Tumors of the Pituitary Gland

Clinical Features.

Lactotroph adenomas, also called PRL-secreting adenomas and prolactinomas, constitute nearly 80% of functioning pituitary tumors and about 40% of all pituitary adenomas. However, most patients with lactotroph adenomas are treated clinically with dopamine agonist therapy. Therefore the frequency of prolactinomas in surgical series tends to be smaller; in our institution, lactotroph adenomas represent approximately 20% of tumor specimens. Most lactotroph adenomas are microadenomas occurring in reproductive-age women who present with oligomenorrhea, galactorrhea, and infertility. Conversely, in men and elderly women, lactotroph adenomas are usually macroadenomas and are most commonly associated with symptoms of a tumoral mass, including headaches, neurologic defects, and visual loss. Impotence and decreased libido are also common symptoms of hyperprolactinemia in males.

Lactotroph adenomas arise from Pit-1-lineage adenohypophyseal cells and express mainly prolactin (PRL). These tumors are classified into three distinct histologic subtypes: sparsely granulated lactotroph adenoma, densely granulated lactotroph adenoma, and acidophil stem cell adenoma.

Histopathology.

The majority of lactotroph adenomas are sparsely granulated adenomas and composed of midsize cells with chromophobic cytoplasm and a central, oval nucleus ( Fig. 17.9 ). Small nucleoli can be present. The minority of the adenomas are densely granulated with cells containing copious eosinophilic cytoplasm. Microcalcifications that occasionally are so abundant as to form a so-called pituitary stone are commonly seen in lactotroph adenomas ( Fig. 17.10 ). The adenomas may also produce an amyloid-like substance, forming small hyaline bodies. Calcifications and amyloid bodies, although frequently seen in these tumors, are not pathognomonic of this type of adenoma but occur more frequently in lactotroph adenomas than in other adenoma types.

As commented previously, the majority of patients with PRL-secreting adenomas are treated to some degree with dopamine agonists before undergoing surgical resection. These drugs have direct effect on the tumor cells, inducing atrophy of lactotrophs with resultant tumor shrinkage. Histologically these treated lactotroph adenomas are composed of smaller tumor cells with shrinkage of the cytoplasm and hyperchromasia of the nuclei, in addition to variable degrees of perivascular and interstitial tumoral fibrosis ( Fig. 17.11 ).

Immunohistochemistry.

In the majority of these adenomas (i.e., sparsely granulated adenomas) immunohistochemistry shows reactivity for PRL in a pattern of staining that is very characteristic, with localization near the nucleus in a dotlike pattern (see Fig. 17.9B ). This pattern is termed Golgi pattern by some authors, reflecting hormone localization in the Golgi complex. In densely granulated adenomas, strong and diffuse PRL expression is present. Lactotroph adenomas show nuclear expression of the acidophilic lineage-linked transcription factor Pit-1.

Ultrastructure.

Sparsely granulated adenomas resemble actively secreting lactotrophs of the normal pituitary gland. The adenoma cells are characterized by prominent rough endoplasmic reticulum, conspicuous Golgi complex, and a sparse number of small (150–300 nm) secretory granules ( Fig. 17.12 ). Misplaced exocytosis, that is, granule extrusions on the lateral cell surfaces, is typical of these tumors.

Clinical Features.

Somatotroph adenomas constitute approximately 20% of pituitary adenomas. Patients have signs and symptoms of acromegaly or gigantism, and high serum levels of GH and insulin-like growth factor I (IGF-I). Acromegaly affects both sexes with similar incidence, and the mean age at diagnosis is 40 to 45 years. Symptoms of acromegaly usually progress slowly, with an average delay until diagnosis of approximately 10 years. Adenomas arising in children and adolescents before the epiphyseal closure of the long bones result in gigantism. Most patients with acromegaly have macroadenomas when first diagnosed, many of them with suprasellar expansion and parasellar invasion. Consequently, symptoms secondary to an expanding tumor mass, including headaches and visual field defects, may also be present in patients with large tumors. In about 30% to 50% of the patients, cosecretion of PRL with GH by the tumor results in signs and symptoms of hyperprolactinemia. The mixed GH and PRL-secreting tumors will be discussed in a following subsection.

Histopathology.

Pure somatotroph adenomas are divided into two histologic subtypes: densely granulated somatotroph adenoma and sparsely granulated somatotroph adenoma. These histologic attributes reflect the amount of secretory granules present in the cell cytoplasm. The densely granulated somatotroph adenomas are characterized by eosinophilic tumor cells in which the cytoplasm shows considerable granularity, reflecting great numbers of secretory granules seen at the ultrastructural level ( Fig. 17.14 ). The nucleus tends to be central and oval, with prominent nucleoli. The sparsely granulated somatotroph adenomas are composed of smaller tumor cells with chromophobic cytoplasm and an eccentric nucleus ( Fig. 17.15 ). In the cytoplasm are paranuclear eosinophilic structures called fibrous bodies. These structures represent accumulations of intermediate filaments and tubular formations at the ultrastructural level and are strongly immunoreactive for cytokeratin ( Fig. 17.16 ).

The distinction between the two subtypes of somatotroph adenomas is of importance because these tumors have different clinical behavior. The sparsely granulated adenomas exhibit more aggressive biologic behavior than the densely granulated adenomas. In addition, the response of tumors to adjuvant medical treatment also differs according to the subtype of somatotroph adenoma.

Immunohistochemistry.

Immunohistochemical stains show a variable degree of GH immunoreactivity. In the densely granulated adenomas, the GH immunostain diffusely occupies the entire cytoplasm of the tumor cells and tends to be dispersed diffusely throughout the entire tumor (see Fig. 17.14 ). By contrast, in the sparsely granulated adenomas, GH immunostaining is focal within the tumor and tends to be localized in a paranuclear distribution (see Fig. 17.15 ) similar to the Golgi pattern seen in lactotroph adenomas. In addition, in these sparsely granulated adenomas, fibrous bodies are strongly positive for CK [45] (see Fig. 17.16 ). Some somatotroph adenomas show secondary reactivity for other pituitary hormones. Immunopositivity for PRL can be seen focally even in patients without clinical or biochemical evidence of hyperprolactinemia. Similarly, the presence of immunoreactivity for the glycoprotein hormones β-FSH, β-LH, α-SU, and less frequently β-TSH can be demonstrated in some somatotroph adenomas. Apart from the well-characterized mixed GH and PRL-secreting adenomas (see later discussion), plurihormonal differentiation is not clinically symptomatic in the majority of cases.

Immunohistochemical staining for low molecular weight CK is essential for further characterization of the two subtypes of somatotroph adenomas. The sparsely granulated adenomas are unique for the presence of dotlike cytokeratin staining of fibrous bodies, while the densely granulated adenomas show more diffuse cytoplasmic cytokeratin staining.

Somatotroph adenomas strongly express the acidophilic linkage transcription factor Pit-1.

Ultrastructure.

The two subtypes of somatotroph adenomas, densely and sparsely granulated, are well characterized by ultrastructural analysis. However, as commented earlier, the distinction between these two clinically relevant somatotroph adenomas subtypes can be made based on immunohistochemistry for GH and CK patterns with no necessity for electron microscopy analysis on a routine basis. The densely granulated adenoma is composed of adenomatous cells that resemble the normal somatotrophs of the pituitary gland and are characterized by a well-developed rough endoplasmic reticulum network, prominent Golgi complexes, and numerous large (300–600 nm) secretory granules ( Fig. 17.17 ). The sparsely granulated adenomas have fewer and smaller (100–250 nm) secretory granules ( Fig. 17.18 ). The most characteristic feature of the sparsely granulated adenomas is the presence of fibrous bodies, which consist of an accumulation of intermediate filaments and tubular smooth-surfaced endoplasmic reticulum.

As in prolactinomas, medical therapy for acromegaly with somatostatin receptor ligands, mainly octreotide, is common practice in endocrinology. Unlike dopamine agonists, significant reduction of tumor cell size, resulting from involution of rough endoplasmic reticulum and Golgi membranes, is uncommonly seen in treated somatrotroph adenomas. The most common changes are varying degrees of perivascular and interstitial fibrosis.

Clinical Features.

Corticotroph adenomas constitute two major groups: (1) endocrinologically active tumors associated with either Cushing disease or, very rarely, Nelson syndrome; and (2) tumors that are clinically nonfunctioning, the so-called silent corticotroph adenomas. Corticotroph adenomas associated with Cushing disease represent approximately 10% to 15% of all adenomas. Cushing disease tends to be more frequent in females (3.5 : 1 ratio) and affects patients of varying age, with a peak between 30 and 40 years. In children, Cushing disease is rare and tends to have a more aggressive clinical course and lower cure rate than in adults. In contrast to its occurrence in adults, Cushing disease arising in prepubertal children is more common in males than females. The great majority of corticotroph adenomas are microadenomas, and approximately 15% are invasive at the time of surgery.

Histopathology.

Corticotroph adenomas are usually densely granulated, basophilic by H&E stain, and often strongly periodic acid–Schiff (PAS) positive. The cytoplasm is very granular, and the nucleus is large with coarse chromatin and a prominent nucleolus ( Fig. 17.21 ). Some degree of nuclear pleomorphism can be present. The cells have very distinct cytoplasmic borders and tend to touch each other in a tilelike arrangement. Papillary formations are very common. Adenomas with a more chromophobic appearance and less granular cytoplasm are also seen and designated as sparsely granulated corticotroph adenomas. Occasionally tumor cells exhibit hyaline bundles encircling the cytoplasm, giving a so-called target cell appearance, representing Crooke hyaline change. These hyaline bodies correspond to accumulation of CK intermediate filaments. Corticotroph adenomas showing extensive hyaline change, the so-called Crooke cell adenoma ( Fig. 17.22 ), appear more often to be locally invasive and recurrent.

Crooke changes are also present in the normal pituitary gland of patients with Cushing disease and in patients with other pathologic or iatrogenic hypercortisolemic states; this cellular alteration appears to be a direct action of high serum levels of cortisol on the corticotroph cells.

Nelson syndrome, which is now quite rare, represents the syndrome of excess cortisol without any evident pituitary lesion on conventional radiography, leading to inappropriate adrenalectomy and later discovery of the pituitary adenoma. Corticotroph adenomas in this setting are histologically similar to adenomas associated with Cushing disease, with the exception that accumulation of intermediate filaments and Crooke hyaline change are not present.

On rare occasions, corticotroph cell hyperplasia may be the source of Cushing disease. However, controversy exists both from the clinical and pathologic viewpoints regarding this occurrence.

Immunohistochemistry.

Immunohistochemical studies demonstrate the presence of ACTH with varying degrees of immunoreactivity ( Fig. 17.23 ) and the transcription factor Tpit. In addition, corticotroph adenomas may express other peptides related to the POMC precursor molecule, including β-lipotropin, β-endorphin, and α-melanocyte–stimulating hormone. In practice, the demonstration of these related peptides is less relevant than ACTH. Immunostaining for CK shows accumulation in the cytoplasm either diffusely or forming Crooke changes (see earlier discussion).

Ultrastructure.

The ultrastructural features of corticotroph adenomas are characterized by well-differentiated cells that resemble normal corticotrophs. The cells contain well-developed organelles, including rough endoplasmic reticulum, smooth endoplasmic reticulum, and conspicuous Golgi, associated with numerous large (250–700 nm) secretory granules. The secretory granules are often of different shapes (teardrop, spherical, heart shaped) and vary in electron density. Bundles of intermediate filaments adjacent to the nucleus or forming large circles are easily identified. Ultrastructural analysis of clinically functioning corticotroph adenomas is not essential for diagnosis, as histologic and immunohistochemical studies are sufficient to provide an accurate diagnosis.

Clinical Features.

The silent corticotroph adenomas are characterized by immunoreactivity for ACTH despite the fact that the patients have neither clinical signs of Cushing disease nor serum levels reflecting excess ACTH secretion. Because silent adenomas are clinically nonfunctioning, the majority of them are macroadenomas and patients thus present with signs and symptoms of a mass lesion. Characteristically these adenomas show a high tendency for hemorrhage and apoplexy, which may be the presenting symptom in about a third of patients. Silent corticotroph adenomas tend to arise in patients older than those with Cushing disease.

Histopathology and Ultrastructure.

Two types of silent corticotroph adenomas have been described according to tumors’ histologic appearance. The silent corticotroph adenoma subtype 1 (densely granulated adenoma) is morphologically indistinguishable from functioning corticotroph adenomas associated with Cushing disease, both on light microscopy and ultrastructure. The silent corticotroph adenoma subtype 2 shows different morphology from corticotroph adenomas and is characterized by amphophilic or mildly basophilic, sparsely granulated tumors that resemble null cell adenoma (see later discussion). The ultrastructure is less characteristic of a typical corticotroph cell adenoma or silent corticotroph subtype 1 adenoma. However, the morphology of the secretory granules has corticotroph characteristics. The tumor cells normally do not contain CK filaments. Rarely, some silent adenomas lack ACTH immunoexpression, but express the transcription factor Tpit.