Solitary Pulmonary Nodule Workup

Because a malignancy may be curable when present as a solitary pulmonary nodule, great care should be taken in evaluating such lesions. A comprehensive assessment generally includes history, physical examination, evaluation of previous chest radiographs, incorporation of other imaging studies (eg, CT scanning, positron-emission tomography [PET] scanning), and invasive diagnostic procedures.

Determining the pretest probability of malignancy is essential in guiding the management of solitary pulmonary nodules, and, thus, estimating the probability of benignity using a validated quantitative model might be an effective strategy. A number of quantitative risk models have been developed, but three commonly used models are the Mayo Clinic Model, ^[8] the Veterans Administration (VA) Cooperative Model, ^[9] and the Brock University Risk Model. ^[10] Apart from the Brock Model in the British Thoracic Society (BTS) guidelines, ^[11] no one risk model has been specifically ratified by any societies or guidelines. Each has their own nuances, which should be taken into account when deciding on one's preferred risk model.

The Mayo risk model, although well validated, was developed from chest radiography data of incidentally found lung nodules sized 4-30 mm. It performed well in both the derivation and validation cohorts, with the area under the curve (AUC) of the receiver operator curve (ROC) being 0.83 and 0.8, respectively. Comparison with a group of experienced physicians' estimates of malignancy showed that it predicted malignancy no better than physician's predictions. ^[12] The VA model was derived from a predominantly male population with a significant smoking history. Incidentally found nodules measuring 7-30 mm were included. The overall accuracy was also good, with an area under the ROC of 0.79 in the derivation cohort and 0.73 in the validation cohort. ^[13] The Brock University risk model was derived from analysis of the Pan-Canadian Early Detection of Lung Cancer Study (PanCan) cohort, which encompassed those who qualified for low-dose lung cancer screening CT (ie, aged 50-75 years with a current or former history of smoking). It was then validated in an independent cohort from the British Columbia Cancer Agency study (BCCA), which included current or prior smokers aged 50-74 years with a 30 pack-year smoking history. It performed very well, with an area under the ROC greater than 0.9 in both the complete risk model and the parsimonious model. Online access to this risk calculator can be found at https://brocku.ca/lung-cancer-risk-calculator.

Because the evidence is not definitive for many of the management guidelines, clinicians should discuss with patients the risks and benefits of alternative management options and should elicit patient preferences. The probability of malignancy only provides an estimate based on previously published studies and may not be generalized to an individual patient. Therefore, patient preferences and clinician experience are important in planning further management strategies.

Laboratory studies have a limited role in the workup of solitary pulmonary nodules. Anemia or an elevated sedimentation rate may indicate an underlying neoplastic or infectious process, while elevated levels of liver enzymes, alkaline phosphatase or serum calcium may indicate metastases from a solitary bronchogenic carcinoma or from a nonpulmonary malignancy.

Patients who have histoplasmosis or coccidioidomycosis may have high levels of immunoglobulin G and immunoglobulin M antibodies specific to these fungi. If tuberculosis is suspected, besides obtaining the appropriate acid-fast bacilli sputum evaluations, an interferon-gamma release assay (IGRA) or a tuberculin skin test can also be positive. 

Various sputum and serologic biomarkers have been developed to aid in the diagnosis of lung cancer and to help determine the likelihood of malignancy in a solitary pulmonary nodule. ^[14] Assays to detect microRNA and DNA methylation abnormalities are commercially available, ^[15] but they lack the support of large clinical multicenter trials and cost analyses data.

Preoperative tests

A preoperative complete blood cell count and coagulation (prothrombin time [PT] and international normalized ratio [INR], partial thromboplastin time [PTT]) studies are generally performed on all patients planned to undergo tissue sampling. The blood cell count also helps to determine the general health status of the patient and aids in the diagnosis of complications such as pneumonia, anemia, and thrombocytopenia.

If lung resection is being considered, then a renal function panel should also be considered. ^[16] Electrolytes, renal function tests, and liver function tests help to evaluate the presence of an abnormality that may indicate the need for either intervention or further workup before an invasive procedure is performed.

A patient with a carcinoid tumor, with or without carcinoid syndrome, may exhibit a high level of serotonin and urinary 5-hydroxyindoleacetic acid (5-HIAA).

Pulmonary function tests (PFTs) are indicated in all patients being considered for lung resection surgery. Patients must have satisfactory parameters as measured by forced expiratory volume in 1 second (FEV₁) and diffusion capacity of lung for carbon monoxide (DLCO) in order to be considered suitable for surgery. ^[17]

For solitary pulmonary nodules detected on chest radiographs, the initial distinction made is whether the nodule is pulmonary or extrapulmonary in nature. Findings from lateral chest radiography or CT scanning may help to 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 in determining 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. ^[18] The advantages include better resolution of nodules and detection of nodules as small as 3-4 mm. CT scan images also help to 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 employed.

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%, respectively. ^[19] Active granulomas or other infectious lesions may also enhance, limiting the application of this technique. However, a failure to enhance by more than 15-20 HU has a greater than a 95% predictive value for benignity.

Several radiologic characteristics found on CT scanning and radiography (although CT scanning is superior) may help to establish the diagnosis or suggest whether a lesion is benign or malignant. These include the following:

• Size

• Growth rate

• Presence of calcification

• Border characteristics

• Internal characteristics

• 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 reported that the likelihood of malignancy was 50% for 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%. ^[20]

Rate of growth

Growth rate refers to the doubling time of a nodule, which is a doubling of the nodule volume. Because a nodule on chest imaging is seen as a 2-dimensional (2-D) circle rather than a 3-D 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 minimally invasive adenocarcinoma (formerly bronchoalveolar carcinoma), which may require more than 2 years to double in size, and metastases from specific tumors (eg, osteosarcoma) that grow rapidly. ^[21]

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 retrospective series, a volume doubling time of less than 400 days at 3 months and 1 year follow-up was strongly predictive of malignancy. ^[22]

Calcification

Certain patterns of calcification are considered to be benign. The five patterns of calcification usually observed in benign lesions are diffuse, central, laminar, concentric, and popcorn. ^[23] Stippled and eccentric patterns are more suspicious for malignancy and require follow up. See the images below.

Border characteristics

A very irregular edge or corona radiata (numerous strands radiating into the surrounding lung) may indicate a bronchogenic carcinoma. Whereas lobulation and notching may indicate bronchogenic carcinoma, a well-defined, smooth, nonlobulated edge may indicate a benign lesion or metastasis.

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.

The CT-scan 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, and herpes simplex infections.

Internal characteristics

Several characteristics within the nodule itself can indicate a specific cause. For example, demonstration of fat within the lesion is specific for a hamartoma, a benign lesion. See the images below.

Ground-glass opacities may represent a benign lesion, such as atypical adenomatous hyperplasia, or malignancy, such as minimally invasive adenocarcinoma . ^[4] Importantly, malignant ground-glass opacities often grow slower and may require longer follow-up. ^[3]

Subsolid nodules (nodules with both a solid and a ground-glass component) are frequently peripheral adenocarcinomas of the lung. Studies have demonstrated excellent correlation between the Noguchi classification of adenocarcinomas and CT-scan findings. Specifically, atypical alveolar hyperplasia typically manifests as pure ground-glass lesions of less than 5 cm; minimally invasive adenocarcinoma is usually greater than 5 cm. Lesions with a mixed solid component and ground glass correlate with adenocarcinoma, mixed subtype. ^[24]

The presence of air bronchograms within the solitary pulmonary nodule makes bronchogenic carcinoma or metastasis unlikely, although they may be observed with minimally invasive adenocarcinoma 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 to be benign. ^{[22, 25]}

Lung Reporting and Data System (Lung-RADS™)

In an effort to standardize the manner in which low-dose lung cancer screening CTs are reported, the American College of Radiology (ACR) introduced Lung-RADS™ in 2014, with updates in 2019. Similar to the Bi-RADS system for breast cancer, numbered categories corresponding to a particular management recommendation are reported. Categories 1 and 2 correspond to very low risk, likely benign findings for which continued annual low-dose CT surveillance is advised. Category 3 warrants an earlier low-dose CT scan in 6 months’ time and category 4 is split into 4a and 4b. With category 4a, a 3-month low-dose follow-up CT scan is suggested, with consideration for a PET-CT if the solid component of the nodule is 8 mm or wider. For category 4b, either chest CT with or without contrast, PET/CT, and/or tissue sampling depending on the probability of malignancy and comorbidities are recommended. If there is an 8 mm or wider solid component to the nodule, then PET-CT can be considered. Notable 2019 updates are that the size criterion for a category 2 nonsolid nodule has been increased from 20 mm to 30 mm and more attention should be given to the solid component of the nodule. Additionally, category 4B nodules can be imaged after 1 month if there are questions about infection versus malignancy. Finally, volume measurements and perifissural nodules are defined. ^[26]

With regard to performance, when retrospectively compared against the National Lung Cancer Screening Trial (NLST) cohort, a Lung-RADS category 3 or higher yielded a lower false-positive rate (5.3% vs 21.8%) but at the cost of a lower sensitivity (84.9% vs 93.5%) ^[27] when compared with the NLST criteria.

Whether positron-emission tomography (PET) scanning will be useful in a patient’s workup 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. ^{[28, 29]}

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.

Sensitivity and specificity

Several studies have reported the sensitivity, specificity, and accuracy of FDG-PET scanning to be greater than 90%, 75%, and 90%, respectively, ^[30] including a meta-analysis of 40 studies evaluating 1474 focal pulmonary lesions of any size. ^[31] FDG-PET scanning is an accurate and noninvasive imaging test for the diagnosis of pulmonary nodules and larger masses. ^[32] However, not much data are available for nodules smaller than 1 cm in diameter.

FDG-PET scans have several limitations because false-positive findings can occur in other infectious or inflammatory conditions that yield metabolically active pulmonary nodules. Moreover, tumors that have lower metabolic rates, such as carcinoid, lepidic-predominant adenocarcinomas and mucinous adenocarcinomas, may be difficult to distinguish from background activity and hence yield false-negative results. Finally, the FDG-PET scan has lower sensitivity for nodules smaller than 20 mm in diameter and may miss lesions smaller than 10 mm.

One study found that integrated PET-CT scanning is more sensitive and accurate than helical dynamic CT (HDCT) scanning for malignant nodule diagnosis, making it the first-line evaluation tool for solitary pulmonary nodules. 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. ^[33]

PET scanning has low sensitivity in small and slow-growing lesions, such as minimally invasive adenocarcinoma and carcinoid tumors. ^[24] One study showed very high false-negative rates (up to 100%) for minimally invasive adenocarcinoma. ^[34]

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 CT (SPECT) scanning is less expensive than PET scanning. Both modalities have comparable sensitivities and specificities of 95% and 82%, respectively. ^[35] 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.

In a prospective, multicenter trial, Naalsund et al evaluated the efficacy of ^99mTc depreotide in differentiating benign solitary pulmonary nodules from malignant solitary pulmonary nodules and found that SPECT scanning with ^99mTc 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. ^[36]

Rigid and fiberoptic bronchoscopy are each useful for diagnosing endobronchial benign lung tumors. Biopsy or bronchial brushing can be performed with this procedure, as well as excision of a pedunculated endobronchial lesion.

Sensitivity for detection of malignancy is 10-30% when the nodules are peripheral and small (< 2 cm). However, advances in bronchoscopy, such as the development of electromagnetic navigation and endobronchial ultrasonographically guided transbronchial needle biopsy, may offer improved results in the evaluation of pulmonary nodules and mediastinal adenopathy. ^[37]

Bronchoscopic resection also offers an alternative to surgical resection of benign endobronchial tumors. In a study by Luckraz et al, 100% and 94% of completely resected carcinoids were free of disease at 1 and 10 years, respectively. ^[6]

A biopsy of a lung nodule should be performed to determine whether it is malignant. The risks of biopsy and the procedural approach to tissue acquisition must of course take into account the patient's bleeding diathesis and comorbidities.

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

Because the yield from bronchoscopy is only 10-20% when the nodule is less than 2 cm in diameter, bronchoscopy with 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 indicated that the sensitivity of bronchoscopy for suspicious nodules seen on CT scan is only 8.3%. However, if an endobronchial lesion is visualized, the sensitivity increases to 81.8%. ^[38] TBNA may also be helpful in sampling the mediastinal nodes. Fluoroscopy or endobronchial ultrasonography (EBUS) can be used to localize the lesions during TBNA to increase the diagnostic yield to 70% or more. ^{[39, 40, 41]}

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. ^[42] 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 20%, with 2-15% of patients requiring chest tube insertion. ^[43]

Surgical biopsies

Video-assisted thoracoscopic surgery (VATS) can be used to obtain  a biopsy specimen from a superficial, pleural-based lesion, or the lesion can be resected using this approach. ^{[44, 45, 46]} Biopsy using VATS is more frequently performed for the diagnosis of a solitary pulmonary nodule.

Open biopsy may occasionally be required when the etiology of a pulmonary nodule is questioned after a thorough workup.

A small percentage of VATS biopsies are converted to open thoracotomies given technical issues, typically associated with the amount of tissue resected or complexity of the operation associated with the nodule.

Risk factors for false-negative results

In a study of CT scan ̶ guided, transthoracic fine-needle aspiration of pulmonary nodules, Gelbman et al determined that various factors, including nodule size and the occurrence of pneumothorax, influence the rate of false-negative results. The study looked at 170 patients with negative results following fine-needle aspiration, including 18 patients with false-negative findings. ^[47]

Among the differences found between the two groups of patients, it was determined that those with false negatives had larger nodules (mean, 27 mm) than did those with true-negative results (mean, 17 mm). The false-negative patients also had fewer imaging adjustments per needle pass (4.5) than did the true-negative patients (6.4), as well as a greater pneumothorax rate during the procedure (50% vs 22%).

Patient consent

Because invasive procedures such as TTNA, TBNA, and VATS may be associated with risks and complications, informed consent must be obtained before these procedures are conducted.