The Diagnosis and Treatment of Bronchopulmonary Carcinoid
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Background: The spectrum of primary neuroendocrine tumors of the lungs ranges from typical carcinoid tumors, which are relatively benign, to highly aggressive small-cell carcinoma. In this review, we summarize the treatment of bronchopulmonary carcinoid, a disease with an incidence of 0.5 per 100 000 persons per year in Western countries.
Method: We selectively searched the PubMed database for scientific evidence on the treatment of bronchopulmonary carcinoid, considering only articles published up to February 2015. We also performed a survival analysis of 84 patients with this disease who underwent interdisciplinary treatment at the University of Freiburg Medical Center.
Results: Carcinoid tumors account for less than 1% of all lung tumors. They manifest themselves clinically with cough (35%), hemoptysis (25%), and/or bronchial obstruction (40%), depending on their location, size, and pattern of growth. 30% of patients are asymptomatic, and less than 1% have hormone-associated symptoms. Typical and atypical carcinoid tumors are distinguished on a histological basis; the histologic differential diagnosis also includes large-cell neuroendocrine tumors and small-cell carcinoma of the lung. 80% of patients who undergo resection of typical carcinoid tumors survive at least 10 years. Atypical carcinoid tumors recur more commonly than typical ones. If the mediastinal lymph nodes are involved, adjuvant treatment should be considered.
Conclusion: Because of their rarity, the treatment of bronchopulmonary carcinoid tumors presents an interdisciplinary challenge. Surgical resection, the treatment of choice for local carcinoid tumors, generally leads to long-term survival. The existing registers should be made more comprehensive so that the treatment of this disease can be better in the future.
Neuroendocrine tumors (NET) of the lung are rare neoplasms. NET arise from cells that have migrated into the organs from the embryonic neural crest (1). The term carcinoid was originally introduced for enteral tumors and was later also used for pulmonary NET (2). Because of the different clinical symptoms, NET was classified into well differentiated typical carcinoid tumors (TC) and intermediately differentiated atypical carcinoids (AC) in 1972. This classification was adopted by the World Health Organization in 2004 and 2015 (3, 4).
After the gastrointestinal tract, the lung is the second most common location for NET (10%). Less than 1% of all pulmonary tumors are carcinoid tumors (5). In Germany, no comprehensive analyses exist; the incidence of carcinoid tumors in Western countries is 0.5/100 000 (6, 7, 8, 9). Correspondingly, the number of new cases of bronchopulmonary carcinoid in Germany can be assumed to be 400–500. The estimated prevalence is more than 3000 cases (10). Interestingly, it has been observed that the incidence of bronchopulmonary NET is increasing (6, 9). Consumption of nicotine and known carcinogens do not seem to be of any relevance in the pathogenesis (11). Less than 10% of tumors have a genetic cause (12). The average age at diagnosis of a TC is 45 years—the same for both sexes—whereas patients with AC are usually 10 years older and notably more often develop lymph node metastases (50%) and distant metastases (20%) (9, 13, 14, 15). Because of the few studies investigating carcinoid tumors, attempts are being made to integrate data collected on such tumors in databases, such as the German NET Registry (16, 17, 18).
We identified currently available data on the diagnostic evaluation and treatment of bronchopulmonary carcinoid tumors by conducting a selective literature search in PubMed. We searched for articles published up to February 2015. We identified merely individual randomized studies and no meta-analyses for these rare tumors. For this reason, we also included relevant case series.
Three quarters of bronchopulmonary carcinoid tumors are located in the central airways. Airway obstruction or hemorrhages from these characteristically hypervascularized tumors are among the symptoms (Figure 1) (7). The remaining 25%, especially AC, are peripheral, mostly incidentally detected, solitary pulmonary nodules (19). Even when symptoms are present the diagnosis is often delayed. Many patients go through years of diagnostic evaluation, for example, in recurrent occurrences of pneumonia. 30% of patients are asymptomatic, 40% have bronchial obstruction, 35% have a cough, and 25% experience hemoptysis (11). Imaging techniques can be used to show that 75% of carcinoid tumors result in atelectasis owing to bronchial obstruction, which is visible in the thoracic radiograph (20). Except for CT and bronchoscopy, carcinoid patients do not require any further special investigations before the resection (Figure 2) (21).
In contrast to gastroenteropancreatic (GEP) NET (10%), carcinoid syndrome is very rare in bronchopulmonary carcinoid (<1%); however, again differently to GEP-NET, the carcinoid syndrome can occur even in the absence of hepatic metastases (22, 23). Rarely, hormonally active bronchopulmonary carcinoid tumors are also the cause of Cushing's syndrome or acromegaly (24, 25).
Smoking is not considered etiologically relevant in carcinoid tumors, quite in contrast to large-cell-neuroendocrine tumors and small-cell lung cancers (11, 15). Although most of the tumors arise sporadically, 1.4–9.5%—depending on the study—of patients with multiple endocrine neoplasia (MEN)-1 develop bronchopulmonary carcinoid tumors, which usually take an indolent course. MEN-associated carcinoid tumors of the thymus are, however, more aggressive (12, 16). Independently of the MEN-syndrome, familial carcinoid tumors have also been described (27). Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), which is characterized by a generalized proliferation of neuroendocrine cells, is a rare predisposing factor (28). Cell proliferations that break through the basal membrane are known as tumorlets. Surgical resection of the larger lesions is recommended. If the patient’s condition is stable, follow-up examinations should be undertaken (29).
Lung cancers, other lung tumors, metastases, and benign disorders such as asthma or aspirated foreign bodies range among the differential diagnoses. In case of solitary pulmonary nodules, granulomata, hamartoma, arteriovenous malformations, pneumoconiosis, abscesses, septic embolism, fungal infections, or even mycobacterioses should be discussed. Bronchopulmonary carcinoid tumors that trigger Cushing's syndrome owing to ectopic production of ACTH are usually small (<2 mm). Thin-layer CT and somatostatin receptor imaging are helpful in detecting tumors (30, 31).
Diagnostic imaging and staging
CT using contrast medium is the best method for identifying extrabronchial proportions and mediastinal lymph node enlargement in central tumors. Because of their hypervascularization, carcinoid tumors absorb contrast medium and are often seen as well defined, obstructing tumors (Figure 1a and 1b).
Up to 20% of TC are accompanied by hilar or mediastinal lymphadenopathy, which is mostly caused by a reactive inflammatory reaction (32). Most carcinoid tumors are accessible by means of bronchoscopy with transbronchial biopsy, since 75% are centrally localized. In peripherally localized tumors, percutaneous needle biopsy can be undertaken. Half of AC have lymph node metastases. Endobronchial ultrasound guided transbronchial needle aspiration (EPBUS-TBNA) or mediastinoscopy are undertaken for the purpose of staging according to the TNM classification for lung cancer (33). The histological differentiation grade follows the classification of WHO/the International Association for the Study of Lung Cancer (IASLC) (17). TC are mostly diagnosed at stage I, AC mostly at stage II (N1, [hilar] lymph node involvement) or stage III (N2, [mediastinal] lymph node involvement). Hepatic metastases (stage IV) can be detected by using three-phase CT or, alternatively, by using ultrasonography. In analogy to GEP-NET, functional somatostatin receptor (SSTR) imaging using conventional somatostatin receptor scintigraphy (SRS) is used in the diagnostic evaluation. For example, 111Indium (In)-DTPA-octreotide or positron emission tomography (PET) or PET/CT using 68gadolinium-marked somatostatin receptor ligands, such as 68Ga-DOTATATE, are used in this setting. The immunohistochemical SSTR expression correlated in 70% of bronchopulmonary carcinoids with the SRS (34). In other studies, 100% of TC and 80% of AC were confirmed by using somatostatin receptor PET (34, 35, 36, 37). One big advantage of receptor imaging is whole-body imaging, which especially in AC enables the detection of extrapulmonary metastases (Figure 3) (9, 13, 32, 38). Diagnostic evaluation by PET has advantages compared with conventional scintigraphy in terms of higher spatial resolution and stronger SSTR binding affinity (39, 40). Again in analogy to the GEP-NET, diagnostic evaluation using 18fluordeoxyglucose (18F-FDG) positron emission tomography is of lesser importance in well differentiated bronchopulmonary NET, whereas the sensitivity increases with an increasingly lower histological differentiation grade (TC to AC) (36). Imaging is no substitute for tissue sampling in this setting (Figure 2).
In GEP-NET, hormonal activity occurs in some 10% of cases, in bronchopulmonary NET in <1% of cases. The serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA) is detectable in urine. Its concentration may be raised even in the absence of carcinoid syndrome (e1). Chromogranin A (CgA) detected in serum has a sensitivity of 85% and specificity of 96% in NET (e2). Measuring CgA is more used in the follow-up care of patients with (metastatic) disease rather than primary diagnostic evaluation (e3).
Bronchoscopy shows in central localization almost pathognomonically a strongly vascularized tumor that is mostly covered by bronchial epithelium (Figure 1b). Such tumors are mostly broad-based and grow intraluminally as well as extraluminally—the so called iceberg phenomenon. In order to confirm the diagnosis, brush cytology or biopsy should be done. TC and AC can be distinguished only by using a prepared resected tissue specimen (e4, e5). In spite of vascularization, serious problems with hemorrhage are rare during the biopsy procedure (<1%). Where concerns arise, the indication for rigid bronchoscopy should be defined generously. In peripheral tumors that are suspected to be carcinoid tumors, thoracoscopic resection is the method of choice that should be undertaken immediately (Figure 2).
- TC (<2 mitoses/2 mm2 and no necroses)
- AC (2–10 mitoses/2 mm2 and/or confirmed necroses).
Both should be distinguished from large-cell and small-cell lung cancers, although neuroendocrine differentiation manifests in the latter as well as in AC and TC (e7, e8). As proof, either the expression of NCAM/CD56, CgA, or synaptophysin are immunohistochemically determined or the neuroendocrine granula are determined by electron microscopy. Typically, growth patterns in the shape of rosettes or trabeculae are clearly histologically detectable in carcinoid tumors.
The recommendations for surgical treatment are based on retrospective case series and database analyses (13, 18, e5). Surgery is the only curative approach, and, in view of the lack of prospective studies, it is the therapeutic mode of choice in all recommendations (Figures 2 and 4) (18, e5). The most important objective is a microscopically tumor-free resection margin (R0), which is associated with a good prognosis (e9). The European Society of Thoracic Surgeons Neuroendocrine Tumours Working Group showed in 1109 patients with TC that resection is associated with a 5-year survival rate of 94% (e10). A database analysis from the United States including 441 patients with AC showed that surgical resection leads to a 3-year survival rate of 67% (13). A retrospective analysis in 84 patients who had undergone surgical resection that was conducted by the authors also showed that survival after 5 years is excellent: 91% in patients with TC (n=63) and 90% in patients with AC (n=21) (Figure 4). Radical mediastinal lymph node dissection is indicated in TC since lymph node metastases may be present (13, e5). It should be attempted to preserve healthy pulmonary parenchyma; in a peripherally localized tumor, wedge resection therefore seems sufficient (e11). If the tumor is localized in the central airways, complex resections with angioplasty/bronchoplasty are often required (e12). These can be undertaken with low morbidity and mortality, as can be seen from the high proportion (35%) of patients who were successfully treated with extended resection at the University of Freiburg Medical Center (Figure 4). Since 50% of patients with AC develop lymph node metastases, more drastic resections will be necessary in these patients (segmentectomy/lobectomy with radical mediastinal lymphadenectomy). This helps prevent local recurrences in the residual lobe or the mediastinal lymph nodes (18, 21).
Inoperable tumors requiring palliative treatment can be resected bronchoscopically, in order to alleviate symptoms such as retention pneumonia. Even in case of the rare endobronchial growth without expansion through the cartilage, bronchoscopic resection should not be undertaken, although descriptions of this form of limited resection exist (e13).
Long term survival and follow-up care
After complete resection of bronchopulmonary carcinoid tumors, survival rates of more than 80% have been observed consistently (Figure 4) (e14). The prognosis is significantly associated with the degree of differentiation and lymph node metastases. TC have the best prognosis, with a 10-year survival rate of more than 80% (11). The 5-year survival rate in AC without lymph node metastases is 80%, and for AC with lymph node metastases, 60% (Figure 4) (7, 13). A US analysis over 40 years including more than 5500 patients with bronchopulmonary carcinoid tumors showed a 5-year survival rate of 61% (e15).
Since recurrences and distant metastases in TC can develop years after resection of the primary tumor, follow-up care for a minimum of 10 years is indicated (e16). Surgical treatment at the metastatic stage can be considered if the metastases are resectable. Retrospective case series have shown that after resection of neuroendocrine hepatic metastases, the 5-year survival rate is 78% (e17, e18). Furthermore, liver transplantation is an option in NET with diffuse hepatic metastases. An analysis of data from 150 patients showed excellent 5-year survival of 49% after transplantation (e19). But prospectively randomized studies are lacking here too with regard to the selection criteria for transplantation of metastasectomy (number of metastases, length of disease-free intervals/tumor-free period). The authors take the view that interdisciplinary decisions in a center of excellence are required.
Chemotherapy and radiotherapy
Because of the increased risk of recurrence in carcinoid patients with lymph node metastases, adjuvant chemotherapy is desirable. Different drugs have been used with disappointing results (e20). A prospective, randomized study in patients with advanced carcinoid tumors, in whom—among others—5-fluorouracil with streptozotocin was administered, showed a slightly prolonged median survival period, from 16 months to 24 months (e19, e21). Somatostatin receptor analogues (SSA)—for example, octreotide or lanreotide—are primarily indicated for the control of symptoms in carcinoid syndromes. However, a prospective, randomized, placebo-controlled study showed that lanreotide in GEP-NET prolonged progression-free survival (placebo group: median not achieved; lanreotide group: median 18 months) (e21, e22). Compared with a combination of octreotide and placebo, progression-free survival improved in metastatic carcinoid tumors from 11.3 months to 16.4 months if octreotide was given in combination with the mTOR inhibitor everolimus (RADIANT-2 Study) (e23). In addition, the results of a prospective, double blind, randomized multicenter phase III study are expected, which investigated the treatment of metastatic NET with everolimus (versus placebo) (RADIANT-4). A further therapeutic approach is peptide receptor radionuclide therapy (PRRT) using radioactively marked 90Yttrium (Y) or 177Lutetium (Lu)-SSA (e1). In a phase II study, more than 74% of patients with somatostatin-refractory GEP-NET responded to the treatment or stabilized (e20). Pilot studies of the somatostatin receptor ligand 177Lu-DOTATATE showed tumor regression of more than 50% in 28% of patients with bronchopulmonary NET (e24). Furthermore, local ablative palliation should be considered in patients with unresectable hepatic metastases—for example, transarterial chemoembolization (TACE) (Figure 2) (e25).
The role of percutaneous radiotherapy in carcinoid is controversial because the tumors are mostly resistant to irradiation (23). However, since resected AC have a significantly increased risk for local recurrence, adjuvant mediastinal radiotherapy can be considered if lymph nodes are involved. Furthermore, local radiotherapy can be undertaken if the tumor is inoperable, in order to alleviate symptoms (Figure 2) (23, e26).
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 1 December 2014, revised version accepted on
23 April 2015.
Translated from the original German by Birte Twisselmann, PhD.
PD Dr. med. Jussuf T. Kaifi, FACS
Klinik für Thoraxchirurgie, Universitätsklinikum Freiburg
79106 Freiburg, Germany
@For eReferences please refer to:
Center for Pathology at the Medical Center—University of Freiburg: PD Dr. med. Kayser
Department of Nuclear Medicine at the Medical Center—University of Freiburg: PD Dr. med. Ruf
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