Skip to main content
SpringerLink
Log in

Clinical profile and treatment outcomes of patients with ectopic ACTH syndrome compared to Cushing disease: a single-center experience

  • Original Paper
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

We aimed to evaluate and compare the clinical, biochemical and radiological profile and outcomes of patients with ectopic ACTH syndrome (EAS) and Cushing disease (CD) treated over a period of 10 years (2013–2022).

Methods

In this ambispective observational study, we collected data for 146 patients with ACTH-dependent CS (EAS, n = 23; CD, n = 94; occult ACTH source, n = 29). Relevant details were filled in a predesigned proforma and outcomes were ascertained at the most recent visit.

Results

EAS was more common in males (65.2 vs. 27.6%, p < 0.001). Patients with EAS had a shorter duration of symptoms [12 (6–12) vs. 31.5 (15–48) months, p < 0.001] and were more likely to have hypokalemia (82.6 vs. 21.0%, p = 0.001), pedal edema (65.2 vs. 34.2%, p = 0.015), weight loss (34.8 vs. 4.0%, p < 0.001) and systemic infection (30.4 vs. 6.5%, p = 0.006). They also had significantly higher 8 a.m. serum cortisol, midnight serum and salivary cortisol and 8 a.m. plasma ACTH levels. Bronchial carcinoid (n = 10, 43.5%) was the most common etiology of EAS. Bilateral adrenalectomy was performed in 11 (47.8%) patients with EAS. Eight patients (34.8%) with EAS died at the last follow-up, of whom 7 (87.5%) had metastatic disease. In CD group, overall remission rate was 69.4% (56.1%, early and 13.3%, delayed) and 26.3% of patients with an initial remission had recurrence.

Conclusions

Bronchial carcinoid was the most common cause of EAS in our cohort. Bilateral adrenalectomy was performed in approximately every 1 in 2 patients with EAS and approximately every 1 in 3 patients expired till the last follow-up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The data sets generated and analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. S. Wengander, P. Trimpou, E. Papakokkinou, O. Ragnarsson, The incidence of endogenous Cushing’s syndrome in the modern era. Clin. Endocrinol. 91(2), 263–270 (2019)

    Article  CAS  Google Scholar 

  2. J. Newell-Price, X. Bertagna, A.B. Grossman, L.K. Nieman, Cushing’s syndrome. Lancet 367, 1605–1617 (2006)

    Article  CAS  PubMed  Google Scholar 

  3. J. Young, M. Haissaguerre, O. Viera-Pinto, O. Chabre, E. Baudin, A. Tabarin, Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur. J. Endocrinol. 182(4), R29–R58 (2020)

    Article  CAS  PubMed  Google Scholar 

  4. G.W. Liddle, W.E. Nicholson, D.P. Island, D.N. Orth, K. Abe, S.C. Lowder, Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog. Horm. Res. 25, 283–314 (1969)

    CAS  PubMed  Google Scholar 

  5. J.P. Aniszewski, W.F. Young Jr, G.B. Thompson, C.S. Grant, J.A. van Heerden, Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J. Surg. 25(7), 934–940 (2001)

    Article  CAS  PubMed  Google Scholar 

  6. I. Ilias, D.J. Torpy, K. Pacak, N. Mullen, R.A. Wesley, L.K. Nieman, Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J. Clin. Endocrinol. Metab. 90, 4955–4962 (2005)

    Article  CAS  PubMed  Google Scholar 

  7. A.M. Isidori, G.A. Kaltsas, C. Pozza, V. Frajese, J. Newell-Price, R.H. Reznek et al. The Ectopic Adrenocorticotropin Syndrome: clinical features, diagnosis, managment and long-term follow-up. J. Clin. Endocrinol. Metab. 91, 371–377 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. L.R. Salgado, M.C. Fragoso, M. Knoepfelmacher, M.C. Machado, S. Domenice, M.A. Pereira, B.B. de Mendonça, Ectopic ACTH syndrome: our experience with 25 cases. Eur. J. Endocrinol. 155(5), 725–733 (2006)

    Article  CAS  PubMed  Google Scholar 

  9. S. Ejaz, R. Vassilopoulou-Sellin, N.L. Busaidy, M.I. Hu, S.G. Waguespack, C. Jimenez, A.K. Ying, M. Cabanillas, M. Abbara, M.A. Habra, Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer 117(Oct), 4381–4389 (2011)

    Article  CAS  PubMed  Google Scholar 

  10. A.C. Ammini, N. Tandon, N. Gupta, A.S. Bhalla, K. Devasenaspathy, G. Kumar, J.P. Sahoo, S. Chittawar, J. Philip, M.P. Baruah, C.S. Dwarakanath, S. Tripathi, Etiology and clinical profile of patients with Cushing’s syndrome: a single center experience. Indian J. Endocrinol. Metab. 18(1), 99–105 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  11. H.R. Kakade, R. Kasaliwal, V.S. Jagtap, A. Bukan, S.R. Budyal, S. Khare et al. Ectopic ACTH-secreting syndrome: a single-center experience. Endocr. Pract. 19(6), 1007–1014 (2013)

    Article  PubMed  Google Scholar 

  12. S. Sathyakumar, T.V. Paul, H.S. Asha, B.R. Gnanamuthu, M.J. Paul, D.T. Abraham, S. Rajaratnam, N. Thomas, Ectopic Cushing’s syndrome: a ten year experience from a tertiary care centre in Southern India. Endocr. Pract. 23(8), 907–914 (2017)

    Article  PubMed  Google Scholar 

  13. R. Gupta, N. Jain, A. Bhansali, S.K. Bhadada, R. Walia, Demystifying the relevance of size amongst macro-and micro-corticotropinoma: experience in 206 patients. Indian J. Endocrinol. Metab. 26(3), 275–281 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. G. Zada, Diagnosis and multimodality management of Cushing’s disease: a practical review. Int. J. Endocrinol. 2013, 893781 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  15. A. Bhansali, R. Walia, S.S. Rana, P. Dutta, B.D. Radotra, N. Khandelwal, S.K. Bhadada, Ectopic Cushing’s syndrome: experience from a tertiary care centre. Indian J. Med. Res. 129, 33–41 (2009)

    CAS  PubMed  Google Scholar 

  16. L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, V.M. Montori, The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93(5), 1526–1540 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. C.A. Meier, B.M. Biller, Clinical and biochemical evaluation of Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 26(4), 741–762 (1997)

    Article  CAS  PubMed  Google Scholar 

  18. A.C. Ammini, S. Bhattacharya, J.P. Sahoo, J. Philip, N. Tandon, R. Goswami, V.J. Jyotsna, R. Khadgawat, S. Chumber, A. Seth, A.K. Karak, B.S. Sharma, P.S. Chandra, A. Suri, M.S. Sharma, S.S. Kale, M. Singh, Cushing’s disease: results of treatment and factors affecting outcome. Hormones 10(3), 222–229 (2011)

    Article  PubMed  Google Scholar 

  19. S.T. Sharma, L.K. Nieman, Is prolactin measurement of value during inferior petrosal sinus sampling in patients with ACTH-dependent Cushing’s syndrome? J. Endocrinol. Invest. 36(11), 1112–1116 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. B. Zampetti, E. Grossrubatscher, P. DalinoCiaramella, E. Boccardi, P. Loli, Bilateral inferior petrosal sinus sampling. Endocr. Connect. 5(4), R12–R25 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. H. Boro, S. Alam, A. Goyal, S.D. Gupta, N. Damle, D. Kandasamy, R. Khadgawat, N. Tandon, Pituitary acrogigantism and ectopic Cushing’s syndrome. Lancet Diabetes Endocrinol. 9(5), 318 (2021)

    Article  PubMed  Google Scholar 

  22. E. Valassi, A. Santos, M. Yaneva, M. Tóth, C.J. Strasburger, P. Chanson, J.A. Wass, O. Chabre, M. Pfeifer, R.A. Feelders, S. Tsagarakis, P.J. Trainer, H. Franz, K. Zopf, S. Zacharieva, S.W. Lamberts, A. Tabarin, S.M. Webb; ERCUSYN Study Group, The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur. J. Endocrinol. 165(3), 383–392 (2011)

    Article  CAS  PubMed  Google Scholar 

  23. J. More, J. Young, Y. Reznik, G. Raverot, F. Borson-Chazot, V. Rohmer, E. Baudin, R. Coutant, A. Tabarin, Groupe Français des Tumeurs Endocrines (GTE). Ectopic ACTH syndrome in children and adolescents. J. Clin. Endocrinol. Metab. 96(5), 1213–1222 (2011)

    Article  CAS  PubMed  Google Scholar 

  24. A.S. Karageorgiadis, G.Z. Papadakis, J. Biro, M.F. Keil, C. Lyssikatos, M.M. Quezado, M. Merino, D.S. Schrump, E. Kebebew, N.J. Patronas, M.K. Hunter, M.R. Alwazeer, L.P. Karaviti, A.E. Balazs, M.B. Lodish, C.A. Stratakis, Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. J. Clin. Endocrinol. Metab. 100(1), 141–148 (2015)

    Article  CAS  PubMed  Google Scholar 

  25. A. Goyal, U. Gupta, D. Kandasamy, R. Khadgawat, Severe hypercortisolism with hypokalemic alkalosis mimicking ectopic Cushing syndrome in a patient with Cushing disease due to pituitary microadenoma. Indian J. Endocrinol. Metab. 22(6), 860–863 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. A.M. Isidori, E. Sbardella, M.C. Zatelli, M. Boschetti, G. Vitale, A. Colao, R. Pivonello, A.B.C.S. Group, Conventional and nuclear medicine imaging in ectopic Cushing’s syndrome: a systematic review. J. Clin. Endocrinol. Metab. 100(9), 3231–3244 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. K.I. Alexandraki, A.B. Grossman, The ectopic ACTH syndrome. Rev. Endocr. Metab. Disord. 11, 117–126 (2010)

    Article  PubMed  Google Scholar 

  28. A.R. Hayes, A.B. Grossman, The ectopic adrenocorticotropic hormone syndrome: rarely easy, always challenging. Endocrinol. Metab. Clin. North Am. 47(2), 409–425 (2018)

    Article  PubMed  Google Scholar 

  29. P. Bansal, A. Lila, M. Goroshi, S. Jadhav, N. Lomte, K. Thakkar, A. Goel, A. Shah, S. Sankhe, N. Goel, N. Jaguste, T. Bandgar, N. Shah, Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing’s disease. Endocr. Connect. 6(8), 625–636 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. A. Dutta, N. Gupta, R. Walia, A. Bhansali, P. Dutta, S.K. Bhadada, R. Pivonello, C.K. Ahuja, S. Dhandapani, A. Hajela, C. Simeoli, N. Sachdeva, U.N. Saikia, Remission in Cushing’s disease is predicted by cortisol burden and its withdrawal following pituitary surgery. J. Endocrinol. Invest. 44(9), 1869–1878 (2021)

    Article  CAS  PubMed  Google Scholar 

  31. S. Petersenn, A. Beckers, D. Ferone, A. Van Der Lely, J. Bollerslev, M. Boscaro, T. Brue, P. Bruzzi, F.F. Casanueva, P. Chanson et al. Therapy of endocrine disease: outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. Eur. J. Endocrinol. 172(6), R227–R239 (2015)

    Article  CAS  PubMed  Google Scholar 

  32. K.I. Alexandraki, G.A. Kaltsas, A.M. Isidori, H.L. Storr, F. Afshar, I. Sabin, S.A. Akker, S.L. Chew, W.M. Drake, J.P. Monson, G.M. Besser, A.B. Grossman, Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study. Eur. J. Endocrinol. 168(4), 639–648 (2013)

    Article  CAS  PubMed  Google Scholar 

  33. M. Doi, T. Sugiyama, H. Izumiyama, T. Yoshimoto, Y. Hirata, Clinical features and management of ectopic ACTH syndrome at a single institute in Japan. Endocr. J. 57(12), 1061–1069 (2010)

    Article  PubMed  Google Scholar 

  34. W.Q. Wang, L. Ye, Y.F. Bi, H.Y. Zhao, S.Y. Sun, Z.Y. Tang, Y.J. Zhao, W.Q. Fang, Z.Y. Chen, K.M. Chen, X.L. Jin, G. Ning, Six cases of ectopic ACTH syndrome caused by thymic carcinoid. J. Endocrinol. Invest. 29(4), 293–297 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the faculty and residents, present and past, from the Departments of Endocrinology and Metabolism, Radiodiagnosis, Nuclear Medicine, General Surgery, Urology, Neurosurgery, Pathology and Anesthesiology at All India Institute of Medical Sciences, New Delhi for being involved in the care of study participants. We also acknowledge the help provided by the Department of Hospital Administration at our institute for retrieving the medical records of study participants.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

    Bhawna Attri, Alpesh Goyal, Yashdeep Gupta, Atul Dhingra, Viveka P. Jyotsna & Nikhil Tandon

  2. Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

    Mani Kalaivani

  3. Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India

    Devasenathipathy Kandasamy

  4. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

    Shipra Agarwal

  5. Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India

    Shamim A. Shamim & Nishikant Damle

  6. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

    Ashish Suri

Authors
  1. Bhawna Attri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alpesh Goyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mani Kalaivani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Devasenathipathy Kandasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yashdeep Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shipra Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shamim A. Shamim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nishikant Damle
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Atul Dhingra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Viveka P. Jyotsna
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ashish Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nikhil Tandon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by B.A., A.G., M.K. and N.T. The first draft of the manuscript was written by B.A. and A.G. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Alpesh Goyal.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of All India Institute of Medical Sciences, New Delhi (IEC No. IECPG 265/24.03.2021).

Consent to participate

Informed consent was obtained from all individual participants prospectively included in the study.

Consent to publish

The data published in this study have been anonymized and that all identifiers have been irreversibly removed and study subjects are no longer identifiable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Attri, B., Goyal, A., Kalaivani, M. et al. Clinical profile and treatment outcomes of patients with ectopic ACTH syndrome compared to Cushing disease: a single-center experience. Endocrine 80, 408–418 (2023). https://doi.org/10.1007/s12020-022-03298-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-022-03298-z

Keywords

Search

Navigation