Abstract
Objective: Medical thoracoscopy is recommended in the investigation of patients with exudative pleural effusions, especially when pleural fluid analysis is uninformative. The histological finding of ‘nonspecific pleuritis/fibrosis’ is common in thoracoscopic biopsies and presents a great uncertainty for clinicians and patients as the long-term outcome of these patients is unclear, and anxieties about undiagnosed malignancy persist. Method: A retrospective case-note study of 142 patients who underwent medical thoracoscopy over a 58-month period in a tertiary referral centre with a high incidence of mesothelioma. Patients with ‘nonspecific pleuritis/fibrosis’ were followed up until death or for a mean (±SD) period of 21.3 (±12.0) months. Results: A definitive histological diagnosis was achieved in 98 (69%) patients. A total of 44 (31%) patients had ‘nonspecific pleuritis/fibrosis’. Five (12%) were subsequently diagnosed with malignant pleural disease after a mean interval of 9.8 (±4.6) months. All five patients had histologically confirmed mesothelioma. In 26 patients with ‘nonspecific pleuritis/fibrosis’, no cause for the pleural effusion was discovered. The false-negative rate of thoracoscopic biopsy for the detection of pleural malignancy was 5%, with a diagnostic sensitivity of 95% and negative predictive value of 90%. Pleural effusion recurrence was more frequently associated with a false-negative pleural biopsy result. However, there was no correlation with other patient characteristics or the thoracoscopist’s prediction based on macroscopic appearances. Conclusion: Thoracoscopic pleural biopsy is valuable in the diagnosis of pleural malignancies. Patients with ‘nonspecific pleuritis/fibrosis’ require follow-up as a malignant diagnosis (especially mesothelioma) may eventually be established in approximately 12% of cases.
1 Introduction
Pleural effusions are a common presenting feature of a wide range of pleural, pulmonary and systemic diseases. Medical thoracoscopy, also called ‘pleuroscopy’, with direct vision-guided pleural biopsy is recommended by most clinical guidelines and texts for the investigation of exudative pleural effusions, especially if thoracentesis fails to reveal the underlying diagnosis.
Over 55 recognised causes of pleural effusions have been documented and, although malignancy is common, the majority are secondary to benign pathologies [1]. Pleural inflammation (pleuritis) underlies the formation of most exudative pleural effusions, and is a common histological finding irrespective of the underlying aetiology. In a small number of conditions, the presence of additional features (e.g., malignant invasion in pleural cancers and caseating granulomata in tuberculous pleuritis) enables a definitive diagnosis. In the remaining cases, ‘nonspecific pleuritis/fibrosis’ is the only histological finding.
‘Nonspecific pleuritis/fibrosis’ therefore often presents a management dilemma for clinicians: whether the result represents a genuine benign pathology or a sampling error from thoracoscopy — the latter would usually mean subjecting the patient to more invasive procedures (e.g., thoracotomy) with known associated morbidities. The alternative is a lengthy follow-up, which creates significant anxiety for patients, especially as the duration of follow-up required is undefined. This dilemma is heightened in countries where malignant pleural mesothelioma is endemic, as mesothelioma is notoriously difficult to separate from reactive pleural inflammation and fibrosis.
The eventual outcome of patients with ‘nonspecific pleuritis/fibrosis’ on thoracoscopic pleural biopsies has seldom been studied, especially in areas of high incidence of mesothelioma. The frequency of false-negative (benign) diagnoses for these patients and whether such cases can be identified by clinical parameters warrant investigation.
This study aimed to (1) examine the long-term outcome of patients with exudative effusions and benign ‘nonspecific pleuritis/fibrosis’ on thoracoscopic pleural biopsies in a region of high incidence of malignant mesothelioma; and (2) assess potential predictive factors, including the accuracy of the thoracoscopist’s prediction, for patients having a false-negative result following thoracoscopy.
2 Methods
All patients who underwent medical thoracoscopy, in a 58-month period from January 2000, in a tertiary referral pleural unit, were identified from the thoracoscopy database. Prior to the procedure, all patients had completed a detailed medical evaluation, radiological assessment and pleural fluid analyses and, in some cases, closed pleural tissue biopsies. Additional data were obtained from the review of patients’ hospital case notes.
Medical thoracoscopy was performed by respiratory physicians experienced in the procedure. Patients were placed in the lateral decubitus position and conscious sedation and analgesia were administered (usually with intravenous midazolam and fentanyl). Following infiltration of local anaesthesia to the skin and underlying structures (especially the periosteum and parietal pleura), a 7-mm incision was made and a trocar inserted, following simple blunt dissection, into the pleural space. Pleural fluid was evacuated using a sterile suction catheter. The parietal, diaphragmatic and visceral pleura were examined using a rigid thoracoscope (Richard Wolf GmbH, Knittlingen, Germany) with video assistance. Biopsies were taken either with an overriding biopsy forceps through the rigid scope or by forceps introduced via a second entry port.
A histological diagnosis of ‘nonspecific pleuritis/fibrosis’ is defined if the histology report of the pleural tissue revealed any of the following: reactive fibrous pleural thickening, fibrinous pleurisy, fibrosis, florid reactive change, fibrous connective tissue, chronic inflammation, benign change or dense fibrous tissue, in the absence of malignant pleural infiltration, granulomata, pleural vasculitis or evidence of bacterial infection.
A total of 142 patients underwent thoracoscopy, of which 44 (31%) had a histological diagnosis of ‘nonspecific pleuritis/fibrosis’.
2.1 Clinical variables
Demographic data, co-morbid conditions, previous asbestos exposure, smoking status, clinical features [2] and medications were recorded. The documented working diagnosis from the clinician reviewing the patient prior to thoracoscopy was taken from the patients’ hospital notes. If a differential diagnosis list was given, the first entry was taken for analysis.
Pleural fluid biochemistry (protein, lactate dehydrogenase (LDH), glucose and pH values) were recorded and Light’s criteria used to differentiate transudates from exudates [3]. Procedural details pertaining to the thoracoscopy, including the thoracoscopists’ impression of the macroscopic appearances, were documented (as benign, malignant or indeterminate). In particular, the presence of pleural nodularity, thickening, plaques and inflammation were noted.
2.2 Radiology
The size of the pleural effusion on the chest radiograph was subdivided into those occupying over 50% of the hemithorax and those which did not. The availability of computed tomography (CT) or magnetic resonance imaging (MRI) prior to the thoracoscopy was noted.
2.3 Follow-up
Long-term follow-up of all patients with a diagnosis of ‘nonspecific pleuritis/fibrosis’ was carefully conducted. Most patients were followed up in the pleural clinic. An exhaustive search was performed for data regarding all patients. Initially, local medical records and the hospital’s computerised retrieval system were scrutinised. If insufficient information was obtained from these sources, direct communication with other hospitals responsible for patients’ ongoing care and/or their general practitioners was made. Follow-up and outcome data were attained in all but two patients, who were excluded from statistical analyses.
2.4 Statistics
All analyses were performed with SPSS software (version 14.0, SPSS Inc., Chicago, IL, USA). Data of parametric distributions were expressed as mean (±SD) unless otherwise stated. Chi-square or Fisher’s exact test was used (as appropriate) to compare categorical variables, including relationships between the patients’ demographic data, investigation results and final diagnoses. The Student’s unpaired t-test was performed to compare the mean of two groups. All reported p values were two-sided and effects were considered significant if p ≪ 0.05.
3 Results
A total of 142 patients (102 male, mean age 64.6 ± 12.9 years) underwent local anaesthetic thoracoscopy during the period of study. Complete follow-up information was obtained on 140 (99%) patients.
Detailed post-procedure notes were recorded in the medical files in 100% of the patients, which included macroscopic findings of the parietal, diaphragmatic and visceral pleura. The thoracoscopist indicated whether the findings appeared neoplastic or not based on the presence of visible tumour deposits, malignant pleural nodularity or pleural thickening.
Pleural biopsy results were available in 100% of cases and a definitive histological diagnosis from thoracoscopic biopsies was achieved in 98 patients (69%) (Table 1 ).
Histological diagnoses of all patients undergoing thoracoscopic biopsy (n = 142).
The false-negative rate of thoracoscopic pleural biopsy for detection of pleural malignancy was 5/94 (5%, 95% confidence interval (CI) 2.3–12.5%), with a diagnostic sensitivity of 95% (95% CI 87.5–98.0%) and negative predictive value of 90% (95% CI 77.8–96.3%).
3.1 ‘Nonspecific pleuritis/fibrosis’
Forty-four patients (31%) demonstrated ‘nonspecific pleuritis/fibrosis’ on histological analysis. Complete data (hospital records, thoracoscopy outcome and follow-up details) were available for 42 (96%) patients. All patients had an exudative effusion that was negative for cancer cells on cytological examination. The mean pleural fluid protein was 41.9 (±9.5) g l−1 and LDH 602 (±1081) IU l−1.
All patients had a pre-thoracoscopy chest X-ray and thoracic CT imaging was available for 62% of cases. The latter was not mandatory prior to thoracoscopy, particularly if there was a high pre-test probability of underlying pleural malignancy and imaging acquisition would result in a delay in obtaining pleural histology. Follow-up details were available over a mean surveillance period of 21.3 (±12.0) months.
Five patients (12%, 95% CI 4.5–26.4%) with ‘nonspecific pleuritis/fibrosis’ were ultimately found to have underlying pleural malignancy on follow-up (Table 2 ). All five patients presented with a unilateral exudative effusion and their thoracoscopic biopsies were reported as ‘benign’. In all five cases, an eventual histological diagnosis of malignant mesothelioma was established on repeat pleural biopsy or at autopsy. Details of the individual cases are presented below.
Characteristics of patients with false-negative ‘nonspecific pleuritis/fibrosis’.
3.2 Cases
Patient A presented at 39 months following thoracoscopy with ascites and an umbilical nodule. His pleural effusion did not recur. An ascitic aspirate showed mesothelial cell proliferation and subsequent biopsy of the umbilical nodule demonstrated malignant features favouring mesothelioma. Symptomatic relief was achieved with repeated therapeutic paracentesis. He died 1 month later. Pleural and peritoneal biopsies taken at autopsy confirmed malignant mesothelioma.
Patient B, a 51-year-old female, suffered re-accumulation of her pleural effusion 5 months after her initial thoracoscopy. Biopsies taken at a second local anaesthetic thoracoscopy showed malignant epithelioid mesothelioma.
Patient C, a 75-year-old male, experienced symptomatic effusion recurrence after 3 months associated with rapid deterioration in his performance status preventing further pleural interventions. Best supportive care measures were implemented and a histological diagnosis of malignant sarcomatoid mesothelioma was made post-mortem.
In patients D and E, clinical suspicions of pleural malignancies were high and they were closely monitored in the pleural clinic prior to death 13 and 7 months following thoracoscopy. Autopsies revealed malignant mesothelioma.
Of the remaining cases, 26 had no cause established for their effusion after extensive investigation and follow-up (mean duration 19.6 ± 11.0 months). An eventual diagnosis was made in 11/37 cases (30%) based on the clinical information and patients’ disease course (Fig. 1 ). This included four patients with benign asbestos-related pleural effusion (BAPE) in whom no underlying pleural malignancy was evident after a mean follow-up period of 26.0 (±9.9) months. In two patients, medical thoracoscopy was performed as a preoperative assessment tool to exclude pleural involvement, prior to referral for surgical resection of mediastinal tumour. A benign haemangioma and a leiomyoma of uncertain malignant potential were subsequently removed. Both patients are alive with no disease or effusion recurrence 7 and 5 years post-thoracoscopy, respectively.
Eventual diagnosis of patients undergoing medical thoracoscopy.
3.3 Assessment of factors predictive of a false-negative biopsy result
There was a strong association between the referring physicians’ level of clinical suspicion of pleural malignancy prior to thoracoscopy, and the presence of a false-negative ‘nonspecific pleuritis/fibrosis’ result. In cases with a low pre-thoracoscopic clinical suspicion of malignancy, there were no false-negative outcomes; however, five patients from the cohort with a high level of suspicion prior to the test had a false-negative biopsy result (p = 0.14, Fisher’s exact test).
The recurrence of pleural effusion, which occurred in seven patients (17%), was more frequent in those with an ultimate diagnosis of pleural malignancy (n = 2/4) compared with patients with benign disease (n = 5/34) (p = 0.15, Fisher’s exact test).
No association by proportions was seen between the presence of pleural malignancy and effusion size, or with a positive history of asbestos exposure. Similarly, there were no significant differences in symptoms of chest pain, dyspnoea and weight loss at presentation as well as in biochemical pleural fluid parameters between the two groups (Table 3 ).
Baseline, investigation and outcome characteristics of patients with ‘nonspecific pleuritis/fibrosis’.
The thoracoscopist’s supposition, based on macroscopic pleural appearances during the procedure, was not reliable in establishing the benign or malignant nature of the underlying disease. Most commonly, the appearances were recorded as indeterminate (68% and 75% in true and false-negative biopsy cases, respectively). The diagnostic sensitivity and specificity of the thoracoscopist’s opinion for distinguishing pleural malignancy from benign disease (classifying indeterminate appearances as suspicious of malignancy) were 100% (95% CI 39.6–100%) and 21% (95% CI 9.6–39.4%), respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 13% and 100%, respectively.
4 Discussion
The present study shows that medical thoracoscopy, in this tertiary referral unit setting, carries a small but definite false-negative rate for the diagnosis of pleural malignancies. All five cases of false-negative biopsy results were eventually diagnosed as malignant mesothelioma. These cases could not have been predicted by clinical or radiological parameters, or from macroscopic thoracoscopic appearances. This highlights the need to maintain vigilant follow-up for patients with a high suspicion of malignant mesothelioma in whom thoracoscopic biopsies are benign.
Pleural effusions are a common presentation of a range of lung and extra-pulmonary disease. Pleural inflammation and resultant fibrosis were the common histological findings in most of the benign diseases, and are not helpful in revealing the specific underlying aetiology. Pleural malignancy is the second most common cause of an exudative effusion worldwide and accounts for up to 300,000 cases annually in the UK and USA combined. A diagnosis of malignancy on thoracoscopic biopsy is useful but a benign histology can represent a sampling error or genuine benign pleuritis.
Medical thoracoscopy is advocated in patients with an undiagnosed exudative pleural effusion, and offers a diagnostic sensitivity for pleural malignancy of 85–100% comparable to that from video-assisted thoracoscopic surgery (VATS) [4–14]. Significant procedural advancements have occurred since first recorded thoracoscopies [15] and immunohistochemistry and thoracoscopic techniques have improved over time. However, despite this progress, our data that 12% of patients with ‘benign’ pleural histology, or 5% of all patients undergoing thoracoscopic biopsy during this period, were false negatives remains consistent with earlier reports [6,8,13]. This may, in part, be explained by the rapidly growing incidence of malignant mesothelioma, in which histological diagnosis is notoriously difficult (12% in our series compared with 2.5% [6] and 2.9% [13] in previous studies) (Table 4 ).
Comparison of data from this study with other published results.
All cases of false-negative biopsies were in patients with malignant mesothelioma. Several reasons may contribute to this. Although advances in immunohistochemistry have aided the identification of metastatic adenocarcinoma, the separation of malignant (from benign) mesothelial cells remains challenging. Histological evidence of tumour invasion of tissue deep to the pleura defines malignant mesothelioma from reactive changes. Some subtypes of mesothelioma, especially sarcomatoid, can often stain negative for common mesothelial markers for example, calretinin and epithelial membrane antigen (EMA) and evade diagnosis. Further, in mesothelioma, the pleurae are often thickened with fibrotic tissues and are paucicellular. Thoracoscopic biopsy techniques approach the parietal pleura from the surface and can potentially miss histological changes situated deep within the fibrotic pleura. Microscopic parietal pleural involvement in mesothelioma is often patchy and cannot be identified even under direct visual inspection, or with the use of autofluorescence thoracoscopy [16,17].
Our study, in addition to others, suggests further measures are needed to improve the missed diagnosis rate from thoracoscopic biopsy. Taking ‘deep’ biopsies by repeatedly sampling the same parietal pleural site, or using an insulation-tipped diathermic (IT) knife [18,19] may aid diagnosis. Alternatively, a percutaneous approach, for example, imaging-guided cutting needle biopsy of the pleura, has shown a high success rate in selected cases [20]. However, given that only approximately 1 in 10 patients would have an incorrect benign thoracoscopic biopsy result, subjecting all to an open surgical or VATS pleural biopsy is unwarranted and would create unnecessary morbidity.
Future studies are needed to select the appropriate patients with negative or nonspecific pleural biopsies from medical thoracoscopy to undergo more invasive surgical procedures. Several factors should be included in the consideration. No clinical or radiological predictors assessed in our study were accurate enough to aid patient selection. Therefore, this should be considered on a case-by-case basis, depending on the clinical suspicion and whether the patient is fit and willing to tolerate general anaesthesia. The relative merits and limitations of medical thoracoscopy and VATS have been discussed elsewhere [21,22]. One limitation of medical thoracoscopy is the limited visualisation of the pleural cavity in patients with significant pleural adhesions. VATS or open surgical biopsies should be considered in patients with high clinical suspicion of malignancy and incomplete examination of the pleural surfaces by medical thoracoscopy and a histological diagnosis of ‘nonspecific pleuritis/fibrosis’ on thoracoscopic biopsies. Malignant mesothelioma accounted for all the false-negative cases in our series; however, the incidence of this malignancy varies widely around the world. The threshold for subjecting patients with ‘nonspecific pleuritis/fibrosis’ to VATS or open surgical biopsies should reflect the local incidence of mesothelioma (which influences the pre-test probability).
Clinical guidelines recommend close observation of patients with undiagnosed exudative effusions, although the length and follow-up regime is not defined [23]. In our study, no clinical parameter(s) significantly aided differentiation of true benign pleuritis from false negatives. Moreover, in contrast to previous research [13], in an area of high mesothelioma incidence, we did not show an increased likelihood of underlying mesothelioma in the ‘nonspecific pleuritis/fibrosis’ cohort with prior asbestos exposure (p = 0.34).
With the greater acceptability and use of medical thoracoscopy, an increased number of cases with a false-negative benign pleural biopsy result may be predicted. Future strategies need to focus on the identification of other markers to accurately identify this group. For now, this means that lengthy, close follow-up will still be required for most patients in whom there is no definitive cause of pleural inflammation/fibrosis. Clinical judgement remains important in determining which patient(s) should be subjected to further investigations; advances in the field of biomarkers (especially elevated serum or pleural fluid mesothelin levels) [24–26] and imaging technologies (e.g., positron emission tomography (PET)) may aid patient selection. Further large prospective studies of patients with a benign pleural biopsy result in populations with differing incidences of mesothelioma are needed. Such trials should incorporate technical advances in thoracoscopy, new biomarkers and radiological screening.
