Carcinoid Lung Tumors

Background

Carcinoid tumors of the lung are a fascinating but uncommon group of pulmonary neoplasms. In the past, these tumors were grouped with benign or less aggressive malignant pulmonary tumors. Together they were placed in a category of neoplasms called bronchial adenomas.

This unfortunate label, still used by many today, creates the impression that such tumors are benign neoplasms. Subsequent study has revealed, however, that carcinoid lung tumors represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors (NETs) that includes small cell carcinoma of the lung as its most malignant member, as well as several other forms of intermediately aggressive tumors, such as atypical carcinoid.^[1]

Laennec's description of an intrabronchial mass in 1831 was the first written description of what was likely a bronchial carcinoid tumor. Mueller described the first so-called bronchial adenoma in detail in 1882. This probably was a carcinoid tumor because the patient was young and had symptoms of cough with hemoptysis for 8 years.

In 1914, Chevalier Jackson performed bronchoscopic resection of a large intrabronchial tumor. At that time, the tumor was labeled with the pathologic diagnosis of endothelioma, but, after reexamination a number of years later, it was determined to be an adenoma. In 1937 and again in 1945, C L Jackson reported on 12 and 20 cases of bronchial adenomas, respectively. He stated that none of these exhibited signs of metastases or any other evidence of malignant activity. Other experts, however, began to question the apparent benign nature of these tumors.

In 1944, Alexander and Weller classified bronchial adenomas as grade 1 malignancies and reported that they had observed metastases in two of 13 cases. In 1939, Eloesser performed the first bronchotomy for resection of a bronchial tumor. The tumor was called a benign carcinoma at the time but was likely a carcinoid or cylindroma.

Bjork, Axen, and Thorsen in 1952 described the first report of carcinoid syndrome and its relation to metastatic carcinoid tumor; it was associated with an intestinal carcinoid tumor. The first report of this syndrome in association with a bronchial carcinoid tumor was by Stanford, Davis, Gunter, and Hobart in 1958.

In 1972, Arrigoni et al reported a subset of pulmonary carcinoid tumors that had an atypical histologic appearance and behaved more aggressively. They named this group of tumors atypical carcinoid and reported that the tumors often were larger at presentation and developed distant metastases in as many as 70% of cases. Since this study, the idea that a spectrum of neuroendocrine tumors of the bronchopulmonary tree exists has become more accepted.^[2]

Typical carcinoid tumors of the lung represent the most well differentiated and least biologically aggressive type of pulmonary NET. These tumors characteristically grow slowly and tend to metastasize infrequently.

Atypical carcinoid tumors have a more aggressive histologic and clinical picture. They metastasize at a considerably higher rate than do typical carcinoid tumors and, therefore, carry a worse prognosis.

Carcinoid syndrome has been reported in association with very large bronchopulmonary carcinoid tumors or in the presence of metastatic disease. It is noted much less frequently in association with carcinoids of pulmonary origin than those originating within the gastrointestinal (GI) tract. (For more information, see Intestinal Carcinoid Tumor.)

Endocrine syndromes found in association with small cell carcinoma of the lung are found less commonly with carcinoid tumors of the lung; however, some endocrine abnormalities have been attributed to both typical and atypical pulmonary carcinoid tumors.

For patient education resources, see the Procedures Center and Cancer and Tumors Center, as well as Bronchoscopy, Bronchial Adenoma, and Understanding Lung Cancer Medications.

• References

Anatomy

Gross anatomic features of carcinoid tumors include the following:

• Tumors most commonly are found within the cartilaginous portion of the tracheobronchial tree
• Tumors usually are soft masses covered with intact bronchial epithelium
• Tumors are very vascular and pink-to-purplish in color
• Tumors usually are attached to the bronchus by a broad base but occasionally are polypoid with a distinct stalk
• Tumors may be associated with the presence of tumorlets (small foci of atypical hyperplastic bronchial epithelium in adjacent locations), which may represent local metastatic disease or an entirely different histologic abnormality and, when present, may indicate a more aggressive tumor and a poorer prognosis

• References

Pathophysiology

Local

Between 25% and 39% of patients with a carcinoid pulmonary tumor are asymptomatic.

The vast majority of symptomatic patients have symptoms directly involving the bronchopulmonary tree. Carcinoids developing within large airway structures grow slowly and can become quite large. Because of their location and size, these central carcinoids can cause bronchial obstruction. All of the sequelae resulting from bronchial obstruction can follow, including persistent atelectasis, recurrent pneumonia, pulmonary abscess, and bronchiectasis.

Carcinoids characteristically are vascular tumors and can bleed secondary to bronchial irritation.

Although most tumors are broad-based intrabronchial lesions, a few present on a mobile stalk and have a polypoid appearance. If large enough, this latter form can create a ball-valve mechanism within the bronchus, producing hyperinflation in the pulmonary parenchyma distal to the tumor.

Peripheral pulmonary carcinoid tumors most often are asymptomatic and usually are discovered incidentally. They are one of the differential diagnoses considered in evaluation of a solitary pulmonary nodule.

Atypical carcinoid tumors can present in the same locations as typical carcinoids, but they occur more commonly as peripheral lesions. At least 50% of pulmonary atypical carcinoid tumors present in the periphery of the lung. They have a more aggressive nature and a greater tendency to metastasize.^[3]

Systemic

As NETs, carcinoids are capable of producing a variety of biologically active peptides and hormones, including serotonin, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), melanocyte-stimulating hormone (MSH), and others.

Excess serotonin production has been implicated in the development of carcinoid syndrome. This syndrome is characterized by a constellation of symptoms, including tachycardia, flushing, bronchoconstriction, hemodynamic instability, diarrhea, and acidosis, and is reported in 2-12% 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 have been reported in association with typical and atypical carcinoid tumors. Although fewer 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.

The syndrome of inappropriate AVP (arginine vasopressin) secretion or syndrome of inappropriate secretion of ADH (SIADH) can be produced by pulmonary carcinoid tumors, though it more commonly is associated with small cell lung carcinoma. The production of excess circulating AVP creates hyponatremia secondary to water retention. Patients present with weight gain, weakness, lethargy, and mental confusion and, in severe cases, can develop convulsions and coma.

• References

Etiology

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.

Although these neoplasms are capable of producing a variety of substances, including biologically active peptides and hormones, most are inactive.

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.

• References

Epidemiology

The GI tract is the most common area in which carcinoid tumors most commonly arise.

Bronchopulmonary carcinoid tumors are reported to represent about 10% of all carcinoid tumors. Between 1% and 6% of all lung tumors are carcinoid tumors. Some 80-90% of tumors develop within a bronchus of subsegmental size or greater. About 10-15% of tumors arise in a mainstem bronchus; however, they rarely appear in the trachea. About 10-20% of tumors are located in the pulmonary periphery.

Atypical carcinoid tumors account for about 10% of all pulmonary carcinoid tumors. Carcinoid syndrome occurs in about 2% of cases of pulmonary carcinoid tumors, much less frequently than it does in cases associated with GI carcinoid tumors.^[3]

The average age of people at occurrence of typical carcinoid tumors is 40-50 years, but typical carcinoid tumors have been reported in virtually every age group. Atypical carcinoid tumors appear in slightly older people than typical carcinoids do. Carcinoid tumors occur in equal numbers of males and females.

• References

Prognosis

Carcinoid tumors of the lung generally have a better prognosis than other forms of pulmonary malignancy. They have an overall 5-year survival rate of 78-95% and a 10-year survival rate of 77-90%.

Typical carcinoid tumors have been found to have a much better prognosis than do the atypical variety.^[4] Atypical carcinoid tumors have been associated with a 5-year survival rate of 40-60% and a 10-year survival rate of 31-60%, depending on the series.

Regardless of histologic type, the presence of lymph node metastases at the time of resection has a significant effect on prognosis in many series,^[5] producing 5-year survival rates of 37-80% and 10-year rates of 22-80%. This wide variation is likely related to the percent of atypical carcinoid tumors present in each analyzed series. N1 disease does not affect prognosis in typical carcinoids, and it tends to decrease survival in atypical carcinoids; however, N2 disease has a dismal prognosis.^[6]

The presence of tumorlets associated with the primary tumor appears to worsen the prognosis. In a retrospective single institution study from Australia, age greater than 60 years and atypical histology were negative predictors of survival; patients in the atypical subgroup were found to be significantly older.^[7]  Whether or not tumor size is a prognostic risk factor is uncertain.

The presence of carcinoid syndrome or other paraneoplastic syndromes in the absence of lymph node or distant metastases does not seem to affect prognosis adversely.^{[8, 9, 10, 11, 12]}

• References

History and Physical Examination

About 25% of patients with pulmonary carcinoid tumors are asymptomatic at the time of discovery.

In symptomatic patients, the most common clinical findings are those associated with bronchial obstruction, such as persistent cough, hemoptysis, and recurrent or obstructive pneumonitis. Wheezing, chest pain, and dyspnea also may be noted.

Although uncommon, various endocrine or neuroendocrine syndromes can be initial clinical manifestations of either typical or atypical pulmonary carcinoid tumors. Carcinoid syndrome, hypercortisolism and Cushing syndrome, inappropriate secretion of antidiuretic hormone (ADH), increased pigmentation secondary to excess melanocyte-stimulating hormone (MSH), and ectopic insulin production resulting in hypoglycemia are some of the endocrinopathies that can be produced by a pulmonary carcinoid tumor in a patient who is otherwise asymptomatic.

In cases of malignancy, the presence of metastatic disease can produce weight loss, weakness, and a general feeling of ill health. Carcinoid syndrome is observed most commonly when metastatic disease to the liver is present.

• References

Laboratory Studies

No biochemical study exists that can be used as a screening test to determine the presence of a carcinoid tumor or to diagnose a known pulmonary mass as a carcinoid tumor. Assays of specific hormones or other circulating neuroendocrine substances may establish the existence of a clinically suspected syndrome produced by a carcinoid tumor.

Assay of 5-hydroxyindoleacetic acid (5-HIAA), a breakdown product of serotonin metabolism, is only of value if carcinoid syndrome is suspected clinically in an individual with a pulmonary tumor. The practitioner should perform further diagnostic evaluation for metastatic disease, particularly hepatic involvement.

Whereas one or several hormone or peptide assays (eg, adrenocorticotropic hormone [ACTH], melanocyte-stimulating hormone [MSH], or growth hormone [GH]) may be elevated secondary to ectopic production by a pulmonary carcinoid tumor, serum assays of these substances are not warranted unless clinical symptoms associated with them are present.

In the vast majority of these (rare) cases, the patient initially presents with the symptoms produced by ectopic hormone production. After serum assays are performed to confirm that elevated serum levels of the culprit hormone are present, a search begins for the source of the ectopic hormone production. If the pituitary gland and appropriate endocrine organs are ruled out as the source, ectopic sources are sought.

At this point in the workup, a carcinoid tumor or other pulmonary neoplasm may be found. This latter point especially is true because many cases of pulmonary carcinoid tumors that cause ectopic hormone production are small peripheral lesions and often are not readily found on initial plain chest radiograph.^[13]

• References

Imaging Studies

Chest radiography

An abnormal finding on chest radiography (see the images below) is present in about 75% of patients with a pulmonary carcinoid tumor. Findings include either the presence of the tumor mass itself or indirect evidence of its presence observed as parenchymal changes associated with bronchial obstruction from the mass. Changes associated with bronchial obstruction include persistent atelectasis, consolidation secondary to pneumonia, and changes of bronchiectasis and hyperinflation.

View Image

Posteroanterior chest radiograph of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelec....

View Image

Lateral chest radiograph of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelectasis.

View Image

Posteroanterior chest radiograph showing a carcinoid lung tumor presenting as a coin lesion in the right lower lobe of a 40-year-old, asymptomatic wom....

View Image

Lateral chest radiograph showing a carcinoid lung tumor presenting as a coin lesion in the right lower lobe of a 40-year-old, asymptomatic woman.

Computed tomography

High-resolution computed tomography (CT) is the best type of CT examination to obtain for evaluation of a pulmonary carcinoid tumor. It can demonstrate more detail about nodules, masses, or suspicious parenchymal changes, such as persistent atelectasis or obstructive pneumonia found on plain chest radiography (see the image below). It may reveal nodules or masses that are not well visualized on plain chest radiography by virtue of their small size or their position, such as those located in a retrocardiac position.

View Image

Computerized tomographic study of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelecta....

In the evaluation of a solitary pulmonary nodule, CT can provide specific information about pulmonary nodules, such as size, position within the lung, density, and edge configuration. The presence and distribution of calcium within a nodule also can be readily observed on CT. Certain pulmonary nodules possess characteristic calcium distributions, the identification of which can strongly suggest that the nodule is benign or malignant. Carcinoid tumors of the lung often possess some calcifications, though no characteristic pattern is known.

High-resolution CT can reveal the presence of an air bronchogram within a pulmonary nodule, a finding that indicates the intimate relation of the tumor and the tracheobronchial tree. This feature may indicate that the lesion is more likely to be malignant. Because the majority of carcinoid tumors are intrabronchial, this should be a common feature of carcinoid tumors on CT.

Intravenous (IV) contrast in CT also can be useful in differentiating malignant from benign lesions. Malignant lesions generally have increased vascularity and show greater enhancement than benign lesions on contrast CT. Because carcinoid tumors are highly vascular, they also possess this feature.

In a 2011 report on CT features, peripheral carcinoid tumors presenting as solitary pulmonary nodules were found to have lobulated nodules of high attenuation with contrast enhancement; densely enhanced nodules with contrast administration; calcification; subsegmental airway involvement on thin-section analysis; and nodules associated with distal hyperlucency, bronchiectasis, or atelectasis.^[14]

Magnetic resonance imaging

Magnetic resonance imaging (MRI) generally provides information similar to that provided by CT. Dynamic MRI may be a useful complimentary examination in selected cases.^[15]

Positron emission tomography

Positron emission tomography (PET) makes use of the fact that malignant cells possess a higher metabolic activity rate than healthy cells do.^[16] A tagged glucose molecule, FDG (2-[fluorine-18]-fluoro-2-deoxy-D-glucose), is administered, and metabolic analysis of this substance within the cells of the imaged organ system or the whole body is conducted. Gallium-68 dotatate is increasingly being used with PET/CT to localize somatostatin receptor–positive neuroendocrine tumors.^[17]  A combination of these two approaches has been proposed (NETPET score).^[18]

PET appears to have considerable sensitivity and specificity for the identification of malignant lesions.

Although highly vascular, carcinoid tumors of the lung do not show increased metabolic activity on PET and would be incorrectly designated as benign lesions on the basis of findings from this study.

Radionuclide studies

Somatostatin receptors are present in many tumors of neuroendocrine origin, including carcinoid tumors. Nuclear imaging with somatostatin analogues reveals increased tracer activity in these tumors and their metastases.^[19]

This study is excellent for evaluation of the thorax and mediastinum. One drawback to this type of study is the fact that some uptake of the tracer typically occurs in a number of organs, including the liver, thyroid, kidneys, and spleen; thus, lesions in these areas may be obscured.^{[20, 21]}

• References

Diagnostic Procedures

Bronchoscopy

About 75% of pulmonary carcinoids are visible on bronchoscopy. In most cases, the physician makes the diagnosis of pulmonary carcinoid tumor on the basis of the findings from bronchoscopy plus a combination of radiologic studies.

Severe hemorrhage has been reported in association with biopsy of a bronchial carcinoid tumor during bronchoscopy. Although these are vascular tumors, the vast majority of reports of severe hemorrhage associated with them are related to attempts at partial or total removal at the time of bronchoscopy.

At present, most endoscopists perform bronchoscopic biopsy of these lesions for histologic diagnosis. Because these masses are located beneath the bronchial epithelial layer, deeper biopsies may be required than for other types of bronchial neoplasms. Some endoscopists have a dilute solution of epinephrine available to apply to the biopsy site for vasoconstriction. Others advocate obtaining a biopsy of these tumors with general anesthesia and rigid bronchoscopy.

Transbronchial fine-needle biopsy

Transbronchial fine-needle biopsy of a submucosal carcinoid mass may be performed, though the small amount of tissue obtained may make histologic analysis challenging. Both typical and atypical carcinoid tumors share a number of histologic characteristics with small cell carcinoma of the lung, and inadequate sampling, especially in frozen section analysis, may increase the likelihood of misdiagnosis. Fortunately, permanent pathologic examination using hematoxylin and eosin stains and others is used to establish the correct diagnosis in the vast majority of cases.

Transthoracic needle biopsy

Percutaneous needle biopsy may be useful for tissue sampling of peripheral pulmonary nodules.

As with transbronchial biopsy, the amount of tissue sampled may be quite limited, making exact histologic determination difficult.

The diagnostic yield for a specific benign diagnosis in solitary pulmonary nodules is 12-68%. Nonspecific diagnosis in the absence of malignant cells does not confirm benignity. The negative predictive value of this procedure to exclude malignancy in solitary pulmonary nodules is reported to be 52-88%.

A negative finding on biopsy should not produce a false sense of confidence in the examining physician. A combination of clinical findings, patient risk factors, and data from all completed diagnostic studies should enter into the decision whether to proceed with surgical removal of a pulmonary nodule or to observe it for a longer period. If a suspicion of malignancy exists despite a negative finding on transthoracic biopsy, surgical excision of the nodule and pathologic analysis should be undertaken.

• References

Histologic Findings

Typical carcinoid tumors

In typical carcinoid tumors, cells tend to group in nests, cords, or broad sheets. Cell groupings can take on a glandular or alveolar configuration. Arrangement is orderly, with groups of cells separated by highly vascular septa of connective tissue.

Individual cell features

In pulmonary carcinoid tumors, cells are small and polygonal. They have finely granular eosinophilic cytoplasm, which can range from clear to deeply eosinophilic. Nuclei are small and round. Mitoses are infrequent. Spindle-shaped cells are an accepted variant, especially in peripherally located tumors.

Electron microscopic and immunohistochemical features

Well-formed desmosomes and abundant neurosecretory granules are present. Many pulmonary carcinoid tumors stain positive for a variety of neuroendocrine markers (eg, serotonin, gastrin, MSH, vasopressin, bombesin, somatostatin, and neuron-specific enolase [NSE]), though this staining does not correlate with clinical activity. Immunostaining with chromogranin A is a useful study that helps the physician differentiate pulmonary carcinoid tumors, which stain strongly positive for it, from small cell carcinoma of the lung, which produces negative results.^{[22, 13, 23, 24, 25, 26]}

Atypical pulmonary carcinoid tumors

Atypical tumors have no distinguishing gross characteristics that may be used to differentiate them from typical carcinoids. In many series, they are reported generally to be larger than typical carcinoids, but this is not a distinguishing feature. They are located in the periphery of the lung in about 50% of cases.

Arrigoni identified the chief histologic features that define atypical carcinoid tumors and help the physician to distinguish them from typical carcinoid tumors.^[27] The presence of one or several of these features is found in tumors identified as atypical pulmonary carcinoid tumors. Features include the following:

• Increased mitotic activity in a tumor with an identifiable carcinoid cellular arrangement with roughly one mitotic figure per one or two high-power fields (HPFs)
• 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

Atypical carcinoid tumors have no distinctive electron microscopic features compared to typical carcinoid tumors. Like other neuroendocrine tumors, they stain strongly for a number of immunohistochemical markers but have no specific marker exclusive for them.

In a study of pulmonary carcinoid tumor in Korea, Ha et al suggested that lung parenchymal invasion could be a useful histologic feature for raising suspicion of atypical carcinoid, as well as for predicting the prognosis of carcinoid tumor.^[28]

• References

Staging

At present, staging of pulmonary carcinoid tumors is designated in the same manner as that for bronchogenic carcinoma of the lung. Whereas typical carcinoid tumors, considered the least aggressive form, most commonly present as stage I tumors, 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.

The exact determination of the specific histologic entities within the spectrum of pulmonary neuroendocrine tumors is an area of considerable controversy.

Several authors have renamed the entire spectrum of pulmonary neuroendocrine neoplasms on the basis of more advanced histologic study. One classification system labels typical carcinoid tumors as type 1 Kulchitsky cell carcinoma, atypical carcinoids as type 2 Kulchitsky cell carcinomas, and small cell carcinoma as type 3. Another defines these as well-differentiated, intermediate cell, and small cell neuroendocrine carcinomas.

Additional changes in tumor classification also have been proposed specifically with respect to atypical carcinoid tumors. Several subcategories of atypical carcinoid have been described on the basis of identification of genetic molecular abnormalities.

The addition of genetic marker identification to previous methods of tumor analysis has resulted in further subclassification for some of the more aggressive types of these neuroendocrine tumors. Large cell neuroendocrine and mixed small-large cell neuroendocrine carcinomas have been proposed as high-grade tumors more closely related to small cell carcinoma than to carcinoids, falling into the disease spectrum between atypical carcinoid and small cell carcinoma.

• References

Approach Considerations

All pulmonary carcinoid tumors should be treated as malignancies. Because surgical resection is the only treatment known to achieve cure, all pulmonary carcinoid tumors without evidence of distant metastatic disease should be resected completely as long as no contraindication to surgery exists.

Total resection should be the primary goal of any form of surgical therapy. Lymph node dissection should accompany resection. The most commonly used procedures are formal lobectomy, segmentectomy, and pneumonectomy, but various parenchymal-sparing bronchoplastic procedures, including sleeve resections, have also been utilized with good long-term results. Patients with marginal pulmonary reserve may be good candidates for complete resection and cure if a bronchoplastic or parenchymal-sparing procedure can be performed.

Thoracoscopic or open wedge resection of a peripheral carcinoid tumor should be reserved for patients with limited pulmonary reserve who cannot tolerate anatomic resection. Appropriate lymph node dissection also should be performed in these cases.

Bronchoscopic resection of an intrabronchial carcinoid tumor is recommended only in selected cases. These include preoperative management of symptomatic bronchial obstruction prior to formal resection and palliative treatment in patients who would otherwise not tolerate formal pulmonary resection.

Complete tumor removal is extremely unlikely with this method, because these obstructing intrabronchial tumors usually have penetrated the bronchus and invaded the local pulmonary parenchyma by the time they are discovered. In addition, lymph node staging cannot be accomplished. Palliation, not cure, is the goal of this technique.

Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser photoresection of intrabronchial carcinoid tumors also has been proposed. This form of therapy should not be considered primary and should be reserved for use in the same types of cases for which bronchoscopic resection is indicated.

The limitations of laser photoresection are similar to those of bronchoscopic resection, with one additional drawback. Transbronchial photocoagulation destroys at least a portion of the resected tumor and thwarts thorough analysis of a completely resected specimen. Incomplete specimen analysis may have significant bearing on prognostic determination because the histologic features of pulmonary carcinoid tumors must be scrutinized carefully in order to determine whether typical or atypical carcinoid is present.

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.

Formal resection of carcinoid tumors of the lung only is contraindicated in patients who would not otherwise tolerate the operative procedure or who are found to have widespread metastatic disease.

• References

Medical Therapy

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

In February 2016, everolimus was approved by the US Food and Drug Administration (FDA) for progressive, well-differentiated, nonfunctional neuroendocrine tumors (NETs) of lung origin that are unresectable, locally advanced, or metastatic. Approval was based on the RADIANT-4 trial, in which median progression-free survival was 11 months in the 205 patients allocated to receive everolimus (10 mg/day) and 3.9 months in the 97 patients who received placebo. Everolimus was associated with a 52% reduction in the estimated risk of progression or death.^[29]

• References

Surgical Therapy

Surgical resection is the primary mode of therapy for carcinoid tumors of the lung. Various forms of resection have been utilized successfully and with excellent long-term results.

Some 40-50 years ago, in an era when these tumors were considered more benign in their activity, bronchotomy with local excision of the tumor mass was used for resection of carcinoid tumors located in larger bronchial structures. Within the past two decades, a greater understanding of the malignant nature and biologic activity of these tumors has been acquired, and surgical resection has become more radical, now more closely resembling that for primary carcinoma of the lung.

At present, anatomic lobectomy is the most commonly performed procedure for resection of pulmonary carcinoid tumors. Larger or more proximal lesions may require bilobectomy or pneumonectomy. Smaller lesions in peripheral locations and contained within a single pulmonary segment may be treated with segmentectomy or wedge resection.

Because of the intrabronchial location and slow rate of growth of most carcinoid tumors, a variety of parenchymal-sparing procedures, including sleeve lobectomy and sleeve pneumonectomy, have been proposed and performed successfully with excellent long-term results.

In a large review of the Surveillance Epidemiology and End Results (SEER) database, sublobar resection of carcinoid tumors was not found to compromise oncologic outcomes; rather, factors such as age, sex, race, stage, and histologic types were direct influences on survival rates and the likelihood of patients acquiring other types of cancer. As long as complete resection and adequate mediastinal staging are performed, it is not necessary to perform a lobectomy on typical carcinoid tumors.^[30]

There is a resurgence of interest in local resection of carcinoid tumors. Most of these local resections are bronchoplastic procedures without any parenchymal resection, in which the section of bronchus containing the tumor is excised and the divided ends of the bronchus are reanastomosed.

A renewal of the use of bronchotomy and local excision has been proposed for specific carcinoid tumors that are polypoid in configuration. Regional lymph node dissection at the time of primary tumor resection is advocated by an increasing number of authors for both staging and treatment. A number of patients in several series had a favorable long-term outcome after resection of pulmonary carcinoid tumors and regional lymph nodes, even when lymph node metastases were present.^[31]

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 for these aggressive forms of carcinoid as for cases of pulmonary carcinoma; this includes radical resection with frozen section evidence of tumor-free bronchial margins plus hilar and mediastinal lymphadenectomy.

Wedge resection of small peripheral typical carcinoid tumors without evidence of lymph node metastases may be acceptable in selected cases; however, a more radical resection is indicated for a similar mass found to be atypical.

Bronchoscopic resection using an Nd:YAG laser, with or without photodynamic therapy, also has been utilized in selected cases. As yet, these forms of treatment have been reserved for preresection reduction of intrabronchial tumor mass or for palliative management of airway obstruction in cases where the patient was considered otherwise inoperable.

In the former case, this form of treatment is helpful in reducing bronchial obstruction and clearing postobstructive pneumonia before formal surgical resection. In addition, some experts believe that preresection tumor reduction may allow a more conservative surgical resection. To date, series utilizing this form of therapy have been quite small, and long-term results have yet to be determined. This area has been controversial.^{[8, 32]}

Preparation for surgery

The surgeon must have a clear preoperative understanding of the location of the tumor (particularly if it is intrabronchial) and, to the degree possible, its extent. Many surgeons revisualize the tumor with the bronchoscope in the operating room immediately prior to the resection. This may facilitate decision-making regarding the choice of surgical procedure.

Preoperative evaluation of patients for resection of carcinoid tumors is identical to that for those with carcinoma of the lung.

Evaluation of pulmonary function should be performed prior to any procedure that may require resection of a portion of lung tissue. The same pulmonary function criteria used for patients undergoing pulmonary resection for any other reason applies to individuals having surgery for carcinoid tumors.

Because tissue-sparing procedures can be performed for some carcinoid tumors that are contained entirely within a bronchial structure, the limits of acceptable postoperative pulmonary reserve may be extended for patients with marginal pulmonary function in these cases. However, such procedures should be performed by thoracic surgeons experienced in bronchoplastic techniques.

Cardiac function should be assessed before any intrathoracic procedure.

Only obtain blood or serum assay of serotonin or 5-hydroxyindoleacetic acid (5-HIAA) if carcinoid syndrome is suspected clinically. If this study result is positive, further metastatic workup, especially evaluation for hepatic metastases, should be performed. Evidence of distant metastases often alters the decision about resection.

Operative details

Evaluation of the extent of local disease and the existence of nodal disease must be performed so that the proper choice of procedure can be made. This is especially important in bronchoplastic cases and parenchymal-sparing procedures.

In cases where a solitary pulmonary nodule is resected, accurate frozen section diagnosis is important because the extent of the subsequent resection may vary, depending on the histologic findings. A small, peripheral typical carcinoid tumor may be treated with a more conservative resection, while an atypical carcinoid tumor requires a more radical resection. Hilar and mediastinal nodes also should be sampled and resected if necessary.

Operative procedures are conducted in much the same fashion as other pulmonary resections. At most major centers, a double-lumen endotracheal tube is used to allow single-lung ventilation and facilitate visualization of the surgical field. Intra-arterial monitoring lines are placed for continuous blood pressure monitoring. Continuous transcutaneous oxygen saturation and end-tidal carbon dioxide monitoring are routine.

Careful intraoperative management of fluids is extremely important to avoid fluid overload and pulmonary edema in lung resection cases, especially pneumonectomy. A preoperative understanding between the surgeon and anesthesiologist to limit crystalloid infusion and maintain the patient in a relatively even fluid balance is advisable.

When not contraindicated, placement of an epidural catheter, ideally in the thoracic position, for postoperative pain management is advisable. If this is not possible, an intercostal block using a longer-acting local anesthetic, such as bupivacaine, is helpful for immediate postoperative pain control, though its effective duration is not longer than 4-6 hours.

• References

Postoperative Care

Postoperative management is identical to that employed for any patient undergoing pulmonary resection for any reason.

In the vast majority of cases, discontinuance of assisted ventilation and extubation is possible at the completion of surgery or very shortly thereafter. Most patients who undergo pulmonary resection do not require postoperative ventilation, though patients with significant chronic obstructive pulmonary disease (COPD) or other diseases associated with marginal pulmonary function may require it.

Patients who undergo any formal pulmonary resection or thoracotomy without major resection should be placed in an intensive care setting for at least 24 hours. Intensive care monitoring may not be needed for those who undergo less invasive procedures, such as thoracoscopic biopsy, but this should be decided on an individual basis.

A chest radiograph should be obtained immediately after surgery in the recovery room or intensive care unit (ICU) and daily thereafter. Additional films are warranted if any change in pulmonary status occurs in the course of recovery. A chest radiograph should be obtained immediately after thoracostomy tubes are removed.

Chest tube patency must be maintained, and constant suction with –20 to –25 cm under H₂O seal suction should be established. Chest tubes are removed when the lung is fully expanded on chest radiograph and no evidence of air leak exists.

Pulmonary toilet and pain management are vital for successful management. Incentive spirometry and assisted coughing at scheduled intervals can be very helpful for prevention of atelectasis and clearing of secretions. Nasotracheal suctioning may be required in some patients for aspiration of secretions and to stimulate an effective cough effort. If atelectasis is significant or major amounts of secretions cannot be cleared, bronchoscopy may be needed.

Other forms of pulmonary toilet, such as chest physiotherapy or intermittent positive-pressure breathing, have variable results in patients who undergo pulmonary resection.

Pain management via epidural catheter is ideal in these patients because this method controls pain well without altering the sensorium or diminishing the respiratory effort of the patient as significantly as IV narcotics may. If epidural analgesia is not possible, patient-controlled analgesia (PCA) with well-defined parameters may be used, though it may not be as effective.

The judicious fluid management begun in the operating room should be continued in all patients who undergo a major resection. Volume overload must be avoided. If excessive fluids were administered during the operative procedure, administration of a diuretic may be needed.

If the volume status of a postoperative patient is in question or if cardiac disease is present, placement of a pulmonary artery catheter may be necessary. Some surgeons advise performing this procedure with fluoroscopic guidance after major lung resection to assure proper positioning of the catheter into the nonoperated pulmonary artery.

Postoperative ileus is not common in patients who undergo pulmonary surgery; consequently, oral fluids often can be administered within 24 hours. Maintenance IV fluids should be all that are required until oral intake is adequate, and IV fluids should be discontinued thereafter.

Because airway structures containing secretions and bacteria are divided in pulmonary surgical cases, most surgeons administer a broad-spectrum antibiotic preoperatively and for 2-3 days postoperatively. This coverage is administered primarily to reduce the risk of infection within the pleural space. Wound infections in thoracotomy patients are quite rare.

• References

Complications

Complications that can arise after surgery for resection of pulmonary carcinoid tumors are similar to those that may occur after pulmonary resection for other reasons. In the immediate postoperative period, bleeding, atelectasis, and prolonged air leak are the most common complications.

Bleeding

Bleeding generally is an early postoperative complication and most often manifested is by copious or persistent amounts of blood from the thoracostomy tubes.

In some cases, the measured amount of bleeding from the chest tubes does not itself appear to herald a problem. Other clinical signs (eg, hypotension, tachycardia, decreased urine output, or inordinately low hematocrit) in the immediate postoperative period may alert the physician to significant undrained blood loss. In such cases, chest tubes may not be in proper position for drainage or may be partially clotted, preventing complete evacuation of the chest. A retained hemothorax in these cases is evident on chest radiograph.

Bleeding that is massive, requires large amounts of crystalloid or blood replacement to maintain hemodynamic stability, or is persistent over a number of hours and indicates that re of the thorax is needed.

Atelectasis

Some degree of atelectasis is present postoperatively in all patients undergoing chest surgery. Adequate pain control and vigorous pulmonary toilet are mandatory in order to avoid major problems with atelectasis. If the patient is unable to clear his or her own secretions adequately, nasotracheal suctioning is an effective method of assisting the patient. Bronchoscopy may be used for clearing secretions if nasotracheal suction is unsuccessful or if major areas of lung are collapsed.

Air leak

Air leak is a common postoperative problem after pulmonary resection and usually is produced by the raw surfaces of the lung parenchyma that are created during resection, such as the area in the major fissure. In the vast majority of cases, if the lung is fully expanded on chest radiography, air leak diminishes over a period of a few days and ceases. Persistent air leak is a frustrating problem and may result from a number of causes, including the following:

• Persistent air leak may be caused by a leak within the chest tube drainage system or improper positioning of the chest tube within the thorax; for example, when some of the chest tube openings are located outside of the pleural space, there may appear to be an air leak when none is present
• Incomplete reexpansion related to persistent atelectasis may be the cause of persistent air leak
• In individuals with underlying restrictive lung disease, the remaining lung may not be able to expand enough to completely fill the thoracic space
• Pulmonary resection performed on a lung that has significant emphysematous changes also can result in prolonged air leak

Unlike the leaks that are from the raw, resected parenchymal surface, more serious air leaks arise from lesser bronchial structures within the raw parenchymal tissue in the area of resection or from the bronchial stump or anastomosis itself. These usually persist as leaks of significant volume and may be associated with an incompletely expanded lung on chest radiograph.

Bronchial stump disruption may present as a pneumothorax on chest radiograph or as a new air leak at an interval after surgery, usually about 5-8 days postoperatively. This picture also may be present if a leak occurs at the bronchial anastomosis of a sleeve resection of other bronchoplastic procedures.

Large, prolonged air leaks producing some degree of persistent collapse of the lung usually require reoperation for closure. Thoracoplasty may be considered in cases in which a leak persists in the face of restrictive lung disease.

Postoperative respiratory insufficiency

Postoperative respiratory insufficiency is a devastating postoperative complication that, at best, may result in the patient becoming pulmonologically crippled with extremely limited functional reserve and, at worst, may necessitate some permanent form of ventilatory support.

This complication largely can be avoided by prudent preoperative examination of the pulmonary function and circulatory status of the patient. By doing this, the vast majority of individuals who would not have sufficient pulmonary reserve after the required resection are identified in advance and not subject to this devastating complication.

Postoperative pulmonary edema usually related to injudicious administration of intravenous fluids represents one cause of respiratory insufficiency. This can be a very serious, even lethal, postoperative problem that must be addressed aggressively when found.

A variety of other factors also must be noted in patients who are difficult to weaning from ventilatory support or oxygen post resection. Full lung or lobar expansion must be present and no residual pneumothorax present. Lung condition must be optimal and without infection, and pain management must be adequate.

Slow weaning from the ventilator may be required; if this is successful, long-term oxygen therapy still may be required.

Pleural infection and empyema

Postoperative intrathoracic infections almost always are related to the presence of a bronchopleural fistula. The diagnosis can be made by means of culture of the pleural fluid.

Complete lung expansion must accompany adequate drainage of the space for successful resolution of this problem. Adequate drainage by means of properly placed thoracostomy tubes or ultrasound- or computed tomography (CT)-guided aspiration may be successful, but reoperation for clearance of the infection and decortication and, if necessary, closure of the fistula may be indicated. Various thoracoplasty techniques can be employed to reduce the size of the thorax if full expansion of the remaining lung cannot completely fill the space.

Infection in the postpneumonectomy space is a true challenge and may require a Clagett procedure or the rotation of chest wall muscle flaps into the chest to obliterate the thoracic cavity after the empyema is drained.

Cardiac arrhythmias

Atrial fibrillation or flutter is a well-known complication after pneumonectomy or upper lobectomy, especially in older patients. Prompt identification of the arrhythmia and appropriate medical management is indicated. Electrical cardioversion may be required if the patient is unstable.

Some surgeons administer digitalis to their patients preoperatively in an attempt to avoid this complication. If this is instituted, patients should be fully digitalized and on maintenance therapy with laboratory evidence of therapeutic digitalis levels before the surgical procedure. An attempt at rapid digitalization 24-48 hours before operation usually is not effective.

• References

Long-Term Monitoring

After discharge from the hospital, surgical follow-up for observation of wound healing and determination that no intrathoracic complication has occurred is conducted for 8-12 weeks.

Oncologic follow-up is conducted in a fashion similar to that for pulmonary carcinoma after resection. Patients' cases are followed clinically and with plain chest radiography every 2-3 months for the first year after surgery. If no evidence of recurrence is discovered within this period, surveillance intervals are extended to every 6 months. Additional studies, such as CT, are performed only if suspicion of recurrence arises.

With respect to postoperative surveillance, a multi-institutional study showed that recurrence was rare in typical carcinoids.^[33] Recurrence is more common in atypical carcinoids (26%), yet most recurrences were not detected by routine surveillance protocols; instead, they appeared either after symptoms developed or incidentally on studies done for other reasons. Hence, there are no set recommendations for routine follow-up in patients with pulmonary carcinoid after surgical treatment.

• References

Guidelines Summary

Guidelines Contributor: Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

Grading and staging

Grading schemes for gastroenteropancreatic neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. However, for NETs of the lungs and thymus, the World Health Organization (WHO) includes only mitotic count and assessment of necrosis.^[34] In its 2015 consensus statement on best practices for pulmonary neuroendocrine tumors, the European Neuroendocrine Tumor Society (ENETS) noted that tumor grading based on a combination of Ki-67, mitotic rate, and necrosis may be of clinical importance but lacks validation.^[35]

Under the WHO grading scheme, tumors fall into one of the following three grades:

• Low-grade tumors, < 2 mitoses/10 high power fields (HPFs) and no necrosis
• Intermediate tumors, 2-10 mitoses/HPF and/or foci of necrosis
• High grade tumors, >10 mitoses/10 HPF

Whereas the National Comprehensive Cancer Network (NCCN) recommends use of the WHO scheme for grading, it also recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results.^[36]

The European Society of Medical Oncology (ESMO) and NCCN guidelines recommend staging according to the seventh edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.^{[37, 36]} Bronchopulmonary carcinoids are staged according to the same system used for other pulmonary malignancies.^[38]

The North American Neuroendocrine Tumor Society (NANETS) concluded that although the criteria differ among the various classification systems, the underlying data are similar, and pathology reports should include notation of the systems and parameters used to assign the grade and stage. For NETs of the thorax (including the lungs and thymus), resection margins should be indicated, measuring the distance from the tumor edge to guarantee radical excision on surgical specimens.^[39]

Diagnosis

The ENETS guidelines recommend contrast computed tomography (CT) as the gold standard for diagnosis but note that pathology examination is mandatory for their correct classification. Key pathology recommendations include the following^[35] :

• Pulmonary carcinoids (PCs) are well-differentiated NETs and include low-grade malignant tumors (typical carcinoid) and intermediate-grade malignant tumors (atypical carcinoid)
• Distinguishing a typical carcinoids (TC) from an atypical carcinoid (AC) requires a surgical specimen. Small biopsy and cytology are not adequate
• Neuroendocrine (NE) immunomarkers (chromogranin A, synaptophysin, and/or CD56/NCAM) may be used to confirm NE nature of tumors especially in biopsy/cytology specimens or surgical specimens. In case of metastatic presentation, positive TTF1 staining is suggestive of a lung or thyroid origin 

Treatment

NCCN treatment recommendations are as follows^[36] :

• Stage I, II, and IIIA - Lobectomy or wedge resection for peripheral low-grade neuroendocrine carcinoma and lymph node dissection or sampling
• Stage IIIA low grade nonresectable tumors - Radiation therapy
• Stage IIIA intermediate grade nonresectable tumors - Cisplatin/etoposide and radiation therapy
• Stage IIIB (except for T4 due to multiple lung nodules) - Cisplatin/etoposide with or without radiation therapy
• Stage IIIBm (T4 due to multiple lung nodules) or stage IV - Systemic therapy; no preferred regimen; options include cisplatin/etoposide, temozolomide with or without capecitabine, sunitinib, or everolimus; consider octreotide for symptoms of malignant carcinoid syndrome

The NANETS guidelines and the ESMO guidelines are similar to those of the NCCN, with some minor variances. The ESMO guidelines include the following additional recommendations^[37] :

• Bronchoscopic laser excision should be considered a suboptimal treatment and be reserved for inoperable patients or performed as a preoperative disobliterating procedure
• Lobectomy and sleeve resection are preferred for locoregional tumors and systemic nodal dissection should be performed
• Pneumonectomy should be avoided

Additionally, NANETS suggests that interferon alfa should be considered for metastatic or unresectable disease.^[39]

• References

Medication Summary

Surgical resection is the first line of treatment. Everolimus may be considered for unresectable, progressive neuroendocrine tumors.

• References

Everolimus (Afinitor)

• Dosing, Interactions, etc.

Clinical Context:  Everolimus is an mTOR kinase inhibitor (mammalian target of rapamycin, a serine-threonine kinase, downstream of the PI3K/AKT pathway, which is dysregulated in several human cancers. It is indicated for progressive, well-differentiated, non-functional NET of lung origin that are unresectable, locally advanced or metastatic.

• References

Class Summary

Although surgery is the first line of treatment, everolimus may be considered for progressive, unresectable neuroendocrine tumors (NET) of lung origin.

• References