Background: A solitary pulmonary nodule (SPN) is defined as a single discrete pulmonary opacity that is surrounded by normal lung tissue and is not associated with adenopathy or atelectasis. The finding of an SPN on a chest radiograph is a diagnostic dilemma often faced by many clinicians. The differential diagnosis may be broad but implications rest on whether the lesion is benign or malignant.
Radiographically, a nodule is defined as a lesion smaller than 3 cm. Anything larger than 3 cm is termed a mass.
Pathophysiology: Pathophysiology of pulmonary nodules depends on etiology.
Frequency:
- In the US: SPNs are fairly common. Screening studies in adults reveal SPNs in 1-2 per 1000 chest radiographs. In the United States, an estimated 150,000 SPNs are detected annually. Overall, incidence of malignancy ranges from 10-70%. The higher incidence is largely the result of a selection bias, depending on the population under study (eg, age, smoking status, referral pattern, location of the study).
Mortality/Morbidity: Prognosis depends on whether the lesion is benign or malignant and the stage of the lung cancer on presentation.
Following resection of a solitary bronchogenic carcinoma (stage IA), the 5-year survival rate is approximately 80-90%.
Race: No racial difference in the prevalence and incidence of malignant nodules has been described. Geographic variations exist in the incidence of benign lesions, especially infectious granulomas.
Sex: No difference in incidence exists between males and females.
Age: Solitary nodules can occur at all age levels. Early on, they usually are secondary to a benign lesion. The risk of malignancy increases with age (see Clinical Details).
Clinical Details: Most SPNs are asymptomatic. The goal of investigating an SPN is to differentiate a benign lesion from a malignant lesion as soon and as accurately as possible.
Important features in the patient history include the following:
- Age - Risk of malignancy increases with age
- Risk of 3% at age 35-39 years
- Risk of 15% at age 40-49 years
- Risk of 43% at age 50-59 years
- Risk of greater than 50% in patients older than 60 years
- Risk of 3% at age 35-39 years
- Smoking history
- Prior history of malignancy
- Travel history - Travel to areas with endemic mycosis (eg,
histoplasmosis, coccidioidomycosis, blastomycosis) or a high
prevalence of tuberculosis
- Occupational risk factors for malignancy - Exposure to asbestos,
radon, nickel, chromium, vinyl chloride, and polycyclic hydrocarbons
- Previous history of tuberculosis or pulmonary mycosis
Preferred Examination: Chest radiograph usually is the initial examination. Most SPNs are discovered as an incidental finding. With recent studies examining the use of low-dose CT chest scans as a screening tool for lung cancer, more smaller nodules will be detected that require evaluation. As more large-scale studies become available, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will become important imaging tools in evaluating an SPN.
Limitations of Techniques: Chest radiographs demonstrate poorer resolution than chest CT scans in determining degree of calcification or size. Visualization of some nodules may be difficult because of superimposed structures.
Chest CT scans are limited by expense and the need for intravenous contrast, which carries a risk of an adverse reaction. CT is not as available and portable as chest radiographs.
Nuclear medicine imaging (PET and SPECT scan) is considerably more expensive than a chest CT scan or MRI study. PET and SPECT are variably available.
DIFFERENTIALS
Aspergillosis, Thoracic
Blastomycosis, Thoracic
Bronchiolitis Obliterans Organizing Pneumonia
Bronchogenic Cyst
Coccidioidomycosis, Thoracic
Histoplasmosis, Thoracic
Lung Cancer, Non-Small Cell
Lung Cancer, Small Cell
Lung, Arteriovenous Malformation
Lung, Carcinoid
Lung, Metastases
Lung, Nontuberculous Mycobacterial Infections
Lung, Postprimary Tuberculosis
Lung, Primary Tuberculosis
Pancoast Tumor
Sarcoidosis, Thoracic
Other Problems to be Considered:
Malignant lesions
Bronchogenic carcinoma - Small cell, large cell, adenocarcinoma, and
squamous
Carcinoids
Solitary metastases
Benign lesions
Benign neoplasms - Hamartomas, lipomas, and fibromas
Vascular lesions - Arteriovenous malformation
Infectious granulomas - Tuberculosis, atypical mycobacterial infection,
histoplasmosis, coccidioidomycosis, and blastomycosis
Other infections - Aspergilloma, ascaris, dirofilariasis, echinococcal
cyst, and bacterial abscess
Noninfectious granulomas - Rheumatoid arthritis, Wegener granulomatosis,
and sarcoidosis
Developmental lesions - Bronchogenic cyst
Others conditions - Hematoma, bronchiolitis obliterans-organizing
pneumonia, pseudotumor, pulmonary infarction, amyloidoma, rounded
atelectasis, and mucoid impaction
X-RAY
Findings: Often, SPNs are discovered first as incidental findings on chest radiographs. The first step is to determine whether the nodule is pulmonary or extrapulmonary. A lateral chest radiograph, fluoroscopy, or CT of the chest often helps determine the location of the nodule.
Usually, nodules are identifiable by the time they are 8-10 mm on chest radiographs. Occasionally, SPNs can be visualized at 5 mm in diameter. Chest radiographs can provide information regarding nodule size, growth rate, margin characteristics, and calcification pattern, which can aid in the assessment of benign versus malignant lesions.
- Nodule size: Nodules greater than 3 cm in diameter are more likely
to be malignant, while those less than 2 cm are more likely to be
benign. Note that size alone is of limited value. In individual
patients, small nodules can be malignant and larger nodules can be
benign.
- Growth rate
- Comparison of previous chest radiographs of the patient allows
assessment of the growth rate. The growth rate refers to the
doubling time of a nodule, ie, doubling in volume. On chest
radiographs, a nodule appears as a 2-dimensional representation of
a 3-dimensional structure. The volume of a sphere equals 4/3 pr3;
therefore, a 26% increase in diameter on a chest radiograph
represents one doubling in volume. For example, an increase from
1-1.3 cm equals one doubling. A 1-2 cm increase relates to an
8-fold increase in volume.
- Bronchogenic carcinomas usually have a doubling time of 20-400
days.
- Doubling times shorter than 20-30 days are seen in infections,
infarction, lymphoma, or fast-growing metastases.
- Doubling times greater than 400 days are typically benign.
- On occasion, a low-grade carcinoid tumor may have a doubling
time greater that 400 days.
- Absence of change in size of a nodule over 2 years is highly
suggestive of a benign lesion.
- Determination of size of small nodules is not without error. On chest radiographs, a 3-mm enlargement may be difficult to appreciate. The use of digitally enhanced films may allow for more accurate measurements of size.
- Comparison of previous chest radiographs of the patient allows
assessment of the growth rate. The growth rate refers to the
doubling time of a nodule, ie, doubling in volume. On chest
radiographs, a nodule appears as a 2-dimensional representation of
a 3-dimensional structure. The volume of a sphere equals 4/3 pr3;
therefore, a 26% increase in diameter on a chest radiograph
represents one doubling in volume. For example, an increase from
1-1.3 cm equals one doubling. A 1-2 cm increase relates to an
8-fold increase in volume.
- Margin characteristics: Benign lesions tend to have
well-circumscribed smooth borders. Malignant nodules typically have
irregular, lobulated, or spiculated (corona radiata) borders. Of the
margin descriptions, the spiculated border is the most sensitive in
predicting malignancy; however, it is not unusual for a malignant
lesion to have a smooth contour.
- Calcification: Calcification within a nodule is more likely to be seen in a benign nodule; however, approximately 10% of malignant nodules demonstrate calcification. In benign lesions, 5 patterns of calcification are seen commonly, including diffuse, central, laminar, concentric, and popcorn (chondroid) calcifications. The popcorn pattern typically is described in hamartomas. A stippled or eccentric pattern is seen most commonly in malignant lesions. CT allows a more accurate detection and assessment of the calcification pattern than plain film.
False Positives/Negatives: Some SPN mimics include nipple shadows, soft tissue tumors, bone shadows, pleural plaques, pseudotumors, and round atelectases.
CAT SCAN
Findings: In addition to the features seen also on plain film (see X-ray), CT of the chest allows better assessment of nodules. The advantages of CT over plain film include the following:
- Better resolution: Nodules as small as 3-4 mm are detectable.
Morphologic features of specific diagnosis are better visualized (eg,
rounded atelectasis, arteriovenous malformations).
- Areas that are difficult to assess on plain radiography are
visualized better on CT, such as the lung apices, perihilar regions,
and costophrenic angles.
- Multiple nodules can be detected on CT scans.
- Malignancy can be staged using CT.
- CT can help guide needle biopsy.
CT densitometry
CT densitometry measures the attenuation coefficients of a particular lesion to determine its density. The results are expressed in Hounsfield units (HU). Some examples of attenuation coefficients are as follows:
- Air: -1000 HU
- Fat: -50 to -100 HU
- Water: 0 HU
- Blood: 40-60 HU
- Noncalcified nodule: 60-160 HU
- Calcified nodule: Greater than 200 HU
- Bone: 1000 HU
CT densitometry allows for detection of occult calcification that may not be appreciated visually, even on high-resolution thin-section CT of the chest. The difficulties with this technique have been in determining the appropriate level of the attenuation coefficients used to classify a lesion with a high probability of being benign. One study looking at 91 nodules known to be malignant or benign proposed a cutoff of greater than 164 HU for benign lesions. In another study of 85 nodules classified as benign using 185 HU as a cutoff, 9% were found to be malignant at biopsy. Densitometry in this setting may provide useful information if used in context with other clinical and radiologic features but overall its use has fallen out of favor.
Densitometry also allows detection of fat within a nodule, which is a common feature of benign nodules, especially in hamartomas.
Other features of CT include the following:
- Contrast enhancement: Malignant nodules tend to have greater
vascularity than benign nodules. Assessment of enhancement involves
repeated measurement of attenuation of a nodule over a 5-minute
period. Nodular enhancement of less than 15 HU suggests that a lesion
is benign, and enhancement of greater than 20 HU is more likely
associated with malignancy (sensitivity 98%, specificity 73%).
- Feeding vessel sign: This sign may be seen in hematogenous or
vascular causes of pulmonary nodules such as metastatic deposits or
septic emboli.
- Cavity wall thickness: Cavitation can be seen in both malignant and benign nodules. While a thin-walled cavity is highly suggestive of a benign lesion (<1 mm), a thick-walled cavity usually is indeterminate and is present in both benign and malignant lesions.
MRI
Findings: MRI provides better imaging for pleural, diaphragm, and chest wall disease than CT when staging lung cancer. MRI is comparable to CT in assessing mediastinal involvement and is less useful in assessing the lung parenchyma (especially assessing pulmonary nodules) because of poorer spatial resolution. Since MRI costs more and is less available, MRI use is reserved for tumors that are difficult to assess on CT (eg, Pancoast tumors).
ULTRASOUND
Findings: Ultrasound is not commonly used in the evaluation of an SPN. Ultrasound has a limited role in percutaneous biopsy of larger peripherally based lesions.
NUCLEAR MEDICINE
Findings: Recently, nuclear medicine imaging has been studied for use in evaluation of SPNs. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging have been approved for use in the United States for evaluating pulmonary nodules.
PET imaging
Malignant cells have a higher metabolic rate than normal cells; therefore, glucose uptake is higher. Thoracic PET imaging uses the isotope fluorine-18 bound to a glucose analog to make fluorine-18-fluorodeoxyglucose (FDG). Increased FDG uptake is seen in most malignant tumors and is the basis of the PET study used to differentiate malignant from benign nodules.
FDG uptake can be quantified using the standardized uptake ratio (SUR) to normalize measurements for a patient's weight and injected dose of radioisotope. This allows comparison of uptake between different lesions and patients. SURs greater than 2.5 have been used by some as a marker of malignancy.
An additional advantage of FDG-PET imaging is better detection of mediastinal metastases, improving the staging of lung cancers.
SPECT imaging
SPECT scanners have the advantage of being more readily available than PET scanners. Depreotide is a somatostatin analog labeled with technetium Tc 99m, which has been shown to bind to somatostatin receptors expressed on nonsmall cell carcinomas.
Use of SPECT scanning has not been evaluated in a larger series.
Overall, both FDG-PET and SPECT imaging are promising noninvasive techniques for differentiating malignant lesions from benign lesions and aiding in the assessment of indeterminate lesions.
Degree of Confidence: In a recent meta-analysis, the mean sensitivity and specificity for detecting malignancy in focal pulmonary lesions of any size were 96% and 73.5%, respectively. In SPNs, the mean sensitivity and specificity were 93.9% and 85.8%, respectively.
In a study of a small series of patients, depreotide uptake demonstrated a sensitivity and specificity of 93% and 88%, respectively, for malignancy.
False Positives/Negatives: Limitations of FDG-PET imaging include the following:
- False-positive findings can occur in other metabolically active
conditions that produce pulmonary nodules, such as infectious
granulomas or inflammatory lesions.
- False-negative findings can be seen in the following:
- Small tumors: The resolution of current PET scanners is 7-8 mm;
therefore, they may miss tumors smaller than 10 mm.
- Tumors with low metabolic rates, such as carcinoid tumors and
bronchioalveolar cell carcinomas, may not be distinguishable from
background uptake.
- High serum glucose concentrations compete in cells with FDG; therefore, uptake of the radioisotope is reduced.
- Small tumors: The resolution of current PET scanners is 7-8 mm;
therefore, they may miss tumors smaller than 10 mm.
INTERVENTION
Intervention: After clinical and radiologic assessment of an SPN, all patients can be divided into 1 of 3 groups as follows:
- Patients with benign lesions: Benign status is based on patient age
younger than 35 years without other risk factors, stability of the SPN
over 2 years on chest radiograph, or a benign pattern on chest
radiograph. Patients have a low likelihood for malignancy and should
be followed with serial chest radiograph or CT every 3-4 months for
the first year and every 4-6 months in the second year.
- Patients with malignant lesions: Malignant status occurs with
clinical and radiologic features in patients who have a high
likelihood for a malignant lesion that will progress to a thoracotomy
for removal.
- Patients with indeterminate lesions: Most patients fall into this category. As many as 75% of these patients have malignant nodules on further evaluation.
Bronchoscopy
- Usefulness is limited in lesions smaller than 2.0 cm.
- In lesions larger than 2.0 cm, the yield for malignancy varies from
40-69%.
- Yield is higher for nodules located in the inner one third of the lung fields or in close approximation to a bronchus on CT scans.
Percutaneous needle biopsy
- This technique can be performed under fluoroscopy or with CT
guidance.
- Needle aspiration can be performed using a 21-gauge needle or needle
aspiration plus core biopsy can be performed using an 18-gauge or
19-gauge needle (higher yield with greater risk for pneumothorax).
- Yield is highest for peripheral nodules.
- Sensitivity and specificity for malignant lesions is 80-95% and
50-88%, respectively.
- Sensitivity for a specific benign diagnosis (eg, granuloma,
hamartoma) is 11-68%.
- Controversy exists concerning needle aspirations/biopsies with
negative results (ie, without a specific benign diagnosis). The
negative predictive value of transthoracic needle aspiration to
exclude malignancy varies from 52-88%. Options such as observation,
repeat biopsy, or thoracotomy depend on the pretest probability for
malignancy and patient-related factors, such as comorbid illness that
may preclude a thoracotomy. A thoracotomy is indicated in patients who
still have a high likelihood of malignancy.
- Using on-site cytologic analysis increases sensitivity of
percutaneous biopsy. The presence of a cytologist at the time of
biopsy aids in assuring the adequacy of specimens. This can both
decrease complications by reducing unnecessary collection of
additional samples and increase the yield by informing the radiologist
of the need to obtain additional samples.
- Complications
- Pneumothorax is seen in as many as 30% of these patients and
approximately 5% require a chest tube.
- Hemoptysis is seen in 5-10% of these patients and usually is
minor and resolves spontaneously.
- Fatal hemorrhage and air embolism are rare.
- Pneumothorax is seen in as many as 30% of these patients and
approximately 5% require a chest tube.
- Contraindications
- Limited pulmonary reserve (forced expiratory volume in second of
<1.0 L)
- Emphysema or blebs in the path of the needle
- Coagulopathy
- Inability to breath hold
- Severe pulmonary hypertension
- Contralateral pneumonectomy
- Limited pulmonary reserve (forced expiratory volume in second of
<1.0 L)
Thoracoscopy or thoracotomy
- A thoracotomy and lobectomy with lymph node sampling is the
treatment of choice for patients with stage IA bronchogenic carcinoma.
- In patients with an indeterminate nodule and a high probability of
malignancy, a thoracotomy should be performed if the patient has
adequate pulmonary reserve.
- Recently, video-assisted thoracoscopy surgery (VATS) has been used for removal of peripheral nodules with a wedge resection. If at the time of VATS the frozen section is positive for malignancy, an open thoracotomy can be performed for proper anatomic resection. If a benign lesion is found, the procedure saves the patient from the invasiveness of a full thoracotomy and lobectomy.
Medical/Legal Pitfalls:
- The major concern in the evaluation of SPNs is missing a malignancy that is potentially curable with surgery. All factors must be taken into consideration as part of the evaluation, ie, history, physical examination, and laboratory investigations including various radiologic investigations.
- Patient preferences must be considered as part of the evaluation, especially when proceeding to an invasive test such as a percutaneous needle biopsy. All patients should be aware of the risks/complications that can occur with invasive intervention.
Special Concerns:
- In determining the most effective strategy for investigating an SPN and treating the patient, developing an estimate of the probability that the nodule is malignant is important. Bayesian analysis uses likelihood ratios of malignancy for various clinical and radiologic factors. The ratios are combined to produce a probability of malignancy (PCa).
- When the probability of malignancy is high (PCa >70%), a resection is warranted. Similarly, if the probability is low (PCa <5%), observation is recommended. For lesions with an indeterminate probability, further evaluation is necessary.
- Calculations of probabilities only provide an estimate of malignancy, and based on published probability ratios, may not be able to be generalized to all patients. Including the patient's preference in the decision for further intervention is important.
PICTURES
| Caption: Picture 1. Solitary pulmonary nodule. Cavitating nodule secondary to an abscess. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 2. A solitary pulmonary nodule in the right lower lobe adjacent to the fissure in the periphery. Biopsy confirmed the diagnosis of a coccidioidoma. | |
 |
|
| Picture Type: CT | |
| Caption: Picture 3. Chest radiograph of a left upper lobe solitary pulmonary nodule. Biopsy demonstrated this to be hemartoma. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 4. CT scan of a small solitary pulmonary nodule in the left upper lobe (same patient as Image 3) | |
 |
|
| Picture Type: CT | |
| Caption: Picture 5. Solitary pulmonary nodule. CT scan of the chest showing neurilemoma (same patient as Images 6-7). Note how the neurilemoma arises adjacent to the rib. | |
 |
|
| Picture Type: CT | |
| Caption: Picture 6. Solitary pulmonary nodule. Neurilemoma - Lung window view. | |
 |
|
| Picture Type: CT | |
| Caption: Picture 7. Solitary pulmonary nodule. Large well-circumscribed mass in the periphery of the right upper lobe later was determined to be a neurilemoma. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 8. Solitary pulmonary nodule. Pulmonary arteriovenous malformation in left lower lobe. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 9. Solitary pulmonary nodule. Close-up view of a pulmonary arteriovenous malformation. Note the feeding vessels. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 10. Solitary pulmonary nodule. Posteroanterior chest radiograph shows a mass lesion abutting the left upper mediastinum. Features are noted that suggest this is a mediastinal rather than a parenchymal lesion (obtuse margins, continuation of opacity). | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 11. Solitary pulmonary nodule. Close-up view highlights features that suggest this is a mediastinal tumor (same patient as Image 10). | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 12. Solitary pulmonary nodule. CT scan that shows a lesion to be posterior mediastinal (same patient as Image 10). The differential diagnosis includes neurogenic tumors, mediastinal cysts, malignancy, and infectious lesions. | |
 |
|
| Picture Type: CT | |
| Caption: Picture 13. Solitary pulmonary nodule. Right upper lobe nodule in a lifelong smoker. Percutaneous needle biopsy confirmed a diagnosis of adenocarcinoma. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 14. Right upper lobe mass. Features of the lesion are not in keeping with the definition of solitary pulmonary nodule and the mass is likely to be a malignant lesion. In this patient, the lesion was squamous cell carcinoma. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 15. A solitary pulmonary nodule along the rib can be a callus formation secondary to rib fracture. Oblique views may be helpful. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 16. Solitary pulmonary nodule. Special attention must be paid to the apices so as not to miss the lesion in these areas. Apical lordotic views can demonstrate the lesions well. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 17. Solitary pulmonary nodule. Close-up chest radiograph (same patient as Image 16). | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 18. Solitary pulmonary nodule. Findings show a right-sided pulmonary nodule. The differential is long; however, CT scan may be helpful in narrowing the differential diagnosis. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 19. Solitary pulmonary nodule. CT scan of the thorax (same patient as Image 18). Multiple pulmonary nodules were identified. The differential diagnosis includes metastasis and infectious granulomas. | |
 |
|
| Picture Type: CT | |