High-Resolution CT of the Lung
3rd Edition

Chapter 7
Diseases Characterized Primarily by Cysts and Emphysema
This disparate group of diseases has in common the presence of focal, multifocal, or diffuse parenchymal lucencies and lung destruction, which may be associated with the presence of lung cysts or emphysema. These diseases include pulmonary Langerhans cell histiocytosis (LCH), lymphangioleiomyomatosis (LAM), and different types of emphysema. Other causes of focal parenchymal lucencies or cysts, including airways diseases (both large and small), pulmonary fibrosis with honeycombing, and infectious diseases with resulting pneumatoceles or cavities, are discussed in Chapters 3, 4, 6, and 8.
Pulmonary Langerhans Cell Histiocytosis (Pulmonary Histiocytosis X)
Collectively, the term Langerhans cell histiocytosis (LCH) refers to a group of diseases of unknown etiology often recognized in childhood, in which Langerhans cell accumulations involve one or more body systems, including bone, lung, pituitary gland, mucous membranes and skin, lymph nodes, and liver [1,2]; this disease is also referred to as histiocytosis X or eosinophilic granuloma. Lung involvement in LCH is common and may be an isolated abnormality. In a review of 314 patients who had histologically proven LCH, pulmonary LCH was identified in 129 patients (40.8%), with isolated pulmonary involvement occurring in 87 patients (28%) [1]. In patients who had multisystem disease in addition to pulmonary involvement, sites most often affected included bone and the pituitary gland [1].
In its early stage, pulmonary LCH is characterized by the presence of granulomas containing large numbers of Langerhans cells and eosinophils, resulting in destruction of lung tissue [3]. LCH lesions are strikingly peribronchiolar in distribution, leading some to consider LCH a form of cellular bronchiolitis [2]. In its later stages, the cellular granulomas are replaced by fibrosis and the formation of lung cysts [4,5].
In normal subjects, Langerhans cells are exclusively found scattered among bronchial and bronchiolar epithelial cells. Functionally, they serve as antigen presenting cells or sentinels, processing and transporting antigens to regional lymph tissue with subsequent T-cell activation. Although studies have shown that LCH represents a clonal proliferation of cells [6], it is not thought that this disease is neoplastic. It is more likely that LCH in adults represents an uncontrolled or abnormal immune response initiated in situ by Langerhans cells in response to an unidentified antigenic stimulus [7]. Evidence that the lesions in LCH result from cellular recruitment

rather than neoplastic cell proliferation include a lack of cellular atypia, absence of focal tissue invasion, and near-complete absence of Langerhans cells in late lesions.
In addition to peribronchiolar lesions, it has become apparent that in patients who have late-stage disease, LCH is also associated with a form of pulmonary vasculitis that leads to severe pulmonary hypertension in up to 80% of cases [3]. In one study of 21 patients who had end-stage pulmonary LCH associated with severe pulmonary hypertension, histopathologic evaluation revealed a proliferative vasculopathy involving muscular arteries and veins, with evidence of medial hypertrophy and intimal and subintimal fibrosis with resulting arterial obliteration in 60% of the cases [8]. Strikingly, these findings occurred in regions unaffected by Langerhans cells. Furthermore, follow-up histologic evaluation showed progression of vascular lesions in the absence of progression of granulomatous disease. In comparison to patients who have pulmonary hypertension due to end-stage idiopathic pulmonary fibrosis (IPF) or emphysema, pulmonary hypertension in patients who have LCH is significantly more severe despite significantly better expiratory function, suggesting that pulmonary hypertension in these patients represents a specific entity and not simply the result of chronic hypoxia. In addition to arterial disease, patients who have severe LCH are also predisposed to develop pulmonary venoocclusive disease [8,9].
Clinical Findings
LCH is an uncommon lung disease. Gaensler et al. [10] found LCH in only 3.4% of 502 patients who had open-lung biopsy for chronic, diffuse infiltrative lung disease.
More than 90% of patients who have pulmonary LCH are smokers, and this disease is considered to be related to smoking in most patients [3,11,12,13,14,15,16]. In a review of 87 patients who had isolated pulmonary involvement by LCH, only three were nonsmokers [1]. The majority of patients who have pulmonary LCH are young or middle-aged adults (average age, 32 years). Although previous reports have stressed a male preponderance, studies confirm that men and women are equally affected, likely the result of increasing tobacco use by women. Common presenting symptoms include cough and dyspnea [4,5]. Up to 20% of patients present with pneumothorax [11].
Compared to patients who have multisystem disease, the prognosis in patients who have isolated pulmonary involvement is good; the disease regresses spontaneously in 25% of patients and stabilizes clinically and radiographically in 50% of patients. In the remaining 25% of cases, the disease follows a progressive downhill course, resulting in diffuse cystic lung destruction. In a small minority of cases, death results from respiratory insufficiency, pulmonary hypertension, or both [1,2]. For example, in a review of 87 patients who had isolated pulmonary disease, 74 patients (85%) ultimately became disease-free, and three patients had progressive disease resulting in severe pulmonary fibrosis and pulmonary hypertension [1]. In two patients, coexisting lung carcinomas were also identified.
Although spontaneous regression of disease is common, disease recurrence has been documented to occur up to 7.5 years after the initial presentation [17]. Furthermore, there is no clear correlation between smoking history and recrudescence of disease, with nodules recurring in some patients after smoking cessation.
Radiographic Findings
The radiographic findings of LCH include reticular, nodular, and reticulonodular patterns, and honeycombing, often in combination [11,12,13,14,18]. Abnormalities are usually bilateral, predominantly involving the middle and upper lung zones, with relative sparing of the costophrenic angles [11,12]. Lung volumes are characteristically normal or increased.
High-Resolution Computed Tomography Findings
High-resolution computed tomography (HRCT) findings of pulmonary LCH have been reported by a number of authors [19,20,21,22]. HRCT findings closely mirror the gross pathologic appearances of this disease. In almost all patients, HRCT demonstrates cystic airspaces, which are usually less than 10 mm in diameter (see Figs 3-113, 3-114, 3-115; Figs. 7-1 and 7-2);

these cysts are characteristic of LCH [19,20,23,24] and were seen in 17 of 18 patients studied by Brauner et al. [20] and all 12 patients studied by Giron et al. [24] (Table 7-1).
FIG. 7-1. Autopsy specimen from a patient who had pulmonary Langerhans cell histiocytosis. Fine cystic spaces predominate in the upper and middle lung zones. The lung bases are relatively spared. (From Müller NL, Miller RR. Computed tomography of chronic diffuse infiltrative lung disease: part 2. Am Rev Respir Dis 1990;142:1440-1448, with permission.)
FIG. 7-2. Cystic pulmonary Langerhans cell histiocytosis (LCH). A: HRCT at the level of the right upper lobe bronchus in a 37-year-old man shows cystic airspaces with thin but well-defined walls. Some cysts are confluent or appear irregular in shape. Note the much milder disease in the superior segment of the right lower lobe. B: HRCT through the lung bases in the same patient shows that these are relatively spared. An upper-lobe predominance of abnormalities is characteristic of pulmonary LCH. C: Target-reconstructed image through the right lung in another patient who has documented LCH also showing extensive cystic lung disease. Note again the presence of bizarre-shaped cysts associated with architectural lung distortion.
On HRCT, the lung cysts have walls that range from being thin and barely perceptible (see Fig. 3-113; Fig. 7-2) to being several millimeters in thickness (see Fig. 3-115; Fig. 7-3). In a study by Grenier et al. [22], 88% of 51 patients who had LCH showed thin-walled (less than 2 mm) cysts on HRCT, whereas 53% of patients showed thick-walled (greater than 2 mm) cysts. The presence of distinct walls allows differentiation of these cysts from areas of emphysema, which can also be seen in some

patients. Although many cysts appear round, they can also have bizarre shapes, being bilobed, cloverleaf shaped, or branching in appearance (see Figs. 3-113, 3-114, 3-115; Fig. 7-2) [19]. These unusual shapes are postulated to occur because of fusion of several cysts, or perhaps because the cysts sometimes represent ectatic and thick-walled bronchi [19]; in the series reported by Brauner et al. [20], confluent or joined cysts with persisting septations were seen in more than two-thirds of patients. An upper lobe predominance in the size and number of cysts is common (see Fig. 3-113; Figs. 7-1 and 7-2). Large cysts or bullae (larger than 10 mm in diameter) are also seen in more than half of cases; some cysts are larger than 20 mm [20].
TABLE 7-1. HRCT findings in Langerhans cell histiocytosis
Thin-walled lung cysts, some confluent or with bizarre
shapes, usually smaller than 1 cma,b
Thick-walled cystsb
Nodules, usually smaller than 1 to 5 mm, centrilobular and
peribronchiolar, may be cavitary, may be seen in association
with cystsa,b
Progression from 3 to 2 to 1b
Upper-lobe predominance in size and number of nodules
or cysts, costophrenic angles spareda,b
Fine reticular opacities
Ground-glass opacity
Mosaic perfusion or air-trapping
a Findings most helpful in differential diagnosis.
b Most common findings.
In some patients, cysts are the only abnormality visible on HRCT, but in the majority of cases, small nodules (usually smaller than 5 mm in diameter) are also present (see Fig. 3-59; Fig. 7-4) [19,20]; nodules were seen in 14 of 18

patients in Brauner’s series, and in 14 of 17 patients in Moore’s series [19,20]. Larger nodules, sometimes exceeding 1 cm, may also be seen, but they are less common. In the study by Grenier et al. [22], 47% of 51 patients who had LCH showed nodules smaller than 3 mm in diameter, whereas 45% of patients showed nodules ranging between 3 mm and 1 cm in diameter, and 24% of patients showed nodules exceeding 1 cm in size. Nodules can vary considerably in number in individual cases, probably depending on the activity of the disease; nodules can be few in number or myriad [19,20]. The margins of nodules are often irregular, particularly when there is surrounding cystic or reticular disease. On HRCT, many nodules can be seen to be peribronchial or peribronchiolar and therefore centrilobular in location; in this disease, there is a tendency for granulomas to form around the bronchioles [20]. HRCT may be valuable in directing lung biopsy to areas showing lung nodules [20].
FIG. 7-3. HRCT in a 44-year-old man who has Langerhans cell histiocytosis and a history of cigarette smoking and shortness of breath. A: HRCT through the upper lobes shows numerous thick- and thin-walled lung cysts. Some cysts are very irregular in shape. The intervening lung parenchyma appears normal, and there is no evidence of diffuse fibrosis. B: Near the lung bases, cysts are smaller and less numerous. The presence of irregularly shaped cysts with an apical predominance is typical of Langerhans cell histiocytosis.
The nodules are usually homogeneous in appearance, but some nodules, particularly those larger than 1 cm in diameter, may show lucent centers, presumably corresponding to small cavities (Fig. 7-5) [25]. These cavities, however, may sometimes represent a dilated bronchiolar lumen surrounded by peribronchiolar granulomas and thickened interstitium [20]. In the study by Grenier et al. [22], 25% of 51 patients who had LCH showed cavitary nodules. In some patients, progression of cavitary nodules to cystic lesions has been observed [21,24]; this progression is characteristic and is described further below.
FIG. 7-4. Nodular Langerhans cell histiocytosis in a 30-year-old man. A: HRCT at the level of the right upper lobe bronchus shows several nodules (arrows). Some are solid, others are cavitated; some have smooth margins, others have irregular or poorly defined margins. B: HRCT through the right lower lung zone shows relative sparing of the lung bases. C: Histologic section from an open-lung biopsy shows a characteristic appearance of a poorly marginated granuloma surrounding a terminal bronchiole.
FIG. 7-5. Nodular Langerhans cell histiocytosis. Section below the carina showing diffuse, centrilobular thick-walled cavitary nodules in a more advanced state than that shown in Figure 7-3A.

In many patients who have cysts or nodules, the intervening lung parenchyma appears normal on HRCT, without evidence of fibrosis or septal thickening [19,20]. However, in a small percentage of cases, irregular interfaces (the interface sign) are present, or a fine reticular network of opacities is visible (Fig. 7-6) [20,24]. These fine reticular opacities may correlate with intralobular fibrosis or early cyst formation, or with the progression and confluence of cysts [24]. Ground-glass opacity is also sometimes seen but is not a prominent feature of this disease.
HRCT shows no consistent central or peripheral predominance of lesions [20,22], but in nearly all cases, the lung bases and the costophrenic sulci are relatively spared [19,26]. In Brauner’s series [20] of 18 patients, two had abnormalities localized to the upper lobes and nine had disease that was predominant in the upper or middle lung zones; two patients had diffuse disease, but no patient had disease with a lower lung predominance. An upper lobar predominance was reported in 57% of Grenier’s 51 patients [22], whereas a middle lung or basal predominance was never observed.
The evolution of lesions identified by CT has been reported. As documented by Brauner et al., in a study of 212 patients who had LCH, although nodular lesions were twice as frequent as cysts on initial CT studies, follow-up CT examinations showed cystic lesions twice as often as nodular disease [21]. Nodular opacities and thick-walled cysts typically underwent regression with time; at the same time, thin-walled cysts, linear densities, and emphysema either remained unchanged or progressed. These data support the previously noted conjecture that lesions in LCH undergo a predictable pathologic and radiologic evolution, beginning with centrilobular nodules (Fig. 7-4) and followed by cavitation (Fig. 7-5) and the formation of thick-walled cysts (Fig. 7-3), and, finally, the development of thin-walled cysts (Fig. 7-2). Whereas nodular lesions may regress spontaneously or be replaced by cysts, once formed, cystic lesions persist, eventually becoming indistinguishable from diffuse emphysema.
Evidence of mosaic perfusion on inspiratory scans and air-trapping on expiratory scans may also be seen in patients who have LCH and show nodular opacities or lung cysts (Fig. 7-7) [27]. This may reflect the presence of bronchiolar obstruction or air-trapping in cystic lung regions.
Utility of High-Resolution Computed Tomography
HRCT is superior to chest radiographs in demonstrating the morphology and distribution of lung abnormalities in patients who have LCH [19,20] and in making a specific diagnosis of this disease [22]. In fact, in many patients who have LCH and plain radiographic findings of reticular abnormalities, HRCT shows that the plain film findings reflect the presence of numerous superimposed lung cysts. As compared with chest radiographs, HRCT is significantly more sensitive in detecting small and large cysts and nodules smaller than 5 mm in diameter [20,22].
LCH is not associated with any consistent pattern of pulmonary function test (PFT) abnormalities, although airways obstruction is common [28] and probably related to peribronchiolar and bronchiolar luminal fibrosis [3]. In a study by Moore et al. [19], the extent of disease on HRCT correlated better (r = -0.71) with impairment in gas exchange, as assessed by the percent predicted carbon monoxide diffusing capacity, than did plain radiographic findings (r = -0.57). In another study [28], significant correlation (r = 0.8) between HRCT and diffusing capacity was also found. However, no correlation has been shown between CT findings and PFT findings of obstruction [19,28]. Air-trapping in association with lung cysts has

been reported on expiratory HRCT in a patient who had LCH, despite the absence of evidence of airways obstruction on PFT [27].
FIG. 7-6. End-stage pulmonary Langerhans cell histiocytosis in a 50-year-old woman. A: HRCT at the level of the right upper lobe bronchus shows extensive fibrosis with small honeycomb cysts. The disease involves the lung diffusely at this level. B: Conventional 10-mm collimation CT scan through the lung base is virtually normal.
Differential Diagnosis
In patients who show nodules as the only HRCT abnormality, the differential diagnosis is extensive; differentiation from sarcoidosis, silicosis, metastatic disease, and tuberculosis may be impossible, although the typical distribution of the nodules can be valuable [29]. Nodules in LCH tend to be centrilobular (Figs. 7-4 and 7-5), whereas septal, subpleural, and peribronchovascular nodules are typically seen in sarcoidosis, silicosis, and lymphangitic carcinomatosis [29]. Sparing of the costophrenic angles should raise the possibility of pulmonary LCH, but it can be seen in these diseases as well. The cystic changes that are seen, on the other hand, can be easily distinguished from the honeycombing that is seen in end-stage IPF. Pulmonary LCH characteristically involves the upper two-thirds of the lungs diffusely, with relative sparing of the costophrenic angles (Figs. 7-2 and 7-3) [19,20]; IPF and other causes of honeycombing primarily involve the subpleural lung regions and the lung bases [30]. Also, in patients who have IPF, the honeycomb cysts are surrounded by abnormal parenchyma, which


shows findings of extensive fibrosis, whereas most of the cysts in LCH are surrounded by normal lung. Lung volumes are normal or increased in cystic LCH, whereas they are generally reduced in patients who have IPF and show honeycombing.
FIG. 7-7. Langerhans cell histiocytosis with small nodular opacities and mosaic perfusion due to air-trapping. HRCT at three levels (A-C) shows small nodular opacities associated with areas of relative lucency (arrows), representing mosaic perfusion due to air-trapping.
In a woman, cystic lesions identical to those seen in pulmonary LCH can be seen in LAM or tuberous sclerosis (Figs. 7-11, 7-12, 7-13) [31,32,33,34,35,36]. LAM very rarely occurs in men. In patients who have LAM, the lower one-third of the lungs is usually involved, and nodules are rarely seen.
The cysts in pulmonary LCH, when adjacent to blood vessels, can mimic the signet ring sign of bronchiectasis (Fig. 7-5). However, distinction from bronchiectasis is straightforward because the cysts in LCH lack the characteristic continuity of dilated bronchi seen on contiguous slices in patients who have bronchiectasis [19].
Centrilobular emphysema typically has an upper lobe predominance similar to that seen in LCH. However, in many patients who have centrilobular emphysema, focal areas of lung destruction lack visible walls, distinguishing them from the lung cysts typical of this disease (Figs. 7-16, 7-17, and 7-19). On the other hand, in some patients who have centrilobular emphysema, areas of emphysema show very thin walls on HRCT, mimicking the appearance of LCH (Fig. 7-18). The presence of thick walls and large cystic spaces would favor a diagnosis of LCH.
Cystic airspaces are also common in a variety of fibrotic interstitial lung diseases, particularly end-stage IPF [30,37,38]. However, the upper lobe distribution of cysts in LCH is quite different from the basal distribution typical of IPF, and IPF typically shows a subpleural predominance that is lacking with LCH. The presence of findings of extensive fibrosis in patients who have IPF also allows their differentiation.
Multiple thin-walled lung cysts are also seen in patients who have lymphocytic interstitial pneumonia (see Figs. 4-36 and 5-19) [39,40,41]. Other findings in patients who have lymphocytic interstitial pneumonia include small subpleural nodules, centrilobular nodules, interlobular septal thickening, and ground-glass attenuation [41].
In patients with pneumonia particularly due to Pneumocystis carinii, lung cysts or pneumatoceles may be seen (see Figs. 6-57 6-58, 6-59 and 6-60). These cannot be easily distinguished from cysts seen in patients who have LCH, other than by history or because of ancillary findings of pneumonia seen on HRCT [42,43,44].
Despite these similar appearances in various cystic lung diseases, the accuracy of HRCT in distinguishing three diseases that cause lung cysts (LCH, pulmonary LAM, and emphysema) was assessed in a study. Two radiologists were confident of the diagnosis of LCH in 84% of HRCT scans, of LAM in 79%, and of emphysema in 95% [45]. When confident, the observers were correct in 100% of the cases. Also, agreement between the observers was good for confident diagnoses (LCH, κ = 0.77; LAM, κ = 0.88; emphysema, κ = 1) [45]. Differentiation of LCH from other diseases is also possible in children [46], although disease progression may be more rapid than in adults [47].
LAM is a rare multisystem disease characterized by progressive proliferation of immature-appearing smooth muscle cells (LAM cells) in the lung parenchyma (Fig. 7-8) and along axial lymphatic vessels in the chest and abdomen [48,49,50]. The hallmark of this disease is cystic destruction of the lung parenchyma (Fig. 7-9). Spindle cell proliferation can also involve the hilar, mediastinal, and extrathoracic lymph nodes, sometimes resulting in dilatation of intrapulmonary lymphatics and the thoracic duct. Involvement of the lymphatics can lead to chylous pleural effusions or ascites. Proliferation of cells in the walls of pulmonary veins may cause venous obstruction and lead to pulmonary venous hypertension with resultant hemoptysis.
FIG. 7-8. Low-power microscopic view of an open-lung biopsy specimen from a patient who has lymphangioleiomyomatosis. Characteristic cystic spaces with atypical spindle cells lining their walls are seen throughout the specimen.
FIG. 7-9. Lymphangioleiomyomatosis. A: Open-lung biopsy specimen shows large cysts. (From Templeton PA, McLoud TC, Müller NL, et al. Pulmonary lymphangioleiomyomatosis: CT and pathologic findings. J Comput Assist Tomogr 1989;13:54-57, with permission.) B: Whole-lung specimen from a patient who had extensive cystic changes. (Case courtesy of Peter Kullnig, M.D., University of Graz, Graz, Austria.)

The lesions of pulmonary LAM can be divided into early (active) and late phases [51,52]. In its early phases, LAM results in a proliferation of cells primarily in terminal bronchioles and alveolar walls (Fig. 7-8). Along the periphery of smooth muscle infiltrates, findings similar to those seen in other causes of emphysema are identified, due to the destructive effects of metalloproteinases expressed by the LAM cells. The result is proximal acinar and irregular emphysema, although similar changes may be seen resulting from more distal smooth muscle proliferation with normal-appearing proximal bronchioles [53].
Evidence of fibrogenesis, including the presence of abundant fibronectin, may also be identified. These changes result in dilated emphysema-like spaces, within which may be identified hyperplastic type II pneumocytes and hemosiderin-laden macrophages, presumably the result of hemorrhage [51,53]. Later in the course of disease, cellular infiltrates regress, leaving markedly dilated alveolar spaces associated with smooth muscle hyperplasia and diffuse collagen deposition.
Although proliferation of spindle cells causes circumferential narrowing and obstruction of bronchioles, leading to air-trapping and the development of thin-walled emphysematous cysts, airways obstruction with resulting emphysema also has been shown to result from loss of alveolar support. Using detailed morphometric analysis of postmortem lungs obtained from two patients who had LAM, Sobonya et al. [54] have shown that of these two mechanisms, it is likely that the loss of parenchymal interdependence resulting from diffuse cystic disease and consequent loss of alveolar support may be the more important of the two.
The smooth muscle cells found in LAM have been shown to be phenotypically heterogeneous, smooth muscle, actin-positive cells derived from myoid precursors. Immunohistochemical studies show that approximately 80% of proliferating cells in LAM patients stain positively for estrogen receptors, whereas nearly all stain positively for progesterone receptors, in distinction to normal smooth muscle cells [53]. LAM cells also differ from normal smooth muscle cells because they react with HMB-45, a monoclonal antibody that identifies a 100-kDa glycoprotein (gp 100) that is located in premelanosome antigens in the cytoplasm of melanoma cell lines [50,51,53,55]. HMB-45 staining is also found in patients who have angiomyolipomas of the kidney, multifocal micronodular pneumocyte hyperplasia [56,57], and clear cell tumors of the lung [55]. Although the significance of immunohistochemical staining with HMB-45 remains uncertain, this finding has proved useful in improving the accuracy of transbronchial biopsy for diagnosing LAM.
Clinical Findings
LAM occurs almost exclusively in women of childbearing age, usually between 17 and 50 years old. However, rarely, it may be seen in postmenopausal women [58]. It has also been

reported to occur in at least one male patient. Identical clinical, radiologic, and pathologic pulmonary changes may be seen in approximately 1% of patients who have tuberous sclerosis. Although tuberous sclerosis affects both genders equally, the pulmonary changes have been described almost exclusively in women.
The majority of patients presents with dyspnea and pneumothorax, cough, or both. The mean time interval from the onset of symptoms to diagnosis is typically between 3 and 5 years [50,59]. Sixty percent develop chylous pleural effusions, up to 80% develop pneumothoraces, and 30% to 40% develop blood-streaked sputum or frank hemoptysis at some time in the course of the disease [48,49,60]. Nearly all patients present with abnormal pulmonary function [50,59,61]. In a study of 35 patients who had LAM, the most common abnormality was decreased carbon monoxide-diffusing capacity (DLco) occurring in 83% of patients, followed by hypoxemia in 57% of patients, airflow obstruction in 51% of patients, and combined obstruction, restriction, or both in 26% of patients [50]. Of these, the most important are measures of airflow obstruction, as these have been shown to most closely correlate with prognosis [61].
Although improvement has been reported clinically after treatment with progesterone, tamoxifen, or other antiestrogen agents, ablation of ovarian function after administration of luteinizing-release hormone analogues, radiotherapy, or oophorectomy, responses to such treatments are variable [51,58,59,62]. Most patients die within 5 to 10 years of the onset of symptoms. As a consequence, LAM is now listed as an indication for lung transplantation, with over 60 cases performed internationally as of 1997 [51]. Similar to patients who have sarcoidosis and giant cell interstitial pneumonia, disease recurrence in transplanted lungs has also now been reported [63].
Radiographic Findings
The plain radiographic manifestations of LAM include reticular, reticulonodular, miliary, and honeycomb patterns [60,64]. More than 50% of patients have radiographic evidence of pneumothorax at the time of first presentation [51]. Lung volumes can be increased in patients who have this disease. The radiologic findings may precede, accompany, or postdate other manifestations of the disease, such as pneumothorax and chylous pleural effusion. Not infrequently, radiographs fail to reveal the presence of diffuse lung cysts subsequently verified surgically [60]. As documented by Chu et al., chest radiographs were interpreted as normal in nine of 35 (26%) patients who had proven LAM [50].
High-Resolution Computed Tomography Findings
On HRCT, patients who have LAM characteristically show numerous thin-walled lung cysts, surrounded by relatively normal lung parenchyma (see Figs. 3-116, 3-117 and 3-118; Figs. 7-10, 7-11 and 7-13) [31,32,33,34,35,36,50,65,66,67,68] (Table 7-2). These cysts usually range from 2 mm to 5 cm in diameter, but they can be larger. Their size tends to increase with progression of the disease [36]. In patients who have mild disease, the cysts usually measure smaller than 5 mm in diameter. In patients who have more extensive disease, in which 80% or more of the lung parenchyma is involved, the cysts tend to be larger, most being larger than 1 cm in diameter. The walls of the lung cysts are usually thin and faintly perceptible, but they may range up to 4 mm in thickness [32,36]. Irregularly shaped lung cysts, as are seen in patients who have LCH (Fig. 7-3), are uncommon. Lung cysts seen on HRCT correlate with the presence of the lung cysts that are common pathologically in this disease; these cysts are partially surrounded by the abnormal spindle cells typical of LAM.
In the majority of patients, the cysts are distributed diffusely throughout the lungs, and no lung zone is spared (Fig. 7-13); diffuse lung involvement is seen even in patients who have mild disease. In reported series [32,36], there is no evidence of lower lung zone, central, or peripheral predominance on CT scans. Thus, the HRCT findings do not support the previous impression that the lesions initially have a predominantly basal distribution [49].
In most patients, the lung parenchyma between the cysts appears normal on HRCT (Figs. 7-10, 7-11 and 7-13). In some cases, however, a slight increase in linear interstitial markings [33,68], interlobular septal thickening [32,68], or patchy areas of ground-glass opacity [36] are also seen. The latter probably represent areas of pulmonary hemorrhage. Small nodules are occasionally seen but are not a prominent feature of this disease, as they are with LCH. Although these variations have led some to conclude that there is no pathognomonic CT appearance of LAM [68], in our experience, in the vast majority of cases, a specific CT diagnosis is warranted in the presence of characteristic diffuse lung cysts, especially when identified in women of childbearing age. Pneumothorax may be seen to be associated with cysts in patients who have this disease (Fig. 7-14).
Other features of LAM that can be seen on HRCT include hilar, mediastinal, and retrocrural adenopathy. Adenopathy was visible in four of the seven patients who had complete chest CT scans reported by Sherrier et al. [34]. Not surprisingly, pleural effusions, pneumothoraces, or both are frequently identified and can be helpful in distinguishing LAM from Langerhans histiocytosis. In one large series, they were identified in five [14%] and two [6%] patients, respectively [50]. Air-trapping on expiratory scans may also be seen [27].
Less well appreciated is the fact that abnormalities may also be frequently identified in the abdomen. Most important is the finding of renal angiomyolipomas. These have been noted to occur in up to 57% of patients who have LAM, and they are frequently bilateral. Chu et al. detected a total of 31 solid renal masses in 18 of 35 (51%) patients, including six patients (17%) who had multiple angiomyolipomas and four (11%) who had bilateral involvement. Typically, these are large at the time of diagnosis, usually larger than 4 cm in diameter, and have a well-known tendency to cause retroperitoneal bleeding. In addition to renal tumors, retroperitoneal

adenopathy is also frequent, occurring in up to three-quarters of patients in one report [50]. Ascites may also be identified, usually in conjunction with chylothoraces.
FIG. 7-10. Lymphangioleiomyomatosis in a 30-year-old woman. A, B: HRCT targeted to the left lung shows multiple cystic airspaces of varying sizes. These have walls ranging from being barely perceptible to 2 mm in thickness. The lung parenchyma between the cystic airspaces is normal. The cysts are primarily round in shape, but some are confluent. As contrasted with Langerhans cell histiocytosis, the upper and lower lobes are involved to a similar degree. (From Templeton PA, McLoud TC, Müller NL, et al. Pulmonary lymphangioleiomyomatosis: CT and pathologic findings. J Comput Assist Tomogr 1989;13:54-57, with permission.)
Utility of High-Resolution Computed Tomography
HRCT is superior to chest radiography in determining the extent and distribution of air cysts in this disease, and it can demonstrate extensive abnormalities in patients who have normal radiographic findings [32,34,36]. The cystic changes of LAM are also much easier to assess and are better defined on HRCT than on conventional CT (Fig. 7-12). Cysts visible on HRCT were rarely seen on chest radiographs, unless they were larger than 1 cm.
Disease extent as assessed on CT correlates better than do radiographic findings with clinical and functional impairment in patients who have LAM [51]. Typically, PFTs reveal decreased diffusing capacity and, less commonly, airflow obstruction with reduced forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity (FVC) ratio, accompanied by a reduction in elastic recoil. Significant correlations have been documented between a reduced FEV1/FVC ratio, increased total lung capacity (TLC), and prognosis [61]. On CT, the best correlations have been observed between the extent of disease and impairment in gas transfer as assessed by the carbon monoxide diffusing capacity [32,36,67]. Although significant correlations have also been

demonstrated between extent of cystic disease and severity of airways obstruction [32,67], this has proved more controversial. In the study by Aberle et al. [67], for example, good correlation was reported between CT scores and measures of airways obstruction, in particular the FEV1/ FVC ratio (r = -0.92; p <.002). Similarly, Lenoir et al., in a study of 11 patients who had LAM (n = 9) and tuberous sclerosis (n = 2), found good correlation between CT findings and FEV1/FVC ratios and DLco [32]. In distinction, although good correlations between CT scores and DLco have also been reported by Müller et al. in their study of 14 patients who had LAM, similar good correlation was not seen with lung volumes or airflow parameters [36].
FIG. 7-11. HRCT targeted to the right lung in a patient who has documented tuberous sclerosis and lymphangioleiomyomatosis. Note the similarity between this case and that illustrated in Figure 7-10.
FIG. 7-12. Lymphangioleiomyomatosis in a 58-year-old woman. A: Conventional 10-mm collimation CT scan through the right upper lobe shows lucent areas. This appearance is similar to that of emphysema. B: HRCT demonstrates that the cystic airspaces have well-defined walls, allowing easy distinction from emphysema.
Crausman et al. have assessed the use of quantitative CT (QCT) measurements as a means to predict prognosis in LAM patients [69,70]. Using two end-expiratory HRCT images (at the carina and just above the diaphragm), these authors used a density mask program using a threshold of -900 Hounsfield units (HU) to obtain a QCT index in ten patients who had documented LAM. Defined as the amount of cystic lung expressed as a percent of total lung area for the two slices combined, good correlation was found between the QCT index and the FEV1 (r = -0.9; p = .0005), residual volume (r = 0.7; p = .02), DLco (r = -0.76; p = .01), and exercise performance measured as maximum workload (r = -0.84; p = .002), among other measurements [69]. These data are significant given previously noted correlations between measurements of airflow obstruction and prognosis [61]. As is discussed in greater detail later in this chapter, there are important limitations to the use of expiratory HRCT images for assessing both the extent and severity of emphysema that likely also apply to the use of expiratory CT for evaluating patients who have LAM [71].
The presence of many small, thin-walled, cystic airspaces scattered through both lungs in a young woman is highly suggestive of LAM. However, definitive diagnosis traditionally has required open-lung biopsy. This is because lung tissue from LAM patients, especially when obtained by transbronchial biopsy, may be mistaken for any disease that involves smooth muscle hyperplasia, including IPF. As previously discussed, it has been shown that immunohistochemical staining with HMB-45 is positive in patients who have LAM, improving the usefulness of transbronchial biopsy for this diagnosis [72,73]. CT is advantageous in demonstrating parenchymal abnormalities in symptomatic patients who have normal or questionably abnormal findings on chest radiographs, thus indicating the need for biopsy. It should be noted, however, that normal findings at CT examination do not rule out parenchymal disease in patients who have LAM [26].
Patients who have lung transplantation for LAM have increased morbidity and mortality due to complications


related to their underlying disease [74]; these LAM-related complications can be diagnosed or suggested with CT. In a review of 13 patients who had unilateral (n = 8) or bilateral (n = 5) lung transplantation for LAM, complications found during and after transplantation included excessive pleural adhesions (n = 4), native lung pneumothorax (n = 3) (Fig. 7-14), chylous effusion (n = 1), chylous ascites (n = 3), complications from renal angiomyolipomas (n = 4), and recurrent LAM (n = 1). One patient died as a result of complications of LAM [74].
FIG. 7-13. A-C: Lymphangioleiomyomatosis in a 35-year-old woman with tuberous sclerosis. HRCT shows numerous discrete, round, thin-walled lung cysts. Cysts are thinner-walled and more regular in size and shape than those seen in patients who have Langerhans cell histiocytosis. Intervening lung parenchyma appears normal. Cysts are diffusely distributed, and cysts at the lung bases (C) are similar in size and number to those seen at the lung apices (A). These abnormalities were associated with adenoma sebaceum, shortness of breath, airway obstruction on pulmonary function tests, and low diffusing capacity.
Table 7-2. HRCT findings in lymphangioleiomyomatosis
Thin-walled lung cysts, usually round in shapea,b
Diffuse distribution, costophrenic angles involveda,b
Mild septal thickening or ground-glass opacity
Small nodules
Pleural effusionb
a Most common findings.
b Findings most helpful in differential diagnosis.
Differential Diagnosis
Lung cysts very similar to those seen in LAM have also been described in patients who have pulmonary LCH [19,20]. However, three findings usually allow the differentiation of these two diseases. In many patients who have pulmonary LCH, a nodular component is also present (Fig. 7-5); this is uncommon with LAM. Irregularly shaped cysts, as are commonly seen in patients who have LCH (Figs. 7-2 and 7-3), are much less frequent with LAM. LCH characteristically involves the upper two-thirds of the lungs and spares the costophrenic angles (Fig. 7-3), whereas LAM involves the lungs diffusely [19,20]. In some patients, however, the HRCT findings of these two conditions can be identical.
A number of other cystic lung diseases and emphysema, delineated in the discussion of LCH above, may mimic the appearance of LAM. However, careful attention to the appearances of the cystic lesions, their distribution, and their clinical history can allow their distinction in many cases. The accuracy of HRCT in distinguishing LCH, LAM, and emphysema is excellent. In a study, two observers were confident of the diagnosis of LAM in 79% of cases and were correct in all of these [45].
FIG. 7-14. Lymphangioleiomyomatosis before and after lung transplantation. A: Targeted reconstruction through the left lung shows diffuse lung cysts associated with a pneumothorax. Pneumothoraces occur commonly in this disease. B: Section in the same patient obtained following unilateral lung transplantation. Note subtle narrowing of the left upper lobe bronchus at the site of anastomosis. An occult right-sided pneumothorax is also identifiable anteriorly.

As defined by the American Thoracic Society, emphysema is “a condition of the lung characterized by permanent, abnormal enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls” [75,76,77]. This definition also includes the caveat “without obvious fibrosis” [78]; however, some observations have established that some degree of associated fibrosis is not uncommon [75,76].
It is generally accepted that emphysema results from an imbalance in the dynamic relationship between elastolytic and antielastolytic factors in the lung, usually related to smoking or enzymatic deficiency [79,80,81]. Abnormal or unopposed elastase activity in the lung is thought to lead to the tissue destruction representing the primary pathologic abnormality present in patients who have this disease.
Inhaled tobacco smoke attracts macrophages to distal airways and alveoli. Macrophages, in turn, along with airway epithelial cells, release chemotactic substances that serve to attract neutrophils and induce them to release elastases and other proteolytic enzymes [82,83]. Macrophages also release proteases in response to tobacco smoke. These elastases have the ability to cleave a variety of proteins, including collagen and elastin. Lung elastin is normally protected from excessive elastase-induced damage by alpha-1-protease inhibitor (alpha-1-antiprotease or antitrypsin) and other circulating antiproteinases. However, tobacco smoke tends to interfere with the function of alpha-1-antiprotease. In combination, these interactions result in structural damage in the distal airways and alveoli in smokers, leading to emphysema. Inherited deficiency in alpha-1-antiprotease may similarly result in lung destruction and emphysema.
Classification of Emphysema
Emphysema is usually classified into three main subtypes, based on the anatomic distribution of the areas of lung destruction, but the names applied to these subtypes by different investigators often differ [77,84]. These subtypes are: (i) proximal acinar, centriacinar, or centrilobular emphysema; (ii) panacinar or panlobular emphysema; and (iii) distal acinar or paraseptal emphysema. Although from an anatomic or pathologic point of view, it is most appropriate to refer to these types of emphysema relative to the presence and type of acinar abnormalities (i.e., proximal acinar, panacinar, and distal acinar), from the standpoint of understanding the use of HRCT, it is more appropriate to refer to them relative to the way in which we perceive them at the lobular level (i.e., centrilobular, panlobular, and paraseptal). As indicated in Chapter 2, acini cannot be resolved on HRCT. In the remainder of this chapter, the terms centrilobular, panlobular, and paraseptal are used to describe these three types of emphysema.
Centrilobular emphysema (proximal acinar emphysema, centriacinar emphysema) predominantly affects the respiratory bronchioles in the central portions of acini, and therefore involves the central portion of the lobule. Panlobular emphysema (panacinar emphysema) involves all the components of the acinus more or less uniformly, and therefore involves the entire lobule. Paraseptal (distal acinar emphysema) predominantly involves the alveolar ducts and sacs, with areas of destruction often marginated by interlobular septa.
Centrilobular emphysema usually results from cigarette smoking. It mainly involves the upper lung zones. In contrast, panlobular emphysema is classically associated with alpha-1-protease inhibitor (alpha-1-antitrypsin) deficiency, although it may also be seen without protease deficiency in smokers, in the elderly, distal to bronchial and bronchiolar obliteration, and associated with drug use [78]. Paraseptal emphysema can be an isolated phenomenon in young adults, often associated with spontaneous pneumothorax, or can be seen in older patients with centrilobular emphysema [78,85]. In their early stages, these three forms of emphysema can be easily distinguished morphologically. However, as they become more severe, their distinction becomes more difficult.
Bullae can develop in association with any type of emphysema, but they are most common with paraseptal or centrilobular emphysema. A bulla, by definition, is a sharply demarcated area of emphysema measuring 1 cm or larger in diameter and possessing a wall smaller than 1 mm in thickness [86]. In some patients who have emphysema, bullae can become quite large, resulting in significant compromise of respiratory function; this syndrome is sometimes referred to as bullous emphysema. Bullae have been classified by Reid according to their location and the type of emphysema with which they are associated [87]. According to this classification, type 1 bullae are subpleural in location and occur in patients who have paraseptal emphysema; type 2 bullae are also subpleural but are associated with generalized emphysema (centrilobular or panlobular); type 3 bullae are associated with generalized emphysema, but occur within the lung parenchyma rather than in a subpleural location.
Irregular airspace enlargement is an additional type of emphysema occurring in patients who have pulmonary fibrosis; this form of emphysema is also referred to as paracicatricial or irregular emphysema [78,84].
Emphysema, Chronic Obstructive Pulmonary Disease, and Clinical Findings
In patients who have emphysema, PFTs usually show findings of chronic airflow obstruction and reduced diffusing capacity. Airflow obstruction in patients who have emphysema is due to airways collapse on expiration, largely resulting from destruction of lung parenchyma and loss of airways tethering and support. Abnormal diffusing capacity is due to destruction of the lung parenchyma and the pulmonary vascular bed.
It is important to keep in mind that many patients who have emphysema also have chronic bronchitis, because both are smoking-related diseases. Chronic bronchitis is a poorly

characterized entity that, for lack of a better definition, is considered to be present if a patient has chronic sputum production that is not caused by a specific disease such as bronchiectasis or tuberculosis [88]. Morphologic correlates with chronic bronchitis have been difficult to define, although common pathologic findings include bronchial wall thickening, mucous gland enlargement, smooth muscle hyperplasia, inflammation, and small airways abnormalities.
The term chronic obstructive pulmonary disease or COPD is often used to describe patients who have chronic and largely irreversible airways obstruction, most commonly associated with some combination of emphysema and chronic bronchitis [88]. The term indicates some uncertainty as to the exact pathogenesis of the functional abnormalities present [88]. Furthermore, COPD may be used to refer to diseases usually associated with airways obstruction, such as emphysema and chronic bronchitis, even if no obstruction is demonstrated on PFTs.
Respiratory symptoms in patients who have COPD usually include chronic cough, sputum production, and dyspnea. Although in patients who have COPD, cough and sputum production are largely manifestations of chronic bronchitis, the relative contributions of airways disease and emphysema to respiratory disability are often difficult to determine. However, in patients who have early alpha-1-protease inhibitor (alpha-1-antitrypsin) deficiency, airways disease is typically absent, and functional abnormalities primarily reflect the presence of emphysema. These include reduced FEV1/FVC, FEV1, and DLco [89]. In patients who have more long-standing emphysema associated with alpha-1-protease inhibitor deficiency, chronic cough and sputum production are common, likely due to increased susceptibility to infection [90] and the development of bronchiectasis [81].
Radiographic Findings
Radiographic abnormalities in patients who have emphysema generally reflect increased lung volume, lung destruction (reduced vascularity or bullae), or both [91,92,93,94,95,96]. When both findings are used as criteria for diagnosis, a sensitivity as high as 80% has been reported for chest films [91], although the likelihood of a positive diagnosis depends on the severity of disease [77]. When only findings of lung destruction are used for diagnosis, plain films are only 40% sensitive [96]. Although the accuracy of chest radiographs in diagnosing emphysema is somewhat controversial, it can be reasonably concluded from the studies performed that moderate to severe emphysema can be diagnosed radiographically, whereas mild emphysema is difficult to detect.
The presence of increased lung volume, or overinflation, can be very important in making the diagnosis of emphysema on plain radiographs, but overinflation is an indirect sign of this disease; findings of increased lung volume are nonspecific and can be lacking in some patients who have emphysema while being present in patients who have other forms of obstructive pulmonary disease. A number of plain radiographic findings of overinflation have been validated in patients who have COPD, although their sensitivity and specificity vary. These include (i) a lung height of 29.9 cm or more, measured from the dome of the right diaphragm to the tubercle of the first rib; (ii) flattening of the right hemidiaphragm on the lateral projection, with a height of less than 2.7 cm measured from anterior to posterior costophrenic angles; (iii) flattening of the right hemidiaphragm on a posteroanterior radiograph, with the highest level of the dome of the right hemidiaphragm less than 1.5 cm above a perpendicular line drawn between the costophrenic angle laterally and the vertebrophrenic angle medially; (iv) an increased retrosternal airspace, measuring more than 4.4 cm at a level 3 cm below the manubrial-sternal junction; and (v) the right hemidiaphragm at or below the level of the anterior end of the seventh rib [93,93,94,95,97,98,99].
The presence of bullae on chest radiographs is the only specific sign of emphysema, but this finding is infrequent and may not reflect the presence of generalized disease. A reduction in size of pulmonary vessels or vessel tapering can also reflect lung destruction, but this finding lacks sensitivity and can be unreliable.
High-Resolution Computed Tomography Findings
On HRCT, emphysema is characterized by the presence of areas of abnormally low attenuation, which can be easily contrasted with surrounding normal lung parenchyma if sufficiently low window means (-600 HU to -800 HU) are used [100,101,102]. In most instances, focal areas of emphysema can be easily distinguished from lung cysts or honeycombing; focal areas of emphysema often lack distinct walls (see Chapter 3) [45,100,101].
Although various CT findings of increased lung volume may also be seen in patients who have COPD and emphysema [103], their identification is usually secondary to the more direct observation of lung destruction characteristic of the various types of emphysema. In a study of 74 patients (44 who had normal lung function and 30 who had COPD), significant correlations were observed between FEV1/FVC and the tracheal index (transverse/anteroposterior diameter; r = 0.578; p <.0001), anteroposterior/transverse thoracic diameters at the tracheal carina (r = -0.523; p <.0001) and 5 cm below (r = -0.533; p <.0001), and lung bulging in the intercostal spaces (r = -0.462; p <.0001) [103].
Centrilobular Emphysema
Centrilobular emphysema of mild to moderate degree is characterized on HRCT by the presence of multiple small, round areas of abnormally low-attenuation, several millimeters in diameter, distributed throughout the lung, but usually having an upper lobe predominance. Areas of lucency often appear to be grouped near the centers of secondary pulmonary lobules, surrounding the centrilobular artery branches (see Figs. 3-119 and 3-120; Figs. 7-15, 7-16 and 7-17) (Table 7-3)

[100,101,102,104,105]. These lucencies correspond to the well-circumscribed centrilobular or centriacinar areas of lung destruction seen pathologically in patients who have centrilobular emphysema [100,101,104,105,106,107]. Although the centrilobular location of lucencies cannot always be recognized on CT or HRCT [101,104,105], the presence of multiple small areas of emphysema scattered throughout the lung is diagnostic of centrilobular emphysema (see Figs. 3-121, 3-122 and 3-123; Figs. 7-16, 7-17 and 7-18). In most cases, the areas of low-attenuation lack visible walls [45] (Figs. 7-16 and 7-17), although

very thin and relatively inconspicuous walls are occasionally seen on HRCT (Fig. 7-18), probably related to surrounding fibrosis; it has been shown that centrilobular emphysema is commonly associated with some fibrosis [75,76]. In patients who have centrilobular emphysema, bullae within the lung may have visible walls, and paraseptal emphysema and subpleural bullae are often seen (Figs. 7-19 and 7-20).
FIG. 7-15. Centrilobular or centriacinar emphysema. A low-power microscopic view of a lung specimen from a patient who has mild centrilobular emphysema. Areas of lung destruction measuring 3 to 10 mm in diameter are visible (arrows).
FIG. 7-16. Centrilobular emphysema in a 70-year-old smoker. HRCT at the level of the aortic arch shows localized areas of abnormally low attenuation measuring 2 to 10 mm in diameter, which can be seen to be centrilobular (they surround arteries in the lobular core). The areas of destruction lack recognizable walls.
FIG. 7-17. Centrilobular emphysema with small focal lucencies. Lucencies lack visible walls, as is common in patients who have centrilobular emphysema. Some lucencies can be seen to surround small vessel branches. This appearance indicates that the emphysema has a centrilobular location. A small nodule in the right upper lobe represents an adenocarcinoma. See also Figure 7-36.
Table 7-3. HRCT findings in centrilobular emphysema
Multiple, small, spotty or centrilobular lucenciesab
Upper-lobe predominanceab
Lucencies may have thin walls
May be associated with paraseptal emphysema or bullae
a Most common findings.
b Findings most helpful in differential diagnosis.
With more severe centrilobular emphysema, areas of destruction can become confluent. When this occurs, the centrilobular distribution of abnormalities is no longer recognizable on HRCT, or pathologically; the term confluent centrilobular emphysema is sometimes used to describe this occurrence (see Figs. 3-125 and 3-126; Figs. 7-21 and 7-22). This appearance can closely mimic the appearance of panlobular emphysema, and a distinction between these is of little clinical significance.
Panlobular Emphysema
Panlobular emphysema is characterized by uniform destruction of the pulmonary lobule, leading to widespread areas of abnormally low-attenuation (see Fig. 3-124; Figs. 7-23, 7-24, 7-25, 7-26, 7-27) (Table 7-4) [85,105,106,108]. Thurlbeck describes this entity as a “diffuse ‘simplification’ of the lung structure with progressive loss of tissue until little remains but the supporting framework of vessels, septa and bronchi” [84]. Involved lung appears abnormally lucent [108], a finding easy to appreciate in patients who have had unilateral lung transplantation (Figs. 7-24 and 7-26). Pulmonary vessels in the affected lung appear fewer and smaller than normal and may be quite inconspicuous. In contrast to centrilobular emphysema, panlobular emphysema almost always appears generalized or most severe in the lower lobes (Fig. 7-26).
Although it may lead to extensive destruction of the lung parenchyma, focal lucencies having the appearance of centrilobular emphysema are relatively uncommon, but they may be seen in less abnormal lung regions (Fig. 7-27). Associated paraseptal emphysema and bullae are relatively uncommon, despite the severity of lung destruction. In one study [108], frank bulla were seen in seven of 17 patients and were not considered a major feature of the disease.
In severe panlobular emphysema, the characteristic appearance of extensive lung destruction and the associated paucity of vascular markings are easily distinguished from normal lung parenchyma (Fig. 7-26). On the other hand, mild and even moderately severe panlobular emphysema can be very subtle and difficult to detect [107]. Furthermore, diffuse panlobular emphysema unassociated with focal areas of lung destruction or bullae may be difficult to distinguish from diffuse small airways obstruction and air-trapping resulting from bronchiolitis obliterans.
FIG. 7-18. Centrilobular emphysema. Some of the focal areas of lung destruction appear to be outlined by very thin walls (white arrows), probably due to fibrosis. Subpleural lucencies (black arrows) represent paraseptal emphysema, which can coexist with centrilobular emphysema.
Alpha-1-antitrypsin deficiency may be associated with bronchiectasis or bronchial wall thickening (Fig. 7-26B) [109]. Presumably, as described previously, patients who have alpha-1-antitrypsin deficiency are more susceptible to airways damage during episodes of infection than are normal patients because of the same protease-antiprotease imbalance that leads to emphysema. In a study by King et al. [81], 6 of 14 (43%) patients who had alpha-1-antitrypsin deficiency had CT evidence of bronchiectasis, a finding associated with symptoms of infection. Two patients had diffuse cystic bronchiectasis. Similarly, in a study by Guest et al. [108], bronchial wall thickening, dilatation, or both were present in seven of 17 (41%) patients who had alpha-1-antitrypsin deficiency, with gross cystic bronchiectasis visible in one patient. Histologic findings in a patient who had alpha-1-antitrypsin deficiency and bronchiectasis visible on CT showed destruction of elastic lamina in ectatic bronchi and bronchioles [81].
The progression of panlobular emphysema associated with alpha-1-antitrypsin deficiency may be assessed using HRCT with densitometric measurements of lung attenuation [110,111] and has been found to be more sensitive than PFTs [111]. In one study [111], 23 patients were scanned twice at a 1-year interval. HRCT was obtained at 90% of the vital capacity (VC), at the level of the carina, 5 cm above the carina, and 5 cm below the carina. During the follow-up period, mean lung densities decreased by 14.2 ± 12.0 HU above the carina, by 18.1 ± 14.4 HU at the carina, and by 23.6 ± 15.0 HU below the carina. In another study [110], 22 patients who had moderate


emphysema associated with alpha-1-antitrypsin deficiency were followed for 2 to 4 years with an annual lung CT. A highly significant decline in CT-measured lung density was found in low-density areas, corresponding to a mean annual loss of lung tissue of 2.1 g per L lung volume.
FIG. 7-19. Centrilobular and paraseptal emphysema. A: Areas of centrilobular emphysema (white arrows) are seen as focal lucencies in the central lung, without visible walls. Paraseptal emphysema in the subpleural regions (black arrows) is also visible, and thin walls are typically visible on HRCT. B: At a lower level, small bullae (white arrows) are associated with centrilobular emphysema. These have thin walls. C: At a level below B, centrilobular emphysema, intraparenchymal bullae, and paraseptal emphysema are all visible.
FIG. 7-20. Centrilobular emphysema with extensive paraseptal emphysema. Subpleural bullae and bullae within the lung parenchyma are both associated with centrilobular emphysema in this patient.
Paraseptal Emphysema
Paraseptal emphysema is characterized by involvement of the distal part of the secondary lobule and is therefore most striking in a subpleural location (see Figs. 3-127, 3-128 and 3-129; Figs. 7-18, 7-19 and 7-20 and 7-28, 7-29 and 7-30). Areas of subpleural paraseptal emphysema often have visible walls, but these walls are very thin; they often correspond to interlobular septa. As with centrilobular emphysema, some fibrosis may be present. Even mild paraseptal emphysema is easily detected by HRCT (Table 7-5) [107].
When larger than 1 cm in diameter, areas of paraseptal emphysema are most appropriately termed bullae (Figs. 7-20 and 7-29 through 7-31). Subpleural bullae are frequently considered to be a manifestation of paraseptal emphysema, although they may be seen in all types of emphysema and as an isolated phenomenon; regardless of the cause of the subpleural bullae, they usually have thin walls that are visible on HRCT.
Lesur et al. [112] have shown that CT may be useful in the early detection of apical subpleural bullae in patients who have idiopathic spontaneous pneumothorax. This form of pneumothorax occurs most often in tall young adults [113] and is thought to be due to rupture of a subpleural bulla [112]. Out of 20 patients (mean age, 27 ± 7 years), CT demonstrated emphysema in 17 patients with a predominance in the lung apices, and in a subpleural location in 16 patients.
Bense et al. [114] have also demonstrated that emphysema is seen on CT in the majority of nonsmoking patients who have spontaneous pneumothorax. They compared the CT findings in 27 nonsmoking patients who had spontaneous pneumothorax to the CT findings in ten healthy subjects who had never smoked. Emphysema was present on CT in 22 of 27 nonsmoking patients who had spontaneous pneumothorax and in none of the 10 control subjects. The emphysema was present mainly in the periphery of the upper lung zones, a distribution consistent with paraseptal emphysema. In none of the cases was emphysema detected on a chest radiograph.
Similarly, in a prospective study of 35 patients who had primary spontaneous pneumothorax [115], the value of CT in detecting bullae was compared to that of chest radiographs. CT showed bullae or areas of subpleural emphysema in 31 of 35 (89%) patients, whereas chest radiographs showed these in only 11 patients (31%). Six patients had a recurrent pneumothorax during follow-up; no correlation between recurrence and the number, size, and distribution of bullae as assessed by CT was found.
FIG. 7-21. Confluent centrilobular emphysema. Focal areas of centrilobular emphysema are visible on HRCT in the left upper lobe, whereas in the right upper lobe, areas of emphysema are large and confluent.
FIG. 7-22. Confluent centrilobular emphysema. Areas of centrilobular and paraseptal emphysema are associated with extensive areas of lung destruction. This appearance mimics that of panlobular emphysema, shown in Figure 7-27, but it is more patchy and was associated with a distinct upper lobe predominance.

Bullous Emphysema
The term bullous emphysema does not represent a specific pathologic entity but refers to the presence of emphysema associated with large bullae; it is generally seen in patients who have centrilobular emphysema, paraseptal emphysema, or both (Figs. 7-30, 7-31 and 7-32) [87]. A syndrome of bullous emphysema, or giant bullous emphysema, has been described on the basis of clinical and radiologic features and is also known as vanishing lung syndrome, type 1 bullous disease, or primary bullous disease of the lung [116]. Giant bullous emphysema is often seen in young men and is characterized by the presence of large, progressive, upper lobe bullae, which occupy a significant volume of a hemithorax and are often asymmetric (Figs. 7-31 and 7-32). Arbitrarily, giant bullous emphysema is said to be present if bullae occupy at least one-third of a hemithorax [116].

Most patients who have giant bullous emphysema are cigarette smokers [117], but this entity may also occur in nonsmokers.
FIG. 7-23. Panlobular emphysema. A pathologic specimen shows diffuse involvement of the parenchyma with simplification of lung architecture.
FIG. 7-24. Panlobular emphysema in a patient who had a left lung transplant. The emphysematous right lung is relatively large and lucent and shows fewer and smaller vessels than are visible on the left. This appearance is typical of panlobular emphysema.
FIG. 7-25. Panlobular emphysema due to alpha-1-antiprotease deficiency in a 50-year-old woman. HRCT at the level of the aortic arch shows marked simplification of the architecture of the pulmonary parenchyma and areas of abnormally low attenuation. The areas of emphysema involve the entire secondary lobule and are easily distinguished from the localized 2- to 10-mm diameter areas of abnormally low attenuation seen in centrilobular emphysema.
In nine patients who had giant bullous emphysema reported by Stern et al. [116], the most striking HRCT finding was the presence of multiple large bullae, varying in size from 1 to 20 cm in diameter, but usually between 2 and 8 cm in diameter (Figs. 7-31 and 7-32). Bullae were visible in a subpleural location and within the lung parenchyma, but subpleural bullae predominated. Bullae were often asymmetric, with one lung being involved to a greater degree. HRCT better depicted the presence of associated paraseptal and centrilobular emphysema than did chest radiographs. In this study [116], paraseptal emphysema was visible on HRCT in all subjects and was the predominant associated finding; centrilobular emphysema of varying degrees was present in eight of nine subjects.
Typically, bullae increase progressively in size. However, rarely, bullae may spontaneously decrease in size or disappear, usually as a result of secondary infection or obstruction of the proximal airways [118]. Spontaneous pneumothorax is common and may be recognized only on CT [112,115].
Irregular Airspace Enlargement
Irregular airspace enlargement, previously known as irregular or cicatricial emphysema, is commonly found adjacent to localized parenchymal scars, diffuse pulmonary fibrosis, and in the pneumoconioses, particularly progressive massive fibrosis (see Fig. 5-47) [119]. It is most easily recognized on CT when the associated fibrosis is identified. However, this type of emphysema may also be seen associated with microscopic fibrosis, in which case radiologic distinction between irregular and centrilobular emphysema may be impossible [120].
Quantitative Evaluation of Emphysema Using Computed Tomography
Technical Considerations
Our ability to diagnose and quantitate the extent and severity of emphysema using CT is influenced by a number of technical factors, including collimation, window settings,

threshold values for diagnosing emphysema, radiation dose, reconstruction algorithm, phase of respiration, use of intravenous contrast media, number of sections assessed, and differences among individual scanners [71,121,122,123,124,125,126,127,128]. Awareness of these factors is a necessary prerequisite to accurate qualitative and quantitative evaluation of CT images.
FIG. 7-26. Panlobular emphysema associated with alpha-1-antitrypsin deficiency in a patient who had left lung transplantation. A: The emphysematous lung is lucent compared to the normal transplant and contains fewer and smaller vessels. Focal lucencies, as are seen in patients who have centrilobular or paraseptal emphysema, are absent in this patient, as are paraseptal emphysema and bullae. B: Findings of panlobular emphysema are also evident in the middle lung. Note bronchial wall thickening (arrow) as compared to the opposite side. The presence of bronchiectasis and bronchial wall thickening may be seen in patients who have alpha-1-antitrypsin deficiency. C: At the lung bases, findings of extensive emphysema are also visible. In panlobular emphysema, diffuse lung involvement is typical.
Although emphysema may be detected using CT scans obtained using 10-mm collimation or spiral technique with collimation of 7 to 8 mm, thick collimation reduces the ability of CT to detect a mild degree of abnormality. Except when obtaining volumetric CT data, such techniques are not recommended for the diagnosis of emphysema.
It has been suggested that routine lung window settings, using a window level of approximately -700 HU and a window width of 1,000 HU, are acceptable for diagnosing emphysema [129]. Use of a window width of 1,500 HU is also satisfactory but reduces contrast between normal and emphysematous lung, making visual assessment more difficult. A narrow window width (e.g., 500 HU) with a low window mean (e.g., 800 HU) may be used to accentuate contrast between normal and emphysematous lung, although such a window setting would not be appropriate for routine HRCT [77,100,106].
At present, there is no generally agreed-on minimum number of sections necessary for accurate assessment of

emphysema. Genevois et al., in an attempt to determine the least number of 1-mm sections necessary for accurate quantification, assessed progressively fewer sections obtained at 1-cm intervals and came to the conclusion that no standard number of HRCT images could be recommended due to wide variations from patient to patient [124]. Also, methods by which the lungs are segmented for the purposes of regional analysis also impact the accuracy of CT quantification. A variety of methods has been suggested, including manual, semiautomatic, and automated methods [130].
FIG. 7-27. A, B: Panlobular emphysema associated with alpha-1-antitrypsin deficiency. Although extensive lung destruction is present, some lung regions are less severely involved. In these regions, focal lucencies are visible, mimicking the appearance of centrilobular emphysema.
Milliampere (mA) settings used for HRCT are also important. Mishima et al. [126], in a study comparing a variety of mA scan settings ranging between 50 and 250, found that in patients who had mild emphysema, in whom the percent ratio of low-attenuation areas pathologically proved to be less than 30%, the mean low-attenuation area obtained by CT using less than 150 mA was significantly larger than that obtained using 250 mA; these authors concluded that a minimum current of greater than 200 mA is requisite for accurate quantification. These data may be pertinent in those cases in

which an attempt is made to combine emphysema quantification with low-dose screening techniques.
Table 7-4. HRCT findings in panlobular emphysema
Lucent lung containing small pulmonary vesselsa,b
Diffuse or lower lobe predominancea,b
Focal lucencies and bullae less common than with
centrilobular emphysemab
Bronchiectasis or bronchial wall thickening
a Most common findings.
b Findings most helpful in differential diagnosis.
Although possible variation among different scanners in lung densitometry also needs to be considered, as noted by Kemerink et al. in a comparison of a variety of different scanners, CT numbers for air proved independent of section thickness or reconstruction algorithm, suggesting that densitometric evaluation of moderate and severe emphysema is relatively immune to serious variations among scanners [122].
Morphologic Considerations
Despite widespread acceptance of the definition of emphysema as proposed by the American Thoracic Society, it should be noted that there is little consensus concerning how abnormal enlargement or destruction [78] should be quantified for the purpose of comparison with HRCT [77,131].
The extent and severity of emphysema may be assessed using either macroscopic or microscopic criteria [77,124,125,132,133]. Most CT studies have relied on the macroscopic morphometric panel grading system established by Thurlbeck et al. [77] for correlation [100,107,121,134,135,136]. Use of the panel grading system is based on a visual comparison of the extent of emphysema in a specific case to a series of 16 paper-mounted sagittal whole lung sections (Gough-Wentworth sections), arranged to provide visual standards of increasing disease severity. This approach has been criticized for its reliance on comparisons between different (axial and sagittal) planes, the visual detection of emphysema, and its subjective nature [125,133]. Despite these objections, the panel grading system remains an important validated standard for assessing QCT studies [131].
Gevenois and coworkers, in a series of reports, have recommended the use of computer-assisted evaluation of cross sectional Gough-Wentworth lung sections as a means for obtaining more accurate CT/pathologic correlations and as an alternative to a standard panel grading system [124,132,133,137,138]. Using this approach, macroscopic whole lung sections are divided into 7 × 7 cm fields, which are then digitized, enabling subsequent computer evaluation of the number of pixels in areas of emphysema identified by alterations in assigned gray scale. In turn, this allows direct comparison of the surface area of emphysema measured macroscopically, with macroscopic surface area measurements obtained by QCT analysis. Although the advantage of this approach may seem intuitive, it has been noted that assigning gray-scale levels to emphysematous regions on lung sections remains subjective.
FIG. 7-28. Paraseptal emphysema. HRCT shows small, focal, subpleural lucencies (arrows) typical of paraseptal emphysema. These are commonly marginated by visible walls, usually representing interlobular septa. In some patients, areas of emphysema enlarge to form subpleural bullae.
Alternative approaches have emphasized microscopic evaluation of emphysema. One such microscopic method involves a determination of the destructive index–a measurement of, among other findings, the number of breaks in alveolar walls identified microscopically [136,139]. This measurement has been shown to be increased in smokers in the absence of enlarged airspaces. Other measurements suggested as definitive are measurements of the mean linear intercept, mean interwall distance, and airspace wall per unit volume (AWUV) [77,125,131]. These latter point-counting techniques require placing a test line across a microscopic field and then counting the number of times the line crosses alveolar walls as a means to calculate alveolar surface area. As emphasized by Müller and Thurlbeck, however, these techniques are tedious to perform and are of less value in the presence of macroscopic emphysema [131].
It is apparent that there is little agreement as to which anatomic measurement or measurements of emphysema constitute a gold standard for determining disease extent and severity. Much of this controversy applies to defining minimal degrees of emphysema; the more extensive the disease, the less important are small differences between techniques. Most practical indications for the use of QCT involve assessing patients who have extensive disease [136].
Visual Quantification of Emphysema
The simplest method for estimating the severity of emphysema involves assigning a grade based on visual examination of CT scans [106,107,136,140,141,142]. Typically, this approach


calls for assessing individual HRCT sections, using a 4- or 5-point scale, as either normal or showing less than 25% lung involvement by emphysema, between 25% and 50% lung involvement, between 50% and 75% lung involvement, or greater than 75% involvement, with the total score expressed as percentage of total lung at that level [134]. Alternatively, a grid may be used to overlay the scan as a means of quantifying the extent of emphysema [107,143].
FIG. 7-29. A, B: HRCT sections through the carina and middle lung, respectively, show characteristic pattern of paraseptal emphysema with subpleural cystic changes resulting in a stacked coin appearance. Note that on the left side in B, subpleural cysts extend medially along the fissure. It is easy to see why chest radiographs in such patients have been described as having a “dirty lung” appearance. Cysts larger than 1 cm are best termed bullae.
FIG. 7-30. Paraseptal emphysema with a large subpleural bulla. This patient presented with pneumothorax. The small hole in the bulla wall (arrow) was presumably the site of air leak.
Table 7-5. HRCT findings in paraseptal emphysema
Multiple, subpleural lucencies in a single layer, usually
less than 1 cma,b
Upper lobe predominancea,b
Thin walls are commonly visiblea,b
May be associated with centrilobular emphysema or
Pneumothorax may occur
a Most common findings.
b Findings most helpful in differential diagnosis.
In general, visual inspection has yielded good correlations between CT and pathologic measures of the extent and severity, especially of centrilobular emphysema, in all but the mildest cases [137,143]. Bergin et al., for example, using areas of low-attenuation and vascular disruption as evidence of emphysema on contiguous 10-mm sections, reported good correlation between CT scores for the total lung assessed by three independent observers and pathologic scores of between .63 and .88 (all p <.01) [134].
Using HRCT in a study of postmortem lung specimens, Hruban et al. [100] were able to accurately identify centrilobular emphysema, even of a mild degree. The correlation between the in vitro CT emphysema score and the pathologic grade was excellent (r = 0.91). The ability of HRCT to accurately demonstrate the location and extent of emphysema in lung specimens was also shown by Webb et al. [101].
Although it may be possible to obtain a near one to one correlation between CT and pathologic specimens in vitro, it is not possible to obtain such a good correlation in vivo; minimal emphysema can sometimes be missed by HRCT. Miller et al. [107] found a CT-pathologic correlation of r = 0.81 when using 10-mm collimation scans and a correlation of r = 0.85 when using 1.5-mm collimation scans. In this series, 33 of 38 patients had emphysema; out of these 33, four patients who had mild centrilobular emphysema were interpreted as normal on CT. Although Kuwano et al. [136] found no significant difference between the HRCT and the pathology scores in 42 patients who had mild to moderate emphysema, with correlation between the CT scores and the pathology scores in this study ranging between 0.68 for 1-mm sections and 0.76 for 5-mm sections, respectively, the absence of patients who have minimal emphysema is a major limitation [77]. Furthermore, significant inter- and intraobserver variability was also reported.
Similar findings have been reported in patients who have panlobular emphysema. Spouge et al. [144] assessed the accuracy of CT in diagnosing and quantifying emphysema in ten patients who had pathologically proven panlobular emphysema and five normal controls. They compared the visual assessment and severity of emphysema on CT with pathologic assessment. The correlation between the assessment of extent of panlobular emphysema on CT and the pathologic grade was r = 0.90, p <.01 for conventional CT, and r = 0.96, p <.01 for HRCT. Also, there was significantly less interobserver variation in the grading of emphysema on HRCT than with conventional CT. The observers missed three cases of mild panlobular emphysema on conventional

CT and two on HRCT. They concluded that HRCT allows improved correlation with the pathologic score, and decreased interobserver variation than conventional CT in patients with panlobular emphysema.
FIG. 7-31. Bullous emphysema. In this patient, HRCT shows large, bilateral subpleural bullae, associated with areas of paraseptal emphysema (best seen on the right) and centrilobular emphysema (best seen on the left).
FIG. 7-32. Severe emphysema related to cigarette smoking in a 67-year-old man. Bullae are present bilaterally. Although there is extensive emphysema, the patient improved symptomatically after right bullectomy.
The accuracy of visual assessment of emphysema severity has been challenged [124]. Using a computer-assisted method for obtaining objective quantification of horizontal, paper-mounted lung sections as a gold standard, Bankier et al. compared HRCT densitometric evaluation of mean lung attenuation with subjective visual assessments by three readers in 62 consecutive patients evaluated before lung resection [138]. These authors found that subjective grading of emphysema was significantly less accurate than objective CT densitometric results (r = 0.44 to 0.51; p <.05 vs. r = 0.56 to 0.62; p <.001, respectively) when correlated to pathologic scores. Importantly, analysis of visual scoring data suggested systematic overestimation of emphysema by all three readers [138].
Computer-Assisted Quantification of Emphysema
Given the inherent limitations of subjective visual scoring, it is not surprising that early in the use of CT for emphysema assessment, attention was focused on the potential for direct analysis of digital data obtained from the CT scan [135,143,145,146,147]. In general, three different approaches have been used. These include: (i) use of a threshold value below which emphysema is considered to be present [density mask or pixel index (PI)] [135,147], (ii) assessment of the range of lung densities represented in a lung slice (histogram analysis) [146,148], and (iii) determining overall lung density, often in combination with volumetric imaging [111,130,149,150].
Hayhurst et al. first demonstrated the usefulness of a threshold attenuation value for the diagnosis of emphysema on CT scans by showing that patients who had pathologically proved emphysema contained more pixels between -900 HU and -1,000 HU than patients who did not have emphysema (p <.001) [145]. In a classic article, Müller et al. [135] made use of a standard software program called density mask that highlights voxels within any preselected range (Figs. 7-33 and 7-37). Using this technique with 10-mm-thick sections and highlighting all voxels less than -910 HU, these authors found good correlation (r = 0.89) between the extent and severity of emphysema, as measured preoperatively on a single section and a modified panel-grading system in 21 patients who had pathologic evidence of emphysema after lung resection. Three cases with emphysema scores less than ten were missed, however, and a diagnosis of emphysema was made in one normal patient. In comparison, the correlation between the mean of visual scores of two independent observers and the pathologic score was .90 (p <.001), leading these investigators and others to conclude that visual scoring was nearly as precise and clinically more practical than quantitative assessment [121,135].
The relationship between appropriate threshold values for diagnosing emphysema and slice thickness must be kept in mind. In the study described in the previous paragraph, using 10-mm collimation, Müller et al. compared the percentage of lung area with an attenuation level lower than three thresholds, -900, -910, and -920 HU, with pathologic grades of emphysema. They found that the highest correlation between CT and pathology made use of a threshold of -910 HU [135]. Similar good results using -910 HU have been reported by others. Gevenois et al. have shown that using 1-mm sections without intravenous contrast administration, the optimal threshold for HRCT images when compared to morphometric data is -950 HU, regardless of whether macroscopic or microscopic measures of emphysema were used for validation


(Fig. 7-33) [71,124,125]. It should be kept in mind, however, that despite the fact that a threshold of -950 HU is generally accepted as appropriate for the diagnosis of emphysema, variation in lung density may be present in normal subjects. In a study by Gevenois et al. [151] of 42 healthy subjects ranging from 23 to 71 years in age, the authors found that lung density is influenced by TLC and, to a lesser degree, by age. In the healthy subjects, there was no significant difference between genders and no significant correlation between age and the mean lung density (MLD), but a significant correlation was found between age and the relative area of the lung with attenuation values lower than -950 HU. In addition, a significant correlation was found between the TLC expressed as absolute values and both the RA950 and the MLD. Similarly, as reported by Adams et al. [127] in an evaluation of factors affecting lung density in patients who did not have morphologic evidence of emphysema, the mean CT lung density varied from -770 HU to -875 HU, and the cross-sectional area of pixels ranging between -900 and -1,000 HU varied from 9.6% to 58%.
FIG. 7-33. Quantitative CT. A: A 1-mm section through the upper lobes shows evidence of confluent centrilobular emphysema. The right lung has been manually segmented. B: Density mask visually highlights all pixels measuring less than -950 HU. Mean lung density for the right lung measures -970 HU (SD, 13.5). C: A 7-mm section obtained in the same patient at approximately the same level as in A and B. The density mask highlights all pixels in the right lung less than -910 HU. Mean lung density measures -941 HU (SD, 21.3). Note that results differ dramatically depending on the choice of section thickness and threshold. In general, high-resolution images assessed with lower thresholds (i.e., -950 HU) have proved more accurate in assessing the extent and severity of emphysema on individual sections. This may prove important as multidetector-row scanners become more widely available, allowing whole lung volumes to be scanned with high-resolution techniques. Continued D: Three-dimensional rendering in this patient, obtained during a single breath hold using contiguous 7-mm sections (pitch = 2). E: Volumetrically rendered coronal section in the same patient shows marked heterogeneity of lung density with extensive emphysema largely restricted to the upper lobes. This patient subsequently underwent successful lung volume reduction surgery.
Alternatively, computerized analysis of HRCT data may be used to produce a histogram of the frequency distribution of pixel density values in a given lung region (Fig. 7-34). All areas that have densities lower than the lowest fifth of the histogram or fall within a preselected range of densities may be defined as emphysematous [152]. Using this approach, it has been reported that the lowest fifth percentile of the histogram in patients who have emphysema correlates well with the surface area of walls of distal airspace wall per unit volume (AWUV) [146]. Using a similar approach in 28 patients who had emphysema, Gould et al. found significant correlations between the lowest fifth percentile of Hounsfield number values and both the mean value of the surface area of the walls of distal AWUV (r = -0.77) and the extent of emphysema (r = 0.5) [146].
FIG. 7-34. Quantitative CT–three-dimensional evaluation. A: Whole-lung histogram with select axial images through the upper, middle, and lower lung fields shown to the left, respectively, obtained from a spiral CT study using 7-mm collimation and a pitch of 1.5. In this case, three separate lung volumes were independently analyzed. All pixels less than -910 HU are highlighted. The numbers to the right indicate the percentage of each of the three lung volumes with pixel densities below -910 HU. In this case, there is marked heterogeneity with more extensive disease in the upper lobes clearly identified. This patient subsequently had lung volume reduction surgery. B: Corresponding histogram of the entire right lung. The mean lung density measures -956 HU (SD, 17.4). Using -910 HU as a threshold, 22.6 percent of this lung is emphysematous. Note that whole-lung density measurements are less informative than quantitative evaluation of separate lung volumes for selecting optimal candidates for lung reduction surgery (compare with A). (Courtesy of Warren Gefter, M.D., Hospital of the University of Pennsylvania.)

An additional approach has been used, in which the MLD of either a given section or entire lung volumes may be computed as a means of defining the presence and extent of emphysema [110,111]. Good correlation has been reported between these methods and a variety of pathologic grading systems as well as measures of pulmonary function, especially DLco. It should be emphasized that the development of sophisticated computer programs, coupled with spiral CT scanners, now allows practical quantitative three-dimensional (3D) CT assessment of either select regions or entire lung volumes in a single breath-hold period [130,149,150] (Figs. 7-33 and 7-34). Using 5- and 7-mm collimation with a pitch of 1.5, Park et al. [153] found good correlation between 3D assessment of both mean lung attenuation values and frequency distribution histograms of whole lungs compared with routine two-dimensional analysis (r = 0.98 to 0.99) and visual scoring (r = 0.74 to 0.82), respectively. Correlation was also noted to be reasonable between 3D densitometric quantification and a range of physiologic parameters, including the DLco (r = -0.57 to -0.64), the TLC (r = 0.62 to 0.71), and the ratio of FEV1 to FVC (r = -0.75 to -0.82). It should be noted that the introduction of multidetector-row CT scanners now makes it feasible to reconstruct contiguous thin 1- to 2-mm sections through the entire lung volume. However, whether this will result in more accurate quantification of disease remains to be determined.
Although routine axial images typically suffice for evaluating emphysema, minimum intensity projection (MinIP) images may also be of value, especially in cases with subtle disease (Figs. 7-35 and 7-36) [154,155]. Comparing MinIP images with high-resolution 1-mm sections, Remy-Jardin found that in 13 patients who had subtle emphysema, MinIP was more sensitive than HRCT (81% vs. 62%, respectively) [155]. Furthermore, in four of 16 cases interpreted as normal on routine 1-mm images, subtle foci of emphysema could be identified on the corresponding minimum-intensity


projection images. In this study, minimum projection images obtained from 8-mm slabs (i.e., eight contiguous 1-mm sections) proved optimal for suppressing vascular structures. It should be noted that similar findings have been reported using MinIP images to identify subtle areas of decreased attenuation in patients who have small airways disease [156]. Comparing high-resolution images obtained in both inspiration and expiration with MinIP images through the lower lobes in 47 consecutive patients who had chronic sputum production, Fotheringham et al. showed that although expiratory images identified a greater extent of disease, interobserver variability was lowest for MinIP images. Although at present there is no indication for the routine use of MinIP images for diagnosing either emphysema or small airways disease, the likelihood of using these images may be enhanced as multidetector-row scanners capable of routinely generating contiguous 1-mm sections gain widespread use.
FIG. 7-35. Maximum- (MIP) and minimum- (MinIP) intensity projection imaging in emphysema in the same patient as shown in Figure 7-33. A: 1-mm section through the upper lobes shows diffuse centrilobular emphysema. B, C: MinIP and MIP images, respectively, derived from five contiguous 1-mm sections centered around the image shown in A. By suppressing vascular structures, MinIP images allow more precise definition of areas of low attenuation. In distinction, on MIP images (C), visualization of the pulmonary vasculature is enhanced, allowing more precise anatomic localization of disease. In this case, note the presence of vessels crossing zones of low density characteristic of emphysema as distinct from other causes of focal low lung density (C).
FIG. 7-36. Minimum- (MinIP) (A) and maximum- (MIP) (B) intensity projection images in a patient who has centrilobular emphysema. This is the same patient as shown in Figure 7-17. A: MinIP image formed from six adjacent 1-mm-thick HRCT scans shows focal lucencies typical of centrilobular emphysema. A small adenocarcinoma is visible in the right upper lobe. B: The emphysema is much less conspicuous on the MIP image, although the carcinoma and its relation to vascular structures are better seen.
To this point, densitometric evaluation primarily has focused on the use of mean lung attenuation, regional percent of emphysematous lung (so-called emphysema index), and histogram analysis of the distribution of CT numbers to detect and quantify the extent of emphysema. In fact, due to partial volume averaging, even using HRCT techniques, these simple density-based methods are relatively insensitive. As suggested by Uppaluri et al., these methods could be improved by additionally assessing the underlying pattern of disease [152]. Using an experimental automated so-called texture-based adaptive multiple feature methodology, these authors were able to merge adjacent pixels to form regions in which the difference between the gray levels of adjacent pixels was small.

This enabled a number of otherwise unfamiliar features to be analyzed, including first-order features such as variance, skewness, kurtosis, and gray level entropy, and second-order features such as gray level nonuniformity, entropy, inertia, and contrast, among others. Although this type of analysis is clearly in its infancy, it may be anticipated that with the aid of more and more sophisticated computed programs, at least some of these features may ultimately prove of clinical value.
Expiratory Imaging in Emphysema
The effect of differing phases of respiration on CT densitometry in patients who have emphysema has been evaluated by a number of investigators. In some studies, this is based on measurement of the pixel indent (PI). The PI is defined as the percentage of pixels in both lungs on a single scan that shows an attenuation lower than a predetermined threshold value (usually -900 HU) (see Fig. 3-155) [147,157]. Although the inspiratory PI has wide normal range, the expiratory PI is relatively constant. The normal PI at full inspiration ranges from 0.6 to as much as 58 when the threshold is -900 HU [127], although the mean value for PI ranges from 10 to 25, depending on the level scanned and on the CT scan collimation [157]. At full expiration with a threshold value of -900 HU, the normal range of PI is rather small, with a mean of less than 1.04 (SD, 1.30) [157]. Thus, in normals, the area of lung having an attenuation of less than -900 HU at full expiration in normals can generally be regarded as less than a few percent.
The expiratory PI can be used to quantitatively assess the area of low-attenuation lung in patients who have emphysema (see Fig. 3-155). In one study [147], 64 patients underwent both inspiratory and expiratory CT correlated with pulmonary physiology. There were 28 patients who had an inspiratory PI (measured as less than -900 HU) of more than 40, and 14 of these patients had an expiratory PI of more than 15. This group showed markedly abnormal PFT values suggestive of emphysema, whereas other patients showed normal lung function. Also, an expiratory PI over 15 accurately reflected and quantitated the degree of emphysema estimated by various PFTs.
Some researchers have attempted to standardize expiratory lung density measurements by use of spirometrically gated CT [123,147,158,159,160]. Lamers et al. [159] showed that images obtained 5 cm above and below the carina at both 90% and 10% of VC allowed accurate differentiation between patients who had emphysema on the one hand, and patients who had chronic bronchitis and controls on the other. Similarly, Beinert et al. [160] compared mean lung densities measured at three levels (at the carina and 5 cm above and below) at 20%, 50%, and 80% of VC in 11 patients who had emphysema and in 24 healthy controls. Although significant differences could be identified between emphysematous patients and controls at all levels, based on a twofold variation in the anteroposterior density gradient at 20% VC and for reasons of intra- and intersubjective comparability, these authors concluded that emphysema is best evaluated at an intermediate lung volume.
Although spirometric gating has not achieved widespread clinical use, the role of expiratory CT scans as a means for evaluating diffuse and focal air-trapping is widespread [149,161,162]. Although the use of expiratory scans to evaluate emphysema has been suggested [147], this has been discredited by Gevenois et al. [71]. In this latter study, 59 patients who had subsequently confirmed emphysema were scanned preoperatively with 1-mm-thick sections during both inspiration and expiration and subsequently evaluated with a variety of threshold values. Relative areas of low attenuation were then correlated to both macroscopic and microscopic indices of emphysema extent and severity to determine optimal expiratory CT thresholds. These proved to be -820 HU and -910 HU using microscopic and macroscopic standards of emphysema, respectively. Significantly, inspiratory scans using a previously validated threshold of -950 HU [124,125] proved superior to expiratory scans for quantifying emphysema, regardless of the method of pathologic correlation. Furthermore, although the relative area of decreased lung attenuation measured on inspiration scans most closely correlated with DLco (r = -0.49; p <.01) (also measured in inspiration), the relative area of decreased lung attenuation on expiration most closely correlated with FEV1/FVC (r = -0.63; p <.001) and residual volume (r = 0.46, p <.001). Based on these data, it can be concluded that the extent and severity of emphysema are best measured on scans obtained in inspiration, whereas expiratory scans are more accurate means of assessing airways obstruction with resulting air-trapping [71].
Utility of Computed Tomography
Standard chest radiography and PFTs are insensitive for the diagnosis of early emphysema [84,96]. CT is undoubtedly more sensitive than chest radiographs in diagnosing emphysema and in determining its type and extent. HRCT is also advantageous relative to conventional CT [77,100,106,107,134,140,145,163,164]. However, before the development of surgical treatments for emphysema, HRCT was rarely indicated as a method for diagnosing emphysema. In fact, the combination of (i) a smoking history, (ii) a low DLco, (iii) airways obstruction on PFTs, and (iv) an abnormal chest radiograph showing large lung volumes is usually sufficient to make the diagnosis.
On the other hand, some patients who have early emphysema can present with clinical findings more typical of interstitial lung disease or pulmonary vascular disease–namely, shortness of breath and low DLco–without evidence of airways obstruction on PFTs [136,165]. In such patients, HRCT can be valuable in detecting the presence of emphysema and excluding an interstitial abnormality as a cause of respiratory dysfunction (Fig. 7-37). If significant emphysema is found on HRCT, no further evaluation is necessary; specifically, lung biopsy is not needed. For example, in a study of 470 HRCT examinations by Klein et al. [165], there were 47 cases in which emphysema was the dominant or sole


parenchymal abnormality. Of these 47 cases, 16 cases lacked chest radiographic findings of emphysema, and 10 of these 16 cases had decreased single breath diffusing capacity (DLco <80% predicted) without evidence of airways obstruction (FEV1/FVC and FEV1 >80% predicted). In these patients, the severity of emphysema scored on the HRCT correlated closely (r = 0.8) with decreasing DLCO.
FIG. 7-37. HRCT diagnosis of emphysema in a patient who has a normal chest radiograph, reduced diffusing capacity (50% of predicted), normal expiratory flow, and clinical suspicion of either interstitial lung disease or pulmonary vascular disease. A: Chest radiograph appears normal. B: HRCT through the upper lobes shows patchy lucency typical of centrilobular emphysema, explaining the patient’s disability. C: Density mask image highlights the extent of emphysema.
Furthermore, HRCT has a high specificity for diagnosing emphysema; emphysema is rarely overcalled in normal individuals or in patients who have severe hyperinflation due to other causes [166]. Also, emphysema is accurately distinguished from other causes of cystic lung disease [45]. In one study of patients who had cystic lung diseases, including emphysema [45], HRCT allowed two radiologists to be confident of the diagnosis of emphysema in 95% of cases. When confident, the observers were correct in 100% of the cases, and agreement between the observers was perfect for a confident diagnosis of emphysema κ = 1).
It should also be noted that HRCT may be of value in differentiating between patients who have emphysema and those who have other obstructive airways diseases, such as asthma [151,157,166,167]. Although areas of low density may be identified in the lungs of asthmatic patients, these largely are a reflection of air-trapping and not anatomic emphysema. Newman et al. evaluated 18 asthmatics and 22 normal controls using a threshold of -900 HU, in both full inspiration and expiration using 1.5- and 10-mm sections, and found significantly more extensive low-attenuation areas in asthmatics as compared to controls, especially on high-resolution images obtained just above the diaphragm; however, the absence of low-attenuation lung on inspiratory scans excluded emphysema [157]. Gevenois et al. measured the extent of low-attenuation areas in ten mild asymptomatic asthmatics, seven severe asthmatics with documented airflow obstruction and hyperinflation, and 42 normal controls, using a density mask of -950 HU; no significant differences in the proportion of low-density regions was found between any of these groups [151].
Generally speaking, although PFT findings of airways obstruction are common in patients who have emphysema, the degree of airways obstruction correlates poorly with the anatomic extent of emphysema, with r values ranging from 0.40 to 0.70. Furthermore, emphysema can involve 30% of the lung parenchyma without airflow obstruction’s being present [91,92,93,168]. At least partially, the lack of a close correlation between emphysema extent and airways obstruction reflects the fact that emphysema is often associated with chronic bronchitis, which may also contribute to lung function abnormalities in patients who have COPD and is more likely responsible for airways obstruction [131]. In one study of patients who had COPD and fixed expiratory airflow limitation, there was poor correlation between the extent of emphysema and FEV1 (r = -0.20) or FEV1/FVC (r = -0.36) [169], leading the authors to suggest that airflow obstruction in these patients is likely due to associated airways disease.
Similarly, in a study by Gevenois et al. [71] using inspiratory and expiratory HRCT, inspiratory scans were found to be most accurate in showing the extent of pathologic emphysema, whereas expiratory scans correlated best with PFT measures of airways obstruction, a fact which may be related to the presence of associated airways disease. The correlations between the extent of low-attenuation lung (< -950 HU) measured on inspiratory scans and FEV1 and FEV1/FVC were -0.50 and -0.63, respectively (both p <.001), whereas on expiratory scans correlation between the extent of low-attenuation lung (< -910 HU) increased to 0.68 and 0.72 (both p <.001), respectively. Abnormalities of diffusing capacity are also common in emphysema. In the study by Gevenois et al. [71], correlations between various measures of Dlco and low-attenuation lung measured on either inspiratory or expiratory scans ranged from -0.41 to -0.50 (p <.01 to p <.001).
Preoperative Assessment of Emphysema
HRCT can be valuable in the preoperative assessment of patients before surgical treatment of emphysema using bullectomy, lung transplantation, or volume reduction surgery [170,171]. HRCT has become routine in the evaluation of such patients before and after operation.
Bullectomy refers to the surgical removal or decompression of large bullae, which have the effect of compressing relatively normal adjacent lung [172,173]. Most series show little postsurgical improvement when the bullae occupy less than one-third of a hemithorax [174]. However, bullectomy in appropriate patients may result in a decrease in lung volume, improved spirometry, and improved gas exchange [174].
CT has been reported to be of value in the preoperative assessment of patients who have bullous emphysema [175,176,177]. The majority of patients referred for bullectomy have well-demarcated bullae and varying degrees of emphysema [117]. CT allows for an assessment not only of the extent of bullous disease but also the degree of compression and the severity of emphysema in the remaining lung parenchyma (Figs. 7-31 and 7-32) [117,174,176,177,178]. In one study [175], CT showed well-defined bullae that were potentially resectable in 23 of 43 patients; 20 patients had bullae in association with generalized emphysema that were not amenable to surgical excision. Surgery is generally impossible if bullae are associated with extensive emphysema. Bullectomy is most effective when localized giant bullae are associated with localized paraseptal emphysema [117].
Lung Transplantation
Lung transplantation has become an important treatment for patients with severe emphysema. In 1998, 1,170 heart-lung (n = 103), single lung (n = 582), or double lung (n = 485) transplantations were registered with the International Heart-Lung Transplantation Registry (http://www.ishlt.org).

Approximately 6.7% of heart-lung transplants, 55.8% of single lung transplants, and 30.1% of double lung transplants were for emphysema.
Various criteria have been developed to enable selection of the most appropriate candidates for lung transplantation [170,171]. CT scans are routinely obtained to search for malignancy [179]. Furthermore, in patients who have a single lung transplantation, the side chosen for lung transplantation depends on the severity of the underlying disease in each lung, which may vary, and the presence of pleural disease, which may result from prior infection, thoracotomy, or other diseases [180]. Ideally, the more abnormal lung is removed, although the presence of markedly abnormal pleura would direct the surgeon to the opposite lung. In one study [179], the chest radiographs and CT scans of 190 transplant candidates were reviewed. CT prompted a change in the determination of which lung was more severely diseased in 27 of 169 (16%) patients. Of the 45 patients who subsequently underwent transplantation, CT prompted a change in the determination of which side to transplant from that made on the basis of plain radiography for four patients (9%). Solitary nodules detected in three patients proved to be bronchogenic carcinomas; two of these lesions were identified only on CT scans.
Lung Volume Reduction Surgery
First introduced by Brantigan in 1957, and reintroduced by Cooper, lung volume reduction surgery (LVRS) promises to transform our approach to the management of patients who have severe emphysema [181,182]. Currently, it is estimated that 2 million people have emphysema in the United States, accounting for more than 90,000 deaths annually, along with other forms of COPD [183]. Overall, it is the fourth-leading cause of death, with a mortality rate of approximately 50% [184].
Only cigarette smoking cessation has been shown to slow the progression of disease, whereas only oxygen therapy has been documented to decrease mortality in hypoxic patients [183]. Before LVRS, the only surgical options for the treatment of emphysema were bullectomy or lung transplantation. Although the precise mechanisms by which LVRS palliates the breathlessness of severe pulmonary emphysema are uncertain, it is likely that removal of nonfunctional lung tissue (downsizing) leads to decreased thoracic distension, allowing the chest wall and diaphragm to assume a more normal configuration. This results in a combination of increased elastic recoil, decreased air-trapping, improved expiratory airflow, and decreased ventilation-perfusion mismatching [148].
Although selection criteria for LVRS have been proposed, these are largely subjective and include patients who have an appropriate clinical presentation, radiographic evidence of bilateral emphysema, and poor pulmonary function despite optimal medical therapy (Table 7-6) [183]. Although PFTs are routinely obtained, usual criteria, including an FEV1 of less than 30% predicted, residual volume greater than or equal to 180% of predicted, or TLC greater than or equal to 11% of predicted, have proved to be insensitive and unreliable predictors of response to surgery.
Table 7-6. Lung volume reduction surgery: patient inclusion and exclusion criteria
Inclusion criteria:
  Radiographic evidence of bilateral emphysema
  Studies demonstrating severe air-flow obstruction
   (FEV1 = 10-40% of predicted; residual volume >180%
   of predicted; total lung capacity >110% of predicted)
   Attainment of preoperative performance goals; smoking
Exclusion criteria:
  Age >80 yr
  Previous thoracic surgery (sternotomy; lung resection)
  Ischemic heart disease (arrhythmias; history of
   congestive failure or myocardial infarction within past
   6 mo); uncontrolled hypertension
  History of recurrent infections: bronchiectasis
  Diffuse interstitial lung disease
  Abnormal pulmonary function: Paco2 >50 mm Hg;
   carbon monoxide diffusing capacity <20% of predicted;
   ventilator dependence; need for supplemental oxygen
Giant bullae
  Pulmonary hypertension (peak systolic pressure >45
   mm Hg)
  Solitary pulmonary nodule (relative contraindication)
  Chest wall deformities/pleural adhesions
  Evidence of systemic disease/neoplasia felt to
   compromise survival during 5-year follow-up period
CT evidence for diffuse emphysema judged unsuitable for
   lung volume reduction surgery
Modified from Rationale and design of the National Emphysema Treatment Trial (NETT): a prospective randomized trial of lung reduction surgery. J Thorac Cardiovasc Surg 1999;118:518-528; Cleverley JR, Hansell DM. Imaging of patients with severe emphysema considered for lung reduction surgery. Br J Radiol 1999;72:227-235; and Kazerooni EA, Whyte RI, Flint A, et al. Imaging of emphysema and lung volume reduction surgery. Radiographics 1997;17:1023-1036.
As a consequence, considerable attention has focused on the potential use of CT to improve selection criteria [148,170,185,186,187,188,189,190,191,192,193]. Evaluating the relative merits of various studies is difficult due to the wide range of CT techniques and interpretive criteria used by different investigators (Table 7-7). In general, two broad approaches to the use of CT have been used. The first is based on visual inspection [187,188,189,191]. Typically, this combines estimates of disease severity as mild (<25% of the lung), moderate (25% to 50% of the lung), marked (50% to 75% of the lung), or severe (75% to 100% of the lung) with estimates of heterogeneity [188,194]. Alternatively, emphysema may be evaluated using QCT analysis, using a variety of measurements including MLD and the percent of lung involvement (so-called emphysema index), among others [148,185,186,190,192].
Table 7-7. CT methods for lung volume reduction surgery assessment
Study Collimation Phase of respiration Technique: image analysis parameters
Bae (n = 10)a Contiguous 10-mm scans; incremental Inspiratory/expiratory scans Quantitative CT: histogram evaluation (-900 HU); emphysema index
Holbert (n = 28)b 5 mm scans at 8 mm intervals; 10 mm scans at 10 mm intervals; incremental Inspiratory scans Quantitative CT: density mask (-910 HU); histogram display (mean CT number); three-dimensional modeling
Becker (n = 28)c Contiguous 10-mm scans; spiral Inspiratory scans Quantitative CT: individual lung total capacity, residual volume, emphysema index, ratio of airspace to tissue volume
Gierada (n = 70)d Contiguous 8- and 10-mm scans; spiral Inspiratory scans Quantitative CT: indices of global emphysema (-900 HU; -960 HU), regional emphysema severity, heterogeneity, and volume of lung tissue (-850 to -701 HU)
Gierada (n = 46)e Contiguous 8- and 10-mm scans; incremental Inspiratory scans See above
Hunsacker (n = 20)f Six select 1-mm HRCT scans Inspiratory scans Visual scoring: severity and extent (4-point scale); total emphysema score
Hamacher (n = 37)g 1-mm scans every 15 mm, contiguous 8-mm scans; spiral Inspiratory scans Visual scoring: degree of heterogeneity; upper versus lower lobe distribution
Slone (n = 50)h Contiguous 8- and 10-mm scans; spiral Inspiratory scans Visual scoring: emphysema severity, degree of heterogeneity (5-point scale); degree of hyperinflation/lung compression
a Bae KT, Slone RM, Gierada DS, et al. Patients with emphysema: quantitative CT analysis before and after lung volume reduction surgery. Work in progress. Radiology 1997;203:705-714.
b Holbert JM, Brown ML, Sciurba FC, et al. Changes in lung volume and volume of emphysema after unilateral lung reduction surgery: analysis with CT lung densitometry. Radiology 1996;201:793-797.
c Becker MD, Berkmen YM, Austin JH, et al. Lung volumes before and after lung volume reduction surgery: quantitative CT analysis. Am J Respir Crit Care Med 1998;157:1593-1599.
d Gierada DS, Tusen RD, Villanueva IA, et al. Patient selection for lung volume reduction surgery: an objective model based on prior clinical decisions and quantitative CT analysis. Chest 2000;117:991-998.
e Gierada DS, Slone RM, Bae KT, et al. Pulmonary emphysema: comparison of preoperative quantitative CT and physiologic index values with clinical outcome after lung volume reduction surgery. Radiology 1997;205:235-242.
f Hunsaker A, Ingenito E, Topal U, et al. Preoperative screening for lung volume reduction surgery: usefulness of combining thin-section CT with physiologic assessment. AJR Am J Roentgenol 1998;170:309-314.
g Hamacher J, Bloch KE, Stammberger U, et al. Two years’ outcome of lung volume reduction surgery in different morphologic emphysema types. Ann Thorac Surg 1999;68:1792-1798.
h Slone RM, Pilgram TK, Gierada DS, et al. Lung volume reduction surgery: comparison of preoperative radiologic features and clinical outcome [see comments]. Radiology 1997;204:685-693.

Hamacher et al., using a simplified morphologic classification, divided patients into three groups based on the pattern of distribution of disease as either homogeneous, moderately heterogeneous, or markedly heterogeneous [191]. By definition, heterogeneous disease implies marked regional variation in the severity of disease; patients who have centrilobular emphysema characteristically have more extensive involvement in the upper lobes, compared with patients who have alpha-1-antitrypsin deficiency and more extensive disease in the lung bases. Using this approach, these authors showed that functional improvement after LVRS was most pronounced in patients who had markedly heterogeneous disease, with an increase from preoperative FEV1 of 31% predicted to 52% postoperatively [191]. In distinction, patients who had either moderately heterogeneous or homogeneous distribution showed significantly less improvement in their postoperative FEV1 (from 29% to 44% and 26% to 38%, respectively). Interestingly, at 24 months, whereas improvement continued to be greatest in the group with markedly heterogeneous disease, significant improvement could still be identified in all three groups, suggesting that the ability of visual grading to accurately preoperatively predict individuals unlikely to improve is limited.
In this regard, Hunsacker et al. evaluated 20 preoperative patients using a four-point scale to visually assess the extent and severity of emphysema using six noncontiguous 1-mm sections (total score, 0 to 144) [189]. Using a postoperative change in FEV1 of greater than or less than 150 mL to differentiate between responders and nonresponders, respectively, these authors showed that no patient who had mild emphysema (CT score <50) responded. However, in eight of the remaining 16 patients who had moderate to severe disease (CT scores >50) and in whom inspiratory resistance was measured, seven in whom inspiratory resistance measurement exceeded 8.5 cm H2O per L per second failed to respond to surgery, suggesting to these investigators that optimal preoperative screening

requires both radiologic and physiologic assessment [189]. It should be noted that the necessity to use esophageal balloon catheters to obtain these measurements has limited widespread acceptance of this approach.
Despite good results reported for visual grading, ideally, optimal preoperative evaluation should use more objective measurements of disease extent and severity. Currently, although not widely available, the use of QCT has been advocated as a more precise method for assessing morphologic alterations in the lung [148,185,186,190,192]. Bae et al., in an attempt to better define mechanisms of palliation after LVRS, assessed the accuracy of QCT by evaluating both inspiratory and expiratory images in ten patients before and after surgery using semiautomated segmentation methods [148]. Evaluating the frequency distribution of lung density histograms and measuring lung volumes, these authors found good correlation between CT emphysema indices and routine measurements of pulmonary function. In particular, postoperative changes in lung morphology were shown to correlate with improvement in exercise tolerance and pulmonary function.
Holbert et al., using density mask software to calculate the volume of the lungs and the volume of emphysema, also emphasized the ability of QCT to evaluate lung morphology [185]. In this study of 28 patients evaluated before and after LVRS, these authors showed that although the lung volume reduced surgically decreased by 22%, the remaining lung volume increased by only 4%, confirming that unilateral lung reduction does not cause statistically significant worsening of the remaining emphysematous lung. Similar results have been reported by Becker et al. [190].
In the most extensive study to date, Gierada et al. compared CT findings in 70 patients selected for bilateral LVRS with 32 patients denied LVRS based on subjective interpretation of the extent and severity of emphysema on chest radiographs, CT scans, and perfusion scintigraphy [192]. Using the percent of severe emphysema (defined as lung density less than or equal to -960 HU), the ratio of upper lung to lower lung emphysema (threshold = -900 HU), and the residual volume to model selection decisions, these authors reported an overall correct prediction rate of 87%, including 91% of selected patients and 78% of excluded patients. Furthermore, patients who had higher selection probabilities based on QCT indices showed better postoperative improvements in physiologic measurements and exercise tolerance [192]. Based on these data, these authors concluded that QCT may play an important role in presurgical selection by improving the consistency by which selection criteria are applied.
In addition to improving selection of patients for LVRS, it should be emphasized that CT also plays an invaluable role in excluding potential candidates by identifying otherwise unsuspected pathology. Such patients include those who have bronchiectasis; unexpected coexisting interstitial lung disease, in particular IPF (Fig. 7-38); diseases that may radiographically mimic emphysema, such as bronchiolitis obliterans or end-stage LCH; dilated pulmonary arteries due to pulmonary hypertension; and subtle chest wall abnormalities (Table 7-6) [193]. It should be emphasized that the presence of emphysema may lead to a mistaken diagnosis of underlying interstitial disease, especially when complicated by acute airspace consolidation (Fig. 7-39). Awareness that acute pathologic processes may appear unusual in the presence of underlying emphysema usually obviates the problem clinically.
Most important is the identification of occult lung neoplasms (Figs. 7-17 and 7-36). It has now been shown that up to 7% of patients will have otherwise unsuspected neoplasms [179,195]. In one study of 148 patients selected for LVRS, 11% proved to have suspicious nodules; of these, nine lesions in eight patients proved to be malignant [196]. Most important, eight of these nine lesions proved to be Stage I cancers. Conversely, it should also be noted that in a significant percentage of cases evaluated for LVRS, lung cancers not identified on preoperative CT studies are often


identified at surgery. As documented by Hazelrigg et al. in a study of 281 patients having LVRS, 17 of 78 (22%) nodules proved malignant: of these, 14 were not identified prospectively by CT [197].
FIG. 7-38. A: HRCT section through the upper lobes in a patient being evaluated for lung volume reduction surgery (LVRS) shows extensive emphysema. B: HRCT section through the lung bases in the same patient shows findings characteristic of diffuse lung fibrosis. CT is especially valuable in assessing potential candidates for LVRS by disclosing otherwise unexpected diffuse infiltrative lung diseases.
FIG. 7-39. A: HRCT section through the midlungs shows apparent honeycombing in the left lung. Extensive centrilobular emphysema is present on the right side. B: Section at the same level several weeks later, after a course of antibiotics, shows that apparent honeycombing in A actually represents acute airspace consolidation superimposed on severe underlying emphysema, in this case due to bacterial pneumonia.
Despite these data, the role of CT as a means for preoperative evaluation of potential candidates for LVRS has yet to be determined. It should be noted that in several studies, chest radiographs have proven as accurate as CT in predicting response to LVRS [187,198]. Maki et al. assessed preoperative radiographs in 57 patients and showed that marked heterogeneity and unequivocal lung compression were 100% predictive of a favorable outcome (measured as a 30% improvement in either FEV1, or the 6-minute walk test), whereas a lack of heterogeneity and lack of lung parenchymal compression were 94% and 92% predictive of an unfavorable outcome, respectively [198]. Based on these data, these authors concluded that chest radiographs alone may be sufficient to preoperatively evaluate potential LVRS candidates. Radiographic evidence of hyperinflation failed to prove a significant predictor of outcome [198]. Similarly, poor predictive values have also been noted for measurements of diaphragmatic excursion comparing inspiratory with expiratory radiographs [199]. It should be noted that, although similar evaluations have been performed using fast gradient-echo, breath-hold magnetic resonance imaging through the thorax in both full inspiration and expiration, this technique has not proved generally useful [200].
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