The Solitary Pulmonary Nodule: Morphologic Clues for Benign Versus Malignant Lesions

Solitary pulmonary nodules are discrete, well-marginated opacities whose diameters are 3 cm or less.^[1] They present a diagnostic dilemma, as these lesions may be due to a vast array of benign and malignant etiologies. Although some patients are eligible for imaging follow-up, certain patients will require tissue diagnosis. This slideshow reviews clues to differentiating between benign and malignant etiologies of solitary pulmonary nodules, including features such as nodule growth rate, calcification, intranodular fat, border, cavitation, attenuation, and size.

The chest radiograph demonstrates a right upper lobe lesion (circle) that was found to be adenocarcinoma on biopsy.

Image courtesy of Medscape.

Growth Rate
Growth rate is an important factor used to assess the likelihood of malignancy of indeterminate pulmonary modules. In addition, growth rate provides the basis for the rationale behind serial follow-up studies for indeterminate pulmonary nodules.^[2] (Eg, Bronchogenic carcinoma doubles in volume, on average, every 4-8 months.^[3]) A doubling time of less than 1 month is usually indicative of infection or inflammation. A doubling time of more than 18 months suggests a benign process such as a granuloma, hamartoma, or rounded atelectasis.^[3] A nodule that is stable for more than 2 years is almost certainly benign.^[2,3]

The computed tomography (CT) scan shows a left lower lobe well-circumscribed carcinoid tumor (circle). Although carcinoid tumors grow slowly and may be asymptomatic for many years, which can cause them to be mistaken for benign lesions, these tumors actually represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors that includes small cell carcinoma of the lung as its most malignant member and several other forms of intermediately aggressive tumors, such as atypical carcinoid.^[4]

Image courtesy of Medscape.

Calcification
A calcified pulmonary nodule is a common finding, especially on CT scan. However, calcification may be difficult to detect on chest radiographs. Although the majority of calcified nodules are benign, some have important malignant etiologies.^[5] Malignant lesions with a propensity for calcification include osteogenic sarcoma, mucinous carcinoma, and chondrosarcoma. Additionally, metastatic lesions may undergo calcification after treatment with chemotherapy or radiation therapy.^[5] Stippled or eccentric calcification (shown) patterns are associated with malignancy.^[2]

Which of the following is a benign calcification pattern?

1. Diffuse
2. Central
3. Laminated
4. Popcorn
5. All of the above

Image courtesy of Lars Grimm, MD, MHS.

Answer: E. All of the above^[5]

The radiograph demonstrates central calcification due to previous infection with histoplasmosis. The presence of a residual calcified solitary pulmonary nodule may be the only evidence of prior histoplasmosis.

Histoplasmosis is caused by the inhalation of spores from soil infected by bird or bat feces.^[6] It is endemic to the central and eastern United States, where the majority of the population may have been infected. Active infection may lead to malaise, fever, nonproductive cough, and chest pain. The symptoms of the vast majority of patients resolve without any complications.^[6]

Image courtesy of Medscape.

Pulmonary hamartomas are a common source of calcified pulmonary nodules, as seen in this radiograph in which popcorn calcifications are present in the left lung nodule.

Pulmonary hamartomas are usually located in the lung periphery with smooth, well-circumscribed margins, and they are composed of varying amounts of fat, connective tissue, muscle, and cartilage.^[2,5] In approximately one third of cases, popcorn calcifications can be identified.^[7]

What key finding on CT scan is virtually diagnostic of a hamartoma?

1. Peripheral location
2. Swirl of vessels
3. Fat
4. Central necrosis

Image courtesy of Medscape.

Intranodular Fat
Answer: C. Fat^[5]

Fat is identified in up to 50% of pulmonary hamartomas.^[5] Pulmonary lesions that contain fat include hamartomas, lipomas, and lipoid pneumonias. However, only hamartomas have the appearance of a solitary nodule with calcifications.^[5] Even the smallest foci of fat in a solitary nodule with calcifications are usually sufficient for the diagnosis of a pulmonary hamartoma; the lesion does not need to be completely filled with fat.

Hamartomas and lipoid pneumonias are benign processes that require no additional follow-up. Pulmonary lipomas are uncommon and also considered benign.^[8] The CT scan demonstrates a hamartoma with popcorn calcifications and a central foci of fat (arrow).

Image courtesy of Medscape.

Clinicians must always be aware of potential benign pitfalls. The left chest x-ray shows a solitary pulmonary nodule (circle) that could easily be dismissed as a nipple, given its round shape and its location. Repeat imaging with nipple markers (right) revealed that the nodule was separate from the breast and that additional work-up was needed.

It is important to note that patients who have undergone mastectomy may have only one nipple. When in doubt as to whether imaging results show a nipple or a potential solitary pulmonary nodule, repeat the imaging with nipple markers.

Images courtesy of Drs Ayush Goel and Vinod G Maller, Radiopaedia.org.

Diagnostic Considerations
Solitary pulmonary nodules may also be due to vascular causes, including arteriovenous malformations (AVMs), pulmonary infarcts, and hemangiomas.^[9] Pulmonary AVMs result from an abnormal communication between the pulmonary artery and vein.^[10] They are an important cause of right-to-left shunts, which may result in emboli to the brain.^[10,11] Although AVMs are often indistinguishable from other causes of solitary pulmonary nodules, occasionally a large vessel (arrow) can be seen entering the nodule (circle).

What genetic condition is associated with multiple pulmonary AVMs?

1. Kasabach-Merritt syndrome
2. Osler-Weber-Rendu syndrome
3. Pick disease
4. Sturge-Weber syndrome

Image courtesy of Dr Andrew Dixon, Radiopaedia.org.

Answer: B. Osler-Weber-Rendu syndrome^[10,12]

On CT scan, pulmonary AVMs often appear as a tangle of vessels with very sharp margins (circle).^[12] A draining vein can often be traced centrally to the hilum.^[12]

In Osler-Weber-Rendu syndrome, also known as hereditary hemorrhage telangiectasia (HHT), patients develop vascular malformations in the brain and lungs.^[12,13] They often present with recurrent epistaxis due to multiple capillary telangiectasias. If pulmonary AVMs are present, a high risk of brain abscesses and stroke exists, especially when multiple AVMs are found.^[13] Fortunately, pulmonary AVMs often respond well to embolization.

Image courtesy of Dr Andrew Dixon, Radiopaedia.org.

Pulmonary infarcts due to pulmonary embolism may give the illusion of a pulmonary nodule, referred to as a Hampton hump (circle).^[12] The infarcted pulmonary arteries cause cell death and hemorrhage, resulting in the opacification seen. The Hampton hump is located peripherally^[2] because of the poor blood supply distally. It may take weeks or months to resolve, depending on the degree of infarction. In addition, it may leave behind a residual scar.^[2]

Image courtesy of Medscape.

In children, pulmonary nodules and masses are more likely the result of infection due to unique physiologic parameters of the developing lungs than the result of malignancy. In this population, the collateral air pathways, the channels of Lambert and pores of Kohn, are not well developed, localizing the infection.^[14,15]

Round pneumonia, an entity that is much more common in children than in adults, gives the appearance of a pulmonary nodule or mass (yellow circle) and is usually caused by a bacterial infection.^[14-16] The infected tissue has the appearance of a round, well-circumscribed lesion, very different from the greater tissue consolidation that is typically seen in adults.^[14] A round pneumonia is treated like any other pulmonary infection and typically resolves completely (blue circle).

Image courtesy of Dr M Osama Yonso, Radiopaedia.org.

Border
Border characteristics are another potential discriminator between benign and malignant lesions.^[2,5] Lesions with very irregular edges or corona radiata (numerous strands radiating into the surrounding lung) may indicate a bronchogenic carcinoma. Unfortunately, false positives are common.

The CT image shows a right lower lobe lesion with irregular margins. Lung cancer must be ruled out in this case if remote prior studies are not available for comparison. In this patient, the nodule had been stable for several years and was presumed benign.

Which lesions tend to have smooth margins (more than one choice may apply)?

1. Metastases
2. Infarction
3. Infectious lesions
4. Atelectasis

Image courtesy of Lars Grimm, MD, MHS.

Answer: A and C (metastases and infectious lesions)

Both metastases and infectious lesions tend to have smooth margins. This CT scan is from a patient with extensive pulmonary metastatic disease (circles). Multiplicity favors the diagnosis of metastatic disease over a primary lung cancer.^[5] In addition, metastases are more likely to involve the lower lungs (shown) owing to their increased blood supply, which facilitates hematogenous spread.

Image courtesy of Lars Grimm, MD, MHS.

Cavitation
Cavitation within a solitary pulmonary nodule can be found in malignancy, as well as in infectious or noninfectious inflammatory lesions.^[2] A thin and smooth-walled cavitation is likely due to a lung abscess or a benign lesion^[3]; a thick-walled cavitation is usually due to an underlying malignancy^[2] but can be seen in benign lesions as well.^[3] Unfortunately, these are only general guidelines at best.

This radiograph demonstrates an upper left lobe thick-walled cavitation (circle). Percutaneous needle biopsy revealed active pulmonary tuberculosis.

Image courtesy of Medscape.

The CT scan demonstrates another example of thicker-walled calcifications due to infection, in this case actinomycosis.

Cavitation from pulmonary infections is most commonly due to Streptococcus pneumoniae, Aspergillus, Legionella, and Staphylococcus aureus.^[17] Enlarged hilar and mediastinal lymph nodes may be reactive, which prevents differentiation of infection from malignancy. Frequently, a fine-needle aspiration is needed to help differentiate infection from malignancy and to guide therapy.

Image courtesy of Medscape.

Attentuation
The attenuation of the lung immediately surrounding a pulmonary nodule can be an important clue to diagnosis.^[3,5] The CT halo sign refers to ground-glass attenuation surrounding a nodule due to hemorrhage (arrow).^[2,12,18,19] It is classically associated with invasive Aspergillus.^[2,12,18,19] Other less common infections include tuberculosis, cytomegalovirus, and herpes simplex virus infection.

However, certain hemorrhagic tumors can also induce the same imaging appearance, as in this case of metastatic melanoma. Tumors with a propensity to hemorrhage include melanoma, renal cell carcinoma, choriocarcinoma, and thyroid carcinoma.^[18,19] Although it is uncommon for a malignant lung tumor to bleed, malignant lung tumors must be included in the differential diagnosis.

Image courtesy of Lars Grimm, MD, MHS.

Indeterminate Nodules
Ultimately, despite the best efforts to differentiate benign from malignant lesions due to size, growth rate, density, calcifications, margins, and other features, as well as patient history, many lesions remain indeterminate (shown).^[9] The American College of Chest Physicians characterizes an indeterminate pulmonary nodule as one "that is not calcified in a benign pattern and that has not been shown to be stable after >2 years of follow-up."^[2]

In these cases, percutaneous biopsy can often be safely performed under CT guidance.^[2] The risk of pneumothorax depends on the distance that the needle will need to travel and the gauge of needle used. Fortunately, a fine-needle aspiration is often sufficient to differentiate infection from benign or malignant tissue.^[20] When this is the case, the use of larger core needle biopsies can be avoided.

Image courtesy of Medscape.

Fleischner Society Guidelines
The Fleischner Society guidelines for radiologic follow-up of solid solitary pulmonary nodules are based on the nodules' size and whether patients are at low (LR) or high risk (HR) for malignancy: (1) ≤4 mm: LR, no follow-up needed; HR, CT at 12 months — if stable, no further follow-up; (2) >4-6 mm: LR, CT at 12 months — if stable, no further follow-up; HR, CT at 6-12 months — if stable, repeat at 18-24 months; (3) >6-8 mm: LR, CT at 6-12 months — if stable, repeat at 18-24 months; HR, CT at 3-6 months — if stable, repeat at 9-12 and 24 months; and (4) >8 mm: LR/HR, CT at 3, 9, 24 months; obtain dynamic contrast-enhanced CT, positron emission tomography scanning, and/or biopsy.

These recommendations apply only to those aged 35 years or older, with incidentally detected nodules. Risk factors that discriminate LR from HR include smoking; family history; and exposure to asbestos, radon, or uranium. Chest x-rays 5 years apart show a high-density solitary pulmonary nodule (arrows) remaining unchanged, courtesy of Khan AN, Al-Jahdali HH, Allen CM, et al. Ann Thorac Med. 2010;5(2):67-79. [Open access.] PMID: 20582171, PMCID: PMC2883201.^[5]