Pulmonary cysts as a diagnostic indicator of Birt-Hogg-Dubé syndrome in patients with renal neoplasm

Amreen Shakur; Grant D. Stewart; Timothy J. Sadler; Judith L. Babar; Anne Y. Warren; Stephen Scullion; Abhishekh H. Ashok; Sumit Karia; Igor Chipurovski; James Whitworth; Stefan J. Marciniak; Eamonn R. Maher; Maria TA Wetscherek

doi:10.1186/s13244-025-02053-y

Pulmonary cysts as a diagnostic indicator of Birt-Hogg-Dubé syndrome in patients with renal neoplasm

Amreen Shakur, Grant D. Stewart, Timothy J. Sadler, Judith L. Babar, Anne Y. Warren, Stephen Scullion, Abhishekh H. Ashok, Sumit Karia, Igor Chipurovski, James Whitworth, Stefan J. Marciniak, Eamonn R. Maher, Maria TA Wetscherek^*

^*Corresponding author for this work

Cambridge University Hospitals NHS Foundation Trust, Department of Radiology, Addenbrooke’s Hospital, Cambridge, UK, ROR: https://ror.org/04v54gj93, GRID: grid.24029.3d, ISNI: 0000 0004 0383 8386
Cambridge Biomedical Campus, Department of Surgery, University of Cambridge, Cambridge, UK, ROR: https://ror.org/013meh722, GRID: grid.5335.0, ISNI: 0000 0001 2188 5934
University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Department of Radiology, Cambridge, UK, ROR: https://ror.org/04v54gj93, GRID: grid.24029.3d, ISNI: 0000 0004 0383 8386
University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Department of Pathology, Cambridge, UK, ROR: https://ror.org/04v54gj93, GRID: grid.24029.3d, ISNI: 0000 0004 0383 8386
West Suffolk Hospital NHS Foundation Trust, Department of Radiology, Bury St Edmunds, UK, ROR: https://ror.org/02ts7ew79, GRID: grid.417049.f, ISNI: 0000 0004 0417 1800
Cambridge Biomedical Campus, Department of Urology, University of Cambridge, Cambridge, UK, ROR: https://ror.org/013meh722, GRID: grid.5335.0, ISNI: 0000 0001 2188 5934
University of Cambridge and NIHR Cambridge Biomedical Research Centre, Department of Medical Genetics, Cambridge, UK, GRID: grid.529246.e, ISNI: 0000 0004 8340 8617
Royal Papworth Hospital NHS Foundation Trust, Respiratory Medicine, Cambridge, UK, ROR: https://ror.org/01qbebb31, GRID: grid.412939.4, ISNI: 0000 0004 0383 5994

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Abstract

Objectives: To assess the presence and CT features of pulmonary cysts (PCs) in patients with renal neoplasms (RN) as a hallmark of Birt-Hogg-Dubé syndrome (BHDS). Materials and methods: Single institution retrospective study of all patients with histological RN between May 2014 and May 2020. Individuals with non-renal neoplasm, nephroblastoma, benign cysts, < 18 years old, or without thoracic CT were excluded. Demographics, history of smoking, pneumothorax and cutaneous fibrofolliculomas/trichodischomas, family history of pneumothorax or RN, and genetic testing were recorded. Number, location, distribution and morphology of PCs were assessed on thoracic CT. Differences between patients with positive (BHD+) and negative (BHD−) genetics were analysed. An independent cohort of 10 BHDS patients was added to calculate the diagnostic accuracy of cyst features. Results: Of 1475 patients with RN, 127 (8.6%) had PCs; 40 underwent genetic testing (median age 56 [49–68], 28 men), and 6/127 (4.7%) individuals tested positive for BHDS. BHD+ had significantly more and larger cysts, affecting more lobes (p < 0.01). Higher prevalence of PCs with a perivascular (100% vs. 37%; p = 0.01) and interlobular septal location (100% vs. 16%; p < 0.001), and perilymphatic distribution (100% vs. 5%; p < 0.001) was found in BHD+. All BHD+ had elliptical, irregular, and variable shape PCs, compared to a lower prevalence of these in BHD− (p < 0.01). Traversing vein sign was more common in BHD+ (83% vs. 24%; p = 0.01). The highest accuracy was achieved for perilymphatic distribution (97%), followed by irregular shape (94%) and interlobular septal location (91%). Conclusion: Specific CT features of PC in patients with RN can be highly indicative of BHDS. Critical relevance statement: Radiologists can play a crucial role in the diagnosis of Birt-Hogg-Dubé syndrome (BHDS) by recognising specific CT features of pulmonary cysts; a diagnosis of BHDS has implications for family testing and timely, life-long screening for renal neoplasm. Key Points: Birt-Hogg-Dubé syndrome (BHDS) should be considered in patients with renal neoplasms and multiple pulmonary cysts. A lower zone predominant, perilymphatic distribution of pulmonary cysts is a strong indicator of BHDS. Identifying specific CT features of pulmonary cysts can improve recognition of BHDS.

Original language	English
Article number	169
Number of pages	11
Journal	Insights into Imaging
Volume	16
Early online date	6 Aug 2025
DOIs	https://doi.org/10.1186/s13244-025-02053-y
Publication status	Published - 6 Aug 2025

Bibliographical note

Copyright © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

Funding

The following authors receive research support from the following institutions: G.D.S. receives research support from Cancer Research UK, YCR and NIHR. A.Y.W. receives research support from Cancer Research UK Cambridge Centre [C9685/A25177] and NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]. A.H.A. [NIHR ACF-2019-14-004] and E.R.M. [NIHR203312] receive research support from NIHR. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. J.W. receives research support from the University of Cambridge. S.J.M. receives research support from the Myrovlytis Trust [MT21_1] and [MT22_15], and from the LifeArc Centre. M.T.A.W. receives research support from the Myrovlytis Trust [MT22_15]. No funding was received to conduct this specific study.

Keywords

Birt-Hogg-Dubé syndrome
Cystic lung disease
Renal cancer
Computed tomography

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10.1186/s13244-025-02053-yLicence: CC BY 4.0

Pulmonary cysts as a diagnostic indicator of Birt-Hogg-Dubé syndrome in patients with renal neoplasm
Copyright © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
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Cite this

Shakur, A., Stewart, G. D., Sadler, T. J., Babar, J. L., Warren, A. Y., Scullion, S., Ashok, A. H., Karia, S., Chipurovski, I., Whitworth, J., Marciniak, S. J., Maher, E. R., & Wetscherek, M. TA. (2025). Pulmonary cysts as a diagnostic indicator of Birt-Hogg-Dubé syndrome in patients with renal neoplasm. Insights into Imaging, 16, Article 169. https://doi.org/10.1186/s13244-025-02053-y

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abstract = "Objectives: To assess the presence and CT features of pulmonary cysts (PCs) in patients with renal neoplasms (RN) as a hallmark of Birt-Hogg-Dub{\'e} syndrome (BHDS). Materials and methods: Single institution retrospective study of all patients with histological RN between May 2014 and May 2020. Individuals with non-renal neoplasm, nephroblastoma, benign cysts, < 18 years old, or without thoracic CT were excluded. Demographics, history of smoking, pneumothorax and cutaneous fibrofolliculomas/trichodischomas, family history of pneumothorax or RN, and genetic testing were recorded. Number, location, distribution and morphology of PCs were assessed on thoracic CT. Differences between patients with positive (BHD+) and negative (BHD−) genetics were analysed. An independent cohort of 10 BHDS patients was added to calculate the diagnostic accuracy of cyst features. Results: Of 1475 patients with RN, 127 (8.6%) had PCs; 40 underwent genetic testing (median age 56 [49–68], 28 men), and 6/127 (4.7%) individuals tested positive for BHDS. BHD+ had significantly more and larger cysts, affecting more lobes (p < 0.01). Higher prevalence of PCs with a perivascular (100% vs. 37%; p = 0.01) and interlobular septal location (100% vs. 16%; p < 0.001), and perilymphatic distribution (100% vs. 5%; p < 0.001) was found in BHD+. All BHD+ had elliptical, irregular, and variable shape PCs, compared to a lower prevalence of these in BHD− (p < 0.01). Traversing vein sign was more common in BHD+ (83% vs. 24%; p = 0.01). The highest accuracy was achieved for perilymphatic distribution (97%), followed by irregular shape (94%) and interlobular septal location (91%). Conclusion: Specific CT features of PC in patients with RN can be highly indicative of BHDS. Critical relevance statement: Radiologists can play a crucial role in the diagnosis of Birt-Hogg-Dub{\'e} syndrome (BHDS) by recognising specific CT features of pulmonary cysts; a diagnosis of BHDS has implications for family testing and timely, life-long screening for renal neoplasm. Key Points: Birt-Hogg-Dub{\'e} syndrome (BHDS) should be considered in patients with renal neoplasms and multiple pulmonary cysts. A lower zone predominant, perilymphatic distribution of pulmonary cysts is a strong indicator of BHDS. Identifying specific CT features of pulmonary cysts can improve recognition of BHDS.",

keywords = "Birt-Hogg-Dub{\'e} syndrome, Cystic lung disease, Renal cancer, Computed tomography",

author = "Amreen Shakur and Stewart, {Grant D.} and Sadler, {Timothy J.} and Babar, {Judith L.} and Warren, {Anne Y.} and Stephen Scullion and Ashok, {Abhishekh H.} and Sumit Karia and Igor Chipurovski and James Whitworth and Marciniak, {Stefan J.} and Maher, {Eamonn R.} and Wetscherek, {Maria TA}",

note = "Copyright {\textcopyright} The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.",

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T1 - Pulmonary cysts as a diagnostic indicator of Birt-Hogg-Dubé syndrome in patients with renal neoplasm

AU - Shakur, Amreen

AU - Stewart, Grant D.

AU - Sadler, Timothy J.

AU - Babar, Judith L.

AU - Warren, Anne Y.

AU - Scullion, Stephen

AU - Ashok, Abhishekh H.

AU - Karia, Sumit

AU - Chipurovski, Igor

AU - Whitworth, James

AU - Marciniak, Stefan J.

AU - Maher, Eamonn R.

AU - Wetscherek, Maria TA

N1 - Copyright © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

PY - 2025/8/6

Y1 - 2025/8/6

N2 - Objectives: To assess the presence and CT features of pulmonary cysts (PCs) in patients with renal neoplasms (RN) as a hallmark of Birt-Hogg-Dubé syndrome (BHDS). Materials and methods: Single institution retrospective study of all patients with histological RN between May 2014 and May 2020. Individuals with non-renal neoplasm, nephroblastoma, benign cysts, < 18 years old, or without thoracic CT were excluded. Demographics, history of smoking, pneumothorax and cutaneous fibrofolliculomas/trichodischomas, family history of pneumothorax or RN, and genetic testing were recorded. Number, location, distribution and morphology of PCs were assessed on thoracic CT. Differences between patients with positive (BHD+) and negative (BHD−) genetics were analysed. An independent cohort of 10 BHDS patients was added to calculate the diagnostic accuracy of cyst features. Results: Of 1475 patients with RN, 127 (8.6%) had PCs; 40 underwent genetic testing (median age 56 [49–68], 28 men), and 6/127 (4.7%) individuals tested positive for BHDS. BHD+ had significantly more and larger cysts, affecting more lobes (p < 0.01). Higher prevalence of PCs with a perivascular (100% vs. 37%; p = 0.01) and interlobular septal location (100% vs. 16%; p < 0.001), and perilymphatic distribution (100% vs. 5%; p < 0.001) was found in BHD+. All BHD+ had elliptical, irregular, and variable shape PCs, compared to a lower prevalence of these in BHD− (p < 0.01). Traversing vein sign was more common in BHD+ (83% vs. 24%; p = 0.01). The highest accuracy was achieved for perilymphatic distribution (97%), followed by irregular shape (94%) and interlobular septal location (91%). Conclusion: Specific CT features of PC in patients with RN can be highly indicative of BHDS. Critical relevance statement: Radiologists can play a crucial role in the diagnosis of Birt-Hogg-Dubé syndrome (BHDS) by recognising specific CT features of pulmonary cysts; a diagnosis of BHDS has implications for family testing and timely, life-long screening for renal neoplasm. Key Points: Birt-Hogg-Dubé syndrome (BHDS) should be considered in patients with renal neoplasms and multiple pulmonary cysts. A lower zone predominant, perilymphatic distribution of pulmonary cysts is a strong indicator of BHDS. Identifying specific CT features of pulmonary cysts can improve recognition of BHDS.

AB - Objectives: To assess the presence and CT features of pulmonary cysts (PCs) in patients with renal neoplasms (RN) as a hallmark of Birt-Hogg-Dubé syndrome (BHDS). Materials and methods: Single institution retrospective study of all patients with histological RN between May 2014 and May 2020. Individuals with non-renal neoplasm, nephroblastoma, benign cysts, < 18 years old, or without thoracic CT were excluded. Demographics, history of smoking, pneumothorax and cutaneous fibrofolliculomas/trichodischomas, family history of pneumothorax or RN, and genetic testing were recorded. Number, location, distribution and morphology of PCs were assessed on thoracic CT. Differences between patients with positive (BHD+) and negative (BHD−) genetics were analysed. An independent cohort of 10 BHDS patients was added to calculate the diagnostic accuracy of cyst features. Results: Of 1475 patients with RN, 127 (8.6%) had PCs; 40 underwent genetic testing (median age 56 [49–68], 28 men), and 6/127 (4.7%) individuals tested positive for BHDS. BHD+ had significantly more and larger cysts, affecting more lobes (p < 0.01). Higher prevalence of PCs with a perivascular (100% vs. 37%; p = 0.01) and interlobular septal location (100% vs. 16%; p < 0.001), and perilymphatic distribution (100% vs. 5%; p < 0.001) was found in BHD+. All BHD+ had elliptical, irregular, and variable shape PCs, compared to a lower prevalence of these in BHD− (p < 0.01). Traversing vein sign was more common in BHD+ (83% vs. 24%; p = 0.01). The highest accuracy was achieved for perilymphatic distribution (97%), followed by irregular shape (94%) and interlobular septal location (91%). Conclusion: Specific CT features of PC in patients with RN can be highly indicative of BHDS. Critical relevance statement: Radiologists can play a crucial role in the diagnosis of Birt-Hogg-Dubé syndrome (BHDS) by recognising specific CT features of pulmonary cysts; a diagnosis of BHDS has implications for family testing and timely, life-long screening for renal neoplasm. Key Points: Birt-Hogg-Dubé syndrome (BHDS) should be considered in patients with renal neoplasms and multiple pulmonary cysts. A lower zone predominant, perilymphatic distribution of pulmonary cysts is a strong indicator of BHDS. Identifying specific CT features of pulmonary cysts can improve recognition of BHDS.

KW - Birt-Hogg-Dubé syndrome

KW - Cystic lung disease

KW - Renal cancer

KW - Computed tomography

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Pulmonary cysts as a diagnostic indicator of Birt-Hogg-Dubé syndrome in patients with renal neoplasm

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