The data presented by Reuling and colleagues [1] in the current issue of Respiration provide new additional support challenging the dogmatic recommendation of surgical treatment as the sole curative treatment in all neuroendocrine tumors (NETs) and carcinoids in particular.
Pulmonary NETs represent a minority of the total number of tumors in the lung. NETs are a heterogeneous group of malignant tumors with neuroendocrine morphology and differentiation. These include the well-differentiated, low-grade, typical carcinoids (TC), intermediate-differentiated, intermediate-grade atypical carcinoids (AC), and the poorly differentiated, high-grade neuroendocrine carcinomas (small-cell lung carcinoma and large-cell neuroendocrine carcinomas). Both TC and AC often occur in the central airways and patients present with cough, recurrent infections, or symptoms mimicking asthma or COPD often for many years prior to the diagnosis (Fig. 1). Peripherally located carcinoids are often asymptomatic.
High-definition bronchscopy image of a representative case of a typical carcinoid located in the left main bronchus of a 61-year-old female who presented with pneumonia (the patient provided her written consent for reproduction of the images). The left panel shows a high-definition image with surface enhancement imaging, the right panel an image with surface and tone enhancement (i-scan technology obtained with Pentax EB1990i videobronchoscope and EPKi-7000 processor). This 16-mm large typical carcinoid was endobronchially resected. SMS scanning did not reveal any avidity after resection and a 4-year close surveillance follow-up with CT scans, repeat bronchoscopy, and biopsy of the endobronchial resection margin was uneventful.
High-definition bronchscopy image of a representative case of a typical carcinoid located in the left main bronchus of a 61-year-old female who presented with pneumonia (the patient provided her written consent for reproduction of the images). The left panel shows a high-definition image with surface enhancement imaging, the right panel an image with surface and tone enhancement (i-scan technology obtained with Pentax EB1990i videobronchoscope and EPKi-7000 processor). This 16-mm large typical carcinoid was endobronchially resected. SMS scanning did not reveal any avidity after resection and a 4-year close surveillance follow-up with CT scans, repeat bronchoscopy, and biopsy of the endobronchial resection margin was uneventful.
Regardless of the grade or exact localization, all current guidelines and recent reviews advocate surgical resection as the sole curative option in localized NETs [2-6]. The National Comprehensive Cancer Network (NCCN) guideline states: “Resection is the primary treatment approach for most localized carcinoid tumors” and “Surgery, including lobectomy or other anatomic resection and mediastinal node dissection or sampling, is recommended for patients with stage I, II, and IIIA bronchopulmonary tumors” [2]. In Europe, the European Neuroendocrine Tumor Society (ENETS) consensus states: “Surgical removal is the treatment of choice” and “For patients with central airway tumors, lung parenchymal-sparing surgery is the favored surgical objective” [3]. However, these latter experts recognize a distinct role for the interventional pulmonologist in case of TC without extraluminal invasion; yet in their final recommendation, this role for interventional pulmonology is missing and endobronchial resection as a treatment option is reserved for patients unfit for surgical resection or as a bridge to surgery only [3].
However, the evidence supporting a distinct role of the interventional pulmonologist in the treatment of centrally located endobronchial carcinoids is growing and this current paper further supports endobronchial resection as an excellent alternative to upfront surgical resection in selected cases [1, 7-12].
In this current issue, Reuling and colleagues [1] describe their single (expert) center experience with first-line endobronchial treatment in both typical and atypical bronchial carcinoids in a group of 125 patients treated in the past 25 years. They present excellent results and identify a cutoff size of 20 mm and CT characteristics indicative for pure endoluminal localization as predictors of a successful outcome of endobronchial resection. This finding is in line with earlier reports from this and other groups [7-12].
Given this growing body of evidence, I feel that a modification of the guidelines is opportune and a distinct role of the interventional pulmonologist in the multidisciplinary board is warranted in the evaluation and treatment of patients with pulmonary NETs.
In our center, we have implemented endobronchial resection as the first-line treatment in the past decade and offer this option to all our patients with endoluminal bronchial TC (Fig. 1). With the newly presented data presented here, I would like to recommend the following items for an optimal clinical workup in patients with a suspected bronchial NET:
Refer patients to a center with an experienced multidisciplinary team with interventional pulmonologists and a surgical team experienced in lung parenchyma-sparing surgery, sleeve resections, and major airway surgery.
Perform a contrast CT (high-resolution setting, 1 mm slide thickness) and – when a diagnosis is highly suspected or already available upon referral – somatostatin receptor-based imaging with a 68Ga-dotatate PET/CT. Alternatively, a somatostatin receptor scintigraphy can be obtained. When the 68Ga-dotatate PET/CT is obtained after the endobronchial resection, this may be used to detect residual disease or detect metastatic disease sites.
For endobronchial resection: combine the interventional rigid bronchoscopy for diagnosis and treatment or debulking with a combined EBUS and EUSb to determine nodal involvement and tumor stage. Treat the base of the carcinoid preferably with cryotherapy [7]. The endobronchial resection specimen will offer the pathologist ample tissue to diagnose the NET and differentiate between TC and AC [2-4, 6].
In case of a TC with a diameter of < 20 mm and no signs of transbronchial invasion on imaging and upon bronchoscopy, and when a successful endobronchial resection was performed: plan a close surveillance for follow-up (see below).
In case of an AC: despite size and possibly successful endobronchial resection, I would still like to advice lung parenchyma-sparing surgical resection in combination with nodal staging (argumentation see below).
In case of a TC or AC larger than 20 mm, transbronchial invasion, metastatic disease, or unsuccessful EBR, refer for surgical resection and or combined treatment [2, 3].
When complete endobronchial resection is not possible, endobronchial debulking is likely to improve symptoms of post-obstruction pneumonia, renders detailed anatomical information for the surgeon, and may reduce the extent of resection needed and may thus spare valuable lung parenchyma in these, often young, patients.
Proposed follow-up schedule after endobronchial resection of a limited TC: after 6 weeks, bronchoscopy and contrast CT (and 68Ga-dotatate PET/CT when not available prior to diagnosis), followed by contrast CT and bronchoscopy after 6 months, followed by annual follow-up including chromogranin A biomarker testing. Total follow-up 10 years with contrast CT, bronchoscopy, and chromogranin A biomarker testing (adapted from [2]).
In conclusion, I would like to propose that for intraluminal TC < 20 mm, endobronchial resection is the first choice of treatment. However, for AC, the evidence to withhold from patients a surgical resection is very limited. Most papers studied curative endobronchial treatment in TCs and one study [8] showed that in AC, endobronchial resection was curative in 17% as compared to 51% in TC. In the current study histology was not found to be an independent predictor of outcome, but the group size of AC patients was much smaller (n = 19) in comparison to the TC group (n = 105). Given these findings, I would therefore advice surgical resection combined with systematic nodal dissection for patients with AC based on the current evidence.
A further point of concern is the duration of follow-up. The NCCN guideline advice is a 10-year follow-up period [2]. In my experience, long-term follow-up is indeed warranted. In the past year alone in our center, we found recurrent TC at, respectively, 3, 4, and 5 years after endobronchial resection for which a surgical resection was performed in patients (now aged 21, 31, and 20 years). This underlines the need for intensive follow-up and shows that despite all efforts, the resection margins of an endobronchial resection must be considered as microscopically not free (R1), which forms a risk factor for local recurrence. Therefore, long-term and intensive follow-up is indicated after endobronchial resection and patients should be aware of this when the choice of treatment between endobronchial resection or surgical resection is discussed. The big advantage of endobronchial resection of course is that endobronchial resection is the ultimate lung parenchyma-sparing treatment, and as the current paper shows, can be considered as a treatment with curative intent when the TC is limited in size and limited to intraluminal growth.
In case of bronchial NETs, the interventional pulmonologist should be consulted first as an essential member of the multidisciplinary tumor board.
