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Eur J Cardiothorac Surg 2002;21:621-626
© 2002 Elsevier Science NL

Does lung biopsy help patients with interstitial lung disease?

^a Department of Thoracic Surgery, The Cardiothoracic Centre-Liverpool, Thomas Drive, Liverpool L14 3PE, UK
^b Department of Research and Clinical Audit, The Cardiothoracic Centre-Liverpool, Thomas Drive, Liverpool L14 3PE, UK

Received 25 September 2001; received in revised form 22 December 2001; accepted 3 January 2002.

* Corresponding author. Tel.: +44-151-228-1616; fax: +44-151-220-8573
e-mail: richard.page{at}ccl-tr.nwest.nhs.uk

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objectives: The decision to perform lung biopsy in the evaluation of interstitial lung disease (ILD) is based on the probability that this examination will yield a specific diagnosis, leading to a change in treatment. The purpose of this study was to identify factors that influence the diagnostic yield of lung biopsy for ILD. Methods: One hundred patients underwent lung biopsy for ILD over a 5-year period. There were 59 men and 41 women; with a median age of 51.5 years. Thirty percent underwent open lung biopsy, while 70% had videothoracoscopic biopsy. Patient and disease characteristics, prior diagnostic studies, pre-operative therapy, biopsy type, site, size, number, and laterality were compared to identify factors that might influence diagnostic yield. Results: Forty-two percent had a specific diagnosis, while 58% had a non-specific diagnosis. Right side was selected in 57.1% of patients with a specific diagnosis and 48.3% of patients without a specific diagnosis (P=0.381). Right lower lobe was the main site for biopsy in the specific diagnosis group compared to the non-specific group (35.7 versus 20.7%, P=0.095). Left upper lobe was the main site for biopsy in the non-specific diagnosis group compared to the specific diagnosis group (41.4 versus 23.8%, P=0.067). Mean volume of biopsy was 12.3 cm³ in the specific diagnosis group and 12 cm³ in the non-specific diagnosis group (P=0.373). Two or more biopsies were carried out in 38.1% of the specific diagnosis group compared to 25.9% of the non-specific diagnosis group (P=0.192). There were no significant factors in predicting a diagnostic yield. Of those patients with a specific diagnosis, 59.5% had therapy altered, compared to 55.2% of those with a non-specific diagnosis (P=0.664). Conclusions: Lung biopsy does not always provide a specific diagnosis and does not always change therapy. The site, size, number, and laterality of the biopsy specimen have no definite influence on diagnosis. There is a trend to improve diagnostic yield by carrying out two or more biopsies on the right lung.

Key Words: Interstitial lung disease • Lung biopsy • Diagnostic yield

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Interstitial lung disease (ILD) is a generic term representing a heterogeneous group of lung disease classified together because of several common features [1]. Surgical lung biopsy encompasses both open and video-assisted thoracic surgery (VATS) procedures for obtaining large samples of lung tissue necessary for diagnosis and staging of disease activity in patients with ILD. The decision to perform lung biopsy in these patients is based on the likelihood that pathologic examination of the tissue obtained will yield specific information about the cause of the disease process and that this information can be used to alter the treatment being received by the patient.

Generally, lung tissue is still required for the diagnosis of ILD in approximately a third of patients [2] who do not have a clearly defined environmental exposure or obvious systemic illness that frequently involves the lung. However, the role of this procedure remains controversial and many clinicians are reluctant to allow this invasive procedure to a high-risk group of patients without assurances that results will lead to a change in therapy for a significant number.

Similarly, none of the previous studies have attempted to identify factors, which could improve diagnostic yield of lung biopsy for ILD. Therefore, this study was carried out to evaluate the benefits of lung biopsy after less invasive techniques failed to yield a diagnosis in a series of patients with diffuse pulmonary infiltrates of uncertain origin and to identify factors that might influence diagnostic yield.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
A total of 100 patients undergoing lung biopsy for ILD between 1 January 1995 and 31 December 1999 were retrospectively analysed. There were 59 men and 41 women; with a median age of 51.5 (fifth and 95th centiles: 29–71) years. Seventy patients had a VATS procedure, whereas 30 underwent an open lung biopsy. The latter was because of surgical preference (five patients) or because the presence of pleural adhesions precluded the use of the thoracoscope (25 patients).

Inclusion criteria included radiological evidence of ILD. Patients with a solitary nodule or other focal pulmonary processes were excluded. Most patients had been previously investigated with spirometry, chest computer tomography (CT) scan, sputum specimen for culture and cytologic examinations. Mediastinal lymphadenopathy was not in evidence in any of the patients. Serological evaluations of rheumatoid factor, antinuclear antibody, antinuclear cytoplasmic antibodies, and angiotensin-converting enzyme were also carried out in selected cases. No patients were operated on while being artificially ventilated.

2.1. Operative technique
2.1.1. Videothoracoscopic lung biopsy
Patients underwent general anaesthesia and were intubated using an endobroncheal tube to allow selective ventilation of the contralateral lung. Arterial monitoring and continuous pulse oximetry were used. The patients were placed in the postero-lateral thoracotomy position. A 10-mm trocar for telescope was inserted through the eighth intercostal space opposite the tip of scapula. Two additional trocars (5–11 mm) were placed under direct vision, with one anteriorly through the fifth or sixth intercostal space towards the mid-clavicular line and the other posteriorly through the fifth or sixth intercostals space in the posterior axillary line. The biopsy site was selected on the basis of CT scan data and intra-operative findings, and biopsy was performed by wedge resection using endo-cavity linear staplers (Auto suture, United States Surgical, Norwalk, CT, USA). At the end of the operation one 28-F chest tube was placed via the anterior port site to the apex under vision and was connected to a underwater seal drainage system. Lung re-expansion was checked visually and port sites were sutured in two layers following infiltration with 5–10 ml of 0.5% bupivacaine.

2.1.2. Open lung biopsy
Patients were anaesthetised and positioned as for a VATS procedure. A 12-cm incision was made anteriorly over the fifth intercostal space. The chest wall muscles were retracted rather than divided when possible and the ribs distracted with a spreader. The exposed lung was biopsied with a linear stapler as per VATS technique. The minithoracotomy was closed in layers and was infiltrated with 10–20 ml of 0.5% bupivacaine.

Each speciman was processed in a routine fashion and four histology sections were prepared from each tissue block. Individual slides were stained with haematoxylin and eosin, pentachrome stain (which demonstrates elastic tissue, collagen, and mucopolysachride rich stroma), prussian blue (iron stain), and a trichrome stain (which demonstrates collagenised connective tissue and muscle).

2.2. Post-operative care
Patients were extubated in the operating theatre and monitored for 2–3 h in the recovery room. A chest X-ray was performed in every patient and decision to apply suction to chest drain was individualised. Post-operative administration of analgesics was adapted to individual requirements (oral analgesia). Epidural analgesia was not employed.

2.3. Data analysis
Data was collected on the following variables from patients' medical records: age, sex, pulmonary symptoms (dry cough, cough and sputum, haemoptysis, wheeze, and chest discomfort), prior diagnostic studies (chest X-ray, CT scan, bronchoscopy, transbronchial biopsy, and bronchial washings), 1-s forced expiratory volume (FEV1), forced vital capacity (FVC), pre-operative therapy (corticosteroid, immunosuppressant, antibiotics, bronchodilators, oxygen, chemotherapy, and radiotherapy) operative priority, biopsy type, site, size, and number, histology, diagnostic yield, change of therapy, and post-operative morbidity and mortality.

Diagnostic yield and non-diagnostic yield groups, were created based on specific diagnosis achieved as a result of lung biopsy thus effecting overall patient management and were compared to identify factors that influence diagnostic yield.

Statistical analysis was performed with SAS for Windows Version 8. Continuous variables are shown as median with fifth and 95th centiles, and categorical variables are shown as percentages with 95% confidence intervals (CI). Comparisons were made with the Wilcoxon rank sum test and chi-square test as appropriate. Logistic regression was used to identify any independent factors that influence diagnostic yield of lung biopsy for ILD. In all cases a P value <0.05 was considered significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Overall, 42 of the 100 biopsies (42%) had a specific diagnosis, while 58% had a non-specific diagnosis.

Table 1 lists patient and disease characteristics based on patients having a specific or non-specific diagnosis after lung biopsy. Twenty-seven were already on corticosteroid and/or immunosuppressive therapy prior to referral for biopsy. There were no differences between patients with a specific or non-specific diagnosis according to age, sex, pulmonary function tests, pulmonary symptoms, prior diagnostic studies, pre-operative therapy, and operative priority.

Of those patients with a specific diagnosis, 59.5% (95% CI: 43.3–73.9) had therapy altered, compared to 55.2% (95% CI: 41.6–68.1) of those with a non-specific diagnosis (P=0.664).

The most frequent diagnosis obtained was interstitial fibrosis (n=42) (Table 3). Sarcoidosis and metastatic carcinoma were the main histologies in the specific diagnosis group, while interstitial pulmonary fibrosis and fibrosing alveolitis were the predominant histology in the non-specific group. Interestingly none of the patients with pulmonary sarcoidosis had identifiable mediastinal lymphadenopathy.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

A specific diagnosis was reached in 42% of our cohort while, 34–98% is reported in other series [3–5]. These series, however, dealt exclusively with immunocompromised patients. Our results compare with the 36–46% specific diagnosis rate in other series in which patients with chronic interstitial infiltrates were evaluated [2,3].

Previously the demand for lung biopsy was relatively small but since the advent of VATS techniques, there has been a steady increase in the number of referrals for lung biopsy. This change may reflect a change in attitude among the physicians toward commencing potent medical treatment without a definitive histological diagnosis or a greater acceptance of a procedure, which they feel, is less invasive than open lung biopsy.

Nevertheless, it is important to keep certain caveats in mind. Despite VATS apparent low morbidity and high accuracy, the standard indications for operation should not be altered. Specifically high yield and low risk methods such as bronchoscopy, bronchalveolar lavage, transbronchial biopsy, transthoracic needle biopsy should still be considered as initial diagnostic tests [4,6,7]. If there is mediastinal lyphadenopathy, mediastinoscopy should be used in preference to lung biopsy as being a less invasive procedure. Also, to initiate a diagnostic evaluation, thorough medical and occupational histories are essential and often provide the most important clue(s). Several serological tests can be useful in confirming a diagnosis and/or for monitoring response to treatment.

Thoracotomy for open lung biopsy has been a standard surgical approach for many years [2]. Recently, the use of VATS lung biopsies for diagnosis of diffuse ILD has increased. In a randomised trial, of VATS versus limited thoracotomy for diagnostic lung biopsy in ILD, no difference in post-operative pain, narcotic requirement, operation time, adequacy of biopsy, duration of chest drain, length of stay, spirometry, and complications were demonstrated [8]. We would agree that both limited thoracotomy and VATS are acceptable choices for diagnostic lung biopsy in ILD.

A question of the approximate site of biopsy has entertained controversy since the reports of Gaensler and Carrington [2] who maintained that the lingula and middle lobe tip should be avoided. In contrast, studies by Wetstein [9] and Miller et al. [10] have shown no reason to avoid the lingula and right middle lobe. In fact, Newman et al. [11] suggest avoiding the tip of any lobe other than the lingula. Our results did not show any significant difference of site selection on diagnostic yield. We agree with Mathieson et al. [12] that conventional and high resolution computed tomography (HRCT) of the chest has proved to be highly effective in selecting the appropriate biopsy site in all forms of ILD. Ground-glass appearance on HRCT generally denotes active disease and can be helpful in identifying fruitful biopsy sites.

Regarding number of biopsies, Winterbauer et al. [13] noted considerable intralobar variation in diagnosis but did not report whether there were similar interlobar discrepancies. Chechani et al. [14] studied the benefits of obtaining multiple open biopsy samples. The same histological diagnosis was reached for each of the two biopsy samples in all patients. They concluded that there was no need for multiple open biopsy specimen when a representative region of the radiographically most involved lobe was sampled. We feel from our experience that there are more chances of yielding specific diagnosis if more than one biopsy is carried out. The histologic variability of interstitial pneumonitis is conspicuous and intuitively assumed that multiple sites should be sampled to compensate for this variability. Radiographic findings often serve as a guide to the most appropriate area for biopsy, although, approximately 10% of patients with histologically confirmed chronic diffuse infilterative lung disease may have a normal chest X-ray [15] and a small number of patients may also have normal HRCT findings [16]. We believe that if feasible, multiple biopsies from overtly abnormal and adjacent or remote normal appearing areas may be helpful because biopsy samples obtained from less involved areas of the lung will generally show an active and diagnosable process [2,16] rather than end stage non-specific fibrosis.

Flint et al. [17] suggested that a single generous sample (2-cm or greater diameter) obtained from representative region of the radiographically most involved lobe will be sufficient for diagnostic and evaluation purposes. In our series, although there was considerable variation of biopsy sizes, mean volume was not statistically different between the specific diagnosis and non-specific diagnosis group. We agree with Vidone and Librtin [18] that a good general rule regarding the number of biopsies is to select two or three samples of approximately 3x2x1 cm³.

Assessment of the effect lung biopsy has on patient management is difficult. Various reported series show a change in patient management based on biopsy results in 27–73% of patients undergoing this procedure for diffuse infiltrates [19,20]. In our series, therapy was changed in 57% of the patients because of the biopsy results. Therapy was more likely to be changed when a specific diagnosis was made compared to when a non-specific diagnosis resulted.

Conditions such as interstitial pneumonia, diffuse interstitial pneumonia, interstitial pulmonary fibrosis, fibrosing alveolitis, broncholitis obliterans, organizing pneumonia, sarcoidosis, hypersensitivity pneumonitis, or eosinophilic pneumonia may all require steroid treatment if the patient is symptomatic [3]. If one of these conditions is suspected on clinical grounds without a definite tissue diagnosis, a therapeutic trial should be considered. This is based on the fact that even after lung biopsy was performed, administration of steroids was the commonest form of therapy in our series.

Most forms of ILD rarely remit and feature periods of exacerbation superimposed on a chronic or worsening baseline of symptoms. As treatment is far from satisfactory, it is something of an art to keep patients functional, hopeful, and moderately satisfied with their medical care. Thus, the careful selection of patients for surgical lung biopsy is crucial in overall clinical use and whether the patient will benefit from this procedure should be considered. Perhaps earlier lung biopsy and institution of steroids will increase the response to steroids, but at present we support the conclusion of Hiatt et al. [21] that open lung biopsy has only a modest clinical impact and should be used conservatively.

In conclusion, lung biopsy does not always provide a specific diagnosis and does not always change therapy. The site, size, number, and laterality of the biopsy specimen have no influence on diagnosis. There is a trend to improve diagnostic yield by carrying out two or more biopsies on the right lung.

	Footnotes

 
Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Mr D. Waller (Leicester, UK): I am very pleased you have done this study because it is what I suspected all along. The physicians, certainly in the UK, are very keen to ask for these diagnostic lung biopsies, and I always ask them how is it going to change your therapy, and it seems very difficult for them to answer in some cases, and so I am very glad that you have shown that these operations probably don't change the management of the majority of these people. So how has this changed your practice in Liverpool? Are you now less likely to do these biopsies?

Mr Qureshi: I think the clinical implication, what I have noticed are fears of litigations among many physicians. As we put forward these results over to them, they say that they have to provide some sort of diagnosis for litigation purpose and to ensure many patients that they are doing something for them or everything has been done for their disease.

Mr Waller: Do you ask your physicians to give a trial of steroid therapy before a biopsy?

Mr Qureshi: We have suggested this because in our study there were about 33% of patients who came on steroids and 50% went on steroids. This question has been addressed in a detailed article, which I have submitted to the European Journal. We have noticed that there have been a lot of demands from physicians for lung biopsy. Surprisingly, in some cases, the physicians just reviewed the X-ray and refer to us for the lung biopsy. The reason most likely seems to be the VATS procedure. I think as most of you will agree that they think this procedure provides them some sort of safety and they can tell the patients that everything has been done.

Mr Waller: Yes, I agree with you.

Dr M. Furrer (Chur, Switzerland): You showed us that you performed half of the operations by VATS and half by an open technique. What was the decision-making for one or the other procedure?

Mr Qureshi: I think 70% in our cohort were VATS procedure while 30% were open procedure, and that reflects a specific surgeon's preference.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 

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