2.1 Pulmonary Function Tests

Pulmonary function tests (PFTs) are essential, non-invasive diagnostic tools for some respiratory diseases, which are usually applicable to moderate to large-size tumors, and are especially critical for the diagnosis, care, and prognosis of chronic respiratory disorders [31, 32]. However, it is not advisable to perform PFTs in patients with severe cardiopulmonary impairment, inability to comply with the operator's instructions, or other unstable conditions [33]. For patients with PTBTs, the FEV1/FVC ratio and peak inspiratory and expiratory flow rates decreased when the tracheal lumen narrowed. Orton et al. reported a case in which a patient who underwent PFT exhibited a notch in the flow-volume curve, which was further diagnosed as PTBTs [34]. Therefore, the flow-volume curve can be utilized to assess tracheal obstruction. Incidentally, 50% of the patients' forced spirometry changes depending on the cause, degree, location, and type of tracheal obstruction [35]. Therefore, flow-volume curves can be employed as screening tools for PTBTs. PTBTs should be suspected when the flow-volume curve demonstrates flattening of the expiratory limb [36, 37]. However, since the flow-volume curve is not a specific diagnostic tool for PTBTs and may be complicated by concurrent respiratory diseases such as asthma, COPD, etc., it is important to consider further examinations using other screening tools when PTBTs are clinically suspected.

2.2 Chest Radiography Examination

Chest radiography (CXR) is the most common imaging test in clinical practice and is an important tool for identifying many types of chest tumors. The major benefits of CXR include low radiation exposure, cost-effectiveness, and appropriate sensitivity to a wide range of disorders [38-40]. However, owing to the anatomical location of the trachea, the interpretation of CXR results of PTBTs is susceptible to the influence of the imaging of surrounding tissues, including the mediastinum, heart, and sternum. Consequently, most PTBTs, especially those in the early stages, have negative CXR results, and only 18%–28% of patients with PTBTs are appropriately diagnosed using CXR [41]. Although CXR has limited value as a confirmatory test for PTBTs, it is efficient as an initial diagnostic tool and method to exclude other histological diseases. Owing to the rapid advancement in deep learning and artificial intelligence technologies, CXR may play a vital role in the diagnosis of PTBTs in the future [42, 43].

2.3 Computed Tomography

Compared with CXR, computed tomography (CT) has a higher resolution. It can provide a clearer demonstration of the location, extent of infiltration, invasion, surrounding lymph nodes, and mediastinal metastases of PTBTs, which is of great significance for the diagnosis and surgical treatment of PTBTs [44, 45]. However, CT may not be advisable as an initial screening imaging test because of its higher cost and longer scanning duration (range, 15–30 min), compared with CXR [46]. Meanwhile, CT is not recommended for patients with severe heart failure, an inability to comply with the operator's instructions, or other unstable conditions. Nevertheless, some studies have shown that traditional CT techniques are not sufficiently accurate in the evaluation of PTBTs, with the percentage of false negatives being up to 9% [47]. Approximately 9% of patients evaluated by CT and deemed fit for surgical resection are found to have tumor invasion exceeding the scope of CT evaluation, rendering intraoperative intervention unfeasible [48, 49]. In recent years, the diagnostic value of CT for PTBT has increased with the development of CT imaging technology and image processing software. For example, multidetector CT, third dimensional (3D) reconstruction, and virtual simulation endoscopy have enabled more accurate assessment of PTBTs.

2.4 Fiberoptic Bronchoscopy

Fiberoptic bronchoscopy (FOB) is recognized as the gold standard for diagnosing PTBTs, enabling visual observation of the size, morphology, and location of tumors, and the degree of tracheal lumen obstruction [50, 51]. The indications for FOB can be classified into two categories: Diagnostic and therapeutic. FOB can be used for patients with atelectasis, hemoptysis, localized wheezing, and chest radiography findings suggestive of neoplasms. For therapeutic indications, FOB is primarily used for conditions such as hemoptysis, acute lobar collapse, challenging endotracheal intubation, and endoscopic tumors [52]. However, FOB may not be advisable for patients with conditions such as severe cardiopulmonary disease, hemodynamic instability, serious hypoxemia, and coagulation disorders [53, 54]. A major advantage of FOB is that a biopsy can be performed simultaneously with the examination to obtain a pathological diagnosis and perform treatment. Nonetheless, Lam et al. concluded that FOB did not possess satisfactory sensitivity for nonvisible tumors (approximately 50%) [55]. The development of bronchial ultrasound technology and electromagnetic navigation may further compensate for the deficiency of FOB in assessing the degree of PTBTs [56-58]. When it becomes essential to assess whether the tumor has invaded the lymph nodes, direct sampling represents the most definitive methodology for evaluating lymph node involvement. Minimally invasive procedures employ needle biopsy techniques to procure tissue specimens from mediastinal lymph nodes. These needle biopsy modalities encompass transbronchial needle aspiration (TBNA), transthoracic needle aspiration, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) [59-61]. EBUS-TBNA, a minimally invasive method for mediastinal biopsy under direct real-time endobronchial ultrasound guidance, can access the paratracheal lymph node stations (groups 2R, 2 L, 4R, 4 L), subcarinal lymph nodes (group 7), and hilar, interlobar, and lobar lymph nodes (groups 10, 11, and 12). Furthermore, mediastinoscopy facilitates the direct interrogation of specimens derived from the paratracheal lymph nodes (lymph node stations 2R, 2 L, 4R, 4 L), the pre-vascular subcarinal lymph nodes (lymph node station 7), and the hilar lymph nodes (lymph node station 10) [62]. However, as patients with PTBTs have varying levels of tracheal stenosis, placing fiberoptic bronchoscopes in the trachea for examination may further aggravate the patient's hypoxic symptoms, leading to asphyxia or even death in critical cases [63]. Therefore, conducting a thorough assessment before the examination and preparing for emergency measures is important. For patients with tracheal tumors that severely obstruct the trachea (< 50% lumen occlusion), CT rather than FOB examinations should be performed to avoid grave consequences [64].

3.1 Surgical Treatment

3.2 Chemotherapy

The effects of chemotherapy on PTBTs remain unclear due to the limited availability of case reports. The main chemotherapeutic agents for tracheal tumors utilized in current research include platinum, etoposide, 5-fluorouracil, and paclitaxel, which may cause side effects, including diarrhea, dermatitis, esophagitis, and peripheral neuropathy [89, 90]. Chemotherapy mainly functions as an adjuvant treatment to radiotherapy or immunotherapy for patients with unresectable PTBTs. Jiang et al. reported two cases that adopted chemotherapy plus immune checkpoint inhibitors as neoadjuvant treatments and achieved satisfactory outcomes. One patient underwent three cycles of chemotherapy (docetaxel 75 mg/m2 + carboplatin) plus nivolumab (360 mg) every 21 days and was disease-free for 18 months after surgery due to shrinkage of the cancerous tumors. Another patient underwent three cycles of chemotherapy (paclitaxel 200 mg/m2 + carboplatin) plus nivolumab (360 mg) every 21 days and eventually had the opportunity to have surgery [66]. These two cases revealed satisfactory clinical outcomes of chemotherapy plus immunotherapy for PTBTs, which may diminish the need for resection. Despite the satisfactory results of the case reports, further prospective investigations are warranted to evaluate the effectiveness of chemotherapy for PTBTs.

3.3 Immunotherapy

Immunotherapy is a novel therapeutic approach that targets immune checkpoint molecules, which has shown promising therapeutic outcomes in multiple types of neoplasms. However, its applicability to PTBTs remains uncertain. In contrast to other palliative therapies such as chemotherapy, immunotherapy can accomplish the full progression of tumor remission. Current studies on immunotherapy for PTBTs are limited to case reports. Massachusetts General Hospital first published a study in 2017 on a 67-year-old man with recurrent tracheal SCC who received 7 months of navulizumab treatment, with the aim of achieving complete remission. Despite multiple therapies and tumor reduction surgeries after recurrence, he ultimately died from recurrent tumor growth blocking the lumen [67]. In 2019, a research team used pembrolizumab to treat patients with recurrent tracheal SCC. In 2019, Maller et al. used pembrolizumab to treat patients with recurrent tracheal SCC and observed complete tumor remission 3 months after therapy [91]. Although the results indicate the potential for long-term remission in PTBTs through immunotherapy [67, 91], they were not convincing because of the small sample size, ambiguous theoretical mechanism, and inadequate representation. Understanding the tumor immune microenvironment is fundamental to immunotherapy. The basic principle involves activating CD8+ T cells and other tumor-killing immune cells, a prerequisite for the clinical immunotherapy implementation [92, 93]. To date, only a few studies have investigated the immune microenvironment of PTBTs. Wang et al. analyzed 25 cases of ACC and conducted whole-exome sequencing and T-cell receptor sequencing and found no mutations in common driver genes of lung cancer (such as NOTCH1) in ACC. They also found that the mutation load of ACC was 3.67, which was far lower than that of other solid tumors. Most importantly, most ACC cases were negative for programmed cell death-ligand 1 (PD-L1), with low CD3+ and CD8+ T cell infiltration. This led to the conclusion that immunotherapy, which is applicable to NSCLC, may not necessarily be suitable for ACC [94]. Zheng et al. analyzed 16 cases of ACC and five cases of SCC, assessing the expression of PD-L1 and the infiltration of CD8+, CD16+, CD68+, CD163+, and FOXP3+ cells using immunohistochemistry. SCC samples exhibited higher PD-L1 expression and FOXP3+ cell infiltration, compared with ACC samples, even surpassing CD8+, CD16+, and CD163+ levels. In contrast, FOXP3+ cell infiltration was lower than that of CD8+, CD16+, and CD68+ cells [95].

Despite the lack of studies on the immune microenvironment of tracheal tumors, the conclusions of the above studies are basically consistent: Compared with ACC of the trachea, SCC may benefit more from immunotherapy due to higher levels of PD-L1 expression and a higher degree of immune cell infiltration. Therefore, further research is essential to investigate the role of immunotherapy in PTBTs, including potential markers of immunotherapy, neoadjuvant immunotherapy, and postoperative immunotherapy protocols. A larger number of studies should be conducted to explore the immune microenvironment of PTBTs in greater depth and expand the application of immunotherapy in PTBTs.

3.4 Radiotherapy

Radiotherapy (RT) for PTBTs is usually performed as an adjuvant therapy after surgery, especially for cases involving positive margins. It also served as a palliative therapy for inoperable patients aimed at alleviating symptoms associated with disorders, reducing pain, and relieving airway obstruction [96]. Several studies have suggested that RT can increase the OS rates for PTBTs and decrease the likelihood of tumor recurrence, metastasis, and cancer-related mortality [97, 98]. Ran et al. summarized 1252 cases of ACC and demonstrated that 36.4% of patients who received postoperative RT had 5-year survival rates of up to 97.3%, higher than that of patients who underwent surgery alone (86.4%) [98]. Therefore, surgery with postoperative RT is considered the most effective therapeutic option for PTBTs [24], with ACC being more sensitive to RT than SCC [99]. In a study of 18 patients with ACC who received 66–72.6 Gy RT, side effects of esophagitis, pneumonitis, tracheal stenosis, hoarseness, radiation-induced lung injury, and hematological toxicities were observed, and the 2-year OS and progression-free survival rates were 100% and 61.4%, respectively [100]. Dierkesmann et al. reported that RT may cause large defects in the wall of the trachea [101]. Kaminski et al. suggested that RT can influence the prognosis of tracheal anastomosis. Therefore, it is generally recommended to start RT at approximately 2 months postoperatively [28]. Patients with severe respiratory insufficiency, grossly impaired heart function, a previous diagnosis of non-lung cancer, or all the listed criteria were not eligible for RT [102].

For patients who received adjuvant RT or definitive RT, the RT dose may be a significant influencing factor [103, 104]. After analyzing the results of 20 patients who received adjuvant and definitive RT, Je et al. concluded that patients treated with higher doses of brachytherapy-intensive RT had a better 5-year OS of 83.3%, and that most side effects were tolerable [103]. Dracham et al. reported that improved prognosis was reported more frequently in patients who received high doses of RT (≥ 66 Gy) and had a 5-year local recurrence-free survival (LRFS) rate of 75% versus 16.7% [104]. According to QUANTEC (quantitative analysis of normal tissue effects in the clinic) and some other recommendations, the recommended radiation dose for ACC should be less than 80Gy and greater than 70Gy, while for SCC, it should exceed 60Gy. Following these guidelines can help to reduce the late radiotoxicity associated with central airway stenosis risk [105]. With the advancement of precision radiation technology, such as image-guided RT, stereotactic RT, and volume-rotation intensity-modulated RT, RT can be delivered to improve tumor control rate without additional side effects [106, 107]. However, some studies have suggested that RT may not confer a survival benefit in patients who received adjuvant RT or definitive RT [27, 99, 108]. After investigating a total of 300 patients who received adjuvant RT, Yusuf et al. concluded that adjuvant RT had no statistically significant effect on OS (p > 0.05) in patients with PTBTs who underwent surgery [99]. Similarly, Yang et al. reported a similar 5-year survival rate in patients who did and did not receive adjuvant RT (82% vs. 82.4%; p = 0.80) [108]. Although these studies negated the significance of RT in the treatment of PTBTs, there were some confounding factors, such as the fact that patients who underwent postoperative RT had more severe diseases than those who were eligible for surgical resection. Therefore, a more rigorous examination of the therapeutic properties of RT is required.

3.5 Interventional Therapy

Interventional therapy (IT) can be beneficial for both cure-oriented therapy of early-stage PTBTs, especially those located in the central airways, and alleviative care. For individuals with early-stage PTBTs, endoscopic resection of the tumors may even result in a cure; however, it often appears to yield positive margins and requires postoperative RT [109]. In inoperable individuals, IT is an essential means of relieving respiratory obstruction from PTBTs and decreasing the tumor volume to achieve airway recirculation. IT includes electrocautery, cryotherapy, laser therapy, photodynamic therapy (PDT), brachytherapy, radiofrequency ablation (RFA), argon plasma coagulation (APC), and airway stents [110-113]. The well-adopted IT tactics are as follows: (1) coagulation of tumors to minimize bulk bleeding, (2) debulking, and (3) placement of extra stents if significant luminal narrowing remains [110]. Electrocautery, laser therapy, APC, and airway stenting can offer instant alleviation, whereas cryotherapy, PDT, and brachytherapy have delayed effects. Boxem et al. demonstrated that electrocautery and APC are cheaper, easier to operate, and simpler to apply in clinics than other ITs, such as laser therapy [114]. They can achieve immediate tumor hemostasis and remove obstructing tumors through the heating effect. However, owing to the superficial and heating effects, electrocautery and APC are mainly indicated for carcinomas in situ and superficial neoplasms located in the central airway. Electrocautery can also be used in the lobar and segmental bronchi, whereas APC is typically used to treat bronchial sections starting from the acute angle of the main airway because of their unique characteristics. Furthermore, neither electrocautery nor APC is recommended for use in individuals who require plenty of oxygen (fraction of inspired oxygen (FiO2) > 40%) [115-117]. Cryotherapy is an efficient and reliable treatment for both benign and malignant airway obstructions. It regulates wound healing and mitigates fibrosis [118]. Owing to its good heat deposition function used to treat deep-rooted organs, laser therapy is widely utilized for treating intraluminal neoplasms and obstructive lesions of the airway. The obvious limitations of laser therapy are its inability to significantly enhance respiratory function and the risk of airway perforation bleeding [115]. Bolliger et al. summarized that contraindications for laser therapy include external pressure, hypoxemia, and coagulation disorder [110]. With the experiences from 500 patients treated with PDT, Ross et al. revealed that PDT was suitable for early-stage airway tumor lesions, associated with tolerable complications, and easy to deal with [111]. Zhang et al. evaluated 23 patients with PTBTs treated with PDT and their clinical responses and recurrence-free survival. The results suggested that the mean recurrence-free survival of 23 patients with PTBTs was 8.9 ± 1.8 months (range, 1.3–22.0 months). Approximately 21 patients showed significantly ameliorated clinical conditions and experienced endurable complications [119]. The indications for PDT are the same as those for laser therapy, with a relative contraindication being lesions adjacent to the carina [120]. Brachytherapy can offer a feasible and precise measure for alleviating malignant neoplasms associated with airway obstruction or providing palliative care for intraluminal neoplasms, which can have a rapid impact [121]. Proper placement of brachytherapy catheters may be the most significant issue that requires attention, as it influences the evaluation of therapeutic effects and complications (e.g., radioactive esophagitis) [122]. Jie et al. reported that brachytherapy was the preferred treatment modality for tracheal lobular capillary hemangioma and concluded that brachytherapy performed well in cases with profound and massive defects [123]. RFA is a valid and microinvasive procedure for both malignant obstruction of the central airway and benign tracheal tumors. Liu et al. utilized RFA to treat six patients with tracheal pleomorphic adenoma with a 5-year recurrence-free rate [124]. However, RFA may be limited by thermal damage to the adjacent tissue and the potential for tracheal injury. RFA is considered to have the same contraindications as electrocautery. Airway stents can be used in conjunction with the other ITs mentioned above. Airway stents are primarily composed of silicone, metal, or a combination of both materials. Silicone stents are characterized by ease of placement and retrievability, enabling sequential deployment when necessary. However, their insertion typically requires general anesthesia and may be associated with higher migration rates compared to metallic alternatives. Conversely, metal stents offer enhanced bronchoscopic maneuverability, superior resistance to migration, and improved tolerance to extrinsic compression. Despite these advantages, their permanent nature renders them unsuitable for scenarios requiring stent removal, thereby contraindicating their use in benign airway diseases. As such, metallic stents are generally reserved for palliative management of malignant obstruction [125, 126]. The indications for airway stents are as follows: (1) alleviating extraneous compression from neoplasms or lymph nodes, (2) stabilizing airway patency after endoscopic resection of intraluminal carcinomas, (3) blocking malignant fistulas, such as stumpy fissures or tracheoesophageal fistulas, and (4) addressing benign narrowing. External vascular pressurization of the airway is regarded as an absolute contraindication for airway stents [127, 128]. Considering the complications of stents, such as dislocation, infection, and granulation, it is essential to conduct a rigorous evaluation when determining the appropriate placement of an endotracheal stent to maximize the benefit to the patient.