RCCs of high- and isointensity on T1-weighted images, which contain mucous material within the cyst, may be associated with chronic inflammation that can potentially cause irreversible endocrine dysfunction. In asymptomatic patients with RCCs of these MR intensities, close follow-up with precise endocrinological evaluation and gadolinium-enhanced MRI is necessary to avoid occult progression of the inflammation.

Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one-to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

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.