Eur Radiol (2002) 12:1512–1522 DOI 10.1007/s003300101112

Nobuyuki Tanaka Tsuneo Matsumoto Gouji Miura Takuya Emoto Naofumi Matsunaga

Received: 15 February 2001 Revised: 18 July 2001 Accepted: 30 July 2001 Published online: 2 February 2002 © Springer-Verlag 2002

N. Tanaka (✉) · T. Matsumoto · G. Miura T. Emoto · N. Matsunaga Department of Radiology, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan e-mail: [email protected] Tel.: +1-303-3726129 Fax: +1-303-3726234 Present address: N. Tanaka, University of Colorado HSC, 4200 East Ninth Avenue, Denver, CO 80262, USA

CHEST

HRCT findings of chest complications in patients with leukemia

Abstract High-resolution CT (HRCT) findings of several chest complications occurring in leukemic patients were reviewed. Although most entities show non-specific HRCT findings including groundglass opacity and air-space consolidation, characteristic findings are observed in several pulmonary complications including Pneumocystis carinii pneumonia, fungal infections, miliary tuberculosis, leukemic infiltration, pulmonary edema, bronchiolitis obliterans, and bronchiolitis obliterans organizing pneumonia. A combination of these characteristic HRCT findings and the information obtained from the clinical setting

Introduction Several different pulmonary complications are common in patients with leukemia. Tenholder and Hooper found that 98% of leukemic patient autopsies showed pulmonary complications [1]. Since leukemic patients are often in a serious condition, pulmonary complications are a leading cause of death. In this article, in order to institute appropriate therapy, we illustrate typical high-resolution CT (HRCT) findings of chest complications, some of which are correlated with pathologic findings. Since the frequency of occurrence of pulmonary complications is different between patients who undergo bone marrow transplantation (BMT) and those who do not, these pulmonary complications were divided into two categories: complications not specific for patients who underwent BMT (BMT non-specific complications) and complications specific for patients who underwent BMT (BMT-specific complications). In our institution,

may help in achieving a correct diagnosis of chest complications occurring in leukemic patients. Keywords Leukemia · Complications · Chest · High-resolution CT

from January 1989 to February 2001, there were 80 consecutive leukemic patients with chest complications that were definitively diagnosed by several diagnostic tools including biopsy, sputum culture, or several serologic tests (Table 1). As BMT non-specific complications, bacterial pneumonia, Pneumocystis carinii pneumonia, fungal infection, tuberculosis, drug toxicity, leukemic infiltration, and pulmonary hemorrhage were chosen, while as the BMT-specific complications, cytomegalovirus pneumonia, pulmonary edema, idiopathic pneumonia syndrome, bronchiolitis obliterans, and bronchiolitis obliterans organizing pneumonia were selected. Furthermore, BMT-specific complications occur in a characteristic temporal pattern associated with the period following the procedure [2]. The period after BMT was divided into three phases (Fig. 1). It is often difficult to distinguish one complication from others, since most entities show non-specific HRCT findings such as a combination of ground-glass

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Table 1 Profile of chest complications that occurred in leukemic patients. BMT bone marrow transplant; CMV cytomegalovirus; PCP Pneumocystis carinii pneumonia; BO bronchiolitis obliterOverall patients (n=80) Bacterial pneumonia Leukemic infiltration CMV pneumonia PCP Fungal infections BO BOOP Drug toxicity IPS Pulmonary hemorrhage Miliary tuberculosis HABA Pulmonary edema Pulmonary infarction

n=25 n=13 n=10 n=8 n=6 n=4 n=3

ans; BOOP bronchiolitis obliterans organizing pneumonia; IPS idiopathic pneumonia syndrome; HABA human T-lymphotropic virus (HTLV)-associated bronchiolo-alveolar disorder

Patients who underwent BMT (n=29)

Patients who did not undergo BMT (n=51)

Bacterial pneumonia CMV pneumonia BO BOOP IPS Fungal infections Leukemic infiltration PCP Pulmonary edema Pulmonary hemorrhage

Bacterial pneumonia Leukemic infiltration PCP Fungal infections CMV pneumonia Drug toxicity Miliary tuberculosis Pulmonary hemorrhage Pulmonary infarction HABA

n=7 n=6 n=4 n=3 n=2 n=1

n=18 n=11 n=7 n=4 n=4 n=2 n=2 n=1

n=2 n=1

Fig. 1 Chest complications in leukemic patients. Pulmonary complications often occur in a characteristic temporal pattern associated with bone marrow transplantation (BMT). They may also occur in relation to chemotherapy before BMT

opacity (GGO) and air-space consolidation; however, several complications show characteristic HRCT findings, which can help in approaching the differential diagnosis.

BMT non-specific complications Infectious diseases Sixty to 75% of reported deaths in leukemia are due to infectious diseases [3]. Such infectious diseases tend to occur after chemotherapy or at the neutropenic or early phase following BMT.

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Fig. 2a, b Bacterial pneumonia in a 23-year-old man with chronic myelocytic leukemia 80 days after bone marrow transplantation. a An HRCT scan obtained at the level of the basal segmental bronchus shows patchy ground-glass opacities (GGO) in the right middle and lower lobes. In bacterial pneumonia observed in immunocompromised patients, GGO is frequently observed as a major HRCT finding. b Photomicrograph of a transbronchial lung biopsy specimen indicates mixed pneumonia, showing intra-alveolar exudates and thickening of alveolar septa. (Hematoxylin-eosin, ×100)

Bacterial pneumonia Granulocytopenia is a major predisposing factor for bacterial infections. This entity occurs most frequently among all entities, in our institutions, both in patients who underwent BMT and those who did not. Bacterial pneumonia in BMT recipients occurs usually in the neutropenic phase, and its incidence is estimated to be approximately 20–50% [4]. Gram-negative organisms presumably from the gastrointestinal tract or oral mucosa are the predominant group of bacteria. In bacterial pneumonia, air-space consolidation with centrilobular, acinar, and lobular opacities are observed. Unlike bacterial pneumonia occurring in immunocompetent patients, extensive GGO is often the predominant finding in immunocompromised patients (Fig. 2). Pneumocystis carinii pneumonia Pneumocystis carinii pneumonia (PCP) occurs in leukemic patients who undergo intensive chemotherapy or BMT. In our institution it occurs less frequently in BMT recipients, probably because of the introduction of routine prophylaxis of trimethoprim/sulfamethoxazole. The incidence of PCP in BMT recipients is reported to be

less than 10% [4]. Widespread GGO with a mosaic pattern, which distributed typically at the perihilar regions, is a frequent and characteristic finding (Fig. 3) [5, 6]. Occasionally, reticulation or septal thickening within GGO may be recognized, presumably reflecting a combination of fluid and cellular components within the alveolar space as well as thickening of the alveolar septa. Centrilobular opacities or Y-shaped branching structures are sometimes observed, corresponding to bronchiolitis and bronchioles that are impacted with inflammatory materials [5, 7]. Fungal infections Fungal infection (invasive aspergillosis, candidiasis, and mucormycosis) is a common cause of pneumonia occurring in BMT recipients; however, it also occurs in patients who do not undergo BMT. Granulocytopenia is the most important risk factor [3]. In BMT recipients it usually occurs in the neutropenic phase. The most common pathogen in this entity is Aspergillus. Invasive aspergillosis shows a characteristic CT finding: CT-halo sign (Fig. 4) and air-crescent sign [8]. The CT-halo sign is observed at the period of neutropenia and represents a hemorrhagic infarction, in which the nodular lesion corresponds to a gray-yellow necrotic center, and the groundglass attenuation to a rim of hemorrhage caused by thrombosis of fungi within pulmonary vessels. Aircrescent sign is observed at the period when neutropenia is recovering and represents the cavitation of nodules caused by resorption of necrotic tissue by returning neutrophils. Candidiasis shows multiple nodules with CThalo sign and patchy bronchopneumonia [9]. The CT findings of mucormycosis are indistinguishable from

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Fig. 3a, b Pneumocystis carinii pneumonia in a 40-year-old man with acute lymphocytic leukemia. a An HRCT scan obtained at the level of the left main bronchus shows extensive GGO with mosaic patterns, demonstrating normal lobules (arrow) adjacent to diseased ones (arrowhead). b Photomicrograph of a transbronchial lung biopsy specimen shows intra-alveolar exudates and thickening of the alveolar septa. Ground-glass opacity in HRCT corresponds pathologically to the mixed alveolar and interstitial patterns. (Hematoxylin-eosin, ×100)

those of invasive aspergillosis. Generally, these fungal infections show nodules on CT images. Tuberculosis There may be no statistical increase of tuberculosis with leukemia; however, it must always be considered in any leukemic patients with pulmonary infiltrates. Pulmonary tuberculosis in immunocompromised patients often has an atypical CT pattern compared with that which occurs in immunocompetent patients. This pattern often includes non-segmental distribution and multiple small cavities within lesions [10]. Numerous small nodules with random distribution within secondary pulmonary lobules is a characteristic HRCT finding for miliary tuberculosis (Fig. 5) [11]. Ground-glass opacities may be present along with nodules (Fig. 5). Ground-glass opacities correspond pathologically to widespread interstitial granuloma of a size below the limits of resolution on HRCT [11]. Drug toxicity

Fig. 4 Invasive aspergillosis in a 58-year-old man with chronic myelocytic leukemia. An HRCT scan obtained at the level of right upper lung shows a central high-attenuating nodule with surrounding halo of GGO (arrow) in the right upper lobe

Drug-induced lung diseases must always be considered in the differential diagnosis of pulmonary infiltrates in leukemic patients who are undergoing chemotherapy, although exact incidence is uncertain. In BMT patients, high-dose chemotherapy and total body irradiation (TBI) may potentiate cooperatively the possibility of this entity although, in our series, there were no BMT recipients who developed this entity. Padley et al. divided CT findings of this entity into four types: fibrosis; bilateral patchy GGO; widespread air-space consolidation; and

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Fig. 5a, b Miliary tuberculosis in a 39-year-old man with adult T-cell leukemia. a An HRCT scan obtained at the level of the basal segmental bronchus shows numerous miliary nodules throughout the lung field, some of which are distributed on the pleural surface or on vessels (arrows), showing random distribution of nodules within the pulmonary lobule. Note GGO (arrowhead) in the right lower lobe. b Photomicrograph of a transbronchial lung biopsy specimen shows epithelioid granuloma with caseation necrosis. (Hematoxylin-eosin, ×50)

Fig. 6 Drug-induced lung toxicity due to phosphomycin in a 73-year-old man with chronic myelocytic leukemia. An HRCT scan obtained at the level of the basal segmental bronchus shows GGO and linear opacities distributed mainly in the subpleural zone

bronchiolitis obliterans [12]. Among these types, the frequent CT findings are bilateral GGO and air-space consolidation (Fig. 6). Since these findings are non-specific, it is difficult to diagnose this entity only by HRCT. This entity is usually a disease of exclusion. Leukemic pulmonary infiltration Although leukemic pulmonary infiltration is found at autopsy in 30–66% of leukemic patients, it has been stressed that symptomatic pulmonary disease due to this entity is uncommon (<10%) [3, 13]. However, in our series, this entity was the second most frequent disease that was clinically evident (Table 1); thus, we think that this entity is fairly common. Pathological findings in the literature are noted as being infiltration along the lymphatic route surrounding the peribronchial and perivascular regions, and infiltration within the alveolar septa or alveolar spaces [14]. Corresponding to these pathologic findings, the two frequent and characteristic CT findings are a thickening of the bronchovascular bundles and interlobular septa, usually irregular in shape (Fig. 7). Ground-glass opacification, air-space consolidation, and nodules are seen along the peribronchial region (Fig. 8) [15]. The GGO may be caused by hemorrhage, hemorrhagic infarction, edema, or diffuse alveolar damage (DAD). These conditions may come from the obstructive nature of massive infiltrates of leukemic cells within pulmonary small vasculature [16]. We also reported the CT findings of this entity [17]. Frequent CT findings were thickening of bronchovascular bundles and non-lobular and non-segmental GGO. Furthermore, some of these GGO corresponded to hemorrhage, edema, or DAD.

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Fig. 7a, b Leukemic pulmonary infiltration in a 40-year-old man with adult T-cell leukemia. a An HRCT scan obtained at the level of right upper lobe shows extensive GGO and air-space consolidation. Note the thickening of the bronchovascular bundles from the hilar to the peripheral lung zone and thickening of interlobular septa (arrowheads). The thickening of peripheral bronchovascular bundle is regarded as being a prominence of the peripheral pulmo-

nary arteries (arrows). b Photomicrograph of a specimen obtained at autopsy shows marked infiltration of leukemic cells along the pulmonary arteries, bronchi, and bronchioles (arrowheads), corresponding to the thickening of bronchovascular bundles and prominence of the peripheral pulmonary arteries. (Hematoxylin-eosin, ×10)

Fig. 8a, b Pulmonary hemorrhage in a 15-year-old male with acute myelocytic leukemia. a An HRCT scan obtained at the level of supraphrenic level shows pleural-based GGO and air-space consolidation. Note a lobular-shaped air-space consolidation (arrow). b Photomicrograph of a specimen obtained at video-assisted

thoracoscopic surgery biopsy shows a well-marginated hemorrhagic lesion lobular in shape (arrow). The cause of the pulmonary hemorrhage in this case remains unknown. (Hematoxylin-eosin, ×10)

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Pulmonary hemorrhage

Infectious diseases

Pulmonary hemorrhage occurs associated with complicated thrombocytopenia, infectious diseases, and BMT. Tenholder and Hooper noted that this was the most common cause of non-infectious pulmonary complications [1], and Bodey et al. found that this entity was observed in 54% of 50 autopsied cases of acute leukemia [18]. Diffuse alveolar hemorrhage, which is also observed in approximately 20% of BMT patients [2], occurs especially in the neutropenic phase. The clinical manifestation is acute and nonspecific; it is hardly diagnosed before death since hemoptysis is rare. The causes of this entity are estimated as the damage of pulmonary vasculature by graft-vs-host disease (GVHD), pre-transplantation chemotherapy, or TBI. The most common, but nonspecific, CT findings consist of widespread GGO or consolidation (Fig. 8) [19], within which reticulation is often recognized, showing a “crazy-paving” appearance.

Although any infectious diseases can occur after BMT, especially in the neutropenic or early phase, CMV pneumonia more frequently occurs.

BMT specific complications

Pulmonary edema

Bone marrow transplantation has made it possible to treat leukemia with high-dose chemotherapy and TBI. After BMT, there is a neutropenic phase lasting 2–3 weeks. After the neutropenic phase, an immunosuppressive state continues for approximately 1 year after BMT. This period is usually divided into early phase and late phase; the former continues for approximately 100 days after BMT and the latter continues until 1 year after BMT (Fig. 1) [2, 20]. Chest complications after BMT are also a major problem and occur in 40–60% of such patients [2, 21].

Pulmonary edema is a common complication in the neutropenic phase, although the exact incidence is not known. The causes of this entity are estimated as acute

Cytomegalovirus pneumonia Cytomegalovirus (CMV) infection occurs in 70% of BMT recipients, approximately one-third of whom develop CMV pneumonia [2]. It typically occurs more than 2 months following BMT (early phase). Cytomegalovirus pneumonia shows various CT findings, including patchy or widespread GGO, air-space consolidation (Fig. 9), and poorly defined nodules with CT-halo sign [5, 9, 22]. These findings are non-specific, and it is often difficult to differentiate them from those of other entities including PCP and pulmonary hemorrhage. The GGO and air-space consolidations correspond to DAD (Fig. 9b) and nodules to the hemorrhagic nodules.

Fig. 9a, b Cytomegalovirus pneumonia in a 17-year-old female with acute myelocytic leukemia 53 days after bone marrow transplantation. a An HRCT scan obtained at the level of the right middle lobar bronchus shows extensive GGO or air-space consolidation, some of which show centrilobular and lobular distribution (arrows). b Photomicrograph of a specimen obtained at autopsy shows extensive intra-alveolar exudates, hyaline membrane, and thickening of alveolar septa, showing diffuse alveolar damage. (Hematoxylin-eosin, ×100)

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Fig. 11 Idiopathic pneumonia syndrome in a 27-year-old man with acute lymphocytic leukemia 19 months after peripheral blood stem cell transplantation. An HRCT scan obtained at the level of the lung base shows widespread GGO distributed in the bilateral lung fields, especially in the dependent lung area Fig. 10 Interstitial pulmonary edema in a 22-year-old woman with acute lymphocytic leukemia 5 months after bone marrow transplantation. An HRCT scan obtained at the level of the lung base shows thickening of interlobular septa (arrows) and prominent pulmonary arteries (arrowheads), which appear larger in diameter than the accompanying bronchus

GVHD, cardiac or renal impairment induced by chemotherapy, the increased permeability of pulmonary vessels induced by TBI, and the infusion of large volumes of fluid to administer drugs [2, 20]. Characteristic CT findings include enlargement of pulmonary vessels, GGO or air-space consolidation distributed at the hilar or peribronchial regions, regular thickening of interlobular septa (ILS) [2, 9], and pleural effusion (Fig. 10).

develop chronic GVHD. The cause is uncertain; however, it is believed to be a direct damage to the small airways induced by chronic GVHD [20]. Pathological findings of BO are constrictive bronchiolitis with peribronchiolar infiltration by inflammatory cells. The most reliable CT finding is reported as bronchial dilatation [24]. Centrilobular opacities, tree-in-bud appearance, mosaic pattern, and evidence of air trapping on expiratory scans can also be noted (Fig. 12) [2, 24]. It should be stressed that expiratory CT is needed if BO is suspected in BMT patients. Bronchiolitis obliterans organizing pneumonia

Idiopathic pneumonia syndrome Idiopathic pneumonia syndrome (IPS) is an early-phase complication, and occurs in approximately 12% of allogenic BMT patients [23]. It is defined as diffuse lung injury occurring after BMT for which an infectious etiology is not identified [23]. It is probably caused by toxicity from the pre-transplantation chemotherapy and TBI [2, 21, 23]. Histopathologically, there is DAD with an interstitial mononuclear cellular infiltrate. It is essentially a diagnosis of exclusion because CT findings are nonspecific: There is widespread GGO distributed in bilateral lung fields, especially in dependent areas (Fig. 11). Bronchiolitis obliterans Bronchiolitis obliterans (BO) is a late-phase complication and occurs in approximately 10% of patients who

Bronchiolitis obliterans organizing pneumonia (BOOP) is also a well-recognized late-phase complication in BMT patients. The incidence rate is uncertain. Typical and characteristic CT findings are patchy GGO or airspace consolidation distributed often at the peribronchial and subpleural regions (Fig. 13) [25]. Although consolidation is the more commonly observed finding in immunocompetent patients, GGO or nodules are more frequently observed in immunocompromised patients. Nodules usually show smooth and well-defined margins with random distribution and include air bronchogram in approximately half of the cases [26]. The GGO corresponds pathologically to alveolar septal inflammation or alveolar cellular desquamation, and air-space consolidation to organizing pneumonia [25]. The BOOP reaction may occur secondary to drug-induced lung toxicity.

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Fig. 12a–c Bronchiolitis obliterans in a 30-year-old woman with acute lymphocytic leukemia 10 months after BMT. a Inspiratory HRCT scan obtained at the level of the basal segmental bronchus shows almost no abnormal findings except for slightly decreased peripheral vascular markings. b Expiratory HRCT scan at the same level as Fig. 12a shows little increase in lung attenuation. An increase in lung attenuation from inspiration to expiration at the dependent quarter area in this slice was 104 HU, which is regarded as being under the normal limits; air trapping. c Photomicrograph of a specimen obtained at videoassisted thoracoscopic surgery biopsy shows marked stenosis of bronchiolar lumen by fibroblastic proliferation and inflammatory cells. (Hematoxylineosin, ×100)

Differential diagnosis

▲

Differential diagnosis from the viewpoint of CT findings are shown in Table 2. Some HRCT findings are specific for entities: HRCT findings of nodules with random distribution, CT-halo sign and centrilobular distribution are specific for miliary tuberculosis, fungal infection and infectious diseases progressing along airways, respectively. Thickening of bronchovascular bundle and ILS is specific for pulmonary edema and leukemic infiltration. Existence of air trapping in the expiratory CT with a find-

Fig. 13 Bronchiolitis obliterans organizing pneumonia in a 36-year-old man with chronic myelocytic leukemia 15 months after BMT. An HRCT scan obtained at the level of basal segmental bronchus shows extensive GGO and air-space consolidation, predominantly distributed along the bronchovascular bundle and subpleural zone

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Table 2 Differential diagnosis from the viewpoint of individual HRCT findings. GGO ground-glass opacity; BVB bronchovascular bundle; ILS interlobular septum; CMV cytomegalovirus; PCP Main HRCT finding

Ancillary findings

Pneumocystis carinii pneumonia; BOOP bronchiolitis obliterans organizing pneumonia

Entities

Notes

Most likely Nodules

GGO and/or air-space consolidation

Thickening of BVB and ILS

Next most likely

Numerous and random CT halo

Miliary tuberculosis

Centrilobular

Infectious diseases via airways

Centrilobular

Infectious diseases via airways PCP

CMV-P

Reticulation (crazy-paving) Peri-BVB distribution

Hemorrhage, PCP

CMV-P

Non-specific

Drug toxicity, idiopathic interstitial pneumonia

PCP, CMV-P, hemorrhage and other diseases

Smooth thickening

Pulmonary edema

Leukemic infiltration

Mosaic

Irregular thickening Air trapping

Fungal infection

Sometimes with GGO Shows air-crescent sign in recovery phase

CMV-P

Distributed typically at the perihilar regions

BOOP

Late phase complication of BMT recipients

Leukemic infiltration

Neutropenic phase complication of BMT recipients GGO may be present

Bronchiolitis obliterans

With bronchial dilatation

ing of bronchial dilatation is specific for BO. The GGO and air-space consolidation are the most frequent HRCT findings observed in leukemic patients, and are furthermore the most difficult to be correctly diagnosed. Those with mosaic pattern, those with reticulation, and those with peribronchovascular distribution are relatively specific for PCP, hemorrhage, and BOOP, respectively; however, GGO and air-space consolidation without such ancillary specific findings consist of many entities including drug toxicity and IPS.

Conclusion Several chest complications occur in patients with leukemia in relation to the course and/or the phase of therapy. A combination of the clinical information, including the phase of the therapy and HRCT findings, which are sometimes characteristic for several entities, may help in approaching a correct diagnosis of chest complications in leukemic patients. Acknowledgements The authors thank Y. Oka and Y. Satoh for supplying clinical cases and their clinical information. We also thank S. Gardner for help in article preparation.

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