Abstract
Background
Nearly one-third of the patients with interstitial lung disease (ILD) require surgical biopsy for a definite diagnosis. Video-assisted thoracoscopic surgical (VATS) biopsy has replaced open lung biopsy, but the number of biopsy required to achieve an accurate diagnose is controversial.
Objectives
Our study aims to show that a well-planned single VATS biopsy is as effective as multiple biopsies for the accurate diagnosis of ILD by reduced days of hospital stay.
Methods
We included 111 patients with suspected ILD who underwent VATS biopsy in our study. Patients were separated into three groups according to the number of biopsies obtained. The differences between groups for diagnostic yield, mean time for chest tube removal, perioperative complications, and approximate volume per biopsy were analyzed statistically.
Results
Eighteen single, 74 double, and 19 triple biopsies were made. Mean times of chest tube removal and hospital stay for single, double, and triple biopsy were 3.5, 4.8, and 6.1 days respectively. The number of biopsy and length of hospital stay was strongly related (p = 0.02), but there was no difference for diagnostic yield between single and multiple biopsy groups (p > 0.05). There was no intraoperative complication or perioperative mortality. In postoperative period, eight patients with multiple biopsies had prolonged air leak.
Conclusion
Although classical knowledge suggests multiple biopsies from different locations of the lung are essential, recent reports have shown that the site and the number of biopsy are not as effective as previously thought in achieving the diagnosis for ILD. Our results show that a “single” biopsy, decided with multidisciplinary evaluation, is an effective and safe diagnostic tool, with lesser days of hospital stay.
Main novel aspects
1. The classical knowledge that multiple biopsies should be taken from different regions of the lung in the diagnosis of interstitial lung diseases has changed over time.
2. Diagnostic concordance between multiple biopsy specimens is above 85%.
3. A “single” biopsy, decided with multidisciplinary evaluation, is an effective and safe diagnostic tool with lower days of hospital stay.
Keywords: Interstitial lung disease, Usual interstitial pneumonia, Video-assisted thoracic surgery, Surgical diagnostic technique, Biopsy
Introduction
Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a term defining more than 200 clinicopathologic entities [1, 2]. ILD is known to be related in the development of lung cancers. Even high incidence of postoperative pulmonary complications is reported in patients with preexisting ILD [3]. Approximately one-third of the patients with ILD require lung biopsy for a definitive diagnosis. Until recent years, the golden standard for the diagnosis was open lung biopsy, but presently, there are many reports regarding video-assisted thoracoscopic surgical (VATS) biopsy, with reduced complication rates and increased patient comfort.
The number of biopsies and the site of biopsy have been discussed widely in many reports. While earlier reports suggest that two or more biopsy specimens, from different lobes, are required for an accurate diagnosis, most of the reports published within last 5 years suggest that a single biopsy, with a careful preoperative evaluation, is enough and more cost-effective with similar diagnostic yield ratios. This is the result of increasing use of high-resolution computed tomography and establishing a multidisciplinary committee for evaluation of this group of patients.
In this report, we have evaluated 111 patients retrospectively for the histopathologic diagnosis, size of the biopsy specimen, site of the biopsy, number of biopsies, and their relationship with chest tube removal and length of hospital stay.
Material and method
One hundred and eleven clinically suspected patients with diffuse pulmonary diseases in Ankara Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital undergoing VATS lung biopsy between January 2013 and June 2017 were included in our study. The study was approved by Institutional Review Board at Ankara Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital (IRB #07/12/2017–580). Bronchoalveolar lavage investigation was made for all of the patients, 17 patients (15.3%) underwent transbronchial needle biopsy and 8 patients (7.2%) underwent transthoracic tru-cut biopsy, but both failed to get a definitive diagnosis to establish definitive therapy. All patients were evaluated with high-resolution computed tomography (HRCT); fifteen patients were also evaluated with positron emission tomography (PET).
In March 2016, a multidisciplinary committee was established to evaluate patients with suspicious ILD. The site of biopsy was determined by this multidisciplinary committee, consisting of a pulmonary specialist, a pulmonary pathologist, and a radiologist, experienced in thoracic diseases, and a thoracic surgeon. Before this date, the site and number of biopsies were decided by the surgeons’ intraoperative exploration. So, the last eighteen patients underwent a single biopsy. All of the operations were performed under general anesthesia, with a double lumen intubation by VATS wedge resection technique. While in 98 patients, operations were completed via VATS; 13 of the patients, with diffuse pleural adhesions, required conversion to mini thoracotomy. VATS operations were performed through two ports; a 1.5-cm port in the midaxillary line in the 7th or 8th intercostal space for the camera, and a 3–4-cm utility incision in the midaxillary line in the 5th intercostal space.
Patients were separated into three groups according to the number of biopsies obtained — single, double, and triple biopsy group. Diagnostic yield, mean time for chest tube removal, perioperative complications, approximate volume per biopsy, and demographic characteristics were studied between both groups and also between single and multiple biopsy groups.
Statistical analysis
We used SPSS version 25.0 statistical software package (SPSS Inc., Chicago, IL, USA) for statistical analysis. χ2 and Fisher’s exact tests were used to compare categorical variables, whereas Kruskal–Wallis test was used to compare continuous variables between the three groups. Mann–Whitney-U test was used for subgroup analysis. A p value of less than 0.05 was considered significant.
Results
Sixty-five (58.6%) men and 46 (41.4%) women, with a mean age of 47.8 years (16–76 years) were studied. Eighty-eight (79.3%) patients underwent right-sided, while 23 (20.7%) underwent left-sided operation. Eighteen (16.2%) single biopsy and a total of 93 (83.8%) multiple biopsies were performed (74(79.6%) double and 19(20.4%) triple biopsies). The sites of biopsy are shown in Table 1.
Table 1.
Distribution of the biopsies according to the anatomic site
| Site | n | % |
|---|---|---|
| Right lower lobe (RLL) | 80 | 35.87 |
| Right middle lobe (RML) | 63 | 28.25 |
| Right upper lobe (RUL) | 39 | 17.49 |
|
Left upper lobe (LUL) (Lingula:11) |
25 | 11.21 |
| Left lower lobe (LLL) | 16 | 7.18 |
| Total | 223 | 100 |
Approximate volume per biopsy (three-dimensional scale measured on pathologic specimen) was recorded. The mean volume of biopsy specimen per patient was 27.56cm3 (range 2–216). There was no statistical difference between biopsy volume and the diagnostic yield (p > 0.05). The distribution of the histopathological diagnoses was divided into two main groups as “idiopathic interstitial pneumonia (IIP)” and “others” and is shown in Table 2. Mean times of chest tube removal for single, double, and triple biopsy were 3.5 (2–6), 4.82 (2–14), and 6.16 (3–16) days respectively. In our clinical practice, patients were discharged on the same day of the chest tube removal. Chest tube removal therefore reflects the length of hospital stay. The difference between the three groups was strongly significant (p = 0.02). Subgroup analysis revealed that the difference between both single and double biopsy group (p = 0.01) and single and triple biopsy group (p = 0.03) was statistically significant. But there was no difference between the double and triple biopsy groups in terms of the length of hospital stay (p > 0.05). We also studied the diagnostic yield ratios for single and multiple biopsy groups. We could not achieve an accurate diagnosis in four patients (3.92%). One of the patients in single biopsy group and three of the patients in multiple biopsy groups were undiagnosed. Statistical analysis revealed that there was no significant difference between single and multiple biopsy groups in terms of diagnosis (p > 0.05). Although there were patients who remained undiagnosed in single and double biopsy groups, the reason why there were no patients who were undiagnosed in the triple biopsy group may be due to the fact that the number of cases may not have been sufficient to provide statistical significance. Table 3 shows comparison of the three groups in terms of age, diagnostic yield, and days of chest tube drainage. The effect of histopathologic diagnosis on the length of hospital stay was also studied. While the number of biopsies did not have a significant effect on the length of hospital stay in the IIP, a single biopsy significantly reduced length of hospital stay in other diseases (Table 4).
Table 2.
Distribution of the histopathologic diagnosis
| Single (n) | Multiple (n) | Total | ||
|---|---|---|---|---|
| Diagnose | n (%) | n (%) | n | % |
| Idiopathic interstitial pneumonia | 5 (9.4) | 48 (90.6) | 53 | 47.7 |
| Usual interstitial pneumonia(UIP) | 3 | 32 | 35 | 31.5 |
| Cryptogenic interstitial pneumonia (COP) | 1 | 7 | 8 | 7.2 |
| Respiratory bronchiolitis associated ILD | 0 | 4 | 4 | 3.6 |
| Nonspecific interstitial pneumonia (NSIP) | 1 | 2 | 3 | 2.7 |
| Lymphocytic interstitial pneumonia | 0 | 1 | 1 | 0.9 |
| Desquamative interstitial pneumonia (DIP) | 0 | 1 | 1 | 0.9 |
| Pleuroparenchymalfibroelastosis | 0 | 1 | 1 | 0.9 |
| Other diseases | 13 (22,4) | 45 | 58 | 52.3 |
| Hypersensitivity pneumonia | 3 | 10 | 13 | 11.7 |
| Langerhans cell hystiositosis | 3 | 6 | 9 | 8.1 |
| Granulomatous Inflammation | 3 | 3 | 6 | 5.4 |
| Smoking-related ILD | 0 | 5 | 5 | 4.5 |
| Chronic hypersensitivity pneumonia | 1 | 3 | 4 | 3.6 |
| Emphysema | 0 | 3 | 3 | 2.7 |
| Chronic eosinophilic pneumonia | 0 | 2 | 2 | 1.8 |
| Follicular bronchiolit | 0 | 1 | 1 | 0.9 |
| Hystiocyte accumulation, Niemann Pick | 0 | 1 | 1 | 0.9 |
| Pulmonary alveolar microlithiasis | 0 | 1 | 1 | 0.9 |
| Dystrophic ossification | 0 | 1 | 1 | 0.9 |
| Chronic follicular bronchiolit | 1 | 0 | 1 | 0.9 |
| Allergic bronchopulmonary aspergillosis | 0 | 1 | 1 | 0.9 |
| Occupational exposure | 0 | 1 | 1 | 0.9 |
| Adenocarcinoma | 0 | 1 | 1 | 0.9 |
| Epithelioid hemangioendothelioma | 1 | 0 | 1 | 0.9 |
| T cell dominant B celllymphoma | 0 | 1 | 1 | 0.9 |
| Lymphangioleiomyomatosis | 0 | 1 | 1 | 0.9 |
| Alveolar lipoproteinosis | 0 | 1 | 1 | 0.9 |
| Non-diagnostic | 1 | 3 | 4 | 3.6 |
| Total | 111 | 100 | ||
Italic terms show a group of disease
Table 3.
Comparison of the three groups in terms of age, diagnostic yield and days of chest tube drainage
| Variable | Single (n = 18) | Double (n = 74) | Triple (n = 19) | p-value |
|---|---|---|---|---|
| Mean age | 43.5 (24–76) | 49.72 (18–71) | 44.74 (16–62) | 0.160 |
| Diagnostic yield (%) | 94.4% | 95.9% | 100% | 0.624 |
| Mean chest tube drainage (day)* | 3.5 (2–6) | 4.82 (2–14) | 6.16(3–16) | 0.02 |
Bold values in p value column respect p values that are statistically significant (p < 0.05)
*Mean chest tube drainage (day) also respects length of hospital stay
Table 4.
Comparison the effect of IIP and other diseases on length of hospital stay
| Diagnosis | Median length of hospital stay (days) | |||
|---|---|---|---|---|
| Single | Double | Triple | p-value | |
| IIP (n = 53) | 3.7 | 4.84 | 6.3 | 0.216 |
| Other diseases (n = 58) | 3.3 | 4.73 | 6.3 | 0.04 |
There were no intraoperative complications or perioperative mortality. In the postoperative period, eight patients with multiple biopsy had prolonged air leak (> 7 days). There was no prolonged air leakage in single biopsy group. One patient with usual interstitial pneumonia (UIP) had an acute exacerbation of the disease after hospital discharge but showed significant improvement in a week with medical treatment. No other serious morbidity was seen in remaining patients.
Discussion
DPLD, in other terms ILD, is a broad term for over 200 different clinical entities which vary in clinical course, treatment, and prognosis [4]. They can mainly be divided into two groups, depending on whether the disease developed from a known etiology or not. Far away from the subtype, all of them are characterized by variable degrees of inflammation and fibrosis. While inflammation is the dominant histologic pattern in organizing pneumonia and non-specific interstitial pneumonia, fibrosis is more prominent in UIP (1). In our series, 58 (52.25%) of the patients were diagnosed as IIP, and the most common pathology was UIP (n = 35 (31.5%)). The most challenging issue in diagnosis is discrimination of UIP and nonspecific interstitial pneumonia (NSIP) patterns. There are some reports regarding at least two biopsies from different lobes when clinic and imaging studies are strongly suspicious of NSIP [5, 6]. But diagnostic concordance between multiple biopsy specimens is varied between 12 and 91% [4, 7] in the literature. In our study, the diagnosis was established with a single biopsy in 3 (8.5%) UIP and 1 (3%) NSIP patients. There was a different histopathologic diagnosis for only 8 of the 93 patients with multiple biopsies. We, therefore, had a diagnostic concordance of 86% between multiple biopsy specimens.
Diagnostic examinations begin with the history, blood tests, pulmonary function tests, and radiologic work-up. Some auto-antibodies, including anti-nuclear antibody (ANA), rheumatoid factor (RF), and anti-double strand-DNA (anti-dsDNA), were found to be increased in connective tissue–related ILDs. Pulmonary function tests rarely suggest a specific diagnosis, but they give important information about the degree of the disease and also response to the therapy. The main stem diagnostic technique is a high-resolution computed tomography (HRCT). In some cases, HRCT is reported to be enough for the diagnosis and it may remove the need for further invasive diagnostic procedures (1). The American Thoracic Society / European Respiratory Society (ATS/ERS) consensus statement published in 2013 has defined some definite UIP patterns on HRCT. But only two-thirds of the patients present those findings and the remaining require biopsy for the definitive diagnosis [4].
The second step in diagnosis is the minimally invasive bronchoscopy techniques. These include bronchoalveolar lavage, endobronchial ultrasound with transbronchial biopsy, and recently introduced transbronchial cryobiopsy technique. The latter is reported to be the most successful, but still, its diagnostic yield is only up to 80% [5]. However, many of the patients undergoing these procedures may require surgical treatment due to iatrogenic pneumothorax and prolonged air leak. We cannot perform cryobiopsy in our institution. In our group of patients, seventeen patients underwent transbronchial biopsy, but they remained undiagnosed. Therefore, surgical lung biopsy is still the current gold standard for the diagnosis of this group of diseases. The technique for surgical biopsy was shifted from open lung biopsy towards VATS in recent years. VATS has been shown to be efficacious and reliable technique, with decreased morbidity, mortality, and hospital stay, when compared to open surgical biopsies. Classical multiport and uniportal approaches, and also outpatient scenes, have all been shown to be efficacious in diagnosing the ILDs [8–13]. In our clinical practice, we prefer a two-port technique for VATS biopsy.
ATS/ERS update statement also impresses the importance of a multidisciplinary approach for this group of diseases. In our institution, a comprehensive preoperative evaluation is made by an “interstitial lung disease committee” consisting of a pulmonary physician, a thoracic surgeon, a radiologist, and a pulmonary pathologist experienced in ILD. When first step diagnostic procedures fail to achieve a specific diagnosis, patients are referred to the subject committee to avoid unnecessary biopsies; the decision of the surgical biopsy and the target location were agreed by the committee [4].
In this study, we evaluated a total of 111 patients suspected of having DPLD, who underwent VATS-biopsy in a 5-year period. In our clinical practice, we used to make multiple wedge resections as per the classical knowledge. But our experience showed that there is a high concordance rate between the multiple pathologic specimens and this is compatible with the literature. So, in recent cases, we obtained only a single biopsy. Our results show that with a good preoperative evaluation, single biopsy is clearly relevant in diagnosing ILDs. The distribution of the diagnosis in single biopsy group was similar to the multiple biopsy group (Table 2). The statistical study showed that the number of biopsy is directly related with chest tube removal time and length of hospital stay (p < 0.05). We also showed that the size of the biopsy specimen and the anatomic location of the biopsy are not related with chest tube removal time and the diagnostic yield. Our results were concordant with the literature [14, 15]. To the best of our knowledge, this is the first report studying the relationship between the number of biopsy and chest tube removal and length of hospital stay statistically.
Patients with respiratory failure, extreme hypoxia, pulmonary hypertension, bleeding diathesis, or immune suppression are reported to have higher risk for complications of VATS, independent from the type of the disease. Hypoxic patients, who require mechanical ventilation, have been reported to have a mortality rate of 50% with VATS [16, 17]. In our series, there was no patient requiring mechanical ventilation or intensive care unit stay preoperatively. On the other hand, 5 patients with suspicious ILD who had spontaneous pneumothorax have been treated by tube thoracostomy preoperatively. They faced prolonged air leakage (> 7 days) and underwent a “salvage surgery” to stop the air leakage. All of the subject patients had improved air leakage just after the operation and had an accurate diagnosis of an ILD. So, we suggest “salvage surgery” for the patients with prolonged air leakage secondary to pneumothorax on the ground of an ILD.
Limitations
Our study has some limitations; first, the number of patients with a single biopsy is low to reach a definite opinion. Second, this study is a retrospective analysis and it was not possible to standardize potential effective factors such as patient selection and co-morbid illness. Further randomized-controlled trials should be conducted to come to a definite conclusion.
Conclusion
ILD is a group of diseases in which diagnosis is only possible with obtaining adequate pathologic specimens. When non-surgical diagnostic methods fail to achieve a definite diagnosis, surgical biopsy is the choice of selection. By increasing experience in years, VATS, independent from the type of technique used (needloscopic, uniportal, multiport, etc.), has improved to be as effective as open lung biopsy by thoracotomy. While classical knowledge suggests multiple biopsies from different locations of the lung are essential for achieving a definite diagnosis for ILDs, recent reports in the literature have showed that the site and the number of biopsies are not directly effective in achieving the diagnosis. The more important point in suspected ILD is a careful and multidisciplinary preoperative evaluation including radiological, clinical, and laboratory findings and intraoperative view of the surgeon experienced in this group of diseases. The site of biopsy and the size of the specimen are not related with the success of histopathologic diagnosis. Our results — which have strong statistical significance — show that a well-decided “single” biopsy specimen is an effective and safe diagnostic tool with low morbidity and mortality. The days for chest tube removal, hospital stay, and undoubtedly the costs are directly related to the number of biopsies. If needed, “salvage surgery” should not be denied to the patients with ILD suffering from prolonged air leak.
Funding
None.
Declarations
Institutional review board approval
The study was approved by Institutional Review Board at Ankara Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital (IRB #07/12/2017–580).
Consent to participate
As this is a retrospective study design based on hospital records, informed consent was not required.
Statement of human and animal rights
There was no infringement of human or animal rights in this study.
Conflict of interest
The authors declare that they have no conflict of interests.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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