Diffuse Lung Disease With Calcification and Lipid

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Introduction

Certain diffuse lung diseases are associated with high- or low-attenuation lesions. High-attenuation lesions are most often due to calcium deposition from a variety of mechanisms, but can also be due to the accumulation of other radiopaque substances such as iodine (amiodarone lung toxicity) and talc (talcosis). Low-attenuation lesions are predominantly due to the deposition of lipid-containing substances. These diffuse lung diseases can encompass a large range of causes, including infectious, inflammatory, neoplastic, metabolic, occupational exposures, iatrogenic, and idiopathic processes. To make an accurate diagnosis, radiologists need to be cognizant of the morphologies and distribution patterns of these high- or low-attenuation lesions and must be able to assimilate other relevant imaging features and clinical histories. These important distinguishing characteristics, as well as common problem-solving issues and pitfalls, will be discussed in this chapter.

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Imaging Modalities Used to Assess Diffuse Lung Disease Involving High- or Low-Attenuation Lesions

Radiographs are usually part of the initial workup for diffuse lung disease and can demonstrate large nodules, consolidation, prominent hilar and mediastinal lymphadenopathy, and calcification. Diffuse micronodules and interstitial calcification can present as reticular or reticulonodular opacities on radiographs. However, radiographs have a low sensitivity for detecting smaller lung lesions and often fail to demonstrate fine parenchymal detail and specific attenuation of lung lesions. In addition, diffuse lung disease involving calcification or lipid can mimic pulmonary edema, interstitial lung disease, or atypical infection with radiography. CT with a high-resolution CT (HRCT) technique (thin-slice, high-resolution technique) provides optimal evaluation of diffuse lung disease and is more sensitive and specific in detecting calcification and lipid. On CT, calcified lesions show attenuation similar to that of bone, ranging from 200 to >1000 Hounsfield units (HU). Lesions containing macroscopic fat have negative attenuation values, in general between −50 and −100 HU. Calcification or lipid mixed with other materials, such as soft tissue, will produce intermediate-attenuation values; in addition, volume averaging with adjacent tissue can occur, especially when thicker slices (>1–2 mm) are used for interpretation and when attenuation measurements of very small lesions are attempted. Thin-section CT can also depict the fine parenchymal detail, including patterns of small nodules, that is necessary for the diagnosis of many diffuse lung diseases involving high attenuation or lipid.

Although nuclear medicine examinations such as a technetium-99m methylene diphosphonate ( ^99m Tc-MDP) bone scan and PET can play a role in the evaluation of metastatic disease, they are not the primary modalities for the characterization of diffuse lung disease involving calcification or lipid because uptake of radiotracers can occur in a wide variety of malignant and inflammatory nonmalignant diseases. Chest MRI also has not been traditionally used as a primary method of evaluating these diseases because this modality is inferior to CT in characterizing fine pulmonary parenchymal detail, small nodules, and small foci of fat or calcium.

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Diffuse Lung Disease With Calcification or High Attenuation

Diffuse lung disease with calcification or high attenuation can present with nodules, masses, consolidation, or a combination of these. Ancillary findings in some diseases can include calcified lymphadenopathy, septal thickening, and pleural calcification. Nodules and masses can have a wide range of sizes, from tiny nodules <1 mm to masses >10 cm. Diseases can have an upper lung, lower lung, or no particular craniocaudal predominance.

Of the many diseases presenting with nodules, many can be categorized according to the distribution pattern of the calcified lesions relative to the secondary pulmonary lobule. The distribution pattern can be centrilobular, perilymphatic, or random. Centrilobular nodules are located within the central secondary pulmonary lobule and spare pleural surfaces and interlobular septa. Perilymphatic nodules are distributed along the subpleural interstitium, bronchovascular interstitium, and interlobular septa. In a random distribution, nodules are widely distributed without a particular anatomic relation to the secondary lobule; a subset is distributed along the pleural and interlobular septa.

These distribution patterns serve as a good starting point for narrowing the differential diagnosis; additional imaging and clinical features provide further guidance. Certain rare diffuse lung diseases, such as pulmonary alveolar microlithiasis and pulmonary ossification, can have unique calcification patterns that are not typical of the classic distribution pattern discussed above. The list of differential diagnoses for different distribution patterns is summarized in Box 26.1 . In the setting of solitary, sparse, multiple calcified nodules or nodules that are large enough to distort the pulmonary lobular architecture, which can be observed in healed granulomatous infection, calcified pulmonary metastasis, and hyalinizing granuloma, the distribution pattern can be difficult to determine, making other diagnostic clues such as clinical histories and other associated imaging features important in problem solving. (See Table 26.2 for a summary of the calcification pattern and associated imaging and clinical features of each disease entity that help differentiate between disease entities that share a similar imaging presentation and identify diseases where the calcification pattern alone provides very limited information.) A disease entity also can have multiple presentations on imaging, adding to the complexity of problem solving.

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Diseases Causing Calcified Pulmonary Nodules

These can be in a random, perilymphatic, or centrilobular distribution.

Random Distribution

Healed Granulomatous Infections

Healed granulomatous infections are common causes of solitary and multiple calcified nodules in the lung parenchyma. The nodules usually follow a random distribution or can occur in clusters ( Fig. 26.1A and B ). In the United States, histoplasmosis is the most common cause of granulomatous infection, whereas tuberculosis is the leading cause worldwide. Other rare causes include coccidioidomycosis and blastomycosis. The pulmonary manifestations of acute primary granulomatous infection vary widely and depend on the amount of exposure, the virulence of the infectious organisms, and the strength of the host's immune system. A granuloma is an area of caseating necrosis that was once a focus of infection, later contained by the host's cell-mediated immune response and subsequently encapsulated by fibrotic tissue. Over the course of months to years, dystrophic calcifications develop with the granulomas. Depending on the size of inoculum, the number of granulomas can vary. Calcification of the diseased lymph nodes and hepatic and splenic granulomas can also be seen with healed granulomatous disease. The imaging appearance of healed histoplasmosis and healed tuberculosis can be indistinguishable. However, multiple splenic calcifications and diffuse nodular calcification patterns are much more commonly seen in histoplasmosis; in addition, significant architectural distortion and/or bronchiectasis with asymmetric, upper lung predominance are more common findings in tuberculosis.

Healed Varicella Pneumonia

Varicella pneumonia is the one of the most common and most severe manifestations of disseminated varicella zoster virus infection in adults, with reported mortality rates of 9% to 50%. Its incidence increases with age, with a peak between the third and fifth decades of life. Some of the risk factors for developing varicella pneumonia include lymphoma, leukemia, immunocompromised status (e.g., as with chronic corticosteroid usage), pregnancy, and a history of smoking. Varicella pneumonia typically develops 3 to 5 days after the classic polymorphic rash (blisters, pustules, and crusty lesions). The predominant histologic finding for acute varicella pneumonia is diffuse alveolar damage. On radiographs, acute varicella pneumonia often presents as multiple ill-defined nodules from 5 to 10 mm, usually without associated mediastinal and hilar lymphadenopathy or pleural effusions. CT reveals multiple noncalcified, coalescent 1- to 10-mm pulmonary nodules with surrounding ground-glass opacity (halo sign) in a centrilobular pattern, with multiple patchy areas of ground-glass opacity. Typical management involves acyclovir and supportive care. Depending on the severity of disease, these pulmonary nodules may resolve within days or up to several weeks following clearing of the skin rash. Some of the nodules can become healed granulomas and gradually evolve into diffuse, calcified, small nodules (1–3 mm). Healed varicella pneumonia can mimic healed histoplasmosis. However, concurrent hepatic and splenic calcified granulomas, if present, favor histoplasmosis as the underlying cause.

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