of less differentiated cells with positive GH staining but electron microscope characteristics different from normal cells. The sparsely granulated type is prevalent in younger patients and appears to grow more rapidly.
Pituitary GH-secreting cells have 5 SSTRs: SSTR-1 to SSTR-5, with receptors SSTR-2 and SSTR-5 predominant (90%–95%) in GH-secreting tumors.
The density and expression of SSTRs also have potential clinical significance as clinical predictors of response to pharmacotherapy with SSAs. Somatostatin analog resistance is observed in about one-third of tumors and could be related to density reduction or different receptor expression. In 1 study, for example, both SSTR-1 and SSTR-2 had higher expression levels in patients with normalized GH and IGF-I after treatment with SSAs, and SSTR-3 expression correlated with tumor shrinkage as well. Selecting which SSA to use may, in the future, depend on SSTR analysis of the surgical specimen.
All of the above emphasizes the importance of accurate morphological classification using immunohistochemistry and/or electron microscopy, which in our opinion should be performed on all pituitary pathology specimens.
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