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(Chest. 2005;128:2375-2380.)
© 2005 American College of Chest Physicians

Thoracoscopic Lung Biopsy Is a Safe Procedure in Diagnosing Usual Interstitial Pneumonia*

Leena Tiitto, MD; Ulla Heiskanen, MD; Risto Bloigu, MSc; Paavo Pääkkö, MD, PhD; Vuokko Kinnula, MD, PhD and Riitta Kaarteenaho-Wiik, MD, PhD

* From the Departments of Internal Medicine (Drs. Tiitto, Kaarteenaho-Wiik, and Heiskanen) and Pathology (Dr. Pääkkö), University of Oulu and Oulu University Hospital, Oulu; Department of Medical Informatics Group (Mr. Bloigu), University of Oulu, Oulu; and Department of Medicine (Dr. Kinnula), Division of Pulmonary Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Correspondence to: Riitta Kaarteenaho-Wiik, MD, PhD, Department of Internal Medicine, University of Oulu, PO Box 5000 (Kajaanintie 50), FIN-90014, University of Oulu, Finland; e-mail: Riitta.Kaarteenaho-Wiik{at}oulu.fi


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: To evaluate the effect of lung biopsy on the survival of patients when histopathologic confirmation of usual interstitial pneumonia (UIP) is needed.

Background: Idiopathic pulmonary fibrosis is a distinct clinical entity with histopathologic features of UIP. Surgical biopsy is needed when clinical and radiologic findings are not typical. The safety of lung biopsy is a matter of debate, and the results of short-term mortality (< 30 days) after biopsy are variable.

Methods: Seventy-six patients with UIP, including 34 patients who underwent video-assisted thoracoscopic surgery (VATS) biopsy and 42 patients who underwent open-lung biopsy, were included in this retrospective study. All biopsies were reevaluated for UIP histopathology. Clinical data such as age at the time of biopsy, type of biopsy, preoperative pulmonary function, major postoperative complications, date and cause of death, and survival time after the biopsy were gathered. Median survival was used to compare the survival between different groups, and cumulative survival was estimated using Kaplan-Meyer method.

Results: Thoracoscopic biopsy was safe for diagnosing UIP, with no short-term mortality. In contrast, open-lung biopsy was followed by four deaths (5.3%) within 1 month after the procedure. All fatal cases were accompanied by a histopathologic pattern of diffuse alveolar damage. Age of the patient at the time of biopsy was a significant predicting factor for survival. Patients < 50 years old lived 181 months (range, 119 to 242 months), and patients > 50 years old lived 75 months (range, 55 to 95 months).

Conclusions: VATS biopsy is a safe procedure in diagnosing UIP.

Key Words: idiopathic pulmonary fibrosis • outcome • video-assisted thoracoscopic surgery


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Idiopathic pulmonary fibrosis (IPF) with a histopathologic finding of usual interstitial pneumonia (UIP) is the most common type of idiopathic interstitial pneumonia. Moreover, UIP, like histopathologic pattern, can be detected in several connective tissue diseases.1 The diagnosis of IPF is based on the clinical findings, typical features of IPF on high-resolution CT (HRCT), and exclusion of other diseases.23 Atypical HRCT, however, does not always correlate with histologic findings.45 Although international guidelines67 recommend lung biopsy in these patients, the majority of cases of IPF are diagnosed without biopsy. Biopsy may follow some risks, which may actually reduce the enthusiasm for confirming exact histopathology, knowing also that no effective treatment is available and that the prognosis of IPF/UIP is poor.8 However, verified histopathologic diagnosis not only reduces unnecessary "overmedication," but it also would help other therapeutic decisions and their planning, one example being lung transplantation. This study was carried out to evaluate the effect of lung biopsy on the survival of the patient when histopathologic confirmation of UIP is needed.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and Handling of Specimens
Histopathologically typical cases of UIP were collected from the files of the Department of Pathology, Oulu University Hospital, Oulu, Finland. Biopsies between January 1973 and December 2002 were reevaluated for UIP histopathology (R.K.W., P.P.). Open-lung biopsies were performed from January 1973 to December 1992; after that time, a thoracoscopic technique was mainly used. Altogether, 76 patients (34 women and 42 men) presenting with UIP were included. Lung biopsies were performed under general anesthesia. The site for the biopsy was selected on the basis of chest radiographic or CT findings. In open-lung biopsy, the most common approach used was small anterior or lateral thoracotomy. The biopsy specimen was usually obtained with an automatic suturing device (TLH-30; Johnson & Johnson; Cincinnati, OH; or GIA Auto Suture; United States Medical; Norwalk, CT) from the representative lung parenchyma; frequently the edge of the lobe was suitable. A chest tube and pleural suction or a Heimlich valve were usually used for 1 to 3 days. Video-assisted thoracic surgery (VATS) lung biopsy was always performed with double-lumen endotracheal intubation and single-lung ventilation. The patient was placed in a full lateral position. Three access sites and 5.5-mm ports were used. The thoracoscope was introduced through the seventh or eighth intercostal space on the midaxillary line, and the placement of the latter two additional ports was determined. An endostapler was used to perform the wedge resection. Chest tube insertion was accomplished, and the other two sites were closed. The biopsy samples were taken from right lower lobe in 32 patients, the right middle lobe in 20 patients, the left lower lobe in 13 patients, the lingular segment in 8 patients, and the right upper lobe in 3 patients. Only one specimen was obtained in 75 patients, and the mean size of biopsy specimen was 13.7 cm2. The size of the sample was big enough for the diagnosis of UIP in each case. The biopsy material had been fixed in 10% formalin under vacuum in order to expand the tissue and remove air bubbles9 or perfused by injecting the fixative into the bronchioles as described by Dail and Hammar.10 The specimens were dehydrated and embedded in paraffin. The histopathologic diagnosis was based on light microscopic evaluations using the histologic criteria presented by Katzenstein11 and Dail and Hammar.10 The clinical data were collected from Oulu University Hospital, Päivärinne Hospital, Oulaskangas Hospital, Central Hospital of Länsi-Pohja, and Lapland Central Hospital. The end point of the study was the last visit before December 31, 2002, or the patient's death. The study protocol was approved by the Ethical Committee of the Oulu University Hospital.

Clinical Data
The clinical data included age at the time of the biopsy, sex, smoking status, exposure to asbestos, other diseases, medication in general and, for IPF/UIP, need for home oxygen, date of biopsy, type of biopsy (open or thoracoscopic), major postoperative complications, and date and cause of death. The delay between the first visit and biopsy was calculated, as well as the survival time after the biopsy. The associated symptoms such as exertional dyspnoea and cough were noted. Preoperative spirometry and single-breath diffusion capacity of carbon monoxide (DLCO) were divided into two categories. The radiology involved standard chest radiographs and HRCT. Rheumatoid factor, anti-nuclear antibodies, and arterial blood gases were examined. The cellular analysis of BAL was included to confirm the alternative diagnosis.

Statistical Analysis
Statistical analysis was performed using statistical software (SPSS for Windows, release 11.5.1; SPSS; Chicago, IL). The significance of the associations was determined using a Fisher Exact Probability Test designed for small-sample groups; p values < 0.05 were considered statistically significant. Median survival was used whenever possible to compare the survival between the different groups; if median survival could not be calculated, mean survival was used. Cumulative survivals were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival of the different groups.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Findings and Symptoms
The study population consisted of 42 men (55.3%) and 34 women (44.7%), with a mean age at the time of biopsy of 56.7 years (range, 21 to 77 years). The mean age of the women was 54.7 years (range, 21 to 74 years), and the mean age of the men was 58.3 years (range, 34 to 77 years). A total of 42 patients (55.3%) underwent open-lung biopsy, and 34 patients (44.7%) underwent thoracoscopic procedures. There were 17 current (22.4%) and 23 former smokers (30.3%) with an average smoking history of 22.6 pack-years; 7 of them (9.2%) were < 50 years old. A total of 14 patients (18.4%) had been exposed to asbestos, and 10 of them (71.4%) were dead by the end of the study. Positive anti-nuclear antibodies were found in 11 patients (14.5%), and rheumatoid factor was found in 4 patients (5.3%). The main symptoms were exertional dyspnea in 40 patients (52.6%) and nonproductive cough in 26 patients (34.2%). The physical examination revealed inspiratory crackles in 55 patients (72.4%). Finger clubbing was seen in 24 patients (31.6%; 14 men). Fifteen patients (36.6%) who died of UIP had finger clubbing. The family history of IPF-like disease was found in five patients (6.6%). The characteristics of the patients are presented in Table 1 .


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  		Table 1.. Characteristics of the Patients With Idiopathic UIP and UIP With Connective Tissue Disease*

 
Radiology
Bilateral reticular opacities (34 cases, 44.7%) and fibrosis (50 cases, 65.8%) were the main findings on chest radiography. Since the first biopsy specimens were obtained in 1973 and HRCT came into general use during the 1990s, the preoperative HRCT was available in only 38 cases (50%). The predominant pattern of HRCT was fibrosis in 32 cases (84.2%), including 20 cases (52.6%) of honeycombing; ground-glass opacities were observed in 11 patients (28.9%).

Pulmonary Function and Laboratory Findings
Pulmonary function tests including FVC, FEV1, and DLCO were available in 75 patients. Patients with DLCO ≥ 50% of the predicted value had a median survival of 63 months (range, 3 to 83 months), while the group with DLCO < 50% of the predicted value lived only 49 months (range, 37 to 61 months).

Arterial blood gases at rest were analyzed in 62 patients (81.5%) at diagnosis. Arterial hypoxemia (PaO2 < 80 mm Hg [10.7 kPa]) was found in nine patients (11.8%), of whom seven patients died during the observation. There was no correlation with survival after biopsy. In BAL samples, patients with a poor outcome more often showed a tendency for an elevated total cell count (30 of 44 patients, 68.2%); the association did not reach the statistical significance (p = 0.5932).

Lung Biopsies and Mortality
From the 76 UIP cases, 50 patients (65.8%) died by the end of the study. A total of 41 patients (53.9%) died of UIP itself, and 4 patients (5.3%) died of lung carcinoma. Forty-six of the patients who died (71.9%) had the idiopathic form of UIP, and 39 of them (84.8%) had UIP as the main cause of death. The biopsies in the 1970s (n = 9) and 1980s (n = 24) were all open-lung biopsies. After the 1990s, there were 9 open-lung and 34 VATS lung biopsies. There was one postoperative pneumothorax in patients undergoing a thoracoscopic procedure. The open-lung biopsy group included two cases of pneumothorax, two cases of hemothorax, one case of both pneumonia and pneumothorax, and one case of pneumonia. Altogether, 68% (34 patients) who underwent open thoracotomy and 32% (16 patients) who underwent thoracoscopic procedures were dead by the end of the study.

The median survival after biopsy was 69.9 months (5.8 years; range, 1 to 296 months). There was 20-month difference in median survival depending on the type of biopsy. In the open thoracotomy group, median survival was 51 months (range, 36 to 66 months); in the thoracoscopic group, median survival was 71 months (range, 43 to 99 months). The age of a patient at the time of lung biopsy was a statistically significant predicting factor; 16 patients (21.1%) were < 50 years old, and 60 patients (78.9%) were > 50 years old. Their mean survivals were 181 months (range, 119 to 242 months) and 75 months (range, 55 to 94 months), respectively (p = 0.0095).

Two patients (2.6%) needed additional home oxygen therapy before the biopsy. After the operation, additional ventilatory assistance was needed in eight patients (10.5%), with five of these cases (6.6%) being related to open-lung biopsy. Two patients who died within 30 days belonged to this group.

Four patients (5.3%) died within 1 month after the biopsy. The clinical information of these patients is shown in Table 2 . All these patients underwent open-lung biopsy due to the atypical symptoms or radiologic findings of IPF. The lung biopsies of these four patients revealed the histologic features of UIP with patchy alternation, fibroblasts foci, scar-like old fibrotic areas, and varying degrees of inflammation and normal lung. However, in addition to UIP, the organizing stage of diffuse alveolar damage (DAD) was observed at autopsy in every four cases; one patient also had pneumonia in his autopsy samples. One patient received corticosteroid therapy before the biopsy. None of these patients had connective tissue disease.


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  		Table 2.. Clinical Information of the Patients Who Died Within 30 Days After Biopsy*

 
The patients with connective tissue disease were younger (45.3 years vs 58.9 years), smoked less (13 pack-years vs 23.9 pack-years), had better pulmonary function, and had a better prognosis, with a mean survival of 223 months after the biopsy, vs 73 months in UIP. Four of 12 patients with connective tissue disease were dead at the end of the study, although only 2 patients died of UIP itself (Table 1).

The diagnosis of UIP lead to a treatment change in 58 cases (76.3%). The most commonly used medications were corticosteroids in 21 cases, accompanied by azathioprine in 16 cases and cyclophosphamide in 6 cases. Two patients underwent lung transplantation because of UIP. There were 11 patients who did not receive pharmaceutical treatment, 6 of whom were dead by the end of the study. The patients with no treatment had a median survival of 49 months (range, 26 to 72 months) after biopsy. The patients with altered treatment had a median survival of 61 months (range, 37 to 85 months) after biopsy, and those whose medication was never changed lived for 85 months (range, 38 to 132 months); none of these differences were statistically significant.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The short-term postoperative mortality (< 30 days) in our study was 5.3%, which was considerably lower than that in another study8 of UIP (21.7%), considering the idiopathic type of the disease. In the present study, all four patients who died within 1 month after the operation had undergone open thoracotomy. In patients who underwent thoracoscopy, the preoperative and postoperative mortalities were nonexistent, and also the morbidity was low. Therefore, the thoracoscopic operation can be considered as a safe procedure. However, none of the four patients who underwent thoracotomy and died during 1 month after operation had a perioperative or postoperative complication, since the causes of deaths were the acceleration of UIP, of which the pathogenetic mechanisms are still unclear. Most previous studies1213141516 showing a favorable short-term postoperative prognosis have generally included all kinds of patients with diffuse interstitial lung diseases (ILDs), while in our study only UIP patients were included.

In previous studies,717 HRCT findings have been observed to predict UIP prognosis with somewhat variable results. The most common HRTC finding in our study was a fibrotic appearance with honeycombing, the same observation that was reported earlier.1718 Also, in our study, advanced fibrosis was a sign of a poor prognosis. We could not evaluate the effect of HRCT on the short-term mortality since most open-lung biopsies had been performed before the HRCT era. HRCT is an important diagnostic method for diagnosing UIP, and if radiologic and clinical features are typical for UIP, lung biopsy is not needed. However, the typical finding of UIP is seen in HRCT only in 50 to 60% of the patients with UIP/IPF; thus, lung biopsy is needed in approximately 40% of the patients with UIP for the correct diagnosis.

Overall, 52.7% of our patients were current or ex-smokers, with a better median survival and less reduction of DLCO and lung volumes than never-smokers, a finding that is also in agreement with one earlier study.19 Importantly, the delay between the first arrival in the hospital and the lung biopsy was 3 months longer with current smokers than never-smokers. It is highly likely that both patients and doctors tend to attribute the symptoms and minor clinical findings to smoking. IPF is an independent risk for lung cancer, and there were four lung cancers (5.3%) in our study, which is also consistent with an earlier reported risk for lung cancer (4.4%) in pulmonary fibrosis.20 The most outstanding clinical symptom was progressive exertional dyspnea, while finger clubbing had a high predictive value for a poor outcome, this being also very similar to previous publications.221 Survival time from the initial visit was found to be significantly related to the age at presentation.21 The present study also shows that the age of the patients at the time of the biopsy is a significant predictive factor for survival after biopsy.

The patients with connective tissue diseases were younger than the patients with idiopathic UIP; furthermore, they had better lung function test results and longer survival. Previous studies12–16 of ILDs associated with collagen vascular diseases (CVDs) revealed similar results, even though we had a small number of patients and four different diseases were included in the CVD/ILD group. In our study, all these cases were biopsy-proven UIP, nonspecific interstitial pneumonia was excluded, and thus the question about the influence of an underlying collagen vascular disease on survival remains to be studied.2223 Our study does not exclude whether other lung areas of these patients had nonspecific interstitial pneumonia histopathology. In agreement with the longer survival of the CVD/ILD/UIP patients, no short-term mortality after open-lung biopsy could be observed.

A correct diagnosis is needed for choosing therapy and predicting prognosis. In our study, biopsy did lead to a change in treatment in 76.3% of the patients, but this had no favorable effect on survival. The antiinflammatory and immunosuppressive treatments for UIP have proved to be disappointments.224 Interferon-{gamma}, pirfenidone, and N-acetylcysteine have shown some promising results,252627 although one case report of a temporal connection between acute respiratory failure and interferon-{gamma} therapy of end-stage pulmonary fibrosis has also been published.28 It is therefore easy to understand why many clinicians are reluctant to embark on such an invasive and possibly risky procedure without any clinical benefits. Younger patients should, however, be considered for pulmonary transplantation.29 Moreover different histologic patterns are associated with variable prognosis.3031 In a case of nontypical features of UIP, an accurate histologic diagnosis would help choosing optimal therapies with more optimistic expectations.

In our study, all four patients who died within 30 days after the biopsy had a histologic pattern of DAD. Diminished DLCO was the only clinical similarity in all patients, but none of them fulfilled the criteria of acute exacerbation before the biopsy.32 In one previous study,33 three patients who underwent lung biopsy had clinical signs of acute exacerbations without DAD; all of them survived. This finding is consistent with ours, in that the histopathologic finding at diagnosis may differ from that obtained at autopsy after disease acceleration.3134 Since the factors leading to acute exacerbations of IPF are unresolved, the histopathologic diagnosis, when the noninvasive interventions like HRCT cannot confirm the diagnosis, should be obtained during the early and stable stage of the disease but not during the accelerated phase. The question about the timing of the biopsy procedure may be even more important in the future, since new compounds to prevent the progression of IPF/UIP are under intensive investigation.


   Acknowledgements
 
We thank Dr. Risto Pokela and Dr. Martti Mosorin for their comments on thoracic surgery and VATS. We also thank Mr. Manu Tuovinen and Ms. Päivi Koukkula for technical assistance.


   Footnotes
 
Abbreviations: CVD = connective vascular disease; DAD = diffuse alveolar damage; DLCO = diffusion capacity of the lung for carbon monoxide; HRCT = high-resolution CT; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia; VATS = video-assisted thoracoscopic surgery

Supported by The Finnish Anti-Tuberculosis Association Foundation, Juselius Foundation, Maud Kuistila Foundation and Fundings from Oulu and Helsinki University Hospitals.

Received for publication December 17, 2004. Accepted for publication April 25, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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