Evaluation and Treatment of Pulmonary Carcinoid

A pulmonary, lung or bronchial carcinoid is a rare tumor of the lung, accounting for only 1-2 % of lung cancers. Carcinoid tumors arise from neuroendocrine cells, which produce hormones, or chemicals that regulate other parts of the body. Most carcinoids (55%) occur in the gastrointestinal system, but 25 to 30% can occur in the lung or airway (pulmonary carcinoid). Pulmonary carcinoids are different from the more common lung cancers seen in smokers and have a better outcome in most cases, with higher cure rates and longer survival, even when cure is not possible. They are most common in patients ages 40 to 60 years. Smoking is not a significant risk factor as it is for other lung cancers. They are very rarely due to an inherited genetic mutation, but may be associated with other hormone-producing tumors in Multiple Endocrine Neoplasia (MEN) 1 syndrome.

Signs and symptoms of pulmonary carcinoid tumors

Pulmonary carcinoid tumor presentation depends upon anatomical location within the lungs, hormonal functionality, and associated metastases. These tumors often occur in proximity to the trachea and can cause obstruction of the bronchi (Figure 1), leading to a common presentation of recurrent pneumonia or pneumonia resistant to antibiotic treatment. Such tumors may also cause unilateral wheezing, cough or hemoptysis. Tumors can be quite small (less than 2cm).  The tumors may also have a rich blood supply and can bleed spontaneously, or following biopsy. Other common symptoms include fever, chest discomfort and pain, and shortness of breath. Tumors in peripheral locations may become much larger (5 cm or 2 inches) before becoming symptomatic. Asymptomatic pulmonary carcinoids may present incidentally on chest x-ray or CT imaging performed for other conditions.

Pulmonary carcinoid tumors can be further classified by grade and degree of cellular differentiation. Typical carcinoids are more benign appearing histologically (Figure 2) and behave less aggressively than atypical carcinoids (Figure 3). Typical carcinoids tend to present more centrally, where atypical carcinoids are more peripherally located.  Both grow very slowly and spread to lymph nodes much less often, compared to neuroendocrine small cell- and large cell- lung carcinoma. The atypical tumors are more likely to be seen in patients ages 50-60, while typical carcinoids occur in patients approximately 10 years younger.

Tumor functionality with ectopic hormone secretion or paraneoplastic syndromes such as Cushing’s syndrome are rare.  Carcinoid syndrome is more common in the presence of liver metastases.

Diagnostic investigations for pulmonary carcinoid

Diagnosis of pulmonary carcinoid tumor is suspected when the symptoms above are noted, or based upon x-ray or CT findings. Blood tests or a biopsy may be performed depending upon symptoms and the appearance of the imaging.

Serum serotonin (5-HT) and 24 hour urinary 5-hydroxyindoleacetic acid (5-HIAA) levels should be measured. Chromogranin A is not associated with symptoms but can be frequently elevated in a variety of neuroendocrine tumors. If an elevated level drops following resection, it can be useful as a tumor marker for surveillance.  Pulmonary carcinoids can also produce adrenocorticotropic hormone (ACTH) resulting in Cushing syndrome, or cause acromegaly with the release of growth hormone releasing hormone (GHRH) or growth hormone (GH). Even small carcinoid tumors can be functional and cause significant clinical syndromes. Fortunately, these biochemical changes will usually resolve if the tumor is localized and can be completely resected.

Carcinoid tumor diagnosis can often be made by bronchoscopy.  Tumor brushings or biopsy can be obtained at the time of bronchoscopy for histopathological diagnosis.  Peripherally located tumors can also be biopsied under CT guidance.  Chromogranin A histopathological staining can be used to confirm carcinoid tumor cells.

A chest x-ray may reveal atelectasis or segmental collapse beyond an obstructing carcinoid tumor. When these tumors become larger, they may be visible as smooth ovoid or slightly lobulated masses (Figure 4). Locating and defining the extent of the tumor is often possible with a high-resolution CT scan. If the mass is not visible but there is collapse of a portion of the lung (Figure 5), this can direct further investigation of an obstructing lesion within the bronchial tree. PET scans can be used to assess for metastatic disease, but may be confounded by the presence of infectious or inflammatory conditions.  Lymph node metastases occur in only 10 – 15 % of the cases of typical pulmonary carcinoids.

Most carcinoid tumors have a receptor on the surface that binds to somatostatin, a hormone that regulates neuroendocrine cell growth and secretion function. Octreotide or pentreotide are variations of this hormone that can be labeled for nuclear medicine scans (octreoscan or somatostatin SPECT) Combined with CT scans, these nuclear medicine scans are able to localize carcinoid tumors very precisely. Metastases with functioning somatostatin receptors may also be identified with nuclear medicine scans.  In some cases, occult tumors may be localized with a hand-held Geiger counter in the operating room.

Management of pulmonary carcinoid tumors

Surgery is the main treatment of hormonally active tumors. The treatment goal is to excise the tumor and relieve the symptoms caused by tumor functionality. Sometimes small, non-invasive bronchial carcinoids can be removed with bronchoscopy (Figure 6a. and 6b). The risks of this technique are bleeding, incomplete resection, and risk of tumor recurrence. Local resection of the tumor involves removal of very little to no lung tissue and re-approximation of the bronchus. The risk of leak at this connection is low, but can be a very serious complication when it occurs, particularly when associated with infection. Such resection is usually performed as an open operation known as a sleeve resection. If the tumor is located within the lung parenchyma or remote from the main airway, a portion of lung may need to be resected. This may be done through a minimally invasive or thoracoscopic procedure, usually involving stapling and resection of a small segment of the lung.  If there is more extensive tumor involvement or lung parenchymal damage from infection, a larger segment or lobe of the lung may be resected.  Lymph node resection may improve the outcome in atypical carcinoids, but nodes are usually not involved in typical carcinoids.

In most cases, adjuvant radiation therapy and conventional chemotherapy are not given after surgery for carcinoid tumors, since this has not proven beneficial for tumors which are completely excised.  Tumor markers such as chromogranin A or other hormones detected at time of diagnosis can be used for surveillance.  Repeat bronchoscopy is performed to assess for persistent or locally recurrent disease.  CT imaging and/or nuclear medicine scans can be used for local surveillance and detection of distant disease.  Surgical resection is typically the initial management choice for local recurrence.  If resection is not feasible, cryotherapy may be useful. Radiation therapy may also be used when a tumor is unresectable, but these tumors often do not respond well to radiation treatment.

Somatostatin analogs may be given to somatostatin-receptor positive, metastatic, or slowly progressive disease to improve symptom control and inhibit tumor growth. When these fail due to development of somatostatin receptor resistance, cytotoxic chemotherapy or everolimus may be considered. Conventional cytotoxic chemotherapy use for pulmonary carcinoid remains controversial.