© 2002 American Thoracic Society
Calcium Deposition with or without Bone Formation in the LungDivisions of Pulmonary Sciences, Critical Care Medicine, and Endocrinology, University of Colorado Health Sciences Center; Department of Medicine and Program in Cell Biology, National Jewish Medical and Research Center; and the Denver Veteran Administration Medical Center, Denver, Colorado Correspondence and requests for reprints should be addressed to Edward D. Chan, M.D., K613e, Goodman Building, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: chane{at}njc.org
Pulmonary calcification and ossification occurs with a number of systemic and pulmonary conditions. Specific symptoms are often lacking, but calcification may be a marker of disease severity and its chronicity. Pathophysiologic states predisposing to pulmonary calcification and ossification include hypercalcemia, a local alkaline environment, and previous lung injury. Factors such as enhanced alkaline phosphatase activity, active angiogenesis, and mitogenic effects of growth factors may also contribute. The clinical classification of pulmonary calcification includes both metastatic calcification, in which calcium deposits in previously normal lung or dystrophic calcification, which occurs in previously injured lung. Pulmonary ossification can be idiopathic or can result from a variety of underlying pulmonary, cardiac, or extracardiopulmonary disorders. The diagnosis of pulmonary calcification and ossification requires various imaging techniques, including chest radiography, computed tomographic scanning, and bone scintigraphy. Interpretation of the presence of and the specific pattern of calcification or ossification may obviate the need for invasive biopsy. In this review, specific conditions causing pulmonary calcification or ossification that may impact diagnostic and treatment decisions are highlighted. These include metastatic calcification caused by chronic renal failure and orthotopic liver transplantation, dystrophic calcification caused by granulomatous disorders, DNA viruses, parasitic infections, pulmonary amyloidosis, vascular calcification, the idiopathic disorder pulmonary alveolar microlithiasis, and various forms of pulmonary ossification.
Key Words: lung • metastatic calcification • ossification • calcium • calcinosis
Clinical Classification of Pulmonary Calcification and Ossifi- cation Proposed Mechanisms of Ectopic Lung Calcification and Os- sification Role of Relative and Absolute Calcium Excess Role of an Alkaline Environment Role of Lung Injury or Fibrosis Role of Angiogenesis Imaging Chest Roentgenogram Computed Tomography 99mTc-MDP Bone Scintigraphy Specific Disorders Pulmonary Metastatic Calcification Pulmonary Calcification Associated with Granulomatous Disorders Pulmonary Calcification as a Sequela of Varicella or Other Viral Pneumonias Pulmonary Calcification Associated with Parasitic Infections Pulmonary Calcification Associated with Amyloidosis Pulmonary Vascular Calcification Pulmonary Alveolar Microlithiasis Pulmonary Ossification Conclusion Although direct observation and palpation of thoracic calcification were noted by Laennec in his textbook of physical examination of the lungs (1), the interest in pulmonary calcification began with the advent of chest radiography in the late 19th century (2). Calcification within the thorax results from disparate clinical states. The anatomic location and specific features of the calcification often provide insights into occult diseases and can sometimes explain respiratory symptoms. Ectopic calcification occurs in the chest wall, pleura, lung parenchyma, hilar and mediastinal lymph nodes, and pulmonary arteries (3). This review organizes the classification of the pulmonary parenchymal calcific and ossific disorders, outlines their probable or possible pathogenesis, summarizes methods of detection, and illustrates their clinico–radiographic–pathologic features. A discussion of calcified solitary pulmonary nodules is not included. The potential impact of calcification on diagnosis and treatment is highlighted whenever specific information is available.
Calcification refers to the deposition of calcium salts in tissues, in contrast to ossification, which indicates bone tissue formation (calcification in a collagen matrix), with or without marrow elements. A number of pathologic conditions predispose to soft tissue calcification. Internal organs most commonly affected by ectopic calcification include the stomach, kidneys, lungs, heart, and blood vessels. The lungs seem particularly susceptible to this complication. Pathologic soft tissue calcification can be broadly divided into either (1) metastatic calcification, in which calcium deposits in normal tissues, or (2) dystrophic calcification, in which calcification is superimposed on previously injured lung (Table 1).
Metastatic pulmonary calcification is further subdivided into benign (4–15) and malignant causes (16–21) (Table 1). By far the most common cause of metastatic calcification is seen in patients on hemodialysis for chronic renal insufficiency. The other causes are uncommon (Table 1). Dystrophic calcification follows caseation, necrosis, or fibrosis and may complicate pulmonary infections that include (1) granulomatous infections, for example, Histoplasma capsulatum (22), Coccidioides immitis (23), and Mycobacterium tuberculosis (24); (2) viral infections, for example, varicella virus (25) and smallpox virus (26); and (3) parasitic infections, for example, Paragonimus westermani (27) and Pneumocystis carinii (28) (Table 1). In sarcoidosis, pulmonary calcification can result from either dystrophic calcification or metastatic calcification secondary to hypercalcemia (29, 30). Pulmonary vascular calcification (PVC) is postulated to result from shear stress and is considered to be a variant of dystrophic calcification (31). Dystrophic calcification has also been described in association with amyloidosis and after inhalation exposures in coal workers pneumoconiosis and silicosis. Pulmonary alveolar microlithiasis (PAM) is a unique idiopathic calcific disorder with distinct histologic and radiographic appearances that do not fit into either metastatic or dystrophic calcification (Table 1). Clinical states that result in both calcium deposition and bone formation are listed in Table 2 under the heading of pulmonary ossification. Pulmonary ossification is defined by the histologic presence in the lung of mature bone often containing marrow elements. This can be either a primary idiopathic process or secondary to a number of pulmonary, cardiac, or extracardiopulmonary disorders (Table 2).
The mechanism(s) of lung calcification with or without ossification is not precisely known. No single factor is responsible. Figure 1A shows the factors that may be responsible for metastatic calcification in the lungs. Ectopic metastatic calcification can be influenced by serum calcium and phosphate concentration, alkaline phosphatase activity, and local physicochemical conditions such as pH. On the other hand, dystrophic calcification, by definition, requires injured tissues for calcification to occur (discussed later here). For ossification, other influences such as angiogenesis, chronic venous congestion, lung fibrosis, and/or the influence of various growth factors are thought to be necessary (Figure 1B).
Two physiologic requirements for metastatic calcium deposition are the release of excess calcium salts from bone and their transport through the circulation (10). The inorganic component of bone is comprised of apatite minerals with the chemical formula Ca3(PO4)2 · CaX2 where X2 may represent carbonate (CO3), difluoride (F2), dihydroxide ([OH]2), oxygen atom (O), or sulfate (SO4). For conditions that promote calcium release from bone, such as an elevated hydrogen ion concentration, the liberated Ca3(PO4)2 and CaCO3 salts are transported via the blood in soluble form. This is primarily as calcium hypophosphate (CaHPO4), which then reprecipitates as Ca3(PO4)2 and CaCO3 salts in tissues that have a favorable physicochemical environment such as an alkaline pH and a propitious chemical stoichiometry (10).
Role of Relative and Absolute Calcium Excess Pulmonary parenchymal granulomas and mediastinal and hilar lymphadenopathy associated with fungal diseases, tuberculosis, and sarcoidosis may calcify even in the face of normal serum calcium levels. Although this dystrophic calcification occurs in injured and abnormal tissues, macrophages within granulomas may also produce 1,25 vitamin D, thereby increasing intestinal absorption of calcium and phosphate and providing an additive or synergistic factor that promotes calcification in these tissues (41, 42). This may occur in the absence of detectable increases in serum calcium levels, similar to the ability of supplemental vitamin D and calcium to increase bone density without necessarily raising serum calcium levels.
Role of an Alkaline Environment
In this regard, it is interesting to speculate that the pH of the blood in the lung is more alkalotic compared with other organs because of CO2 removal. Furthermore, it has been suggested that the upper lobe predilection of some pulmonary calcific disorders is explained by a higher blood pH (approximately 7.51) and lower PaCO2 (approximately 30 mm Hg) at the apex compared with the relatively lower pH at the base (Figure 2) (45). This difference is accounted for by the higher ventilation–perfusion ratio at the lung apex (ventilation–perfusion ratio approximately 3.3) compared with the base (ventilation–perfusion ratio approximately 0.63) (46). That a relatively alkaline pH in the upper lung fields may play a role in the pathogenesis of metastatic calcification was inferred by the findings of a patient with Hodgkin's disease, in whom 99mTc-polyphosphate bone scintigraphy revealed dense accumulation of the radioactive tracer in both upper lung fields (47) and of patients with CRF in whom metastatic calcification occurs commonly in the lung apices (48–50). Further evidence that an alkaline environment fosters calcium precipitation is demonstrated by a patient with the milk–alkali syndrome who developed intra-alveolar microlithiasis (51). The patient, a heavy smoker, had severe metabolic alkalosis and mild hypercalcemia from ingestion of excess quantities of bicarbonate and calcium. Pathologic examination revealed pulmonary microliths that were smaller, more irregular in shape, and not as concentrically laminated as those described with (idiopathic) PAM. Mineralization occurred around nidi of desquamated intra-alveolar cells, the latter possibly related to tobacco use. This case of secondary intra-alveolar microlithiasis was unusual in that hypercalcemia and alkalosis, two conditions predisposing to ectopic calcification, typically cause alveolar septal wall calcification rather than intra-alveolar microlithiasis. Given that calcification is not particularly common in patients with either hypercalcemia or alkalosis alone, alkalosis may, synergistically, predispose to ectopic calcification when other risk factors are present. Using similar logic, metastatic pulmonary calcification in CRF has been linked to the relative alkalosis which follows hemodialysis (5).
Cessation of pulmonary blood flow can lead to pulmonary calcification (37, 52). This has also been partially attributed to tissue alkalosis. Bloodworth and Tomashefski described seven patients with localized pulmonary calcification distal to pulmonary artery obstruction from thrombus or intra-arterial tumor (37). This calcification did not require co-existing infarction, pneumonia, or diffuse alveolar damage. They suggested that obstruction of blood flow to a segment of lung resulted in decreased CO2 delivery, and this, in association with hyperventilation resulting from the vascular occlusion, lowered the alveolar PCO2, causing tissue alkalosis and setting the stage for calcium salt deposition. Because several isoforms of alkaline phosphatase, an enzyme that elevates the calcium–phosphate product by catalyzing the production of free phosphate, exhibit optimum activity at an alkaline pH (53), alkalosis may in addition predispose to ectopic calcification by this mechanism (Figure 1A). Alkaline phosphatase also enhances osteoblastic activity and thus may be necessary for pulmonary ossification to occur (Figure 1B). Although the presence of elevated alkaline phosphatase and phosphate levels has not been systematically evaluated in pulmonary calcification or ossification, these compounds are increased in the heterotopic ossification of joints secondary to spinal cord injury (54). Present in practically all tissues, alkaline phosphatase is abundantly expressed by alveolar type II cells and nonciliated bronchiolar (Clara) cells (55). Gomori showed that phosphatase activity colocalized with pathological calcification, suggesting that alkaline phosphatases may indeed play an active role in soft tissue calcification and ossification (56). However, this does not explain why calcification fails to occur in healthy tissues normally rich in alkaline phosphatase, such as the kidney and intestinal mucosa (57). Perhaps other factors, such as a local increase in free calcium ions in injured tissues, lower the threshold for calcification.
Role of Lung Injury or Fibrosis
Accelerated respiratory failure caused by extensive calcification of the alveolar septae has been seen (5, 60, 61). Two patients with hypercalcemia, one caused by B-cell lymphoma and the other caused by multiple myeloma, developed fatal acute respiratory distress syndrome (61). Autopsy revealed widespread calcification in addition to the diffuse alveolar damage. Although chronic hyalinized intra-alveolar exudate may become fibrotic and calcify (61), the calcification in these patients was disseminated and their demise rapid, making it less likely that the acute respiratory distress syndrome per se predisposed to the calcification. Instead, it is more likely that the metastatic calcification predisposed to the lung injury by disrupting the normal alveolar–capillary wall or, alternatively, the two processes were independent events.
Role of Angiogenesis
The extent of physiologic impairment associated with calcium deposition does not necessarily correlate with the degree of macroscopic calcification; that is, some patients with extensive calcification may be asymptomatic, whereas others with more subtle calcification in the face of normal chest radiographs may have significant physiologic impairment. High-resolution computer tomography (HRCT) scan and 99mtechnetium-methylene diphosphate (99mTc-MDP) bone scintigraphy are more sensitive and specific than the chest X-ray for the detection of pulmonary calcification. Their main use is the early recognition of lung calcification or ossification in at-risk individuals, thereby precluding the necessity for surgical lung biopsy to identify unexplained chronic pulmonary infiltrates.
Chest Roentgenogram
Computed Tomography
In a CRF patient with bilateral upper lobe metastatic calcification, lung magnetic resonance imaging revealed nodular lesions with a higher lesion to skeletal muscle signal intensity ratio on T1-weighted imaging than on the T2-weighted imaging (75). However, magnetic resonance imaging is relatively insensitive for detecting pulmonary calcification and is not recommended. The spatial resolution of magnetic resonance imaging is low in the lungs, and in addition, neither calcium nor air in the lung typically transmits a signal, thereby failing to produce a contrast.
99mTc-MDP Bone Scintigraphy
It has been proposed that in uremia, 99mTc-MDP scintigraphy has a lower sensitivity for detecting pulmonary calcification when compared with hyperparathyroidism or malignancy (84). This difference is perhaps due to the relatively lower uptake of 99mTc-MDP by amorphous whitlockite type mineral ([CaMg]3[PO4]2) compared with hydroxyapatite crystals (Ca10[PO4]6[OH]2), the former being the predominant calcium salt in renal failure-associated metastatic calcification (84). Nevertheless, in 23 patients receiving maintenance hemodialysis but without evidence of pulmonary calcification on chest radiograph, 14 (61%) were prospectively found to have a positive 99mTc-MDP bone scan of the lungs. The only distinguishing clinical feature in those with a positive scan was a longer duration of hemodialysis (38 ± 5 months) than for those with negative scans (12 ± 4 months) (85). The standard chest roentgenogram is relatively insensitive for the detection of diffuse pulmonary calcification with or without ossification. Typically, the study is negative or the infiltrates cannot be distinguished from other parenchymal processes. Exceptions are large and densely calcified parenchymal nodules, lymph nodes, or pleura. HRCT mediastinal images and 99mTc-MDP bone scintigraphy are relatively specific for pulmonary calcification and ossification. There are, however, two important caveats concerning the CT diagnosis of ectopic calcification and ossification: (1) The presence of dense lesions on lung window images will not distinguish between noncalcified and calcified opacities and conversely, (2) because of signal averaging, the failure to detect calcification or ossification on mediastinal images does not unequivocably exclude the possibility if the calcified lesions are microscopic, if there is a relatively large soft tissue component, and/or if standard 10-mm slices are imaged. Although bone scintigraphy appears to be more sensitive than CT scans in detecting ectopic calcification and ossification, this observation is based on anecdotal case reports without prospective comparison studies. One advantage of the CT scan is that the thorax and lung parenchyma can also be evaluated in detail. The advantage of scintigraphy is that other organs can be concurrently evaluated for metastatic calcification or ossification.
In this section, we discuss in greater depth specific disorders of pulmonary calcification and ossification that illustrate the mechanistic principles and imaging features described in the previous sections.
Pulmonary Metastatic Calcification In CRF patients undergoing hemodialysis, four conditions predispose to metastatic calcification. First, acidosis leaches calcium and phosphate from bone. Second, there is increased parathyroid hormone secretion caused by a negative calcium balance created by the failure of the kidneys to convert 25 vitamin D to 1,25 vitamin D, resulting in increased calcium and phosphate release from bone. Although patients with this secondary form of hyperparathyroidism are already at risk for metastatic calcification (91, 92), occasionally the stimulated parathyroid gland becomes autonomous, resulting in tertiary hyperparathyroidism and severe hypercalcemia (93). Third, intermittent alkalosis, which often accompanies bicarbonate hemodialysis, predisposes to soft tissue precipitation of calcium salts. This is supported by the observation that metastatic soft tissue calcification is accelerated following hemodialysis (5, 38, 94). Finally, the decreased glomerular filtration of phosphate may contribute to an elevated serum calcium–phosphate product. Elevated serum phosphate levels have been shown to correlate highly with vascular calcification in uremic patients (95). This observation was experimentally confirmed in cultured human aortic smooth muscle cells in which media containing phosphate levels comparable to those seen in hyperphosphatemic patients showed dose-dependent increases in cell culture calcium deposition (95). In contrast to the relatively physiologically benign course of pulmonary calcification in most patients, severe cases have been described (5, 70, 88, 96, 97). For example, in a patient with long-standing renal insufficiency and nephrotic syndrome, widespread metastatic calcification of multiple organs occurred after 3 months of bicarbonate hemodialysis (94). Although the calcium–phosphate product was normal, the free calcium index was elevated because of depressed serum protein, leading to ectopic calcium–phosphate deposition. In 91 patients who underwent orthotopic liver transplantation, chest radiographs, despite their relative insensitivity, detected pulmonary calcification in 5.2% (8). The mechanism is unclear. Complicating renal failure, acid-base abnormalities, and the administration of exogenous calcium and citrate have been proposed as contributing events. Elevated plasma citrate concentrations caused by the administration of packed red blood cells could lead to metabolic alkalosis and calcium chelation, prompting parathyroid release of parathyroid hormone. This gains support from the observation that the patients with calcification had higher levels of phosphorus and calcium postoperatively and had received more intraoperative blood products, all containing exogenous calcium (8). Although metastatic calcification most often accompanies a benign systemic metabolic disorder, it may also be associated with a variety of malignancies in which a common pathophysiologic attribute is the presence of hypercalcemia and/or an elevated calcium–phosphate product (Table 1) (98). Here the hypercalcemia may either be hormonally mediated or may result from metastasis to bone. Metastatic calcification is rare, however, even for these malignancies. In the case of osteogenic sarcoma, the ectopic calcification is secondary to the metastatic tumor itself. The clinical importance of metastatic calcification in slowly progressive cases is the confusion it creates in the evaluation of an abnormal chest radiograph in patients at risk for this process, particularly those undergoing hemodialysis or individuals with elevated calcium–phosphate product. In extensive pulmonary calcification, a restrictive physiology, a decreased diffusion capacity, and hypoxemia result (33). Rarely, progressive respiratory insufficiency and death may ensue (9, 99). 99mTc-MDP scintigraphy or mediastinal images on HRCT scan may be diagnostic of metastatic calcification without need for further investigation. The Von Kossa stain is significantly more sensitive than the standard hematoxylin and eosin stain in detecting calcium in tissues (100). Electron microscopy is even more sensitive and can show specific intracellular and extracellular sites of calcification, although it is not generally clinically available (101). Specific treatment is aimed at correction of isolated hyperphosphatemia or elevated calcium–phosphate product, if present. Successful renal transplantation may ameliorate metastatic pulmonary calcification (91), and conversely, renal graft failure and persistent uremia may accelerate, by some unexplained mechanism, the ectopic calcification (102). Moreover, metastatic pulmonary calcification may inexplicably progress despite a normally functioning renal allograft and normal or near-normal calcium and phosphate levels, although occult tertiary hyperparathyroidism may be responsible for some of these rare cases (96, 97). In severe recalcitrant cases associated with primary or tertiary hyperparathyroidism, parathyroidectomy is indicated (96).
Pulmonary Calcification Associated with Granulomatous Disorders
Pulmonary calcification as a sequela of C. immitis infection is uncommon (109). However, regressive changes of coccidioidal pulmonary lesions may result in single or multiple dystrophic calcified nodules. Tuberculosis produces a number of chest calcifications. Dystrophic calcification may manifest in parenchymal granulomas, mediastinal lymph nodes, and fibronodular areas of lung involvement. Diffuse nodular calcification of the lungs may follow treatment of a hematogenous infection (24). Roussos and coworkers recently showed that patients with tuberculosis can develop hypercalcemia caused by excessive production of endogenous 1,25 vitamin D, thus further predisposing to dystrophic pulmonary calcification (110). In a rabbit model of tuberculosis, early granulomatous inflammation without necrosis lacked phosphatase activity (56). However, when caseous necrosis occurred, there was robust phosphatase activity within the necrotic centers. Subsequent calcification was invariably found in the phosphatase-positive areas. Clinically, tuberculous calcification enhances tissue friability at surgery but is generally inconsequential and does not affect mortality. In unusual instances, sarcoidosis may produce multiple micronodular calcifications, radiographically similar to PAM (111). In contrast, however, their histologic features are distinct: In sarcoidosis, calcification is confined to the epitheloid granulomas, and in PAM, there are distinct intra-alveolar microliths.
Pulmonary Calcification as a Sequela of Varicella or Other Viral Pneumonias
Late development of pulmonary calcification from previous smallpox virus exposure has also been illustrated (26, 114). In nurses who developed flu-like illnesses within days of exposure to a smallpox patient, radiographic studies often showed poorly defined nodular opacities, attributed to a modified variola pneumonia. After clinical resolution of the acute illness, follow-up chest radiographs revealed extensive well-defined punctate calcifications without physiologic abnormalities (26). Other DNA viruses such as herpes simplex have been reported to lead to calcification (115). In an infant who died from presumptive herpes simplex pneumonia, the alveolar septae were extensively calcified (112). This case was unusual because fulminant calcification complicated the acute phase of the disease.
Pulmonary Calcification Associated with Parasitic Infections
Pulmonary Calcification Associated with Amyloidosis
Pulmonary Vascular Calcification Detectable PVCs, although uncommon, usually indicate a significant underlying chronic condition. Because PVCs occur in areas of high flow, they are detected in larger vessels (31). However, little is known about their pathogenesis. Similar to the evolving knowledge of the pathogenesis of calcification in the pulmonary parenchyma, there are parallel advances in understanding regulation of vascular calcification. Atherosclerosis is unusual in the pulmonary circulation, where the mean arterial pressures are significantly lower than in the systemic circulation (127). For atherosclerosis to occur in the pulmonary circulation, it appears to require both an increase of the mean arterial pressure and a pathologic state, which produces high flow. Atherosclerosis may be seen in long-standing pulmonary hypertension in patients with primary pulmonary hypertension (128–130) and those with congenital heart disease (127). Although there is little direct investigation on the cell biology of PVC, parallels between PVC and systemic arterial calcification can be made. In atherosclerotic systemic vessels, calcium deposits and lamellar bone form at the intimal medial interface or within the media of the blood vessel (131). Using in situ hybridization, bone morphogenic protein-2, an osteogenic differentiation factor, is expressed in the calcified vascular lesions (Figure 1B) (131). Pericytes, cells that surround pulmonary vessels and are instrumental in regulating angiogenesis, can differentiate into osteogenic cell lines (132). Thus, they have the potential to orchestrate calcification or bone formation in the pulmonary vasculature. Vascular endothelial growth factor, a potent mitogen involved in the hypoxic vascular response, is one potential link between hypertensive remodeling with calcification or ossification (see The Role of Angiogenesis in Proposed Mechanisms of Ectopic Lung Calcification and Ossification and Figure 1) (133). Further investigation of PVC could provide insights into the role of physical stresses such as high wall shear stress in the modulation of growth factors that redirect differentiated cells into an osteogenic program. Conditions producing increased vascular wall shear stress or high flow are presumed to be important for the formation of dystrophic PVC for the following reasons: (1) There is an increased susceptibility of vascular grafts to calcification (134). (2) There are PVCs in clinical states associated with increases in either vessel wall shear stress or increased pulmonary blood flow and pulmonary hypertension, and (3) in utero development of PVC with severe volume overload has been seen (135). High wall shear stress, the presumed pathogenetic condition that most often leads to calcification, accompanies vascular grafting in the pulmonary circulation. In children with cyanotic congenital heart disease who underwent a modified Blalock-Taussig shunt procedure with placement of vascular grafts, graft removal years later demonstrated areas of active angiogenesis and adjacent graft calcification (134). Sites of pulmonary artery contact with saphenous vein grafts used for coronary artery bypass demonstrate pulmonary artery calcification visible on CT scan (136). Although the mechanisms of graft calcification are unknown, the application of heparin on prosthetic vascular grafts, including pulmonary artery grafts, diminishes calcification, suggesting a role for coagulation (137). High shear forces and calcification also occur in pulmonary hypertension most often as the result of congenital heart disease. Early reports of pulmonary artery calcification described radiographic calcification in the main pulmonary arteries or large branch vessels in severe long-standing pulmonary hypertension with elevated pulmonary vascular resistance and a right to left shunt (Eisenmenger's syndrome) (138). Pulmonary artery calcification has also been reported in a left to right shunt from patent ductus arteriosis and long-standing ventricular and atrial septal defects (138–141). In in utero twins with a common heart and high-flow and volume overload, pulmonary artery calcifications were present in the large vessels adjacent to the functioning heart (135). Histologically, there was hyperplasia of the intimal and medial layers and disruption and calcification of the medial elastic fibers. This appearance is similar to that described in the autosomal recessive disorder of idiopathic arterial calcification of infancy (142). Calcification may also occur with pulmonary venous hypertension and hemosiderosis, particularly in the setting of long-standing mitral stenosis (130). Idiopathic pulmonary hemosiderosis has also been associated with calcification of the elastic lamina of pulmonary arteries, arterioles, and veins (130), possibly through a combination of hemorrhage-induced inflammation with or without increased shear stress. PVC occurs as a result of high shear stress of long duration. The role of injury and inflammation and accompanying angiogenesis and vascular smooth muscle cell reprogramming to an "embryonic osteogenic program" is of possible importance. Recent work suggests that calcification of the medial layer in systemic vessels from end-stage renal disease patients is associated with increased bone morphogenic protein and alkaline phosphatase activity, potentially linking the metastatic calcification process to vascular calcification as well (143). The major clinical importance of finding PVC is the implication of the chronicity and severity of the underlying condition.
Pulmonary Alveolar Microlithiasis Asymptomatic cases, even with extensive radiographic involvement, are often discovered incidentally. Cough and dyspnea are the most common presenting symptoms and usually occur late in the course of the disease. Normal or mild restrictive pulmonary physiology may be present in the asymptomatic individual. With progressive disease, severe lung restriction may ensue with impairment of the diffusing capacity and gas exchange abnormalities. The chest radiograph shows bilateral, sand-like, micronodular calcified densities known as microliths or calcispherites, which are usually less than 1 mm in diameter (149). They appear concentrated in the lower two-thirds of the lung, often obliterating the diaphragmatic, mediastinal, and cardiac borders (Figure 11) . The greater radiographic density at the lung bases is likely due to the larger lower lobe volumes rather than selective predisposition. The predominant HRCT finding is the presence of micronodular calcifications primarily located along the bronchovascular bundles, subpleural regions, and perilobular distribution (149). HRCT may in addition reveal ground glass opacities that are interspersed with microcysts and the calcispherites (149). In addition to the fine nodulation, HRCT may show polygonal-shaped calcified densities caused by the accumulation of microliths in the periphery of the lobules rather than to actual thickening or to deposition of calcium within alveolar septae (149, 150). Although 99mTc-bone scintigraphy can also help confirm the calcific nature of the lesions, the standard chest radiograph is often characteristic for PAM. Identification of microliths in expectorated sputum or bronchoalveolar lavage is diagnostic. Histologically, the lesion of PAM consists of intra-alveolar calcispherites, which represent laminated calcium phosphate concretions (Figure 12) . This appearance is distinct from metastatic and dystrophic calcifications in which the calcification is in the interstitial or vascular compartments. With progression, interstitial inflammation and fibrosis will occur and result in significantly diminished lung volumes, sometimes finger clubbing and eventually right heart failure. There is no known therapy for PAM. Corticosteroids, chelating agents, and bronchoalveolar lavage have demonstrated no benefit, and the role for the use of bisphosphonates remains to be proven (151). The few cases with response to corticosteroids are more likely to be related to attenuation of the accompanying interstitial disease (152). In symptomatic cases, nasal continuous positive airway pressure improves gas exchange by decreasing the physiologic intrapulmonary shunt (153). Bilateral lung transplantation is a viable option for far advanced cases.
Pulmonary Ossification Bone formation with or without marrow components occurring in the interstitial and alveolar compartments is unusual. Pulmonary ossification can be idiopathic or be associated with a variety of underlying pulmonary, cardiac, and systemic disorders (154–160). As can be seen in Table 2, many of the conditions associated with pulmonary ossification also occur with metastatic or dystrophic calcification; thus, ossification could represent a continuation of either process in the lung (161, 162). The pathogenesis of pulmonary ossification is unknown. Serum calcium and phosphorus levels are usually normal. Unlike heterotopic ossification that occurs around joints in association with spinal cord injuries (54), the serum alkaline phosphatase levels in pulmonary ossification are generally within normal limits, although this has not been consistently evaluated. In cases associated with pulmonary venous congestion, chronic intra-alveolar hemorrhage has been implicated as a predisposing factor for subsequent fibrosis and ossification (163). Ossification is the sequela of a series of events beginning with degeneration of the arterial media, followed by inflammation and hyalinization of the perivascular tissue. Growth factors from cells involved in this extracellular matrix formation and resolution of inflammation may also play a role in ossification (Figure 1). Transforming growth factor-ß is elaborated by inflammatory macrophages and damaged epithelial cells and represents a critical growth factor for collagen and the extracellular matrix. Transforming growth factor-ß, strongly implicated in idiopathic pulmonary fibrosis and other fibrotic pulmonary diseases (164), also stimulates osteoblast and chondrocyte proliferation. Another growth factor that may play an important role in ectopic pulmonary ossification is bone morphogenic protein, a member of the transforming growth factor-ß superfamily (165). Bone morphogenic protein, which is likely important in the development of familial primary pulmonary hypertension (166), induces ectopic bone formation in the rat submandibular gland (167). Interleukin-1 has also been shown to enhance bone morphogenic protein–induced hereotopic ossification in laboratory animals (168). The profibrotic cytokine interleukin-4, in conjunction with monocyte-colony stimulating factor, may also transform human alveolar macrophages to osteoclasts, a cell important in bone remodeling (59). Although the role of fibrogenic, angiogenic, and osteogenic growth factors and cytokines in idiopathic and secondary pulmonary ossification is unexplored, their influence may potentially induce ossification in fibroproliferative pulmonary disorders such as idiopathic pulmonary fibrosis. Pulmonary ossification has features of both experimentally induced bone formation and embryologic bone development (169). Local ionic charges, inflammation, and tissue anoxia promote the transformation of cultured fibroblasts into osteoblasts (170, 171). Stress forces that normally shape growing bone also stimulate cell proliferation. In an analogous fashion, shear stresses in noncompliant lung tissue due to fibrosis may induce the conversion of fibroblast to osteoblasts and ultimately bone formation (170). The interstitial deposition of bone can be localized or widely distributed throughout the pulmonary parenchyma. Two histologic types of pulmonary ossification have been described (159): (1) a nodular circumscribed form and (2) a dendriform type. The nodular form is characterized by lamellar deposits of calcified osteoid material situated within the alveolar spaces often without marrow elements (Figure 13A) . Although the lesion shown in Figure 13A is from a patient with idiopathic pulmonary ossification (IPO), the nodular form is typically associated with pre-existing cardiac disorders that result in chronic pulmonary venous congestion such as mitral stenosis, chronic left ventricular failure, and idiopathic hypertrophic subaortic stenosis (170, 172–174) (Table 2). In contrast, dendriform ossification refers to interstitial branching spicules of bone and marrow elements that may protrude into the alveoli. The dendriform type is found in IPO (Figures 13B and 13C) and follows interstitial fibrosis (Figure 13D) (159). Based on this simplified morphologic classification for pulmonary ossification, it is interesting to speculate that some cases of IPO may represent a sequela of previously unidentified lung injuries.
IPO most often is found in men over age 60 but also has been reported in younger adults and in women. Patients can be asymptomatic or have minimal complaints, and IPO represents an unexplained radiographic finding. Many cases are diagnosed at autopsy. A restrictive pulmonary physiology with low diffusion capacity is present when disease is extensive (156, 175). In the secondary forms, signs, symptoms, and the physiologic abnormalities are more likely due to the accompanying disorder. It is uncommon for pulmonary ossification to be seen on the chest radiograph. When present, it involves the lower lobes, appearing as nonspecific reticulonodular densities (74) (Figure 14A) . On a HRCT scan, linear 1- to 4-mm calcific densities are seen (Figure 14B), and occasionally, punctate, miliary, or small nodular calcifications are visible (74). With thin 1-mm slices of the mediastinal images, the bone density of the lesions is confirmed (Figure 14C). Pulmonary ossification may also be detected by 99mTc-MDP nuclear scans (176, 177). Corticosteroids, calcium-binding drugs, and low-calcium diets have no discernable benefit, although they have not been systematically evaluated; the role of bisphosphonates remains to be determined. Because there is no proven treatment for pulmonary ossification, any therapy directed at the ossification should be considered experimental and reserved only for symptomatic cases.
Conclusion Pulmonary calcification and ossification are relatively rare and often asymptomatic. Several predisposing conditions are associated with pulmonary parenchymal calcification with or without ossification. These include hypercalcemia, hyperphosphatemia, alkalosis, and lung injury in the presence or absence of conditions that result in angiogenesis and increased pulmonary blood flow causing elevated vessel wall shear stress. The clinical states associated with pulmonary calcification include several major diseases including CRF, orthotopic liver transplantation, granulomatous infection, infection by DNA viruses or parasites, pulmonary amyloidosis, and pulmonary vascular disease; PAM is considered a unique form of ectopic pulmonary calcification. For some conditions, for example, pulmonary fibrosis or PVC, the calcification may be a marker of disease severity and accelerated morbidity. Pulmonary ossification may be idiopathic or may be secondary to fibrotic lung disorders, cardiac diseases that result in pulmonary venous hypertension, or disorders that raise the calcium–phosphate product levels. The pathogenesis of pulmonary ossification may parallel that of PVC with elevations of left atrial pressure and possible high shear stress forces leading to degeneration of the arterial media, although understanding of the pathogenesis is incomplete. Current diagnostic studies may be useful in revealing pulmonary parenchymal calcification. Bone scintigraphy and HRCT scan with mediastinal images are both superior to standard chest radiography in detecting calcification and ossification when these conditions are clinically suspected.
The authors thank Dr. Robert Quaife for the 99mTc-MDP bone scan of the patient with metastatic calcification and are very grateful to Barry Silverstein for expert illustrative assistance. Supported by grant RO1-HL66112-01A1, a Parke-Davis Atorvastatin Research Award, and the American Lung Association Career Investigator Award (E. C.); a Veterans Affairs Merit Review Award (C. W.); and a National Heart, Lung and Blood Institute–Specialized Center of Research Pulmonary Fibrosis grant HL-67671-01 (M. S.). Received in original form August 13, 2001; accepted in final form March 27, 2002
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