Primary neuroendocrine neoplasms of the lung represent a clinical spectrum of tumors ranging from the relatively benign and slow-growing typical carcinoid to the highly aggressive small-cell lung carcinoma. The rarity of carcinoids has made the role of radiation therapy in their management controversial. This review considers the results of published studies to generate treatment recommendations and identify areas for future research. Surgery remains the standard of care for medically operable disease. Histology plays the most important role in determining the role of adjuvant radiation. Resected typical carcinoids likely do not require adjuvant therapy irrespective of nodal status. Resected atypical carcinoids and large-cell neuroendocrine carcinomas have a significant risk of local failure, for which adjuvant radiation likely improves local control. Definitive radiation is warranted in unresectable disease. Palliative radiation for symptomatic lesions has demonstrated efficacy for all histologies. Collaborative group trials are warranted.
The term carcinoid was first used by Oberndorfer in 1907 to describe tumors more indolent than adenocarcinomas, but earlier reports of bronchial carcinoids described some of their characteristics. Pulmonary carcinoids were originally grouped with adenoid cystic carcinomas under the more general term bronchial adenoma, but this classification was subsequently abandoned. Within the category of carcinoids, a more aggressive atypical carcinoid was first described by Engelbreth-Holm in 1944, but it was not until 1972 that Arrigoni formally separated typical and atypical carcinoids as separate clinicopathologic entities.
Within non-small-cell lung cancer (NSCLC), the large-cell undifferentiated carcinoma with neuroendocrine features was proposed to be a clinically separate entity in 1985, and in 1991 Travis proposed criteria for the large-cell neuroendocrine carcinoma. The current World Health Organization classification of neuroendocrine lung neoplasms recognizes four distinct pathologic entities: the typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung cancer (SCLC).
The true incidence of pulmonary carcinoids is difficult to estimate. The number of all-site carcinoid cases in the United States has been estimated to be about 4,500 cases per year. Of these, bronchial sites account for 23% to 37%.[7,8] This would imply that the annual number of pulmonary typical and atypical carcinoids is about 1,000 to 1,500. However, lung cancer series estimate carcinoids as 2% of all cases, which would place the number at around 3,400.
By contrast, there were an estimated 35,000 small-cell lung cancers in 2004, indicating that high-grade neuroendocrine neoplasms outnumber carcinoids at the minimum by a factor of 10:1. The incidence of LCNEC is also difficult to estimate, in large part due to its recent definition. In a histologic review of 572 lung cancer patients, 87 were found to be LCNECs, accounting for 9% of NSCLCs and 44% of SCLCs reviewed. It would be inappropriate to try to extrapolate the annual incidence from these data, but they do seem to indicate that the number of LCNECs may be significant.
The median age at diagnosis of neuroendocrine lung neoplasms is about 50 years, with TCs tending to occur in younger patients, and ACs and LCNECs occurring in older patients. For patients younger than age 50, women outnumber men in a ratio of 1.6:1. Cigarette smoking appears to be a risk factor for the development of ACs but not TCs. Smoking is almost certainly associated with LCNECs, with 98% of patients having a history of habitual smoking in one series.
The cell of origin is the Kulchitsky cell, a bronchial mucosa cell that can synthesize bioactive amines. Pulmonary carcinoids have stained positive for serotonin, adrenocorticotropic hormone (ACTH), vasoactive intestinal peptide (VIP), bombesin, and leucine enkephalin.
Various genetic mutations have been described, with different lesions associated with different histologies. Both 11q deletions and MEN1 mutations are found in TCs and ACs, but not in LCNECs or SCLCs, while 10q and 13q deletions are found in ACs, LCNECs, and SCLCs.
Classically, the gross description of a carcinoid is a vascular-appearing mass with a smooth surface and pink or yellow color, but this is seen more often with TCs than ACs. Under a light microscope, carcinoids have small nuclei, few nucleoli, and ample cytoplasm. They classically stain with silver, although chromogranin, synaptophysin, and neuron-specific enolase are commonly used today to identify neuroendocrine tumors. Using an electron microscope, neurosecretory granules, which contain biogenic amines, are diagnostic.
TCs and ACs are differentiated from one another by the presence of necrosis and the amount of mitoses per high-power field (Table 1). LCNECs and SCLCs both have high mitotic rates and large amounts of necrosis, but can be differentiated based on light microscopy, with LCNECs having cytologic features similar to NSCLCs. LCNECs can be differentiated from NSCLC either by the presence of neurosecretory granules on electron microscopy, or by positive staining of neuroendocrine markers.
Up to 24% of TCs and 7% of ACs are asymptomatic, with their detection only coming at autopsy. Among the rest of neuroendocrine tumors, local symptoms are the common presenting symptoms, including dyspnea, chest discomfort, unilateral wheezing, bronchial obstruction, hemoptysis, cough, or recurrent pulmonary infections.
Pulmonary carcinoids commonly arise from the lobar bronchi (55%) or segmental bronchi (32%), and less commonly, the mainstem bronchi (13%). The right lung is involved in 60% of cases, and the middle and lower lobes may be involved more often than the upper lobe.
Symptomatic clinical syndromes from the production of functional hormones are rare with primary bronchial neuroendocrine tumors, even in those staining positive for bioactive amines. Carcinoid syndrome is found in 1% of patients and is associated with the presence of liver metastases. It is most often caused by the secretion of serotonin, and the classic clinical manifestations include diarrhea, flushing, and palpitations. Less common sequelae include heart dysfunction and coronary valve fibrosis. Rarely, surgical manipulation can cause pulmonary edema or vasomotor collapse, the so-called carcinoid crisis. ACTH production is found in 1% of cases, resulting in Cushing's syndrome, which is clinically manifested by weakness, hypertension, glucose intolerance, hypokalemia, alkalosis, weight loss, anemia, and hyperpigmentation. Growth hormone-releasing factor causing acromegaly has also been rarely described in cases of pulmonary carcinoid tumor.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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