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.
Object The aim of this study was to analyze clinicopathological characteristics and treatment outcomes in a large single-center clinical series of cases of thyrotropin (TSH)–secreting pituitary adenomas. Methods The authors retrospectively reviewed clinical, pathological, and treatment characteristics of 90 consecutive cases of TSH-secreting pituitary adenomas treated with transsphenoidal surgery between December 1991 and May 2013. The patient group included 47 females and 43 males (median age 42 years, range 11–74 years). Results Sixteen tumors (18%) were microadenomas and 74 (82%) were macroadenomas. Microadenomas were significantly more frequent in the more recent half of our case series (12 of 45 cases) (p = 0.0274). Cavernous sinus invasion was confirmed in 21 patients (23%). In 67 cases (74%), the tumors were firm elastic or hard in consistency. Acromegaly and hyperprolactinemia were observed, respectively, in 14 (16%) and 11 (12%) of the 90 cases. Euthyroidism was achieved in 40 (83%) of 48 patients and tumor shrinkage was found in 24 (55%) of 44 patients following preoperative somatostatin analog treatment. Conventional transsphenoidal surgery, extended transsphenoidal surgery, and a simultaneous combined supra- and infrasellar approach were performed in 85, 2, and 3 patients, respectively. Total removal with endocrinological remission was achieved in 76 (84%) of 90 patients, including all 16 (100%) patients with microadenomas, 60 (81%) of the 74 with macroadenomas, and 8 (38%) of the 21 with cavernous sinus invasion. None of these 76 patients experienced tumor recurrence during a median follow-up period of 2.8 years. Stratifying by Knosp grade, total removal with endocrinological remission was achieved in 34 of 36 patients with Knosp Grade 0 tumors, all 24 of those with Grade 1 tumors, 12 of the 14 with Grade 2 tumors, 6 of the 8 with Grade 3 tumors, and none of the 8 with Grade 4 tumors. Cavernous sinus invasion and tumor size were significant independent predictors of surgical outcome. Immunoreactivity for growth hormone, prolactin, or both hormones was present in 32, 9, and 24 patients, respectively. The Ki-67 labeling index was less than 3% in 71 (97%) of 73 tumors for which it was obtained and 3% or more in 2. Postsurgery pituitary dysfunction was found in 15 patients (17%) and delayed hyponatremia was seen in 9. Conclusions TSH-secreting adenomas, particularly those in the microadenoma stage, have increased in frequency over the past 5 years. The high surgical success rate achieved in this series is due to relatively early diagnosis and relatively small tumor size. In addition, the surgical strategies used, such as extracapsular removal of hard or solid adenomas, aggressive resction of tumors with cavernous sinus invasion, or extended transsphenoidal surgery or a simultaneous combined approach for large/giant multilobulated adenomas, also may improve remission rate with a minimal incidence of complications.
WHO classification of pituitary adenomas was revised in 2017. The two major and significant changes are discussed. (1) The new classification focuses on adenohypophysial-cell lineage for the designation of adenomas, and thus, assessment of pituitary transcription factors is recommended. Its appropriate use has a complementary role in obtaining an accurate diagnosis, particularly in hormone-negative adenomas. Subclassification of nonfunctioning adenomas was revised accordingly and, consequently, null cell adenomas became quite rare. (2) "Atypical adenoma", a previous category, was eliminated due to the poor reproducibility and predictive value. Assessment of tumor proliferation marker and other clinical parameters such as invasion are recommended to predict aggressiveness. "High-risk adenomas" are those with rapid growth, radiological invasion, and a high Ki-67 proliferation index, whereas some special adenoma subtypes commonly show aggressive behavior.
Hypophysitis has been histologically classified into five types: lymphocytic hypophysitis (LYH), granulomatous hypophysitis (GRH), xanthogranulomatous hypophysitis (XGH), xanthomatous hypophysitis (XH), and necrotizing hypophysitis. The present study evaluated 31 cases of hypophysitis to clarify their characteristic clinicopathologic features. The lesions were histologically classified into four groups: LYH (22 cases) including lymphocytic adenohypophysitis (LAH) (19 cases) and lymphocytic infundibuloneurohypophysitis (LINH) (3 cases), GRH (5 cases), XGH (2 cases), and XH (2 cases). In each group, the pituitary gland showed lymphocytic infiltration associated with focal or diffuse hypophysial destruction of variable severity and fibrosis. Histologic and clinical overlap among different types of hypophysitis, especially between LAH and LINH, suggest that these entities may have similar etiologic background and/or represent different stages of the same lesion. Considering the sampling sites and clinical manifestations, LAH may not usually involve the neurohypophysis, but LINH may often extend to the adenohypophysitis. A selective loss of adrenocorticotropic hormone-positive cells was seen in two patients with LAH despite only very slight lymphoplasmacytic infiltration. This suggests that there may be at least two causative mechanisms for hypopituitarism in hypophysitis: nonspecific destruction of all types of adenohypophysial cells by severe inflammation and selective destruction of specific adenohypophysial cells.
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