Lung carcinoids account for 85% of all bronchial gland tumors. Lung carcinoids are rare, malignant neuroendocrine tumors that comprise approximately 2% of primary resected lung tumors.⁷,⁸ Of all carcinoid tumors, approximately 25% are located in the respiratory tract.⁷ The annual incidence is approximately 2.3 to 2.8 cases per 1 million population.⁸ The ratio of women to men is 1.6:1.⁸ This is in contrast with bronchogenic carcinoma in which men still dominate. Information from the U. S. Surveillance Epidemiology and End Results (SEER) database has shown that the annual rates of bronchial carcinoids among white men and women per 100,000 population between 1992 and 1999 were 0.52 and 0.89, respectively, and 0.39 and 0.57, respectively, for black men and women.⁹,¹⁰,¹¹ Patients with pulmonary carcinoid tumors are, on average, 10 years younger than patients with bronchogenic carcinoma.¹² The prevalence of smoking is similar to the general population in patients with typical carcinoid and is twice as high in patients with atypical carcinoid.⁸,¹³ Familial pulmonary carcinoids, although rare, are found and are associated with the syndrome of multiple endocrine neoplasia type I.⁷,¹⁴,¹⁵ There is also a report of familial pulmonary carcinoid that is not associated with multiple endocrine neoplasia type I syndrome.⁷ Rarely, combined tumors of carcinoid and adenocarcinoma have been reported.¹⁶,¹⁷ Carcinoid tumors in children are extremely rare.¹⁸,¹⁹ However, bronchial carcinoids are the commonest primary lung neoplasms in late adolescence.¹⁰ Carcinoid tumors allocated peripherally, or with size more than 3 to 5 cm in diameter, are more likely to be atypical carcinoids. In addition, these patients are usually older than 55 years old and current or former smokers.²⁰

Pulmonary carcinoids produce symptoms as a result of their location within the tracheobronchial tree. Cough, hemoptysis, or recurrent pneumonia are common symptoms. Unilateral wheezing resulting from a bronchial carcinoid has been described.¹²,²¹ Some of these patients have been misdiagnosed as having asthma. These symptoms are common in tumors that arise in the proximal airways. In peripheral lesions, 19% to 39% of patients are asymptomatic, and these are generally discovered as incidental findings on plain chest radiography.²²,²³ Thoracic carcinoid tumors are the commonest cause of ectopic adrenocorticotropic hormone (ACTH) production in patients with Cushing syndrome.¹²,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³² Acromegaly is also a rare manifestation of carcinoid tumors. This is caused by the ectopic production of growth hormone-releasing hormone (GHRH).
Bronchial carcinoids are the commonest cause of extrapituitary GHRH secretion.³³,³⁴,³⁵,³⁶,³⁷ These tumors behave more aggressively.³⁸ Carcinoid syndrome is relatively uncommon in pulmonary carcinoids. Symptoms such as flushing, sweating, or diarrhea occur in 5% to 10% of patients and are reported mainly in those with bronchial tumors larger than 5 cm or in those with tumors metastasized to the liver. Long-term sequelae of prolonged elevated hormone levels such as serotonin include venous telangiectasias, right-side valvular heart disease, and fibrosis in the retroperitoneum and other sites. Pulmonary carcinoids produce lesser quantities of serotonin than do midgut carcinoids. For the uncommon case of carcinoid syndrome, urinary excretion of 5-hydroxy-indole acetic acid (5-HIAA) may be elevated but, certainly, much less than in a case of midgut carcinoid. Measurement of urinary serotonin levels may be of value.³⁹ Very rarely, biopsy of a bronchial carcinoid may induce a carcinoid crisis, which is an acute carcinoid syndrome. Extreme flushing, changes in blood pressure, bronchoconstriction, and confusion are the commonest symptoms. This is caused by massive systemic release of bioactive substances. Although, this syndrome is extremely rare, prophylactic administration of octreotide is of value.⁴⁰,⁴¹

The commonest findings on chest radiograph include a hilar tumor not necessarily accompanied by atelectasis or a peripheral lesion in 25% of cases, which is more often atypical carcinoid.²⁴,⁴²,⁴³ There are several classifications regarding the location of carcinoids. One widely accepted definition of a centrally located mass is one that is visible at the time of bronchoscopy. Tumors that are not visualized at bronchoscopy are considered to be peripherally located.¹² Computed tomography (CT) scan is very useful because it provides a good resolution of tumor extent, location, and the presence or absence of mediastinal lymphadenopathy. The tumor frequently looks like a mixture of intraluminal and extraluminal component. The tumor may have lobular or irregular borders, calcifications, and marked enhancement by contrast-enhanced CT because of the rich vascularity. Cavitation of the tumor is rare, and pleural effusion is unusual. CT scan is useful for the detection of hilar or mediastinal lymphadenopathy, although the predictive value is low.⁴⁴,⁴⁵,⁴⁶ Magnetic resonance imaging (MRI) may be useful to differentiate a small peripheral carcinoid nodule with high-contrast enhancement from pulmonary vessels. MRI is also useful in detecting liver metastasis.⁴⁷ Carcinoid tumors generally demonstrate a low level of uptake of¹⁸F-fluorodeoxyglucose as measured by positron emission tomography (PET). Therefore, patients with carcinoid tumors are more likely to have a negative PET scan,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴ immunoscintigraphy by In-111 octreotide based on the expression of somatostatin receptors is a promising diagnostic tool, although negative results cannot exclude carcinoid tumors.⁷,⁴⁶,⁵⁵,⁵⁶,⁵⁷ Checking for serotonin (HIAA) levels whenever a carcinoid tumor is suspected in the absence of carcinoid syndrome is not recommended.¹² Definite diagnosis of carcinoid tumors is made by bronchoscopy, thoracotomy, and biopsy. The bronchoscopic appearance of centrally located tumors include a rather smooth, polypoid endobronchial mass with brownish or red color. Histologic diagnosis of biopsies is accurate in 54% to 100% of patients.¹² Bronchial carcinoids are vascular tumors, and in spite of that, the incidence of serious bleeding during bronchoscopic biopsy is very low.⁵⁸,⁵⁹ The diagnostic yield of fine-needle aspiration, brushing, washing, or expectorated sputum remains low in the range of 4% to 63%, possibly because the normal bronchial mucosa that covers the tumor remains intact.⁶⁰,⁶¹,⁶² This is an additional reason why preoperative diagnosis is many times difficult. Furthermore, it is difficult to differentiate precisely typical from atypical carcinoids preoperatively. This is reported to occur in less than 20% of cases.¹² Also, frozen section examination during surgery differentiates carcinoid tumors from carcinomas in 26% to 40% of cases.¹² Staging pulmonary carcinoid tumors is similar to that of other lung neoplasms. Typical carcinoid usually present as stage I, whereas more than 50% of atypical carcinoids present with II or III (Table 67.1). Certainly, the prognostic value of staging system in carcinoid tumor is limited, mainly, in typical ones because the long-term survival is not usually affected by the presence or abscence of hilar or mediastinal lymphadenopathy.¹²,⁶³,⁶⁴,⁶⁵ Bronchial carcinoids have generally low serotonin content, and occasionally secrete bioactive amines. Therefore, elevated plasma or urinary hormone levels are rarely detected, and only a few develop clinical paraneoplastic syndrome from peptide secretion. However, measurement of serum levels of chromogranin A (CGA) can be a useful marker to follow disease activity and response to treatment in advanced or metastatic disease.⁶⁶,⁶⁷

Bronchial carcinoids belong to the group of neuroendocrine tumors, which is composed of four main types: typical carcinoid, atypical carcinoid, small cell lung carcinoma, and large cell neuroendocrine carcinoma. These four types of tumors are part of a biologic continuum from the relatively indolent typical carcinoid to a more clinically aggressive atypical carcinoid,
small cell lung carcinoma, and large cell neuroendocrine carcinoma.⁶⁸,⁶⁹ Bronchial carcinoids are characterized by different biologic behavior. Despite their different biologic behavior, these tumors share certain morphologic and biochemical characteristics (i.e., the capacity to synthesize neuropeptides as well as the presence of neuroendocrine granules in the cytoplasm, which can be visualized by electron microscopy).⁶ Pulmonary carcinoid tumors are thought to originate from a specialized bronchial cell, the so called kulchitsky cell, which belongs to a diffuse system of neoroendocrine cells. These tumors have been referred to as amine precursor uptake and decarboxylation (APUD) or apudomas.⁶ Typical carcinoid tumors are composed of bland cells containing round-to-oval nuclei with finely dispersed chromatin and small nucleoli. The cells are mostly polygonal in shape, mitotic figures are scarce and necrosis is absent.⁶ (Fig. 67.1) Typical carcinoids located peripherally usually have a spindle cell growth pattern, and most of them have foci of diffuse DIPNECH and/or tumorlets in the adjacent lung parenchyma, which does not seem to alter prognosis (Fig. 67.2). Atypical carcinoids include all of the above plus the fact that mitotic figures are more numerous and foci of necrosis are present (Fig. 67.3). It is likely that atypical carcinoids derive from progression of typical carcinoids, which derive from a precursor lesion-identified DIPNECH.⁷⁰,⁷¹ Most carcinoids can be diagnosed on routine light microscopy. Immunohistochemical diagnosis of secreted and cytoplasmic products such as synaptophysin, neuron-specific enolase, and chromogranin has replaced silver staining as the best method to confirm neuroendocrine differentiation. Carcinoid tumors with the rare exemption of atypical carcinoids do not express thyroid transcription factor-1 (TTF-1).⁷² The differentiation between typical and atypical carcinoid tumors is based mainly on the mitotic count. The typical carcinoids have less than two mitoses per square millimeter of viable tumor in 10 high-power fields and lack necrosis. Atypical carcinoids have more than 2 to 10 mitoses per square millimeter in 10 high-power fields or have foci of necrosis or both (Table 67.2). The necrosis is more
or less punctuate.⁶ There is an inconsistent correlation between “atypical” histology in carcinoid tumors and DNA aneuploidy. Although aneuploidy seems to be more common in atypical tumors, abnormal DNA content does not provide additional prognostic information.⁷³ Molecular biologic changes may be useful as an adjunctive tool to differentiate typical and atypical carcinoids. E-cadherin impairment expression has been correlated with extensive disease in typical and atypical carcinoids.⁷⁴ Tumor suppressor genes, P53, retinoblastoma gene, P16, and P19 show an increase in frequency of alteration and inactivation in atypical carcinoid compared with the typical one.⁷⁵,⁷⁶,⁷⁷,⁷⁸ Also, proliferation rates assessed by MIB-1 and Ki-67 are higher in atypical carcinoids.⁷,²²,²³ Angiogenesis has not been found to be a useful marker as well as C-erbB-2 protein, which is not expressed.⁶⁶,⁷⁹,⁸⁰,⁸¹,⁸² K-ras-2 analysis showed no evidence of point mutational changes in either typical or atypical carcinoid.⁷⁸ On the contrary, multiple endocrine neoplasia type I gene activation appears to be a specific genetic marker in atypical carcinoid.⁷ Human acute homologue-1 (ASH-1), a transcription factor that plays a crucial role in neuronal endocrine determination and differentiation, is expressed at high levels in SCLC and non-small cell lung cancer (NSCLC) with neuroendocrine feature. It is absent in typical carcinoids although it is expressed in atypical carcinoids⁸³ (Table 67.3).