A new model of the algorithm for differential diagnosis of Cushing’s disease and ectopic ACTH dependent syndrome

SUMMARY: differential diagnosis of ACTH-dependent hypercorticism has certain difficulties, due to the lack of high diagnostic accuracy of noninvasive research methods. Performing catheterization of the inferior petrosal sinuses makes it possible to solve this problem, however, there is practically no information in the literature about personalized patient management tactics depending on the result obtained, especially when using several gradients.

PURPOSE OF THE STUDY: search for a new model of differential diagnosis of Cushing’s disease and ectopic ACTH dependent syndrome.

MATERIALS AND METHODS: cohort single-center retro/prospective study of 70 patients with confirmed ACTHdependent Cushing’s syndrome. A number of indicators were calculated for differential diagnosis (central-peripheral ratio, prolactin-normalized ACTH ratio). Based on the data obtained, we have developed a score scale for assessing the probability of corticotropinoma and an algorithm for differential diagnosis of Cushing’s disease and ectopic ACTHdependent syndrome.

RESULTS: The presented new algorithm for differential diagnosis of Cushing’s disease and ectopic ACTH-dependent syndrome based on bilateral simultaneous catheterization of the cavernous and inferior petrosal sinuses allows timely topical diagnosis with a low risk of diagnostic error, which in turn makes it possible to immediately perform endoscopic adenomectomy, thereby preventing the progression of hypercorticism.

CONCLUSIONS: the developed scoring scale and algorithm allow the clinician to perform not only differential diagnosis of Cushing’s disease and ectopic ACTH–dependent syndrome, but also to determine the further treatment tactics of a particular patient.

1. Ceccato F, Barbot M, Mondin A, et al. Dynamic Testing for D ifferential Diagnosis of ACTH-Dependent Cushing Syndrome: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2023;108(5): e178-e188. http://dx.doi.org/10.1210/clinem/dgac686

2. Chen K, Chen S, Lu L, et al. An Optimized Pathway for the Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome Based on Low-Dose Dexamethasone Suppression Test. Front Endocrinol (Lausanne). 2021;12:720823. Published 2021 Sep 2. http://dx.doi.org/10.3389/fendo.2021.720823

3. Chen S, Chen K, Wang S, et al. The Optimal Cut–off of BIPSS in Differential Diagnosis of ACTH–dependent Cushing’s Syndrome: Is Stimulation Necessary? J Clin Endocrinol Metab. 2020;105(4): dgz194. http://dx.doi.org/10.1210/clinem/dgz194

4. Detomas M, Ritzel K, Nasi-Kordhishti I, et al. Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing’s syndrome: results from a retrospective multicenter study [published online ahead of print, 2023 May 18]. Eur J Endocrinol. 2023; lvad050. http://dx.doi.org/10.1093/ejendo/lvad050

5. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847–875. https://doi.org/10.1016/s2213–8587 (21) 00235‑7

6. Govindarajan V, Lu VM, Clarke JE, et al. Positive predictive value and trends of inferior petrosal sinus sampling (IPSS) in diagnosing cushing disease and ectopic ACTH secretion: A systematic review and meta-analysis. Clin Neurol Neurosurg. 2022;220:107350. http://dx.doi.org/10.1016/j.clineuro.2022.107350

7. Gupta R, Walia R, Ahuja C, et al. Limited Invasive Protocol: Optimizing Diagnostic Modalities in Corticotropin Mediated Cushing Syndrome. Endocr Pract. 2022;28(8):767–773. http://dx.doi.org/10.1016/j.eprac.2022.04.013

8. Honegger J, Nasi-Kordhishti I. Surgery and perioperative management of patients with Cushing’s disease. J Neuroendocrinol. 2022;34(8): e13177. http://dx.doi.org/10.1111/jne.13177

9. Ishida A, Asakuno K, Shiramizu H, et al. Revalidation of inferior petrosal sinus sampling: the latest results from a single-center experience. Endocr J. 2021;68(10):1217–1223. http://dx.doi.org/10.1507/endocrj.EJ21–0156

10. Jones PS, Swearingen B. Pituitary surgery in Cushing’s disease: first line treatment and role of reoperation. Pituitary. 2022;25(5):713–717. http://dx.doi.org/10.1007/s11102‑022‑01254‑8

11. Losa M, Albano L, Bailo M, et al. Role of radiosurgery in the treatment of Cushing’s disease. J Neuroendocrinol. 2022;34(8): e13134. http://dx.doi.org/10.1111/jne.13134

12. Lyu X, Zhang D, Pan H, et al. A noninvasive scoring model for the differential diagnosis of ACTH-dependent Cushing’s syndrome: a retrospective analysis of 311 patients based on easy-to-use parameters. Endocrine. 2022;78(1):114–122. http://dx.doi.org/10.1007/s12020‑022‑03081‑0

13. Lyu X, Zhang D, Pan H, et al. Machine learning models for differential diagnosis of Cushing’s disease and ectopic ACTH secretion syndrome. Endocrine. 2023;80(3):639–646. http://dx.doi.org/10.1007/s12020‑023‑03341‑7

14. Matur AV, Body AM, Johnson MD, et al. An algorithm to improve lateralization accuracy of inferior petrosal sinus sampling: procedural nuances for complex patterns of venous drainage. Patient series. J Neurosurg Case Lessons. 2021;2(13): CASE 21374. Published 2021 Sep 27. http://dx.doi.org/10.3171/CASE 21374

15. Nieman LK. Recent Updates on the Diagnosis and Management of Cushing’s Syndrome. Endocrinol Metab (Seoul). 2018;33(2):139–146. http://dx.doi.org/10.3803/EnM.2018.33.2.139

16. Perlman JE, Johnston PC, Hui F, et al. Pitfalls in Performing and Interpreting Inferior Petrosal Sinus Sampling: Personal Experience and Literature Review. J Clin Endocrinol Metab. 2021;106(5): e1953-e1967. https://dx.doi.org/10.1210/clinem/dgab012

17. Valizadeh M, Ahmadi AR, Ebadinejad A, et al. Diagnostic accuracy of bilateral inferior petrosal sinus sampling using desmopressin or corticotropic-releasing hormone in ACTH-dependent Cushing’s syndrome: A systematic review and meta-analysis. Rev Endocr Metab Disord. 2022;23(5):881–892. http://dx.doi.org/10.1007/s11154–022–09723-y

18. Vassiliadi DA, Mourelatos P, Kratimenos T, et al. Inferior petrosal sinus sampling in Cushing’s syndrome: usefulness and pitfalls. Endocrine. 2021;2;73(3):530–9. http://dx.doi.org/10.1007/s12020‑021‑02764‑4

19. Wang H, Ba Y, Xing Q, et al. Differential diagnostic value of bilateral inferior Petrosal sinus sampling (BIPSS) in ACTH-dependent Cushing syndrome: a systematic review and Meta-analysis. BMC Endocr Disord. 2020;20(1):143. Published 2020 Sep 17. http://dx.doi.org/10.1186/s12902‑020‑00623‑3