title: Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas.
abstract: Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 μg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1-9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2-171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our findings argue against the use of the nomenclature 'silent' for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as 'poorly differentiated Pit-1 lineage adenomas'.
authors.affiliation: Department of Pathology, University Health Network, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Mete
authors.affiliation: Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Gomez-Hernandez
authors.affiliation: Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Walter
authors.initials: W
authors.lastname: Kucharczyk
authors.affiliation: Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rowena
authors.initials: R
authors.lastname: Ridout
authors.affiliation: Department of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Department of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Gentili
authors.affiliation: Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
authors.affiliation: Department of Pathology, University Health Network, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
mesh_terms: D000172:Acromegaly / Q000209:etiology; D000236:Adenoma / Q000737:chemistry* / Q000145:classification / Q000150:complications / Q000601:surgery / Q000648:ultrastructure; D000293:Adolescent; D000328:Adult; D000368:Aged; D000568:Amenorrhea / Q000209:etiology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002454:Cell Differentiation; D019070:Cell Lineage; D005260:Female; D005687:Galactorrhea / Q000209:etiology; D006801:Humans; D006980:Hyperthyroidism / Q000209:etiology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D018365:Neoplasm, Residual; D010911:Pituitary Neoplasms / Q000737:chemistry* / Q000145:classification / Q000150:complications / Q000601:surgery / Q000648:ultrastructure; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D009626:Terminology as Topic; D050817:Transcription Factor Pit-1 / Q000032:analysis*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C494187:POU1F1 protein, human; D050817:Transcription Factor Pit-1