Carcinoid Lung Tumors Workup

• No biochemical study exists as a screening test that can be used to determine the presence of a carcinoid tumor or that can be used 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.
• Assays of specific neuroendocrine substances

  • 5-Hydroxyindoleacetic acid (5-HIAA)
    • Assay of this substance, 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.
  • ACTH, MSH, growth hormone (GH), and other hormone or peptide assays:
    • While one or several of these 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.^[3]

• Chest radiograph (see the images below)

  • An abnormal finding on chest radiograph 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. Posteroanterior chest radiograph of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelectasis. 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. Posteroanterior chest radiograph showing a carcinoid lung tumor presenting as a coin lesion in the right lower lobe of a 40-year-old, asymptomatic woman. 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 scan (see the image below)

  • High-resolution CT scan 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 radiograph, as shown below.
  • High-resolution CT scan may reveal nodules or masses that are not well visualized on plain chest radiograph by virtue of their small size or their position, such as those located in a retrocardiac position.
  • In the evaluation of a solitary pulmonary nodule, use of a CT scan 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 scan. 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, although no characteristic pattern is known.
  • High-resolution CT scan 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 scan.
  • Intravenous contrast in CT scan 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 scan. Because carcinoid tumors are highly vascular, they also possess this feature. Computerized tomographic study of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelectasis.
  • In a 2011 report on CT scan 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.^[4]
• Magnetic resonance imaging

  • MRI generally provides information similar to that of CT studies.
  • Dynamic MRI may be a useful complimentary examination in selected cases.^[5]
• Positron emission tomography^[6]

  • Positron emission tomography (PET) studies utilize the fact that malignant cells possess a higher metabolic activity rate than do healthy cells. 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.
  • PET scan appears to have a 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 scan and would be designated incorrectly as benign lesions based on the findings of 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.^[7]
  • 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.^{[8, 9]}

• Bronchoscopy

  • About 75% of pulmonary carcinoids are visible on bronchoscopy.
  • In most cases, the physician makes the diagnosis of pulmonary carcinoid tumor based on 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. While 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, although 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 in cases of 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 to proceed with surgical removal of a pulmonary nodule or to observe it for a longer period. If a suspicion of malignancy exists in spite of a negative finding on transthoracic biopsy, surgical excision of the nodule and pathologic analysis should be undertaken.

Histologic features of 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. Cytoplasm can vary 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 analysis of pulmonary carcinoid tumors

• Well-formed desmosomes and abundant neurosecretory granules are present.
• Many pulmonary carcinoid tumors stain positive for a variety of neuroendocrine markers, such as serotonin, gastrin, MSH, vasopressin, bombesin, somatostatin, and neuron-specific enolase (NSE), although this 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.^{[10, 3, 11, 12, 13, 14]}

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.^[15] 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 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
• 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.

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.