Pathologic Quiz Case: Pituitary Mass in a 48-Year-Old Woman (2001)

A 48-year-old, previously healthy woman presented to her gynecologist with a complaint of headaches, amenorrhea, and galactorrhea for approximately 1 year. Physical examination was unremarkable, and she had no neurological deficits. Pertinent laboratory values included an elevated prolactin level of 52.5 ng/mL (normal value for a postmenopausal female reported as 1.8–20.3 ng/mL). Whole-brain magnetic resonance imaging showed a 1.5-cm mass within the pituitary fossa that diffusely enhanced following administration of gadolinium contrast material (Figure 1, arrow). The mass extended into the suprasellar cistern, causing slight mass effect on the optic chiasm. The preoperative working diagnosis was a lactotroph macroadenoma. The patient underwent a transsphenoidal resection of the mass. Intraoperatively, a rubbery and nonencapsulated mass that emanated from the neurohypophysis was resected. The adenohypophysis was noted to be uninvolved.Histologic sections stained with hematoxylin-eosin showed round and polygonal cells with eccentric nuclei, occasional nucleoli, and abundant granular eosinophilic cytoplasm (Figure 2). The architecture was predominantly nodular, but focally had a fascicular pattern. Reactions with periodic acid–Schiff showed strong and diffuse staining of the cytoplasmic granules that was resistant to diastase digestion (Figure 3). Immunohistochemical stains showed the cytoplasm of tumor cells to be strongly and diffusely reactive to CD68 (KP-1) and negative to glial fibrillary acidic protein. Reactivity to S100 protein was present in the cytoplasm and nuclei of tumor cells. Immunohistochemical stains for synaptophysin, chromogranin, prolactin, human growth hormone, adrenocorticotrophic hormone, thyrotropin, and human chorionic gonadotropin were negative in the tumor cells and positive only in minute fragments of benign adenohypophysis. Ultrastructurally, the tumor cells were characterized by abundant pleomorphic lysosomes that filled and expanded the cytoplasm (Figure 4). No neuroendocrine-type secretory granules were identified.Embryologically, the pituitary gland has 2 origins. The adenohypophysis, or anterior pituitary, is derived from an evagination of oral ectoderm of the dorsal median region of the stomodeum. The neurohypophysis, or posterior pituitary, is derived from an evagination of the infundibular portion of the diencephalon of the brain. The neurohypophysis proper comprises the median eminence of the tuber cinereum, the infundibulum, the pituitary stalk, and the posterior or neural lobe of the pituitary gland. The neurohypophysis is composed primarily of pituicytes, nerve fibers, axon terminals, and Herring bodies. The infundibulum, in up to 17% of autopsies, contains clinically insignificant clusters or nodules of granular cells described as tumorlets1 or tumorettes.2 Granular cell tumors (GCTs) presumably arise from enlargement of tumorlets. However, the histogenesis of these tumors is controversial, evident by various terms in the literature that have attempted to describe GCT, including choristoma, tumorlet, myoblastoma, and pituicytoma. Currently, the descriptive term granular cell tumor is recommended.3The clinical features of 43 symptomatic parasellar GCTs were recently reviewed.4 GCTs are typically diagnosed in the fourth or fifth decade of life, and the female–male ratio is approximately 2:1. The majority of patients (approximately 90%) present with visual signs and symptoms secondary to optic chiasm compression, including bilateral temporal field deficits, optic atrophy, and decreased visual acuity. Similar to the present case, approximately half of patients will present with signs of partial pituitary insufficiency or hyperprolactinemia, presumably resulting from stalk effect.4 Less commonly, GCTs have been associated with dementia, Parkinson disease, obstructive hydrocephalus, intraventricular hemorrhage, and diabetes insipidus.The neuroimaging of most reported cases of GCTs utilized pneumoencephalography and angiography. Computed tomography typically demonstrates a hyperdense intrasellar mass that strongly enhances with contrast. Few cases have been evaluated by magnetic resonance imaging, which typically shows low signal intensity on T1-weighted images and strong inhomogeneous contrast enhancement. In most cases, the magnetic resonance appearance does not reliably differentiate GCT from pituitary adenoma or meningioma.5 A rare case of GCT with radiographic calcifications suggested craniopharyngioma in the differential diagnosis.4Grossly, GCTs are lobulated, well-demarcated masses that are not encapsulated. Unlike the typical soft texture of pituitary adenomas, GCTs appear firm or rubbery. Microscopically, GCTs are composed of large polygonal-shaped and rounded cells with bland eccentric nuclei. Tumor cells are typically tightly packed and arranged in sheets or nodules. Some tumors may display a fascicular or spindled appearance. The striking feature is the abundant granular and eosinophilic cytoplasm that is periodic acid-Schiff–positive and diastase-resistant. Perivascular lymphocytic aggregates are encountered commonly. Atypical features, such as nuclear pleomorphism and mitotic figures, are rarely seen. In the World Health Organization (WHO) classification of tumors of the nervous system, GCTs correspond histologically to WHO grade 1.6Immunohistochemically, the tumor cells are variably positive for S100 protein, CD68 antigen, α1-antitrypsin, α1-antichymotrypsin, and cathepsin B. Tumor cells are negative for anterior pituitary hormones, keratin, vimentin, desmin, and neuron-specific enolase.7 Although glial fibrillary acidic protein is typically reported as negative in GCTs of the infundibulum, glial fibrillary acidic protein has been demonstrated in tumor cells by electron immunocytochemistry.8 It is suggested that GCTs and their tumorlet precursors derive from pituicytes and thus are astrocytic in nature and therefore a form of glioma.4,5,6,9 The relationship, however, between the histogenesis of GCT and pituicytoma, a distinctive low-grade glioma of the neurohypophysis, remains controversial.10 Approximately one third of GCTs coexist with pituitary adenomas, and common precursor cells for tumorigenesis have been suggested.11Ultrastructurally, the cytoplasm of GCTs is filled with numerous vesicles of varying sizes surrounded by a single membrane. Some vesicles are phagolysosomes containing remnants of mitochondria, endoplasmic reticulum, and myelin-like membranous bodies. Light and dense multivesicular bodies, as well as hybrid cells containing both multiple vesicles and autophagic material, have also been identified. The tumor cells are not surrounded by a basement membrane.12In conclusion, GCTs are the most common tumor of the posterior pituitary and may present as suprasellar, parasellar, or intrasellar masses. Radiographically and clinically, they often mimic the features of pituitary adenomas. However, GCTs of the infundibulum have distinctive histologic, histochemical, and ultrastructural characteristics that distinguish them from the more common adenomas of the adenohypophysis.