Pulmonary nodules

OVERVIEW: What every practitioner needs to know about pulmonary nodules.

A pulmonary nodule is a round lesion less than 3 cm in diameter within the pulmonary parenchyma (completely surrounded by lung tissue). When present as a single lesion, a pulmonary nodule is sometimes referred to as a “solitary pulmonary nodule” (SPN) or “coin lesion.” A lesion larger than 3 cm is characterized as a pulmonary mass. Multiple very small nodules are most frequently referred to as granulomas. These are not discussed here, but are addressed in the chapters devoted to their various causes.

Are you sure your patient has a pulmonary nodule? What are the typical findings for this disease?

Because they are often a convalescent phenomenon, pulmonary nodules are most commonly found coincidentally on radiographs obtained for unrelated signs or symptoms, particularly in children. Depending on the etiology, there may be an associated cough, chest pain or, even less frequently, hemoptysis, but this is the exception rather than the rule. Nodules generally do not cause symptoms unless they result in airway obstruction, pleural invasion, interfere with respiratory mechanics, or involve vasculature or nerves.

What other disease/condition shares some of these symptoms?

Care must be taken to ensure that the finding on the radiograph is not an artifact from an object, such as a clothing button or monitor lead, on the external surface of the chest. This is usually easily determined by either direct examination or by obtaining two views of the chest, most often a posterior-anterior (or anterior-posterior) view and a lateral view. Breast nipples can sometimes be mistaken for pulmonary nodules, as can a mediastinal or hilar lymph node. Careful review of the radiographs will demonstrate, however, that these entities lie outside the thoracic cavity or are not within the pulmonary parenchyma.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

• Definitive diagnosis of the etiology of a nodule will often require biopsy, either needle or excisional, though this is not frequently necessary.

• A Mantoux tuberculin skin test (TST) and, if the TST is positive, a
  QuantiFERON®-TB Gold assay can strongly suggest tuberculosis as the cause of a nodule.

• Fungal etiologies can be sought using serologic studies (coccidiomycosis, histoplasmosis) or urine assays (blastomycosis), although culture is the definitive method of diagnosis.

• Suspected metastatic nodules in patients with a history of malignancy will require biopsy for confirmation of suspicion based on radiographic appearance and history of malignancy.

Would imaging studies be helpful? If so, which ones?

• Chest radiographs: Prior radiographs can be very helpful in determining the time of development and progression of a nodule. If a nodule has not increased in size or has become smaller over a period of 6-24 months, there is a very high likelihood that it is benign. In a healthy child without a history of prior malignancy, serial chest radiographs can be used to follow a nodule.

• High resolution chest CT (HRCT): HRCT can provide important clues as to the etiology of a pulmonary nodule. The presence of a smooth border, calcification, a laminated or central pattern, a classic “popcorn” pattern, or the presence of fat within a nodule all support a benign etiology. A spiculated (“corona radiata sign”) or scalloped surface are relatively specific for malignancy. A bronchus coursing through the nodule is associated with an increased chance that flexible fiberoptic bronchoscopy would yield a definitive diagnosis.

• Positron emission tomography (PET): PET scans are generally not helpful and so not indicated in children without a history of malignancy. Nodules in such children are much more likely to be associated with infection, and so a false positive PET study is common.

Please see Figures 1 through 11 for examples of how different types of nodules appear in imaging exams:

Figure 1, Figure 2, Figure 3,
Figure 4, Figure 5, Figure 6,
Figure 7, Figure 8, Figure 9,
Figure 10, Figure 11

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 11.

If you are able to confirm that the patient has a pulmonary nodule, what treatment should be initiated?

• Any extant prior chest radiographs should be reviewed and compared with current studies to assess the duration and progression of a nodule. If the nodule has remained unchanged or has decreased in size over a period of 6-24 months, it is very likely benign and can be followed up to 24 months after the initial finding. After that, no further action is warranted.

• In the absence of a history of prior malignancy, an otherwise healthy, thriving child with a newly diagnosed pulmonary nodule lacking prior radiographs for comparison can undergo a limited evaluation consisting of placement of TST and appropriate fungal studies (serology for coccidiomycosis or histoplasmosis; urine assay for blastomycosis) as appropriate for the geographic location, and followed by serial radiographs at 3-6 month intervals, assessing for progression.

• Children with a newly diagnosed malignancy or history of malignancy, recent constitutional symptoms, or other concerning symptoms should have the above infectious studies done, as well as a HRCT. However, features on HRCT may not reliably differentiate benign from malignant nodules; therefore, biopsy should be considered in these children.

• If HRCT is not reassuring (i.e., demonstrating features associated with benign nodules described above), consideration of further evaluation is warranted. Peripheral nodules may be amenable to percutaneous needle biopsy. Otherwise, thoracoscopic or open biopsy may be required.

What are the adverse effects associated with each treatment option?

Radiographic studies carry small, but defined risks of future radiation-associated malignancies. Only those studies necessary to adequately evaluate and follow a nodule should be performed. For instance, a child with a stable or regressing nodule and serologic evidence of fungal infection need not be subjected to HRCT. A nodule that is readily apparent on a plain radiograph need not be followed with serial HRCT if the initial CT was reassuring. Serial plain radiographs would be sufficient.

Percutaneous needle biopsy carries risks of bleeding, infection, and pneumothorax requiring chest tube evacuation. Surgical biopsy likewise poses risks of bleeding and infection, and, very rarely, development of a bronchopleural fistula.

What are the possible outcomes of a pulmonary nodule?

Most nodules in otherwise healthy children are benign and require no intervention. Such nodules have no impact on pulmonary function or functional status of the individual. The family and eventually the child should be fully informed of the presence of the nodule so that they will be able to provide that information to future providers who may “discover” the nodule in the future.

Outcomes for non-benign nodules vary with the etiology, as do the risks/benefits of treatment for the particular etiology found.

What causes this disease and how frequent is it?

What causes benign pulmonary nodules?

• Tuberculosis

• Histoplasmosis

• Blastomycosis

• Coccidiomycosis

• Aspergillosis

• Cryptococcosis

• Nocardiosis

• Hamartoma

• Neurofibroma

• Vascular (arteriovenous) malformation

• Pulmonary sequestration or cyst

How do these pathogens/genes/exposures cause pulmonary nodules?

• Post-infectious nodules are the result of activation of macrophages by an antigen from the infectious agent involved, leading to an organized collection of cells such that the individual cell borders are difficult to appreciate. The macrophages may fuse to form multinucleated giant cells (Langhans giant cells), which are sometimes referred to as “epithelioid” because of their resemblance to epithelial cells (larger, elongated nuclei). Granulomas may also contain lymphocytes, neutrophils, eosinophils, multinucleated giant cells, fibroblasts and collagen, the latter leading to fibrosis.

• Hamartomas are abnormal collections of normal tissues, most commonly found in the lung and comprised of cartilage, fat and connective tissue, although other tissue types (bone, teeth) may be present.

• Neurofibromas are the result of hyperplasia of Schwann cells.

• Arteriovenous malformation, pulmonary sequestration and pulmonary cysts represent congenital abnormalities of lung development.

What complications might you expect from the disease or treatment of pulmonary nodules?

If nodules are large and adjacent to an airway, they may result in compression and subsequent development of atelectasis with a predisposition for infection, as well as chronic wheezing.

If located near a vascular structure, circulatory compromise and rarely erosion with bleeding is also possible.

Some nodules (particularly those associated with coccidiomycosis) may cavitate. Such cavitary nodules can be associated with infection, bleeding, and pneumothorax.

Complications of treatment will, of course, vary with the etiology and the treatment for that entity.

How can pulmonary nodules be prevented?

Since pulmonary nodules are secondary to malignant or infectious processes, prevention of those will prevent nodule formation.

Avoidance of risk factors for malignancy (carcinogen exposure) or infection (travel to areas endemic for tuberculosis or fungal disease) may reduce the risk for pulmonary nodules.

What is the evidence?

Ost, D, Fein, AM, Feinsilver, SH. “The solitary pulmonary nodule”. New Engl J Med. vol. 348. 2003. pp. 2535-42. (This very well written comprehensive review provides a background and approach to the solitary pulmonary nodule (SPN) in adults in whom early diagnosis of malignancy is paramount. The information, however is useful in informing the approach to SPN in children.)

Hartman, TE. “Radiologic evaluation of the solitary pulmonary nodule”. Radiol Clin N Am. vol. 43. 2005. pp. 459-65. (Hartman provides a detailed and well referenced review of radiologic evaluation of SPN, again focused on adults, but helpful in approaching SPN in children.)

Partrick, DA, Bensard, DD, Teitelbaum, DH. “Successful thoracoscopic lung biopsy in children utilizing preoperative CT-guided localization”. J Pediatr Surg. vol. 37. 2002. pp. 970-3. (The authors describe a small series of children in which pre-operative CT-guided localization of nodules with methylene blue injection facilitated biopsy by thoracoscopy, obviating the need for thoracotomy.) (Evidence Category C)

Silva, CT, Amaral, JG, Moineddin, R. “CT characteristics of lung nodules present at diagnosis of extrapulmonary malignancy in children”. AJR Am J Roentgenol. vol. 194. 2010. pp. 772-8. (In a study of 111 infants and children with non-CNS solid extra-pulmonary malignancy or lymphoma, none of the features assessed (sidedness, number, distribution, attenuation, shape, margins, calcification, size) reliably differentiated benign from malignant nodules.)

McCarville, MB, Lederman, HM, Santana, VM. “Distinguishing benign from malignant pulmonary nodules with helical chest CT in children with malignant solid tumors”. Radiology. vol. 239. 2006. pp. 514-20. (Evidence Category B)
(In a study of 81 nodules in 41 children (5-21 years of age) with malignant solid tumors, classification of pulmonary nodules as benign or malignant was accurate only 57%-67% of the time. In contrast to adults, sharply defined nodules were more likely to be malignant, while size was not predictive of malignant status.)

Ongoing controversies regarding etiology, diagnosis, treatment

The radiographic differentiation of malignant from benign nodules in children with extrathoracic malignancies remains problematic; hence, the frequent need for biopsy in that setting.

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