Pulmonary Nodules
21.1 Solitary Nodule
By definition, a pulmonary nodule is a rounded opacity in the lung parenchyma measuring up to 3 cm. It is surrounded by aerated lung parenchyma and is smoothly marginated, with no adjacent atelectasis or associated lymphadenopathy.1 This presents a common diagnostic dilemma in the clinical setting.
A large variety of benign and malignant diseases cause pulmonary nodules. ▶Table 21.1 gives an overview of the histologic entities that can manifest as a pulmonary nodule.
21.1.1 Differential Diagnosis
In the vast majority of cases, the radiographic or CT morphology of nodules is not pathognomonic for a particular histologic entity. There are only a few imaging findings that permit a definitive diagnosis of a nodule. For example, detection of fat inside the nodule on CT or of characteristic popcorn-like calcification in a sharply marginated nodule is pathognomonic for a hamartoma (▶Fig. 21.1).
The main focus of differential diagnosis is on distinguishing between the benignity and malignancy of a nodule.
Note 
Radiologic criteria of benignity of solid pulmonary nodules:
At least 2-year stability.
Fat detection.
Detection of a benign calcification pattern:
Homogeneous calcification.
Central calcification.
Lamellar calcification.
Popcorn-like calcification.
Evidence of at least 2-year stability is deemed proof of the benignity of a solid nodule. This is often demonstrated on the basis of previous images in which the finding (possibly only retrospectively) appears identical.
On CT, fat and popcorn-like calcification are found in hamartomas, while the other benign calcification patterns are seen, in particular, in inflammatory residual findings (see ▶Fig. 21.1). All other calcification types, especially eccentric and amorphous types, are also found in malignant tumors (▶Fig. 21.2).
Growth detection is the best noninvasive predictor of malignancy. Volumetry with special software lends itself better than manual determination of the nodule diameter3,4,5 for detection of pulmonary nodule growth. Thin-slice CT datasets are needed to that effect. Based on the tumor volume, the nodule doubling time can be determined using the modified Schwartz formula.6,7 The following doubling time is calculated from the baseline volume and the volume on follow-up:
Table 21.1 Disease entities that can manifest as solitary pulmonary nodule2 | ||||||||||||
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 Fig. 21.1 Benign calcification patterns in nodules. (a) Homogeneous calcification. (b) Central calcification. (c) Lamellar calcification. (d) Popcorn-like calcification. |
 Fig. 21.2 Amorphous calcification in a small cell lung cancer. |
where
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Many volumetry systems automatically calculate the tumor doubling time from the nodule volumes measured. In general, volume doubling times of between 20 and 400 days are considered to be suspicious for malignancy. There have also been reports of rare cases of lung cancers with extremely short (7 days) but likewise very long doubling time (4.5 years).8,9,10,11
Dynamic contrast CT and PET-CT are two other imaging modalities used in this field, with both able to visualize functional parameters (vascularization and glucose uptake) of the nodule. The advantage of contrast dynamic CT is its high negative predictive value (96%). Absence of contrast enhancement of the nodule—or analogously absence or only minimal glucose uptake (SUV [standard uptake value] of less than 2.5) on PET—means that malignancy is very unlikely. Both modalities are suitable for nodules measuring more than 8 mm.
21.1.2 Management
Nodules identified as incidental findings on chest radiography often measure more than 1 cm and should be further investigated since they are viewed as potentially malignant until proven otherwise.12 In general, CT is the next diagnostic modality indicated, with two exceptions that need no further investigation:
If previous images show at least 2-year nodule stability.
If an extrapulmonary location of the nodule is suspected (e.g., mammillary shadows or rib osteoma; this can be further explored on chest radiography using mammilla markings or rotational fluoroscopy, thus with markedly lower radiation exposure than on CT). CT is often able to visualize small, incidentally detected, nodules not found
on chest radiography or only identifiable retrospectively in relation to the CT findings. Several lung cancer screening studies with low-dose CT have already produced extensive data on the potential malignancy of incidentally detected nodules. At least one nodule was identified on CT in up to two-thirds of all study participants at high risk for lung carcinoma. The majority of these nodules were very small. In all studies, more than 95% of these pulmonary nodules proved to be benign.
Note 
The diagnostic dilemma posed by a small nodule derives from the fact that, while it is the most common presentation of early lung cancer, it is also an extremely widespread but only rarely malignant incidental finding.
Growth exclusion is a good predictor of nodule benignity. Two-year stability of solid pulmonary nodules (of soft-tissue density) is generally accepted as a benignity criterion. Subsolid nodules can prove to be a slowly growing adenocarcinoma even after 2-year stability and therefore must be followed up beyond that period up to 5 years.13
Management of pulmonary nodules depends on their likelihood of malignancy and the expected growth pattern. Because the latter differs between solid and subsolid nodules, recommendations vary dependent on nodule attenuation as described below.
Several recommendations for management of incidental pulmonary nodules have been published, starting with the first recommendation for management of solid nodules of the Fleischner Society in 2005,14 followed by a recommendation for management of subsolid nodules in 2013.15 The newest recommendation from 2017 includes recommendations for solid and subsolid nodules and will be presented in more detail below.13
Solid Nodules
If the benignity of a nodule can be demonstrated on the basis of the listed criteria, there is no need for further measures. In all other cases, the choice of further procedure will depend on the nodule size and presence of risk factors.
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Note 
History of smoking (smoker, current or during the previous 10 years, passive smoker).
History of known malignant tumor.
Family history of lung cancer.
Chronic obstructive pulmonary disease.
Lung fibrosis.
Inhalation exposure to:
Asbestos.
Quartz.
Cadmium.
Arsenic.
Beryllium.
Nickel.
Chromium.
Polycyclic aromatic hydrocarbons.
Radioactive substances such as uranium or radon.
▶Table 21.2 lists the recommended procedure for nodules measuring less than 8 mm in relation to diameter size and risk of malignancy13:
Nodules with a mean diameter (average of longest diameter and diameter perpendicular to the longest diameter, rounded to the nearest full millimeter) of less than 6 mm in patients with no risk factors have such a low risk of malignancy that no further investigation or follow-up is recommended. In persons with known risk factors or if the nodule looks morphologically suspicious, a 12-month follow-up CT scan can be performed.
If a decrease in the size of a nodule has been observed during follow-up or the nodule disappears completely, follow-up is no longer required. Nodule benignity is just about proven.
If there is evidence of nodule stability, follow-up is advisable at variable intervals tailored to the individual risk.
Progressive growth of a nodule during follow-up is suggestive of malignancy and normally needs further investigation (histologic confirmation).
Nodules measuring more than 8 mm have a markedly higher risk of malignancy than smaller pulmonary. Hence, further
diagnostic work-up should be considered. A multidisciplinary decision on necessary diagnostic measures is recommended, with pneumonologists and thoracic surgeons taking into consideration the aspects listed in ▶Table 21.3. There is no need for further invasive investigation if malignancy appears unlikely in the context of the described morphology criteria. This may also apply in the individual case if PET or contrast dynamic CT yield a negative result.
diagnostic work-up should be considered. A multidisciplinary decision on necessary diagnostic measures is recommended, with pneumonologists and thoracic surgeons taking into consideration the aspects listed in ▶Table 21.3. There is no need for further invasive investigation if malignancy appears unlikely in the context of the described morphology criteria. This may also apply in the individual case if PET or contrast dynamic CT yield a negative result.
In principle, patients with equivocal or suspicious nodules measuring more than 8 mm should be referred to a specialist center where radiologists, pneumologists, thoracic surgeons, and radiotherapists can take a multidisciplinary decision on the choice of procedure. That decision is based on several aspects:
Medical risk and general condition: If an invasive procedure presents an increased medical risk, caution is exercised when indicating biopsy, especially for nodules with low probability of malignancy. Instead, follow-up is generally recommended and invasive diagnostic exploration is advisable only if there is nodule growth.
Operability: The technical and functional operability are estimated. The latter can be decisive for the choice of ensuing procedure if, as in the case of a central pulmonary nodule, surgery is expected to result in major lung volume loss.Related posts:
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