Recurrent bilateral spontaneous pneumothorax complicating chemotherapy for metastatic sarcoma.

Abstract: We present the case of a 63-year-old woman with metastatic, high-grade pleomorphic sarcoma who had recurrent, bilateral pneumothorax while on a regimen of doxombicin and dacarbazine. We postulate that her doxorubicin-based chemotherapy induced rapid cell lysis and necrosis of peripherally located, metastatic pulmonary nodules, leading to the pneumothoraces. Other potential mechanisms include bronchopleural fistula, rupture of dilated alveoli distal to a stenosis, chemotherapy-induced impairment of repair processes, and persistent local infection. Pneumothoraces related to pulmonary metastases tend to be refractory to conventional therapy and necessitate surgical intervention to prevent recurrences.

Key Words: bilateral pneumothorax, chemotherapy, doxorubicin, pleurodesis, pneumothorax, pulmonary metastases, sarcoma

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Key Points

* Pneumothorax complicates chemotherapy for metastatic sarcoma.

* The acute presentation may mimic asthma.

* Surgical or chemical pleurodesis is often necessary at initial presentation to prevent lethal recurrences.

Case Report

A 63-year-old black woman had unclassified high-grade pleomorphic sarcoma involving the tibia and multiple, metastatic lung nodules (0.3-2.0 cm). Doxorubicin and dacarbazine chemotherapy was started after a left above-knee amputation. One day after starting the second cycle of chemotherapy, she came to the emergency department with a 2-hour history of acute, rapidly progressive shortness of breath. Examination revealed diffuse expiratory wheezes with poor air exchange bilaterally. She denied any trauma. She had no history of asthma and had never smoked. Bedside chest x-ray revealed bilateral moderate-sized pneumothoraces with multiple nodules in the lung parenchyma. The respiratory distress worsened, necessitating intubation and mechanical ventilation within minutes of her presentation. Chest tubes inserted on both sides produced good reexpansion. She was extubated the same day, with no respiratory complaints. On hospital Day 13, she had a mechanical and talc pleurodesis with video-assisted thoracoscopy for a persistent left apical pneumothorax. She was discharged to home on hospital Day 17 and continued the chemotherapy regimen of doxorubicin and dacarbazine as an outpatient. She returned 2 months later with worsening respiratory distress. Chest x-ray film confirmed bilateral pneumothoraces, again necessitating chest tube insertions. Repeated computed tomography (CT) showed enlargement and cavitation of the previously noted lung nodules, in addition to the bilateral pneumothoraces (Figs 1 and 2). She refused further surgical intervention and was discharged to home on hospital Day 7 after apparent resolution of the pneumothorax. One week later, she was brought to the emergency room in cardiopulmonary arrest but could not be revived.

[FIGURES 1&2 OMITTED]

Cancer-related spontaneous pneumothorax is rare, accounting for 0.05% of all pneumothoraces. (1) A few of these are associated with chemotherapy or radiotherapy. We present a case of recurrent bilateral pneumothorax occurring after induction of systemic chemotherapy for high-grade sarcoma.

Discussion

Spontaneous pneumothorax is classified as either primary or secondary. Primary spontaneous pneumothorax is associated with subpleural bullous changes and occurs predominantly between the ages of 20 and 40 years. Secondary spontaneous pneumothorax occurs as a complication of intrathoracic disease. This complication typically presents after the fourth decade of life. Secondary pneumothorax may develop spontaneously with diseases such as emphysema, chronic bronchitis, pulmonary fibrosis, and malignancy. Spontaneous pneumothorax due to malignancy has been reported in patients with sarcoma, lung cancer, germ cell tumors, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. (1)

Spontaneous pneumothorax usually occurs from the rupture of a subpleural apical bleb or from cavitary pulmonary lesions. Ruptured alveoli may allow air to track into the interstitium of the bronchopulmonary bundle and escape toward the mediastinum, producing a pneumomediastinum. When the air leak is sufficiently large, either a pneumothorax or subcutaneous emphysema may ensue. A rupture directly into the pleural space may lead to pneumothorax in the absence of a pneumomediastinum.

The mechanisms involving spontaneous pneumothorax associated with malignancy may be due to rupture into the pleural space of dilated alveoli distal to a stenosis, bronchopleural fistula, or associated emphysematous lung disease. (1) In some cases, the growing nodules can cause a ball valve effect, with subsequent overdistension of alveoli, leading to release of air into interstitial tissue and eventual rupture of a subpleural bleb.

Pleuroparenchymal metastases from sarcomas are a rare but classic cause of spontaneous pneumothorax, especially in children and adolescents. (2) Since the late 1970s, chemotherapy has become part of the standard of care for metastatic sarcoma. Doxorubicin, dacarbazine, and ifosfamide are the three most widely used chemotherapeutic agents in the treatment of adult soft tissue sarcomas. (3,4) In patients more than 50 years old, doxorubicin has been used as a single agent, with objective response rates of 9 to 70%. (3) To date, there have been five reported cases of bilateral secondary spontaneous pneumothorax complicating chemotherapy for metastatic sarcoma. (5-7) A majority of these patients received doxorubicin-based chemotherapy.

The suggested mechanisms for these chemotherapy-associated pneumothoraces include rapid tumor lysis and necrosis of the large metastatic pulmonary lesions, enlargement of a rapidly necrotizing tumor, chemotherapy-induced impairment of repair processes, and/or persistent local infection. (1,5,7) The average intervals from the initiation of chemotherapy to development of pneumothorax have been from 1 to 8 days. (1) In our patient, we postulate that doxorubicin-based chemotherapy induced rapid cell lysis and necrosis of peripherally located metastatic pulmonary nodules, leading to the pneumothoraces. The pneumothoraces were recurrent and bilateral because the metastatic nodules were multiple, bilateral, and of various sizes.

In cancer patients with radiation-associated spontaneous pneumothorax, the usual onset is 3 to 65 months from the start of radiotherapy. (1) Radiation-induced fibrosis, apical pleural or parenchymal injury, and focal emphysema increase the potential for formation and rupture of subpleural blebs, with the subsequent development of pneumothorax. The lung apices are frequently involved, perhaps due to the increased doses of radiation targeted at the smaller thoracic diameter superiorly.

Pneumothorax complicating pulmonary metastases may be recurrent and, in this setting, lung expansion may be difficult to achieve. A persistent pneumothorax despite closed chest tube insertion should prompt a diagnosis of bronchopleural fistula, and definitive surgical intervention should be attempted. In addition, chemical pleurodesis may be considered for patients with recurrent and/or bilateral spontaneous pneumothorax related to chemotherapy. Our experience and review of literature show that surgical intervention may be appropriate in the initial presentation of bilateral pneumothorax to prevent potentially lethal recurrences.

Conclusion

Spontaneous pneumothorax in patients with metastatic sarcoma involving the lung can be a complication of chemotherapy. As this case illustrates, the presentation can be dramatic and may mimic status asthmaticus. A high degree of suspicion is necessary for prompt diagnosis and avoidance of unnecessary therapeutic interventions.

Acknowledgment

We thank Dr. Edward Chu for his helpful suggestions.

References

(1.) Stein ME, Shklar Z, Drumea K, Goralnik L, Ben-Arieh Y, Haim N. Chemotherapy-induced spontaneous pneumothorax in a patient with bulky mediastinal lymphoma: A rare oncologic emergency. Ontology 1997;54: 15 18.

(2.) Spittle MF, Heal J, Harmer C, White WF. The association of spontaneous pneumothorax with pulmonary metastases in bone tumours of children. Clin Radiol 1968;19:400-403.

(3.) Budd GT. Palliative chemotherapy of adult soft-tissue sarcomas. Semin Oncol 1995;22(2 Suppl 3):30-34.

(4.) Pinedo HM, Kenis Y. Chemotherapy of advanced soft-tissue sarcomas in adults. Cancer Treat Rev 1977;4:67-86.

(5.) Fenlon HM, Carney D, Breatnach E. Case report: Bilateral recurrent tension pneumothorax complicating combination chemotherapy for soft-tissue sarcoma. Clin Radiol 1996;51:302-304.

(6.) Arora R, Singh P, Aggarwal RK, Virdi HK, Singh KK, Kang HS. Bilateral spontaneous pneumothoraces in osteogenic sarcoma and extragonadal germ cell tumour. Indian J Chest Dis Allied Sci 1994;36:41-44.

(7.) Markman M, Meek AG, Wingard JR. Spontaneous pneumothorax during adjuvant chemotherapy for soft-tissue sarcoma. Johns Hopkins Med J 1981;148:264-265.

From the Department of Internal Medicine, Pulmonary Division, Yale University School of Medicine, New Haven, CT, and Bridgeport Hospital, Yale-New Haven Health, Bridgeport, CT.

Reprint requests to Anupama Upadya, MD, Department of Medical Education, Bridgeport Hospital, Yale-New Haven Health, 267 Grant Street, Bridgeport, CT 06610-0120. Email: [e-mail]

Accepted November 26, 2001.