Molecular Biology and Therapeutic Targets of Primitive Tracheal Tumors: Focus on Tumors Derived by Salivary Glands and Squamous Cell Carcinoma.

Primary tracheal tumors are rare, constituting approximately 0.1-0.4% of malignant diseases. Squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC) account for about two-thirds of these tumors. Despite most primary tracheal cancers being eligible for surgery and/or radiotherapy, unresectable, recurrent and metastatic tumors may require systemic treatments. Unfortunately, the poor response to available chemotherapy as well as the lack of other real therapeutic alternatives affects the quality of life and outcome of patients suffering from more advanced disease. In this condition, target therapy against driver mutations could constitute an alternative to chemotherapy, and may help in disease control. The past two decades have seen extraordinary progress in developing novel target treatment options, shifting the treatment paradigm for several cancers such as lung cancer. The improvement of knowledge regarding the genetic and biological alterations, of major primary tracheal tumors, has opened up new treatment perspectives, suggesting the possible role of biological targeted therapies for the treatment of these rare tumors. The purpose of this review is to outline the state of knowledge regarding the molecular biology, and the preliminary data on target treatments of the main primary tracheal tumors, focusing on salivary-gland-derived cancers and squamous cell carcinoma.

Survival benefit of radiotherapy and nomogram for patients with primary tracheal malignant tumors: a propensity score-matched SEER database analysis.

PURPOSE: The purpose of this study was to conduct a matched-pair analysis to assess the impact of radiotherapy (RT) on patients with malignant tracheal tumors using the surveillance, epidemiology, and end results database. Additionally, a predictive nomogram was developed for patients with malignant tracheal tumors. METHODS: Propensity score matching (PSM) was used to minimize bias between the RT and no-RT groups. We utilized both univariate and multivariate Cox proportional hazards regression analyses to identify independent prognostic factors for patients and subgroups. We developed a novel nomogram and evaluated its results using the C-index. RESULTS: A total of 648 patients between 1975 and 2019 were included, and 160 patients in RT were 1:1 propensity score-matched with no-RT. The independent prognostic factors for patients with tracheal malignant tumors were surgery, marital status, disease extension, pathology, and age. The independent risk factors for patients without surgery included RT and disease extension. The C-index confirmed that the nomogram accurately predicted the prognosis of patients with tracheal malignant tumors. CONCLUSIONS: Our findings suggest that RT may provide a survival benefit for tracheal cancer patients who did not undergo surgery. The nomogram can be a useful tool for predicting prognosis in patients with tracheal malignant tumors.

Proton Beam Therapy as a Curative Treatment for a Young Case of Unresectable Tracheal Adenoid Cystic Carcinoma.

Primary tracheal adenoid cystic carcinoma (TACC) is a rare malignancy without an established treatment. Central airway obstruction due to TACC often decreases the quality of life and has life-threatening consequences. A 19-year-old man with unresectable TACC and central airway obstruction suffered from progressive cough and dyspnea after exercise. Proton beam therapy (PBT) was selected as the preferred treatment over systemic anti-cancer chemotherapy for TACC. PBT led to complete remission of TACC and the almost complete disappearance of the respiratory symptoms without adverse events. PBT is a useful and safe treatment for unresectable primary TACC.

Radiotherapy for Primary Tracheal Carcinoma: Experience at a Single Institution.

BACKGROUND: There is limited understanding of tracheal carcinoma (TC) because of its rarity. We examined the efficacy of radiotherapy (RT) for patients with primary TC. METHODS: We analyzed the records of 32 patients with primary TC who received RT at our center between November 1996 and December 2016. RESULTS: Thirteen patients received adjuvant RT and 18 received definitive RT. Eight patients achieved complete remission (CR) after definitive RT. Among all patients, the 5-year overall survival (OS) rate was 46.9% and the locoregional progression free survival (LRPFS) rate was 68.1%. Univariate analysis indicated the 5-year OS was better in those with adenoid cystic adenocarcinoma than squamous cell carcinoma (P = 0.001); the 5-year LRPFS was better in patients who received surgical resection than those who did not (92.9% vs 46.4%, P = 0.013) and in patients who received postoperative RT than in those who received definitive RT (91.7% vs 50.1%, P = 0.038). A sub-group univariate analysis indicated the 5-year PFS was better for those who received at least 68 Gy of radiation (44.4% vs 13.0%, P = 0.044). Patients who achieved CR had a better 5-year PFS than those who did not (57.1% vs 10%, P = 0.006). No patients had a toxicity of grade 3 or more. CONCLUSIONS: Adjuvant and definitive RT are safe and effective treatments for TC. Patients who received dosages of 68 Gy or more and who had complete tumor regression following definitive RT seemed to have better long-term survival.

Intensity modulated radiation therapy may improve survival for tracheal-bronchial adenoid cystic carcinoma: A retrospective study of 133 cases.

PURPOSES: This study aimed to evaluate the role of radiotherapy (RT) and intensity modulated radiation therapy (IMRT) in adjuvant and definitive settings of tracheal-bronchial adenoid cystic carcinoma (TACC) treatment. MATERIALS/METHODS: TACC patients (n = 133) treated with surgery and/or RT curatively in our institution between January 1st, 1984 and December 31st, 2017 were analyzed retrospectively. RESULTS: Among the 116 patients undergoing surgery, 50 (43.1 %) achieved complete resections and 66 (56.9 %) had positive surgical margins. For patients with positive margins, overall adjuvant RT was correlated with no significantly improved OS (10-year: 58.0 % vs. 47.9 %; P =  0.340) and a slight LRFS benefit (5-year: 81.9 % vs.75.6 %; P =  0.056), but adjuvant IMRT showed significant superiority in both OS (10-year: 82.9 % vs. 47.9 %; P =  0.031) and LRFS (5-year: 100.0 % vs. 75.6 %; P =  0.001) in comparison with no postoperative RT. Multivariate analysis also identified adjuvant IMRT as a significant favorable factor with OS (HR = 0.186, 95 %CI: 0.039-0.883; P =  0.034). For 17 patients receiving definitive RT, IMRT achieved promising 5-year OS of 88.9 % and LRFS of 64.3 %, yet no significant difference from non-IMRT group was reached (P = 0.447 and 0.706). Different therapies presented no significantly different impact on DMFS, whilst DMFS explained more of the OS variances (P < 0.001, R2 = 0.480) than LRFS (P < 0.001, R2 = 0.323). CONCLUSION: IMRT could confer greatly improved OS and LRFS in postoperative setting for TACC patients with positive surgical margins. IMRT was also a good therapeutic option for definitive TACC with promising survival and local control.

Effective Radiotherapy in Tracheobronchial Adenoid Cystic Carcinoma With Positive Surgical Margin.

BACKGROUND: The study aimed to evaluate the role of postoperative radiotherapy (PORT) in the treatment of trachea and main bronchus adenoid cystic carcinoma (ACC) with a positive surgical margin. METHODS: Patients with pathologically confirmed trachea or main bronchus ACC operated on at Shanghai Chest Hospital were enrolled. Survival, univariate, and multivariate analyses were performed. The χ2 test was applied to analyze the failure patterns among different groups (R0/0: negative margin resection without PORT; R1/0: positive margin resection without PORT; R1/1: positive margin resection with PORT). RESULTS: From January 2001 to December 2014, 77 patients were deemed eligible for the study. Pairwise comparisons showed that the overall survival rate of group R1/1 was comparable to that of group R0/0 (P = .438), and significantly longer than the rate of group R1/0 (P = .032). Additionally, the local disease-free survival rate of group R1/1 was much higher than that of group R0/0 (P = .023) and R1/0 (P = .001). Cox multivariate analysis identified the radiologic feature (P = .012) and PORT (P = .006) as significantly favorable prognostic factors for locoregional disease-free survival. By contrast, for overall survival, PORT (P = .032) was the only corresponding variable identified by univariate analysis. Furthermore, PORT significantly decreased the locoregional recurrence rate (P = .002) but not distant metastases (P > .999). CONCLUSIONS: PORT helped patients with tracheobronchial ACC and microscopic positive surgical margins to achieve a similar outcome as patients with complete resection. R0 resection may not be necessary for tracheobronchial ACC if it is difficult to be completely resected.

Surgery and Proton Beam Therapy for Tracheal Synovial Sarcoma.

Synovial sarcoma (SS) is an uncommon malignant tumor associated with poor prognosis, and SS arising from the trachea is even rarer, with only 3 cases reported previously. We present the case of a 19-year-old man for whom imaging studies revealed a mass of soft tissue density in the lower trachea. An en bloc trachea segmental resection and postoperative proton beam therapy were performed. Diagnosis was confirmed by the SS18-SSX gene rearrangement. The patient was alive without tumor recurrence for 18 months. This case report presents tracheal SS successfully treated with surgery and postoperative proton therapy.

Curing a Patient of Recurrent Tracheal Papillomatosis Using Laser Ablation and Adjuvant Radiotherapy.

We present a 28-year-old man with an early onset of recurrent respiratory papillomatosis at 1 year. The patient had undergone 31 operations over a period of 7 years. After the diagnosis of tracheal papillomatosis, he received a four-time treatment of T-tube insertion combined with laser fulguration. During the last operation, pathologic findings showed moderate dysplasia with malignancy potential. Conformal radiotherapy was then given at 5000 cGY, targeting the tracheal tumor bed. The patient experienced complete remission with no complications. His condition has lasted for 20 years, and has continued up through the time of this report.

Impact of Positive Margins and Radiation After Tracheal Adenoid Cystic Carcinoma Resection on Survival.

BACKGROUND: Achieving negative margins for adenoid cystic carcinoma (ACC) of the trachea can be technically difficult. This study evaluated the impact of positive margins on prognosis and tested the hypothesis that radiation improves survival in the setting of incomplete resection. METHODS: The impact of margin status and adjuvant therapy on overall survival of patients with tracheal ACC in the National Cancer Database (1998 to 2014) who underwent resection with known margin status and with no documented nodal or distant disease was evaluated using Kaplan-Meier and Cox proportional hazard analysis. RESULTS: Of 132 patients who met study criteria, 79 (59.8%) had positive margins after resection. Adjuvant radiation was given to 95 patients overall (72.0%) and to 62 of the 79 patients with positive margins (78.5%). The survival of patients with positive margins was not significantly different from that of patients with negative margins (5-year survival, 82.2% [95% confidence interval (CI), 71.3-89.3] compared with 82.0% [95% CI, 67.0-90.6], P = .97), even after multivariable adjustment (hazard ratio, 1.73; 95% CI, 0.62-4.84; P = .30). In the subset of patients with positive margins, there was no significant difference in survival between patients who did or did not receive postoperative radiation therapy (5-year survival, 82.0% [95% CI, 68.8-89.9] compared with 82.4% [95% CI, 54.7-93.9]; P = .80), even after multivariable adjustment (hazard ratio, 1.04; 95% CI, 0.21-5.25; P = .96). CONCLUSIONS: The majority of tracheal ACC resections performed in this national cohort had positive margins. Adjuvant radiation was commonly used for positive margins but was not associated with an overall survival benefit.

Effects of adjuvant radiation therapy on survival for patients with resected primary tracheal carcinoma: an analysis of the National Cancer Database.

OBJECTIVE(S): To identify predictors for receiving adjuvant radiation therapy (RT) and investigate the impact of adjuvant RT on survival for patients with resected primary tracheal carcinoma (PTC). METHODS: The National Cancer database was queried for patients with PTC diagnosed from 2004 to 2014 undergoing resection. Patients who died within 30 days of resection were excluded to minimize immortal time bias. Kaplan-Meier methods, Cox regression modeling and propensity score weighted (PSW) log-rank tests were considered to assess the relationship between adjuvant RT and overall survival (OS). Logistic regression was performed to identify predictors associated with receiving adjuvant RT. RESULTS: A total of 549 patients were identified with 300 patients (55%) receiving adjuvant RT. Squamous cell carcinoma (SCC) was the most common histology with 234 patients (43%). Adenoid cystic carcinoma (ACC) was second most frequent with 180 patients (33%). Adjuvant RT was not associated with OS by multivariable Cox analysis or PSW log-rank test (P values > 0.05). Patients with positive surgical margins (odds ratio (OR) 1.80, confidence interval (CI) 1.06-3.07) were more likely to receive adjuvant RT than those with negative surgical margins. Patients with ACC (OR 6.53, CI 3.57-11.95) were more likely to receive adjuvant RT compared with SCC. CONCLUSIONS: Adjuvant RT was not significantly associated with OS for patients with resected PTC in this analysis. Surgical margin status and tumor histology were associated with receiving adjuvant RT. Further investigations including prospective registry studies capturing radiation technique and treatment volumes are needed to better define which patients with resected PTC may benefit from adjuvant RT.

ADENOID CYSTIC CARCINOMA OF DISTAL TRACHEA: A CASE REPORT.

Primary malignant tumors of the trachea are very rare with the incidence of less than two per million people per year, and only ten percent of them are adenoid cystic carcinomas. Eighty percent of all tracheal tumors are malignant. Diagnosis is usually late because the symptoms mimic other conditions such as asthma. Clinical picture may sometimes be dramatic when airway is almost closed and emergency recanalization is necessary. Diagnosis is made by chest computed tomography scan or magnetic resonance imaging. Definitive treatment is surgical resection alone or followed by radiation therapy or radiation therapy alone. Radical resection is only accomplished in about half of all cases because of the submucosal tumor growth and limited length of tracheal resection. The role of adjuvant radiation therapy in negative resection margin cases is not clear but all patients with positive resection margin benefit from radiation therapy. We present a case of a 43-year-old patient with primary adenoid cystic carcinoma of distal trachea treated by emergency bronchoscopic recanalization and resection of the tracheal tumor with end-to-end anastomosis.

A 10-year clinical outcome of radiotherapy as an adjuvant or definitive treatment for primary tracheal adenoid cystic carcinoma.

BACKGROUND: To evaluate the role of radiotherapy (RT) as an adjuvant or definitive treatment in primary tracheal adenoid cystic carcinoma (ACC) for local tumor control and survival. METHODS: A retrospective chart review was performed in 22 patients treated with adjuvant or definitive RT for primary tracheal ACC at a single center between November 1994 and December 2008. RESULTS: Thirteen and 9 patients received adjuvant and definitive RT, respectively. Microscopic residual disease after surgery was pathologically reported in 11 patients. The median RT dose was 59.4 Gy for adjuvant and 74.4 Gy for definitive RT. The overall response rate for definitive RT was 77.8%. Six patients in the definitive RT group exhibited local progression (LP), whereas 14 patients in both groups exhibited distant metastasis. The most common recurrence site in cases of treatment failure was the lung parenchyma. The median follow-up duration was 123 months, and the 10-year overall survival (OS) rate was 54.2%. Although LP was the most common cause of death (4 patients), two-thirds of the patients treated with definitive RT lived for >5 years. The 5-year and 10-year LP-free survival (LPFS) rates in the definitive RT group were 66.7 and 26.7%, respectively. Patients with higher RT dose by brachytherapy boost had good 5-year OS, 83.3%, and showed no local progression till 5-years. Most of the RT-induced side-effects were mild and tolerable, but 2 patients died of tracheal stenosis without any tumor recurrence. CONCLUSIONS: Adjuvant RT may be suitable for controlling microscopic residual disease, whereas definitive RT may yield appropriate long-term survival in >50% patients with unresectable tracheal ACC. Dose escalation should be considered to warrant long-term survival in definitive RT.

Percutaneous CT-fluoroscopic-guided radioisotope seed placement for the management of adenoid cystic carcinoma of the trachea.

PURPOSE: Tracheal and paratracheal malignancies present challenges in radiotherapeutic management due to their proximity to sensitive structures, central location, and because of the potential for catastrophic radiation induced fistula. The use of external beam radiation therapy and intraluminal brachytherapy has a limited number of reports in the literature. We have searched for a technique for treating tracheal and paratracheal malignancies allowing application of a high dose of radiation while minimizing dose to normal tissues. Our group has considerable experience in the use of percutaneous CT-guided radioisotope seed implants for intrathoracic malignancies. We have previously reported our technique for percutaneous CT-fluoroscopic-guided radioisotope seed implants in the management of thoracic malignancies. We have now treated several tracheal and paratracheal malignancies with our technique and report our results here. This is to our knowledge the first report of treatment of tracheal malignancy with CT-guided permanent seed implant. METHODS AND MATERIALS: Three patients with tracheal adenoid cystic carcinoma were implanted with 103Pd under CT-fluoroscopic guidance utilizing percutaneous approach. RESULTS: All patients tolerated the procedure well, and at 9-month average followup, all show disease regression, symptom improvement, and no sign of toxicity. CONCLUSIONS: We believe this to be the first published series on CT-directed permanent seed brachytherapy for tracheal malignancies. Review of PubMed literature to 1990 discloses no prior writings on the use of permanent seed implantation for tracheal cancers. Tracheal malignancies provide a vexing radiation therapy challenge to stay within the therapeutic window. CT-directed permanent seed brachytherapy allows a high dose to be delivered to the tumor with a rapid falloff to the surrounding tissues. Short-term results from seed implant are excellent. Our 3 patients responded well in the short term to permanent seed brachytherapy with no chronic side effects and with reduction or relief of cough and pain. CT-fluoro-guided permanent seed implantation is an effective and low morbidity treatment for tracheal malignancies. Long-term followup is needed to further elucidate durability of response and toxicity.

Asymptomatic tracheal MALT lymphoma discovered on spirometric findings presenting with elevated respiratory resistance.

BACKGROUND: Central airway obstruction (CAO) may be caused by various etiologies. However, conventional chest X-rays are rarely diagnostic for patients with CAO. CASE PRESENTATION: We here described a 64-year-old asymptomatic female with tracheal mucosa-associated lymphoid tissue lymphoma discovered on spirometric findings during a complete physical examination. The plateau of forced expiratory flow was consistent with CAO. A decreased peak expiratory flow rate was noted at least 3 years before the diagnosis, and was attributed to an insufficient effort by the patient. Impulse oscillometric measurements, which were taken during quiet breathing and were effort-independent, suggested elevated respiratory resistance. These abnormalities completely disappeared after radiation therapy. CONCLUSION: The addition of impulse oscillometry to spirometry may be useful for screening CAO in routine health examinations.

[Treatment of neoplastic lesions of the central bronchi and trachea using endotracheobronchial surgery, intraluminal brachytherapy, combined radiotherapy and chemoradiotherapy].

There are summarized the foreign and domestic references of recent years devoted to methodology and the efficiency of the use of intraluminal high-dose radiation brachytherapy in patients with lesions of the central bronchi and trachea caused by primary and metastatic malignant tumors. It is presented own experience of applying this method in 207 patients. It is showed that in some patients to ensure the delivery of the radiation source to the area of interest it is advisable to perform firstly endotraheobronhial surgery with recanalization of the lumen of the respiratory pathways. The best is the use of intraluminal brachytherapy with high dose radiation. Palliative intraluminal irradiation of inoperable patients allowed achieving a good immediate results (65-95%), a significant reduction of the main symptoms--hemoptoe (87-95%), dyspnea (75-90%), obstructive pneumonia phenomena (50-85%), and significantly increasing survival median from 1-3 to 9-14 months. Following performance of chemoradiotherapy permitted increasing the survival median up to 15-20 months. The number of complications of intraluminal high-dose radiation brachytherapy was small, usually--pulmonary hemorrhage (2-7%) more likely developing when using large fractions--more than 10 g for 1 session.

Bronchoplastic closure as an alternative approach for tracheal reconstruction following resection of a massive tracheal tumour.

A 47-year old woman presented with large cell carcinoma with extensive lengthwise and circumferential invasion of the lower trachea. End-to-end anastomosis by suture lines alone may be impossible and even harmful, following tumour resection with such extensive tracheal involvement. Thus, we performed a successful tracheal reconstruction with bronchoplastic closure without complications or recurrence at 12-month follow-up. This case highlights the use of this technique for the closure of massive airway defects.

Endotracheal brachytherapy alone: An effective palliative treatment for tracheal tumors.

BACKGROUND: Tracheal tumors are rare. They are usually unresectable and treated primarily with external beam radiation. The use of palliative endotracheal brachytherapy (ETBT) alone in treating patients with tracheal tumors has not been reported. METHODS: Using a prospective database, demographic, treatment, and outcome data of patients with tracheal tumors treated palliatively with ETBT from 2006 to 2014 were analyzed. Tumor and symptom responses were evaluated based on response evaluation criteria in solid tumors criteria. Survival, in-field disease control, symptom response, and duration of symptom responses were evaluated using descriptive analyses. RESULTS: Sixteen ETBT (median, 2) treatments were delivered to 8 patients. Median age was 63.4 years old. Common symptoms were hemoptysis, cough, and dyspnea. Tracheal lengths of 3.5-11 cm were treated with 5-7 Gy/fraction, using 1-3 fractions. The mean overall survival was 5 months and symptom-free survival was 6.8 months, respectively. After ETBT, 88% of patients experienced symptomatic improvement (hemoptysis [n = 3/3], cough [n = 6/7], and dyspnea [n = 4/4]). One patient developed Grade 1 stenosis that did not require intervention. CONCLUSIONS: This is among the largest series of tracheal tumors treated palliatively with ETBT alone. ETBT provided effective palliation with symptom improvement and minimal toxicity.

Airway compromise due to adenoid cystic carcinoma obstructing the distal trachea: a review of current management and clinical trials.

An 84-year-old man presented with a 2-month history of intermittent stridor and worsening difficulty in breathing. Chest X-ray and flexible nasendoscopy were unremarkable but following further deterioration a CT scan revealed an obstructing lesion in the distal trachea. Bronchoscopy revealed an infiltrative tumour arising 3 cm above the carina causing 90% obstruction. The mass was biopsied and surgically debrided to leave a patent airway. Histological analysis revealed a diagnosis of adenoid cystic carcinoma. Transthoracic surgical resection was unsuccessful and the patient continues to be effectively managed with periodic bronchoscopic debulking and radiotherapy. This case highlights the diagnostic and therapeutic dilemmas posed by distal tracheal lesions and the need for specialist input for effective management.

The effect of metallic tracheal stents on radiation dose in the airway and surrounding tissues.

BACKGROUND: Metallic airway stents are often used in the management of central airway malignancies. The presence of a metallic foreign body may affect radiation dose in tissue. We studied the effect of a metallic airway stent on radiation dose delivery in a phantom and an in vivo porcine model. METHODS: A metallic tracheal stent was fitted onto a support in a water phantom. Point dosimeters were positioned in the phantom around the support and the stent. Irradiation was then performed on a linear accelerator with and without the stent. Metallic tracheal stents were deployed in the trachea of three pigs. Dosimeters were implanted in the tissues near (Group 1) and away (Group 2) from the stent. The pigs were then irradiated, and the dose perturbation factor was calculated by comparing the actual dose detected by the dosimeters versus the planned dose. RESULTS: The difference in the dose detected by the dosimeters and the planned dose ranged from 1.8% to 6.1% for the phantom with the stent and 0%-5.3% for the phantom without the stent. These values were largely within the manufacturer's specified error of 5%. No significant difference was observed in the dose perturbation factor for Group 1 and Group 2 dosimeters (0.836 ± 0.058 versus 0.877 ± 0.088, P = 0.220) in all the three pigs. CONCLUSIONS: Metallic airway stents do not significantly affect radiation dose in the airway and surrounding tissues in a phantom and porcine model. Radiation treatment planning systems can account for the presence of the stent. External beam radiation can be delivered without concern for significant dose perturbation.