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Clinical Management of Lung Cancer:
Lessons from the Cleveland Clinic Tumor Board
Online Monograph

Carcinoid Tumors

Sonali Sethi, MD
Siva Raja, MD, PhD


Case Presentation

A 30-year-old male presents with a nonproductive cough and progressive shortness of breath. He denies hemoptysis, fevers, chills, night sweats, weight loss, or diarrhea. During the past year, he occasionally experienced hot flashes after having a hot shower. He also notes intermittent abdominal pain, but he is otherwise healthy. There is no history of lung cancer in his parents or siblings.

Chest radiography reveals a left hilar mass. A CT scan shows a 2.9 x 2.2 x 3 cm left hilar mass with a 1 cm adjacent lymph node in the left hilum. There is no mediastinal adenopathy. Biopsy of the left hilar lymph node revealed an anthracotic lymph node containing a metastatic neuroendocrine tumor. Immunohistochemical studies reveal the neoplastic cells are diffusely strongly positive to chromogranin, CD56, villin, and synaptophysin, and are negative for TTF1, napsin A, cytokeratin 20, and CDX2. These are consistent with a typical carcinoid tumor.

Case Discussion

Lung carcinoid tumors are quite rare, accounting for only 1% to 2% of all lung cancers. There are about 4,500 new cases of lung carcinoid tumors diagnosed in the United States each year.1 In the past, pulmonary carcinoid tumors were believed to be derived from neural crest cells; however, they currently are understood to be of endodermal origin, arising from stem cells of the bronchial epithelium known as Kulchitsky cells.

Carcinoids are classified as either typical or atypical and central or peripheral, based on where they form in the lung. Typical carcinoids tend to grow slowly and only rarely spread beyond the lungs. Approximately nine out of 10 lung carcinoids are typical carcinoids.

Atypical carcinoids grow faster and are more likely to spread to other organs. They have more cells in the process of dividing and look more like a fast-growing tumor. Central carcinoids form in the walls of large airways near the center of the lungs. Most carcinoid tumors are central carcinoids, and nearly all of these are typical carcinoids. Peripheral carcinoids develop in the small airways (bronchioles) toward the outer edges of the lungs. These are more likely to be atypical carcinoids; however, most are still typical carcinoids.2

Approximately 25% to 39% of patients are asymptomatic at the time of discovery. In symptomatic patients, the most common clinical findings are those associated with bronchial obstruction, such as persistent atelectasis, recurrent pneumonia, persistent cough, wheezing, hemoptysis, or dyspnea. As neuroendocrine tumors, carcinoids are capable of producing a variety of biologically active peptides and hormones, including serotonin, adrenocorticotropin hormone (ACTH), antidiuretic hormone (ADH), melanocyte-stimulating hormone (MSH), and others. These peptides and hormones can cause various endocrine or neuroendocrine syndromes in either typical or atypical carcinoid tumors.3

Excess serotonin production has been implicated in the development of a carcinoid syndrome. This syndrome is characterized by a constellation of symptoms, including tachycardia, flushing, bronchoconstriction, hemodynamic instability, diarrhea, and acidosis. It is reported in 2% to 12% of patients with bronchial carcinoid tumors. This syndrome characteristically occurs in the presence of metastatic disease to the liver; however, bronchial carcinoid tumors, especially large ones, are capable of producing the syndrome in the absence of metastatic disease.

Ectopic production of ACTH and Cushing syndrome has been reported in association with typical and atypical carcinoid tumors. Although less than 1% of pulmonary carcinoid tumors produce Cushing syndrome, it is the second most common neuroendocrine syndrome produced by these tumors. In addition, these tumors are responsible for the development of about 1% of cases of Cushing syndrome. When a patient is found to have an ectopic source of ACTH production, the lesion is generally a pulmonary neoplasm of some type.

Inappropriate secretion of ADH, increased pigmentation secondary to excess MSH, and ectopic insulin production resulting in hypoglycemia are some of the other endocrinopathies that can be produced.

The cause of lung carcinoid tumors is unclear. Unlike carcinoma of the lung, no external environmental toxin or other stimulus has been identified as a causative agent for the development of pulmonary carcinoid tumors. They do not seem to be related to smoking, air pollutants, or other chemicals.

There are factors, however, that may increase the risk. Lung carcinoids are more likely to develop in whites than in people of other races, the average age is 40 to 50 years (although they have been reported in virtually every age group), and tend to be present in more women than men. People with a rare inherited disorder called multiple endocrine neoplasia type 1 are at somewhat higher risk for lung carcinoids.

The gastrointestinal tract is the most common area in which carcinoid tumors arise. Bronchopulmonary carcinoid tumors are reported to represent approximately 10% of all carcinoid tumors with 80% to 90% of these developing within a bronchus of subsegmental size or greater. Tumors arise in a mainstem bronchus in 10% to 15% of cases; however, they rarely appear in the trachea. Approximately 10% to 20% of tumors are located in the pulmonary periphery.4

Histologic features
An immunohistochemical analysis of typical carcinoid tumors showed the following features:5

  • Cells are small and polygonal and tend to group in nests, cords, or broad sheets.
  • They have finely granular eosinophilic cytoplasm that can vary from clear to deeply eosinophilic.
  • Mitoses are infrequent.
  • Arrangement is orderly with groups of cells separated by highly vascular septa of connective tissue.
  • Many pulmonary carcinoid tumors stain positive for a variety of neuroendocrine markers, such as serotonin, gastrin, MSH, vasopressin, bombesin, somatostatin, and neuron-specific enolase.
  • Immunostaining with chromogranin A is useful and helps differentiate pulmonary carcinoid tumors (which stain strongly positive) from small cell carcinoma of the lung, which produces negative results.

In contrast, atypical pulmonary carcinoid tumors show the following:

  • Atypical tumors have no distinguishing gross characteristics that may be used to differentiate them from typical carcinoids.
  • Arrigoni and colleagues6 identified chief histologic features that define atypical carcinoid tumors and help distinguish them from typical carcinoid tumors. The presence of one or several of these features is found in tumors identified as atypical carcinoid tumors:
  • Increased mitotic activity in a tumor with an identifiable carcinoid cellular arrangement with roughly 1 mitotic figure per 1-2 high-power fields;
  • Pleomorphism and irregular nuclei with hyperchromatism and prominent nucleoli;
  • Areas of increased cellularity with loss of the regular, organized architecture observed in typical carcinoid;
  • Areas of necrosis within the tumor.

At present, staging of pulmonary carcinoid tumors is designated in the same manner as that for bronchogenic carcinoma of the lung. Typical carcinoid tumors, considered the least aggressive form, most commonly present as stage I tumors, while more than 50% of atypical carcinoid tumors are found to be stage II (ie, bronchopulmonary lymph node involvement) or stage III (ie, mediastinal lymph node involvement) at presentation.

Treatment Options

Medical therapy. No medical therapy exists for the primary treatment of carcinoid tumor of the lung. Chemotherapeutic agents and radiation therapy have been used in the treatment of metastatic disease but have been met with virtually no success. A response rate of 30% to 35% has been reported using a combination of 5-fluorouracil and streptozotocin. Symptomatic relief of carcinoid syndrome from metastatic disease has been achieved by administration of octreotide, which can be administered subcutaneously.

Surgical therapy. All pulmonary carcinoid tumors should be treated as malignances. As long as no contraindication to surgery exists, surgical resection is the primary mode of therapy for carcinoid tumors of the lung. Various forms of resection have been used successfully and with excellent long-term results. Anatomic lobectomy is the most commonly performed procedure. Parenchymal sparing surgeries can be considered for typical carcinoid tumors.7

Recently, a renewal of the use of bronchoscopy and local excision has been proposed for specific carcinoid tumors that are polypoid in configuration. Complete tumor removal is unlikely using this method because the obstructing intrabronchial tumor usually penetrates the bronchus and invades local pulmonary parenchyma. Bronchoscopic resection using an Nd:YAG laser with or without photodynamic therapy also has been used in selected cases. As yet, these forms of treatment have been reserved for preresection reduction of intrabronchial tumor mass or for palliative management.7

Because of their more biologically aggressive nature, greater tendency to metastasize, and poorer general prognosis, it is recommended that atypical carcinoid tumors be treated very aggressively. In general, the same surgical approach should be used in these aggressive forms of carcinoid as is applied to cases of pulmonary carcinoma; this includes radical resection with frozen section evidence of tumor-free bronchial margins plus hilar and mediastinal lymphadenectomy. Resection of distant metastatic lesions is indicated in a select group of patients in whom thorough evaluation has revealed isolated lesions in areas amenable to resection.

The average 5-year survival rate for patients treated for typical carcinoid tumors is 85% to 95%. For atypical lung carcinoids, the 5-year survival rate is 50% to 60%.

Case Recommendation

It is recommended that the patient undergoes surgical resection of the carcinoid tumor in his left hilum, with the possibility of a pneumonectomy.

Learning Points

  • Carcinoid tumors are rare neuroendocrine tumors that can arise at several body sites. The majority originate in the gastrointestinal tract and bronchopulmonary system.
  • As neuroendocrine tumors, carcinoids are capable of producing a variety of biologically active peptides and hormones, including serotonin, adrenocorticotropin hormone, antidiuretic hormone, and melanocyte-stimulating hormone.
  • Carcinoids are classified as either typical or atypical and central or peripheral, based on where they form in the lung. Typical carcinoids tend to grow slowly and only rarely spread beyond the lungs. Atypical carcinoids grow faster and are more likely to spread to other organs.
  • At present, staging of pulmonary carcinoid tumors is designated in the same manner as that for bronchogenic carcinoma of the lung.
  • For patients with either atypical or typical bronchial carcinoid whose medical condition and pulmonary reserve will tolerate it, the recommendation is surgical resection and mediastinal lymph node sampling or dissection.
  • For patients with surgically unresectable but nonmetastatic disease, options for local control of tumor growth include radiation therapy with or without concurrent chemotherapy and palliative endobronchial resection of obstructing tumor.

Multimedia Feature


ACTH = adrenocorticotropin hormone; ADH = antidiuretic hormone; CT = computed tomography; MSH = melanocyte-stimulating hormone.

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