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Keywords:

  • carcinoid;
  • neuroendocrine;
  • neuroepithelial bodies;
  • tumor;
  • lung;
  • bronchnary

Abstract

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Bronchopulmonary neuroendocrine tumors (BP-NETs) comprise ≈20% of all lung cancers and represent a spectrum of tumors arising from neuroendocrine cells of the BP-epithelium. Although they share structural, morphological, immunohistochemical, and ultrastructural features, they are separated into 4 subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC), which exhibit considerably different biological characteristics. The clinical presentation includes cough, hemoptysis, and obstructive pneumonia but varies depending on site, size, and growth pattern. Less than 5% of BP-NETs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing, acromegaly, and SIADH. SCLC is the most common BP-NET, while LCNEC is rare, ≈10% and ≤1%, respectively, of all lung cancers. Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The incidence of BP-carcinoids (TC and AC) in the US was 1.57 of 100,000 in 2003 (an unexplained and substantial increase over the last 30 years, ≈6% per year). No curative treatment except for radical surgery (almost never feasible) exists. The slow-growing TC exhibit a fairly good prognosis (≈88%, 5-year survival), whereas AC demonstrate a 5-year survival of ≈50%, and the highly malignant LCNEC and SCLC5-year survival of 15% to 57% and <5%, respectively. This review provides a broad overview on BP-NETs and focuses on the evolution of the disease, general features, and current diagnostic and therapeutic options. Cancer 2008. © 2008 American Cancer Society.

The report by R. Laennec (1781–1826), published posthumously in 1831,1 of an intrabronchial mass probably represents the first written description of a bronchopulmonary (BP) carcinoid (Fig. 1). BP neuroendocrine tumors (NETs) are a subset of BP neoplasms that share a distinctive basic microscopic appearance, resembling NETs found elsewhere in the body.2 The current basis of BP-NET classification produced by the World Health Organization (WHO) in 2004 is a histologic classification system comprising 4 subtypes of tumors: low-grade typical carcinoid tumor (TC), intermediate-grade atypical carcinoid tumor (AC), and 2 high-grade malignancies, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC).3 TC and AC are categorized together as carcinoids, LCNEC is considered a subgroup of large-cell carcinomas, and SCLC is an independent category. The basic principle of the 4 group classification utilizes the expression of individual neuroendocrine morphologic features. These are organoid or trabecular growth pattern, peripheral palisading of the tumor cells around the periphery of tumor nests, and the formation of rosette structures. Although it was previously considered that that BP-NETs represented a continuum, recent information from histologic, immunohistochemical, and molecular studies suggest that the BP-carcinoid group is distinct from the more malignant LCNEC and SCLC groups.4

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Figure 1. René Théophile Hyacinthe Laennec (1781–1826) taught at the College de France (background) in Paris. Apart from his seminal description of cirrhosis, Laennec also described the stethoscope (left) and was the first to identify a bronchial carcinoid (right).

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The etiology of LCNEC and SCLC is strongly related to tobacco usage,5, 6 whereas a correlation with BP-carcinoids and tobacco smoking is uncertain.7, 8 The 5-year survival rate for BP-carcinoids has decreased drastically (84.7%–47.3%) over the last 30 years (Fig. 2A).8 A plausible explanation for this negative development is that the increased use of neuroendocrine markers in routine histopathology has resulted in the identification of additional poorly differentiated BP-carcinoids. In addition, the increased recognition of NETs by pathologists may explain the rapid increase in incidence (≈6% per year since 1973) noted for BP-carcinoids. The 5-year survival rate of SCLC is very poor, and despite aggressive therapeutic regimens the prognosis has only improved minimally (3.9%–4.8%) over the same 30-year period (Fig. 2B).8

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Figure 2. The 5-year survival trend for: (A) bronchopulmonary (BP)-carcinoids; and (B) small-cell lung cancer (SCLC). The average 5-year survival rates over the entire period (dotted line) indicate a 60.6% survival for BP-carcinoids (the SEER database does not distinguish between typical carcinoid tumor [TC] and atypical carcinoid tumor [AC]) and 4.8% SCLC, respectively. SEER 1973-2003 containing 5622 BP-carcinoids and 44,789 SCLC.8

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This review seeks to provide a summary of the current state of BP-NETs, define current knowledge of the disease process, and present a contemporary management algorithm as well as proposals for alterations or novel directions in therapeutic strategy consistent with current advances in NET biology.

Neuroendocrine System of the Lung

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

The pulmonary neuroendocrine cell (PNEC) system is phylogenetically ancient and originated in the ancestors of the air-breathing vertebrates, the Crossopterygian fish of the Devonian period.9 The structural differences between the lung PNEC system of primitive phyla (amphibians, reptiles) and advanced (birds, mammals) organisms are minor, suggesting a long-standing and fundamentally relevant physiological function.

During lung development, PNECs are the first cell type to form and differentiate within the primitive epithelium, increasing in number as birth approaches and reaching a peak during the neonatal period. Thereafter, they persist throughout life as a viable population.10 Although the embryologic origin of the PNEC system is debated, it is generally accepted that PNECs are of endodermal origin, despite their phenotypic similarity to neurons.11 In the postnatal phase and thereafter the PNEC/NEB complex represents the lung stem cell niche that is central to airway epithelial regeneration and lung carcinogenesis.12 To date, however, no definitive information is available on what constitutes classical pulmonary stem cell hierarchy. Nevertheless, there is substantial descriptive information indicating that a number of lung cell types are able to proliferate and reconstitute the lung epithelium after injury.13 Cell types including the basal and mucus secretory cells of the trachea, the Clara cells of the bronchiole, and the type II pneumocyte of the alveolus have been proposed as putative lung stem cells.14

In the healthy adult, PNEC are sparsely distributed, with approximately 1 PNEC per 2500 epithelial cells.15 The secretory granule-containing cells are typically tall and pyramidal in shape, extending from the basal lamina of the epithelium and possess apical microvilli projecting into the airway lumen. These microvilli function as the sensory part of the cell and upon stimulation, respond by degranulation and exocytosis of amines and neuropeptides, which exert a local paracrine and neurocrine effect on neighboring cells and activate both extrinsic and intrinsic neurons (Fig. 3).16

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Figure 3. Schematic representation of the role for neuroepithelial bodies (NEBs) as airway sensors. (A) NEB initiated neural regulation modulates pulmonary homeostatic processes including airway tone, pulmonary circulation, and control of breathing. Pulmonary vagal afferent fibers1 pass to the brainstem, and dorsal root ganglionic (DRG) afferent fibers2 communicate with the spinal cord. Reflex response signals are transmitted to the lungs via parasympathetic3 and sympathetic nerve fibers, as well as to the diaphragm via the phrenic nerve.4 (B) Magnified schematic diagram demonstrating the mechanism of hypoxia-induced degranulation of NEBs (green). The released dense core vesicles (red) contain signal substances including serotonin, CGRP, bombesin, calcitonin, enkephalin, somatostatin, and cholecystokinin, which activate vagal and DRG afferent neurons as well as adjacent epithelial, vascular, or smooth muscle cells. DRGs in turn activate intrinsic efferent neurons facilitating feedback signaling to the NEBs. A single pulmonary neuroendocrine cell (PNEC) (yellow) with basal extension provides paracrine influence on adjacent mucosal cells.

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Although most PNEC exist as solitary cells, some are aggregated in innervated PNEC clusters referred to as neuroepithelial bodies (NEBs).17 Both solitary PNECs and NEB exhibit similar phenotypes in terms of storage of adenosine triphosphate, serotonin (5-HT), and several other amines and neuropeptides in dense-core vesicles.16 NEBs are innervated and occur exclusively within intrapulmonary airways. Solitary PNECs are located within the epithelium lining the larynx, trachea, and bronchi down to the bronchiole-alveolar junction, and exhibit thin apical or lateral cytoplasmic processes abutting on neighboring cells.17

The precise function of the PNEC system remains unclear, as do the functional relationship between PNECs and NEBs. Serotonin and other peptides (eg, bombesin, calcitonin) with growth factor-like properties are thought to play an important role in normal lung development.18 PNECs are most noticeably present in the perinatal period, particularly in species that are relatively immature at birth such as humans and, in addition to their role in lung development, may have a crucial contribution in adaptation to air breathing at birth.19

NEBs are considered to serve as airway chemoreceptor cells responsive to hypoxia and are thought to activate vagal afferents, thereby participating in the regulation of breathing.16 NADPH oxidase has been shown to function as a molecular oxygen sensor in NEB cells.20 In addition, hypoxia stimulates 5-HT secretion from intact NEBs via inhibition of K+ channels, augmentation of Na+-dependent action potentials, and calcium entry through L-type Ca2+ channels, as well as by positive feedback activation of 5-HT3 autoreceptors.21

NEB cells exhibit mechanosensory and nociceptive properties and ‘stretch’ is a well-defined physiological stimulus responsible for NEB cell 5-HT release that is mediated by mechanosensitive ion channels.12 It is likely that the proximity between the PNEC, neural elements, and smooth muscle facilitates the functionality of the regulatory mechanisms responsible for alteration in bronchomotor and vascular tone.16

Epidemiology

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

The Surveillance, Epidemiology, and End Results SEER database indicates that BP-carcinoids represent 1.2% of a total of 463,338 primary lung malignancies.8 Their incidence in the US has increased rapidly over the last 30 years, ≈6% per year, and was 1.57 of 100,000 in 2003 (Fig. 4A). BP-carcinoids are more prevalent in whites (W) compared with blacks (B) (B:W ratio = 0.45) and Asians (A) compared with non-Asians (NA) (A:NA = 0.52), whereas they are less common in Hispanic (H) compared with non-Hispanic (NH) (H:NH = 0.23).22

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Figure 4. Age-adjusted incidence/100,000 of (A) bronchopulmonary (BP) carcinoids (the SEER registry does not distinguish between atypical carcinoid tumor [AC] and typical carcinoid tumor [TC]), and (B) small-cell lung cancer (SCLC). Men (▴) and Women (○).8

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TCs represent 80% to 90% of BP-carcinoids7 and occur more frequently in the fifth and sixth decades of life; they can, however, occur at any age, and in childhood are the most common lung tumor.

The SEER data indicate that LCNECs comprise ≈0.3% of all lung neuroendocrine tumors, while others have noted a higher incidence: 1% to 3% of all lung cancers.5, 8 LCNECs occur most frequently in the seventh decade, and are 4 times more frequent in men than in women.5, 23, 24

SCLCs are usually diagnosed at a mean age of 60 to 70 years and comprise 9.8% of all lung tumors. In men, the age-adjusted incidence reached a peak in 1988 at 11.1 of 100,000 and has since declined to 8.5 of 100,000 in 2003. In women, an initial steady increase in incidence (7.2 of 100,000 in 2003) over the last 30 years has stabilized but has not yet shown evidence of decreasing (Fig. 4B).8

Pathology

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

DIPNECH is a rare preneoplastic condition that comprises a generalized proliferation of PNECs and NEBs or results in linear proliferation of PNECs. When PNECs extend beyond the basement membrane, this proliferation is identified using the terminology ‘tumorlet,’ which can be further defined as being localized or diffuse. A pulmonary carcinoid tumorlet is, by definition, a nodular proliferation of neuroendocrine cells that constitutes a nodule <5 mm. PNEC proliferations comprising nodules >5 mm in diameter are classified as carcinoid tumors. DIPNECH is considered an adaptive response in persons living at high altitudes and as a reactive response in the setting of lung injury and is thus evident in obliterative broncheolitis,25 interstitial lung disease,26 and in patients with chronic cough.27

BP-carcinoids

The SEER registry (1973–2003) identified the location of BP-carcinoids in 5123 cases (91%) (Fig. 5A), of which right-sided lesions were the most common (59.0%), whereas 10.4% were located in the main bronchi. Davila et al.28 noted that 75% of BP-carcinoids arose in the lobar bronchi, 10% in the mainstem bronchi, and 15% peripherally. The majority of TCs are central in location, whereas ACs tend to be larger and are more commonly located peripherally in the lungs.29

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Figure 5. Distribution of (A) 5123 lung carcinoids, and (B) 35,984 small cell lung cancer (SCLC) registered in the SEER registry.8 The anatomical locations are main bronchi, upper, middle, and lower right lung lobes, and upper and lower left lobes.

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On bronchoscopic examination TC and AC are usually red-brown to bluish-tan endobronchial masses with a smooth surface. They are often highly vascular and in some circumstances have been reported to bleed considerably when biopsied. Care should therefore be exercised and cautery always available. At gross pathological examination TC usually exhibit a white or gray cut surface with minimal evidence of hemorrhage or necrosis.30 AC are usually white-gray on section but can exhibit a color range of tan, pink to yellow brown, and red.31

The WHO diagnostic criteria for TC are: a tumor with carcinoid morphology and <2 mitoses/2 mm2 (10 HPH), lacking necrosis, and tumor 0.5 cm or larger (Fig. 6A). An AC is defined as a tumor with carcinoid morphology with 2 to 10 mitoses/2 mm2 and/or necrosis (often punctuate) (Fig. 6B). Since necrosis and mitosis may occur only focally, small biopsies may not be representative and in such instances the lesions should be classified as a carcinoid tumor until adequate biopsy material is available.4 In contrast to the high-grade BP-NETs, TC and AC rarely occur in combination with other types of adenocarcinomas; however, there is a slightly elevated synchronous risk for breast cancer and prostatic cancer.32, 33

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Figure 6. Photomicrographs showing (A) a typical carcinoid with an endocrine growth pattern (nests, trabeculae), uniformity of cells, and no necrosis. (B) An atypical carcinoid with nuclear pleomorphism, increased cellularity, disorganized architecture and small areas of necrosis. (C) Large-cell neuroendocrine carcinoima with polygonal shaped cells, organoid growth pattern, cellular palisading, rosette-like areas, and large patches of necrosis. (D) Small-cell lung cancer with a very high cellularity and hyperchromatic nuclei, scant cytoplasm. The tumor grows without a specific pattern, but exhibits peripheral palisading. The pictures were kindly provided by Dr. Robert J. Homer, Yale University School of Medicine.

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LCNEC

In the WHO classification, LCNECs are considered NE tumors with >10 mitoses/2 mm2 and cytologic features of a large-cell carcinoma. They consist of polygonal-shaped cells that are about 3 times larger than SCLC (Fig. 6C), grow in an organoid pattern, exhibit cellular palisading or rosette-like areas, and have abundant, often large patches of necrosis.

SCLC

SCLC are usually white-tan, soft perihilar masses with massive lymphadenopathy and direct mediastinal invasion, although a small percentage occur as peripheral lesions. In a study of 63 SCLC, 46 were described as well circumscribed, often lobulated; 9 were endobronchial, somewhat polypoid lesions; 5 were subpleural in location; 1 had an apical Pancoast tumor.34 The cut surface is described as soft, rubbery, firm, wooden, and gritty.34 These tumors have a rapid doubling time, and 60% to 70% have extensive local and metastatic disease at diagnosis.34 SCLCs are slightly more common (56.2%) in the right lung, 22.0% are found in the main bronchi, and there is a predisposition for the upper lobes (Fig. 5B). The WHO classification defines SCLCs as neuroendocrine tumors with >10 mitoses/2 mm2 and small cell cytologic features. The cellularity is typically very high, with hyperchromatic nuclei, absent or very small nucleoli with scant cytoplasm, and a round or fusiform shape and a very high mitotic rate (Fig. 6D). The tumor often grows in sheets without a specific pattern, but most tumors exhibit classic neuroendocrine growth patterns.34 The architecture is, however, often poorly preserved and large areas of necrosis separating small islands of viable tumor are common.

Histopathologic diagnostic pitfalls

Diagnosis of BP-carcinoids can be difficult and they may be mistaken for SCLC, whereas LCNEC can be difficult to distinguish from poorly differentiated adenocarcinomas, squamous cell carcinomas, and basiloid carcinomas.4 LCNEC and SCLC may occur in combination with nonsmall-cell lung cancers as well as with each other. In combination with the histologic appearance, the cell proliferation marker Ki-67 (as per the WHO classification of mitotic counts) seems to be the most useful marker to distinguish between the different subgroups of BP-NETs.3, 35 A variety of peptide and amine markers including chromogranin A (CgA), neuron-specific enolase (NSE), serotonin, synaptophysin, and adrenocorticotrophic hormone (ACTH) have some utility in establishing the differential diagnosis (Fig. 7).

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Figure 7. The frequency of identification of immunohistochemical (IHC) markers in individual bronchopulmonary neuroendocrine tumors. (A) Typical carcinoids (TC), (B) atypical carcinoids (AC), (C) large-cell neuroendocrine carcinomas (LCNEC), and (D) small-cell lung carcinomas (SCLC). Neuron-specific enolase (NSE), chromogranin A (CgA), synaptophysin (Syn), serotonin (Ser), adrenocorticotrophic hormone (ACTH). N indicates the number of cases in which an individual marker has been studied. The data represent a compilation of information derived from 11 studies.124–134

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Staging

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Accurate staging provides prognostic information, and stage determines treatment strategies for all types of lung cancer. Although not generally accepted, the TNM classification for lung tumors is often adapted and useful for staging of BP-carcinoids and LCNEC.4 An analysis of ≈800 BP carcinoids noted that 87% of TC present without lymph node metastases, 10% exhibited N1 disease (involvement of the ipsilateral hilar lymph nodes), 3% disease had N2 (involvement of the ipsilateral mediastinal lymph nodes) while no N3 (central contralateral or supraclavicular lymphatic lymph nodes) disease was identified. In contrast, 43% of AC tumors were lymph node-negative, 29% were N1, 14% were N2, and 14% exhibited N3.7

Metastases are usually seen within intrathoracic lymph nodes, but distant metastases to the liver, skeleton, central nervous system (CNS), skin, and mammary glands occur (3% for TC and 21% for AC). LCNECs often present with an advanced disease at diagnosis. One study staged 87 LCNEC as IA (23%), IB (24%), IIA (3%), IIB (11%), IIIA (20%), IIIB (15%), and IV (3%).5

Because of a bad prediction of survival for the TNM classification, SCLC has been staged as limited disease (restricted to 1 hemithorax with regional lymph node metastases, including hilar, ipsilateral, and contralateral mediastinal and ipsilateral and contralateral supraclavicular nodes) or extensive disease the presence of obvious metastatic disease. In a new proposal from the International Association for the Study of Lung Cancer (IASLC), however, TNM staging is also suggested for SCLC, and it has been recommended that it be evaluated in clinical trials.36 The most common metastatic sites for SCLC are bone (19%-38%), liver (17%-34%), the adrenal glands (10%-17%), and the brain (up to 14%).37

Molecular Genetics

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

BP-carcinoids may occur as a component (≈5%) of the familial endocrine cancer syndrome multiple neuroendocrine neoplasia 1 (MEN1), although the majority occur as nonfamilial (ie, sporadic) isolated tumors. Loss of heterozygosity (LOH) involving several chromosomes, 1p, 1q23, 3p, 4q, 5q21, 6q, 9p, 10p, 10q, 11q13 (MEN1 gene), 13q13 (Retinoblastoma/RB gene), 16q, 17p13 (p53 gene), and 22q, and genetic alterations leading to gain of chromosomes or chromosomal regions involving chromosomes 3q, 5p, 7, 8q, 9q, 15q, 16q, 17q, 19q, 20q, and 22q have been observed in BP-NETs.38–42

Despite some discrepancies concerning the reported incidence,41, 43–50 LOH at several chromosome 3p regions seems to be frequent in BP-NETs and most common in the more malignant tumor types (Fig. 8A).

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Figure 8. Scatterplot showing the frequency of common genetic alterations described in BP-NETs. (A) Genetic alterations on chromosome 3p, (B) MEN-1 gene alterations, and (C) frequency of abnormal p53 protein expression or p53 gene alterations. The data represent a compilation of the results derived from 22 studies. Although the studies were performed using different techniques and therefore are not directly comparable, the figure indicates the ‘global’ frequency of genetic alterations at individual loci. The numbers in parentheses provide an integer reflecting the frequency with which a specific gene alteration was reported (scatterplot with mean).38–50, 53–55, 57–63

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MEN1, an autosomal dominant disorder associated with the gene locus on 11q13, includes neoplasms of the pituitary, pancreas, and parathyroid. In a recent study of 129 MEN1 patients, 5% had in initial records been diagnosed with BP-carcinoids, while retrospective analysis of CT scans indicated the prevalence could be as high as 31%.51 In patients with MEN1, screening for BP carcinoids with CT imaging of the chest is recommended every 3 years with onset at 20 years of age.51, 52 Inactivation of the MEN1 gene by mutation is evident in TC ≈47%, AC ≈70%, LCNEC ≈52%, and in SCLC ≈41% (Fig. 8B).41, 53–55 Onuki et al.43 noted LOH at 11q13 in ≈71% of LCNEC and 67% of SCLC. The high frequency of MEN1 mutations in BP neuroendocrine tumors indicates that genetic screening for MEN1 may (should) be considered in individuals with the less malignant TC and AC. The current recommendation for genetic MEN1 screening, however, is the occurrence of 2 or more MEN1 related tumors.56

The p53 gene on chromosome 17p13 is important in maintaining genomic stability, and is frequently mutated in malignant human tumors. Abnormal expression or LOH and point mutations of the p53 locus have been detected in ≈4% of TC, ≈29% of AC, ≈80% of LCNEC, and ≈75% of SCLC (Fig. 8C).43, 57–63 The different patterns of p53 mutations between TC/AC and LCNEC/SCLC support the hypothesis that these 2 groups are genetically distinct from each other. A study of the frequency of p53 protein expression was 0% for TC, 20% for AC, 42% for SCLC, and 86% in LCNEC, suggesting that it could be used to distinguish between subtypes of BP-NETs.64 In AC, expression of p53 protein is correlated with a higher apoptotic index,65 and in SCLC a high expression of p53 indicates a poor prognosis.66

Telomerase activity in BP-NETs is present in <10% of TC but in ≈90% of LCNECs and SCLCs and telomerase-positive tumors generally showed an immunophenotype consistent with gene product alterations (including high expression of bcl-2, p53, and c-kit, and loss of Rb) and were characterized by a high proliferation index.67

E-cadherin and beta-catenins, transmembrane glycoproteins involved in epithelial cell–cell adhesion, are invariably expressed at a higher level in high-grade BP-NETs (87% and 83%, respectively) than in carcinoids (50% and 37%, respectively).68 Decreased expression of E-cadherin and beta-catenin also correlate with lymph node metastases, suggesting that down-regulation of the E-cadherin-beta-catenin complex plays a role in BP-NET progression.69

The utility of genetic data in the distinction between low- and high-grade tumors, as well as for distinction between the BP-NET subgroups, remains to some extent uncertain due to the variety in distribution reported and the use of different classification schemes for the diverse genetic alterations. Increasing knowledge of molecular genetics will most certainly be necessary for advancing classification, predicting prognosis, and for the development of future, more precise therapeutic strategies.

Clinical Presentation

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

The majority of patients, ≈58% with BP-carcinoids, are symptomatic at presentation, with the most common symptoms, cough 32%, hemoptysis 26%, and pneumonia 24% (classical triad) representing the sequela of luminal obstruction and ulceration of the tumor (Fig. 9).7, 29, 31, 70–74 Symptoms are often present for many years before diagnosis and usually reflect the location of the lesions as opposed to manifestations of secreted bioactive products.24 Of note is the observation that 24% of TC and 7% of AC are incidentally identified at autopsy.24

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Figure 9. Clinical presentation of bronchopulmonary (BP)-carcinoids. The majority present with nonspecific symptoms (≈58%) (cough, pneumonia, hemoptysis, pain, dyspnea), while the carcinoid syndrome is rare (0.8%-3%). The frequency (%) of symptoms reported in 8 separate studies are presented. The integer in parenthesis after each symptom indicates in how many studies the frequency of a specific symptom was reported. The bars represent the mean percent of episodes in each of the positive studies. (mean ± SD).7, 29, 31, 70–74

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A functional presentation with symptoms related to serotonin secretion (diarrhea, flushing, wheezing, and carcinoid heart disease) or other hormonally active tumor products is rare (1%–3%), and reflects that liver metastases are relatively rare ≈2% and ≈5%, respectively, for TC and AC.7, 74 Typically, the carcinoid syndrome occurs when hepatic spread results in hormonally active tumor products exceeding the hepatic capacity for degradation. High concentrations of serotonin and/or other vasoactive substances released by the tumor enter the inferior cava, and subsequently the right side of the heart, and are considered to initiate the pathological process leading to plaque formation on the downstream side of the tricuspid and pulmonary valves.75 The passage of blood through the pulmonary parenchymal circulation enables sufficient degradation to explain the predominance of right-sided heart valve damage. The presence of left heart disease is uncommon but may occur when the venous drainage from a primary BP carcinoid releases serotonin directly into the left heart.76 Cushing syndrome (ectopic production and secretion of ACTH) may occur in ≈2% of BP-carcinoids, whereas <1% of individuals with Cushing syndrome have a BP-carcinoid.77 Other, rare endocrine conditions associated with BP-carcinoids include acromegaly, hypercalcemia, and hypoglycemia.78, 79

LCNECs are often peripheral tumors, and are thus less likely to present with mechanical symptoms. In a series of 21 LCNECs, 6 had chest pain, 5 were asymptomatic, 4 exhibited cough or hemoptysis, and 6 had nonspecific presentations including flu-like symptoms, dyspnea, and night sweats.80 In a separate study of 87 LCNECs, no paraneoplastic symptoms were evident at diagnosis.5

SCLCs are usually centrally located and present with symptoms similar to BP-carcinoids including persistent cough, obstructive pneumonia, and hemoptysis. Invasion of adjacent structures may, in addition, lead to dysphagia, hoarseness, and superior vena cava syndrome. The disease progress is rapid. Paraneoplastic presentations including Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH), Cushing syndrome, and Pancoast syndrome may occur.34 Among these, SIADH is the most common (≈5.5% at date of diagnosis)81 and is caused by excessive secretion of antidiuretic hormone (ADH), resulting in decreased volumes of more highly concentrated urine, reduced plasma osmolarity, and euvolemic hyponatremia. Acute onset of SIADH has also been described in association with tumor lysis after chemotherapy and the resulting electrolyte disturbances, if inadequately dealt with, may result in considerable morbidity and even mortality.82

Diagnosis

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

The recognition of pulmonary or ‘carcinoid’ symptoms or the identification of an unexplained mass lesion should initiate a series of investigations that enable identification of a BP-NET lesion (Fig. 10).

thumbnail image

Figure 10. Diagnostic algorithm for bronchopulmonary neuroendocrine tumors.

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Biochemical markers

Elevation of plasma CgA is a relatively sensitive (≈75%) marker of BP carcinoids, while for SCLC it is positive in ≈60%.83 False-positive elevations of CgA concentrations can occur in renal impairment, atrophic gastritis, and during proton-pump inhibitor therapy. In SCLC, when plasma CgA is increased, it may serve as a marker of the response to treatment and may be useful in monitoring patients for recurrent disease.84 Other markers that may be positive in hormonally active tumors include serotonin, urinary 5-HIAA, ACTH, cortisol, and IGF-1.

Radiology

Many BP-carcinoids are detected incidentally on chest radiographs. Plain X-rays are nonspecific, although BP-carcinoids often appear as an isolated, well-defined hilar or perihilar mass. Once a suspicious lesion is detected on a chest X-ray (CXR), a computed tomography (CT) of the chest and upper abdomen should be undertaken to determine the size, characteristics, extent of the primary tumor, involvement of mediastinal lymph nodes, and presence of distant metastases. TC findings on a CT scan are well-defined, spherical or ovoid masses that narrow, deform, and/or obstruct airways. They tend to be vascular and are located close to central bronchi, often near the bifurcation area, whereas AC usually are located peripherally in the lung.29 Calcification is evident in up to 30% of tumors and manifests in a punctuate or diffuse pattern. TC as well as AC may be associated with hilar infectious or malignant lymphadenopathy.

CT findings of LCNEC are nonspecific and similar to other nonsmall-cell lung cancers. The nodules and masses are usually peripheral and have a well-defined and lobulated appearance, but may also reveal a spiculated margin. Calcification occurs in ≈10% of LCNECs, and nonhomogeneous enhancement due to intratumoral necrosis may also be present.85

Most SCLCs are located centrally and are accompanied by mediastinal and hilar lymphadenopathy, but 5% to 10% occur as nodules without lymphadenopathy.86 Displacement or narrowing of the bronchial tree and major vessels and major athelectasis are also common features.87, 88 The routine imaging staging of SCLC should include CT scans of the chest and abdomen, a CT scan or magnetic resonance imaging (MRI) of the brain, and a bone scan. MRI is not a routine diagnostic modality for lung imaging and is usually utilized to resolve ambiguous CT findings.89 MRI can be helpful in distinguishing ‘small’ carcinoids from adjacent normal vascular structures, and should also be considered when an ACTH-producing carcinoid is suspected but not found at CT. MRI may also be useful if there is concern about neural foramen or brachial plexus involvement.

Somatostatin Receptor Scintigraphy (SRS)

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Approximately 80% of BP-NETs express somatostatin receptors with a predominance of SST2 receptors.90 Radiolabeled somatostatin analogs (111In-octreotide and111In-lanreotide) are used in SRS to localize BP-NETs.91 The overall sensitivity in detection is as high as 93% and 87% (no statistical difference between the tracers), respectively, and in 8 BP-carcinoids all were detected with both techniques.92 Another study, however, found ≈80% sensitivity for primary BP carcinoids, and ≈60% for liver metastases.91 It has also been demonstrated that SRS-positive LCNEC may benefit from adjuvant somatostatin analog treatment.93 Reisinger et al.94 reported 8 studies, including 162 SRS examinations in SCLC with detection rates of 91% for primary tumors and 59% for metastases, respectively.

Positron Emission Tomography (PET)

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

This technique detects accumulation of radiolabeled biological molecules such as18F-fluorodeoxyglucose (FDG), which broadly identifies increased glucose uptake by diverse neoplastic cells. The use of68Ga-DOTA-TOC PET (somatostain receptor targeted) to identify neuroendocrine tumors has a sensitivity of 97%, a specificity of 92%, and an accuracy of 96%.95 In SCLC,18FDG PET has been demonstrated to have a very high sensitivity (100%).96 More specific markers are available for BP-carcinoids including the radiolabeled precursor of 5-HT synthesis,11C-5-hydroxytryptophan. In 42 patients with NETs (7 with BP-carcinoids), a comparison with SRS and CT imaging demonstrated that11C-5-hydroxytryptophan identified tumor lesions in 95%, and in 58% visualized more lesions than SRS and CT.97

Combined Techniques

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Combinations of SRS or PET with CT or MRI imaging systems are especially effective (sensitivity 96%-100%) for NET detection.98, 99 In a recent study of 15 NET patients with abnormal SRS findings, a further examination with a111In-Pentetreotide SPECT/CT imaging system revealed previously unidentified lesions in 7 and altered tumor location in 4 individuals.100 PET/CT altered staging in 5 of 29, and the sensitivity for accurate staging of patients with extensive SCLC disease was 93% for PET and 93% for PET/CT, whereas the specificity was 83% and 100%, respectively.101

Invasive Modalities

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Once a suspicious lesion has been identified by noninvasive imaging, histologic diagnosis before surgical intervention is useful but not mandatory. In 3754 patients with central, endobronchial lesions, the overall sensitivity of flexible fiberoptic bronchoscopy (FB) for detecting lesions was 88%.102 The visual appearance (a firm tumor mass growing into, and possibly obstructing the lumen of a bronchus), may be highly indicative of a carcinoid tumor, and when reachable by FB (35%–70% of BP-carcinoids), remains the most important tool in diagnosing BP-carcinoids. LCNECs are usually not located within reach of FB, but it is a valuable diagnostic tool for SCLCs.

Although FB can diagnose BP-carcinoid, there is difficulty distinguishing TC from AC on a small biopsy. Since 5% to 20% of TC and 30% to 70% of AC metastasize, lymph nodes should be assessed in all BP-carcinoids to ensure adequate staging.31

CT-guided, percutaneous transthoracic needle biopsy is preferred for peripheral lesions, while mediastinoscopy, video-assisted thoracic surgery, and thoracotomy are other alternatives. Fine-needle aspiration specimens or thoracocentesis for patients with pleural effusions can be used to achieve diagnosis, but cytologic specimens are often difficult to classify accurately. A patient with a solitary peripheral lesion that is suspicious of lung cancer, who appears to have early-stage disease and is a surgical candidate, should undergo excisional biopsy, and if the presence of a resectable tumor is confirmed, subsequent surgery.102

Surgery

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

The mainstay and only curative treatment of bronchial carcinoids is surgical resection based on the general principle of complete resection with preservation of as much normal lung tissue as possible. For central, localized TC, conservative resection (consisting of sleeve resection, wedge, or segmental resection) is the preferred treatment.74, 103 Controversy exists regarding the optimal procedure for AC and/or lymph node metastases when recognized preoperatively. Martini et al.104 noted that survival only correlated with cell type (ie, TC vs AC) and not lymph node status and concluded that resection alone was adequate therapy. The adequacy of conservative resection in AC has been questioned and lymph node dissection, in addition to more extensive/aggressive resection (lobectomy, bilobectomy, and pneumonectomy), is commonly advocated.28, 72

Most LCNECs and SCLCs are poor candidates for surgical resection due to local/systemic spread. However, surgical resection with mediastinal dissection confirms diagnosis, and may in combination with radio- and/or chemotherapy be beneficial in limited stage (T1-2, N0) SCLC.105, 106 As surgery itself rarely contributes to prolonged survival for N2 SCLC, mediastinoscopy is recommended to exclude N2 disease before surgery is considered.105 Resection (lobectomy or pneumonectomy) is also preferred in early-stage LCNEC, and without lymph node metastases after mediastinal lymph node sampling survival may improve.80 Among 98 TC and 15 AC, 22 LCNEC, and 51 SCLC the following frequencies (%) of surgical techniques were applied, respectively; pneumonectomy (4, 20, 5, 51), lobectomy (72, 67, 82, 43), bilobectomy (7, 7, 5, 4), segmentectomy (11, 0, 9, 2), nonanatomic resection (4, 7, 0, 0), and sleeve resection (34, 20, 0, 0).107 In a risk factor analysis (hazard ratio) for death among these patients, cell type (TC: 1, AC: 6.7, LCNEC: 6.8, SCLC: 14.7) was the most important factor, followed by stage (T1: 1, T2: 1.7, T3: 2.6, T4: 8.9, and N0: 1, N1: 3.3, N2: 2.2).107

Bronchoscopic Treatment

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

A variety of bronchoscopic resection strategies including Nd-YAG laser, with or without photodynamic therapy before tumor resection of endobronchial carcinoids, have been applied with success in selected patients with proximal bronchial TC tumors with a narrow stalk. In a recent study of FB cryotherapy, 18 of 29 isolated endoluminal TCs were treated successfully.108 After a median follow-up of 55 months, a single recurrence was noted and, unlike other resection techniques, cryotherapy was not associated with long-term complications like bronchial stenosis.108 Despite some encouraging results, endobronchial resection should probably only be considered in individuals where inoperability due to comorbidity is an issue.

Radiotherapy

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

BP-carcinoids are generally resistant to radiation therapy and this modality is reserved for use when surgical resection is not practical or as an adjunct when a resection is incomplete. No rigorous data on radiotherapy in LCNEC exists. Peptide receptor radiotherapy (PRRT) utilizing either111Indium,90Yttrium, or 177Lutetium radionuclides linked to an SST analog allows the targeting of SST receptor ‘over’-expressing tumor cells. 177Lu linked to the SST analog, DOTA0-Tyr3octreotate is considered the most effective agent, producing tumor remission in ≈50% of carcinoid patients.109 The median duration of the therapy response in carcinoids for90Y-DOTA0,Tyr3octreotide and 177Lu-DOTA0Tyr3octreotate is 30 months and more than 36 months, respectively.109 However, the use of 177Lu-DOTA0Tyr3octreotate to treat SCLC was unsuccessful, with all 3 patients exhibiting progression and death within 5 months.110 The standard treatment for limited stage SCLC includes external thoracic radiation in combination with chemotherapy.111 Prophylactic cranial irradiation in patient with SCLC in remission has proved beneficial.112

Chemotherapy

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

The use of various chemotherapeutic agents (doxorubicin, 5-fluorouracil (5FU), dacarbizine, cisplatin, etoposide, streptozotocin, and carboplatin) in the treatment of BP-carcinoids has yielded minimal (≈20%–30%), mostly short-lasting results, and an effective chemotherapeutic regimen for unresectable disease is lacking.31 Combination chemotherapies for BP-carcinoids are usually platinum or streptozotocin-based. Due to the low response rates for chemotherapy in BP-carcinoids, combined with serious side effects (nephrotoxicity and cytopenia), the indication to use currently available chemotherapeutic regimens in the treatment of BP-carcinoid patient is limited.

Little information exists regarding chemotherapy treatment for LCNEC. In small studies, LCNEC has been shown to have a low and partial response rate to chemotherapy but prolongs survival in lower-stage disease.23

The standard of care for limited stage SCLC includes early thoracic radiotherapy combined with cisplatin and etoposide. Although standard combination cytotoxic chemotherapy agents have shown antitumor activity with initial responses seen in 70% to 90% for both limited and extensive stages of SCLC, most patients eventually develop progressive disease. Aggressive combined chemoradiotherapy in limited-stage SCLC can yield a 20% to 25% long-term survival.106

Novel Chemotherapeutic Agents

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

In tissues from 17 TC lesions with distant metastases, 5 stained positive for c-kit, 12 for PDGFR alpha, 9 for PDGFR beta, and 7 for EGFR, indicating that treatment with tyrosine kinase receptors inhibitors may be of utility.113 Clinical trials with imatinib mesylate, an orally bioavailable ‘promiscuous’ inhibitor of several tyrosine kinases in patients with recurrent and refractory c-kit-expressing small-cell lung cancer, however, have not been encouraging.114 Therapies with inhibitors of matrix metalloproteinases (a group of enzymes involved in tumor growth and metastasis), and vaccines for the prevention of relapse have also failed in SCLC.115, 116

Biotherapy

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Interferons IFN-α, IFN-γ, and human leukocyte IFN have been used in the pharmacological management of NETs. The biochemical and tumor response rates are modest, and given the substantial adverse effects, their indications are limited. Despite the high expression of SSTR in BP-NETs, the role of somatostatin analogs in BP-NETs is limited unless carcinoid or Cushing syndromes are dominant clinical issues. Somatostatin analogs have been reported to demonstrate some encouraging effects on long-term survival and are effective in controlling symptoms in AC with liver metastases, and in SRS-positive LCNEC.93, 117

Management of BP-Carcinoid Hepatic Metastases

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

Despite the finding that hepatic metastasis is relatively uncommon (≈2%), debulking of liver metastases should be considered in the presence of carcinoid syndrome. Surgical resection may range in extent from cytoreductive surgery to liver transplantation. A biochemical response rate of 96% and a markedly improved 5-year survival has been reported after resection of hepatic metastases.118 Hepatic artery embolization, with or without intraarterial chemotherapy (adriamycin, cisplatin, epirubicin), is associated with tumor burden reduction, biochemical response, and better control of symptoms from carcinoid liver metastases.119 The risk of carcinoid crisis with profound circulatory collapse, respiratory failure (bronchoconstriction), diarrhea, flushing, acidosis, and renal failure is a rare but serious complication of hepatic artery embolization. It represents the massive systemic release of serotonin and other vasoactive peptides consequent upon tumor necrosis. The treatment of carcinoid crisis is based on premedication with somatostatin analogs and symptomatic treatment.120

Long-term Outcome

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

TCs exhibit a good prognosis, with a 5-year survival of 87% to 89%.7, 24, 121 However, distant metastases from TCs (≈10%) may occur many years after even radical resection of the primary tumor.122 A 10-year follow-up is therefore recommended. ACs are regarded as intermediate in grade and are associated with a poorer prognosis and a 44% to 78% 5-year survival.7, 24, 121 The 5-year survival rate for BP-carcinoids as a group (the SEER database does not distinguish between TC and AC) has significantly decreased (84.7%–47.3%) over the last 3 decades (Fig. 2A).123 LCNEC is associated with a 5-year survival rate of 15% to 57%.5, 23, 24 The 1973-2003 SEER registry demonstrates an overall 5-year survival of 4.8% for SCLC, and the minimal increase in 5-year survival from 3.9% in 1973 to 4.8% in 2003 suggests a lack of efficient treatment strategies (Fig. 2B).

Conclusions

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES

BP-NETs represent a class of tumors originating from the neuroendocrine cells of the BP epithelium. TCs are regarded as benign, but nevertheless may present with metastatic spread and behave like ACs, displaying a poorer prognosis, and need to be treated aggressively. The highly malignant LCNECs and SCLCs are generally widespread at diagnosis and only in rare instances are curable. Their overall prognosis is poor and despite an aggressive approach with extensive surgical resection, multiagent chemotherapy, and radiotherapy, the 5-year survival has not appreciably improved for SCLC over the last 30 years.

Although diagnostic modalities such as CT, PET, SRS, and bronchoscopy are useful in accurate diagnosis and staging, there is a critical requirement for the development of a plasma or genetic marker to predict or identify early lesions. In contrast to their NET counterparts in the gastrointestinal tract, little is known about the exact cell(s) of origin of BP-NETs. Techniques to isolate and divide BP-NE cells into subcategories with regard to their secretory products are required before appropriate comparative analyses can be done to understand the tumorigenesis of BP-NETs. Multiple genetic aberrations and markers for BP-NETs have been identified and appear to be promising targets to develop more precise diagnostic tools and targeted treatment regiments but, to date, however, vaccines, angiogenic, and kinase inhibitors have demonstrated no or limited efficacy.114–116

Increased knowledge about BP-NET biology and the genetic characteristics of the tumors is the key to the evolution of therapy. The dominant goal is the need to develop an early diagnostic test and establish a precise targeted therapeutic strategy.

REFERENCES

  1. Top of page
  2. Abstract
  3. Neuroendocrine System of the Lung
  4. Epidemiology
  5. Pathology
  6. Staging
  7. Molecular Genetics
  8. Clinical Presentation
  9. Diagnosis
  10. Somatostatin Receptor Scintigraphy (SRS)
  11. Positron Emission Tomography (PET)
  12. Combined Techniques
  13. Invasive Modalities
  14. Treatment
  15. Surgery
  16. Bronchoscopic Treatment
  17. Radiotherapy
  18. Chemotherapy
  19. Novel Chemotherapeutic Agents
  20. Biotherapy
  21. Management of BP-Carcinoid Hepatic Metastases
  22. Long-term Outcome
  23. Conclusions
  24. REFERENCES