Methods: A total of 83 patients (42 males, 41 females; mean age: 57.8±15.2 years; range, 18 to 94 years) with secondary pulmonary malignancies who underwent interventional bronchoscopic procedures between January 2009 and December 2019 were retrospectively reviewed. Data including demographic and clinical characteristics of the patients, complications, and success and survival rates were recorded.
Results: The most common secondary pulmonary malignancies were kidney and thyroid tumors with the complaints of cough, shortness of breath, and hemoptysis. The mean duration before the diagnosis was 34.7±52.8 (range, 0.1 to 219.3) months, and the mean survival after the diagnosis were 10±13.1 (range, 0.2 to 44.4) months. A total of 92% of the patients had an airway obstruction of >50% and the interventional bronchoscopic procedures such as argon plasma coagulation, laser, cryo, and mechanical resection were successful in achieving airway patency. Laser application was found to significantly improve survival (p=0.015). Acute complication rate was 8.4% and mortality rate was 0%.
Conclusion: In patients with tracheobronchial lesions due to secondary pulmonary malignancies, interventional bronchoscopic procedures, regardless of the stage of the disease, provide rapid palliation in life-threatening symptoms such as dyspnea and hemoptysis due to airway obstruction, prolonging patient"s survival and gain time for additional treatments to take effect for primary disease.
The lungs are the organs most susceptible to metastatic spread of all malignant tumors. Lung parenchyma and lymphatics are the usual sites affected by secondary pulmonary malignancies; however, the possibility of metastases within the tracheobronchial tree is rare and underestimated.[5-8] Such tumors can be difficult to differentiate from primary pulmonary malignancies, due to very similar appearance and histology.[9] They may present as endoluminal masses with irregular margins, masses causing external compression, or mucosal/submucosal infiltrations.[10]
Tracheobronchial involvement due to secondary pulmonary malignancies is usually a late-stage finding of primary disease, but can occur at any stage.[6] The medical literature contains scant information about secondary pulmonary malignancies requiring interventional bronchoscopic procedures. As they are rarely encountered, the current literature consists either of case reports or series of patients pooled from different centers, rather than large-scale studies.
Irrespective of disease stage, interventional bronchoscopic procedures can provide acute palliation of -life-threatening conditions, such as dyspnea due to airway obstruction, hemoptysis and fistulas, and also improve quality of life, prolong survival, and gain time for treatment addressing the primary disease.[11,12] Therefore, this group of patients should not be overlooked at any stage of their diseases and should be always followed closely according to pulmonary symptoms, clinical course, and radiological findings.[13] In the present study, we aimed to share our single-center experience and to investigate the effect of interventional bronchoscopic procedures on secondary pulmonary malignancies in terms of complications, success, and survival rates.
Patients presenting with preliminary diagnoses such as malignant airway obstruction and hemoptysis were initially evaluated with thoracic computed tomography (CT), and if possible, by fiberoptic bronchoscopy (FOB).
Malignant airway obstruction was defined as more than 50% obliteration in the tracheobronchial system lumen within the reach of a rigid bronchoscope. The degree of obstruction was determined based on the Cotton-Myer grading for tracheal stenosis. Success of treatment was defined as more than 50% relief of the obstruction and reconnection with the distal airway, accompanied by clinical improvement. Bronchoscopic findings in the tracheobronchial system were classified as external compression, mucosal/ submucosal infiltration, endoluminal mass, and fistula.
From the perspective of interventional pulmonology, cases with secondary pulmonary malignancies were first compiled and, then, classified into two categories, according to whether the primary malignancy had an intra- or extrathoracic location. Esophageal, thyroid, parathyroid tumors, and lymphomas were accepted as intrathoracic malignancies. All other secondary pulmonary malignancies, including kidney, colon and breast tumors were considered as extrathoracic malignancies.
Rigid bronchoscopic procedures were performed under general anesthesia. All patients were monitored with electrocardiography and oxygen saturation (SpO2) during the procedure, with arterial blood pressure measured every 5 min. General anesthesia induction was achieved with midazolam 0.05 to 0.10 mg/kg, propofol (maximum dose 1,000 mg), remifentanil (maximum dose 2 mg), and rocuronium bromide (maximum dose 50 mg) according to the patient"s condition. The equipment used in the procedures included the DuMoN™ Series II Rigid Bronchoscope (Efer Endoscopy, La Ciotat, France) with optical system. The argon plasma coagulation (APC) applicator (40 W, blended mode/ continuous flow) was used via an instrument by Erbe Elektromedizin (Erbe Elektromedizin GmbH, Tubigen, Germany). Endoluminal treatment was accomplished with a diode laser operating at a wavelength of 980 nm with 4 to 25 W in pulsed mode (Biolitec® Ceralas D25; Germany). Cryotherapy was performed with the ERBOKRYO® system (Erbokryo®; Erbe Elektromedizin GmbH, Tubingen, Germany).
Statistical analysis
Statistical analysis was performed using the
R software version 3.6.3. Descriptive data were
expressed in mean ± standard deviation (SD), median
(min-max) or number and frequency, where applicable.
For continuous variables, the Student t-test and Mann-
Whitney U test were used, while chi-square and
Fisher's exact tests were used for categorical variables
that met the normality assumption. In survival
analysis, the first interventional bronchoscopic
procedure date was accepted as zero-day, while the
last check date or date of death was accepted as the last day. The Kaplan-Meier survival analysis was used
for univariate survival analysis. Log-rank test was
applied for comparison of survival rates of groups.
A p value of <0.05 was considered statistically
significant.
Table 1. Baseline features of study population (n=83)
The mean time from the diagnosis of the primary tumor until the detection of tracheobronchial involvement was 34.7±52.8 (range, 0.1 to 219.3) months. The longest time interval until tracheobronchial involvement was seen in colon tumors with 83.8±80.1 (range, 24.7 to 219.3) months and lymphomas with 50±57.9 (range, 0.1 to 185) months, while the shortest time interval was in tumors of the esophagus with 8.9±10.8 (range, 0.1 to 37.7) months (Table 2).
Table 2. Pathological characteristics of patients with secondary pulmonary malignancies
The mean survival time after the diagnosis of endobronchial metastasis was 10±13.1 (range, 0.2 to 44.4) months. The shortest survival time was seen in cervix and prostate tumors (Table 2). Considering the four largest groups of malignancies including the majority of secondary pulmonary malignancies, the mean survival times of thyroid was 9.3±10.1 (range, 0.3 to 26.1) months, kidneys were 17.6±15.6 (range 0.4 to 40.5) months, esophagus was 6.2±12.8 (range, 0.2 to 44.4) months, and lymphoma was 6.4±9.6 (range, 1.5 to 28.1) months.
There was a wide variety of subgroups, but the most prominent malignancies in order of frequency were thyroid and kidney tumors (Table 2). According to their origins, the distribution of intra- and extrathoracic origins were detected in close ratios; 49.4% and 50.6%, respectively.
The trachea was the site where secondary pulmonary malignancies were most often detected within the tracheobronchial tree and mostly affected by malignancies of intrathoracic origin (i.e., thyroid and esophageal tumors). Regarding the right and left bronchial systems, malignant lymphomas were the most common in both right and left bronchial systems (Table 3).
Table 3. Distribution of secondary pulmonary malignancies in the tracheobronchial system
According to the degree of obstruction caused by the secondary pulmonary malignancies in the tracheobronchial system, it was over 50% in 77 (92%) of cases and below 50% in seven (8%) cases. These seven cases were treated in our interventional pulmonology unit, as they either could not tolerate FOB under sedation or had hemorrhage.
Based on the bronchoscopic findings, 50.6% of these malignancies most commonly took the mixed form pattern, while the remaining ones were in close ratios of an isolated endoluminal mass, external compression or mucosal/submucosal infiltration. Also, fistulas accompanied other malignant forms in small numbers. Types of bronchoscopic findings from our case series, such as a mixed type of tumoral lesion composed of external compression, endoluminal mass, and mucosal tumoral infiltration due to malignant melanoma (Figure 1a), a mucosal tumoral infiltration due to breast cancer (Figure 1b), an external compression due to lymphoma (Figure 1c), and an endoluminal mass due to thyroid tumor (Figure 1d) are shown in Figure 1.
Mortality was 81% in patients with mixed type lesions and 78% in those with single type lesions. The mean survival time defined as the time from diagnosis until death was 8.7±11.6 (range, 0.3 to 40.4) months for mixed type lesions and 10.2±14.2 (range, 0.2 to 44.4) months for single type lesions.
Interventional bronchoscopic procedures performed through a rigid bronchoscope such as APC, cryo-extraction, cryotherapy, laser, mechanical resection, and stenting were carried out as part of a multimodal therapy. Nineteen (22%) of patients underwent ≥2 interventional procedures. Regarding thermal treatments, APC was performed in 55 (62.3%), cryotherapy in 36 (43.4%), laser in nine (10.8%), and cryo-extraction in 24 (28.9%) cases. Mechanical resection was performed in 40 (48.2%) and stenting was performed in 39 (47%) cases (Table 4).
Table 4. Interventional bronchoscopic procedure options and frequency of applications
Evaluation of the stents according to their shapes revealed that 22 Y-shaped, 20 straight-shaped, and two tracheal stenotic stents were used. Of these, 33 were silicone, eight were polyflex, and three were semi-covered metallic stents. In four patients, more than one stents were applied (Table 4).
For the preferred interventional bronchoscopic procedures, the patients to whom laser was applied (17.2±1.7 days) had longer mean survival time than those who did not (2.2±0.9 days), indicating statistical significance (p=0.015) (Table 5).
Table 5. Relationship between interventional bronchoscopic procedure and survival
Airway patency was achieved through interventional bronchoscopic procedures applied to the lesions (Figure 2a and Figure 2a) and ensured with the support of stents, if needed (Figure 2b and Figure 2b), as seen in bronchoscopic views from our series (Figure 2).
All 80 patients whose clinical progression and outcomes were available for follow-up had symptomatic palliation with a procedure related-mortality rate of 0%. Three patients who required intensive care were not eligible for progression and outcome evaluation. The procedure-related acute complication rate was 8.4%. Acute complications that we encountered were in order of frequency arrhythmia (3.6%), intensive care unit admission for extubation failure due to post-procedural hypoxia and/or hypercarbia (3.6%), and hemorrhage (1.2%).
All patients underwent regular bronchoscopic follow-up after interventional bronchoscopic procedures according to our follow-up and treatment protocol. While there were no complications related to the procedure during stenting, 23 (60%) patients developed stent-related complications during follow-up which were mostly migration, granulation formation, and mucostasis.
Among the stent-related complications such as granulation tissue and mucostasis, 52.1% were seen with Y-shaped stents. As for stents placed for tracheal lesions, complications were seen more often in straight silicone stents than in polyflex stents. The risk of migration of polyflex stents was found to be less than that of straight silicone stents (12.5% vs. 44.4%, respectively). Stent complications were most frequently seen in the patients with an underlying diagnosis of lymphoma.
The likelihood of metastasis to the lung during the course of all malignancies is quite high, with reported rates between 25 and 30%.[15] Around 20 to 50% of all malignancies metastasize to the lungs, 2% of these located within the tracheobronchial tree.[7] Similar to primary lung malignancies, secondary pulmonary malignancies are known to cause life-threatening conditions such as malignant airway obstruction, respiratory distress, hemorrhage, fistula, atelectasis, and post-obstructive pneumonia, leading to loss of life and increased mortality.[6,16,17] However, review of the literature reveals that while there is a plethora of studies in patients with primary lung malignancies treated by interventional pulmonology, the current literature on this subset of patients consists of only case reports or pooled patients from several centers due to the rarity of secondary pulmonary malignancies involving the tracheobronchial tree.[16,17]
In our study, the most common presenting symptoms were cough (32.8%), shortness of breath (19%), and hemoptysis (13.8%) with a significant portion of patients not demonstrating any pulmonary symptoms (13%). The mean time from the diagnosis of the primary tumor until the detection of tracheobronchial involvement was 34.7±52.8 (range, 0.1 to 219.3) months with a similar period of Lee et al.'s[18] study. Different from their study, the longest mean interval until tracheobronchial involvement was seen in colon tumors with 83.8±80.1 (range, 24.7 to 219.3) months, while the shortest interval was in tumors of the esophagus with 8.9±10.8 (range, 0.1 to 37.7) months. The mean survival time after the diagnosis of endobronchial metastasis was 10±13.1 (range, 0.2 to 44.4) months. The mean survival duration from diagnosis to detection of endobronchial metastasis was 16.1 months in the Lee et al.'s[18] study, which may b e due to exclusion of lymphomas which have shorter survival times than the other malignancies.
The most common secondary pulmonary malignancies showing tracheobronchial involvement in our study were tumors of the esophagus, thyroid, kidneys, and lymphomas which is similar to the rates reported by Niu et al.[19] and Madagaira and Gaissert[20] The most common site of involvement was the trachea (67.4%) consistent with the literature.[21] Thyroid and esophageal tumors and lymphomas, due to their adjacency to the trachea and bronchial system, frequently led to findings of external compression detected by bronchoscopy. Similar to the study by Shin et al.,[21] cases with mixed type lesions were found to compose nearly half of the lesions and had a shorter survival time (8.7±11.6; range, 0.3 to 40.4 months) than those with uniform type lesions (10.2±14.2; range, 0.2 to 44.4 months).
Interventional bronchoscopic procedures such as mechanical resection, thermal methods (cryo, argon, laser), and stenting implemented in interventional bronchology specialty centers positively contributes to patients' quality of life and survival, and gains them time to receive their systemic treatment.[5,22] Examination of interventional procedure records of our cases revealed that, in order of frequency, APC, mechanical resection, and stenting were the most commonly performed treatments as the part of a multimodality treatment. While 19 (22%) patients underwent interventional procedures in ≥2 sessions, this rate was 35% in the series of Shin et al.[21]
Modalities such as APC that can also assist in bleeding control, were selected less often, as intrathoracic tumors such as thyroid and esophagus tumors and lymphomas produce mostly external compression. The APC was applied more frequently to the remaining tumors with mucosal/submucosal involvement and also to renal tumors, which are known for their propensity for bleeding. Also, the frequent use of the laser device in the first years of our study has been superseded in recent years by the APC, owing to its lower cost and similar effectiveness profile in bleeding control.[23]
Considering the effects of applied interventional bronchoscopic procedures on survival, a statistically significant relationship was found between laser application and survival, compared to APC, cryo, and mechanical resection.[24] In our study, the success rate of the procedures performed for secondary pulmonary malignancies requiring an interventional bronchoscopic procedure was 97%. This rate is similar to the literature rates reported as 93%, which is the average success rate of all previous studies concerning central airway obstructions,[25] and to the rates reported by Shin et al.[21] as 90.8% in one of the few studies performed in cases with malignant airway obstruction due to secondary pulmonary metastases.
Clinical and symptomatic palliation was observed (97%) in nearly all of our cases, except for cases requiring admission to intensive care following the procedure (3%). All of the patients were referred to the oncology clinic for their oncological treatments. The survival of patients with extrapulmonary malignancies who develop pulmonary metastasis is reported as being less than six months in the literature.[13] In our study, the mean survival was 10 months, and it appears that interventional bronchoscopic procedures improve the survival of patients.
In the present study, the complication rate of 8.4% falls within the range of complications reported (0.9 to 11.7%) in previous studies of cases with malignant central airway obstruction.[22] The procedure-related mortality rate was 0%, indicating a low rate than those reported in previous studies. The complication and mortality rates reported by Shin et al.[21] in cases with central airway obstruction due to secondary pulmonary malignancies were 20.4% and 3.1%, respectively. They attributed their high rates to the fact that most of their patients were terminal cancer patients without other treatment options.[21]
In addition, 58.9% of the patients with stenting who develop stent-related complications were most frequent with Y-shaped stents and, in lymphomas, thyroid and esophageal tumors and these complications were detected during bronchoscopy either for routine follow-up or due to the changes in patients" clinical state. The reason for high complication rates due to Y-shaped stents can be explained by being the most frequently preferred stents in recent years, since they are known for a lower migration risk. The rate of stent-related complications in our series such as granulation formation, mucostasis, migration, and fistula formation were similar to those reported in other studies.[16,19,21,26]
One of the main limitations to this study is that, since our center is a referral hospital, our patients were evaluated in different institutions before their admissions and referred to us to receive further oncological treatment. In addition, if the quality of life questionnaires could have been administered before and after the procedure, a much more objective comparison of the palliative effect of the procedure could have been made.
In conclusion, as the number of patients diagnosed with cancer has been increasing globally, the use of interventional pulmonology procedures in the treatment of secondary pulmonary malignancies, although rare until now, is expected to increase. Patients with extrapulmonary malignancies should be closely monitored, irrespective of pulmonary symptoms. Particularly in the presence of life-threatening lesions in the tracheobronchial system, as in tracheobronchial involvement of primary pulmonary malignancies, interventional pulmonology can palliate the symptoms of these patients and positively contribute to their survival with low mortality and acceptable complication rates.
Declaration of conflicting interests
The authors declared no conflicts of interest with respect to
the authorship and/or publication of this article.
Funding
The authors received no financial support for the research
and/or authorship of this article.
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