In respiratory medicine, pleural effusions are one of the most complicated conditions to diagnose . MT is a minimally invasive method for diagnosing unidentified pleural effusions with a high rate of sensitivity of 85–100% [8,9,10,11,12,13,14,15,16,17]. However, not all patients undergoing MT may receive a definitive diagnosis. Nonspecific histopathology results can suggest the occurrence of a sampling error or genuine benign pleural disease . In our study, a clear aetiological diagnosis was made in 56.5% (87/154) of undiagnosed cases after follow-up, including 19 patients who were eventually diagnosed with pleural malignancy.
Benign diseases continued to be the most common diagnosis during follow-up (68/87 patients; 78.2%). However, the atypical nature of pathology ensures that benign diseases are not easily detected by MT specificity. Even in the case of tuberculous pleurisy, the reaction occurring in the pleura may cause effusion in the absence of granulomatous inflammation . Thus, the diagnosis of benign disease depends upon the patient’s clinical manifestation and the doctor’s empirical treatment.
Although thoracoscopy has a high diagnostic success rate for pleural effusion, it is still not a foolproof method. In our study, 19 of 154 NSP patients were subsequently diagnosed with pleural malignancy, including lung cancer and malignant pleural mesothelioma, which were most common. For patients 5, 9, 11, 13, 15 and 18, there was no direct evidence for malignancy in the pleural biopsy or pleural effusion analyses, but pleural effusion was found repeatedly in these patients during the follow-up. There was no other evidence for causes of pleural effusion except for the malignant tumors diagnosed in other regions. Therefore, we classified it as malignant pleural effusion. Most of the lung cancer patients were relatively easy to diagnose since chest computed tomography imaging is likely to accurately confirm tumors, and all of these individuals were diagnosed within five months. The more difficult disease to diagnose is pleural mesothelioma because its lesion depth makes it difficult to detect using MT. For patient 1, the short delay in the final diagnosis of mesothelioma may be due to a lack of adequate sampling during the MT, and she was finally diagnosed by percutaneous biopsy within a month. However, in comparing our previous  and current research, the rate of missed diagnoses for pleural mesothelioma decreased from 12.5% (5/40) before June 2014 to 5% (1/20) after June 2014. This progress can be attributed to the significant procedural advancements made since the first recorded thoracoscopies  and the ongoing improvements in immunohistochemistry and thoracoscopic techniques. For the histological diagnosis in the 6 mesothelioma patients, only 3 of them had mesothelial dysplasia. We attempted to find a potential 'precancerous' lesion in these patients, but the results were not satisfactory. Indeed, 5 of them had cellulose exudation, inflammatory cell infiltration, or fibrous tissue hyperplasia, but we did not think these lesions can be considered as potential 'precancerous' lesion. These lesions are symptoms of chronic inflammation, which can be seen in many diseases. We hope there will be more sophisticated research in this area in the future.
The factors that may increase the likelihood of underlying malignant disease in patients with NPS remain the same as those found in our previous study, including nodules or plaques in MT and the recurrence of pleural effusion. The presence of any of these lesions may have a marked impact on increasing the incidence of false negatives at thoracoscopy. Patients with these characteristics require close monitoring.
In terms of the follow-up time, our study had a mean follow-up time of 61.5 months, and the maximum time to the diagnosis of malignancy was 10 months. These results further confirm our previous conclusion that, for NSP patients, one year of clinical follow-up is likely sufficient to detect most cases of malignant disease. It should be noted, however, that during our follow-up period, we identified a pleural effusion patient who developed lung cancer two years after thoracoscopy. Since he was initially hospitalized with cardiac insufficiency, the pleural effusion was initially a transudate. The amount of pleural effusion was reduced following the treatment for cardiac insufficiency, so we considered the lung cancer diagnosed two years later to be a new emerging disease. As such, we did not consider his follow-up data in the design of our conclusions.
The causes of pleural effusion during follow-up could not be determined in 67 patients. Among them, we particularly focused on the 21 NSP patients who did not obtain a definitive diagnosis in our previous study. These patients had already undergone a sufficiently long follow-up period, and yet, their diagnosis did not change. This indicates that the conclusions made in our previous study are accurate and reliable.
In conclusion, MT is a useful tool for diagnosing PE. NSP can be diagnosed in a number of patients, and false-negative results can also occur. Although the diagnosis of most NSP patients is benign disease, malignant disease is also a possibility, especially in patients with nodules or plaques following MT and the recurrence of pleural effusion. This study further confirmed our previous study’s main conclusion that one year of clinical follow-up for NSP patients is likely sufficient. We look forward to conducting more multicentre prospective studies to explore the diagnosis and prognosis of NSP patients after MT.