Additional diagnostic potential of transbronchial lung cryobiopsy in bronchoscopic assessment of sarcoidosis and chronic beryllium disease: a retrospective analysis of 321 patients
Department for Pneumology, University of Freiburg, Freiburg, Germany
University Hospital Basel, Basel, Switzerland
Department for Radiology, University of Freiburg, Freiburg, Germany
Abstract
Introduction
Non-necrotising granulomas are the histological hallmark of sarcoidosis and chronic beryllium disease (CBD). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), transbronchial lung forceps biopsy (TBLB) and endobronchial biopsy (EBB) are often used as standard methods for obtaining suitable tissue. Transbronchial lung cryobiopsy (TBLC) is a novel biopsy technique well studied in different fibrosing lung diseases; however, data on its use in sarcoidosis are scarce. This study aimed to assess whether TBLC provides additional diagnostic value compared with standard diagnostic methods in detecting non-necrotising granulomas.
Methods
We retrospectively analysed 321 patients diagnosed with sarcoidosis or CBD between 2010 and 2020 in a single tertiary care centre. Patients who underwent intrathoracic biopsy were analysed to assess the diagnostic yield, factors influencing diagnostic success, as well as complications related to each technique.
Results
Intrathoracic biopsy procedures were performed on 264 patients (EBUS-TBNA n=215, EBB n=61, TBLB n=120 and TBLC n=66). The diagnostic yields for single methods ranged from 56.3% (EBB) to 63.6% (TBLC) (p=0.7643). Combination of EBUS-TBNA with TBLC increased the diagnostic yield to 91.7%. Notably, TBLC provided a superior diagnostic yield compared with TBB in cases without radiologically detected parenchymal involvement. Complication rates were numerically higher following TBLC compared with TBLB (16.7% vs 9.2%, p=0.1561).
Conclusions
The addition of TBLC significantly enhances the diagnostic yield in the workup of sarcoidosis and CBD, particularly in cases without radiologically detected parenchymal involvement. This underscores the added value of TBLC in improving diagnostic accuracy in challenging clinical scenarios.
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Keywords: Sarcoidosis, Bronchoscopy, Histology/Cytology, Rare lung diseases
Article notes
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Received 2025 Feb 3; Accepted 2025 Nov 11; Collection date 2025.
Boxed Text
WHAT IS ALREADY KNOWN ON THIS TOPIC
- Sarcoidosis is a granulomatous disease and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is recommended for the diagnosis of non-necrotising granulomas.
WHAT THIS STUDY ADDS
- EBUS-TBNA may not be sufficient to diagnose sarcoidosis and transbronchial lung cryobiopsy (TBLC) has an additional diagnostic value superior to transbronchial lung forceps biopsy, especially in patients with signs of systemic and/or alveolar inflammation even in the absence of parenchymal involvement.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
- Patients with suspected sarcoidosis, but without histological confirmation, for example, in EBUS-TBNA, may undergo TBLC to confirm the diagnosis.
Introduction
Sarcoidosis is a multisystemic granulomatous disease of unknown aetiology predominantly affecting the lungs and intrathoracic lymph nodes. In addition to a typical clinical presentation and compatible radiological findings, histological evidence of epithelioid non-necrotising granulomas is usually required to confirm the diagnosis and exclude important differential diagnoses such as tuberculosis and malignancy.1 Chronic beryllium disease (CBD) is clinically and histologically indistinguishable from sarcoidosis and requires the same histological diagnosis, in addition to proven beryllium sensitisation.2 In Europe, without existing surveillance programmes for beryllium-exposed persons, CBD is often diagnosed in subsequent work-up after provisional diagnosis of sarcoidosis. During the last decades, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of intrathoracic lymph nodes has become the cornerstone in histological assessment of sarcoidosis because of the low invasiveness and complication rate and better diagnostic yield, compared with parenchymal biopsy.13,7 During the same procedure, endobronchial biopsy (EBB) can be performed to increase the diagnostic yield and is particularly recommended if visible mucosal abnormalities are found during bronchoscopy.1 4 8 Transbronchial lung forceps biopsy (TBLB), which has been recommended 25 years ago, has a higher complication rate compared with EBUS-TBNA and the sensitivity varies between 40 and 90%,9,11 depending notably on the number of obtained biopsies.11 EBUS-TBNA seems to be diagnostically superior to TBLB, especially in radiological types I and II, which are characterised by enlarged intrathoracic lymph nodes,3 9 12 not answering the question whether EBUS-TBNA is also superior to parenchymal lung biopsies in other radiological sarcoidosis types.
Transbronchial lung cryobiopsy (TBLC) is a novel method that has already proven its value for the diagnosis of other interstitial lung diseases.13 14 Compared with TBLB, it allows obtaining larger specimens with fewer squeezing artefacts,15 16 but higher complication rates have been reported, that is, bleeding and pneumothorax.17 18 With respect to sarcoidosis diagnostics, to date, there have only been a few studies with a small number of cases examining the role of TBLC next to EBUS-TBNA and TBLB.15 19 Some studies suggest that the diagnostic yield is higher for TBLC compared with TBLB15 and may be compared with EBUS-TBNA or added, if EBUS-TBNA is negative.19 20
The primary objective of this study was to assess the additional diagnostic value of TBLC compared with other biopsy techniques, both individually and in combination, in patients who underwent bronchoscopy and were subsequently diagnosed with sarcoidosis or CBD. The secondary objective was to investigate patient-related factors and clinical data that may be associated with the diagnostic yield of specific biopsy techniques.
Methods
This retrospective analysis includes all 321 consecutive patients diagnosed with either sarcoidosis or CBD after receiving EBUS-TBNA, TBLB or TBLC in a single tertiary-care centre. Patients with CBD were included in the analysis because both diseases share the same histological presentation and diagnostic approach, with the only difference being evidence of beryllium sensitisation, which in Europe without dedicated surveillance programmes is often diagnosed after established diagnosis of sarcoidosis.21
Data collection
The following data were collected from electronic medical charts over a 10-year period from 2010 to 2020: gender, age, smoking status, body mass index, medication, lung function parameters (analysed as % of the predicted, because z-scores have not been available for the entire cohort), radiographic data, bronchoalveolar lavage fluid, bronchoscopy technique including histological evaluation and complications.
Bronchoscopy
Bronchoscopies and all biopsies were performed or supervised by experienced interventional pneumologists. EBUS-TBNA was generally performed using a 22G needle. TBLB and TBLC were performed under fluoroscopic guidance in regions with parenchymal alterations in CT scan or at different locations in cases without obvious parenchymal alterations. In general, 3–5 biopsies were taken. Indications for parenchymal biopsy were made in interdisciplinary discussion. When patients underwent different biopsy techniques, these were generally performed during the same intervention.
Histopathological assessment
A biopsy was considered ‘positive’ if histological evaluation demonstrated evidence of non-necrotising granulomas without evidence of infectious cause by culture or PCR.
Radiological assessment
The baseline CT of thorax (CT) was evaluated by a board certified radiologist with experience in thoracic radiology. The images were analysed on a standard Picture Archiving and Communication System. The radiologist was blinded to the clinical data. Briefly, the radiologist analysed the mediastinal window for the presence of lymphadenopathy and the size of the largest lymph node. In addition, parenchymal involvement was evaluated. CT images were available from 266 patients, lung function parameters were collected from 300 patients and all patients had bronchoalveolar lavage data.
Diagnosis of sarcoidosis and CBD
According to the joint statement of American Thoracic Society (ATS)/European Respiratory Society/the World Association of Sarcoidosis and Other Granulomatous Disorders,22 the final diagnosis of sarcoidosis was established based on a synopsis of clinical and radiological data as well as positive biopsy outcome. Diagnosis of CBD was established based on compatible clinical and radiological data and positive biopsy outcome in the presence of proven beryllium sensitisation according to the ATS statement.2
Statistical analysis
Quantitative variables were checked for normal distribution and not grouped. Accordingly, continuous variables were compared by Mann-Whitney U or Kruskal-Wallis test. Fisher’s exact test was used for categorical variables. Receiver operating calculation curves, area under the curve and Youden Indices were applied to depict and calculate associations and cut-off values, respectively. The statistical analysis was carried out with GraphPad Prism V.10. Missing data were excluded from the respective analysis.
Patient and public involvement
In discussions with patients and patient advocacy groups, diagnostic uncertainty was reported as increasing disease burden, indirectly initiating the underlying research question. Due to the retrospective character of the analysis, an a priori involvement was not possible. However, the results of the research were presented at different occasions to patients with sarcoidosis (ie, at a dedicated meeting for patients organised by patient advocacy groups). Additionally, the scientific work was honoured with the half sarcoidosis research prize at the German Pneumology Congress 2025 by a patient advocacy group, emphasising the impact of the work for sarcoidosis patients.
Results
Patient population and general characteristics
Of 321 patients with confirmed non-necrotising granulomas in biopsy, 300 were diagnosed with sarcoidosis and 21 additional cases of CBD were identified due to occupational exposure and documented sensitisation.2
57 patients were excluded because of external or missing intrathoracic biopsies (figure 1). The remaining 264 patients underwent EBUS-TBNA (n=215), EBB (n=61), TBLB (n=120) or TBLC (n=66); several underwent multiple procedures (figure 1, online supplemental figure S1).
Mean age was 49.2 years (SD 14.5); 54.9% were male. At biopsy, 10.2% received immunosuppressive therapy. Baseline characteristics were comparable among the biopsy subgroups (table 1). Skin (18.6%) and eyes (14.8%) were the most frequently affected extrapulmonary organs.
| All patients (n=264) | EBUS-TBNA (n=215) | TBLB (n=120) | TBLC (n=66) | P value | |
|---|---|---|---|---|---|
| Demography | |||||
| Age (years) | 49.2 (14.5) | 49.8 (14.6) | 48.0 (13.5) | 50.0 (14.9) | 0.6356 |
| Male, n (%) | 145 (54.9) | 120 (55.8) | 65 (54.2) | 42 (63.6) | 0.4401 |
| Smokers (former or current), n (%) | 116/216 (53.7) | 88/175 (50.3) | 58/98 (59.2) | 27/50 (54.0) | 0.3632 |
| BMI (kg/m2) | 27.9 (5.8) (n=248) | 28.0 (5.8) (n=203) | 27.0 (5.3) (n=109) | 28.6 (5.8) (n=64) | 0.1269 |
| Organ involvement | |||||
| Eyes | 39 (14.8%) | 29 (13.5%) | 17 (14.2%) | 11 (16.7%) | 0.7577 |
| Skin | 49 (18.6%) | 39 (18.1%) | 25 (20.8%) | 9 (13.6%) | 0.4804 |
| Joints | 19 (7.2%) | 16 (7.4%) | 8 (6.7%) | 3 (4.5%) | 0.7960 |
| Heart | 16 (6.1%) | 16 (7.4%) | 6 (5.0%) | 5 (7.6%) | 0.7094 |
| Kidneys | 8 (3.0%) | 6 (2.8%) | 5 (4.2%) | 1 (1.5%) | 0.6694 |
| Spleen | 11 (4.2%) | 7 (3.3%) | 4 (3.3%) | 1 (1.5%) | 0.8510 |
| Liver | 10 (3.8%) | 6 (2.8%) | 5 (4.2%) | 0 | 0.2832 |
| Bones | 6 (2.3%) | 4 (1.9%) | 2 (1.7%) | 1 (1.5%) | >0.9999 |
| Nervous system | 13 (4.9%) | 8 (3.7%) | 5 (4.2%) | 4 (6.1%) | 0.7013 |
| Intestine | 1 (0.4%) | 0 | 1 (0.8%) | 0 | 0.4638 |
| Treatment | |||||
| Immunosuppressive therapy at biopsy, n (%) | 27 (10.2) | 20 (9.3) | 11 (9.2) | 7 (10.6) | 0.9452 |
| Lung function | |||||
| FEV1 (%pred) | 87.3 (20.1) | 87.1 (20.8) | 85.9 (20.1) | 83.4 (18.0) | 0.4180 |
| FVC (%pred) | 94.0 (19.7) | 93.5 (20.5) | 93.0 (20.1) | 89.5 (18.6) | 0.3944 |
| FEV1/FVC | 76.1 (7.6) | 76.1 (7.6) | 75.6 (7.8) | 75.51 (8.0) | 0.9158 |
| TLC (%pred) | 86.4 (14.3) | 86.1 (14.8) | 86.9 (15.7) | 82.3 (13.7) | 0.1002 |
| DLCOcSB (%pred) | 79.3 (16.9) | 78.9 (16.8) | 76.2 (17.2) | 77.5 (17.3) | 0.5101 |
| BAL | |||||
| BAL % Alveolar macrophages | 62.0 (44.0, 75.0) | 62.0 (44.0, 75.0) | 60.0 (41.3, 74.8) | 59.0 (39.8, 70.3) | 0.5662 |
| BAL % Neutrophils | 1.0 (0.5, 3.0) | 1.5 (0.5, 3.0) | 1.0 (0.5, 3.0) | 2.0 (1.0, 4.0) | 0.4495 |
| BAL % Lymphocytes | 35.0 (21.3, 50.0) | 34.0 (21.0, 50.0) | 36.5 (24.0, 54.0) | 35.0 (23.8, 53.5) | 0.7285 |
| BAL CD4/CD8 | 4.4 (2.4, 7.3) (n=222) | 4.4 (2.3, 7.7) (n=181) | 4.3 (2.5, 6.8) (n=104) | 3.6 (1.7, 6.4) (n=57) | 0.2397 |
| BAL CD4/CD8≥3.5 | 141/22222 (63.5%) | 115/181 (63.5%) | 65/104 (62.5%) | 29/57 (50.9%) | 0.2255 |
| Serology | |||||
| sIL2-R (U/mL) | 889 (523.5, 1486) (n=237) | 901.5 (517, 1516) (n=192) | 935 (631, 1430) (n=109) | 844 (475, 1785) (n=56) | 0.6331 |
| Neopterin (nmol/L) | 12.9 (9.4, 20.9) (n=223) | 13.3 (9.6, 21.6) (n=179) | 12.6 (8.9, 18.6) (n=109) | 14.6 (10.7, 21.5) (n=52) | 0.1533 |
| ACE (U/L) | 57.2 (36.4, 80.3) (n=161) | 55.9 (38.7, 83.9) (n=121) | 56.2 (33.2, 70.5) (n=89) | 47.1 (38.9, 92.7) (n=37) | 0.6562 |
Endobronchial ultrasound-guided transbronchial needle aspiration
Granulomas were detected in 56.3% of EBUS-TBNA samples (table 2). Baseline characteristics were similar between positive and negative results (online supplemental table S1).
| Biopsy technique | Positive/total (% yield) | Difference (%) | P value |
|---|---|---|---|
| Overall | <0.0001 | ||
| EBUS-TBNA | 121/215 (56.3) | ||
| EBUS-TBNA+EBB | 32/43 (74.4) | ||
| vs EBUS | + 18.1 | 0.0281 | |
| EBUS-TBNA+TBLB | 58/86 (67.4) | ||
| vs EBUS | + 11.2 | 0.0911 | |
| vs EBUS+EBB | - 7.0 | 0.5423 | |
| EBUS-TBNA+TBLC | 52/59 (88.1) | ||
| vs EBUS | +31.9 | <0.0001 | |
| vs EBUS+EBB | +13.7 | 0.1131 | |
| vs EBUS+TBLB | +20.7 | 0.0053 | |
| EBUS-TBNA+EBB+TBLB | 11/16 (68.8) | ||
| vs EBUS | +12.5 | 0.4353 | |
| vs EBUS+TBLC | −19.4 | 0.1161 | |
| EBUS-TBNA+EBB+TBLC | 11/12 (91.7) | ||
| vs EBUS | +35.4 | 0.0159 | |
| vs EBUS+TBLC | −3.5 | >0.9999 |
More lymph node stations were punctured in patients with pronounced lymphadenopathy on CT, resulting in higher diagnostic yield (online supplemental tables S2–S5 and figure S2a).
Transbronchial parenchymal biopsies (TBLB and TBLC)
Diagnostic yields were 59.2% for TBLB and 63.6% for TBLC, not significantly different from EBUS-TBNA or from each other (p>0.3) (online supplemental table S6). Combining TBLC with EBUS-TBNA increased the yield to 88.1% (p<0.0001), whereas adding TBLB did not (67.4%, p=0.091) (table 2).
Baseline characteristics of patients with positive and negative TBLB were similar (online supplemental table S7). However, patients with positive TBLC showed more restrictive lung function, higher alveolar lymphocyte counts and elevated serological activity markers than those with negative TBLC (figure 2, online supplemental table S8) and skewed likelihood to obtain positive biopsies to TBLC compared with TBLB (figure 2, online supplemental tables S9 and S10). Positive and negative predictive values as well as cut-off values based on a calculated Youden index are provided in online supplemental tables S9–S11.
Parenchymal involvement (Scadding II–IV) was present in 86.1% of TBLB and 67.8% of TBLC patients and correlated with biopsy success (table 3, online supplemental figure S2c). Yields were similar with parenchymal disease (62.1% vs 70%, p=0.43), but TBLC tended to outperform TBLB without parenchymal involvement (52.6% vs 28.6%, p=0.29) (table 3). In six patients with both procedures, TBLC detected granulomas in four cases with negative TBLB (online supplemental table S12). Biopsy sample size did not differ between positive and negative samples (online supplemental tables S13 and S14).
| TBLC | TBLB | P value ORs (95% CI) | |
|---|---|---|---|
| Parenchymal involvement Positive/total (%) | 28/40 (70) | 54/87 (62.1) | 0.4296 1.426 (0.6447 to3.308) |
| No parenchymal involvement Positive/total (%) | 10/19 (52.6) | 4/14 (28.6) | 0.2857 2.778 (0.5895 to10.00) |
| P value, ORs (95% CI) | 0.2483, 2.1 (0.639 to 6.245) | 0.0384, 4.091 (1.194 to12.44) |
Endobronchial biopsy
EBB increased diagnostic yield when added to EBUS-TBNA (74.4%, p=0.028) and in combination with TBLC (91.7%) (table 2). Radiologically detectable airway involvement was associated with a higher EBB yield (87.5% vs 42.9%, p=0.005), whereas parenchymal changes were not (online supplemental tables S15 and S16).
Adverse events
Adverse events occurred only after parenchymal biopsies with numerically higher percentage in TBLC. Pneumothorax rates were 6.7% for TBLB and 10.6% for TBLC (p=0.40), and major haemorrhage occurred in 2.5% and 6.1%, respectively (p=0.25, online supplemental table S17). Cohort size might preclude demonstrating statistically meaningful differences.
Discussion
In this retrospective analysis, we assessed the diagnostic value of different bronchoscopic techniques for detecting granulomas in patients with sarcoidosis or CBD focusing on TBLC in comparison and combination with standard bronchoscopic techniques. The role of TBLC for diagnosing sarcoidosis remains controversial23 24 and prior studies have been limited by small sample size.15 19 20 Our cohort, including more than 60 TBLCs, represents one of the largest series to date and demonstrates a clear additive diagnostic value (table 2, online supplemental figure S2b).
TBLC maintained a relatively high positivity rate even in patients without CT-detectable parenchymal involvement and tended to outperform TBLB in this subgroup (table 3). This may indicate subtle, radiologically undetectable parenchymal disease. Consistent with this, inflammatory markers such as alveolar lymphocytosis and elevated sIL-2R or neopterin levels were associated with higher TBLC yields—an observation not noted for TBLB (figure 2, online supplemental tables S8–S11). Nevertheless, this positive prediction should be carefully weighed against the numerically elevated risk of complications in TBLC compared with TBLB (online supplemental table S17), especially considering cohort size that may preclude detection of statistically significant differences in complication rate.
Our findings extend current knowledge, as previous reports mainly described TBLC in patients with manifest parenchymal disease or presenting with a clinical picture highly suspicious for sarcoidosis.15 20
In our cohort, the diagnostic yield of EBUS-TBNA (56.3%, table 2) was lower than in prospective trials such as the GRANULOMA trial.12 This likely reflects real-world experience, where smaller lymph nodes and less extensive sampling commonly result in lower sensitivity.3 In the GRANULOMA trial, larger lymph nodes and multiple aspirates were obtained, and endobronchial showed lower sensitivity, compared with oesophageal access (66% vs 88%).12 In line with this, several patients underwent EBUS-TBNA despite smaller lymph nodes and with less extensive sampling, resulting in the reported sensitivity (online supplemental tables S2 and S3).
The addition of EBB to combinations of other biopsies improved granuloma detection, particularly but not exclusively in cases with visible airway involvement (table 2, online supplemental table S15). This finding suggests including this low-risk intervention routinely in bronchoscopic evaluations of suspected sarcoidosis.
Limitations include the retrospective single-centre design, potential selection bias and absence of standardised procedural criteria. Although the diagnostic strategy resulted from an interdisciplinary discussion, procedural choice varied and may have favoured TBLC in certain cases. Despite the relatively large number of procedures, some comparisons—such as TBLC versus TBLB superiority or complication rates—may remain underpowered. Nevertheless, this study analyses the largest cohort of patients with sarcoidosis undergoing TBLC and identifies clinical settings and parameters that may help select the appropriate diagnostic procedure.
In summary, the results of this study indicate an additional benefit of TBLC over conventional biopsy techniques in diagnosing sarcoidosis and CBD, particularly in cases of high inflammatory activity without radiologically overt parenchymal involvement.
Supplementary material
Acknowledgements
We thank the patients and patient advocacy groups helping us to improve care of them. Special thanks also to the bronchoscopy team of the Department of Pneumology, University Medical Center, Freiburg and the team of the outpatient ward. We appreciate tecnical support from Andreas Hoheisel
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The sponsor has no influence on the focus, content or format of scientific clinical or basic research studies, nor is there any access to data.
Footnotes
Footnote Group
Data availability statement
Data are available on reasonable request.
References
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Associated Data
Supplementary Materials
Data Availability Statement
Data are available on reasonable request.