Pulmonary transplantation for advanced bronchioloalveolar carcinoma☆☆☆

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.

CPB, Cardiopulmonary bypass.

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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.

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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.