Other Primary Tumors of the Lung

Epidemiology

Bronchopulmonary carcinoid tumors account for one quarter of all carcinoid tumors, represent 1.2% of all primary lung tumors in adults, and are the most common primary lung tumor in children. Overall, when all carcinoids are accounted for, they are distributed almost equally between males and females; however, in the bronchopulmonary subset, they are found predominantly in females. The incidence is significantly higher in white patients than in black, Asian, and Hispanic patients. Compared with bronchogenic carcinomas, carcinoid tumors occur more frequently in younger patients and are less likely to be associated with a significant smoking history.

Bronchopulmonary carcinoid tumors arise from neuroendocrine cells and are thus positioned on the neuroendocrine tumor spectrum, which includes the more aggressive large-cell neuroendocrine carcinomas and small-cell lung carcinomas. Bronchopulmonary carcinoid tumors are classified as either typical or atypical on the basis of histologic features. Typical carcinoid tumors account for three quarters of bronchopulmonary carcinoids, are often centrally located, and rarely metastasize. In contrast, atypical carcinoid tumors are located more frequently in the lung periphery and metastasize in more than 40% of cases. Atypical carcinoid tumors occur more often with increasing age and are rarely seen in patients younger than 30 years. Unlike high-grade bronchopulmonary neuroendocrine tumors (large-cell and small-cell variants), typical and atypical bronchopulmonary carcinoids rarely occur in combination with other adenocarcinomas; however, the risk of synchronous breast and prostate cancer is slightly elevated.

Pathology

Most bronchopulmonary carcinoid tumors, particularly typical carcinoids, are centrally located. Fink et al reported that 68% of bronchopulmonary carcinoid tumors were located in the major bronchi (13% in the mainstem bronchi and 55% in lobar bronchi), with the remaining 32% in peripheral locations. Because of the predominance of central location, these tumors can often be visualized bronchoscopically, demonstrating a sessile, red-brown to bluish-tan endobronchial mass with variable vascularity and a smooth surface. On gross pathologic examination, typical carcinoids appear as a white or gray cut surface without evidence of hemorrhage or necrosis. In contrast, atypical carcinoids tend to be located peripherally in the lungs. On gross pathologic examination, atypical carcinoids appear white-gray on section but can exhibit a color of tan, pink to yellow-brown, and red.

The World Health Organization (WHO) classification of pulmonary neuroendocrine tumors is based on morphologic and histologic features, which clearly influence tumor behavior and prognosis. The spectrum of neuroendocrine tumors includes low-grade typical carcinoids, intermediate-grade atypical carcinoids, and high-grade large- and small-cell variants. Typical carcinoid tumors have fewer than 2 mitoses per 10 high power fields (HPF), have no evidence of necrosis, and are larger than 0.5 cm. Tumors smaller than 0.5 cm are classified as carcinoid tumorlets and are addressed later in this chapter. Atypical carcinoid tumors have 2 to 10 mitoses per 10 HPF or necrosis. Figure 22-1 demonstrates the histologic appearance of a typical and an atypical carcinoid tumor. In comparison, large- and small-cell carcinomas contain greater than 10 mitoses per 10 HPF and are further distinguished on the basis of other morphologic characteristics. Although the WHO classification places these four subtypes under the general heading of bronchopulmonary neuroendocrine tumors, the results of histopathologic and immunochemical studies support the idea that bronchopulmonary carcinoids are distinct from the more malignant and high-grade neuroendocrine tumors.

Gustafsson and colleagues discussed a separate entity termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). This rare preneoplastic condition features proliferation of pulmonary neuroendocrine cells and neuroepithelial bodies. When this proliferation extends beyond the basement membrane, the group of cells is identified as a carcinoid tumorlet. These tumorlets are nodular, carcinoid-like proliferations of neuroendocrine cells less than 5 mm in size; those that proliferate to greater than 5 mm are classified as carcinoid tumors. DIPNECH can be both an adaptive response, as seen in persons living at high altitudes, and a reactive response to lung injury, as seen in patients with obliterative bronchiolitis, chronic cough, and interstitial lung disease. Table 22-1 describes the major distinctions among DIPNECHs, tumorlets, and carcinoids.

Genetics and Biochemistry

Molecular genetic analysis has demonstrated that multiple genes are involved in the development and progression of carcinoid tumors. One important genetic mechanism is loss of heterozygosity (LOH), which can occur in multiple chromosomes, including but not limited to 3p, 5q21 (MCC/APC), 9p21 ( p16 gene), 11q13 ( MEN1 gene), 13q14 (retinoblastoma [RB] gene), and 17p13 ( p53 gene). LOH at chromosome 3p is the most frequent change in bronchopulmonary neuroendocrine tumors and has been observed in 40% of typical carcinoids and 73% of atypical carcinoids. p53 mutations and loss of 5q21 occur in higher-grade tumors and are associated with worse survival.

Bronchopulmonary carcinoids are known to occur as components of familial endocrine cancer syndromes, namely multiple endocrine neoplasia 1 (MEN1), although this rarely occurs. The MEN1 gene is inactivated by mutation in approximately 47% of typical carcinoids and 70% of atypical carcinoids. More recently, a study evaluated 129 patients with MEN1 and found that 6 of these (5%) had been diagnosed with bronchopulmonary carcinoids on initial diagnosis. An additional 32 patients had chest computed tomography (CT) scans for review, and 12 of these (38%) had pulmonary nodules suspicious for bronchopulmonary carcinoid, 4 of which were histologically confirmed to be a carcinoid. This study demonstrated that the incidence of bronchopulmonary carcinoid in MEN1 is much higher than previously believed; therefore, it is recommended that patients with MEN1 be screened for bronchopulmonary carcinoids with chest CT imaging every 3 years, with onset at 20 years of age.

The p53 gene (chromosome 17p13) is important for maintaining genomic stability, in addition to numerous other functions. LOH or abnormal expression at the p53 locus has been detected in 4% of typical carcinoids and 29% of atypical carcinoids. Kobayashi et al evaluated the frequency of p53 protein expression in several bronchopulmonary carcinoid tumors and found that the sampled typical carcinoids did not demonstrate any expression; in contrast, 20% of the sampled atypical carcinoids had expression.

Clinical Presentation

The presentation of bronchopulmonary carcinoid tumors is dependent on both the size and the location of the tumor; given the high proportion of centrally located carcinoid tumors, most patients are symptomatic at presentation. The most common symptoms are cough, hemoptysis, dyspnea, wheezing, and recurrent upper respiratory infections or pneumonia, caused by endoluminal obstruction by the tumor. Symptoms may be present for many years before diagnosis is made and almost entirely reflect the anatomic location of the lesion, as opposed to the secreted bioactive products. Although some patients with bronchopulmonary carcinoid tumors may initially have carcinoid syndrome (diarrhea, flushing, bronchoconstriction, and heart failure), in general this is exceedingly rare. Infrequently, bronchopulmonary carcinoids may secrete adrenocorticotropic hormone (ACTH) (Cushing syndrome), growth hormone, or other bioactive substances. Carcinoid tumors are one of the most frequent causes of ectopic secretion of ACTH. Box 22-1 depicts common endocrinopathies associated with carcinoid tumors. A quarter of patients are asymptomatic, and thus many of these tumors are found incidentally or are never discovered. A population-based study in Denmark showed that 24% of typical carcinoids and 7% of atypical carcinoids were discovered on autopsy.

Diagnosis

Imaging

Chest radiographs (CXRs) are nonspecific for bronchopulmonary carcinoids but may demonstrate an isolated, well-defined hilar or perihilar mass, occasionally with associated atelectasis or postobstructive pneumonia. Suspicious lesions should be examined further with chest CT, which is the preferred diagnostic imaging study and which allows for determination of tumor size, location, and potential lymph node involvement. On CT, carcinoids appear as well-defined, homogeneous, spherical/ovoid, endobronchial masses ( Fig. 22-2 ) that exert mass effect or cause distal airway obstruction. Spiculation is absent. Typical carcinoids are often vascular and more commonly centrally located. In contrast, atypical carcinoids are usually located peripherally, and 30% have calcifications.

Most bronchopulmonary neuroendocrine tumors (80%) express somatostatin receptors, predominantly SST ₂ receptors. Somatostatin receptor scintigraphy (SRS) with radiolabeled somatostatin analogs ( In-octreotide and In-lanreotide) can be used to locate bronchopulmonary carcinoid tumors or metastatic lesions. However, only two thirds of these carcinoids will have positive findings on SRS, and CT is generally superior for visualizing both primary and metastatic lesions. Furthermore, benign pathologic results can produce false-positive findings on SRS. Given these limitations and the superiority of CT scans, SRS should rarely be used in the diagnosis or workup of bronchopulmonary carcinoids.

The role of positron emission tomography (PET) in diagnosing bronchopulmonary carcinoids is not as well defined as that of either CT or SRS but has been investigated in several small, single-institution series and may benefit select patients. PET functions by detecting the accumulation of radiolabeled biological molecules (most commonly F-fluorodeoxyglucose [FDG]) within neoplastic cells. Historically, the use of FDG-PET has been fraught with false-negative results in patients with solitary bronchopulmonary carcinoids, because they are often hypometabolic on FDG-PET. More recently, however, FDG-PET, particularly when combined with CT, has shown improvement in the staging of select patients, particularly those with atypical carcinoid tumors. Typical carcinoids generally demonstrate significantly lower average standardized uptake values (SUVs), compared with atypical carcinoids. Chong et al reviewed FDG-PET scans of typical carcinoids ( n = 2) and atypical carcinoids ( n = 5) for maximum SUV. The typical carcinoids had an SUV range of 3.2 to 3.4, with both specimens exhibiting less than mediastinal uptake. Three of the five atypical carcinoids had a higher SUV (4.0 to 7.1) than the mediastinum. One of the five atypical carcinoids had a maximum SUV of 1.7, with an ipsilateral hilar lymph node measuring an SUV of 11.2. A further potential benefit of FDG-PET is its ability to identify lymph node and distant metastases in some cases, although it does not identify these metastases in all cases. In summary, the role of FDG-PET is evolving, and in the future it will likely play a role in the workup of select patients, particularly those with suspected atypical carcinoid tumors. Given the possibility for false-negative results in FDG-PET scans, a lesion that is suspicious for carcinoid on CT should be treated as such.

Staging

The TNM ( t umor, n odes, m etastasis) classification for lung cancer remains the most widely used staging classification for bronchopulmonary carcinoid tumors. Fink et al analyzed 142 bronchopulmonary carcinoids, of which 128 were typical and 14 were atypical. Lymph node metastases were less common in the subset of typical carcinoids (N0 = 87%, N1 = 10%, N2 = 3%), compared with atypical carcinoids (N0 = 43% N1 = 29%, N2 = 14%, N3 = 14%). As for other histologic variants of lung cancer, for bronchopulmonary carcinoids, N1 disease is defined as ipsilateral hilar lymph node involvement, N2 disease is defined as ipsilateral mediastinal lymph node involvement, and N3 disease is defined as contralateral or distant nodal involvement. None of the patients with typical carcinoid was found to exhibit N3 disease. Distant metastatic disease (M1) was found in 2% of typical and 21% of atypical carcinoid tumors.

A larger, more recent Italian study retrospectively analyzed 252 patients, 174 with typical and 78 with atypical carcinoid tumors, during a 38-year period and found that 96% of patients with typical carcinoids presented without nodal metastases, 3.4% presented with N1 disease, and 0.6% presented with N2 disease. In contrast, only 72% of patients with atypical carcinoids presented without nodal metastases, 17% presented with N1 disease, and 11% presented with N2 disease. Thus, typical carcinoids rarely have nodal disease, whereas atypical carcinoids commonly have either N1 or N2 disease—again highlighting the different tumor biology between these two tumors. The two previously mentioned studies and others are summarized in Table 22-2 .

Management and Treatment

Prognosis

With an increase in the number of chest imaging studies performed, as well as the enhanced quality of the imaging techniques, there has been an increase in the incidence of bronchopulmonary carcinoids. Despite what could be perceived as earlier detection of all carcinoid tumors, a review of the SEER database demonstrated a decrease in the 5-year survival of patients with all carcinoids (including atypical ones) during the past 30 years. Reasons for this decrease in survival are unclear but may be related to an increase in the incidence of the atypical carcinoid histologic profile.

It is well known that typical carcinoids have a superior prognosis, compared with atypical carcinoids. This difference is primarily attributable to the differences in tumor biology between the two histologic profiles. Recent studies have shown the 5-year and 10-year survival rates for patients with typical carcinoids to be 89% to 99% and 82% to 93%, respectively. In contrast, the 5-year and 10-year survival rates for patients with atypical carcinoids are 70% to 77% and 52% to 67%, respectively.

The prognostic significance of lymph node involvement in atypical carcinoid tumors cannot be overstated and has been addressed by multiple studies (see Table 22-2 ). The 5-year survival for atypical carcinoids with node-positive disease is 59% to 60%, compared with 83% to 100% for node-negative disease. For typical carcinoids, however, the presence or absence of nodal disease does not correlate with survival.

Epidemiology

A carcinoid tumorlet is a nodular proliferation of pulmonary neuroendocrine cells that extends beyond the basement membrane but is less than 5 mm in size; those that proliferate to greater than 5 mm are classified as carcinoid tumors. Carcinoid tumorlets and carcinoid tumors have long been associated in the literature, but a definitive relationship has not been firmly established. Studies have demonstrated the presence of tumorlets in normal lungs or in association with carcinoid tumors. There have also been case reports of isolated peribronchial and hilar lymph node metastases, which point to the possible neoplastic potential of carcinoid tumorlets. In each of these circumstances, the lymph nodes appeared normal on gross examination; however, on pathologic examination, microscopic metastases were found.

Pathology

Carcinoid tumorlets develop from Kulchitsky cells, which are hyperplastic neuroendocrine cells in the bronchial and bronchiolar mucosa. Tumorlets can be single or multiple, are less than 5 mm in size, and have a carcinoid-like appearance. It has been suggested that these cells secrete neuropeptides that can elicit peribronchiolar reaction, leading to fibrotic lung disease.