The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas

Abstract

Clinically nonfunctioning pituitary adenomas (NFAs) may be hormonally inactive tumors of differentiated cells, mainly not only gonadotroph adenomas (GAs) but also silent corticotroph adenomas (SCAs) and other differentiated silent adenomas. Recently, the use of transcription factors has been recommended to confirm cytodiffererentiation of these neoplasms. Our objective was to assess the clinical significance of the new classification system using transcription factors. Five hundred sixteen consecutive NFAs were studied retrospectively. They were initially classified based on hormone immunohistochemistry as follows: 119 hormone-negative adenomas (23.1 %), 300 GAs (58.1 %), 51 SCAs (9.9 %), and 46 other silent adenomas. The 119 hormone-negative adenomas were further evaluated for expression of transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-α (ERα), pituitary-specific transcription factor 1 (Pit-1), and t-box transcription factor (Tpit). One hundred thirteen of 119 (95 %) hormone-negative adenomas showed mutually exclusive lineage-specific differentiation as gonadotrophs (SF-1 positive), corticotrophs (Tpit positive), or somatotrophs/mammosomatotrophs/lactotrophs/thyrotrophs (Pit-1 positive) in 79 cases (66.4 %), 32 cases (26.9 %), and 2 cases, respectively. The 32 ACTH-negative and Tpit-positive adenomas had higher pro-opiomelanocortin mRNA expression levels compared with GAs (P = 0.0001) on quantitative real-time PCR. They showed a female preponderance (P < 0.0001) and were more frequently giant adenomas (P = 0.0028) associated with marked cavernous sinus invasion (P < 0.0001) compared with GAs. These clinical features were identical to those of the 51 ACTH-positive SCAs. Our results justify the complementary role of transcription factors in the precise classification of NFAs that can more accurately characterize biological behavior. Our data suggest that more than one quarter of hormone-negative adenomas are SCAs that share distinct clinicopathological features with ACTH-expressing SCAs.

NG2 targets tumorigenic Rb inactivation in Pit1-lineage pituitary cells

“…It may be due to abnormal regulation of hormone synthesis and secretion, as is thought to be the case in most gonadotroph tumors (Snyder 1987, Asa et al 1988, Penabad et al 1996, or to abnormal processing of prohormone products, as has been suggested for silent corticotroph tumors (Lloyd et al 1990, Chabre et al 1991, Stefaneanu et al 1991. However, as these two examples indicate, there is no strict relationship between hormone functionality and tumor aggressiveness, because silent gonadotroph tumors are not thought to be aggressive (Nishioka et al 2015), whereas other silent neoplasms, including those of Pit1 lineage and silent corticotroph tumors, can be highly invasive and lack responsiveness to conventional therapies .…”

How Valuable Is the RT-qPCR of Pituitary-Specific Transcription Factors for Identifying Pituitary Neuroendocrine Tumor Subtypes According to the New WHO 2017 Criteria?

“…Nishioka et al recently assessed the usefulness of the pituitary-specific transcription factors in the characterization of a large series of sPitNETs [9]. By studying 119 NC tumors by evaluating the expression of Pit-1, Tpit, SF-1, and estrogen receptor-α (ERα), the authors were able to reclassify 95% of the tumors as GTs, CTs, or Pit-1-derived tumors (LTs, STs, or TTs).…”

Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

“…The silent gonadotroph NFPAs (GAs) are the most common (75%) of all the immunohistochemical subgroups of NFPAs (2). Gene expression profiling analyses have shown to be of importance in identifying molecular markers, as well as to determine essential signaling pathways for correct histological stratification and thereby adequate treatment of a wide range of cancers (3).…”