Neuroendocrine cells are derived from primitive pluripotent cells and are characterized by production of neurotransmitters and lack of axons and synapses. The tumors they produce in various organs are classified into 3 groups, anterior, middle and posterior, according to their embryonic origin in the gastrointestinal tract. These tumors may arise not only from the lung but from various regions of the digestive system.1,2 Pulmonary neuroendocrine tumors (PNT) represent approximately 25%–30% of primitive lung cancers (LC). Of these, 80% are anaplastic small cell lung cancers (SCLC), 12% are large cell neuroendocrine carcinomas (LCNEC) and the remaining 8% are typical carcinoid (TC) and atypical carcinoid (AC) tumors, the latter being the most uncommon.3–5 As discussed below, the prognosis for these tumors is very variable and although some, such as TCs, are associated with good life expectancy, they should not be described as “benign” as they all have metastatic potential.3 At present, these tumors are classified according to their grade of malignancy as: low grade (TC), intermediate grade (AC) and high grade (LCNEC and SCLC) (Table 1). The latest World Health Organization lung tumor classification (2004) also includes other entities, such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets.6–8 The latter are accumulations of neuroendocrine cells generally found in the airways that invade the basement membrane. Their appearance is similar to that of carcinoid tumors but they measure less than 0.5cm. They are usually found by chance and do not cause symptoms.7 Although the significance and natural history of DIPNECHs has not been well determined, they are considered by many as the earliest manifestation of neuroendocrine disease and classed as precancerous lesions.8 They are often associated with chronic bronchopulmonary lesions, such as bronchiectasis and fibrosis, so in this setting they are considered reactive lesions. They rarely occur in previously normal lungs, and if they do, they may develop into carcinoid tumors.3

With regard to the histological classification of these tumors, some criteria for the definition of the various types are shown in Table 1. Surgical specimens often have to be examined to determine diagnosis, particularly in the case of LCNEC. When only small biopsy specimens from fiberoptic bronchoscopy are available, it may be very difficult to establish a precise diagnosis. In addition to the mitotic index, the presence or absence of necrosis and the structure of the tumor, the immunohistochemical detection of various neuroendocrine markers, such as chromogranin A, synaptophysin or CD56 and other molecular changes may be an aid to identification.3,7,9 LCNEC does not always display all the features that characterize this lineage; therefore, in terms of the overall group of large cell carcinomas, the possible spectrum of neuroendocrine differentiation varies widely6,7 (Table 2). Moreover, the Ki-67 proliferation marker has recently been identified as possibly useful for distinguishing between low and high grade tumors, particularly when only small biopsies or cytological specimens are available.3,8 Despite the availability of these techniques, differential diagnosis of the disease is often complicated and careful evaluation by experienced pathologists is required.8 Recent studies suggest that as LCNEC is relatively rare and difficult to diagnose, it may be underdiagnosed, and although it frequently resembles conventional non-small cell lung cancer (NSCLC) both clinically and morphologically, its biological characteristics and prognosis are different, and more importantly, its sensitivity to various chemotherapy (CT) regimens appears to be closer to that of SCLC.9

Low grade PNTs appear at an earlier age (mean 40–50 years) than most LCs and are not clearly associated with tobacco smoking or gender, while high grade PNTs are mainly diagnosed in men over 60 years of age and are closely related with smoking. Carcinoid tumors are central in 75% of the cases and initial symptoms are cough, hemoptysis, wheezing, recurrent pneumonia or chest pain.2,5 Paraneoplastic syndromes are uncommon: carcinoid syndrome, considered characteristic, is more common in the gastrointestinal presentation of the disease and only appears in 1%–3% of tumors of pulmonary origin. Others, including Cushing's syndrome (1%–2% of cases), acromegaly, etc., are even less common. However, when a thorough endocrine evaluation is performed, hypersecretion may be found in up to 15% of patients, the majority of whom do not have clinical symptoms.5

Peripheral pulmonary carcinoid tumors are usually detected by chance. The biological behavior of LCNEC and SCLC is more aggressive, so they are more likely to produce metastasis and are often advanced when diagnosed. SCLC commonly occurs with paraneoplastic syndromes of various types (endocrine, neuromuscular, hematological, etc.), the most common of which is insufficient antidiuretic hormone secretion that may occur in up to 40% of cases.10

Like other more common LCs, the starting point for suspected diagnosis is generally an abnormal image on chest X-ray. Other imaging tests to be performed for defining the anatomical characteristics of the tumor and possible distant metastases, including chest computed tomography (CT), magnetic resonance, scintigraphy, etc., are also similar, so the guidelines for the diagnosis and staging of LC in general11–13 are also applicable in these patients. Since most tumors are central, a biopsy specimen is usually obtained by fiberoptic bronchoscopy. If the tumor is peripheral, transthoracic biopsy or aspiration may be the first option, although the small size of cytological specimens and biopsies can be a limiting factor for precise diagnosis, as has been mentioned previously. Thus, after the specimen has been examined, a larger specimen may have to be obtained in a second intervention.

For staging, carcinoid tumors show some specific biological features that limit the efficacy of tests such as positron emission tomography (PET). These slow-growing tumors have low glucose uptake, so 18F-fluordeoxyglucose PET is of little use, particularly in TCs.2 However, new radiotracers, such as 111In-octreotide or 68Ga-DOTATATE, have been developed that, given their special affinity for the somatostatin receptors often present in low grade tumors, are of great utility in diagnosis and staging.5 The usefulness of both 18F-fluordeoxyglucose and 68Ga-DOTATATE was recently evaluated with PET/CT in a group of neuroendocrine tumors of different grades. The authors found an inverse infinity for both radiotracers for low and high grade tumors. High grade tumors showed great avidity for 18F-fluordeoxyglucose and low avidity for 68Ga-DOTATATE, while the opposite was true in low grade tumors.1468Ga-DOTATATE is not yet available in many centers, but it is currently thought to be of great value in planning interventions and for detecting recurrence of low grade carcinoid tumors.

As discussed below, the most common therapeutic option for low grade PNTs is surgery, but the rapid dissemination of high grade tumors often rules out this approach. However, classification using the tumor, node, metastasis (TNM) system is useful for both groups. The latest edition of the TNM classification is not only more accurate, but has also shown greater universality and its prognostic value in both SCLC and carcinoid tumors has been confirmed.15–18

As mentioned above, the PNT spectrum encompasses a range of tumors with important pathological, biological and clinical differences. Consequently, life expectancy also differs greatly. Most carcinoid tumors are diagnosed in TNM stages I and II, are mostly operable, and 5-year survival is over 90%. In contrast, most LCNECs and SCLCs are diagnosed in advanced stages, are candidates only for treatment with CT and radiotherapy, and long-term survival is very low (Table 3).2,9,19

The Spanish Neuroendocrine Tumor Group (EMETNE) analyzed survival data from a large series of resected carcinoid tumors, finding that the histological subtype, the presence or absence of mediastinal node involvement and distant metastases were the factors that most influenced prognosis.20,21 Other authors studying the AC subgroup found that a high mitotic index, size of primary tumor >3.5cm and female sex were independent indicators for poor prognosis.22

Given the difficulties encountered in the pathological diagnosis of LCNECs and their rarity, few studies analyzing prognostic factors have been published, although TNM staging appears to be of value in this respect.5,9 Although survival among resected patients varies widely depending on staging, it seems that, if staging is similar, patients with LCNEC have poorer life expectancy that those with NSCLC.9 Lastly, in the case of SCLCs, many studies on prognostic indicators have been available for some time.23 In this review, only the expediency of using the new TNM classification in this entity is mentioned, although the simple and traditional subdivision into two groups, limited or extended disease (limited to one hemithorax or extended beyond that), still has practical value.

If SCLCs are excluded, PNTs represent a small proportion of primitive lung cancers and the various types show wide biological heterogeneity. This explains the insufficient number of clinical trials comparing large, homogeneous patient groups, and the consequent low grade of scientific evidence for many of the treatment regimens discussed. With the exception of SCLCs, there are few randomized studies supporting the currently used regimens. This does not mean that there are no firm indications backed up by experience, such as resection of most TNM stage I and II carcinoid tumors, given the excellent survival results of this procedure. The treatment of each of the various PNT groups is discussed individually below.

This paper did not receive funding from any source.

There are no conflicts of interests associated with this paper.