Pituitary adenomas are classified clinically into two main groups: clinically functioning adenomas and clinically nonfunctioning adenomas, according to whether an endocrine syndrome is present. Most adenomas are functioning tumors, which may produce prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH), or thyroid-stimulating hormone (TSH) [4]. However, about a third of all pituitary adenomas are unassociated with either clinical or biochemical evidence of hormone excess [5]. This group includes gonadotroph adenomas, which produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the less differentiated null-cell adenomas, and the silent adenomas. These clinically nonfunctioning adenomas commonly present with symptoms related to local mass effect, such as headaches, neurologic deficits in the cranial nerves (including visual field disturbances), and mild hyperprolactinemia due to pituitary stalk compression (the so-called stalk effect).

According to tumor size and gross anatomic features, adenomas are divided into microadenomas (tumors <1 cm in diameter) and macroadenomas (tumors ≥1 cm in diameter). Giant adenomas (tumors > 4 cm) are rare. Macroadenomas show an increased tendency toward suprasellar extension, gross invasion, and recurrence.

A number of attempts to histologically classify pituitary adenomas have been made over the years. The recommended World Health Organization (WHO) classification from 2004 [6], which is used by most laboratories, incorporates the clinical and radiological presentation of the tumor with its morphologic features, immunohistochemical profile, and ultrastructural appearance (Table 4.2). Pituitary adenomas are classified according to the hormone content of the tumor cells as assessed by immunohistochemical stains. The immunohistochemical classification provides significant information for clinical practice [4], but immunohistochemistry alone does not discriminate between a number of specific subtypes of tumors that have prognostic clinical significance. In these instances, analysis of the ultrastructure of adenomas is necessary [4].

The WHO classification employs updated lineage studies that result in new and appropriate clustering of a variety of tumor subtypes. This classification not only has changed our understanding of the pathogenesis of these tumors but also opens new avenues of pharmacological treatment, which may result in increasing levels of hormonal control. A few highlights of the WHO classification include the continuing evidence that morphological features, including ultrastructure, may correlate with aggressive tumor behavior, as seen in the sparsely granulated GH adenoma, the mammosomatotroph cell adenoma, the acidophilic stem cell adenoma, and the silent adenoma subtype III.

Perhaps the most controversial aspect of the WHO classification is the introduction of a grading system for pituitary endocrine tumors. These tumors are now categorized as typical pituitary adenoma (ICD code 8272/0), atypical pituitary adenoma (8272/1), and pituitary carcinoma (8272/3).

Most pituitary adenomas are typical, with bland histologic features, infrequent mitotic figures, and a Ki-67 proliferative index less than 3 %. The designation of atypical adenoma is reserved for tumors that show “atypical morphologic features suggestive of aggressive behavior such as invasive growth” [7]. Other features also seen in these tumors include elevated mitotic index, a Ki-67 labeling index greater than 3 %, and extensive nuclear staining for the p53 protein by immunohistochemistry [7]. Close follow-up of patients with atypical adenomas is recommended.

Pituitary carcinomas are very rare, comprising less than 1 % of all pituitary neoplasms [7–9]. By definition, pituitary carcinomas are characterized by demonstration of either craniospinal dissemination or systemic metastases [7]. The majority of cases are endocrinologically functioning tumors; the most common are PRL-secreting tumors, followed by ACTH-secreting tumors [8, 9]. Nonfunctioning carcinomas (about 15–20 % of cases) include gonadotroph, silent corticotroph, and rarely null-cell carcinomas [8, 9].

There are no morphologic criteria to distinguish locally aggressive or even markedly atypical adenomas from carcinomas when the tumor is confined to the sella turcica. Standard morphologic features associated with malignancy, including hypercellularity, nuclear and cellular pleomorphism, increased mitotic activity, necrosis, and dural or bony invasion, are commonly present but are not necessarily diagnostic of carcinoma. Ki-67 labeling indices are quite variable and show considerable overlap with ordinary pituitary adenomas, but they are often higher in metastatic deposits. Additionally, unlike pituitary adenomas, carcinomas appear to show overexpression of the p53 protein by immunohistochemistry [8].

Pituitary adenomas either grow expansively or invade adjacent structures. In the first case, the tumors are usually small, well demarcated, and restricted to the sella turcica. Invasive adenomas usually have a more rapid growth rate, spreading into neighboring tissues such as the sphenoid sinus, the cavernous sinus, and, in some cases, the brain [10].

The mechanisms of progression of pituitary adenomas to more aggressive, invasive tumors are not yet totally understood. A proliferative continuum from benign adenoma to invasive adenoma and carcinoma has not been demonstrated in the great majority of tumors. The propensity of pituitary adenomas to infiltrate locally and invade adjacent structures appears to be independent of histologic features of the tumors. Invasive adenomas do not necessarily show histologic features of tumor aggressiveness, including pleomorphism, nuclear atypia, and mitotic activity, as seen in atypical adenomas. Although both clinically functioning and nonfunctioning adenomas may present as invasive tumors, gross invasion appears to be more frequent in functioning tumors [10]. On the other hand, there is an apparent relationship between invasiveness and tumor size: macroadenomas have a higher frequency of invasion than microadenomas [10].