Pulmonary neuroendocrine/carcinoid tumors

A review article

Authors


Abstract

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well-differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors. Cancer 2009. © 2009 American Cancer Society.

Well-differentiated neuroendocrine, or carcinoid, tumors are a unique class of malignancies capable of producing hormones identical to those from the nervous system. Although the first carcinoid tumor described was in the ileum, neuroendocrine malignancies are a family of malignancies found throughout the body. Tumors of the bronchial tree in particular account for approximately 25% of all well-differentiated neuroendocrine tumors (Table 1).1-3 However, compared with other malignancies of the bronchoalveolar tree, these well-differentiated neuroendocrine tumors are rare, accounting for only 1% of all lung cancers.3

Table 1. Carcinoid Incidence by Location
 Location% of Patients
  1. Adapted from Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934-959.

ForegutThymus0.4%
Lung, bronchi, trachea29.8%
Stomach4.9%
MidgutSmall intestine30.4%
Gallbladder, pancreas1%
HindgutAppendix5.1%
Colon, excluding appendix9.2%
Rectum14.5%

The pathologic spectrum of neuroendocrine malignancies ranges from low-grade carcinoid to aggressive small cell lung cancer. The low-grade and intermediate-grade neuroendocrine malignancies, also known as typical and atypical carcinoid, will be the focus of this review. The distinct features of this malignancy include its pathologic characteristics, clinical behavior, epidemiology, prognosis, and treatment.

Pathology

The neuroendocrine cell system is divided into cell types that form glands (ie, adenohypophysis, parathyroid, etc.) and diffusely distributed cell types. This second group is collectively known as the diffuse neuroendocrine system (DNES), and its representatives are found in the lung, gastrointestinal tract, skin, thyroid, thymus, pancreas, biliary, and urogenital tracts.4 Neuroendocrine tumors of the lung arise from bronchial mucosal cells known as enterochromaffin cells or Kulchitsky cells, which are part of the DNES. These specialized cells are capable of producing bioactive amines, such as adrenocorticotropic hormone (ACTH) and serotonin, which cause the carcinoid syndrome if released into the bloodstream by the tumor.5, 6

A very rare disorder known as diffuse idiopathic neuroendocrine cell hyperplasia is considered a precursor lesion for tumorlets (typical carcinoid tumors that measure ≤5 mm).7 It happens most commonly as a reactive hyperplasia secondary to airway fibrosis and/or inflammation8 and occurs at any age, being more common between the fifth and sixth decades. By definition, tumorlets are comprised of increased numbers of individual cells, small groups of cells, or nodular aggregates of cells confined to the bronchial/bronchiolar epithelium (with larger lesions bulging into the lumen but not breaking the subepithelial basement membrane).9 Once they break through the basement membrane, they give rise to tumorlets (≤5 mm) and then carcinoid tumors (>5 mm).

The classification of neuroendocrine malignancies has been an evolving process. These classifications date back to 1972, when atypical carcinoid was initially defined according to histologic criteria, including the number of mitoses per high–power field, the presence of necrosis, increased cellularity with disorganization, nuclear pleomorphism, hyperchromatism, and an abnormal nuclear–to–cytoplasmic ratio.10, 11 In 1991, Travis et al proposed 4 categories of neuroendocrine lung tumors: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell neuroendocrine carcinoma (SCNEC).12 Key histologic differences between the different grades of neuroendocrine tumors are presented in Table 2 and Figures 1 and 2.

Table 2. Histologic Criteria for Pulmonary Neuroendocrine Tumors
 Typical CarcinoidAtypical CarcinoidLCNECSCNEC
  • LCNEC indicates large cell neuroendocrine carcinoma; SCNEC, small cell neuroendocrine carcinoma; HPF, high-power fields; +, present; N/C, nuclear/cytoplasmic.

  • *

    Azzopardi effect: basophilic DNA (from tumor cells) surrounding blood vessels.

  • Modified from Travis WD, Gal AA, Colby TV, Klimstra DS, Falk R, Koss MN. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol. 1998;29:272-279.42

Mitoses<2/10HPF2-10/10 HPF≥11/10 HPF; Median, 70/10 HPF≥11/10 HPF Median, 80/10 HPF
Necrosis+ (punctate)+ (large zones)+ (large zones)
Nuclear pleomorphism, hyperchromatismUncommonSometimesFrequentSmall cells (pleomorphic cells are rare unless mixed SCNEC/LCNEC)
N/C ratioModerateModerateLowHigh
NucleoliOccasionalCommonVery commonAbsent or inconspicuous
Nuclear chromatinFinely granularFinely granularUsually vesicular, may be finely granularFinely granular
ShapeRound, oval, spindledRound, oval, spindledRound, oval, polygonalRound, oval, spindled
Nuclear smearNoNoUncommonCommon
Azzopardi effect*NoNoUncommonOccasional
Figure 1.

Classic carcinoid tumor (original magnification × 40) demonstrating the typical organoid (zellballen), pattern with no evidence of mitotic activity or necrosis is shown. Notice the finely granular nuclear chromatin and occasional nucleoli.

Figure 2.

Poorly differentiated neuroendocrine carcinoma of the lung (original magnification × 40), with increased mitotic activity (arrows) and moderate to marked pleomorphism with inconspicuous nucleoli, is shown. Extensive necrosis (not depicted) was found throughout this tumor.

The 2004 World Health Organization categorization of tumors with neuroendocrine features is likewise based on common microscopic, immunologic, and morphologic features identifiable by light microscopy. The classic carcinoids include low-grade TC and intermediate-grade AC. The high-grade malignancies include LCNEC and SCNEC.13, 14

An alternative classification for neuroendocrine tumors of the lung has been proposed by pathologists to clarify the nomenclature of these malignancies. Rather than typical versus atypical, the tumors are differentiated into grades. Grade 1 represents tumors formerly classified as TC, grade 2 represents AC or well-differentiated tumors, and grade 3 represents the poorly differentiated tumors. Grade 3 is further divided according to cell type: small cell or large cell. These grades allow for pathologic classification to correlate more closely with clinical outcomes.13

The molecular biology and cytogenetics of carcinoid (well-differentiated neuroendocrine) tumors are an area of ongoing study. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant genetic disorder associated with the tumors of multiple endocrine organs. Neuroendocrine tumors of the lung (carcinoid) have been described only rarely in this syndrome. Sporadic neuroendocrine/carcinoid tumors, however, have been associated with loss of heterozygosity at the MEN1 gene on chromosome 11q13.15, 16 Deletions of chromosome 11q were identified in 66% of AC and 47% of TC tumors in 1 study. In contrast, the 11q deletion was rarely identified in poorly differentiated lung neuroendocrine cancers (both small and large cell).17

Clinical

The clinical behavior of these tumors was historically believed to be benign but has been recognized as malignant over the past 20 years. Large population-based studies have been used to determine clinical behaviors and outcomes as related to cell type and differentiation and stage (Table 3).1, 18, 31, 33, 34

Table 3. Summary of Recent Studies
StudyNo. of PatientsMean Age, yLocation, %Histology, %Surgery, %Survival, %
CentralPeripheralTypicalAtypicalLobectomyPneumonectomy5-Year10-Year
  • NA indicates data not available.

  • *

    Radical resection indicates that the type of surgery was not specified in article.

Fink 2001181425268329010NANA8779
Cooper 2001317757.942NA64.96.4671245 (3-y survival)NA
Ducrocq 1998341394773.426.6100061.8592.488.3
Skulladitor 200230Typical, 105; atypical, 192Typical, 60; atypical, 64NANA3564Radical resection*: Typical, 41 Atypical, 3687 (typical) 44 (atypical)NA
Modlin 19971208450-56NANANANANANA76NA
Rea 2007332524577.322.7693155.249083

Epidemiology

Carcinoid tumors tend to occur at a younger age than other lung cancers, with the average age at the time of diagnosis ranging from 50 years to 56 years in various studies.1, 18, 19 In the case of bronchopulmonary carcinoid malignancies, there tends to be a female predominance, which is distinct from lung cancer in general; both nonsmall cell lung carcinoma and small cell lung carcinoma are more common in men.18, 19 Of interest, and in contrast to pulmonary carcinoid tumors, the presentation of carcinoid tumors at all sites is gender-neutral.19 Race has also been evaluated, but no significant trends were found for pulmonary disease.1

Tobacco use is always a consideration in bronchopulmonary tumors. In contrast to the more common LCNEC and SCNEC, smoking remains an uncertain variable in pulmonary carcinoid tumors. Although strongly linked to the incidence of small cell lung cancer, a poorly differentiated neuroendocrine malignancy, tobacco use appears to have no clear correlation in carcinoid tumors. In 1 study, smoking history was positive in 64% of patients with AC tumors, but was positive in only 33% in patients with TC tumors.18 The difference in the degree of differentiation between TC and AC tumors raises many questions. In particular, smoking may be linked to an increased incidence of less-differentiated tumors.

Presentation

Carcinoid tumors of the lung present in a manner that is similar to that of other pulmonary ailments. Central bronchial obstruction with obstructive pneumonia or atelectasis is 1 of the most common symptoms, particularly in AC tumors. Other common symptoms include cough, wheezing, and hemoptysis. It is interesting to note that wheezing does not necessarily connote carcinoid syndrome caused by the secretion of bioactive amines, but is more commonly due to central airway obstruction. Unlike their counterparts in the gut, classic carcinoid syndrome with flushing and diarrhea is rare and is generally associated with metastatic disease. In addition, up to 25% to 30% of patients are asymptomatic and carcinoid tumors are found incidentally or even postmortem.13, 18, 20

Imaging

Radiologic imaging remains an essential tool for the diagnosis and staging of nonsmall cell lung cancer, including pulmonary carcinoid tumors.

Computed tomography (CT) and positron emission tomography (PET) imaging may be used to identify and stage carcinoid tumors of the lung. Well-defined, centrally located tumors involving the airway with calcification, punctate or diffuse, are considered characteristic on CT scan.21 However, additional investigation and staging with fluorodeoxyglucose (FDG) -PET scanning remains controversial. Due to the lower metabolic activity of carcinoid tumors, FDG uptake in PET scanning often demonstrates low uptake (equivocal in comparison to mediastinal uptake) compared with high-grade nonsmall cell cancers. A prospective study by Erasmus et al suggested that PET scanning had a low sensitivity (14.2%) for identifying TC tumors due to low standard uptake value (SUV) (average, 2.3; values >2.5 are considered significant).22 However, this study was limited by its small size (7 patients). Kruger et al demonstrated similar findings; greater than half of their 13 patients had TC tumors with an SUV uptake <2.5.23 Subsequent studies have suggested a higher degree of sensitivity; in particular, detecting TC (sensitivity, 72.7%) and AC (sensitivity, 80%) tumors on PET based on relative SUV uptake (greater than mediastinal uptake visually is considered positive). Due to the relatively low uptake of glucose in these slow-growing malignant lesions, FDG-PET imaging is not ideal for carcinoid tumors.24 PET imaging using tracers other than glucose has been evaluated in pilot studies and may be more sensitive than 18F-labeled glucose.25

Somatostatin receptor scintigraphy, also known as octreotide scanning, has a role in addition to CT and PET imaging. The use of octreotide scanning has been investigated because of the presence of somatostatin receptors on tumor cells and because of the clinical utility of octreotide in controlling symptoms of carcinoid syndrome in patients with metastatic well-differentiated neuroendocrine tumors of the pancreas. More recently, the role of this imaging for bronchial carcinoids has been examined more closely. In bronchial carcinoids, octreotide scans appear to play a role that is complementary to CT for perioperative staging and follow-up evaluation for recurrent local or metastatic disease. A small series reported a sensitivity of 90% with a specificity of 83% in detecting both primary and metastatic bronchial carcinoids.26 There is also evidence to suggest that octreotide scans are useful in occult ACTH-secreting tumors, including those of bronchial origin.26-28

Staging

Location is an important factor in carcinoid tumors. It has implications for staging, in addition to the signs and symptoms noted at presentation. Staging of typical and atypical neuroendocrine malignancies follows the TNM guidelines as used for other nonsmall cell lung cancers. As with most malignancies, early stage disease is associated with a better prognosis. TC is most commonly identified as early stage localized disease (80%-90%); however, AC tends to be more aggressive and approximately 50% of tumors are stage I at the time of diagnosis1, 18, 29 (Table 4). Regional disease with spread to local lymph nodes occurs most frequently in AC tumors. Previous studies have cited a rate of lymph node spread of anywhere from 20% to 60% of cases.1, 18, 30 Distant metastases to other organs, including bone, adrenal glands, liver, and brain, are a relatively rare phenomenon in pulmonary carcinoid tumors.20 As expected, AC accounts for most of the cases of metastatic disease, with as many as 25% of patients developing distant disease, even years after initial diagnosis.13

Table 4. Incidence of Carcinoid by Stage
StageTypical Carcinoid, %Atypical Carcinoid, %
  1. Adapted from Fink G, Krelbaum T, Yellin A, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest. 2001;119:1647-1651.

I8743
II1029
III328
IV221

Central tumors are considered those associated with the cartilaginous airways, whereas peripheral tumors include those not associated with the airway. The most commonly reported location for pulmonary carcinoid tumors is the major bronchi; up to 68% of tumors are found in the mainstem and lobar bronchi. Only 10% to 20% of carcinoid tumors are in the lung periphery and are often identified as coin lesions or solitary pulmonary nodules on imaging studies. It has also been reported that tumors are more common in the right lung, presumably related to the larger at–risk area of lung.13, 18, 21

Prognosis and Survival

Survival is generally good, especially in patients with early stage disease, with reported 5-year survival rates of between 44% and 97%.10, 18, 30, 31 This variability in survival can be attributed to different histologic subtypes of carcinoid as well as different stages of disease reported by the different studies. AC is associated with more aggressive disease and lower rates of survival as opposed to TC, which is classically indolent.

The prognosis is better than that for other primary thoracic malignancies and is closely related to classification and stage of disease. The 5-year survival rate for TC has been reported to be 87% to 100%, with 10-year survival rates of 87% to 93%. Likewise, the 5-year survival for AC ranges from 40% to 59%, with a 10-year survival rate of 31% to 59%.13, 30, 32 Although metastatic disease has a much poorer 5-year survival rate (14%-25%), this is distinctly better than what is reported (or expected) from patients with either small cell or nonsmall cell lung cancer.1, 29

Treatment

Currently, surgery remains the treatment of choice and the only curative option for patients with typical and atypical pulmonary carcinoid tumors. Aggressive surgical interventions have been justified for patients with good performance status given the generally good survival data and lack of effective alternative therapeutic maneuvers.

Bronchoscopy plays an important role and is often used to identify, localize, and diagnose carcinoid malignancies before surgical intervention.33 Both lung-conserving and radical resections have been used, and all procedures involve lymph node dissection or sampling. Anatomic resection, involving pneumonectomy or lobectomy, remains the most common procedure and accounts for approximately 60% to 75% of cases (Table 3).18, 31, 33 However, lung-sparing procedures, such as wedge resection, segmentectomy, or sleeve resections, are gaining in popularity as surgical techniques become more advanced. Survival has been studied for various surgical approaches and the clearly identified prognostic factor is the presence or absence of lymph node involvement.18, 32-34 Other local approaches, such as chemoembolization for liver metastases, have not to our knowledge been well evaluated in pulmonary carcinoid tumors.

Additional treatments currently under investigation include chemotherapy and radiation, particularly for patients diagnosed with unresectable or metastatic disease at the time of the initial presentation.6, 10 Due to the small number of patients in these categories, clinical data are limited. Responses to standard chemotherapy in prior studies have been poor. Proposed chemotherapy regimens are varied; the use of agents including interferon-α, etoposide-based regimens, streptozotocin, and 5-fluorouracil have been reported.33, 35, 36 The best reported overall response rate to chemotherapy with or without radiation was only 22%, as measured by serial imaging.35 Although octreotide is helpful in the control of carcinoid syndrome, to our knowledge it has not been established that this treatment is of benefit in patients without this syndrome.

Molecularly targeted agents, particularly those that target angiogenesis (such as the vascular endothelial growth factor, the platelet–derived growth factor, and the mammalian target of rapamycin (mTOR) pathways, have recently received renewed attention and enthusiasm. Phase 1 and phase 2 clinical trials that use these agents in patients with advanced carcinoid tumors have demonstrated promising results. Recent reports have suggested that bevacizumab,37 RAD001 (everolimus),38 and sunitinib39 have efficacy in advanced carcinoid tumors. However, to our knowledge, these studies have not been restricted to pulmonary carcinoid tumors, and in fact they tend to be under-represented in clinical trials.

Bevacizumab was studied in a phase 2 trial, alone and in combination with pegylated (PEG) interferon-α-2b. The study population included 44 patients with metastatic carcinoid tumors; only 4 patients had the lung as the primary tumor site. The study divided the patients into 2 groups for the first stage of the study: 18 weeks of single-agent bevacizumab or PEG interferon. For the second stage of the study, patients received both medications. The results were encouraging for single-agent bevacizumab; 21 of the 22 patients acheived a partial response or stable disease after 18 weeks. In contrast, 16 of 21 patients in the PEG interferon arm had stable disease. The overall median progression-free survival for all patients was 63 weeks. Functional CT scans also indicated significant decreases in whole tumor blood flow, blood volume, and permeability surface with bevacizumab.37

RAD001 (everolimus) has also been studied in combination with long-acting release octreotide acetate. RAD001 is a novel oral inhibitor of mTOR, a conserved serine/threonine kinase that regulates cell cycles. The target population was metastatic low-grade neuroendocrine tumors (carcinoids); 30 carcinoid patients were included but only 4 patients had lung primary tumors. Partial responses and stable disease were observed in 97% of patients: 5 patients acheived partial response and 24 patients had stable disease. The median progression-free survival for carcinoid patients was 63 weeks.38 It is interesting to note that a pharmaceutically sponsored phase 3 study of RAD001 in patients with advanced neuroendocrine tumors was specific for tumors originating in the pancreas and specifically excluded metastatic neuroendocrine tumors arising from the lungs.

Sunitinib, a multitargeted oral tyrosine kinase inhibitor, has also been studied in the treatment of advanced carcinoid tumors. A phase 2 study of single–agent sunitinib assessed efficacy and safety. A total of 41 patients with carcinoid tumors were included; 14 of these patients had lung or stomach (foregut) primary tumors. Partial responses were observed in 2.4% of patients, and stable disease was observed in 82.9% of patients. The median time to disease progression, however, was only 10.2 months.39

Radiotherapy alone has been gaining attention as an adjuvant therapy in patients with carcinoid tumors; however, randomized studies are limited by the relative rarity of carcinoid tumors. Reported studies have shown possible benefit, particularly in patients with lymph node-positive disease.5, 31, 40 However, to our knowledge, definitive radiotherapy without chemotherapy has not been shown to improve survival.35, 41 Palliation with radiation may also have a role in the treatment of unresectable disease.5 Further investigation is warranted to clarify the appropriate use of radiotherapy for this malignancy.

Conclusions

Carcinoid, or well-differentiated neuroendocrine pulmonary tumors represent an uncommon malignancy with limited medical therapeutic options. Given the indolent nature of this disease, aggressive local modalities of care including surgery and radiotherapy are appropriate, although in the advanced, metastatic setting, chemotherapy remains an alternative option. Upcoming targeted therapy such as angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors need to be explored in phase 3 trials for well-differentiated neuroendocrine tumors arising above the diaphragm.

Conflict of Interest Disclosures

The authors made no disclosures.

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