A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing's syndrome

Background: Clinical care of patients with cyclic Cushing's syndrome (CS) is challenging. Classical pitfalls include incorrect subtyping, unnecessary surgical procedures and delayed definite treatment. Case presentation: A 43-year-old female suffered from a rapidly cycling ectopic CS. She experienced six cycles of severe hypercortisolism within a 2 year period (maximum plasma cortisol 5316 nmol/L, normal range 124.2-662.4 nmol/L; maximum urinary free cortisol 79,469 nmol/24 h, normal range < 414 nmol/24 h) lasting 2-9 weeks. The episodes were associated with pronounced hypokalemia (lowest K+ value recorded 2.4 mmol/l) and progressive signs and symptoms of CS. A bilateral inferior petrosal sinus sampling (BIPSS) performed during a trough phase was false positive for pituitary ACTH overproduction resulting in unnecessary transsphenoidal surgery while a second BIPSS performed during an active phase was indicative for ectopic CS. The 18F-DOPA PET/CT showed a pancreatic lesion, which was subsequently partially removed. Surprisingly, the histopathology was conclusive for ACTH-positive lymph node metastasis located in the retro-duodenal tissue of an occult neuroendocrine tumor WHO grade II. The primary tumor has not been identified so far and, because of the persistent hypercortisolism, the patient underwent bilateral adrenalectomy. Two years later, ACTH levels started to increase progressively. Percutaneous biopsy of a newly identified suspected lesion in the fifth thoracic vertebra revealed a metastasis with positive staining for ACTH, synaptophysin and chromogranin A. Therapy with carboplatin and etoposide was started and, since then, the patient underwent 12 cycles of chemotherapy. Conclusions: We report the challenging case of a rapidly cycling CS secondary to ACTH-secreting neuroendocrine intestinal tumor of unknown primary. We highlight the importance of performing diagnostic tests only during the phases of active cortisol secretion and as soon as first symptoms appear to avoid pitfalls

Chemosensory dysfunction in Cushing's syndrome

PURPOSE Cushing's syndrome (CS) can lead to structural changes in the brain and cognitive impairment, but chemosensory function has not been investigated yet. The aim was to analyze sense of smell and taste in patients with CS and explore the effect of therapy. METHODS The study cohort comprised 20 patients with florid CS treated between 2018 and 2020 in the outpatient clinic of the LMU Munich. We compared these 20 patients with CS to 40 healthy subjects matched for age, sex, and smoking status. Patients' sense of smell and taste was examined at diagnosis and 3 months after successful therapeutic surgery leading to clinical and biochemical remission. Odor threshold, discrimination, and identification were measured with \textquotedblSniffin' Sticks\textquotedbl, taste was measured with \textquotedblTaste Strips\textquotedbl. Perceived sense of smell and taste was retrieved via a questionnaire. RESULTS Patients with florid CS had significantly reduced smell (total smell score 30.3 vs. 34.4, p < 0.0005) and taste scores (9.5 vs. 12.0, p < 0.0005) compared to controls and significantly more frequently hyposmia (55 vs. 2.5%, p < 0.0005), hypogeusia (40 vs. 0%, p < 0.0005), and self-reported chemosensory impairment (60 vs. 0%, p < 0.0005). Three months after successful surgery, CS patients showed significant improvement of odor threshold (8.1 vs. 7.0, p < 0.0005), odor discrimination (12.0 vs. 11.0, p = 0.003), total smell score (33.4 vs. 30.3, p < 0.0005), and taste (11.5 vs. 9.5, p = 0.003). CONCLUSIONS Chemosensory dysfunction is a novel and clinically relevant feature of CS

Recurrence after pituitary surgery in adult Cushing's disease: a systematic review on diagnosis and treatment

PURPOSE Recurrence after pituitary surgery in Cushing's disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. METHODS We systematically screened the literature regarding recurrent and persistent Cushing's disease using the MESH term Cushing's disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review. RESULTS AND CONCLUSIONS Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient

Personality traits and physical complaints in patients with acromegaly : a cross sectional multi-center study with analysis of influencing factors

Objective: Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities. Design: Cross sectional, multicentric. Methods: 129 patients (M/W 65/64, 58.3±12.7 ys., 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented. Results: Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable. Conclusions: We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity

TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome

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

Genetic and epigenetic characterization of posterior pituitary tumors

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets