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'.

NG2 targets tumorigenic Rb inactivation in Pit1-lineage pituitary cells

“…Targeted silencing of Rb by NG2 resulted in adenohypophysial tumors with immunohistochemical and ultrastructural features that resemble those of aggressive Pit1-lineage tumors in humans, previously called 'silent subtype 3 adenomas' (Mete et al 2016). These tumors are composed of cells that exhibit Pit1-lineage differentiation, but they are not differentiated somatotrophs, mammosomatotrophs, lactotrophs, or thyrotrophs; they most closely resemble thyrotrophs (Mete et al 2016). As the original name suggests, these tumors are usually not associated with florid hormone excess in humans, similar to what we identified in the current mouse model.…”

Epidemiology and biomarker profile of pituitary adenohypophysial tumors

“…The tumors were subclassified according to previously published criteria [10]. Somatotroph, mammosomatotroph or mixed tumors with predominant growth hormone reactivity numbered 167 (52.8%), lactotroph or acidophil stem cell tumors with predominant prolactin reactivity were 88 (27.8%), 7 were thyrotroph tumors (2.2%), poorly differentiated Pit-1 lineage tumors [12] numbered 44 (13.9%) and 10 tumors were classified as not-otherwise-specified (3.2%). The patients in this group included 132 males and 183 females with one lacking gender identification.…”

“…There were 44 poorly differentiated tumors of Pit-1 lineage (4.2%), formerly classified as Silent Subtype 3 adenomas. The initial 31 cases have recently been reported [12]. These tumors all expressed Pit-1 and there was variable, often focal expression of growth hormone, prolactin, β-thyrotropin, α-subunit, and ER.…”

Clinical implications of accurate subtyping of pituitary adenomas: perspectives from the treating physician

“…Silent subtype 3 pituitary adenomas are monomorphous plurihormonal Pit-1 lineage adenomas that may be clinically silent (3,5). However, the term "silent" is a misnomer, since these tumours can cause acromegaly, hyperprolactinemia (albeit generally due to stalk effect) or hyperthyroidism (8,(21)(22)(23). These tumours tend to be invasive macroadenomas or giant adenomas ( Figure 3a) and they present at an earlier mean age than gonadotroph adenonomas (7,8,22,23).…”