The British Journal of Radiology, 78 (2005), 708713 DOI: 10.

1259/bjr/74299224

2005 The British Institute of Radiology

Imaging of diffuse metastatic and dystrophic pulmonary calcication in children after haematopoietic stem cell transplantation
1

A GUERMAZI, MD, 2H ESPEROU, MD, 2F SELIMI, MD and 2E GLUCKMAN, MD

Departments of 1Radiology and 2Bone Marrow Transplantation, Saint-Louis University Hospital, AP-HP, 1 avenue Claude Vellefaux, 75010 Paris, France

Abstract. The authors describe three cases of diffuse pulmonary calcication; two metastatic in children with acute transitory renal failure and the other dystrophic in a child with leukaemia. All three patients underwent haematopoietic stem cell transplantation (HSCT). Chest radiographs disclosed diffuse calcication within the lungs. The distribution of this calcication was bilateral but asymmetric. Diagnosis was made in two cases by high resolution computed tomography (HRCT) and in one case by HRCT and bone scan. Radiological characteristics, scintigraphic features, pathological mechanism and clinical outcome of such pulmonary calcication are discussed.

Diffuse pulmonary calcication is well-known in adults, but rare in children [1, 2]. Most patients are asymptomatic, even with extensive parenchymal involvement. The pathophysiology of these calcium precipitations is uncertain and complex, but abnormalities in acid-base balance leading to alkalosis is thought to be important [14]. The diagnosis of pulmonary calcication remains a challenge for both clinician and radiologist. This report presents three children in whom pulmonary calcication occurred after haematopoietic stem cell transplantation (HSCT) and was demonstrated on dual-energy digital chest radiographs. The diagnosis was conrmed by the more sensitive techniques of HRCT and bone scintigraphy [5, 6].

Patients
Patient one
A 15-year-old girl was treated for acute myeloid leukaemia (FAB type 4) diagnosed at the age of 6 years. She was treated under the French paediatric protocol acute myeloid leukaemia 91. Induction and salvage courses failed. She then underwent allogenic bone marrow transplantation (BMT) from an unrelated HLA identical donor. The BMT was preceded by fractionated total body irradiation (12 Gy5662 Gy), cyclophosphamide 120 mg kg21, thiotepa 10 mg kg21 and antilymphocyte serum. A whole body CT scan before BMT was normal. Graft-versus-host disease (GvHD) prophylaxis consisted of associated cyclosporine A and short-course methotrexate. The haematopoietic reconstitution was complete within 1 month of the BMT. She experienced a grade II acute GvHD which was successfully treated with 2 mg kg21 of methylprednisone. 45 days after the BMT,
Received 16 August 2004 and in revised form 4 January 2005, accepted 15 March 2005. Current address for Dr Ali Guermazi, Department of Radiology Services, Synarc Inc., 575 Market Street, 17th Floor, San Francisco, CA 94105, USA.

the patient had an interstitial pneumonia, which resolved quickly with empiric antibiotics. Dual energy chest radiography showed diffuse consolidation predominantly in the middle lobe. No organism was identied by bronchoalveolar lavage. Renal function was normal, as was the blood calcium level. 64 days after BMT, the pneumonia recurred. Dual energy radiography showed calcication within the initial zones of pulmonary abnormality (Figure 1a,b). An anti-tuberculosis and anti-pneumocystosis treatment was initiated without bacteriological proof and quickly discontinued. Because of the persistence of the calcication on consecutive dual energy chest radiographs, an HRCT scan was performed. It showed diffuse bilateral calcication of the lungs predominantly in the anterior zones and also demonstrated calcication within the heart, arteries, diaphragm, trachea, bronchi and muscles (Figure 1c,d). A bone scan using technetium-99m methylene-diphosphate conrmed the calcic nature of the lung deposits. Her renal function remains normal. 9 years after the BMT, the patient has mild restrictive pulmonary function treated by steroid inhalors. The radiographic abnormalities are still present but less marked (Figure 1e).

Patient 2
A 14-year-old girl had Fanconi anaemia with pancytopaenia diagnosed at the age of 5 years. She received an HLA identical cord blood cell graft after a conditioning regimen of 5 Gy thoraco-abdominal irradiation and cyclophosphamide 20 mg kg21. A whole body CT scan performed before BMT was normal. Her renal function was normal. GvHD prophylaxis consisted of cyclosporine A alone. 15 days after BMT, a stage III GvHD reaction was diagnosed and treated by methylprednisone 5 mg kg21 and antilymphocyte serum. The pulmonary physical examination and chest X-ray were still normal. 31 days after BMT, she experienced hypoxaemic interstitial pneumonia with fever and severe acute renal failure (creatinine 247 mmol l21, uraemia 22 mmol l21). No assisted ventilation was required, but the patients
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Diffuse pulmonary calcication after stem cell transplantation

(a)

(b)

(c)

(d)

Figure 1. (a) Anteroposterior and (b) lateral dual energy radiographs of the chest show diffuse pulmonary calcication predominantly within the middle lobe. (c) Axial high resolution CT scan at lung windowing shows the diffuse pulmonary calcication in the middle lobe. (d) The same CT slice at mediastinal windowing shows the calcic nature of the consolidation and also demonstrates calcication around the bronchi and within the heart. (e) Anteroposterior dual energy radiograph performed 7.5 years later shows the pulmonary calcication is still present but less diffuse.

(e)

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A Guermazi, H Esperou, F Selimi and E Gluckman

respiration was supplemented with 6 l min21 of oxygen. Her renal function very quickly worsened (creatinine 579 mmol l21, uraemia 54 mmol l21) necessitating 3 haemodialysis sessions. There was also a concomitant elevation of her serum calcium and phosphate, which returned to normal 5 days later. Dual energy radiography showed multiple small foci of pulmonary consolidation predominantly in the left anterior zone. No organism was found on bronchoalveolar lavage. The suggested diagnosis was intra-alveolar haemorrhage secondary to the antilymphocyte serum administration. 2 weeks later, calcication

appeared in the same zone as the consolidation (Figure 2a,b). An HRCT scan demonstrated diffuse bilateral pulmonary calcication (Figure 2c). Her pulmonary physical examination was normal. Her renal function revealed a creatinine level of 237 mmol l21 and a urea level of 25 mmol l21 1 month after BMT; and a creatinine level of 107 mmol l21 and a urea level of 7.6 mmol l21 after 6 months. 9 years after the BMT, the patient is well, not on medication. She has persistent very mild renal failure and the pulmonary calcication is still present on followup chest radiographs.

(a)

(b)

Figure 2. (a) Anteroposterior and (b) lateral dual-energy radiographs of the chest show bilateral diffuse pulmonary calcication most marked within the left lung. (c) Axial high resolution CT scan at lung windowing shows the pulmonary calcication more clearly than conventional radiography.

(c)

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Diffuse pulmonary calcication after stem cell transplantation

Patient 3
A 6-year-old boy had Fanconi anaemia with pancytopaenia diagnosed at the age of 2 years. He received an unrelated cord blood cell graft after a conditioning regimen with 4.5 Gy total body irradiation (TBI) and cyclophosphamide 40 mg kg21. A whole body CT scan performed before BMT was normal. His renal function was normal. GvHD prophylaxis consisted of cyclosporine A and boluses of corticosteroids. 3 weeks after BMT, he experienced hypoxaemic interstitial pneumonia without fever and with acute renal failure (creatinine 138 mmol l21, uraemia 24.6 mmol l21). No assisted ventilation was required but his respiration was supplemented with 2 l min21 of oxygen. Dual energy chest radiography showed diffuse and bilateral alveolar consolidation. 4 days later, he was markedly improved with no pulmonary signs and normalization of his renal function (creatinine 53 mmol l21, uraemia 3 mmol l21). A concomitant increase of serum calcium and phosphate occurred which normalized 3 days later. No organism was found on bronchioalveolar lavage. The suggested diagnosis was of intra-alveolar haemorrhage secondary to the antilymphocyte serum administration. 1 month after BMT, dual energy chest radiography showed that the diffuse and bilateral alveolar consolidation was stable (Figure 3a). An HRCT scan demonstrated diffuse bilateral pulmonary calcication located predominantly in the right upper lobe. It also showed calcication of the trachea, bronchi, and diaphragm (Figure 3b,c). Despite this diffuse calcication,

physical pulmonary examination was normal. 3 months later, he died from haemolytic uraemic syndrome.

Discussion
Pulmonary calcication in children may be either focal or diffuse, dystrophic or metastatic [7]. Dystrophic calcication occurs in patients with leukaemia as well as following varicella infection. They refer to the deposition of calcium in damaged tissue in the setting of a normal calcium-phosphorus product. The previous damage could be caused by infection, intrapulmonary bleeding or oedema. Metastatic calcication is dened as calcium deposition in tissue secondary to an abnormality of calcium metabolism without prior soft tissue damage. The most common causes of metastatic calcication are chronic renal failure, primary or secondary hyperparathyroidism, hypercalcaemia in patients with multiple myeloma, lymphoma, leukaemia or bone metastases, excessive vitamin D intake, steroid therapy, acute renal failure or following renal or liver transplantation, and following cardiac surgery [15, 816]. In our patients, diffuse pulmonary calcication appeared in children following HSCT. In all three cases, steroids had been given for treatment or GvHD prophylaxis. It is likely that metastatic calcication was responsible in our cases but we can not rule out dystrophic calcication, especially in the patient with leukaemia. This child may have had dystrophic calcication following pulmonary infection.

(a)

(b)

Figure 3. (a) Anteroposterior dual-energy radiograph of the

chest demonstrates bilateral diffuse pulmonary consolidations predominantly in the right upper lobe. Axial high resolution CT scan at (b) lung and (c) mediastinal windowings show the pulmonary consolidation to be of calcic nature. They also demonstrate calcication around the bronchi (arrow).

(c)

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The stomach, kidneys, blood vessels, and lungs are the most common organ sites of calcium deposition. Calcication of the myocardium, small pulmonary arteries and veins, and bronchial walls is also commonly noted [2, 3, 5, 8, 16]. Clinically, the degree of respiratory distress often does not correlate with the degree of macroscopic pulmonary calcication. Patients with extensive calcication may be asymptomatic, while others with subtle calcication or normal conventional chest radiographs may have severe respiratory compromise [8]. Symptoms include dyspnoea and chronic, non-productive cough. The pathophysiology of pulmonary calcication has not been precisely dened, but calcium-phosphate metabolism, excessive vitamin D ingestion, and secondary hyperparathyroidism have all been implicated [3]. Nevertheless, abnormalities in acid-base balance are considered to be important [2, 3]. Asymptomatic alveolar lesions appear rapidly within the rst 5 weeks after surgery, acute renal failure, disorders of phosphorus and calcium metabolism with hypercalcaemia, or liver transplantation [1, 2, 4]. All patients reported in the literature and our patients had normal pre-operative and pre-transplantation chest radiographs. They were rst diagnosed with possible infection or oedema and secondarily identied as having pulmonary calcication [2]. This calcication appears in areas where parenchymal opacities were previously noted. The parenchymal opacities represent a primary pulmonary reaction to the deposition of calcium salts in the wall of alveoli [1]. Calcication occurred in the anterior portions of the lung in our patients, who were kept in the supine position for several weeks after BMT was performed. The disappearance of metastatic calcication has been reported after the return of normal renal function, parathyroidectomy, or renal transplantation, indicating potential therapy for this condition if it can be recognized early [2, 4]. Calcication is rarely identied on conventional chest radiographs [17]. Initially, when abnormalities are present, the radiograph shows bilateral air-space consolidation which may be mistaken for pneumonia, oedema, or infarction, but which may show a progressive increase in opacity [2, 5]. Visible calcication may remain stable for many years or may develop rapidly. Calcication can be unilateral or diffuse and tends to be localized to the upper, or less frequently, lower lobes of lungs [5]. The calcic nature of these varying patterns can be difcult to recognize with current high kilovoltage technique, especially when the calcication is mild or moderate. It is now well-known that dual-energy digital radiography is more sensitive and accurate than current techniques in detecting small amounts of calcium in pulmonary nodules [6, 18]. Our ndings conrm the sensitivity of dual-energy digital chest radiography for the detection and earlier diagnosis of pulmonary calcication. HRCT is useful for the early detection of metastatic calcication when conventional chest radiography is negative [6]. In one case, only the high-resolution sections depicted the calcic nature of the nodules. This nding is not surprising, as the detection of calcium in solitary pulmonary nodules is best demonstrated using thin-section CT [19]. In addition to the pulmonary calcication, CT scans may also show extensive calcication of the myocardium, small pulmonary arteries, and the dura of
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the dorsal spine [5, 19, 20]. The combination of calcied nodules and calcied vessels in the chest wall on CT scans may be characteristic, and an important factor in determining the cause of pulmonary calcication [19]. Although no pathological conrmation is available in most cases in the literature, bone scintigraphy characteristically reveals extensive increased uptake in the same zonal distribution as the parenchymal opacication seen on HRCT [5]; conrming the metastatic nature of the calcication [20].

Conclusion
Diffuse pulmonary calcication is rare in children. It is dystrophic or metastatic. Most patients have no clinical signs or symptoms, and the condition is rarely identied on conventional chest radiography. Diffuse bilateral pulmonary consolidation in the setting of acute renal failure or after BMT in children with minimal or no clinical symptoms should raise the possible diagnosis of metastatic or dystrophic pulmonary calcication. Dualenergy digital radiography has been shown to be more sensitive than conventional chest radiography for the detection of calcication. In addition, recognition of diffuse pulmonary calcication on HRCT or bone scintigraphy may obviate the need for more invasive procedures, such as open-lung biopsy, to determine the cause of a non-resolving pulmonary inltrate.

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