Nodular disease is a systemic disease of unknown origin, characterized by non-caseating granulomas. Because it most often involves the lungs and thoracic lymph nodes (more than 90%), most cases present to respiratory medicine either with respiratory symptoms or with abnormalities found on chest radiographs. Although nodal disease is not uncommon in clinical practice, its diagnosis has been one of the challenges faced by respiratory physicians. 1. What are the consistent clinical, imaging and pathological findings needed to establish the diagnosis? To establish the diagnosis of nodular disease, two conditions must be met: (1) consistent clinical and imaging findings with nodular disease; and (2) biopsy of one or more organs showing non-caseating epithelioid granuloma without histological evidence of pathogenic bacteria or foreign particles [1]. In clinical practice, however, one might think that a typical “textbook” case of nodular disease can be diagnosed clinically without the need for pathologic biopsy evidence. This is not the case! Because tuberculosis is more common in China, even in “typical” cases, pathologic evidence should be actively sought, and it is not advisable to make an established diagnosis of nodular disease easily, much less to give glucocorticoid test treatment hastily. Epithelioid granuloma is a nonspecific lesion and has no diagnostic value in itself for nodular disease and other diseases. Among the diseases that need to be excluded are branchial, fungal and parasitic infections, chronic beryllium disease and other pneumoconioses, allergic pneumonia, and Wegener’s granulomatosis; granulomatous lesions can be seen in the lungs even in HIV infection and certain neoplastic diseases [2]. Even after multiple tests, a number of granulomas are still difficult to identify the cause, and not every disease characterized by unexplained non-caseating granulomas is nodular disease [3]. Therefore, strict clinical, radiological and pathological criteria must be used for the diagnosis of nodular disease. The diagnosis of nodular disease should be made with great caution when the pathology shows large focal necrotic lesions in necrotizing granulomas, lesions involving only extrathoracic organs, or inconsistent clinical and radiological manifestations. The diagnosis of nodular disease is reliable when the clinical and radiological manifestations are consistent with nodular disease and there is a biopsy specimen showing a pathogen-negative non-caseating granuloma with clinical manifestations or pathology confirming a multisystemic lesion and no evidence of bacterial, mycobacterial or fungal infection. The so-called “pathogen-negative non-caseating granuloma” emphasizes that pathologic findings of granulomatous lesions, even without necrosis, should be routinely stained with antacid and, if necessary, fungal stains (silver or PAS staining). As can be seen, the diagnosis of nodular disease is a complex process that requires the completion of a series of diagnostic tests. The following points need to be particularly emphasized [1]: (1) the diagnosis of nodular disease may be conclusive when the chest imaging features and clinical presentation are consistent with nodular disease, along with pathologic biopsy showing non-caseating granulomas and excluding other etiologies that can lead to granulomas; (2) pathologic biopsy is indicated for the vast majority of patients with suspected nodular disease; (3) the pathologist is able to identify granulomas, but their final The diagnosis should not rely solely on pathological findings. 2. Biopsies should be obtained first by using the least invasive method and selecting organs with high positivity and specificity The principle of obtaining nodular disease pathology specimens is to use the least invasive method and to select organs with high positivity and specificity. The most accessible organs involved, such as the skin and peripheral lymph nodes, are selected first [1]. Although biopsies of the liver and oblique muscle fat pads often show “positive” results, they are no longer recommended for the diagnosis of nodular disease because non-caseating granulomas from other causes are common in these areas, and because biopsies of these areas are relatively invasive [1, 2]. The chest is most frequently involved in nodular disease and is therefore the most commonly used site for pathological biopsy. In particular, transbronchoscopic biopsy, including bronchial mucosal biopsy and transbronchial lung biopsy (TBLB), has a positive rate of more than 85% and is relatively less invasive, making it the preferred method for the diagnosis of thoracic nodular disease. Mediastinal and hilar lymph node biopsy should only be considered in a few cases where transbronchial mucosal biopsy and TBLB are negative. Transbronchial needle aspiration biopsy (TBNA, or endoscopic ultrasound TBNA) to obtain intrathoracic lymph nodes has a positive diagnostic rate of more than 80%, largely replacing mediastinoscopy. It should be emphasized that regardless of which method is used to obtain the material, the specimen can only be considered positive for nodal disease if it shows non-caseating granulomatous structures. 3. how to improve the positive rate of transbronchoscopic biopsy From the literature and clinical experience, the positive rate of combined bronchial mucosal biopsy and TBLB for the diagnosis of nodular disease can be more than 85% [4, 5]. The mucosal manifestations should be carefully observed during the operation, and even if there are no obvious abnormalities in the mucosa, mucosal biopsies should be taken from multiple sites, and sometimes positive results can be obtained. It is important to perform TBLB at the same time to obtain positive findings even in stage I nodal disease. Although the literature has emphasized that transbronchoscopic biopsy is highly recommended, it seems from several groups of cases reported in China that the proportion of nodular disease diagnosed by bronchoscopic biopsy varies, and most of the cases are not high. To improve the positive rate of bronchoscopic biopsy, multi-site bronchial mucosal biopsy combined with TBLB is the key. In addition, bronchial mucosal changes in nodal disease are relatively common and characteristic, but they are easily overlooked or masked if not carefully observed or if the patient coughs violently during the operation. For example, we once saw a patient with suspected nodular disease, but the clinical and imaging manifestations could not yet exclude tuberculosis, and bronchoscopy was performed in a foreign hospital, which reported “no abnormality” and no bronchial mucosa biopsy was done. The bronchoscopy was repeated when the patient came to Tongren Hospital in Beijing and revealed scattered yellow patchy elevations in the trachea and bronchi, and the biopsy showed non-caseating granuloma. This mucosal manifestation is rarely seen in other diseases, but can be easily missed if not carefully observed or if it is not well recognized. Shorr et al [6] have observed the positive rate of bronchoscopy in patients with suspected nodular disease. They performed both mucosal biopsy and TBLB, taking six tissue specimens each. For those found to have abnormalities in the airway, four blocks were taken at the site of the lesion and two at the tracheal ridge; for those with no abnormalities in the airway, four blocks were taken at the secondary ridge and two at the tracheal ridge. The criteria for positive biopsies were that the specimens showed non-caseous necrotizing granulomas and were negative for specific staining for fungi and mycobacteria. As a result, 61.8% of the 34 patients were positive for mucosal biopsy and 58.8% for TBLB; the combined mucosal biopsy increased the positive rate of bronchoscopy by 20.6%. Moreover, in airways with normal visual observation, 30% of mucosal biopsies were positive. The results suggest that bronchial mucosal lesions are common in nodular disease and that mucosal biopsies should be routinely performed in patients suspected of having nodular disease. The use of TBNA to obtain mediastinal/portal lymph node specimens for the diagnosis of nodular disease has been reported in a number of recent publications.Trisolini et al [7] evaluated the diagnostic value of TBNA in nodular disease (stage I) with enlarged lymph nodes in the hilum and/or mediastinum.Of the 55 patients, nodular disease was diagnosed in 32 cases and the other 23 cases were diagnosed pathologically.TBNA in 32 cases of nodular disease TBNA revealed diagnostic non-caseating granulomas in 23 of the 32 cases (72%). Among the 15 patients who underwent both TBNA and TBLB, the positive rate of TBNA (11/15, 73%) was higher than that of TBLB (6/15, 40%), with TBNA alone diagnosing 7 cases (47%); TBNA combined with TBLB resulted in a positive rate of 87%. It was concluded that TBNA may be of great value in the diagnosis of stage I nodal disease and is recommended to be used in combination with TBLB. Endoscopic ultrasound-guided TBNA (EBUS-TBNA) has also been reported to further improve the positive diagnostic rate.Tremblay et al [8] randomly assigned 50 patients with enlarged hilar and/or mediastinal lymph nodes and clinically suspected nodal disease to the EBUS-TBNA group (24 patients with a 22G puncture needle) and the conventional TBNA group (26 patients with a 19G puncture needle). The positive rate of EBUS-TBNA for the diagnosis of nodular disease was found to be 83.3%, compared with 53.8% for conventional TBNA. In conclusion, although the application of minimally invasive endoscopic techniques has brought more options for the diagnosis of chest diseases, conventional bronchial mucosal biopsy and TBLB should be given priority in the diagnosis of nodular disease, both in terms of diagnostic efficiency, invasiveness of the examination, and technical proficiency. Various biopsy techniques for mediastinal/portal lymph nodes should be considered only for those who fail to diagnose by conventional bronchoscopy.