Abstract

Neuroendocrine neoplasms (NENs) causing ectopic Cushing's syndrome (ECS) are rare and challenging to treat. In this retrospective cohort study, we aimed to evaluate different approaches for bilateral adrenalectomy (BA) as a treatment option in ECS. Fifty-three patients with ECS caused by a NEN (35 females/18 men; mean +/- SD age: 53 +/- 15 years) were identified from medical records. Epidemiological and clinical parameters, survival, indications for surgery and timing, as well as duration of surgery, complications and surgical techniques, were collected and further analysed. The primary tumour location was thorax (n = 30), pancreas (n = 14) or unknown (n = 9). BA was performed in 37 patients. Median time from diagnosis of ECS to BA was 2 months (range 1-10 months). Thirty-two patients received different steroidogenesis inhibitors before BA to control hypercortisolaemia. ECS resolved completely after surgery in 33 patients and severe peri- or postoperative complications were detected in 12 patients. There were fewer severe complications in the endoscopic group compared to open surgery (p = .030). Posterior retroperitoneoscopic BA performed simultaneously by a two surgeon approach had the shortest operating time (p = .001). Despite the frequent use of adrenolytic treatment, BA was necessary in a majority of patients to gain control over ECS. Complication rate was high, probably as a result of the combination of metastatic disease and metabolic disorders caused by high cortisol levels. The two surgeon approach BA may be considered as the method of choice in ECS compared to other BA approaches as a result of fewer complications and a shorter operating time.


Authors

Lase, Ieva;  Gronberg, Malin;  Norlen, Olov;  Stalberg, Peter;  Welin, Staffan;  Janson, Eva Tiensuu

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  • pre-publication peer review (FINAL ROUND)
    Decision Letter
    2021/08/10

    10-Aug-2021

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    Reviewer(s)' Comments to Author:

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    Author Response
    2021/08/06

    Manuscript ID JNE-21-0063-OA

    Uppsala August 2021

    Dear Editor in Chief,

    Thank you for considering our manuscript "Adrenalectomy in Ectopic Cushing’s syndrome: a retrospective cohort study from a tertiary care centre" by Ieva Lase, Malin Grönberg, Olov Norlén, Peter Stålberg, Staffan Welin and Eva Tiensuu Janson for publication. We are grateful for the thorough review of our manuscript. Please see our responses to the reviewer’s comments below. All added/modified parts are highlighted in yellow throughout the manuscript.
    We hope you will find the responses satisfactory.
    Please see our response to reviewers in the attached file.
    If you have any questions, do not hesitate to contact us.

    It should be noticed that one of the authors Eva Tiensuu Janson is already previously registered in the system with an incorrect surname and it was not possible for me to change it: the correct surname is Eva Tiensuu Janson.

    Sincerely yours,

    Ieva Lase



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  • pre-publication peer review (ROUND 1)
    Decision Letter
    2021/06/29

    29-Jun-2021

    Dear Dr Lase,

    Manuscript ID JNE-21-0063-OA entitled "Adrenalectomy in Ectopic Cushing’s syndrome: a retrospective cohort study from a tertiary care centre".

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    Reviewer(s)' Comments to Author:

    Referee: 1

    Comments to the Author
    This study investigates the usefulness of BA in ectopic Cushing’s syndrome. The study has limitations, mostly mentioned by the authors. I am concerned about the novelty of data.

    Strength:
    -large series of patients with ECS (n=53)

    Weakness:
    -monocentric study
    -retrospective case series
    -long study time (1984-2019) increasing heterogeneity of patient characteristics

    Novel aspects:
    -comparison of endoscopic vs open surgery group
    -posterior retroperitoneal bilateral adrenalectomy vs laparoscopic BA
    -Grading of complications using Clavien-Dindo classification

    Confirmatory data:
    -causes of ectopic CS
    -time to diagnosis
    -BA as treatment of ECS
    -open vs laparoscopic BA
    -overall survival
    -steroidogenesis inhibitors in ECS

    Major Criticism:

    Introduction: I am missing a hypothesis.

    Line 95: “none of the patients had small-cell lung cancer…”. This is unusual and can only be explained by a bias, an a-priori exclusion of these patients. However, this aspect should be elucidated and explained by the authors.

    Patients and methods: the authors do not elaborate on imaging techniques performed in ECS patients to localize the source of ECS. Since DOTATATE PET has been introduced 15 years ago it would be interesting to know whether the occult ectopic group has been shrinking over the decades.

    Line 191 ff: please define, what you mean by “ECS resolved completely…”. It is quite unlikely, that all features of CS resolved, such as obesity, diabetes, hypertension or osteoporosis. And in line 279, authors mention that still one third of patients suffered from residual hypertension and diabetes.

    Line 210: please give details of “multiple hormone secretion”

    Discussion: please define in more detail, which of your data are novel, and which are confirmatory

    Minor criticism:
    Line 48, prevalence of ECS: true ectopic CRH syndrome is extremely rare, and this should be mentioned here, otherwise it could be falsely assumed, that ectopic ACTH and CRH syndrome are similar in prevalence

    Line 62, CT-guided percutaneous adrenal ablation: the references 7-10 are all case reports, and no head-to-head comparison has been performed between surgical BA and this method. Therefore, in my view, suggesting it as an alternately to BA is preliminary and should be avoided.

    Line 183 ff, hydrocortisone: please also give dose of mineralocorticoid replacement (i.e. fludrocortisone)

    Referee: 2

    Comments to the Author
    Always tricky to make constructive comments on this type of paper. Small numbers, rare condition, collected from 3 centres over nearly 30 year period. Medicine has changed so much in this time period that it is difficult to draw too many conclusions and the authors recognise this.

    Plus points: Raises awareness of a rare topic and may help to stimulate further research into the topic. ENETS already has set up a working group which will be covering part of this topic. The recommendation of laparoscopic surgery is not unexpected, however 5 of the 18 seemed to need conversion to open if i read correctly, quite a high%.

    Early surgery seemed to be recommended although in this series many of the early cases had higher risk factors. It is hard and harsh to be too critical about this kind of paper mainly because there is less evidence base to support or challenge.
    So well done on collecting the series, it is flawed but at least we have some further information to inform our decision making in this challenging condition.

    Line 119 should read analgesics

    Table 3 ketoconazole is erratically spelled

    Reference 11 - is that correct?? H Y?? please confirm

    Decision letter by
    Cite this decision letter
    Reviewer report
    2021/06/21

    Always tricky to make constructive comments on this type of paper. Small numbers, rare condition, collected from 3 centres over nearly 30 year period. Medicine has changed so much in this time period that it is difficult to draw too many conclusions and the authors recognise this.

    Plus points: Raises awareness of a rare topic and may help to stimulate further research into the topic. ENETS already has set up a working group which will be covering part of this topic. The recommendation of laparoscopic surgery is not unexpected, however 5 of the 18 seemed to need conversion to open if i read correctly, quite a high%.

    Early surgery seemed to be recommended although in this series many of the early cases had higher risk factors. It is hard and harsh to be too critical about this kind of paper mainly because there is less evidence base to support or challenge.
    So well done on collecting the series, it is flawed but at least we have some further information to inform our decision making in this challenging condition.

    Line 119 should read analgesics

    Table 3 ketoconazole is erratically spelled

    Reference 11 - is that correct?? H Y?? please confirm

    Reviewed by
    Cite this review
    Reviewer report
    2021/05/17

    This study investigates the usefulness of BA in ectopic Cushing’s syndrome. The study has limitations, mostly mentioned by the authors. I am concerned about the novelty of data.

    Strength:
    -large series of patients with ECS (n=53)

    Weakness:
    -monocentric study
    -retrospective case series
    -long study time (1984-2019) increasing heterogeneity of patient characteristics

    Novel aspects:
    -comparison of endoscopic vs open surgery group
    -posterior retroperitoneal bilateral adrenalectomy vs laparoscopic BA
    -Grading of complications using Clavien-Dindo classification

    Confirmatory data:
    -causes of ectopic CS
    -time to diagnosis
    -BA as treatment of ECS
    -open vs laparoscopic BA
    -overall survival
    -steroidogenesis inhibitors in ECS

    Major Criticism:

    Introduction: I am missing a hypothesis.

    Line 95: “none of the patients had small-cell lung cancer…”. This is unusual and can only be explained by a bias, an a-priori exclusion of these patients. However, this aspect should be elucidated and explained by the authors.

    Patients and methods: the authors do not elaborate on imaging techniques performed in ECS patients to localize the source of ECS. Since DOTATATE PET has been introduced 15 years ago it would be interesting to know whether the occult ectopic group has been shrinking over the decades.

    Line 191 ff: please define, what you mean by “ECS resolved completely…”. It is quite unlikely, that all features of CS resolved, such as obesity, diabetes, hypertension or osteoporosis. And in line 279, authors mention that still one third of patients suffered from residual hypertension and diabetes.

    Line 210: please give details of “multiple hormone secretion”

    Discussion: please define in more detail, which of your data are novel, and which are confirmatory

    Minor criticism:
    Line 48, prevalence of ECS: true ectopic CRH syndrome is extremely rare, and this should be mentioned here, otherwise it could be falsely assumed, that ectopic ACTH and CRH syndrome are similar in prevalence

    Line 62, CT-guided percutaneous adrenal ablation: the references 7-10 are all case reports, and no head-to-head comparison has been performed between surgical BA and this method. Therefore, in my view, suggesting it as an alternately to BA is preliminary and should be avoided.

    Line 183 ff, hydrocortisone: please also give dose of mineralocorticoid replacement (i.e. fludrocortisone)

    Reviewed by
    Cite this review
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