Solitary Pulmonary Nodule Workup

Laboratory studies have a limited role in the workup of solitary pulmonary nodules (SPNs).

• Anemia or an elevated sedimentation rate may indicate an underlying neoplastic or infectious process.
• Elevated levels of liver enzymes, alkaline phosphatase, or serum calcium may indicate metastases from a solitary bronchogenic carcinoma or extrapulmonary malignancy.
• Patients who have histoplasmosis or coccidioidomycosis may have high levels of immunoglobulin G and immunoglobulin M antibodies specific to these fungi.

Chest radiography and computed tomography

Because solitary pulmonary nodules are first detected on chest radiographs, the initial distinction is whether the nodule is pulmonary or extrapulmonary in nature. Findings from a lateral chest radiography, fluoroscopy, or CT scanning may help confirm the location of the nodule. Although nodules of 5 mm in diameter are occasionally visualized on chest radiographs, solitary pulmonary nodules are quite often 8-10 mm in diameter.

Chest radiographs can provide information regarding size, shape, cavitation, growth rate, and calcification pattern. All of these radiologic features can help determine whether the lesion is benign or malignant. However, none of these features is entirely specific for lung carcinoma.

CT scanning of the chest has many advantages over plain chest radiography.^[4] Advantages include better resolution of nodules and detection of nodules as small as 3-4 mm. CT scan images also help better characterize the morphologic features of various lesions. Multiple nodules and regions that are difficult to assess on chest radiographs are better visualized on CT scan images. See the images below.

CT densitometry measures the attenuation coefficients of a lesion and aids detection of occult calcification. Attenuation coefficients are expressed in Hounsfield units (HU); a value of more than 185 HU has been suggested as a cutoff for benign lesions. However, prospective studies have indicated low sensitivity and specificity for CT densitometry measurements; thus, these measurements are no longer routinely used.

With regard to dynamic contrast enhancement, a greater degree of contrast enhancement on repeated measurements of attenuation indicates that the nodule is malignant. Enhancement of greater than 20 HU is associated with malignancy, whereas less than 15 HU suggests a benign lesion. A multicenter study, using a cutoff value of 15 HU, found a sensitivity and specificity of 98% and 58%.^[5] Active granulomas or other infectious lesions may also enhance, thus limiting the application of this technique. However, a failure to enhance by more than 15-20 HU has greater than a 95% predictive value for benignity.

Several radiologic characteristics, both on CT and radiography (although CT is superior), may help establish the diagnosis or suggest if a lesion is benign or malignant. These include (1) size, (2) growth rate, (3) presence of calcification, (4) border characteristics, (5) internal characteristics, and (6) location.

• Size: Although a well-defined nodule of smaller size that is clearly visible on chest radiographs may be calcified and benign, small lesions may very well be early-stage bronchogenic carcinoma. A lesion greater than 4 cm in diameter is very likely a bronchogenic carcinoma, although exceptions include lung abscess, Wegener's granulomatosis, lymphoma, round pneumonia, rounded atelectasis, and hydatid cyst. Midthun et al indicated that the likelihood of malignancy was 50% in nodules greater than 20 mm and 18% for those 8-20 mm in diameter. With lesions smaller than 8 mm, a sharp decline is noted, with nodules of 4-7 mm having a likelihood of malignancy of only 0.9% and those less that 3 mm only 0.2%.^[6]
• Rate of growth: Serial chest radiographs facilitate estimation of the growth rate of a nodule.

  • Growth rate refers to the doubling time of a nodule, which is doubling of the nodule volume. Because a nodule on a chest radiograph is seen as a 2-dimensional circle rather than a 3-dimensional sphere, an increase in diameter of 26% corresponds to a doubling of nodule volume.
  • Bronchogenic carcinoma generally doubles in 1-18 months (average 4-8 mo). Although a doubling time of less than 1 month or longer than 18 months makes bronchogenic carcinoma unlikely, it does not exclude the diagnosis completely. Important exceptions are bronchoalveolar carcinoma, which may require more than 2 years to double in size, and metastases from specific tumors (eg, osteosarcoma, choriosarcoma), which grow rapidly.^[7]
  • In general, doubling times of less than 1 month suggest infections; doubling times of more than 18 months suggest benign processes such as granuloma, hamartoma, bronchial carcinoid, and rounded atelectasis. If a nodule remains the same size for 2 years, it is very likely benign; however, further follow-up monitoring may be indicated.
  • In one restrospective series, a volume doubling time of < 400 days at 3 month and 1 year followup was strongly predictive of malignancy (OR 15.6 [4.5-53.5] and 213.3 [18.7-2430.9) respectively)^[8]
• Calcification: Chest radiographs may demonstrate calcification, which often indicates that the lesion is benign. (The CT scan is the most sensitive technique for detection of calcification.) The 5 patterns of calcification usually observed in benign lesions are diffuse, central, laminar, concentric, and popcorn. A stippled or eccentric pattern is associated with malignancy. See the images below. Close-up view of a right lower lobe nodule demonstrating central calcification. The most likely diagnosis is histoplasmosis. A "popcorn" calcification in the left lung nodule indicates a benign lesion or hamartoma. No further tests or observations are needed for this patient. Right upper lobe nodule shows peripheral calcification and high Hounsfield unit enhancement, suggesting that the lesion is a calcified benign pulmonary nodule.
• Border characteristics

  • A very irregular edge or corona radiata (numerous strands radiating into the surrounding lung) may indicate a bronchogenic carcinoma.
  • A well-defined, smooth, nonlobulated edge may indicate a benign lesion or metastasis, whereas lobulation and notching may indicate bronchogenic carcinoma.
  • Cavitation with a thin, smooth wall may indicate lung abscess or a benign lesion, whereas thick-walled cavitations imply an underlying malignant neoplasm. See the images below. Left upper lobe cavitating solitary nodule eventually identified as active pulmonary tuberculosis from percutaneous needle biopsy findings. Cavitating right lower lobe nodule later confirmed to be primary pulmonary lymphoma. Calcium deposits may also be present in the lesion.
  • The CT halo sign (ie, ground-glass attenuation surrounding a nodule on CT scan image) most commonly indicates infection with an invasive Aspergillus species. Other less common possibilities include TB, cytomegalovirus infection, or herpes simplex infections.
• Internal characteristics: Several characteristics within the nodule itself can indicate a specific cause.

  • Demonstration of fat within the lesion is specific for a hamartoma, a benign lesion. See the images below.Left upper lobe 1.5-cm nodule shows negative CT scan numbers, suggesting fat in the lesion consistent with hamartoma. The parenchymal lesion in this CT scan demonstrates low attenuation within the lesion, indicating the presence of fat. Fat density is only observed in hamartoma and lipoid pneumonia. The likely diagnosis is hamartoma.
  • Ground-glass opacities may represent a benign lesion, such as atypical adenomatous hyperplasia, or malignancy, such as bronchoalveolar carcinoma (BAC).^[3] Importantly, malignant ground-glass opacities often grow slower and may require longer follow up.^[2]
  • Subsolid nodules (nodules with both solid and ground glass component) are frequently peripheral adenocarcinomas of the lung. Studies have demonstrated excellent correlation between the Noguchi classification of adenocarcinomas and CT findings. Specifically, atypical alveolar hyperplasia typically manifests as pure ground glass lesions less than 5cm; BAC is usually greater than 5cm; lesions with mixed solid component and ground glass correlate with adenocarcima, mixed subtype.^[9]
  • The presence of air bronchograms within the solitary pulmonary nodule makes bronchogenic carcinoma or metastasis unlikely, although they may be observed with bronchoalveolar carcinoma or lymphoma. Invasion of the adjacent bone by the nodule is pathognomic of bronchogenic carcinoma.
• Location

  • Nodules that are attached to pleura, vessels or fissures are likely benign^{[8, 10]}

Positron-emission tomography

Whether positron-emission tomography (PET) scanning will be useful depends on (1) the clinical pretest probability of malignancy, (2) nodule morphology, (3) the size and position of the nodule, and (4) the scanning facility available.^[11]

Because malignant nodules have increased glucose metabolism compared with benign lesions and healthy lungs, enhancement of the lesion makes it likely to be malignant. Injection of analogue 18-F-2 fluorodeoxyglucose (FDG) is used to assess the metabolic activity. FDG-PET scans may be analyzed semiquantitatively using standardized uptake values (SUVs) to normalize measurements for the patient's weight and the injected dose of radioisotope. Although visual analysis findings (depending on the experience and judgment of the nuclear medicine physician) may match SUV calculations, an SUV of less than 2.5 is considered indicative of a benign lesion.

FDG-PET scans are quite helpful in detecting mediastinal metastases, thus improving staging of noninvasive lung cancer. FDG-PET scans have several limitations because the false-positive findings occur in other metabolically active pulmonary nodules, which are either infectious or inflammatory. Tumors that have lower metabolic rates, such as carcinoid and bronchoalveolar carcinoma, may be difficult to distinguish from background activity. Finally, the FDG-PET scan has lower sensitivity for nodules smaller than 20 mm in diameter and may miss lesions smaller than 10 mm.

Several studies have reported the sensitivity, specificity, and accuracy of FDG-PET scanning to be greater than 90%, 75%, and 90%, respectively,^[12] including a meta-analysis of 40 studies evaluating 1474 focal pulmonary lesions of any size.^[13] FDG-PET scanning is an accurate and noninvasive imaging test for the diagnosis of pulmonary nodules and larger masses.^[14] However, not much data are available for nodules smaller than 1 cm in diameter.

One study compared the diagnostic accuracy of helical dynamic CT (HDCT) scanning and integrated PET/CT scanning for pulmonary nodule characterization. The sensitivity, specificity, and accuracy for malignancy with HDCT scanning were 81% (64 of 79 nodules), 93% (37 of 40 nodules), and 85% (101 of 119 nodules), respectively, whereas the values for integrated PET/CT scanning were 96% (76 of 79 nodules), 88% (35 of 40 nodules), and 93% (111 of 119 nodules), respectively.^[15] Integrated PET/CT scanning is more sensitive and accurate than HDCT scanning for malignant nodule diagnosis, making it the first-line evaluation tool for solitary pulmonary nodules. Because of the high specificity and acceptable sensitivity and accuracy of HDCT scanning, it may be a reasonable alternative if PET/CT scanning is unavailable.

PET scanning has low sensitivity in small and slow growing lesions, such as BAC and carcinoid tumors.^[9] One study showed very high false negative rates (up to 100%) for BAC.^[16]

Single-photon emission computed tomography

Single-photon emission computed tomography (SPECT) scanning is less expensive than PET scanning, but both modalities have comparable sensitivity and specificity. SPECT imaging is performed using a radiolabeled somatostatin-type receptor binder, technetium Tc P829. SPECT imaging has not been evaluated in a large series of patients; in a smaller series, the sensitivity fell significantly for nodules less than 20 mm in diameter.

Naalsund et al evaluated the diagnostic performances of technetium Tc 99m depreotide in differentiating benign solitary pulmonary nodules from malignant solitary pulmonary nodules.^[17] They also compared the diagnostic accuracy of^99m Tc with FDG-PET scanning in a prospective, multicenter trial. SPECT scanning with^99m Tc depreotide revealed a sensitivity, specificity, and diagnostic accuracy of 89%, 67%, and 81%, respectively. Furthermore, in patients who underwent both^99m Tc depreotide SPECT imaging and FDG-PET imaging, the sensitivity, specificity, and diagnostic accuracy were identical for both modalities.

Biopsy

Biopsy of solitary pulmonary nodule can be performed bronchoscopically or via transthoracic needle aspiration (TTNA).

Because the yield from bronchoscopy is only 10-20% when the nodule is less than 2 cm in diameter, bronchoscopy and transbronchial needle aspiration (TBNA) may be helpful when the lesion is either endobronchial in location or near a large airway. Prospective data from the NELSON lung cancer screening trial indicate that the sensitivity of bronchoscopy for suspicious nodules seen on CT is only 8.3%. However, if an endobronchial lesion is visualized, the sensitivity increases to 81.8%.^[18] TBNA may also be helpful in sampling the mediastinal nodes. Fluoroscopy or endobronchial ultrasound can be used to localize the lesions during TBNA to increase the diagnostic yield to 70% or more.^{[19, 20, 21]}

TTNA reportedly has an accuracy of 90-95% when the lesion is 2 cm or larger in diameter, although the diagnosis is less accurate (60-80%) in lesions smaller than 2 cm. Confirming a specific benign diagnosis is more difficult (approximately 70% accuracy); therefore, most benign lesions are characterized as nondiagnostic following TTNA. The rate of pneumothorax following TTNA is approximately 25%, with approximately 7% requiring chest intubation.^{[22, 23]}