Volume 125, Issue 1 , Pages 45-48, January 2003
Pulmonary transplantation for advanced bronchioloalveolar carcinoma☆☆☆
Article Outline
Abstract
Background: No effective therapy is currently available for the diffuse stage of bronchioloalveolar carcinoma. Objective: We tested the hypothesis that total lung replacement with standard lung transplantation techniques would provide curative therapy. Methods: Nine patients aged 31 to 58 years with bronchioloalveolar carcinoma were entered in the study. Five patients initially had bilateral diffuse tumor. Four patients had recurrence in the contralateral lung after pulmonary resection. Results: Between 1993 and 1998, all 9 patients underwent transplantation (2 single-lung and 7 bilateral transplants, 1 reoperative single-lung transplant, and 1 reoperative bilateral transplant). Two patients had mediastinal node metastasis (level 7) at the time of transplantation, and 1 of these had a frankly invasive adenocarcinoma. Of the 8 patients with pure bronchioloalveolar carcinoma, 6 had recurrent pulmonary tumor after transplantation. In 2 of these patients the tumor was localized and could be resected with left lower lobectomy in one case and left pneumonectomy in the other. One is alive 89 months after transplantation; the other died 82 months after transplantation. Four other patients had a diffuse pattern of pulmonary recurrence. Two died of progressive pulmonary failure; 1 of these had retransplantation with recurrence. A third patient died of cerebral edema shortly after bilateral retransplantation. The other patient is alive with recurrence 39 months after transplantation and has bronchiolitis obliterans. Two patients without recurrence are well with unrestricted performance levels 87 and 76 months after transplantation. Conclusions: Transplantation produces a powerful palliative outcome in patients with advanced bronchioloalveolar carcinoma, but the recurrence rate is high. Transplantation for this indication remains controversial.
J Thorac Cardiovasc Surg 2003;125:45-8
See related editorial on page 20.
Bronchioloalveolar carcinoma (BAC) comprises about 3% of the malignant tumors of the lung. It is characterized as a subset of pulmonary adenocarcinoma in which well-differentiated tumor cells grow along the walls of alveoli with preservation of the underlying lung architecture. The more malignant histologic features of adenocarcinoma (severe cytologic pleomorphism, solid tumors that destroy the lung architecture, and invasive fibroblastic stroma) are absent. BAC usually is seen as a localized lesion, and surgical resection yields good long-term survival.1, 2 When the disease is diffuse and bilateral, however, survival beyond 2 years from the time of diagnosis is uncommon.3, 4, 5 Disability and death are caused by pulmonary failure from tumor replacement of functioning lung, usually before regional or distant metastases occur. Effective treatment programs with radiotherapy and chemotherapy have not been established. We tested the hypothesis that total lung removal and replacement with standard single- and double-lung transplantation techniques could be curative for the diffuse form of BAC when confined to the lung.
Methods
Before lung transplantation, the histologic data from previous pulmonary resections and biopsy specimens of the original tumor were reviewed. Open lung biopsies were repeated as needed. At the time of open lung biopsy, a substantial pulmonary resection was required to ensure sampling of the central portion of the tumor. Mediastinal lymph nodes not accessible to mediastinoscopy were sampled at the time of open lung biopsy. All patients underwent bone scan, brain scan, computed tomographic scans of the thorax and upper abdomen, liver ultrasonography, and mediastinoscopy to exclude evidence of distant or regional metastasis. All patients underwent a standard pulmonary transplant evaluation in addition to these studies. All study patients underwent transplantation between 1993 and 1998.
The study patients and their previous therapies are summarized in Table 1.
Table 1. Lung transplantation for BAC
| Case | Age (y) | Sex | Previous therapy | Transplant procedure |
|---|---|---|---|---|
| 1 | 41 | F | Right lower lobectomy | Bilateral with CPB |
| 2 | 34 | F | Left pneumonectomy | Right single with CPB |
| 3 | 50 | M | Right upper and right lower lobectomies, chemotherapy | Bilateral with CPB |
| 4 | 53 | M | None | Bilateral with CPB |
| 5 | 48 | F | Right pneumonectomy, radiation therapy | Left single with CPB |
| 6 | 41 | F | None | Bilateral with CPB |
| 7* | 50 | M | Chemotherapy | Bilateral |
| 8 | 58 | F | None | Bilateral with CPB |
| 9 | 31 | F | Chemotherapy | Bilateral |
| *Stage IV adenocarcinoma. | ||||
Fig. 1.
Waiting time for transplantation in days. Cases 5 and 9 underwent retransplantation.
Survival curves were performed with the method of Kaplan and Meier.6 Follow-up was through May 31, 2001. This study protocol was approved by the institutional review board, and study patients gave informed consent.
Results
The outcomes after transplantation are summarized in Table 2.
Table 2. Results of lung transplantation for BAC
| Recurrence | ||||||
|---|---|---|---|---|---|---|
| Case | Rejection and treatment | Infection | Survival* (mo) | Status | Time† (mo) | Treatment |
| 1 | A3 and A2, bolus steroids (×2) | None | 89 | Unrestricted | 39 | Left lower lobectomy |
| 75 | Wedge resection of right middle and right lower lobes | |||||
| 2 | A2 ×2, bolus steroids (×2) | None | 87 | Unrestricted | None | |
| 3 | None | None | 82 | Dead | 49 | Left lung, pneumonectomy |
| 68 | Right lung, no treatment | |||||
| 4 | None | None | 76 | Unrestricted | None | |
| 5 | None | Pneumonia, Staphylococcus aureus and Klebsiella pneumoniae | 33 | Dead | 12 | Retransplantation |
| 32 | None | |||||
| 6 | A2 ×3, bolus steroids (×2), bronchiolitis obliterans, photophoresis | Cytomegalovirus | 53 | Severely restricted | 27 | None |
| 7‡ | None | None | 38 | Dead | Cerebral metastasis, chemotherapy, gamma knife | |
| Right rib metastasis, local radiation | ||||||
| 8 | A2 ×2, bolus steroids (×2) | Herpes zoster | 15 | Dead | 10 | None |
| 9 | A2 ×4, bolus steroids (×4) | CMV | 21 | Dead | 9 | Gene therapy |
| 21 | Retransplantation | |||||
| *From date of transplantation; latest follow-up in cases of living patients. †From date of transplantation. ‡Stage IV adenocarcinoma. | ||||||
Fig. 2.
Survival and freedom from recurrence (Kaplan-Meier plot) after lung transplantation for 8 patients with pathologically confirmed BAC and survival for total lung transplantation population during same period. UAB, University of Alabama at Birmingham.
Tumor recurrences in the transplanted lungs have occurred in 6 of the 8 patients with true BAC. Two patterns of recurrence were noted: (1) one or more isolated lesions and (2) many small nodular lesions throughout the lung parenchyma. In 2 patients, secondary pulmonary resections for localized recurrent tumor were accomplished at 39 and 49 months after transplantation, but tumor has recurred again subsequently in both of these patients.
All patients achieved full rehabilitation and initial good quality of life after the transplant procedure. Pulmonary graft function has been good and stable (until the development of recurrent BAC) except in 1 patient who had bronchiolitis obliterans develop and has been treated with OKT3, tacrolimus, and photophoresis. Figure 2 shows the Kaplan-Meier depiction of overall survival and recurrence-free survival. Among the 8 patients with true BAC, 3 deaths were of pulmonary failure related to recurrent tumor in the transplanted lungs. The fourth death occurred after retransplantation for recurrent tumor. Two patients had postmortem examinations, and no tumor was found in case 9. Case 5 had recurrent tumor in the lung parenchyma but no regional or distant metastasis.
Discussion
Compared with the natural history of diffuse BAC,3, 4, 5 complete pulmonary resection and transplantation resulted in improved survival and dramatic relief of severe dyspnea. Survival in these patients was comparable to that of patients undergoing lung transplantation for other types of end-stage lung disease. Twenty-five percent of our patients with true BAC had no apparent disease at 5 years. The main problem in pursuing this treatment method is the high rate of tumor recurrence. The mechanism of this is not understood, but the available evidence seems to indicate that the tumor is the same as the original lesions.7 Effective treatment for recurrence has not been demonstrated. For those patients with localized lesions, resection may be a temporizing strategy, but its value is not established. No evidence of distant metastasis has been seen in the patients with true BAC, despite of long-term immunosuppression.
Our group stopped this study because of the high recurrence rate. A secondary reason was the increasing waiting time for transplantation. No patients died while waiting for transplantation, but several were desperately ill from pulmonary failure before transplantation. In our view, an argument can be made for using bilateral lung transplantation selectively for palliation in this disease if timely procurement of donor lungs is possible.
Conclusions
In this small group of patients with BAC, 5-year survival after standard lung transplantation was 52%. The deaths were caused by pulmonary failure related to tumor recurrence in the lung allografts. The recurrence rate was 75% at 5 years. The mechanism of recurrence is not clear, and effective treatment for it is not available. Most patients had dramatic relief of their severe dyspnea and could return to an active lifestyle. Transplantation for this indication remains controversial.
Acknowledgements
We thank Dr John T. Carpenter for his advice regarding chemotherapy and Robert N. Brown, BS, ChE, for his help with Kaplan-Meier survival graphing.
References
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- Bronchioloalveolar carcinoma of the lung: recurrences and survival in patients with stage I disease. J Thorac Cardiovasc Surg. 2001;121:42–47
- . Bronchoalveolar cell carcinoma of the lung. Ann Thorac Surg. 1996;41:652–656
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- . Alveolar cell carcinoma of the lung: A retrospective analysis of 205 patients. Ann Thorac Surg. 1988;46:502–507
- . Recurrence of bronchioloalveolar carcinoma in transplanted lungs. N Engl J Med. 1999;340:1071–1074
- . Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481
☆ Address for reprints: George L. Zorn, Jr, MD, Department of Surgery, The University of Alabama at Birmingham THT 720, 1900 University Blvd, Birmingham, AL 35294-0016 (E-mail: gzorn@uab.edu).
☆☆ 0022-5223/2003 $30.00+0
PII: S0022-5223(02)73319-9
doi:10.1067/mtc.2003.72
© 2003 American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Refers to article:
- The ABCs of LTX for BAC
Volume 125, Issue 1 , Pages 45-48, January 2003
