Version May 2024
INTRODUCTION — Lung neuroendocrine tumors (NETs) are an uncommon group of pulmonary neoplasms that are characterized by neuroendocrine differentiation and relatively indolent clinical behavior.
Like NETs at other body sites, lung NETs are thought to derive from peptide- and amine-producing neuroendocrine cells. NETs can arise at a number of sites throughout the body, including the thymus, lung, gastrointestinal tract, and ovaries. The gastrointestinal tract is the most frequently involved site, while lung is the second most common. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
The epidemiology, classification, clinical features, diagnosis, and staging of lung NETs will be reviewed here. The treatment and prognosis of lung NETs, as well as the clinical characteristics of NETs arising in other sites, are discussed elsewhere. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis" and "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
EPIDEMIOLOGY AND RISK FACTORS — Lung neuroendocrine tumors (NETs) account for approximately 1 to 2 percent of all lung malignancies in adults and roughly 20 to 30 percent of all NETs [1-4]. Lung NETs are the most common primary lung neoplasm in children, typically presenting in late adolescence. Typical NETs, which are low-grade tumors with a low mitotic rate, are approximately four times more common than atypical NETs, which are intermediate-grade tumors with a higher mitotic rate and/or necrosis. (See 'Classification, histology, and histochemistry' below.)
Globally, incidence rates range from 0.2 to 2 per 100,000 population per year, and most series suggest a higher incidence in women as compared with men and in White as compared with Black populations [1-3,5-7].
●In a nationwide registry-based Swedish series, the annual incidence rates of lung NETs among men and women were 0.2 and 1.3 per 100,000 population [3].
●In data from the United States Surveillance, Epidemiology, and End Results (SEER) database, the annual incidence of lung NETs between 2000 and 2012 was 1.49 per 100,000 population [7].
Several reports suggest that the incidence of lung NETs is increasing over time [2,3,7]; this may be at least partly related to the heightened use of advanced medical viewing techniques that detect more asymptomatic tumors.
The average age of an adult diagnosed with a typical lung NET is 45 years, while in many series, individuals with atypical tumors are approximately 10 years older [8,9].
Risk factors — Whether there is an association between lung NETs and smoking is unclear. In many studies, between one-third and two-thirds of all patients have been smokers [10-14]. A case-control study reported that cigarette smoking was a risk factor for lung NETs (odds ratio 1.50, 95% CI 1.0-2.40) [15]. Some note a higher prevalence of smoking in patients with atypical as compared with typical tumors [5,13].
Despite these reports, causality is not proven, and the epidemiologic data linking smoking with the development of any NET are not nearly as convincing as they are for bronchogenic cancers. (See "Cigarette smoking and other possible risk factors for lung cancer".)
No other known carcinogens or exposure to environmental agents has been implicated in carcinogenesis [16].
Inherited predisposition — Nearly all lung NETs are sporadic; however, they can rarely occur in the setting of multiple endocrine neoplasia type 1 (MEN1). Rare familial lung NETs not associated with the MEN syndrome have also been described [17].
CLASSIFICATION, HISTOLOGY, AND HISTOCHEMISTRY — Histologically, lung neuroendocrine tumors (NETs) are part of a spectrum of NETs arising in the lung that are characterized by strikingly different biologic behavior. At one end of the spectrum are typical NETs, which are low-grade (well-differentiated), slowly growing neoplasms that rarely metastasize to extrathoracic structures. At the other end of the spectrum are the high-grade (poorly differentiated) neuroendocrine carcinomas (NECs), as typified by small cell lung cancer (SCLC) and large cell NEC, which behave aggressively, with rapid tumor growth and early distant dissemination. The biologic behavior of atypical NETs is intermediate between typical NETs and SCLC. (See "Pathobiology and staging of small cell carcinoma of the lung".)
Despite their heterogeneous clinical behavior, lung NETs share certain morphologic and biochemical characteristics. These include:
●The capacity to synthesize neuropeptides
●The presence of submicroscopic cytoplasmic dense-core (neuroendocrine) granules, which can be visualized by electron microscopy
World Health Organization classification — The classification of lung NETs has been the subject of considerable controversy, and there are multiple competing classification schemes [18]. In the 2015 World Health Organization (WHO) classification, the spectrum of lung NETs ranges from preinvasive diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) to NETs (carcinoid tumors) to the high-grade small cell (SCLC) and large cell NECs (table 1) [19]. (See "Pathology of lung malignancies".)
In contrast to gastrointestinal NETs, the terms "typical" and "atypical" are still used to describe low- versus intermediate-grade tumors arising in the lung, and the mitotic rate (rather than Ki-67 index) and the presence of necrosis are the primary determinants of grade. However, the terms well-differentiated NET, low grade (typical carcinoid), and well-differentiated NET, intermediate grade (atypical carcinoid), are preferred and will be used throughout this topic.
Histology — Typical low-grade lung NETs are composed of cytologically bland cells containing regular round to oval nuclei with finely dispersed chromatin and inconspicuous small nucleoli. The cells are usually polygonal in shape and are arranged in distinct organoid, trabecular, or insular growth patterns with a delicate vascular stroma (picture 1A-B). Mitotic figures are scarce (<2 per 10 high-powered fields [HPF]), and necrosis is not seen.
Peripheral low-grade NETs have a prominent spindle cell growth pattern, and up to 75 percent have foci of neuroendocrine cell hyperplasia (DIPNECH) and/or tumorlets (neuroendocrine cell foci smaller than 5 mm in diameter) in the adjacent lung parenchyma. Coexpression of these preinvasive neuroendocrine cell lesions does not seem to affect prognosis, although the number of series with long-term follow-up is limited [20,21]. (See 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia' below.)
Histologic criteria for intermediate-grade (atypical) NETs include the presence of NET morphology and either necrosis (picture 2A-B) or 2 to 10 mitoses per 10 HPF. Cytologic atypia is also characteristic, but it is insufficiently diagnostic in the absence of these features. However, at the individual patient level, none of these features enables a reliable prediction of clinical outcome [22]. Compared with low-grade NETs, intermediate-grade tumors present more often with hilar or mediastinal nodal metastases (20 to 60 versus 4 to 27 percent), and they have a higher recurrence rate. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Prognosis'.)
There is a category of patients with relatively well-differentiated tumors that have higher mitotic rate than 10 per 10 HPF. These cancers are akin to well-differentiated G3 gastrointestinal NETs, and are clinically and biologically distinct from large cell or small cell NEC. These tumors are not adequately recognized in the current WHO classification [23-25]. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade well-differentiated tumors'.)
A more detailed discussion of the pathology of lung NETs is presented separately. (See "Pathology of lung malignancies", section on 'Well-differentiated NETs'.)
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia — DIPNECH is a generalized proliferation of pulmonary neuroendocrine cells that may be confined to the mucosa of the airways, invade locally to form "tumorlets," or develop into invasive NETs (carcinoid tumors). Although idiopathic by definition, DIPNECH may be a consequence of unrecognized pulmonary injury, which also causes the mild inflammatory and fibrotic airway changes that often accompany this diagnosis. However, it is also possible that these changes are secondary to a local effect of amines and peptides released by the proliferating neuroendocrine cells [26-28].
Histologically, the cells are round to oval or spindle shaped and have a moderate amount of eosinophilic cytoplasm with round to oval nuclei that have a salt-and-pepper chromatin pattern. The proliferating neuroendocrine cells may remain confined to the mucosa as small groups or a monolayer, may form aggregates that protrude into the lumen as nodular or papillary growths, or may invade across the basal lamina to form tumorlets. There is generally a close association with obliterative bronchiolar fibrosis. Tumorlets are poorly defined, with irregular infiltrative margins and a conspicuously fibrotic stroma; they are intimately related to an airway and are ≤5 mm in diameter (figure 1) [28]. Larger lesions are defined as well-differentiated NETs. The full range of neuroendocrine markers is almost always expressed in DIPNECH. (See 'Immunohistochemistry' below.)
Due to the frequent presence of neuroendocrine tumorlets and hyperplasia in the background of resected peripheral well-differentiated lung NETs, DIPNECH is considered by the WHO to be a preinvasive lesion and a likely precursor to pulmonary NETs. At diagnosis, approximately one-half of patients with DIPNECH have a synchronous well-differentiated NET [20,26,27]. It is unknown what proportion of patients with DIPNECH will eventually develop invasive NETs, but it is probably the minority [28]. Most of the NETs that develop in this context are low grade (typical), but occasional intermediate-grade (atypical) NETs with more aggressive behavior are described [20,26-28]. DIPNECH is not associated with an increased incidence of small cell NEC of the lung.
The clinical presentation is discussed below. (See 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia' below.)
Immunohistochemistry — Immunohistochemical identification of secreted and cytoplasmic products such as synaptophysin, neuron-specific enolase, and chromogranin can confirm neuroendocrine differentiation [29]. Approximately 50 percent of lung NETs stain positive for thyroid transcription factor 1 (TTF1), although the staining is often weak and focal [30].
CLINICAL FEATURES
Well-differentiated neuroendocrine tumors
Presenting signs and symptoms — The majority of tumors arise in the proximal airways, and many are symptomatic from an obstructing tumor mass or bleeding due to hypervascularity [8]. Patients may have a cough or wheeze, hemoptysis, chest pain, or recurrent pneumonia in the same pulmonary segment or lobe due to bronchial obstruction. Due to misdiagnosis, the diagnosis of a lung neuroendocrine tumor (NET) is often delayed, and patients may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed. (See 'Disorders with similar clinical manifestations' below.)
On chest radiograph, most tumors appear as round or ovoid opacities that range in size from 2 to 5 cm and may be associated with a hilar or perihilar mass (image 1) [31-33]. If a central tumor results in bronchial obstruction, atelectasis and mucoid impaction may be visible radiographically. Cavitation is rare. Pleural effusions are unusual but may occur with postobstructive pneumonia.
Approximately one-fourth of cases present in the periphery as an asymptomatic solitary pulmonary nodule (image 2 and picture 3). These tumors are frequently discovered on a routine chest radiograph, most commonly as a solitary pulmonary nodule. (See "Diagnostic evaluation of the incidental pulmonary nodule".)
The differential diagnosis of the radiographic presentation is discussed below. (See 'Disorders with similar radiographic manifestations' below.)
Clinical syndromes related to peptide production — Lung NETs are thought to arise from a specialized bronchial cell (the Kulchitsky cell), which belongs to the diffuse system of neuroendocrine cells.
Carcinoid syndrome and carcinoid crisis — Carcinoid syndrome is caused by systemic release of vasoactive substances such as serotonin and other bioactive amines (table 2). Acute symptoms include cutaneous flushing, diarrhea, and bronchospasm; long-term sequelae of prolonged elevated hormone levels include venous telangiectasias, valvular heart disease, and fibrosis in the retroperitoneum and other sites. (See "Clinical features of carcinoid syndrome" and "Carcinoid heart disease", section on 'Pathologic findings'.)
Lung NETs produce lesser quantities of serotonin than do midgut NETs (table 3), accounting for a much lower rate of carcinoid syndrome compared with other primary sites, particularly the small bowel [29]. Among patients with localized disease (the vast majority of cases of typical lung NET), carcinoid syndrome is encountered uncommonly and most often with tumors of large size (>5 cm) [34]. Although it is encountered more often in patients with liver metastases, carcinoid syndrome is uncommon overall, even in patients with disseminated disease. As an example, in a population-based series derived from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, 3002 of the 9512 patients with NETs had origin in the lung or other respiratory organs; 229 (8 percent) had carcinoid syndrome at the time of initial diagnosis (compared with 31 percent of those with a small bowel primary) [35]. The frequency of carcinoid syndrome among those with localized tumors was 83 of 1044 (8 percent); among those with regional disease, it was also 8 percent (19 of 239), and among those with distant metastases, it was 15 percent (30 of 196). In contrast, among patients with small bowel primary NETs, the rates of carcinoid syndrome at diagnosis for patients with localized, regional, and distant disease were 19, 37, and 56 percent, respectively.
When carcinoid syndrome occurs in the setting of a lung NET, symptoms may be atypical, with episodes of flushing and related manifestations that are particularly prolonged and/or severe, and accompanied by other symptoms. In some cases of atypical carcinoid syndrome, blood serotonin or urine 5-hydroxyindoleacetic acid (5-HIAA) levels are normal. (See "Clinical features of carcinoid syndrome", section on 'Lung NET variant syndrome'.)
In contrast to other NETs (particularly in the setting of extensive liver metastases), the risk of carcinoid crisis with lung NETs is very low and prophylactic administration of octreotide prior to tumor manipulation (biopsy or resection) is not indicated. Nevertheless, all clinicians caring for these patients should be aware of the potential for carcinoid crisis with manipulation of an actively secreting tumor and the life-saving benefits of octreotide in this setting. (See "Treatment of the carcinoid syndrome", section on 'Carcinoid crisis: prevention and management'.)
Cushing's syndrome — Approximately 1 to 2 percent of lung NETs (both typical and atypical tumors) are associated with Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (ACTH) [36-39]. Lung NET is the most common cause of ectopic ACTH production.
Among patients with lung NETs, symptoms of Cushing's syndrome can be the initial reason for seeking medical attention. The onset is usually acute, and hypokalemia is often present. (See "Epidemiology and clinical manifestations of Cushing syndrome".)
At least some data suggest that ACTH-producing lung NETs behave more aggressively than do hormonally quiescent tumors [40,41]. However, others conclude that outcomes are not worse as long as patients undergo a complete anatomic resection that includes complete mediastinal lymphadenectomy [42].
Recommended measurements if ectopic Cushing's syndrome is suspected include serum cortisol, 24-hour urine-free cortisol, and ACTH [43].
Acromegaly — Acromegaly from ectopic production of growth hormone-releasing hormone (GHRH) or insulin-like growth factor 1 (IGF-1) [44] is a rare manifestation of lung NETs [45-51]. However, lung NETs are the most common cause of extrapituitary GHRH secretion. (See 'Disorders with similar clinical manifestations' below and "Diagnosis of acromegaly", section on 'Other studies'.)
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia — There are two major presentations of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Most symptomatic patients present with a long history of cough, breathlessness, and wheezing, often misdiagnosed as asthma [52]. In two series totaling 30 patients with DIPNECH, symptoms were present for an average of 8.6 and 15.8 years before diagnosis, respectively [26,53,54]. The majority are middle-aged females who are nonsmokers [26,27,53,54]. Other cases are identified incidentally, typically during high-resolution computed tomography performed for other conditions or at the time of histologic review of a resected lung NET.
Most patients with DIPNECH have respiratory symptoms, evidence of airflow obstruction on pulmonary function tests, air trapping on chest imaging, and evidence of constrictive obliterative bronchiolitis [53,55,56]. Radiographic imaging shows nodular bronchial wall thickening caused by intraluminal protrusion of proliferating cells; bilateral pulmonary nodules; ground-glass attenuation; and bronchiectasis [27,53,54]. The term "DIPNECH syndrome" has been proposed to distinguish this clinical pattern of disease presentation with prominent respiratory complaints from asymptomatic patients with well-differentiated NETs who have prominent neuroendocrine cell hyperplasia in the surgical specimen [56].
The pulmonary nodules are all assumed to be well-differentiated lung NETs. Most express somatostatin receptors, as reflected by uptake on gallium Ga-68 DOTATATE positron emission tomography scanning [54]. Tumor markers (eg, chromogranin A) may also be elevated [54]. (See 'Somatostatin receptor-based imaging techniques' below and 'Tumor markers' below.)
DIAGNOSTIC AND STAGING WORKUP — Lung neuroendocrine tumors (NETs) may present in a manner that is similar to other primary lung malignancies, with cough or hemoptysis; however, they are increasingly diagnosed incidentally as asymptomatic peripheral pulmonary nodules. Computed tomography (CT) is the most useful imaging procedure, and the diagnosis is generally confirmed either by bronchoscopic biopsy (for central lesions) or by transthoracic needle biopsy (for peripheral lesions). Approximately three-fourths of lung NETs are centrally located and amenable to bronchoscopic biopsy. (See "Diagnostic evaluation of the incidental pulmonary nodule" and "Overview of the initial treatment and prognosis of lung cancer" and "Diagnosis of carcinoid syndrome and tumor localization" and 'Bronchoscopy and biopsy' below.)
Staging system — Lung NETs are staged using the same tumor, node, metastasis (TNM) classification from the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) that is used for bronchogenic lung carcinomas. The most recent (eighth edition, 2017) version is outlined in the table (table 4) [57]. Low-grade (typical) lung NETs most commonly present as stage I tumors, while more than one-half of intermediate-grade (atypical) tumors are stage II (bronchopulmonary nodal involvement) or III (mediastinal nodal involvement) at presentation.
Cross-sectional imaging — Compared with a chest radiograph, CT provides better resolution of tumor extent, tumor location, and the presence or absence of mediastinal adenopathy. CT gives excellent morphologic characterization of peripheral and especially centrally located lung NETs, which may be purely intraluminal (polypoid configuration), exclusively extraluminal, or more frequently, a mixture of intraluminal and extraluminal components (an "iceberg" lesion). CT may also be helpful for differentiating tumor from postobstructive atelectasis or bronchial obstruction-related mucoid impaction.
Tumors may have lobulated or irregular borders and punctate or eccentric calcification [58,59]. Contrast-enhanced CT scans frequently show marked enhancement due to the vascular nature of the tumors.
Between 5 and 20 percent of typical (low-grade) lung NETs are associated with hilar or mediastinal adenopathy, but lymphadenopathy may represent a local inflammatory reaction. The sensitivity of CT for detecting metastatic hilar or mediastinal nodes is high, but specificity is as low as 45 percent [60]. In one study, the positive predictive value of CT-detected lymphadenopathy as an indication of nodal metastases was only 20 percent [61].
As noted above, for patients with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), radiographic imaging typically shows nodular bronchial wall thickening caused by intraluminal protrusion of proliferating cells; bilateral pulmonary nodules; ground-glass attenuation; and bronchiectasis [27,53,54]. (See 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia' above.)
Other imaging procedures — A number of other imaging procedures have a more limited role in patients suspected of having a lung NET but are useful in selected patients:
Somatostatin receptor-based imaging techniques — Approximately 80 percent of low-grade (typical) lung NETs and 60 percent of intermediate-grade (atypical) lung NETs express somatostatin receptors by immunohistochemistry and may be imaged using gallium Ga-68 DOTATATE (Ga-68 DOTATATE), gallium Ga-68 DOTATOC (Ga-68 DOTATOC), or copper Cu-64 DOTATATE (Cu-64 DOTATATE) positron emission tomography (PET) scan (image 3), or somatostatin receptor scintigraphies (OctreoScan). One benefit of somatostatin receptor imaging over CT/magnetic resonance imaging (MRI) is that it can image the whole body and identify metastatic disease, particularly outside the lung [61]. It is important to note that non-neuroendocrine lesions can sometimes express somatostatin receptors, albeit at low levels. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques' and "Neuroendocrine neoplasms of unknown primary site", section on 'Initial workup'.)
Clinical utility — Baseline imaging using one of the somatostatin receptor-based imaging techniques is generally recommended in patients with advanced NETs, both as an adjunct to routine cross-sectional imaging and because evidence of somatostatin receptor expression (based on a positive scan) can be predictive of a clinical response to therapy with somatostatin analogs, such as octreotide and lanreotide [62], as well as peptide receptor radioligand therapy. For most patients we prefer PET-based imaging rather than OctreoScan because of its greater sensitivity. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)
Whether these studies are indicated in patients with an apparently localized lung NET is less certain. We suggest not performing somatostatin receptor-based imaging for patients with clinical stage I typical lung NETs given the rarity of extrathoracic metastatic disease in this setting (5 percent in one series of 525 lung NETs [1]) but consider use of Ga-68 DOTATATE PET, Ga-68 DOTATOC PET, or Cu-64 DOTATATE PET for those with large (>3 cm) and/or clinically node-positive NETs. Where available, we prefer PET-based imaging over OctreoScan because of greater sensitivity. A positive scan may indicate a higher likelihood of benefit from somatostatin analog treatment and peptide receptor radioligand therapy. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Somatostatin analogs' and "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Lutetium Lu-177 dotatate'.)
There is no consensus on this issue and guidelines differ:
●Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [63] suggest "considering" DOTATATE PET in patients with a lung NET.
●Updated guidelines for diagnosis and management of patients with lung NETs from the Commonwealth Neuroendocrine Tumour Research Collaboration (CommNETs) and the North American Neuroendocrine Tumor Society (NANETS) state that DOTATATE PET can be used in patients to detect metastatic disease, but that the clinical utility in small primary lung NETs without evidence of metastatic disease on contrast-enhanced cross-sectional imaging is limited [64].
●European Society for Medical Oncology (ESMO) guidelines suggest somatostatin receptor-based imaging for all patients with a lung NET [65].
Fluorodeoxyglucose positron emission tomography scans — Fluorodeoxyglucose (FDG)-PET scans are usually positive in patients with intermediate-grade (atypical) lung NETs (mean standardized uptake value [SUV] approximately 8) [31] and may be weakly positive in low-grade (typical) tumors. However, the added benefit of FDG-PET beyond conventional CT scan in the staging of patients with a lung NET is uncertain [11,66-68]. (See "Diagnostic evaluation of the incidental pulmonary nodule".)
Liver imaging — We restrict staging CT or MRI of the abdomen to those patients with a large (>3 cm) and/or node-positive lung NET. Small low-grade (typical) lung NETs only rarely metastasize. While intermediate-grade (atypical) NETs have a greater tendency to metastasize, the diagnosis is almost never made preoperatively. In patients with evidence of mediastinal involvement, a relatively high mitotic rate, or evidence of carcinoid syndrome, liver imaging is appropriate.
However, guidelines from expert groups differ. As an example, updated CommNETs/NANETS guidelines recommend liver imaging for all patients with a lung NET [64], as do guidelines from the NCCN [69] and ESMO [65].
The most common metastatic site for all NETs, including those arising in the lung, is the liver. Cross-sectional imaging (CT, MRI) is typically performed to evaluate for liver metastases. CT scans should be performed both before and after the administration of intravenous contrast with arterial and portal-venous phases (ie, multiphasic contrast-enhanced CT) because NET liver metastases are often hypervascular, becoming isodense relative to the liver parenchyma after contrast administration. As a result of its greater sensitivity for liver metastases, some physicians prefer MRI over CT for assessing the status of the liver in patients with NETs. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Cross-sectional imaging'.)
Tumor markers — Serum levels of chromogranin A (CgA) are lower with lung NETs than they are with NETs at other sites, and they overlap with those seen in patients who have nonmalignant conditions associated with increased CgA levels (table 5). Thus, this marker is generally of limited utility for patients with localized tumors, and we generally do not assay CgA at baseline. Even in the setting of metastatic disease, the utility of CgA as an adjunct to radiographic assessment is questionable [60,70]. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Role of nonhormonal tumor markers in clinical practice' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Biochemical monitoring'.)
Bronchoscopy and biopsy — Approximately three-fourths of lung NETs are centrally located and amenable to biopsy at the time of bronchoscopy. The bronchoscopic appearance is a typically pink to red vascular mass with intact overlying bronchial epithelium. NETs are generally attached to the bronchus by a broad base but can be polypoid and create a ball-valve effect (picture 4).
The bronchoscopic appearance may be sufficiently characteristic for an experienced bronchoscopist to make a presumptive diagnosis, although it is preferable that brushings or biopsy be performed to confirm the diagnosis.
Cytologic study of bronchial brushings is more sensitive than sputum cytology, but the diagnostic yield of brushing is low overall (4 to 63 percent) [71-73]. The intact bronchial mucosa overlying the NET prevents cells from exfoliating. Furthermore, the cells may be too few in number or benign in cytologic appearance for an accurate diagnosis.
Lung NETs are vascular, and there has been concern for bleeding in the past, particularly after flexible bronchoscopy with biopsy [74]. However, in many contemporary series, the incidence of serious bleeding complications during bronchoscopic biopsy is very low [5,60,75]. The administration of a diluted epinephrine solution before and after biopsy of a suspected endobronchial NET may have reduced the risk of severe bleeding. (See "Flexible bronchoscopy in adults: Overview".)
Peripheral pulmonary nodules — For peripheral NETs that present as solitary pulmonary nodules, CT-guided transthoracic needle aspiration is often the initial diagnostic maneuver. The primary risk with this approach is pneumothorax. However, sometimes patients with a solitary pulmonary nodule proceed directly to surgical excision if the likelihood of malignancy is high. (See "Diagnostic evaluation of the incidental pulmonary nodule".)
DIFFERENTIAL DIAGNOSIS
Disorders with similar clinical manifestations — The differential diagnosis of a patient with symptoms of bronchial obstruction, hemoptysis, or wheezing includes (see "Asthma in adolescents and adults: Evaluation and diagnosis" and "Clinical manifestations of lung cancer"):
●Obstructing bronchial carcinoma
●Endobronchial metastasis
●Reactive airway disease, such as asthma
●Aspirated foreign body
For the rare patient who presents with carcinoid syndrome (cutaneous flushing, diarrhea, with or without bronchospasm), the differential diagnosis includes other causes of flushing, diarrhea, and reactive airways disease. In addition, neuroendocrine tumors (NETs) arising at other sites, including the gastrointestinal tract (carcinoid syndrome is most common in patients with liver metastases from a small bowel NET) and thymus (which are only rarely associated with carcinoid syndrome), should be considered in the differential diagnosis. (See "Approach to flushing in adults" and "Approach to the adult with chronic diarrhea in resource-abundant settings" and "Diagnosis of carcinoid syndrome and tumor localization" and "Thymic neuroendocrine (carcinoid) tumors".)
The differential diagnosis of Cushing's syndrome includes exogenous administration of glucocorticoids, primary adrenal disease (adenoma or carcinoma), and a pituitary or non-pituitary adrenocorticotrophic hormone (ACTH)-secreting tumors (which may be benign or malignant). The diagnosis of a NET-related Cushing's syndrome may be difficult because the production of ACTH by lung NETs can be suppressed by dexamethasone, unlike other tumors that produce ectopic ACTH [76]. (See "Establishing the cause of Cushing syndrome" and "Dexamethasone suppression tests", section on 'Low-dose DSTs'.)
The majority of lung NETs in patients who present with Cushing's syndrome are small (<2 cm) and may be radiographically occult, making it even more difficult to establish the correct diagnosis [42,77]. High-resolution computed tomography with 1 mm sections may be particularly helpful in such cases to identify the primary tumor (image 1). Another option is somatostatin receptor scintigraphy [78]. (See 'Other imaging procedures' above.)
Disorders with similar radiographic manifestations — Most lung NETs appear as round or ovoid opacities that may be associated with a hilar or perihilar mass. The differential diagnosis includes:
●Primary lung carcinoma, both small cell and non-small cell
●Metastatic tumor involvement
●Other benign causes of a solitary pulmonary nodule (eg, infectious granuloma, hamartomas, and dirofilariasis) or multiple pulmonary nodules (eg, pulmonary arteriovenous malformations, pneumoconioses, abscesses, septic emboli, and infection with fungi, flukes, and mycobacteria)
Although the findings on cross-sectional imaging may favor one diagnosis over another, there are no pathognomonic radiographic findings of lung NETs, and tissue sampling is needed to definitively establish the diagnosis. (See 'Bronchoscopy and biopsy' above and "Diagnostic evaluation of the incidental pulmonary nodule".)
SUMMARY AND RECOMMENDATIONS — Lung neuroendocrine tumors (NETs; bronchial carcinoids) are malignant neoplasms that are characterized by neuroendocrine differentiation and indolent clinical behavior.
●Epidemiology – Lung NETs account for approximately 1 to 2 percent of all lung malignancies in adults and roughly 20 to 30 percent of all NETs. Bronchial NETs are the most common primary lung neoplasm in children. Nearly all are sporadic. (See 'Epidemiology and risk factors' above.)
●Classification and histology
•Histologically, bronchial NETs are part of a spectrum of NETs arising in the lung that are characterized by strikingly different biologic behavior; low-grade (typical) lung NETs, which account for the majority of tumors, are well-differentiated, slowly growing neoplasms that rarely metastasize to extrathoracic structures.
At the other end of the spectrum are the high-grade (poorly differentiated) neuroendocrine carcinomas (NECs), as typified by small cell lung cancer (SCLC) and large cell NEC, with aggressive behavior, rapid tumor growth, and early distant dissemination. The biologic behavior of intermediate-grade (atypical) lung NETs is intermediate between low-grade (typical) NETs and SCLC/large cell NEC. (See 'Classification, histology, and histochemistry' above.)
•Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a generalized proliferation of pulmonary neuroendocrine cells that may be confined to the mucosa of the airways, invade locally to form "tumorlets," or develop into invasive NETs (carcinoid tumors). (See 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia' above.)
●Clinical features
•Most patients have a centrally located tumor and are symptomatic from the tumor mass, with coughing, hemoptysis, wheezing, or recurrent postobstructive pneumonia. Peripheral lesions present most often as an asymptomatic solitary pulmonary nodule. (See 'Clinical features' above.)
•Rarely, patients present with symptoms related to hormone production by the tumor, including carcinoid syndrome (which is uncommon overall), Cushing's syndrome, and acromegaly. (See 'Clinical syndromes related to peptide production' above.)
●Diagnostic and staging workup
•CT of the chest is the most useful imaging procedure, and the diagnosis is generally confirmed either by bronchoscopic biopsy (for central lesions) or by transthoracic needle biopsy (for peripheral lesions). (See 'Diagnostic and staging workup' above.)
•Additional preoperative staging studies, such as CT or magnetic resonance imaging of the abdomen, and somatostatin receptor-based diagnostic imaging, are not indicated routinely for stage I typical lung NETs. We would consider somatostatin receptor-based imaging and abdominal imaging in a patient with a large (>3 cm) primary tumor and/or clinical evidence of nodal metastases. (See 'Other imaging procedures' above.)
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