Miscellaneous disorders involving the pulmonary parenchyma
An exhaustive description of all the remaining diseases of unknown etiology affecting the pulmonary parenchyma cannot be presented here. Instead, a brief description of several additional diseases will acquaint the reader with their major features. They include (1) PLCH, (2) lymphangioleiomyomatosis (LAM), (3) Goodpasture syndrome, (4) granulomatosis with polyangiitis (GPA), (5) chronic eosinophilic pneumonia, and (6) pulmonary alveolar proteinosis (PAP). For each of these relatively uncommon disorders, certain pathologic, clinical, or radiographic features distinguish them from the diffuse parenchymal lung diseases described earlier in this chapter. However, the defining feature for each of these disorders is a relatively specific pathologic appearance involving various components of the pulmonary parenchyma.
Pulmonary langerhans cell histiocytosis
PLCH, previously called eosinophilic granuloma of the lung or pulmonary histiocytosis X, is thought to represent part of a spectrum of disorders involving histiocytic infiltration of one or more organ systems. Although multisystem involvement in Langerhans cell histiocytosis or histiocytosis X is typically seen with the childhood disorders called Letterer-Siwe disease or Hand-Schüller-Christian disease (not discussed here), isolated or predominant pulmonary involvement in PLCH occurs mainly in young to middle-aged adults.
Pulmonary Langerhans cell histiocytosis (previously called eosinophilic granuloma of the lung or pulmonary histiocytosis X) enters into the differential diagnosis of unexplained interstitial disease, particularly in the young or middle-aged adult.
The responsible histiocytic cell is a dendritic cell of monocyte/macrophage lineage called a Langerhans cell. Recently, mutations in mitogen-activated protein kinase (MAPK) pathways and clonal origins have been identified in these dendritic cells leading to the classification of PLCH as an inflammatory myeloid neoplasm. An interesting ultrastructural feature of these cells is the presence of cytoplasmic rodlike structures called X bodies (hence the name histiocytosis X) or Birbeck granules, which can be seen by electron microscopy. These cells are also notable for positive immunohistochemical staining for S-100 protein. Light microscopic examination of the lung, in addition to demonstration of these histiocytes, reveals infiltration by eosinophils, lymphocytes, macrophages, and plasma cells. The process initially involves the lungs in a peribronchiolar distribution and subsequently becomes more diffuse. The disease occurs almost exclusively in current and former smokers, and it appears that dendritic cells harboring the MAPK mutations accumulate in the lungs in response to cigarette smoke. This leads to activation and migration of immune cells and to the formation of peribronchiolar nodules and the destruction of tissue.
Patients often present clinically with dyspnea, cough, or both. On chest radiograph, PLCH typically features a pattern of nodular or reticulonodular disease, which tends to be more prominent in the upper lung zones. HRCT scans show small cysts in addition to the nodular or reticulonodular changes (Fig.
11.8). The cysts occasionally rupture, leading to a spontaneous pneumothorax, which may be the presenting feature of the disease. In some cases, progression results in a pattern of extensive cystic disease and honeycombing. Unlike the typical restrictive pattern in most of the diffuse parenchymal lung diseases, pulmonary function testing in PLCH may show restrictive changes, obstructive changes, or both. The presence of air-filled cysts typically leads to normal or large lung volumes on chest radiography,
despite the presence of interstitial disease.
FIGURE 11.8 Chest CT scan demonstrates multiple cysts of variable size in a
patient with pulmonary Langerhans cell histiocytosis. Source: (Courtesy Dr. Seth
Kligerman.)
The natural history of the disease is variable. In some patients, the disease is self-limited, and the radiographic and functional changes may stabilize over time, especially with cessation of smoking. In other patients, extensive disease and significant functional impairment follow. No clearly effective treatment is available, although corticosteroids are sometimes tried if smoking cessation alone is ineffective.
Lymphangioleiomyomatosis
LAM is a rare pulmonary disease, now considered to be a neoplasm, that is characterized by proliferation of atypical smooth muscle cells around lymphatics, blood vessels, and airways, accompanied by numerous small cysts throughout the pulmonary parenchyma. LAM occurs almost exclusively in women of childbearing age. This demographic, as well as the fact that LAM cells express receptors for estrogen and progesterone, suggests that hormonal influences play a role in the development of disease. In addition to occurring sporadically, LAM also develops in 30% to 40% of female patients with the genetic condition tuberous sclerosis complex (TSC). An interesting aspect is that the pathologic process seen in the lungs in LAM is essentially identical to that seen in multiple organ systems in TSC, suggesting a common pathogenetic mechanism. Germ cell mutations in two genes, TSC1 and TSC2, are associated with TSC, whereas in LAM the abnormal smooth muscle cells have a mutation in the TSC2 gene.
Lymphangioleiomyomatosis is characterized by proliferation of atypical smooth muscle cells within the lung.
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The normal products of TSC1 and TSC2 are proteins forming a complex that acts as a potent suppressor of cell growth and proliferation through the mechanistic target of rapamycin (mTOR) pathway. Thus, the abnormal proteins lead to loss of this suppressor activity, resulting in uncontrolled growth. Patients with LAM appear to have developed an acquired mutation in smooth muscle cells in the lung, whereas patients with TSC appear to have an inborn genetic error. Furthermore, the gene product of TSC2 also interacts directly with intracellular estrogen receptors to cause inhibition of cell growth. Presumably, a mutation in the TSC2 gene leads to loss of this function accounting for some of the hormonal influences in LAM. The LAM cells also express a lymphangiogenic growth factor called vascular endothelial growth factor D, and the finding of elevated levels of this growth factor may be helpful in establishing the diagnosis.
The clinical manifestations of LAM result from the presence of cysts and disease involvement of lymphatics, blood vessels, and airways. The overall pathologic process in the pulmonary parenchyma may lead to dyspnea and cough. Vascular involvement may result in hemoptysis, lymphatic obstruction may produce chylous (milky-appearing) pleural effusions, and airway involvement may produce airflow obstruction. Rupture of subpleural cysts can lead to development of a spontaneous pneumothorax. LAM is also often accompanied by benign tumors of the kidney called angiomyolipomas.
The chest radiograph typically shows a reticular pattern, and cystic changes may be seen. HRCT scanning is far superior to plain chest radiography for demonstrating cystic disease throughout the pulmonary parenchyma (Fig. 11.9). The mechanism of cyst formation is thought to be a combination of a ball-valve phenomenon resulting from small airway obstruction by the abnormal smooth muscle proliferation and destruction of tissue attributable to elaboration of metalloproteinases by LAM cells. As is true for PLCH, results of pulmonary function testing are not typical of most diffuse parenchymal diseases, because patients may demonstrate obstructive disease, restrictive disease, or both. Similarly, lung volumes on chest radiograph appear normal or increased rather than decreased due to air trapping in the cystic regions.
FIGURE 11.9 Chest CT scan showing countless cysts bilaterally in a patient with
lymphangioleiomyomatosis. Source: (Courtesy Dr. Seth Kligerman.)
Pharmacological treatment targets enhancement of the mTOR pathway-mediated suppression of smooth muscle cell proliferation, which is lost with TSC2 gene mutations. Sirolimus is an inhibitor of cell growth and proliferation through the same pathway as the TSC2 gene products. Sirolimus (also called rapamycin) blocks mTOR signaling and thus restores some of the functions of the abnormal TSC2 gene product. Sirolimus has been shown to be effective in stabilizing lung function and improving symptoms and quality of life in patients with LAM. Previously, patients were commonly treated with hormonal manipulation to block the effects of estrogen on the aberrant smooth muscle growth; however, routine antiestrogen treatment is no longer recommended.
Goodpasture syndrome
Goodpasture syndrome is a disease that has become well known not because of its incidence, which is extremely low, but because of its interesting pathogenetic and immunologic features. Two organ systems are involved in this syndrome: the lungs and the kidneys. In the lungs, patients have episodes of pulmonary hemorrhage, and pulmonary fibrosis may develop, presumably as a consequence of the recurrent episodes of bleeding. In the kidneys, patients have a glomerulonephritis characterized by linear deposits of antibody along the glomerular basement membrane (GBM). Studies on peripheral blood have demonstrated that patients have circulating antibodies against a component of type IV collagen in their own GBM, often abbreviated as anti-GBM antibodies. These antibodies cross-react with antigens within the basement membrane of the alveolar wall, causing injury that is responsible for the clinical manifestations of the disease in both organ systems.
In Goodpasture syndrome, autoantibodies directed against the glomerular basement membrane may cross-react with the basement membrane of alveolar walls.
Why these true autoantibodies develop in patients with Goodpasture syndrome is not clear. In some patients, onset of disease appears to follow influenza infection or exposure to a toxic hydrocarbon. Presumably, injury to basement membranes and release of previously unexposed antigenic determinants are involved, or incidental formation of antibodies (against an unrelated antigen) may cross-react with alveolar and glomerular basement membranes. The disease is associated with certain human leukocyte antigens, suggesting an underlying genetic susceptibility.
Unlike many diseases associated with autoantibodies, the anti-GBM antibodies are clearly pathogenetic. Therapy for Goodpasture syndrome is based on decreasing the burden of anti-GBM antibodies presented to the lung and kidney. Plasmapheresis is capable of directly removing anti-GBM antibodies from the circulation. Immunosuppressive therapy (e.g., glucocorticoids plus cyclophosphamide), aimed at decreasing the formation of anti-GBM antibodies, usually is given in conjunction with plasmapheresis.
Granulomatosis with polyangiitis
A group of disorders termed the granulomatous vasculitides may affect the alveolar wall as part of a more generalized disease. The most well known of these disorders is GPA (formerly called Wegener granulomatosis), a disease characterized primarily but not exclusively by involvement of the upper respiratory tract, lungs, and kidneys. The pathologic process in the lungs and upper respiratory tract consists of a necrotizing small-vessel granulomatous vasculitis, whereas a focal glomerulonephritis is present in the kidney. On chest radiograph, patients commonly have one or several nodules (often large) or infiltrates, often with associated cavitation of the lesion(s) (Fig. 11.10). Pulmonary hemorrhage is another potential manifestation of respiratory tract involvement. Unlike most of the other disorders of the
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pulmonary parenchyma discussed in Chapter 10 and this chapter, diffuse parenchymal lung disease is not common in this entity.
FIGURE 11.10 Chest radiograph shows multiple cavitary pulmonary nodules in a
patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis is characterized pathologically by granulomatous vasculitis of the lung and upper respiratory tract and by glomerulonephritis. The clinical corollary is pulmonary, upper respiratory tract, and renal disease.
Patients with GPA typically have antibodies in the serum directed against proteinase 3, a serine protease present in the azurophil granules found in the cytoplasm of neutrophils. These antibodies can be detected by immunofluorescent techniques, which demonstrate a coarse, diffuse cytoplasmic pattern of staining when the patient’s serum is incubated with normal neutrophils. The presence of antineutrophil cytoplasmic antibodies (ANCA), specifically with a cytoplasmic staining pattern (c-ANCA), is an important component of the diagnostic evaluation for GPA, although some patients may have negative results, especially with limited disease. Antibody levels correlate with disease activity, and these antibodies likely play some role in the pathogenesis of disease. However, other factors are probably
involved as well.
Although GPA once was considered an aggressive and fatal disease, its prognosis has improved dramatically since cytotoxic agents, specifically cyclophosphamide, have been used in its treatment. Prednisone is also generally added for the initial period of therapy. More recently, rituximab, a monoclonal antibody directed against CD20 antigen found primarily on B lymphocytes, has come to play an important role in treating this disease. Although the mean survival time without treatment was 5 months, patients frequently achieve complete and long-term remissions with institution of appropriate therapy. Most patients require maintenance therapy, and rituximab is most commonly used due to a better side-effect profile compared with cyclophosphamide.
Chronic eosinophilic pneumonia
Chronic eosinophilic pneumonia is a disorder in which the pulmonary interstitium and alveolar spaces are infiltrated primarily by eosinophils and, to a lesser extent, by macrophages. The clinical presentation typically occurs over weeks to months, with systemic symptoms such as fever and weight loss accompanying dyspnea and a nonproductive cough. The clues suggesting this diagnosis are often found on the chest radiograph and the routine white blood cell differential count. The radiograph frequently shows pulmonary infiltrates with a peripheral distribution and a pattern more suggestive of alveolar filling than of interstitial disease (Fig. 11.11). Because the typical radiographic pattern of pulmonary edema with congestive heart failure has central pulmonary infiltrates with sparing of the lung periphery, the prominent peripheral pattern often seen in chronic eosinophilic pneumonia has been described as the “photographic negative of pulmonary edema.” The majority of patients also have increased numbers of eosinophils in peripheral blood, although this finding is not uniformly present and therefore is not critical for the diagnosis. Bronchoalveolar lavage typically shows a high percentage of eosinophils, reflecting the pathologic process within the pulmonary parenchyma.
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FIGURE 11.11 Chest radiograph shows pattern of peripheral pulmonary infiltrates
characteristic of chronic eosinophilic pneumonia.
Chronic eosinophilic pneumonia is often suggested on chest radiograph by a pattern of peripheral pulmonary infiltrates.
Treatment is gratifying for both patients and physicians alike because chronic eosinophilic pneumonia characteristically shows a dramatic response to corticosteroid therapy. Clinical improvement and radiographic resolution generally occur within days to weeks, although therapy often must be prolonged for months to prevent recurrence.
Pulmonary alveolar proteinosis
PAP is a parenchymal lung disease in which the primary pathologic process affects the alveolar spaces, not the alveolar walls. Alveolar spaces are filled with a proteinaceous phospholipid material that represents components of pulmonary surfactant. Accumulation of surfactant components is due to either decreased degradation or surfactant dysfunction. PAP is classified as autoimmune, secondary (usually related to hematologic malignancies), or congenital/hereditary. Autoimmune PAP (formerly known as primary or idiopathic PAP) is by far the most common of the three types and is discussed here.
In autoimmune PAP, the underlying mechanism is production of an autoantibody to granulocytemacrophage colony-stimulating factor (GM-CSF). GM-CSF, acting through alveolar macrophage-specific transcription factors, affects several essential macrophage functions, including regulation of surfactant degradation, intracellular lipid metabolism, and phagocytosis. Thus, inhibiting the activity of GM-CSF via autoantibodies leads to abnormal macrophage function and decreased clearance of surfactant from the alveolar spaces. The disease mechanism was fortuitously discovered when it was noted that GM-CSF knockout mice (in which both alleles for GM-CSF are disabled) consistently developed a pulmonary process with pathology essentially identical to that seen in human PAP.
Defective uptake of surfactant by alveolar macrophages, attributable to a decreased amount or effect of GM-CSF, underlies the pathogenesis of pulmonary alveolar proteinosis.
Patients with alveolar proteinosis present primarily with dyspnea and cough. The chest radiograph is notable for bilateral alveolar infiltrates. HRCT generally shows a distinctive but not entirely pathognomonic appearance called a crazy paving pattern (produced by thickening of interlobular septa accompanied by ground-glass alveolar filling) that suggests the diagnosis (Fig. 11.12). Patients are susceptible to certain types of superimposed respiratory infections that are uncommon in normal hosts, especially with the organism Nocardia. The susceptibility to unusual pathogens appears due to abnormal macrophage function as well as to abnormalities in neutrophil function also mediated by GM-CSF.
FIGURE 11.12 Chest CT scan in a patient with pulmonary alveolar proteinosis
showing the characteristic “crazy paving” pattern representing thickened
interlobular septa superimposed upon ground-glass opacification.
For patients with moderate to severe disease, the primary treatment of PAP is whole-lung lavage, which involves washing out the material filling the alveolar spaces while the patient is under general anesthesia. Administration of inhaled or subcutaneous recombinant GM-CSF may be used as an alternative therapy but is still under investigation. The prognosis of the disease is relatively good,
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