Amyloidosis is a metabolic disease characterized by the deposition of amyloid in lung tissues. Amyloidosis is presently regarded as a protein-misfolding disease [1, 2]. Normally four proteins are folded into a complex with the help of chaperones. Many different forms of amyloid proteins have been identified. Misfolding can occur in several different compositions of amyloid [3]. Most common are amyloid A and P; however, microglobulin 2β, transthyretin, and others can also be seen in pulmonary amyloidosis. These misfolded proteins are much less soluble and therefore are deposited along blood vessels in different organs, among them also the lung.

The reason for amyloid deposition can be a tumor; one of the best-known examples is plasmocytoma. In this case, amyloid is formed out of misfolded immunoglobulins secreted by the tumor cells. Chronic inflammation such as collagen vascular diseases can also cause amyloid deposition [4, 5]. Amyloid deposition can occur as a tumorlike deposit, either along the bronchial tree or within the lung periphery (nodular form), or it can be diffuse perivascular and interstitial (Figs. 12.1 and 12.2). Nodular amyloidosis most often is associated with primary amyloidosis. Peribronchial amyloidosis most often imitates a tumorlike pattern on X-ray and HRCT pattern (Fig. 12.3), parenchymal deposits, if nodular, also imitates a tumor; diffuse deposition can be peribronchial or parenchymal and is most often caused by systemic amyloidosis [6–8]. Amyloid stains eosin red and orange by the Congo red stain; it can be demonstrated by immunohistochemistry using specific antibodies for the different components [9]. If a Congo red stain is applied, the tissue section should be examined under polarized light, where the stain exhibits a green birefringence – this is essential because immune complexes might show an identical staining pattern, but do not polarize light (Figs. 12.4 and 12.5). Amyloid deposits very often will cause a tissue reaction with lymphoplasmacytic infiltrates and foreign body giant cells forming granulomas at the border of the deposits; in addition calcification and metaplastic bone formation do occur (Fig. 12.6). The major differential diagnosis to amyloidosis is IgG4-mediated fibrosis and hyalinosis; however, the dense lymphoplasmacytic infiltrations will lead to the correct diagnosis.

Specific metabolic surfactant disturbances due to genetic defects/disorders are seen in children and adults. In some instances, these are based on defects in surfactant apoprotein or transporter genes (congenital type), namely, surfactant protein B and C (SP-B, SP-C), and ATP-binding cassette transporter family member mutations (ABCA3) [24–28]. Other factors causing alveolar proteinosis are associated with the metabolic degradation pathway as GM-CSF, GM receptor gene, located on chromosomes 2, 5, and 22, respectively [29]. In these cases, most often autoantibodies against GM-CSF or the receptor has been found [30–32]. Also the downregulation of GM-CSF synthesis might induce alveolar proteinosis [33]. Whereas in children alveolar proteinosis is most often inherited and based on gene function loss, in adults, it is most often acquired. The etiology in the adult form in many cases is based on autoantibodies for GM-CSF; mutations of surfactant genes and transporter genes are absent. In addition exposure to dusts or chemicals, insecticides, silica, aluminum, or titanium dust, as well as infections such as tuberculosis, HIV infection in immunosuppressed patients, and finally hematological malignancies may cause alveolar proteinosis [30, 34]. There exists a rare autosomal recessive multisystem disorder called lysinuric protein intolerance that occurs in Finland and Italy, which also produces alveolar proteinosis [35–37]. The mechanisms on how these diverse diseases cause alveolar proteinosis are still to be discovered. The histology of alveolar proteinosis can present with different morphology depending on the underlying abnormality.

Alveolar proteinosis is characterized by a deposition of proteinaceous material usually within the alveoli, but sometimes also in alveolar walls. The material is composed of proteins, lipids, and surfactant components (Fig. 12.14). In adults usually no inflammatory infiltrations are seen. A bronchoalveolar lavage is almost diagnostic: on recovery a milky fluid is seen with high lipid content. On cytology there are few cells, but a proteinaceous material, positively stained by PAS. High-resolution CT shows a panlobular distribution of increased alveolar density and a superimposed reticular pattern, called “crazy paving.” Chronic alveolar proteinosis is rarely seen in young patients suffering from idiopathic alveolar proteinosis. After several years of treatment, there is mild, however, functionally important diffuse fibrosis of the alveolar walls (Fig. 12.15).