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  • Author: Luis G. Pérez‐Rivas x
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Luis G Pérez-Rivas, Marily Theodoropoulou, Troy H Puar, Julia Fazel, Mareike R Stieg, Francesco Ferraù, Guillaume Assié, Monica R Gadelha, Timo Deutschbein, Maria C Fragoso, Benno Kusters, Wolfgang Saeger, Jürgen Honegger, Michael Buchfelder, Márta Korbonits, Jérôme Bertherat, Günter K Stalla, Ad R Hermus, Felix Beuschlein, and Martin Reincke

Objective

Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing’s disease (CD). Corticotroph tumor progression, the so-called Nelson’s syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson’s tumors has not been studied in detail so far.

Design and Methods

Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing.

Results

Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson’s tumor.

Conclusion

Somatic mutations in USP8 are common in Nelson’s tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson’s tumor.

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Martin Reincke, Adriana Albani, Guillaume Assie, Irina Bancos, Thierry Brue, Michael Buchfelder, Olivier Chabre, Filippo Ceccato, Andrea Daniele, Mario Detomas, Guido Di Dalmazi, Atanaska Elenkova, James Findling, Ashley B. Grossman, Celso E Gomez-Sanchez, Anthony P Heaney, Juergen Honegger, Niki Karavitaki, Andre Lacroix, Edward R Laws, Marco Losa, Masanori Murakami, John Newell-Price, Francesca Pecori Giraldi, Luis G. Pérez‐Rivas, Rosario Pivonello, William E Rainey, Silviu Sbiera, Jochen Schopohl, Constantine A Stratakis, Marily Theodoropoulou, Elisabeth F.C. van Rossum, Elena Valassi, Sabina Zacharieva, German Rubinstein, and Katrin Ritzel

BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson’s syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing’s disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28th, 2018.

RESULTS: Data covered definition and incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.