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  • 1
    Online Resource
    Online Resource
    Multiple tumorous lesions of the pituitary gland
    Springer Science and Business Media LLC ; 2022
    In:  Hormones Vol. 21, No. 4 ( 2022-12), p. 653-663
    Details
    In: Hormones, Springer Science and Business Media LLC, Vol. 21, No. 4 ( 2022-12), p. 653-663
    Abstract: Multiple tumorous lesions in one pituitary gland are rare and mostly described in case reports. Their incidences and combinations are defined in larger collectives. Therefore, we analyzed our large collection for double tumors and combinations of tumors, cysts, and inflammation. Methods The German Registry of Pituitary Tumors, including cases from 1990 to 2018, served as the database. Our collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with hematoxylin–eosin and PAS. Monoclonal (prolactin, TSH, FSH, LH, and α subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factors Pit-1, T-Pit, and SF-1 have been used in difficult cases. The criteria of the 2017 WHO classification have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H & E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed. Results Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions. Conclusion From our studies, we conclude that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended.
    Type of Medium: Online Resource
    ISSN: 1109-3099 , 2520-8721
    URL: Article
    DOI: 10.1007/s42000-022-00392-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2581819-3
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  • 2
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    Online Resource
    The USP 8 mutational status may predict long‐term remission in patients with Cushing's disease
    Wiley ; 2018
    In:  Clinical Endocrinology Vol. 89, No. 4 ( 2018-10), p. 454-458
    Details
    In: Clinical Endocrinology, Wiley, Vol. 89, No. 4 ( 2018-10), p. 454-458
    Abstract: Almost half of the cases of Cushing's disease ( CD ) tumours carry recurrent activating somatic mutations in the ubiquitin‐specific protease eight gene ( USP 8 ). The USP 8 mutational status could predict remission in patients with CD , so our objective was to correlate the presence of somatic USP 8 mutations with the rate of recurrence after transsphenoidal surgery ( TSS ) retrospectively. Design Biochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP 8 mutational status was determined from corticotroph tumour samples. Association between USP 8 mutational status, remission and recurrence was investigated. Patients Patients with Cushing's disease from a single‐centre cohort who underwent TSS between 1991 and 2012. Measurements Long‐term remission and recurrence rate after TSS with at least 6 months follow‐up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre‐operative hormonal levels. USP 8 mutational status. Results Patients with USP 8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (mean ±  SD 46 ± 10 years vs 53 ± 11 years; P  =   0.028) and presented with higher pre‐operative 24‐hour urinary‐free cortisol levels (median IQR μg/24 hours 1174.0, 1184.5 vs 480.0, 405.3; P  =   0.045). The incidence of recurrence in a 10‐year follow‐up was significantly higher in patients with USP 8 mutant tumours after the initial remission (58% vs 18% P  =   0.026). Recurrence appeared significantly earlier in these patients (months 70, 44‐97 95% CI vs 102, 86‐119 95% CI ; P  =   0.019). Conclusion Recurrence appears to be more frequent and earlier after TSS in patients with USP 8 mutant corticotroph tumours.
    Type of Medium: Online Resource
    ISSN: 0300-0664 , 1365-2265
    URL: Issue
    URL: Article
    DOI: 10.1111/cen.2018.89.issue-4
    DOI: 10.1111/cen.13802
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2004597-9
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  • 3
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    TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Communications Vol. 10, No. 1 ( 2022-09-19)
    Details
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2022-09-19)
    Abstract: Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing’s disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    URL: Article
    DOI: 10.1186/s40478-022-01437-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2715589-4
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  • 4
    Online Resource
    Online Resource
    Improved pasireotide response in USP8 mutant corticotroph tumours in vitro
    Bioscientifica ; 2022
    In:  Endocrine-Related Cancer Vol. 29, No. 8 ( 2022-08-01), p. 503-511
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 29, No. 8 ( 2022-08-01), p. 503-511
    Abstract: Cushing’s disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing’s disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing’s disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 ( Sstr5 ) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-22-0088
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2022
    detail.hit.zdb_id: 2010895-3
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  • 5
    Online Resource
    Online Resource
    Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles
    Springer Science and Business Media LLC ; 2021
    In:  Pituitary Vol. 24, No. 6 ( 2021-12), p. 904-913
    Details
    In: Pituitary, Springer Science and Business Media LLC, Vol. 24, No. 6 ( 2021-12), p. 904-913
    Abstract: Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5–1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. Methods Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). Results In accordance with the literature, combinations of GH/prolactin/TSH–FSH/LH adenoma (4/12), GH/prolactin/TSH–ACTH adenoma (3/12), and ACTH–FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. Conclusion Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.
    Type of Medium: Online Resource
    ISSN: 1386-341X , 1573-7403
    URL: Article
    DOI: 10.1007/s11102-021-01164-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2008775-5
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