Cellular Classification of Pituitary Tumors
Pituitary adenomas can be classified according to staining affinities of the cell cytoplasm, size, endocrine activity, histologic characteristics, hormone production and contents, ultrastructural features, granularity of the cell cytoplasm, cellular composition, cytogenesis, and growth pattern. Recent classifications, however, omit criteria based on tinctorial stains (i.e., acidophilic, basophilic, and chromophobic) because of the poor correlation between staining affinities of the cell cytoplasm and other pathological features of pituitary tumors, such as the type of hormone produced and cellular derivation.[1,2]
A unifying pituitary adenoma classification incorporates the histological, immunocytochemical, and electron microscopic studies of the tumor cells, and stresses the importance of hormone production, cellular composition, and cytogenesis. This classification emphasizes the structure-function relationship and attempts to correlate morphologic features with secretory activity.
Pituitary adenomas may be classified based on:
- An anatomical approach, which classifies pituitary tumors by size based on radiological findings. Tumors are divided into microadenomas (i.e., the greatest diameter is <10 mm) and macroadenomas (i.e., the greatest diameter is ≥I0 mm). Most pituitary adenomas are microadenomas. Historically, the most widely used radioanatomical classification was based primarily on a neuroradiological examination including skull x-rays, pneumoencephalography, polytomography, and carotid angiography  and subsequently validated by the application of more accurate computed tomography (CT) and magnetic resonance imaging (MRI).
An MRI scan is now considered the imaging modality of choice for the diagnosis of pituitary disorders because of its multiplanar capability and good soft tissue contrast enhancement. Sagittal T1-weighted images, clearly displaying the anterior and posterior lobes and the stalk on the same plane, and coronal images, displaying the relation between the pituitary and cavernous sinuses, are optimal for identifying a pituitary adenoma. A 3-mm thin slice typically is used to obtain optimal resolution. A computed tomography (CT) scan may also be a useful diagnostic tool with coronal scans providing the optimal view; however, CT scans appear to be less sensitive than MRI scans in this application. For each imaging technique, a focal hypointensity within the pituitary gland is considered abnormal and suggestive of an adenoma. An MRI scan is also the best diagnostic imaging choice for pituitary carcinomas; metastases may be found in the cerebral lobes, cerebellum, spinal cord, leptomeninges, and subarachnoid space.
This radioanatomical classification places adenomas into 1 of 4 grades (I–IV). (Refer to the Stage Information For Pituitary Tumors section of this summary for more information.) The grades are as follows:
- Stage I are microadenomas (<1 cm) without sella expansion.
- Stage II are macroadenomas (≥1 cm) and may extend above the sella.
- Stage III are macroadenomas with enlargement and invasion of the floor or suprasellar extension.
- Stage IV is destruction of the sella.
- Histological criteria, which use:
- Immunohistological characterization of the tumors in terms of hormone production. Immunocytochemical staining for pituitary hormones generally correlates with hormone serum levels. Twenty percent of pituitary adenomas have no readily identifiable hormone production.
- Ultrastructural criteria, which can confirm that nonfunctional lesions are of pituitary origin and characterize the cytological differentiation of tumor cells in terms of anterior pituitary cell types.
- Functional criteria, which are used to define tumors in terms of their endocrine activity. Clinical endocrinologists often use the functional classification of pituitary adenomas and define these tumors based on their hormonal activity in vivo. A retrospective review of the pituitary adenoma literature indicates that prolactinomas are by far the most common form of pituitary adenoma as determined by immunohistochemical criteria; tumors secreting adrenocorticotropic hormone (ACTH), growth hormone (GH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) follow in decreasing frequency.[3,10] Functionally inactive pituitary adenomas, however, comprise approximately 30% to 35% of the pituitary tumors in most series and are the most common type of macroadenoma.
Using functional criteria, pituitary adenomas can be characterized as:
- Prolactin (PRL)-producing, also known as lactotroph, adenomas causing hyperprolactinemia and its clinical sequelae.
- ACTH-producing, also known as corticotroph, adenomas associated with Cushing or Nelson syndromes.
- GH-producing, also known as somatotroph, adenomas associated with acromegaly and/or gigantism.
- Rare thyrotropin TSH-producing, also known as thyrotroph, tumors.
- The large group of clinically nonfunctioning (i.e., the endocrine-inactive) adenomas. This group is comprised predominantly of gonadotroph adenomas. Gonadotroph adenomas synthesize follicle-stimulating hormone-(FSH) and/or LH, or the alpha or beta subunits of these heterodimers. They are usually detected incidentally or because of the presence of neurologic symptoms. Gonadotroph adenomas are inefficient secretors of the hormones they produce, so they rarely result in a clinically recognizable hormonal hypersecretion syndrome.
- Because of the relative abundance of adenomas that secrete both GH and PRL, the category of mixed adenomas has also become a designation.
Hormone-secreting pituitary carcinomas may elicit similar signs and symptoms according to the particular hormone that is secreted; they may also produce signs and symptoms related to malignant spread. Because no unequivocal histopathologic features of carcinoma exist, the diagnosis of malignancy is reserved for pituitary neoplasms that have metastasized to remote areas of the central nervous system (CNS) or outside of the CNS.[12-14] In a review of 95 cases of pituitary carcinoma, 68% of the cases were found to be hormone-producing and PRL (26%) and ACTH (25%) were the most common hormonal subtypes. Pituitary carcinomas producing GH were the second most common of the hormonal subtypes, and FSH/LH-producing and TSH-producing carcinomas were even more rarely reported. Other reports indicate that as many as 88% of pituitary carcinomas are endocrinologically active, and ACTH-secreting tumors are the most common. Although only 2% to 10% of pituitary adenomas are ACTH-secreting, the percentage of pituitary carcinomas that secrete ACTH is estimated to be much higher at 25% to 34%.[15-19] In a series of 15 cases, carcinomas showed a greater tendency toward systemic metastasis than craniospinal metastasis; the rate of systemic metastasis was 71% for PRL-producing cell tumors and 57% for ACTH-producing tumors.
Prolactin (PRL)-Producing Pituitary Tumors
PRL-producing pituitary tumors, also known as prolactinomas and lactotroph adenomas, secrete PRL and are typically an intrasellar tumor. In women, these adenomas are often small (<10 mm). In either sex, however, they can become large enough to enlarge the sella turcica. These adenomas represent the most common hormone-producing pituitary tumors and account for 25% to 41% of tumor specimens.
Adrenocorticotrophic Hormone (ACTH)-Producing Pituitary Tumors
The major manifestation of ACTH-producing pituitary tumors, also know as corticotroph adenomas, is secretion of adrenocorticotropic hormone (ACTH), which results in Cushing syndrome. These tumors are initially confined to the sella turcica, but they may enlarge and become invasive after bilateral adrenalectomy (i.e., Nelson syndrome). These adenomas represent the second or third most common hormone-producing pituitary tumors, depending on the series; in one series, these tumors accounted for 10% of all tumor specimens.[1,3]
Growth Hormone (GH)-Producing Pituitary Tumors
GH-producing pituitary tumors, also known as somatotroph adenomas, produce GH, resulting in gigantism in younger patients and acromegaly in others. Suprasellar extension is not uncommon. These adenomas represent the second or third most common hormone-producing pituitary tumors, depending on the series; in one series these adenomas accounted for 13% of tumor specimens.[1,3]
Thyrotropin-Producing Pituitary Tumors
Thyrotroph-producing pituitary tumors, also known as thyrotroph adenomas, secrete thyroid-stimulating hormone (TSH), also known as thyrotropin, which results in hyperthyroidism without TSH suppression. Many are large and invasive, may be plurihormonal, and secrete both GH and/or PRL. These tumors are rare and account for no more than 2% of tumor specimens.[1,3,20]
Gonadotroph (FSH-Producing and/or LH-Producing) Adenomas
Gonadotroph adenomas may secrete FSH and/or LH, or the alpha or beta subunits that comprise these heterodimers, which, depending on gender, may result in ovarian overstimulation, increased testosterone levels, testicular enlargement, and pituitary insufficiency caused by compression of the pituitary stalk or destruction of normal pituitary tissue by tumor. Many gonadotroph tumors, however, are unassociated with clinical or biochemical evidence of hormone excess and may be considered to be nonfunctioning or endocrine-inactive tumors. Functional, clinically detectable gonadotroph adenomas are rare.
Plurihormonal tumors produce more than one hormone. Morphologically, they can be either monomorphous or plurimorphous. Monomorphous plurihormonal adenomas consist of one cell population that produces two or more hormones. The adenoma cells often differ from nontumorous adenohypophysial cells, and their cellular derivation may remain obscure despite extensive morphological studies. Plurimorphous plurihormonal adenomas consist of two or more distinct cell types, and each produces one hormone. Thyrotroph adenomas are often plurihormonal.
Nonfunctioning (Endocrine-Inactive) Adenomas
These tumors arise from the adenohypophysis and cause symptoms when they extend beyond the sella, which results in pressure on the surrounding structures rather than secretion of a hormonally active substance. Endocrine-inactive adenomas show positive immunostaining for one or more pituitary hormones; however, they are not associated with clinical and biochemical evidence of hormone excess. Gonadotrophic hormones, as detected by antisera to beta-FSH and beta-LH, are present in many clinically nonfunctioning adenomas. Some of these adenomas are recognized by electron microscopy to have gonadotrophic differentiation, but some have characteristics of less well-differentiated cells and resemble the null cells that were initially thought to be undifferentiated precursors of adenohypophysial cells. Endocrine-inactive pituitary adenomas comprise approximately 30% to 35% of the pituitary tumors in most series and are the most common type of macroadenoma.
Oncocytic tumors of the pituitary, also known as pituitary oncocytomas, are characterized by an abundance of mitochondria, which may fill up to 50% of the cytoplasmic area, which is normally around 8%, and obscure other organelles. These tumors are usually unassociated with clinical and biochemical evidence of hormone excess; in some cases, they may be accompanied by various degrees of hypopituitarism and/or mild hyperprolactinemia. Oncocytic change may occur in several other pituitary tumor types.
Pituitary carcinomas are usually endocrinologically functional, and ACTH-producing and PRL-producing tumors are the most frequent.[2,8] The histological and cytological characteristics of pituitary carcinomas vary from bland and monotonous to frankly malignant. Carcinomas show a variable degree of nuclear atypia and cellular pleomorphism, but they also show significantly higher mitotic rates and cell proliferation indices than adenomas. Carcinomas account for 0.1% to 0.2% of all pituitary tumors.[8,16]
Breast and lung cancer are the most common primary neoplasms metastasizing to the pituitary. Although tumors that are metastatic to the pituitary have been reported to be as high as 28% in autopsy series, the majority of metastatic tumors are clinically silent.
Other tumors that arise in the pituitary include craniopharyngiomas, meningiomas, and germ cell tumors; the rare granular cell tumors, pituicytomas, and gangliogliomas; and the even rarer gangliocytomas, lymphomas, astrocytomas, and ependymomas.
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