Page 732 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

718 C H A P T E R 19 Endocrine System MORPHOLOGY
are lesions associated with endocrine abnormalities. In
addition, nonfunctioning adenomas may cause hypopi- The usual pituitary adenoma is a well-circumscribed, soft
tuitarism as they encroach on and destroy adjacent ante- lesion that may, in the case of smaller tumors, be confined
rior pituitary parenchyma. by the sella turcica. Larger lesions may compress the optic
chiasm and adjacent structures (Fig. 19–3), erode the sella
PAT H O G E N E S I S turcica and anterior clinoid processes, and extend locally
into the cavernous and sphenoidal sinuses. In as many as
With recent advances in molecular techniques, substantial 30% of cases, the adenomas are nonencapsulated and infil-
insight has been gained into the genetic abnormalities trate adjacent bone, dura, and (uncommonly) brain. Foci
associated with pituitary adenomas: of hemorrhage and/or necrosis are common in larger
• Guanine nucleotide–binding protein (G protein) mutations adenomas.

are the best-characterized molecular abnormalities in Pituitary adenomas are composed of relatively uniform,
these neoplasms. G proteins have a critical role in signal polygonal cells arrayed in sheets, cords, or papillae. Support-
transduction, transmitting signals from cell surface ing connective tissue, or reticulin, is sparse, accounting for
receptors (e.g., growth hormone–releasing hormone the soft, gelatinous consistency of many of these tumors.
receptor) to intracellular effectors (e.g., adenyl The nuclei of the neoplastic cells may be uniform or pleo-
cyclase), which then generate second messengers (e.g., morphic. Mitotic activity usually is scanty. The cytoplasm
cAMP). Gs is a stimulatory G protein that has a pivotal role of the constituent cells may be acidophilic, basophilic, or
in signal transduction in several endocrine organs, includ- chromophobic, depending on the type and amount of
ing the pituitary. Gs exists as an inactive protein, with secretory product within the cell, but it is fairly uniform
guanosine diphosphate (GDP) bound to the guanine throughout the neoplasm. This cellular monomorphism
nucleotide–binding site of the alpha subunit of Gs, encoded and the absence of a significant reticulin network
by the GNAS1 gene. On triggering of the hormone recep- distinguish pituitary adenomas from non-neoplastic
tor, GDP dissociates, and guanosine triphosphate (GTP) anterior pituitary parenchyma (Fig. 19–4). The func-
binds to Gsα, activating the G protein. GTP-bound Gsα tional status of the adenoma cannot be reliably predicted
directly interacts with and activates its effectors (such as from its histologic appearance. Adenomas that harbor
adenyl cyclase), with a resultant increase in intracellular TP53 mutations often demonstrate brisk mitotic activity
cAMP. The cAMP acts as a potent mitogenic stimulus for and higher proliferation rates and are designated atypical
a variety of endocrine cell types, promoting cellular pro- adenomas to reinforce their potential for aggressive
liferation and hormone synthesis and secretion. The acti- behavior.
vation of Gsα and the resultant generation of cAMP are
transient because of an intrinsic GTPase activity in the Figure 19–3 Pituitary adenoma. This massive, nonfunctioning adenoma
α-subunit, which hydrolyzes GTP into GDP. A mutation has grown far beyond the confines of the sella turcica and has distorted
in the α-subunit that interferes with its intrinsic the overlying brain. Nonfunctioning adenomas tend to be larger at the
GTPase activity therefore results in constitutive time of diagnosis than those that secrete a hormone.
activation of Gsα, persistent generation of cAMP,
and unchecked cellular proliferation. Approximately
40% of growth hormone–secreting somatotroph cell
adenomas and a minority of adrenocorticotropic hormone
(ACTH)–secreting corticotroph cell adenomas bear
GNAS1 mutations.
• As stated previously, approximately 5% of pituitary adeno-
mas arise as a consequence of an inherited predisposition.
Four genes have been identified thus far as a
cause of familial pituitary adenomas: MEN1,
CDKN1B, PRKAR1A, and AIP. Germline inactivating
mutations of the MEN1 gene are responsible for multiple
endocrine neoplasia syndrome type 1 (MEN-1) (discussed
in detail later on). The product of the CDKN1B gene is the
cell cycle checkpoint regulator p27 or KIP1; germline
mutations of CDKN1B are responsible for a subset of
patients with a “MEN-1 like” syndrome who lack MEN1
abnorm­ alities. The gene encoding the aryl hydrocarbon
receptor–interacting protein (AIP) is a recently
described pituitary adenoma predisposition gene, and
patients with AIP germline mutations often develop
GH-secreting adenomas at a younger age (before 35
years) than that typical for sporadic GH adenoma patients.
• Mutations of TP53 in pituitary adenomas are associated
with a propensity for aggressive behavior, such as invasion
and recurrence.