Özet

Methods: We retrospectively reviewed medical records of 202 patients (91 males, 111 females; mean age 49±12 years; range 18 to 78 years) who underwent surgical lung biopsy in our hospital between May 2008 and December 2014. We recorded patients’ demographic characteristics, surgery type, number and localization of biopsies, and final diagnoses established in light of histopathological findings. According to the final diagnoses, we divided patients into two groups as patients with an established specific diagnosis (group 1) and patients without an established specific diagnosis (group 2). We investigated the effect of surgical procedure on final diagnosis.

Results: Left lung was more frequently sampled (72%) and 75% of the procedures ended up with a single biopsy. Total number of biopsies was 255. Of all samples, 44% were taken from the middle lobe or lingula. Rate of patients with a histopathologically established and clinically and radiologically verified final diagnosis was 80% (group 1). Gender (p=0.161), number of samples (p=0.541), lung side (p=0.954), or lung segment (p=0.592) did not affect the rate of establishing a diagnosis. Of the patients, mortality was observed in 2%, major complications in 1.5%, and minor complications in 9.5%. No relationship was detected between localization or number of biopsies and development of complications (p>0.05).

Conclusion: Albeit with low probability, surgical lung biopsies are correlated with morbidity and mortality. Not all procedures result in a specific diagnosis. Localization, type or number of biopsies do not affect the diagnosis rate significantly.

Specific diagnosis of ILD is important for prognostic purposes and determining the patient treatment regimen. The most important issue here is to differentiate idiopathic pulmonary fibrosis (IPF) since the clinical prognosis is poor and corticosteroids are not used in the treatment.[2,3]

Despite all diagnostic methods, surgical lung biopsy (SLB) is required in one third of ILD patients. Surgical lung biopsy is often discussed in terms of its diagnostic value, mortality and morbidity.[4-6] Even though there has been continuous practice of SLB for decades, there is still no consensus on the site and number of the surgical biopsies. Lingula and middle lobe have been reported to be common sites of inflammatory, fibrotic and vascular changes so that segments other than lingula and middle lobe are suggested to be sampled. However, lingula and middle lobe are more frequently preferred by the surgeon since the tissue is delivered easily.[7,8] There are reports concluding that the site of the biopsy, whether lingula, middle lobe or other segments, do not affect the diagnosis rate.[9,10] Furthermore, both positive and negative results have been reported on the effect of the number of biopsies on the diagnosis rate.[6,9] Therefore, in this study, we aimed to investigate the diagnostic yield of SLB for the differential diagnosis of ILD and the factors affecting diagnosis.

Yöntem

Patients with interstitial involvement are evaluated for surgery when specific diagnoses cannot be made upon medical history, clinical laboratory, and radiological findings.[1] Biopsy is avoided when radiological findings are suggestive of a definite usual interstitial pneumonia (UIP) pattern. [3] Surgery decision is made by the consultation of a pulmonologist and thoracic surgeon, taking the consent of the patient.

Site of biopsy was decided according to high resolution computed tomography findings. In patients with widespread involvement, either lingula or middle lobe was sampled. Otherwise, the involved segment was sampled. The number of biopsy was decided by the surgeon during the procedure, based on the intraoperative exploration findings. Mini-thoracotomy was performed more often until 2010, while later on, most biopsies were obtained by VATS.

We obtained the medical files of the patients from the archive of the hospital. We recorded patients’ demographic characteristics and examinations prior to surgery. Also, we recorded the side, site, and number of biopsies from the operation notes.

We coded biopsy sites as (i) segments of the upper lobes except lingula, (ii) lingula or middle lobe, and (iii) segments of the lower lobe. We investigated postoperative duration of hospital stay (day) and procedure-related complications. We accepted death within the first 30 days of the procedure as postoperative mortality. We considered prolonged air leak (>96 hours) and wound infection as minor complications. We accepted respiratory failure and rethoracotomy requirement as major complications.[11] Then, we compared patients with complications (minor/ major complications and death) to patients without complications.

We recorded the final diagnosis based on histopathological findings along with radiological findings and clinical follow-up. We grouped patients with a definitive diagnosis as group 1 and patients with no definitive diagnosis as group 2. We compared the diagnostic yield of the procedure between the two groups. The study was approved by the local Ethics Committee of the Institution (Dr. Lufti Kırdar Training and Research Hospital, Reference Number: 89513307/1009/410) and it proceeded in accordance with the ethical principles stated in the Declaration of Helsinki.

Statistical analysis
Categorical variables were compared using the Fisher’s exact test. Continuous variables are presented as the mean ± standard deviation and were analyzed with the Student’s t-test. All tests were two-tailed, and a p value of < 0.05 was accepted as significant. All analyses were performed using SPSS version 16.0 statistical software package (SPSS Inc., Chicago, IL, USA).

Bulgular

Mini-thoracotomy was carried out in 72 (36%) and VATS in 130 (64%) patients. The left lung was more frequently sampled (72%, n=145). Biopsy was performed from one site in 152 patients (75%) and multiple times in 50 patients (25%) (Figure 1). Number of samples totally was 255. Thirty-one samples (12%) were from the upper lobes except lingula, while 111 (44%) were from middle lobe or lingula (Figure 2). Median duration of postoperative hospital stay was two days (range, 1 to 18 days). In total, 162 of 202 patients (80%) had a specific diagnosis (group 1) whereas 40 patients (20%) were not specifically diagnosed (group 2).

Figure 1: Number of biopsies performed.

Figure 2: Selected site according to number of biopsies.

The most frequent diagnosis was UIP (26.7%), followed by sarcoidosis, hypersensitivity pneumonia, and non-specific interstitial pneumonia (NSIP). Ten patients were diagnosed as cancer (nine had adenocancer and one had thyroid anaplastic carcinoma metastasis) (Table 1).

Table 1: Final diagnoses

We detected no gender difference between the two groups (p=0.161). Of 152 patients with single biopsy, 120 (79%) were specifically diagnosed. Number of biopsies did not influence the diagnosis rate (p=0.541).

An analysis of the impact of biopsy segments on the diagnosis rate revealed that 74% of the samples taken from the upper lobes, 79% of the lingula or middle lobe samples, and 78% of the lower lobe samples resulted in a specific diagnosis. The site of the biopsy did not have significant effect on diagnosis (p=0.592). Also, sampling from either right or left lung did not make any difference (p=0.954) (Table 2).

Table 2: Comparison between groups

Postoperative mortality (within 30 days) was recorded in four patients (2%). Major complications developed in three (1.5%) and minor complications in 19 (9.5%) patients. Non-complicated patient rate was 87% (n=176). Major complications were respiratory failure (n=1), respiratory failure and cerebrovascular attack (n=1), and bleeding and re-thoracotomy (n=1). Minor complications were prolonged air-leak (n=18) and wound infection (n=1).

Duration of hospital stay of patients with complications was significantly longer (6.2 days vs. 2.3 days, respectively) (p<0.001). Mean age was similar between the complicated and noncomplicated patients (50 vs. 49) (p=0.751). There was no significant difference in gender, type of surgery, lung side, the number of biopsies, and diagnosis rate between the complicated and noncomplicated patients (Table 3).

Table 3: Comparison of patients with and without complication

Tartışma

Some patients cannot be clearly classified as ILD.[12] The main reasons for this are: inadequate clinicalradiological- pathological findings, discordance between clinical-radiological-pathological findings, and coexistence of multiple radiological and/or histological patterns.[12,13] More than one pattern in the same patient’s biopsy is mostly reported for NSIP and UIP. Additionally, there may be multiple patterns in smokers. In this situation, multidisciplinary discussion is necessary for final diagnosis and adequate approach to patient management.[14-17]

Sarcoidosis, tuberculosis, and malignancy can also be diagnosed in patients with a preliminary diagnosis of ILD. Lee et al.[18] identified infectious etiology in 31% in a series of 196 patients. Sigurdsson et al.[19] obtained non-interstitial diagnoses in 10% of patients. Granulomatous diseases have been reported in 5 to 16% and malignancy in 5 to 13.3% of patients.[5-7,18,20,21] In the published series, the diagnostic yield of SLB ranged between 34 to 98% and the most common diagnosis was reported as IPF.[19,20] In the current study, final diagnosis was reached in 80% and the most common diagnosis was UIP, which complies with the existing literature. Also, diagnoses of sarcoidosis and tuberculosis were reached in 12.4% and 4%, respectively, while malignancy was diagnosed in 5% of the patients.

Various results have been reported on how many biopsies should be taken. The main reasons in preference of a single biopsy by the surgeon are to prevent extension of operation duration and decrease costs and complications. However, taking multiple biopsies have been suggested in the first published reports and in current guidelines.[3,4,22] In 2013, Blackhall et al.[6] reported that a median of two biopsies significantly increases the probability of reaching a definitive diagnosis. On the other hand, sampling from either a single biopsy or multiple biopsies have not made a significant difference in providing a diagnosis in other reports.[19,21] Chechani et al.[9] indicated that single biopsy would be enough when a radiologically convenient segment is sampled. In the last few years, two studies consisting 224 and 194 patients concluded that the number of biopsies has no effect on reaching a specific diagnosis and taking less biopsies was defended since less inflammation and less injury would be provided in lung parenchyma.[20,23] In the present study, the number of biopsies was mostly decided during the procedure and the number of biopsies did not make a significant difference on diagnostic yield.

Another issue regarding the number of biopsies is the possibility of a misdiagnosis. It is suggested that interstitial involvement may vary among lobes, especially in the distinction of NSIP and UIP. When more than one biopsy preparations of the same patients were evaluated discretely, UIP and NSIP discord was reported as 12% and 26%, respectively.[14,24] However, with similar methods, Flint et al.[25] did not find a statistically significant difference in diagnosis.In the current study, we did not evaluate the specimens in this regard. Since the most discussed issue is misdiagnosed NSIP, we reevaluated patients with NSIP. Among 11 patients, single biopsy was taken in nine (collagen vascular disease-associated NSIP diagnosis was established in three and corticosteroid treatment was effective in six patients). In the other two patients, two biopsies were taken. One patient died with an acute exacerbation in the fourth year of the diagnosis. The other patient underwent lung transplantation in the third year of the diagnosis. The results of the present study is not sufficient to comment on the possibility of misdiagnosis. Prospective studies with larger series may shed further light on this issue. In our opinion, it may be reasonable to take more than one biopsy in patients with a high probability of NISP or UIP.

Biopsy localization is another subject under discussion. Sampling radiologically less-involved segments without 'honeycomb' pattern has been proposed.[7,24,26] Lingula and middle lobe biopsies are more frequently preferred by the surgeon but those segments are suggested to be avoided since inflammatory, vascular, and fibrotic changes are seen more often.[7,8,25,27] In recent studies, the site of biopsy has been reported to have no influence on the diagnosis rate (Table 4).[9,10,19,21,28] Similarly, in this study, we found that the site of biopsy does not affect the diagnosis rate. We believe that it is important to evaluate radiological involvement in the selection of the appropriate segment.

Table 4: Comparison of the reported series

Compatible with the literature, diagnostic yield of thoracotomy and VATS was found to be similar.[21] In the literature, median postoperative duration of hospital stay were reported as four days, with a range of 2 to 10 days.[23,29] In line with the literature, the median duration of hospital stay was two days in the present study.

Perioperative morbidity has been reported to be between 3.8 to 16%, while 30-day mortality have been reported to be 0 to 6.7%.[5,19,20] The most frequent complication has been described as prolonged air leak.[6,19] In our study, mortality rate was 2%, and rates of major and minor complications were 1.5% and 9.5%, respectively. The most common minor complication was prolonged air leak. No significant risk factors were identified for mortality.

The present study has some limitations. Firstly, this is a retrospective and single-center study. Secondly, the histopathologic specimens were not evaluated separately in terms of misdiagnosis.

In conclusion, surgical lung biopsy may cause morbidity and mortality, albeit with a low probability. Although non-interstitial diagnosis can be established, specific diagnosis cannot be achieved in some patients. With respect to radiological involvement, the site and number of biopsies do not seem to affect the diagnosis rate. Nevertheless, we believe that patients should be approached from a multidisciplinary perspective in this regard.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

Kaynaklar

1) Xaubet A, Ancochea J, Blanquer R, Montero C, Morell F, Rodríguez Becerra E, et al. Diagnosis and treatment of diffuse interstitial lung diseases. Arch Bronconeumol 2003;39:580-600. [Abstract]

2) American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304.

3) Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.

4) Branley HM, Lake FR. 2008 British guidelines on the management of interstitial lung diseases. What are the key new messages for clinical practice? Pol Arch Med Wewn 2009;119:112-4.

5) Rena O, Casadio C, Leo F, Giobbe R, Cianci R, Baldi S, et al. Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease. Eur J Cardiothorac Surg 1999;16:624-7.

6) Blackhall V, Asif M, Renieri A, Civitelli S, Kirk A, Jilaihawi A, et al. The role of surgical lung biopsy in the management of interstitial lung disease: experience from a single institution in the UK. Interact Cardiovasc Thorac Surg 2013;17:253-7.

7) Gaensler EA, Carrington CB. Open biopsy for chronic diffuse infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg 1980;30:411-26.

8) Ray JF, Lawton BR, Myers WO, Toyama WM, Reyes CN, Emanuel DA, et al. Open pulmonary biopsy. Nineteenyear experience with 416 consecutive operations. Chest 1976;69:43-7.

9) Chechani V, Landreneau RJ, Shaikh SS. Open lung biopsy for diffuse infiltrative lung disease. Ann Thorac Surg 1992;54:296-300.

10) Wetstein L. Sensitivity and specificity of lingular segmental biopsies of the lung. Chest 1986;90:383-6.

11) Lettieri CJ, Veerappan GR, Helman DL, Mulligan CR, Shorr AF. Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005;127:1600-5.

12) Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733-48.

13) Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J 2013;42:750-7.

14) Monaghan H, Wells AU, Colby TV, du Bois RM, Hansell DM, Nicholson AG. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest 2004;125:522-6.

15) Ryu JH, Colby TV, Hartman TE, Vassallo R. Smokingrelated interstitial lung diseases: a concise review. Eur Respir J 2001;17:122-32.

16) Aubry MC, Wright JL, Myers JL. The pathology of smokingrelated lung diseases. Clin Chest Med 2000;21:11-35.

17) Vassallo R, Jensen EA, Colby TV, Ryu JH, Douglas WW, Hartman TE, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic, and functional correlations. Chest 2003;124:1199-205.

18) Lee YC, Wu CT, Hsu HH, Huang PM, Chang YL. Surgical lung biopsy for diffuse pulmonary disease: experience of 196 patients. J Thorac Cardiovasc Surg 2005;129:984-90.

19) Sigurdsson MI, Isaksson HJ, Gudmundsson G, Gudbjartsson T. Diagnostic surgical lung biopsies for suspected interstitial lung diseases: a retrospective study. Ann Thorac Surg 2009;88:227-32.

20) Kayatta MO, Ahmed S, Hammel JA, Fernandez F, Pickens A, Miller D, et al. Surgical biopsy of suspected interstitial lung disease is superior to radiographic diagnosis. Ann Thorac Surg 2013;96:399-401.

21) Qureshi RA, Ahmed TA, Grayson AD, Soorae AS, Drakeley MJ, Page RD. Does lung biopsy help patients with interstitial lung disease? Eur J Cardiothorac Surg 2002;21:621-6.

22) Klassen KP, Andrews NC. Biopsy of diffuse pulmonary lesions. A seventeen-year experience. Ann Thorac Surg 1967;4:117-24.

23) Fibla JJ, Molins L, Blanco A, Royo I, Martínez Vallina P, Martínez N, et al. [Article in English, Spanish] Videoassisted thoracoscopic lung biopsy in the diagnosis of interstitial lung disease: a prospective, multi-center study in 224 patients. Arch Bronconeumol 2012;48:81-5.

24) Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164:1722-7.

25) Flint A, Martinez FJ, Young ML, Whyte RI, Toews GB, Lynch JP. Influence of sample number and biopsy site on the histologic diagnosis of diffuse lung disease. Ann Thorac Surg 1995;60:1605-7.

26) Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol 2002;26:1567-77.

27) Yung RC, Weinacker AB, Steiger DJ, Miller TR, Stern EJ, Salmon CJ, et al. Upper and middle lobe bronchoalveolar lavage to diagnose Pneumocystis carinii pneumonia. Am Rev Respir Dis 1993;148:1563-6.

28) Gaensler EA, Moister VB, Hamm J. Open-lung biopsy in duffuse pulmonary disease. N Engl J Med 1964;270:1319-31.

29) Kramer MR, Berkman N, Mintz B, Godfrey S, Saute M, Amir G. The role of open lung biopsy in the management and outcome of patients with diffuse lung disease. Ann Thorac Surg 1998;65:198-202.

30) Newman SL, Michel RP, Wang NS. Lingular lung biopsy: is it representative? Am Rev Respir Dis 1985;132:1084-6.

31) Miller RR, Nelems B, Müller NL, Evans KG, Ostrow DN. Lingular and right middle lobe biopsy in the assessment of diffuse lung disease. Ann Thorac Surg 1987;44:269-73.

32) Park JH, Kim DK, Kim DS, Koh Y, Lee SD, Kim WS, et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg 2007;31:1115-9.