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Update in Pulmonary Carcinoid Tumors: A Review Article

From the Heart Lung Centre Utrecht, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands (RH, JMMvdB); Heart Lung Centre Utrecht, Department of Thoracic Surgery, University Medical Centre, Utrecht, the Netherlands (ABdlR); and St. Antonius Hospital, Department of Pathology, Nieuwegein, the Netherlands (CAS).

Correspondence: Address correspondence and reprint requests to: J. M. M. van den Bosch, MD, PhD, St. Antonius Hospital, Department of Pulmonology, PO Box 2500, 3435 EM Nieuwegein, the Netherlands; Fax: 31-30-605-2001; E-mail: j.vandenbosch{at}antonius.net

	ABSTRACT

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Pulmonary carcinoid tumors are neuroendocrine malignant tumors that make up 1% to 2% of all lung tumors. According to histopathologic criteria, carcinoids can be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids can be placed in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC to intermediate AC to high-grade large-cell neuroendocrine carcinoma and small-cell lung carcinoma. Familial pulmonary carcinoids are rare. The most common symptoms are hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and chest pain, unilateral wheezing, and shortness of breath. Paraneoplastic syndromes are rare and include carcinoid syndrome, Cushing’s syndrome, and ectopic growth hormone–releasing hormone secretion. The diagnosis is usually established by flexible bronchoscopy and biopsy, although occasionally this can result in severe hemorrhage. Immunoscintigraphy by somatostatin analogs can also be useful in diagnosis. The treatment of choice is surgical resection, and prognosis is relatively good in TC, although it is worse in AC. The role of radiotherapy and chemotherapy as part of multimodality treatment or palliation is still debated.

Key Words: Pulmonary carcinoid • Pathology • Classification • Diagnosis • Treatment

	HISTORY

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Carcinoid tumors are malignant neuroendocrine tumors, first described in 1888 in the ileum.¹ When neuroendocrine cells were first discovered, they were called clear cells and, later, APUD system cells (amine precursor uptake and decarboxylation).² The term neuroendocrine was introduced with the finding that these cells are capable of synthesizing hormonal products and that a number of these products are identical to cells of the nervous system. The difference between TC and AC was first defined by the histological criteria of Arrigoni et al. and later modified by Travis et al., eventually resulting in the generally accepted classification.^3–5

	EPIDEMIOLOGY

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Male and female patients are almost equally distributed. However, in patients under the age of 50 years, carcinoid was seen almost twice as often in women.⁶ The mean age is approximately 47 years, but atypical carcinoid (AC) tumors occurred in significantly older patients in the series of Skuladottir et al.,⁷ Filosso et al.,⁸ and El Jamal et al.⁹ Although this theory is speculative, this might be due to smoking as a risk factor in AC. This is supported by the finding that the frequency of molecular changes that are often seen in smoking-related lung tumors increases in the spectrum of neuroendocrine tumors, from AC (a few cases) to large-cell neuroendocrine carcinoma (LCNEC; more frequently) to small-cell lung carcinoma (SCLC; very frequently).¹⁰

Several studies support the hypothesis that smoking may be a risk factor in the development of AC. In one study of 106 patients, smoking history was positive in 44 of 63 patients, with mean-pack years of 28¹¹; in another study, 33% of patients with typical carcinoids (TC) and 64% with AC were smokers,¹² whereas other authors report 30% and 80%, respectively.¹³

Of all carcinoid tumors, approximately 25% are located in the respiratory tract. The pulmonary carcinoids comprise 1% to 2% of all lung tumors.^14,15 Most pulmonary carcinoids are confined to the main or lobar bronchi.¹⁶ Regional lymph node involvement is seen in 10%.¹⁶ The incidence of pulmonary neuroendocrine tumors, especially of TC, seems to be sharply increasing.⁷ It is unknown whether this is because of a true increase or because of a more accurate diagnosis when more advanced medical viewing techniques detect asymptomatic carcinoids.

	PATHOLOGY

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Biological Behavior
Carcinoid tumors contain many neurosecretory granules that can be seen by electron microscopy. These granules are capable of synthesis, storage, and release of substances such as serotonin, histamine, prostaglandins, kallikrein, and dopamine. Among these substances, serotonin (5-hydroxytryptamine; 5-HT) is seen most frequently. Degradation of 5-HT results in 5-hydroxyindoleacetic acid (5-HIAA), an oxidative deamination catalyzed by monoamine oxidase. An indicator of 5-HT production in the body is 5-HIAA, which is excreted in urine. When released in the systemic circulation, 5-HT can result in a large range of actions. Important actions can be excitation of smooth muscle (leading to increased gastrointestinal motility or bronchoconstriction), platelet aggregation, and many possible actions on CNS neurons. Also, vascular constriction (direct and via sympathetic innervation) and dilatation (endothelium dependent) can be achieved by the action of 5-HT. These actions can lead to the carcinoid syndrome.

These tumors can be placed in a spectrum of malignant neuroendocrine tumors. At one end of the spectrum are the low-grade TCs, followed by the intermediate-grade ACs, whereas at the other extreme end of the spectrum are the high-grade LCNECs and SCLCs (Table 1). The distinction between TC and AC is clinically important, because it is based on the number of mitoses, which is the best predictor of prognosis. Also, the presence of necrosis is important. TC is defined as <2 mitoses per 2 mm² with no necrosis, whereas AC is defined as 2 mitoses but <10 mitoses per 2 mm², coagulative necrosis, or both.³

In accordance with the classification in TC and AC on pathologic and clinical grounds, molecular studies also show differences between TC and AC and also between AC and the other neuroendocrine tumors (LCNEC and SCLC).^10,18–25 Abnormalities in tumor-suppressor genes and oncogenes are seen more in AC compared with TC.

In TC and AC, DNA underrepresentations of 11q are frequent, whereas these are rare in LCNEC and SCLC.²⁶ In AC, there are also often losses of 10q and 13q, and these can also be seen in LCNEC and in SCLC. Losses of 10q and 13q probably indicate more aggressive behavior in AC.

Although very rare, familial pulmonary carcinoids are found. Familial carcinoids of the lung are associated with the syndrome of multiple endocrine neoplasia type 1 (MEN1). MEN1 is a familial tumor syndrome with an autosomal-dominant inheritance that is characterized by a high frequency of endocrine malignancies. Inactivation of the MEN1 gene by mutation has been reported in both AC (25%) and TC (67%), whereas these mutations are absent in SCLC^27,28 and are very rare in LCNEC.²⁸ Recently, Oliveira et al.²⁹ described familial pulmonary carcinoids that are not associated with the MEN1 syndrome; they are probably based on an occult mutation specific for the development of familial pulmonary carcinoids.

Location
Tumor location is in the major bronchi (approximately 70%), and approximately a third of the tumors are located in the periphery of the lungs (segmental bronchi or beyond). They occur more (61%) in the right than in the left lung, especially in the middle lobe.^30,31

Pattern of Spread
ACs present more often with nodal metastases and a higher recurrence rate compared with TC. A study in 142 patients showed that in TC there was N1 disease in 10%, N2 in 3%, and no N3, whereas these rates were 29%, 14%, and 14%, respectively, in AC.³²

In a large retrospective search that included 517 patients at the Mayo Clinic from 1976 to 1997 with pulmonary carcinoid, 36 patients had positive regional thoracic lymph nodes at the time of surgical resection (pT1–3, N1/2, M0). When these cases were reviewed, 23 were diagnosed as TC, 11 as AC, and 2 as another neuroendocrine tumor.³³ In the TC and AC groups, systemic metastases were demonstrated in two and seven patients, respectively. In the patients with positive nodes, 19 TC patients, but only 4 AC patients, had no evidence of disease at the last follow-up. The conclusion of this study was that in AC with positive N1 or N2 lymph nodes, the risk of recurrence is higher and prognosis is significantly worse compared with TC.

Distant metastases are most commonly found in liver, bone, brain, adrenal glands, and ovary.¹¹ They have been described more often in male and smoking patients.³¹ Other, more uncommon, sites are breast, abdominal wall, spleen, pancreas, pituitary, skin, and the retro-orbital region.³⁴ Also, the brain as the first manifestation of metastatic disease in AC has been reported.³⁵

	CLINICAL FEATURES

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Signs and Symptoms
Most patients with pulmonary carcinoid are symptomatic; symptoms have been reported ranging from 52%⁸ to 92%³⁶ (Table 1). Reported symptoms were hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and chest pain, unilateral wheezing, and shortness of breath (Table 2). A total of 14.2% of patients had been treated for asthma for up to 3 years before the tumor was discovered.⁸ In another study, 41% of the patients presented with evidence of bronchial obstuction.³² However, a large Danish study showed that 24% of all TC and 7% of all AC were detected by coincidence at autopsy.⁷ Uncommonly, a paraneoplastic syndrome can be the first presentation of a carcinoid.

Another complication can be right- and left-sided valve disease of the heart. Often this is due to fibrosis of the tricuspidalis valve of the heart, probably because the highest concentration of vasoactive substance is in the right side of the heart.⁴⁰ When it is metabolized in the lung, in the left side of the heart the concentration of this substance is lower. In the end, this can lead to right heart failure with secondary pulmonary hypertension. However, left-sided valve disease has also been reported.⁴¹ Surgery for valvular heart disease should be considered in these cases.

Cushing’s Syndrome
Another paraneoplastic syndrome is Cushing’s syndrome (CS), which is present in approximately 2% of patients with pulmonary carcinoid. This is characterized by ectopic adrenocorticotropic hormone (ACTH) production, i.e., synthesis and hypersecretion of ACTH by nonpituitary tumors, resulting in hypercortisolism. Ectopic ACTH production resulting in CS is seen in a small number of malignancies. Bronchial carcinoid is the most frequent cause (25%), whereas SCLC (11%) and disseminated neuroendocrine tumors of unknown primary source (7%) are less frequent.⁴²

In contrary to most patients with SCLC, in whom CS with atopic ACTH production is mostly obvious, the source of ectopic ACTH production in pulmonary carcinoids can be more occult. Frequent signs of hypercortisolism are weakness, hypertension, glucose intolerance, hypokalemia, alkalosis, weight loss, anemia, and hyperpigmentation. The typical features of CS are more frequent in slowly progressing tumors.

Ectopic Growth Hormone–Releasing Hormone Synthesis
Carcinoid tumors are the most frequent causes of ectopic production of growth hormone (GH)-releasing hormone, leading to high levels of GH and insulin-like growth factor-1 with classic acromegaly. Surgical resection of the carcinoid leads to a decrease in GH, with regression of the acromegaly features. In case of irresectability, long-acting somatostatin analogs can be given, which suppress both ectopic GH-releasing hormone and pituitary GH.⁴³

	DIAGNOSTIC STUDIES

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Radiology
Chest imaging shows a mean lesion size of approximately 3 cm, although much larger lesions are also frequent. They are mostly centrally located; only approximately one third are located in the periphery of the lung. Intratumoral calcification is visible in <10%.

Somatostatin Receptor Scintigraphy
Immunoscintigraphy by somatostatin analogs (for example, octreotide, lanreotide, and pentetreotide) is potentially a useful diagnostic study for neuroendocrine lung tumors, although its role has still not been fully clarified.^44–46 This technique is based on the overexpression of somatostatin receptors on carcinoids. Scintigraphic detection of carcinoid tumors with octreotide has a sensitivity of 86%, whereas combined iodine-131–metaiodobenzylguanidine and indium-111–pentetreotide yields a sensitivity of 95%.⁴⁷ A recent study with indium-111–octreotide showed in all cases the primary tumors and all cases of recurrent or metastatic disease, sometimes even before the appearance of symptoms.⁴⁶ Because scintigraphy is also positive in many other tumors, granulomas, and autoimmune diseases, specificity is low. Also, this technique can not be relied on to exclude a carcinoid tumor. In conclusion, immunoscintigraphy seems very promising, but it will be a preliminary diagnostic tool until more data are available.

Positron Emission Tomography
Preoperative diagnosis can be difficult to make. When a solitary nodule is evaluated, use of positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) imaging often shows false-negative results with pulmonary carcinoids, which are hypometabolic on FDG-PET.⁴⁷ However, in a retrospective study of tumors 3 cm, five of six carcinoids in one study showed positive FDG-PET scans.⁴⁸

Bronchoscopy
By bronchoscopy, the tumor typically has a highly vascular appearance, with a pink/reddish or yellow smooth-looking surface. Often, the overlying epithelium is intact, making cytological washings or brushing almost always unrewarding, in contrary to biopsy specimens.

	MANAGEMENT

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Biopsy
In patients with centrally localized carcinoids, especially when rigid bronchoscopy is used, biopsy positivity can be 100%. In more distal tumors, this can be more difficult. In daily clinical practice, endobronchial biopsy of a carcinoid tumor seems to be quite safe. In the past, major hemorrhage with biopsy by fiberoptic bronchoscopy was feared. However, Fink et al.³² reported no significant bleeding after bronchoscopy with endobronchial biopsy, whereas bronchoscopy was diagnostic in 72 patients (51%). In another 20 patients, diagnosis was obtained by fine-needle biopsy or aspiration, and diagnosis by thoracotomy was obtained in 50 patients (35%). In a review of 587 biopsies by flexible and rigid bronchoscopy, there was significant hemorrhage in 15 (2.6%) patients, and 11 (1.9%) of them did not require transfusion or emergency surgery. In four patients (.7%), emergency thoracotomy was necessary because of massive uncontrollable hemorrhage.⁴⁹ In the study of McCaughan et al.,³¹ bronchoscopic biopsy was not routinely performed, with a view of the risk of hemorrhage. There were 46 patients with a centrally localized carcinoid visible at bronchoscopy. Of these patients, 25 underwent bronchoscopy (13 flexible and 12 rigid). Only three of the patients who underwent rigid bronchoscopy had massive bleeding after biopsy, and none required emergency thoracotomy. To reduce the risk of massive bleeding, epinephrine solution administered through the bronchoscope before the biopsy is taken can be useful. Alternatively, biopsy samples can be taken in the operating room with a rigid bronchoscope while the patient is under general anesthesia. Using the rigid bronchoscope also has the advantage of larger, more reliable biopsy samples. In case of difficult-to-control bleeding with biopsy by rigid bronchoscopy, a neodymium:yttrium-aluminum-garnet laser can be used, if available.

Relief of Bronchial Obstruction
Endobronchial laser treatment can be useful, both to treat airway obstruction before surgery and to look behind the tumor to estimate the extent of bronchoplastic surgery.³⁶ Endobronchial laser treatment alone may not be considered as curative, because carcinoids mostly spread extraluminally (the so-called iceberg phenomenon).

Surgery
Surgery offers the only chance of cure and is the treatment of choice. In case of endobronchial localization of a TC, bronchoplastic parenchyma-sparing surgery is the standard surgical procedure. Lobectomy (with or without bronchoplastic procedures) is the most frequent resection (51%–58%). Other surgical resections include bilobectomy (9%–15%), segmentectomy or wedge resection (2%–15%), bronchoplastic procedures (5%–18%), and pneumonectomy (6%–16%).^{8,31,32,36,50,51}

The study of Marty-Ané et al.⁵¹ showed that AC presented as peripheral nodules (63%) and a central mass or atelectasis (37%). In contrary to TC, parenchyma-sparing surgery is not considered as sufficient in AC. Therefore, the same surgical treatment as in non-SCLC is advocated (i.e., at least a lobectomy). With a pre- or intraoperative diagnosis of AC, or if there is doubt during surgery about the diagnosis, the same treatment as in non-SCLC has to be performed.^31,51

Endobronchial Therapeutics or Resection
Endobronchial laser treatment can be used as an alternative treatment option in patients not fit to undergo surgical resection. In highly selected patients, however, some authors advocate a more conservative wait-and-see policy after bronchoscopic tumor removal.^52–56 With high-resolution computed tomography and endobronchial ultrasonography (EBUS), the bronchial wall can be screened for residual tumor and depth of tumor invasion after bronchoscopic tumor removal. With EBUS, the EBUS probe can be inserted through the working channel of the flexible bronchoscope while the other end is connected to an ultrasound unit. The detection threshold for high-resolution computed tomography is 2 mm, and for EBUS it is even better.

Chemotherapy
Until recently, only a few small older studies describing combined-modality treatment were available.^57–59 These regimens were platinum based (cisplatin and etoposide) or included cyclophosphamide, doxorubicin, and vincristine. Survival data have to be interpreted with caution.

In metastatic disease, chemotherapy results are discouraging. Granberg et al.⁶⁰ report a regimen of interferon alfa as first-line treatment in patients with pulmonary carcinoid metastases. To achieve symptomatic relief in case of carcinoid syndrome, this was combined with octreotide. Also, in other studies, somatostatin analogs or metaiodobenzylguanidine has been used for incapacitating symptoms of the carcinoid syndrome.⁴⁷ Octreotide is now registered for the treatment of carcinoid syndrome and has a symptomatic and biochemical response rate of approximately 60% and 70%, respectively.⁶¹

Second-line therapy consists of streptozotocin and 5-fluorouracil, whereas in third-line therapy, in analogy to SCLC, cisplatin and etoposide are given. When most of the tumor burden is present as liver metastases, embolization with gel foam has been used. For several patients, up to three liver embolizations have been performed.

Response can be monitored by clinical improvement, biochemical markers, and radiological regression. The most sensitive marker to monitor disease activity is plasma chromogranin A, a glycoprotein that plays an important role in the storage and secretion of neuroendocrine substances within vesicles of the neuroendocrine cell.^60,62 However, this marker cannot be used as screening tool, because the specificity is far too low.⁶² For monitoring disease activity in carcinoid syndrome, urinary 5-HIAA can also be used. Increases in 5-HIAAA have been reported in approximately two thirds of patients with a carcinoid syndrome.⁶⁰

Radiotherapy
In some studies, all node-positive patients received adjuvant radiotherapy^35,50; in another study, only those with N2 disease received adjuvant radiotherapy.⁶ In this last-mentioned study, radiotherapy was not proven to be beneficial.

	OUTCOMES

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TC Tumors: N0, N1, and N2
The distinction between TC and AC is important for prognosis. Patients with TC have a good prognosis, with a 5-year survival of 87% to 100% and a 10-year survival of 82% to 87% (Table 3). However, worse survival data have been published.³⁰

AC Tumors: N0, N1, and N2
With AC, survival is worse: 5-year survival is 56% to 75%, 10-year survival is 35% to 56%, and 15-year survival is 28%.^3,11,32 AC with lymph node metastases has a reported 5-year survival of 25% to 69% and a 10-year survival of 25% to 59%. Of patients with nodal metastases, 63.6% have distant metastases.³³ According to tumor-node-metastasis stage, Beasley et al.¹¹ showed a 5-year survival in stage I of 71%, stage II of 46%, and stage III of 37%.

	NEW DEVELOPMENTS AND HORIZONS

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Various clinical trials for patients with carcinoids are currently recruiting patients. It should be emphasized, however, that the listed trials particularly target patients who have advanced disease, and these individuals by definition usually have gastrointestinal carcinoids rather than pulmonary carcinoids. As noted earlier in this review, the frequency of metastatic disease related to pulmonary carcinoids is actually very low.

A phase II trial supported by the Mid-Atlantic Oncology Program and the Cancer Biotherapy Research Group is investigating the effect of 5-fluorouracil plus interferon alfa in advanced metastatic carcinoids. Another phase II trial (National Cancer Institute and Memorial Sloan-Kettering Cancer Center) is investigating the effect of thalidomide in patients with neuroendocrine tumors, on the basis of the rationale that thalidomide may stop the growth of these tumors by stopping blood flow to the tumor. Radiofrequency ablation, using a computed tomography–guided high-frequency electric current to kill tumor cells, is being tested in a phase II trial (sponsored by the National Cancer Institute and Jonsson Comprehensive Cancer Center) for a wide range of pulmonary malignancies.

Another area of research is the overexpression of somatostatin receptors in carcinoids.⁶³ Somatostatin receptors can be used for both diagnosis (described previously) and treatment. Treatment can be achieved by controlling symptoms with somatostatin analogs. Another treatment option could be labeling somatostatin analogs for somatostatin-targeted radiotherapy. However, adverse events can be expected from healthy tissues throughout the body that express somatostatin receptors. Renal and hematological toxicity, especially, have been reported. The results of large clinical trials are expected in the near future.

	FOOTNOTES

 
Pulmonary carcinoids are malignant neuroendocrine tumors and can be classified as typical or atypical carcinoids. In this review, epidemiology, pathology, clinical features, diagnosis, management, and prognosis are discussed.

Received for publication September 30, 2002. Accepted for publication February 21, 2003.

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