eMedicine Specialties > Pulmonology > Lung Tumors

Solitary Pulmonary Nodule: Differential Diagnoses & Workup

Author: Nader Kamangar, MD, FACP, FCCP, FAASM,, Associate Professor of Clinical Medicine, Director of Hospitalist/Intensivist Program, Division of Pulmonary, Critical Care and Sleep Medicine, David Geffen School of Medicine at University of California Los Angeles; Associate Director, Combined Pulmonary and Critical Care Fellowship Program, Cedars-Sinai/Olive View-UCLA/West Los Angeles Veterans Affairs Medical Center
Coauthor(s): Asif Alavi, MD, Resident Physician, Department of Internal Medicine, University of California, Los Angeles, David Geffen School of Medicine, Olive View Medical Center; Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital; Sri R Navaratnam, MBBS, PhD, FRCPC, Assistant Professor, Department of Internal Medicine, Section of Hematology/Oncology, University of Manitoba; Consulting Medical Oncologist, Department of Hematology/Oncology, Cancer Care Manitoba
Contributor Information and Disclosures

Updated: Sep 11, 2009

Differential Diagnoses

Workup

Laboratory Studies

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.

Imaging Studies

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 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.

• 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 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.
• 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.

• 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.

• 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.

• Ground-glass opacities may represent a benign lesion, such as atypical adenomatous hyperplasia, or malignancy, such as bronchoalveolar carcinoma.³ Importantly, malignant ground-glass opacities often grow slower and may require longer follow up.²
• 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.

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.

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,⁸ including a meta-analysis of 40 studies evaluating 1474 focal pulmonary lesions of any size.⁹ FDG-PET scanning is an accurate and noninvasive imaging test for the diagnosis of pulmonary nodules and larger masses. 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.¹⁰ 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.

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.¹¹ 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.

Procedures

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. 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.^12,13
• 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.¹⁴

• Search for CME/CE on This Topic »

• Solitary Pulmonary Nodule (Radiology)
• Transthoracic Needle Biopsy (Radiology)
• Hamartoma, Lung (Radiology)

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