Short Communication

BLEOMYCIN AND CYCLOPHOSPHAMIDE TOXICITY SIMULATING METASTATIC NODULES TO THE LUNGS IN CHILDHOOD CANCER

Myriam Weyl Ben Arush, MD, and Ariel Roguin, MD Pediatric Hematology-Oncology Department, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Eli Zamir, MD

Ronit El-Hassid, MD n Pediatric Hematology-Oncology Department, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Diana Pries, MD Pathological Department, Hadassah Medical Center, Jerusalem, Israel

Diana Caitini, MD Radiology Department, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Ari Dale, MD, and Sergy Postovsky, MD Pediatric Hematology-Oncology Department, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Surgical Department, Meir Hospital, Kfar Sava, Israel

Two pediatric oncology patients with Ewing's sarcoma and one with mixed germ cell tumor were treated with drug regzrnens that included blewmycin or cyclophosphamide. Despite progress to up pnrently complete remission, all manijested pulmonary nodules on computed tomography during or at the end of treatment. Thoracoscopic biopsy to confirm metastasis revealed instead fibrotic lesions apparently attributable to bleomycin or cyclophosphamide. After cessation of chemotherapy, the pulmonary levions resolved and all three patients sustained their remissions. The case histories and comments on the diagnosis and management ofpulmonnly nodules are reviewed.

Keywords bleomycin, cyclophosphamide, pediatric malignancies, pulmonary nodules

In children who are undergoing chemotherapy, the appearance of a new pulmonary nodule may suggest either toxicity of treatment or metas- tases. Computed tomography (CT) cannot differentiate small malignant

Received 6 November 1996; accepted 2 January 1997. Address correspondence to M. Weyl Ben Arush, MD, Pediatric Hematology-Oncology Department,

Rambam Medical Center, P.O. Box 9602, Haifa 31096, Israel.

Pediatric Hemulology nnd On,colugy, 14:381-386, 1 997 Copyright 0 1997 luylor 0.' Francis O888-0018/97 $12.00 c .OO

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from small benign lesions, and diagnostic certainty is possible only upon biopsy or if the nodule disappears completely after chemotherapy [ 11.

At our institution, there have been three recent cases of benign pulmo- nary nodules in pediatric oncology patients who had received bleomycin or cyclophosphamide; thoracoscopic biopsy established the benign nature of the nodules. We report the clinical history, treatment, and pulmonary his- topathology of these patients.

CASE REPORTS

Case 1

In November 1994, a 15-year-old Arab girl was admitted to our hospital with weight loss (10 kg) and abdominal pain. Physical examination sug- gested a pelvic mass; abdominal ultrasonography and CT confirmed a 20- cm mass in the left ovary and mesenteric lymphadenopathy. The a-fetopro- tein blood level was 96,000 units.

Salpingoopherectomy and omentectomy established the diagnosis of mixed germ cell tumor. The young patient was then given six courses of adjuvant chemotherapy, each cycle consisting of 5 days of cisplatin (20 mg/m2/d) and etoposide (100 mg/m2/d) and 1 day of bleomycin, 30 U/m2/d. By the end of the treatment, the patient had received 180 U/m2 of bleomycin.

The pulmonary function tests were normal throughout, and by April 1995 the a-fetoprotein blood level had dropped to 15 units (normal below 10 units). At this time, the second series of CT scans showed only normal abdominal findings; however, the chest scan revealed a subpleural nodule suggestive of metastasis (Figure 1 ) . The patient promptly underwent com- plete thoracoscopic excision of the nodule.

Pathological findings included areas of organizing pneumonia with areas of bronchiolitis obliterans (Figure 2); the diagnosis was bleomycin toxicity. A subsequent lung scan was normal.

Case 2

In July 1994 a 10-year-old girl was admitted with pain in the left lumbar area, where, on physical examination, there was a palpable mass. CT and magnetic resonance imaging (MRI) scans established the presence of a solid tumor (2 x 5 cm) on the 10th rib. The histopathological diagnosis after open biopsy was Ewing’s sarcoma.

With all laboratory parameters normal and without signs of metastases, she immediately began chemotherapy according to the protocol (POG

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PULMONARY NODULES MIMICKING METASTASES 383

Figure 1. A cross-sectional computed tomographic scan of the thorax of patient number 1 shows a nodule in the posterior part of the left lung.

S85O/CCSG 7881) proposed by the Intergroup Ewing's Sarcoma Study (IESS); this protocol includes cyclophosphamide (total dose 9600 mg/m2). After three courses, she underwent total excision of the 10th and 11th ribs. She completed chemotherapy in August 1995 and, at that time, the lung CT showed a pleural nodule in the lower lobe of the right lung. Thoracoscopic biopsy established a fibrotic rather than a metastatic lesion, which was prob- ably cyclophosphamide induced, Eighteen months later, she is in complete remission.

Case 3

A left supraclavicular swelling led to the admission for diagnosis of a 4year-old boy. Destruction of the left first rib in proximity to a large soft

Figure 2. Pulmonary tissue showing polypoid plugs of fibroblastic tissue filling air spaces, with their characteristic oval to elongated shape, compatible with BOOP (bronchiolitis obliterans organizing pneumonia) (patient 1 ) .

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384 M. W. BEN ARUSH E l AL.

tissue mass was seen on radiography; only in this area was there uptake on ”“Tc methyldiphosphonate (MDP) bone scan. Chest CT and MRI con- firmed these findings and showed extension of the mass from the supra- clavicular region to the boy’s left lateral neck.

Incisional biopsy confirmed Ewing’s sarcoma (round cell tumor with little stainable reticulation). The patient was started on the IESS protocol and, after four courses, underwent excision of the first and second ribs and surrounding soft tissue with sparing of the brachial plexus. He also received intraoperative radiotherapy.

After 1 year of chemotherapy, the bone scan and chest wall MRI were normal; however, a worrisome subpleural nodule was seen on the lung CT (Figure 3 ) . Thoracoscopic biopsy revealed a fibrotic lesion, probably also attributable to cyclophosphamide. Eight months after this biopsy, he has sustained his complete remission.

DISCUSSION

Pulmonary nodules developing in patients during or after chemo- therapy present a vexing diagnostic dilemma. Nodules detected by chest radiography may suggest round pneumonia, atelectasis, radiation pneumo- nitis [2] (all of which can be distinguished by CT together with clinical history), histoplasmosis, inflammatory pseudotumor, histiocytoma, hamar- toma, nodular scar formation [ 31, and, rarely, granulomas. However, pul- monary nodules detected on CT point to viable or sterilized tumor. Ulti- mately benign findings (sterilized tumor or granuloma) for such nodules are seen in up to 60% of adults [4], but for children the results are less promising, ranging from 33% [ 3 ] down to 10% [ 5 ] .

Figure 3. A cross-sectional computed tomographic scan of the thorax of patient number 3 shows a nodule in the posterior part of the right lung.

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PULMONARY NODULES MIMICKING METASTASES 385

For diagnostic certainty in a cancer patient, thoracoscopy is necessary. Although without complications in our experience, this procedure has re- cently been improved and rendered therapeutic through the use of video camera technology and percutaneous endoscopic staplers, allowing safe wedge resection [6, '71.

Antineoplastic agents with known potential to cause pulmonary toxicity include bleomycin and methotrexate as well as cyclophosphamide and sev- eral other alkylators [8-221. Bleomycin, with a 3-10% incidence of this side effect, is most frequently implicated [8-111. The effects, which are dose and age related, are classically manifested as a diffuse interstitial process (bron- chiolitis obliterans organizing pneumonia) [23] ; less frequent presenta- tions include hypersensitivity reactions with eosinophilia [ 241 and focal nodular lesions [S-151. Microscopic findings have been described as con- sisting of interstitial mononuclear (mainly lymphoplasmocytic cell) infiltra- tion and hypertrophy of the lining alveolar cells.

Pulmonary toxicity due to cyclophosphamide in adults has occasionally appeared in the literature [17, 181 but we found only one allusion to it in children [ 191.

The management of pulmonary nodules in symptomatic patients is of- ten unsuccessful; despite drug cessation, progression to pulmonary insuffi- ciency may occur. Corticosteroids may be of help, especially where eosino- philia is a feature [ 13,241. Because our patients were asymptomatic and had normal pulmonary function tests, we decided on a course of observation only. The good outcomes in all three cases have been quite durable.

These three cases of chemotherapy-induced pulmonary nodules under- score the importance of bearing in mind a diagnosis other than metastasis when radiographic CT examination yields the alarming finding of lung nodules.

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