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Br J Radiol. April 2016; 89(1060): 20150787.
Published online 2016 February 8. doi:  10.1259/bjr.20150787
PMCID: PMC4846207

Cardiothoracic manifestations of neuroendocrine tumours

Ramin Mandegaran, MB BS, BSc,corresponding author1 Sarojini David, MB BS, FRCR,2 and Nicholas Screaton, MB BS, FRCR3

Abstract

Cardiothoracic neuroendocrine tumour (NET) manifestations encompass a vast disease spectrum. Pulmonary neuroendocrine tumours represent a range of tumour grade and differentiation characteristics from pre-malignant diffuse neuroendocrine cell hyperplasia, well-differentiated, low-grade carcinoid tumours with excellent outcomes, through to high-grade small-cell lung carcinoma and large-cell neuroendocrine carcinoma with poor prognoses. Rarer thymic NETs represent a similarly wide neoplastic spectrum. Cardiac carcinoid is a paraneoplastic manifestation of the carcinoid syndrome and often the cause of mortality in NETs with hepatic metastases. Cardiothoracic NET manifestations are reviewed herein from a radiologists' perspective, discussing the diverse clinical presentations, spectrum of neoplastic and paraneoplastic manifestations, imaging features and treatment options.

INTRODUCTION

The neuroendocrine (NE) cell system comprises a heterogeneous group of cells sharing common phenotypes characterized by simultaneous expression of cell-specific hormonal products and characteristic protein markers.1 Neuroendocrine tumours (NETs) encompass a heterogeneous group varied in location, degree of cell proliferation and clinical presentation.2 With the exception of small-cell lung cancer (SCLC), NETs are uncommon entities with estimated incidence of 2.5–5 per 1,00,000,3 most commonly gastroenteropancreatic (60%), followed by bronchopulmonary tumours (25%) owing to the high density of Kultschitzky cells (pulmonary NE cells) within the bronchopulmonary epithelium.46

Pulmonary neuroendocrine tumours (PNETs) form a diverse pathologic and prognostic spectrum ranging from pre-malignant diffuse neuroendocrine cell hyperplasia [termed “diffuse idiopathic neuroendocrine cell hyperplasia” (DIPNECH)], well-differentiated low-grade carcinoid tumours with excellent outcomes to high-grade SCLC and large-cell neuroendocrine carcinoma (LCNEC) with poor prognoses.4 Thymic NETs are uncommon and typically highly aggressive.7,8 Cardiac carcinoid is a paraneoplastic manifestation secondary to high circulating levels of serotonin and its metabolites. This article presents a review of cardiothoracic NET manifestations and discusses each of these entities in turn.

NEUROENDOCRINE TUMOURS OF THE LUNGS

PNETs are classified according to World Health Organization criteria devised by Travis et al into the following categories: typical carcinoid (TC), atypical carcinoid (AC), SCLC and LCNEC.911 PNETs account for 25% of all lung cancers, with SCLC being the most common one (20%), followed by LCNEC (3%), TC (3%) and AC (0.2%).12 Differentiation of categories is on the basis of mitotic rate and the extent of necrosis: SCLC and LCNEC are considered high grade, whilst AC and TC are considered intermediate and low grade, respectively (Table 1).10,13 Immunohistochemistry and electron microscopy is additionally required for LCNEC classification, utilizing positive immunohistochemical staining for one or more NE markers and/or NE granules by electron microscopy.11,14 Immunohistochemistry also aids differentiating variable PNET growth patterns from other tumours (e.g. adenocarcinoma, paraganglioma and mesenchymal tumours).12

Table 1.
Grading and diagnostic criteria of pulmonary neuroendocrine tumours summarized according to World Health Organization 2004 criteria10

Traditionally, NE markers with greatest utility for this purpose included chromogranin A, synaptophysin and CD56.12 However, all these may not be expressed in a given PNET, whilst non-PNET tumours may also express certain NE markers, leading to diagnostic uncertainty.12,15 An example of this is cytokeratin-negative nested carcinoid and paraganglioma, since the aforementioned NE markers are typically expressed in both of these tumour types. In such cases, ancillary differentiating features are sought to differentiate between PNET and non-PNET tumour types (which includes the identification of S100-positive sustentacular cells in this case, which are typical of paraganglioma but not of carcinoids12). Similarly, the combination of Ki-67 and CD56 has recently been shown to be significantly more sensitive and specific at detecting and differentiating SCLC from non-small-cell lung carcinoma (NSCLC) compared with the traditional immunohistochemical panel of chromogranin A and synaptophysin.16 New immunohistochemical markers, such as BAI3, CDX2 and VIL1 in the differentiation of SCLC from LCNEC described by Bari et al14 continue to be identified, which will aid stratification of tumours and influence choice of therapies.

Typical and atypical carcinoid tumours of lungs

TCs represent 80–90% of bronchopulmonary carcinoid tumours, are more indolent compared with the more aggressive AC and differentiated histologically by lacking focal punctate necrosis of AC (although, this is prone to sampling error) (Table 1).10,12,17,18 In small crushed biopsies, Ki-67, a cell-proliferation marker, is useful to separate TC (proliferation rate ≤5%), AC (proliferation rate 10–25%) and high-grade LCNEC or SCLC with much higher rates of proliferation.19,20

Clinical features

TCs present most commonly in the 4th–5th decade, but represent the most common childhood primary pulmonary neoplasm, typically presenting in adolescence with no gender predilection.2124 Most TCs (57%) are symptomatic secondary to mechanical endoluminal tumour effects including cough (32%), recurrent pneumonia (24%) and haemoptysis from tumour ulceration (26%). Approximately, 25% TCs are asymptomatic and detected incidentally.5

ACs typically affect a slightly older age group, occurring in the 5th–6th decade, associated with smoking and slightly higher male predilection.25 Unlike TCs, most patients are asymptomatic owing to the typically peripheral location of the tumour. Whilst ectopic hormone secretion is frequently encountered in cases of gastrointestinal carcinoids, it is exceedingly uncommon in bronchopulmonary carcinoids, occurring in just 1–3% of cases. Furthermore, bronchopulmonary carcinoids rarely manifest with classical carcinoid syndrome, reflecting the infrequency of liver metastases arising from bronchopulmonary carcinoids.17 Rare endocrine manifestations include Cushing's syndrome (<2% patients with AC), acromegaly, hypercalcaemia and hypoglycaemia.26,27

Imaging features

Radiographically, lesions appear well defined, round or ovoid, often hilar/perihilar. Additional findings secondary to bronchial obstruction/mucus impaction may be seen.28

On CT, TCs are well defined, round/lobulated slow-growing lesions, usually < 3 cm in diameter (Figure 1).5,21 TCs may be elongated, with the long axis parallel to adjacent bronchi or pulmonary artery branches.21 75% of TCs arise from central airways, often endobronchial within the main, lobar or segmental bronchi.29 The remaining 25% are peripheral, typically round/ovoid tumours.12,21 Thin-section CT (1 mm or 2 mm) permits assessment of tumour relationship to bronchi as well as smaller nodules beyond subsegmental bronchus lesions.30 Ancillary CT features of endobronchial tumours include distal obstructive pneumonitis, atelectasis and air trapping caused by ball-valve mechanism (Figure 2).21,30

Figure 1.
A 49-year-old female with left upper lobe typical carcinoid. (a) plain PA radiograph and (b) corresponding axial CT (lung windows) demonstrating the round, well-defined, homogeneous left upper lobe soft-tissue mass.
Figure 2.
A 48-year-old female with an intermittently obstructing central left typical carcinoid. Plain PA radiographs demonstrating (a) complete atelectasis of the left lung with ipsilateral mediastinal shift at Day 1 of presentation, (b) resolution by Day 3, ...

ACs are more frequently lobulated, peripheral and larger than TCs, although morphological imaging cannot reliably differentiate the two (Figure 3).25,30 30% of TCs and ACs demonstrate calcification on CT, although patterns are variable (irregular, central, eccentric or occasionally diffuse mimicking broncholithiasis) (Figure 4).5,21,31 Similarly, both TCs and ACs demonstrate marked homogeneous enhancement following intravenous contrast (net enhancement >30HU on dynamic contrast enhancement studies), aiding differentiation from areas of atelectasis or mucous plugging.21,32 Volume-rendered images of CT bronchoscopy can aid lesion detection, although it is time consuming and not routinely used.33

Figure 3.
A 63-year-old male with lobulated atypical carcinoid. Axial CT (a) lung window and (b) soft-tissue window images demonstrating the lobulated tumour within the apical segment of the left lower lobe (arrows) with distal pneumonitis.
Figure 4.
(a) A 54-year-old female and (b) 56-year-old male with typical carcinoid tumours demonstrating calcification. (a) Bone window axial CT demonstrating eccentric calcification (arrow) in peripheral typical carcinoid of the right upper lobe. (b) Soft-tissue ...

Somatostatin receptor scintigraphy (SRS) using 99mtechnetium- or 111indium-labelled (111In) somatostatin analogues (e.g. octreotide, lanreotide) is effective in functional identification of PNETs owing to high expression of somatostatin receptors in 80% of bronchopulmonary carcinoids.34 Sensitivity of detecting primary bronchopulmonary carcinoid using 111In-octreotide and lanreotide is high, reportedly 93% and 87%, respectively.35 For detection of uncommon hepatic metastases, 111In-octreotide is superior to 111In-lanreotide, although still only demonstrates a sensitivity of approximately 60%.35,36 Fludeoxyglucose (FDG)-positron emission tomography (PET) is of some utility in bronchopulmonary carcinoid (Figure 5): Moore et al37 demonstrated low-grade FDG uptake in 29 TC patients and higher standardized uptake values (SUVs) in all 6 patients with AC studied, concluding that biological behaviour of bronchopulmonary carcinoids correlates well with SUV. However, other studies dispute the utility of FDG-PET, reporting lower than mediastinal uptake in both TC and AC, thereby simulating benign tumours.38

Figure 5.
A 70-year-old female with 18-fludeoxyglucose (FDG)-positron emission tomography (PET)/CT images of an atypical carcinoid tumour of the left upper lobe. Although the extent of FDG uptake is debated, (a) axial lung window CT with (b) axial PET reconstruction ...

PET/CT using 68gallium-labelled somatostatin analogues (e.g. 68Ga-DOTATOC) has emerged as the functional modality of choice for detection of bronchopulmonary carcinoids, with sensitivity and specificity for NETs reported as high as 97% and 92%, respectively39,40 (Figure 6). A 51-patient study of histologically confirmed NET but negative/equivocal uptake on 111In-DTPAoctreotdide SRS demonstrated significant 68Ga-DOTATOC uptake amongst 41 patients, altering management of 36 patients.40

Figure 6.
Two patients with 68Ga-DOTATOC positron emission tomography/CT images of proximal carcinoid tumours. (a) Axial fusion image demonstrating intense uptake within a left upper lobe carcinoid tumour. (b) Axial fusion image in a different patient demonstrating ...

35–70% of carcinoids are reachable by bronchoscopy (particularly, the typically more central TCs).5 Carcinoids are usually red-brown to bluish-tan smooth endobronchial masses, often highly vascular demonstrating contact bleeding (Figure 2E).5,12

Staging, treatment and prognosis

Carcinoids have been staged according to tumour–node–metastasis (TNM) criteria since their inclusion in the International Association for the Study of Lung Cancer (IASLC) 7th edition TNM classification.41 The same staging criteria as NSCLC are therefore applied. Regional lymph node and distant metastases (most commonly to liver and bone) are uncommon in TC, occurring in 10–15% and 3–5% cases, respectively.15,42 AC is significantly more aggressive, with higher frequency of nodal (50%) and distant (20%) metastases.17,18 Hence, TC and AC are defined as low- and intermediate-grade malignancy, respectively. Late metastases are well documented and 10-year minimum follow-up is recommended.17,42

Complete surgical resection of the primary tumour mass represents the gold standard treatment. Conservative surgical treatment options for TC include bronchotomy and excision, sleeve resection and sublobar resection.43,44 Transbronchial Nd:YAG laser and bronchoscopic cryotherapy have been shown as viable alternatives in selected cases of isolated endoluminal TC.45,46 AC is treated with more aggressive resection strategies similar to NSCLC, including lobectomy, bilobectomy and pneumonectomy.43,44

Chemoradiotherapy has limited role in carcinoid tumours. Despite high expression of somatostatin receptors, the role of somatostatin analogues is limited in TC/AC unless carcinoid or Cushing's syndromes coexist, where they have been shown to effectively reduce symptoms of paraneoplastic syndromes.5

TC has a good prognosis with 5-year survival >87%, although only 60% for the more aggressive AC.42

DIFFUSE IDIOPATHIC PULMONARY NEUROENDOCRINE CELL HYPERPLASIA

Normal bronchopulmonary NE cells exist as single cells or small clusters (<10) within bronchial/bronchiolar epithelium.12 Proliferation beyond this represents neuroendocrine cell hyperplasia (NECH), commonly a reactive process in chronic lung injury (e.g. bronchiectasis or fibrosis) or rarely, a diffuse primary process in the context of otherwise normal lung, known as DIPNECH.47,48 NE proliferations may form carcinoid “tumourlets” if ≤5 mm—differentiated from NECH by extension beyond the respiratory epithelial basement membrane. When these tumourlets grow beyond 5 mm in size, they are arbitrarily defined as carcinoid tumour.

Whilst progression to carcinoid tumour is unusual in reactive NECH/tumourlets, DIPNECH is characterized by widespread NECH/tumourlets progressing to TC and AC; hence, the World Health Organization 2004 classification of DIPNECH as a pre-neoplastic condition.10,48 Of note, Gosney et al observed that carcinoid tumours with presumed DIPNECH origins are invariably low grade and peripheral.49

Clinical features

Reports of DIPNECH describe female, non-smoker predilection, typically 45–65 years.48,50,51 Up to 50% are asymptomatic, identified incidentally on CT imaging, whilst a systematic overview identified chronic cough (71% of patients), dyspnoea (63% of patients), wheeze (25% of patients) and obstructive pulmonary lung function profile (54% of patients) as common features.48,50 Ectopic hormone production is rare.

Imaging features

Often normal chest radiography may show nodules (33%), subsegmental atelectasis or reticular infiltration.48 Imaging findings are best demonstrated on CT, with reported features reported including ≥1 nodule (in 63% of patients), ground-glass attenuation (in 29% of patients), mosaic attenuation (in 17% of patients), bronchiectasis (in 21% of patients) and associated tumourlets (in 68% of patients).48 High-resolution CT (HRCT) is preferable for identifying mosaicism secondary to air trapping (in 38% of patients).50 Tumourlet nodules may demonstrate solid or ground-glass attenuation, with a typically centrilobular predilection.50 The presence of bronchial wall thickening and peribronchiolar fibrosis is suggestive of an associated obliterative bronchiolitis and is a poor prognosticator.50

Ultimately, identification of mosaic attenuation with multiple pulmonary nodules amongst middle-aged females is suggestive of DIPNECH (Figure 7). However, it should be noted that patients who are asymptomatic are reportedly less likely to demonstrate mosaicism, presenting as multiple pulmonary nodules, thereby causing confusion with metastatic lung nodules.48,50,52

Figure 7.
A 53-year-old female patient diagnosed with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Axial CT (a) lung window image demonstrating lobules of air trapping and small nodules (solid arrows) and (b) corresponding soft-tissue window appearances ...

Diagnosis, treatment and prognosis

DIPNECH diagnosis requires histopathological confirmation of NE proliferations confined to large-/small-airway epithelium.53 Since not all airways are involved and transbronchial yields are low, surgical biopsy represents the gold standard sampling method.48

Optimal treatment is unestablished, given the limited reports of describing a variable clinical course.48 Inhaled and systemic corticosteroids and bronchodilators are considered when obstructive reversibility is demonstrated, with lung-sparing surgical resection often performed in patients with carcinoid tumour.48

Prognosis is typically good with 83% 5-year survival.50,54 However, rapid deterioration progressing to obliterative bronchiolitis and respiratory failure necessitating lung transplantation is also reported.55

LARGE-CELL NEUROENDOCRINE LUNG CARCINOMA

LCNEC is an aggressive PNET with poor prognosis. Its incidence is not clearly defined, although reported between 2.8% and 3.5% within surgically resected cases.56 It is strongly associated with smoking; LCNEC occurs in older age groups (6th–7th decade), with a mean age of 65 years and a male predilection.35,56

Clinical features

Clinical presentation varies from identification of an asymptomatic nodule to chest pain, non-specific flu-like symptoms, dyspnoea and night sweats. Unlike other PNET subtypes, paraneoplastic syndromes have not been frequently observed in cases of LCNEC.24,56,57 Disease is often advanced at diagnosis.57

Histopathological diagnosis of LCNEC requires demonstration of specific criteria, which are as follows: NE morphology (organoid nesting, palisading or rosette-like structures) and non-small-cell cytological features (e.g. low nuclear:cytoplasmic ratio; large cell size; high mitotic rate; large patches of necrosis; NE differentiation demonstrated by immunohistochemistry or electron microscopy).10

Imaging features

80% of LCNECs occur as a peripheral mass; the remainder occur as central mediastinal tumours, whilst mean tumour size is typically 3–4 cm (range 0.9–12 cm) at presentation.56,58 Multidetector CT features are non-specific and similar to other NSCLC, consisting of a peripheral, well-defined, lobulated and heterogeneously enhancing soft-tissue mass.59 Larger tumours typically demonstrate heterogeneous attenuation on enhanced studies owing to the characteristic patchy foci of necrosis, although smaller tumours may appear homogeneous in spite of this.58 Tumour calcification is uncommon, although dystrophic calcification occurs in approximately 10% of LCNECs.58 Other reported primary tumour morphological features include air bronchograms, cavitation and bubble lucency.58 According to data from the Surveillance, Epidemiology and End Results (SEER) programme of the US National Cancer Institute, Varlotto et al60 identified 1211 patients with LCNEC, 7.6% of patients presenting with malignant pleural effusion at initial diagnosis, 3.6% of patients with multiple lesions in the same lobe, 2% of patients with separate nodules in different lobes and 2.7% of patients with contralateral lung nodules.

Functional imaging has been shown to be of limited value in LCNEC thus far. In a study of 26 patients, SRS demonstrated 100% sensitivity in identifying LCNEC primary lung tumours, but 0% sensitivity in detecting liver metastases.61 Utility of fluorine-18-FDG PET/CT has not been fully established, although Chong et al38 demonstrated increased but varying levels of tracer uptake amongst 15/15 primary tumours.

Staging, treatment and prognosis

LCNEC is staged using TNM staging as for NSCLC, a point supported by the 1211 cases identified in the SEER programme, concluding that LCNEC staging should follow that of other large-cell carcinomas (LCC), owing to histopathological and biological features bearing more similarity to LCC than SCLC.60 In view of its aggressive behaviour, adjuvant chemoradiotherapy is generally used, although a definite advantage of post-operative adjuvant therapy has not been established.56 SEER data describe 1- and 4-year survival of 76% and 41%, respectively—similar to that of LCC.60

SMALL-CELL LUNG CANCER

SCLC is the most common and aggressive PNET, characterized by a mitotic rate of >10 per high power field and extensive necrosis. This is reflected in the typically advanced stage of disease at presentation, where 60–70% of patients have regional and extra-thoracic metastasis to the liver, bone and brain. SCLC is strongly associated with smoking, such that the diagnosis in non-smokers should be reconsidered.62 Characteristic histological features include small cell size, inconspicuous nucleoli, fine granular nuclear chromatin and scant cytoplasm, with immunohistochemistry only required in cases of uncertain histopathology/cytology.62

Clinical features

SCLC typically presents in the 6th–7th decade with male predilection. Presenting features may be a combination of constitutional symptoms (fatigue, reduced appetite, weight loss), primary tumour effects (cough, haemoptysis, dyspnoea), pressure effects/local invasion from primary tumour and metastatic deposits and paraneoplastic syndromes. Superior vena cava (SVC) compression symptoms occur in 10% of patients.63 Paraneoplastic syndromes include syndrome of inappropriate antidiuretic hormone secretion (10%), Cushing's syndrome (5%) and less commonly neurologic syndromes such as Lamberts–Eaton myasthenic syndrome.63

Imaging features

Radiographically, primary tumours are typically central. Rapid spread to mediastinal and hilar lymph nodes may appear as mediastinal widening and hilar/perihilar masses.

A large central tumour mass, distal atelectasis or obstructive pneumonitis are common. SCLC more frequently involves the right lung (56.2%) and upper lobes, with 22% of SCLC arising from main bronchi.5 23% of primary tumours demonstrate calcification. Ancillary features such as additional parenchymal masses and pleural effusions are seen in 41% and 38% of patients, respectively. Mediastinal and hilar lymph nodes are frequently enlarged, often forming confluent nodal masses, which may cause displacement and narrowing of nearby structures, e.g. tracheobronchial tree (in 68% patients) and SVC compression (in 10% patients) (Figure 8).21,63

Figure 8.
A 90-year-old female with small-cell lung cancer. Soft-tissue window coronal CT image demonstrating the right-sided ill-defined mediastinal soft-tissue mass causing almost complete obstruction of the superior vena cava (arrow).

Less than 5% SCLC presents as a non-specific peripheral nodule without associated lymphadenopathy—typically a well defined, lobulated, homogenously attenuating nodule, displaying marginal ground-glass opacity from local oedema/haemorrhage.63,64 Whilst the extent of tumour enhancement post contrast is variable in SCLC, greater enhancement has been shown to be a predictor of better chemotherapeutic response, related to a greater extent of underlying tumour angiogenesis.65

With regard to functional imaging, FDG-PET/CT has greater sensitivity and specificity for identifying metastatic lymph nodes vs conventional imaging (100% and 98% vs 70% and 94%, respectively),66 with similar sensitivity and specificity for detecting distant metastases.67 Ultimately, FDG-PET/CT has been shown to upstage tumours relative to CT or FDG-PET alone and has become an important adjunct in the staging and follow-up of SCLC.68

Staging, treatment and prognosis

Current American College of Chest Physicians guidelines recommend both the old Veterans Administration staging classification of limited stage (LS) and extensive stage (ES), as well as the latest IASLC 7th edition TNM classification to be used for SCLC staging.69 LS is defined as confined ipsilateral hemithoracic disease that can safely be encompassed within a tolerable radiation field (i.e. equivalent to any T/N stage and M0—except T3–T4 with multiple lung nodules outside a tolerable radiation field). ES represents disease beyond the ipsilateral hemithorax (i.e. any T/N stage with M1a/M1b). Distant liver, bone, brain and adrenal metastases are present at time of diagnosis amongst 20%, 18%, 15% and 6% of patients, respectively.70

In LS, chemoradiotherapy with curative intent provides the mainstay of treatment. The American College of Chest Physicians guidelines advocate early thoracic radiotherapy with platinum agent and etoposide-based chemotherapy.69 Curative surgery may be considered in selected Stage 1 disease. ES is palliated with similar chemotherapy regimens.69

Prognosis depends on stage and disease extent but is overall poor. Elevated lactate dehydrogenase, poor performance status, weight loss and paraneoplastic ectopic hormone production are further poor prognosticators.71 5-year survival for treated LS SCLC is 20–25% and negligible for ES SCLC, with a median survival of 8–10 months.69

THYMIC CARCINOIDS

Thymic carcinoids are rare, representing 2–4% of all mediastinal tumours.7 They represent a wide neoplastic spectrum from slow-growing well-differentiated tumours to aggressive, poorly differentiated carcinomas (applying the same mitotic rate-grading criteria as PNETs) and stain for conventional NE markers.72

Clinical features

Typically presenting at 40–50 years, thymic carcinoids demonstrate a 3 : 1 male-to-female predilection, with a third of tumours detected as an asymptomatic incidental finding on routine chest radiography.73 Given their anterior mediastinal position, presenting symptomatology include chest pain and tracheal/SVC compressive symptoms. Furthermore, up to 50% of thymic carcinoids are functionally active, associated with endocrinopathies including Cushing's syndrome and multiple endocrine neoplasia (males) Types I and II.74,75 Rarer associations include polyarthropathy, proximal myopathy, peripheral neuropathy, hypertrophic osteoarthropathy and Eaton–Lambert syndrome.75 Similar to pulmonary carcinoids, only a small percentage of thymic carcinoids (0.6%) are associated with carcinoid syndrome.76 Greater than 20% of patients have metastases at presentation (typically the liver, lungs, pleura, pancreas and bone).

Imaging features

Radiographs typically demonstrate an anterior mediastinal mass, often large in non-functioning tumours. Multidetector CT findings range from a well-defined nodule to an ill-defined unencapsulated mass of 2–20 cm with internal necrotic and haemorrhagic foci.77 Lesions typically enhance heterogeneously with contrast and may demonstrate punctate and dystrophic calcification.77,78 However, differentiating thymic carcinoids and other thymic tumours on cross-sectional imaging is difficult and reported case series are typically small.79,80 Aggressive behaviour (e.g. adjacent structure invasion) aids differentiation from thymomas and was observed in 7/8 cases in one series (involving the pleura, pericardium and/or great vessels).81 In the series by Ferrozzi, thymic carcinoids demonstrated hypointense signal characteristics on T1 weighted and proton density sequences, with inhomogeneously hyperintense signal on T2 weighted sequences.80

As with all carcinoids, thymic carcinoids demonstrate high somatostatin receptor expression; thus, SRS may be used for tumour detection (Figure 9). However, thymoma and thymic carcinoma also demonstrate high octreotide uptake, preventing differentiation of tumour type with SRS alone, whilst sensitivity in detection of primary and metastatic bone lesions in a seven-patient study was inferior to CT and/or MRI.82 Recent case reports and small case series describe high FDG uptake with thymic carcinoids and higher SUV vs thymomas, potentially aiding differentiation on imaging.83 In contrast to the high sensitivity of 68Ga-DOTATOC PET/CT for bronchopulmonary carcinoids, efficacy regarding thymic carcinoids is less certain: in one study, only one of four patients demonstrated radiotracer uptake.84

Figure 9.
A 58-year-old male with atypical thymic carcinoid. The patient had undergone debulking and palliative chemotherapy 2 years prior. 111In-octreotide scan was performed to assess recurrent disease. (a) Whole-body scan shows increased tracer uptake in the ...

Staging, treatment and prognosis

TNM thymic tumour staging applies to thymic carcinoids. Surgical resection is the management mainstay, with two case series reporting surgical resection in 88% and 100% of patients, respectively, although recurrence was shown to be common in both studies (64% and 37%, respectively). Post-operative radiotherapy may help prevent local recurrence, whilst chemotherapy has thus far demonstrated little benefit in reducing recurrence and increasing survival.85 Higher mitotic number and paraneoplastic endocrine syndromes, as with PNETS, are poor prognosticators, with an overall poor prognosis, which at best is equivalent to atypical bronchial carcinoids.86 One series reported 71-, 30- and 5-month median survival for patients undergoing total resection, partial resection or biopsy, respectively.87

CARCINOID HEART DISEASE

20–50% patients with carcinoid syndrome develop carcinoid heart disease (CHD), a disease process characterized by fibrous plaque deposits primarily affecting right-heart valve leaflets. Valves become thickened, fixed, retracted and unable to fully coapt, manifesting as combined stenotic and regurgitant right-sided cardiac disease.88 Although pathogenesis is uncertain, elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) strongly implicate serotonin and other vasoactive peptides released by hepatic metastases into hepatic venous circulation as key mediators.89 Left-sided cardiac involvement is uncommon (15%) owing to vasoactive peptide inactivation within the pulmonary circulation, thereby occurring in the minority of patients with right–left shunts (e.g. patent foramen ovale) and rarely actively secreting bronchial carcinoid.90

Clinical features

CHD usually occurs in the 5th–7th decade. Symptomatology of carcinoid syndrome (flushing, diarrhoea and wheezeing89) and right-heart failure (peripheral oedema and exertional fatigue) may coexist, associated with hepatomegaly and a pansystolic regurgitant tricuspid murmur.89,91 Urinary 5-HIAA is typically >10 times reference values.89

Imaging features

Chest radiography may demonstrate cardiomegaly (18%) and pulmonary nodules (11%).91 Echocardiography is the principal imaging tool: Consensus European Neuroendocrine Tumour Society guidelines require annual echocardiographic surveillance of known CHD.92 Two-dimensional transthoracic echocardiography (TTE) demonstrates valvular/subvalvular thickening.93 However, the superior spatial resolution of transoesophageal echocardiography permits accurate measurement of atrioventricular valve and right atrial wall thickening, demonstrates better right-heart volume (which is typically enlarged) and function measurement reproducibility vs TTE.93,94 A Mayo Clinic series reported echocardiographic tricuspid valve disease in 97% patients, with moderate–severe tricuspid regurgitation (characterized by a “dagger-shaped” spectral Doppler profile with early peak pressure and rapid decline) in 90% of patients.91 Pulmonary stenosis and regurgitation were reported in 49% and 39% of patients, respectively.91

In the minority of patients with left-sided valve disease, TTE with microbubble contrast has been shown to be useful in the identification of an associated patent foramen ovale, with a study of 15 patients with CHD with known mitral and/or aortic valve thickening demonstrating microbubble flow across a patent foramen ovale in 13 patients.95 Three-dimensional echocardiography more accurately assesses the extent of leaflet involvement (since three valve leaflets are simultaneously visualized).96

Cardiac MRI cine sequences demonstrate similar valve thickening and retraction, reduced excursion and semi-open fixed positions with disease progression (Figure 10).90 Furthermore, MRI offers the advantage of precise and reproducible functional and anatomical information without the operator dependency of echocardiography.93

Figure 10.
A 44-year-old female with carcinoid heart disease secondary to liver metastases. Single-frame four-chamber view from a cine SSFP sequence, systolic frame images: (a) horizontal long axis; (b) two-chamber view demonstrate dilated right atrium and ventricle ...

CT has little role in the diagnosis and surveillance of CHD, although features of right-heart impairment is often evident (i.v. contrast reflux into the inferior vena cava/hepatic veins, enlarged right-heart chambers), with ancillary findings of multiple avidly enhancing hepatic carcinoid metastases.97

Treatment and prognosis

The treatment aims of CHD are twofold: (i) to prevent CHD progression; and (ii) to minimize symptoms of right-heart failure and carcinoid syndrome.92 Therapies aimed at decreasing 5-HIAA levels (somatostatin analogues, hepatic artery embolization/hepatic resection) are effective in reducing carcinoid syndrome symptoms, albeit with little reported effect on CHD progression.98,99 General measures to treat right-heart failure include loop diuretics, digoxin therapy and salt and water restriction.92 Mechanical/bioprosthetic valve replacement and balloon valvuloplasty may be performed in established valvular disease.92

Prognosis remains poor, but reports suggest improved median survival from 1.2 years (1981–1989) to 4.4 years (1995–2000), in line with improved valve replacement perioperative mortality rates.92,100

CONCLUSION

Cardiothoracic NET manifestations are vast, comprising a range of lung and thymic malignancies of varying grade, all of which share certain NE characteristics. Some, like DIPNECH, are relatively new clinical entities and not yet fully understood but demonstrate specific radiological features, whilst paraneoplastic conditions such as CHD are unique to this tumour class. Clinical course and prognosis vary greatly and radiological presentation depends on type and tumour site, with a wide differential diagnosis and overlap of findings; yet, there are certain defining characteristics. Good knowledge of these features will aid appropriate imaging investigations and prompt diagnosis.

ACKNOWLEDGMENTS

Figure 2E bronchoscopic image was provided by Dr M Slade, Papworth Hospital NHS Foundation Trust. Figure 6 was provided by Professor A Groves and Mr J Hoath, Department of Nuclear Medicine, University College London Hospitals NHS Foundation Trust. Figure 9 was provided by Dr G Gnanasegaran, Department of Nuclear Medicine, Guy's and St Thomas' NHS Foundation Trust. Figure 10 was provided by Professor R Mohiaddin, CMR Unit, Royal Brompton and Harefield NHS Trust.

REFERENCES

1 . Capella C, , Heitz P, , Höfler H, , Solcia E, , Klöppel G.. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Archiv 1995 ; 425: 547–60. doi: http://dx.doi.org/10.1007/BF00199342 [PubMed]
2 . Solcia E, , Capella C, , Klöppel G, , Heitz PU, , Sobin LH, , Rosai J.. Endocrine tumours of the gastrointestinal tract. In: Solcia E, , Klöppel G, , Sobin LH, editors. , eds. Histologic typing of endocrine tumours. WHO international histological classification of tumours. Heidelberg, Germany: Springer Verlag; 2000 . pp. 57–67.
3 . Öberg K, , Castellano D.. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011 ; 30: 3–7. doi: http://dx.doi.org/10.1007/s10555-011-9292-1 [PubMed]
4 . Modlin IM, , Lye KD, , Kidd M.. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003 ; 97: 934–59. doi: http://dx.doi.org/10.1002/cncr.11105 [PubMed]
5 . Gustafsson BI, , Kidd M, , Chan A, , Malfertheiner MV, , Modlin IM.. Bronchopulmonary neuroendocrine tumors. Cancer 2008 ; 113: 5–21. doi: http://dx.doi.org/10.1002/cncr.23542 [PubMed]
6 . Ito T, , Nogawa H, , Udaka N, , Kitamura H, , Kanisawa M.. Development of pulmonary neuroendocrine cells of fetal hamster in explant culture. Lab Invest 1997 ; 77: 449–57. [PubMed]
7 . Duh QY, , Hybarger CP, , Geist R, , Gamsu G, , Goodman PC, , Gooding GA., et al. . Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 1987 ; 154: 142–8. doi: http://dx.doi.org/10.1016/0002-9610(87)90305-9 [PubMed]
8 . Viebahn R, , Hiddemann W, , Klinke F, , Von Bassewitz DB.. Thymus carcinoid. Pathol Res Pract 1985 ; 180: 445–8. doi: http://dx.doi.org/10.1016/S0344-0338(85)80119-9 [PubMed]
9 . Bajetta E, , Catena L, , Procopio G, , Bichisao E, , Ferrari L, , Della Torre S., et al. . Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? Ann Oncol 2005 ; 16: 1374–80. doi: http://dx.doi.org/10.1093/annonc/mdi258 [PubMed]
10 . Chapter 1 tumours of the lung. Travis WD, , Brambilla E, , Muller-Hermelink HK, , Harris CC, editors. . Pathology and genetics of tumours of the lung, pleura, thymus and heart. Vol 10. France: World Health Organization Classification of Tumours IARC Press Lyon; 2004 . pp. 9–124.
11 . Travis WD.. Advances in neuroendocrine lung tumors. Ann Oncol 2010 ; 21(Suppl. 7): vii65–vii71. doi: http://dx.doi.org/10.1093/annonc/mdq380 [PubMed]
12 . Rekhtman N.. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med 2010 ; 134: 1628–38. doi: http://dx.doi.org/10.1043/2009-0583-RAR.1 [PubMed]
13 . Klimstra DS, , Modlin IR, , Coppola D, , Lloyd RV, , Suster S.. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010 ; 39: 707–12. doi: http://dx.doi.org/10.1097/MPA.0b013e3181ec124e [PubMed]
14 . Bari MF, , Brown J, , Nicholson AG, , Kerr KM, , Gosney JR, , Wallace WA., et al. . BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lungcarcinomas. Histopathol 2014 ; 64: 547–56. doi: http://dx.doi.org/10.1111/his.12278 [PubMed]
15 . Rossi G, , Mengoli MC, , Cavazza A, , Nicoli D, , Barbareschi M, , Cantaloni C.. Large cell carcinoma of the lung: clinically oriented classification integrating immunhistochemistry and molecular biology. Virchows Arch 2014 ; 464: 61–8. doi: http://dx.doi.org/10.1007/s00428-013-1501-6 [PubMed]
16 . Zheng G, , Ettinger DS, , Maleki Z.. Utility of the quantitative Ki-67 proliferation index and CD56 together in the cytologic diagnosis of small cell lungcarcinoma and other lung neuroendocrine tumors. Acta Cytol 2013 ; 57: 281–90. doi: http://dx.doi.org/10.1159/000346394 [PubMed]
17 . Fink G, , Krelbaum T, , Yellin A, , Bendayan D, , Saute M, , Glazer M., et al. . Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001 ; 119: 1647–51. doi: http://dx.doi.org/10.1378/chest.119.6.1647 [PubMed]
18 . Beasley MB, , Thunnissen FB, , Brabilia E, , Hasleton P, , Steele R, , Hammer SP., et al. . Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000 ; 31: 1255–65. doi: http://dx.doi.org/10.1053/hupa.2000.19294 [PubMed]
19 . Iyoda A, , Hiroshima K, , Moriva Y, , Mizobuchi T, , Otsuji M, , Sekine Y., et al. . Pulmonary large cell neuroendocrine carcinoma demonstrates high proliferative activity. Ann Thorac Surg 2004 ; 77: 1891–5. doi: http://dx.doi.org/10.1016/j.athoracsur.2003.10.119 [PubMed]
20 . Pelosi G, , Rodriguez J, , Viale G, , Rosai J.. Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol 2005 ; 29: 179–87. doi: http://dx.doi.org/10.1097/01.pas.0000149690.75462.29 [PubMed]
21 . Chong S, , Lee KS, , Chung MJ, , Han J, , Kwon OJ, , Kim TS.. Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings. Radiographics 2006 ; 26: 41–57. doi: http://dx.doi.org/10.1148/rg.261055057 [PubMed]
22 . Wang LT, , Wilkins EW, Jr, Bode HH.. Bronchial carcinoid tumors in pediatric patients. Chest 1993 ; 103: 1426–8. doi: http://dx.doi.org/10.1378/chest.103.5.1426 [PubMed]
23 . Travis WD.. Lung tumours with neuroendocrine differentiation. Eur J Cancer 2009 ; 45(Suppl. 1): 251–66. doi: http://dx.doi.org/10.1016/S0959-8049(09)70040-1 [PubMed]
24 . Asamura H, , Kameya T, , Matsuno Y, , Noguchi M, , Tada H, , Ishikawa Y., et al. . Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006 ; 24: 70–6. doi: http://dx.doi.org/10.1200/JCO.2005.04.1202 [PubMed]
25 . Choplin RH, , Kawamoto EH, , Dyer RB, , Geisinger KR, , Mills SE, , Pope TL.. Atypical carcinoid of the lung: radiographic features. AJR Am J Roentgenol 1986 ; 146: 665–8. doi: http://dx.doi.org/10.2214/ajr.146.4.665 [PubMed]
26 . Francia G, , Davi MV, , Montresor E, , Colato C, , Ferdeghini M, , Lo Cascio V.. Long-term quiescence of ectopic Cushing's syndrome caused by pulmonary neuroendocrine tumor (typical carcinoid) and tumorlets: spontaneous remission or therapeutic effect of bromocriptine? J Endocrinol Invest 2006 ; 29: 358–62. doi: http://dx.doi.org/10.1007/BF03344109 [PubMed]
27 . Zatelli MC, , Maffei P, , Piccin D, , Martini C, , Rea F, , Rubello D., et al. . Somatostatin analogs in vitro effects in a growth hormone-releasing hormone-secreting bronchial carcinoid. J Clin Endocrinol Metab 2005 ; 90: 2104–9. doi: http://dx.doi.org/10.1210/jc.2004-2156 [PubMed]
28 . Jeung MY, , Gasser B, , Gangi A, , Charneau D, , Ducroq X, , Kessler R., et al. . Bronchial carcinoid tumors of the thorax: spectrum of radiologic findings. Radiographics 2002 ; 22: 351–65. doi: http://dx.doi.org/10.1148/radiographics.22.2.g02mr01351 [PubMed]
29 . Nessi R, , Basso Ricci P, , Basso Ricci S, , Bosco M, , Blanc M, , Uslenghi C.. Bronchial carcinoid tumors: radiologic observations in 49 cases. J Thorac Imaging 1991 ; 6: 47–53. doi: http://dx.doi.org/10.1097/00005382-199104000-00011 [PubMed]
30 . Naidich DP.. CT/MR correlation in the evaluation of tracheobronchial neoplasia. Radiol Clin North Am 1990 ; 28: 555–71. [PubMed]
31 . Shin MS, , Berland LL, , Myers JL, , Clary G, , Zorn GL.. CT demonstration of an ossifying bronchial carcinoid simulating broncholithiasis. AJR Am J Roentgenol 1989 ; 153: 51–2. doi: http://dx.doi.org/10.2214/ajr.153.1.51 [PubMed]
32 . Aronchick JM, , Wexler JA, , Christen B, , Miller W, , Epstein D, , Gefter WB.. Computed tomography of bronchial carcinoid. J Comput Assist Tomogr 1986 ; 10: 71–4. doi: http://dx.doi.org/10.1097/00004728-198601000-00015 [PubMed]
33 . Ferretti GR, , Thony F, , Bosson JL, , Pison C, , Arbib F, , Coulomb M.. Benign abnormalities and carcinoid tumors of the central airways: diagnostic impact of CT bronchography. AJR Am J Roentgenol 2000 ; 174: 1307–13. doi: http://dx.doi.org/10.2214/ajr.174.5.1741307 [PubMed]
34 . Bruns C, , Weckbecker G, , Raulf F, , Kaupmann K, , Schoeffter P, , Hoyer D., et al. . Molecular pharmacology of somatostatin-receptor subtypes. Ann N Y Acad Sci 1994 ; 733: 138–46. doi: http://dx.doi.org/10.1111/j.1749-6632.1994.tb17263.x [PubMed]
35 . Rodrigues M, , Traub-Weidinger T, , Li S, , Ibi B, , Virgolini I.. Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2006 ; 33: 532–40. doi: http://dx.doi.org/10.1007/s00259-005-0020-3 [PubMed]
36 . Granberg D, , Sundin A, , Janson ET, , Oberg K, , Skogseid B, , Westlin JE.. Octreoscan in patients with bronchial carcinoid tumours. Clin Endocrinol 2003 ; 59: 793–9. doi: http://dx.doi.org/10.1046/j.1365-2265.2003.01931.x [PubMed]
37 . Moore W, , Freiberg E, , Bishawi M, , Halbreiner MS, , Matthews R, , Baram D., et al. . FDG-PET imaging in patients with pulmonary carcinoid tumor. Clin Nucl Med 2013 ; 38: 501–5. doi: http://dx.doi.org/10.1097/RLU.0b013e318279f0f5 [PubMed]
38 . Chong S, , Lee KS, , Kim BT, , Choi JY, , Yi CA, , Chung MJ., et al. . Integrated PET/CT of pulmonary neuroendocrine tumors: diagnostic and prognostic implications. AJR Am J Roentgenol 2007 ; 188: 1223–31. doi: http://dx.doi.org/10.2214/AJR.06.0503 [PubMed]
39 . Gabriel M, , Decristoforo C, , Kendler D, , Dobrozemsky G, , Heute D, , Uprimny C., et al. . 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med 2007 ; 48: 508–18. doi: http://dx.doi.org/10.2967/jnumed.106.035667 [PubMed]
40 . Buchmann I, , Henze M, , Engelbrecht S, , Eisenhut M, , Runz A, , Schafer M., et al. . Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2007 ; 34: 1617–26. doi: http://dx.doi.org/10.1007/s00259-007-0450-1 [PubMed]
41 . Raptis CA, , Bhalla S.. The 7th edition of the TNM staging system for lung cancer: what the radiologist needs to know. Radiol Clin North Am 2012 ; 50: 915–33. doi: http://dx.doi.org/10.1016/j.rcl.2012.06.001 [PubMed]
42 . Ferolla P, , Daddi N, , Urbani M, , Semeraro A, , Ribeacchi R, , Giovenali P., et al. . Tumorlets, multicentric carcinoids, lymph-nodal metastases, and long-term behavior in bronchial carcinoids. J Thorac Oncol 2009 ; 4: 383–7. doi: http://dx.doi.org/10.1097/JTO.0b013e318197f2e7 [PubMed]
43 . Cardillo G, , Sera F, , Di Martino M, , Graziano P, , Giunti R, , Carbone L., et al. . Bronchial carcinoid tumors: nodal status and long-term survival after resection. Ann Thorac Surg 2004 ; 77: 1781–5. doi: http://dx.doi.org/10.1016/j.athoracsur.2003.10.089 [PubMed]
44 . Yendamuri S, , Gold D, , Jayaprakash V, , Dexter E, , Nwogu C, , Demmy T.. Is sublobar resection sufficient for carcinoid tumors? Ann Thorac Surg 2011 ; 92: 1774–8. doi: http://dx.doi.org/10.1016/j.athoracsur.2010.08.080 [PubMed]
45 . Neyman K, , Sundset A, , Naalsund A, , Espinoza A, , Solberg S, , Kongerud J., et al. . Endoscopic treatment of bronchial carcinoids in comparison to surgical resection: a retrospective study. J Bronchology Interv Pulmonol 2012 ; 19: 29–34. doi: http://dx.doi.org/10.1097/LBR.0b013e3182446b52 [PubMed]
46 . Bertoletti L, , Elleuch R, , Kaczmarek D, , Jean-Francois R, , Vergnon JM.. Bronchoscopic cryotherapy treatment of isolated endoluminal typical carcinoid tumor. Chest 2006 ; 130: 1405–11. doi: http://dx.doi.org/10.1378/chest.130.5.1405 [PubMed]
47 . Aguayo SM, , Miller YE, , Waldron JA, Jr, , Bogin RM, , Sunday ME, , Staton GW., Jr, et al. . Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992 ; 327: 1285–8. doi: http://dx.doi.org/10.1056/NEJM199210293271806 [PubMed]
48 . Nassar AA, , Jaroszewski DE, , Helmers RA, , Colby TV, , Patel BM, , Mookadam F.. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med 2011 ; 184: 8–16. doi: http://dx.doi.org/10.1164/rccm.201010-1685PP [PubMed]
49 . Gosney JR.. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors. Chest 2004 ; 125: 108S. doi: http://dx.doi.org/10.1378/chest.125.5_suppl.108S [PubMed]
50 . Davies SJ, , Gosney JR, , Hansell DM, , Wells AU, , du Bois RM, , Burke MM., et al. . Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax 2007 ; 62: 248–52. doi: http://dx.doi.org/10.1136/thx.2006.063065 [PMC free article] [PubMed]
51 . Cohen AJ, , King TE, Jr, , Gilman LB, , Magill-Solc C, , Miller YE.. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 1998 ; 158: 1593–9. doi: http://dx.doi.org/10.1164/ajrccm.158.5.9712019 [PubMed]
52 . Darvishian F, , Ginsberg MS, , Klimstra DS, , Brogi E.. Carcinoid tumourlets simulate pulmonary metastases in women with breast cancer. Hum Pathol 2006 ; 37: 839–44. doi: http://dx.doi.org/10.1016/j.humpath.2006.02.005 [PubMed]
53 . Dacic S.. Pulmonary preneoplasia. Arch Pathol Lab Med 2008 ; 132: 1073–8. doi: http://dx.doi.org/10.1043/1543-2165(2008)132[1073:PP]2.0.CO;2 [PubMed]
54 . Swigris J, , Ghamande S, , Rice T, , Farver C.. Diffuse idiopathic neuroendocrine cell hyperplasia. an interstitial lung disease with airway obstruction. [In Portuguese.] J Bronch 2005 ; 12: 62–4. doi: http://dx.doi.org/10.1097/01.laboratory.0000147030.83001.3c
55 . Terminella L, , Duarte A.. Obliterative bronchiolitis due to diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest 2005 ; 128: 467S–8S. doi: http://dx.doi.org/10.1378/chest.128.4_MeetingAbstracts.467S-a
56 . Fernandez FG, , Battafarano RJ.. Large-cell neuroendocrine carcinoma of the lung. Cancer Control 2006 ; 13: 270–5. [PubMed]
57 . Paci M, , Cavazza A, , Annessi V, , Purtrino I, , Ferrari G, , De Franco S., et al. . Large cell neuroendocrine carcinoma of the lung: a 10-year clinicopathologic retrospective study. Ann Thorac Surg 2004 ; 77: 1163–7. doi: http://dx.doi.org/10.1016/j.athoracsur.2003.09.070 [PubMed]
58 . Oshiro Y, , Kusumoto M, , Matsuno Y, , Asamura H, , Tsuchiya R, , Terasaki H., et al. . CT findings of surgically resected large cell neuroendocrine carcinoma of the lung in 38 patients. AJR Am J Roentgenol 2004 ; 182: 87–91. doi: http://dx.doi.org/10.2214/ajr.182.1.1820087 [PubMed]
59 . Franks TJ, , Galvin JR.. Lung tumors with neuroendocrine morphology: essential radiologic and pathologic features. Arch Pathol Lab Med 2008 ; 132: 1055–61. doi: http://dx.doi.org/10.1043/1543-2165(2008)132[1055:LTWNME]2.0.CO;2 [PubMed]
60 . Varlotto JM, , Medford-Davis LN, , Recht A, , Flikinger JC, , Schaefer E, , Zander DS., et al. . Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas? J Thorac Oncol 2011 ; 6: 1050–8. doi: http://dx.doi.org/10.1097/JTO.0b013e318217b6f8 [PubMed]
61 . Nocuń A, , Chrapko B, , Gołębiewska R, , Stefaniak B, , Czekajska-Chehab E.. Evaluation of somatostatin receptors in large cell pulmonary neuroendocrine carcinoma with 99mTc-EDDA/HYNIC-TOC scintigraphy. Nucl Med Commun 2011 ; 32: 522–9. doi: http://dx.doi.org/10.1097/MNM.0b013e32834508b3 [PubMed]
62 . Travis WD.. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Mod Pathol 2012 ; 25: S18–30. doi: http://dx.doi.org/10.1038/modpathol.2011.150 [PubMed]
63 . Krug LM, , Peitanza MC, , Kris MG, , Rosenzweig K, , Travis MD.. Cancer of the lung: small cell and otherneuroendocrine tumors of the lung. In: Devita VT Jr, , Lawrence TS, , Rosenberg SA, , DePinho RA, , Weinberg RA, editors. , eds. DeVita, Hellman and Rosenberg's cancer, principles and practice of oncology philadelphia: Philadelphia, PA: Wolters Kluwer, Lippincott Williams and Wilkins; 2008 . pp. 946–71.
64 . Quoix E, , Fraser R, , Wolkove N, , Finkelstein H, , Kreisman H.. Small cell lung cancer presenting as a solitary pulmonary nodule. Cancer 1990 ; 66: 577–82. doi: http://dx.doi.org/10.1002/1097-0142(19900801)66:3<577::AID-CNCR2820660328>3.0.CO;2-Y [PubMed]
65 . Choi JB, , Park CK, , Park DW, , Kim Y, , Kim YS, , Chhoi YW., et al. . Does contrast enhancement on CT suggest tumor response for chemotherapy in small cell carcinoma of the lung? J Comput Assist Tomogr 2002 ; 26: 797–800. doi: http://dx.doi.org/10.1097/00004728-200209000-00021 [PubMed]
66 . Brink I, , Schumacher T, , Mix M, , Ruhland S, , Stoelben E, , Digel W., et al. . Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 2004 ; 31: 1614–20. doi: http://dx.doi.org/10.1007/s00259-004-1606-x [PubMed]
67 . Thomsona D., , Hulseb P., , Loriganc P, , Favre-Finna C.. The role of potiron emission tomography in management of small cell lung cancer. Lung Cancer 2011 ; 73: 121–6. doi: http://dx.doi.org/10.1016/j.lungcan.2011.03.013 [PubMed]
68 . Fischer BM, , Mortensen J, , Langer SW, , Loft A, , Berthelsen AK, , Petersen BI., et al. . A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol 2007 ; 18: 338–45. doi: http://dx.doi.org/10.1093/annonc/mdl374 [PubMed]
69 . Jett JR, , Schild SE, , Kesler KA, , Kalemkerian GP.. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 ; 143(Suppl. 5): e400S–19S. doi: http://dx.doi.org/10.1378/chest.12-2363 [PubMed]
70 . Nakazawa K, , Kurishima K, , Tamura T, , Kagohashi K, , Ishikawa H, , Satoh H., et al. . Specific organ metastases and survival in small cell lung cancer. Oncol Lett 2012 ; 4: 617–20. doi: http://dx.doi.org/10.3892/ol.2012.792 [PMC free article] [PubMed]
71 . Gandhi L, , Johnson BE.. Paraneoplastic syndromes associated with small cell lung cancer. J Natl Compr Canc Netw 2006 ; 4: 631–8. [PubMed]
72 . Piciu D.. Chapter 10: neuroendocrine tumours (NET). Nuclear endocrinolgy. London, NY: Springer Heidelberg Dordrecht; 2012 . p. 201–10.
73 . Moran CA, , Suster S.. Primary neuroendocrine carcinoma (thymic carcinoid) of the thymus with prominent oncocytic features: a clinicopathologic study of 22 cases. Mod Pathol 2000 ; 13: 489–94. doi: http://dx.doi.org/10.1038/modpathol.3880085 [PubMed]
74 . Teh BT.. Thymic carcinoids in multiple endocrine neoplasia type 1. J Intern Med 1998 ; 243: 501–4. doi: http://dx.doi.org/10.1046/j.1365-2796.1998.00329.x [PubMed]
75 . Wick MR, , Rosai J.. Neuroendocrine neoplasms of the thymus. Pathol Res Pract 1988 ; 183: 188–99. doi: http://dx.doi.org/10.1016/S0344-0338(88)80046-3 [PubMed]
76 . Soga J, , Yakuwa Y, , Osaka M.. Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg 1999 ; 5: 285–92. [PubMed]
77 . Chaer R, , Massad MG, , Evans A, , Snow NJ, , Geha AS.. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg 2002 ; 74: 1733–40. doi: http://dx.doi.org/10.1016/S0003-4975(02)03547-6 [PubMed]
78 . Wick MR, , Scheithauer BW, , Weiland LH, , Bernatz PE.. Primary thymic carcinomas. Am J Surg Pathol 1982 ; 6: 613–30. doi: http://dx.doi.org/10.1097/00000478-198210000-00003 [PubMed]
79 . Xiang ZM, , Liang CM, , Ye HM, , Tan LL, , Hu YS, , Zhou YF.. CT manifestations of the thymic carcinoid and literature review. [In Chinese.] Nan Fang Yi Ke Da Xue Xue Bao 2010 ; 30: 557–9. [PubMed]
80 . Ferrozzi F, , Ganzetti A, , Mugnoli E, , Campodonico F, , Campani R.. Thymic carcinoid: CT and MR findings. [In Italian.] Radiol Med 1997 ; 9: 652–6. [PubMed]
81 . Wang DY, , Chang DB, , Kuo SH, , Yang PC, , Lee YC, , Hsu HC., et al. . Carcinoid tumours of the thymus. Thorax 1994 ; 49: 357–60. doi: http://dx.doi.org/10.1136/thx.49.4.357 [PMC free article] [PubMed]
82 . Gibril F, , Chen YJ, , Schrump DS, , Vortmeyer A, , Zhuang Z, , Lubensky IA., et al. . Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2003 ; 88: 1066–81. doi: http://dx.doi.org/10.1210/jc.2002-021314 [PubMed]
83 . Benveniste MF, , Moran CA, , Mawlawi O, , Fox PS, , Swisher SG, , Munden RF., et al. . FDG PET-CT aids in the preoperative assessment of patients with newly diagnosed thymic epithelial malignancies. J Thorac Oncol 2013 ; 8: 502–10. doi: http://dx.doi.org/10.1097/JTO.0b013e3182835549 [PMC free article] [PubMed]
84 . Dutta R, , Kumar A, , Julka PK, , Mathur SR, , Kaushal S, , Kumar R., et al. . Thymic neuroendocrine tumour (carcinoid): clinicopathological features of four patients with different presentation. Interact Cardiovasc Thorac Surg 2010 ; 11: 732–6. doi: http://dx.doi.org/10.1510/icvts.2010.237651 [PubMed]
85 . Moran CA, , Suster S.. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000 ; 114: 100–10. doi: http://dx.doi.org/10.1309/3PDN-PMT5-EQTM-H0CD [PubMed]
86 . Han B, , Sun JM, , Ahn JS, , Park K, , Ahn MJ.. Clinical outcomes of atypical carcinoid tumors of the lung and thymus: 7-year experience of a rare malignancy at single institute. Med Oncol 2013 ; 30: 479–86. doi: http://dx.doi.org/10.1007/s12032-013-0479-x [PubMed]
87 . De Montpreville VT, , Macchiarini P, , Dulmet E.. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg 1996 ; 111: 134–41. [PubMed]
88 . Kulke MH, , Mayer RJ.. Carcinoid tumors. N Engl J Med 1999 ; 340: 858–68. doi: http://dx.doi.org/10.1056/NEJM199903183401107 [PubMed]
89 . Fox DJ, , Khattar RS.. Carcinoid heart disease: presentation, diagnosis and management. Heart 2004 ; 90: 1224–8. doi: http://dx.doi.org/10.1136/hrt.2004.040329 [PMC free article] [PubMed]
90 . Bhattacharyya S, , Davar J, , Dreyfus G, , Caplin ME.. Carcinoid heart disease. Circulation 2007 ; 116: 2860–5. doi: http://dx.doi.org/10.1161/CIRCULATIONAHA.107.701367 [PubMed]
91 . Pellikka PA, , Tajik AJ, , Khandheria BK, , Seward JB, , Callahan JA, , Pitot HC., et al. . Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993 ; 87: 1188–96. doi: http://dx.doi.org/10.1161/01.CIR.87.4.1188 [PubMed]
92 . Dobson R, , Burgess MI, , Pritchard DM, , Cuthbertson DJ.. The clinical presentation and management of carcinoid heart disease. Int J Cardiol 2014 ; 173: 29–32. doi: http://dx.doi.org/10.1016/j.ijcard.2014.02.037 [PubMed]
93 . Dobson R, , Cuthbertson DJ, , Burgess MI.. The optimal use of cardiac imaging in the quantification of carcinoid heart disease. Endocr Relat Cancer 2013 ; 20: R247–55. doi: http://dx.doi.org/10.1530/ERC-13-0152 [PubMed]
94 . Ramage JK, , Ahmed A, , Ardill J, , Bax N, , Breen DJ, , Caplin ME., et al. . 2012 Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETS). Gut 2011 ; 61: 6–32. doi: http://dx.doi.org/10.1136/gutjnl-2011-300831 [PMC free article] [PubMed]
95 . Bhattacharyya S, , Toumpanakis C, , Burke M, , Taylor AM, , Caplin ME, , Davar J.. Features of carcinoid heart disease identified by 2- and 3-dimensional echocardiography and cardiac MRI. Circ Cardiovasc Imaging 2010 ; 3: 103–11. doi: http://dx.doi.org/10.1161/CIRCIMAGING.109.886846 [PubMed]
96 . Lang RM, , Badano LP, , Tsang W, , Adams DH, , Agricola E, , Buck T., et al. . EAE/ASE recommendations for image acquisition and display using three-dimensional echocardiography. Eur Heart J Cardiovasc Imaging 2012 ; 13: 1–46. doi: http://dx.doi.org/10.1093/ehjci/jer316 [PubMed]
97 . Mollet NR, , Dymarkowski S, , Bogaert J.. MRI and CT revealing carcinoid heart disease. Eur Radiol 2003 ; 13: L14–18. doi: http://dx.doi.org/10.1007/s00330-002-1806-3 [PubMed]
98 . Moller JE, , Connolly HM, , Rubin J, , Seward JB, , Modesto K, , Pellikka PA.. Factors associated with progression of carcinoid heart disease. N Engl J Med 2003 ; 348: 1005–15. [PubMed]
99 . Bhattacharyya S, , Toumpanakis C, , Chilkunda D, , Caplin ME, , Davar J.. Risk factors for the development and progression of carcinoid heart disease. Am J Cardiol 2011 ; 107: 1221–6. doi: http://dx.doi.org/10.1016/j.amjcard.2010.12.025 [PubMed]
100 . Møller JE, , Pellikka PA, , Bernheim AM, , Schaff HV, , Rubin J, , Connolly HM.. Prognosis of carcinoid heart disease: analysis of 200 cases over two decades. Circulation 2005 ; 112: 3320–7. [PubMed]

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