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Background Bronchioloalveolar carcinoma is a distinctive subtype of typical adenocarcinoma of the lung that tends to metastasize widely throughout the lungs but less commonly elsewhere. Because conventional therapies for intrapulmonary metastatic bronchioloalveolar carcinoma are generally ineffective, we treated seven patients who had intrapulmonary metastatic bronchioloalveolar carcinoma with lung transplantation.
Methods Seven patients with biopsy-proved bronchioloalveolar carcinoma and no evidence of extrapulmonary disease received transplants of either one or two cadaveric lungs. At transplantation, all native lung tissue was removed and replaced with a donor lung or lungs. The patients received the usual post-transplantation care given at the institution.
Results Four of the seven patients had recurrent bronchioloalveolar carcinoma within the donor lungs; the recurrences appeared from 10 to 48 months after transplantation. All recurrences were limited to the donor lungs. Histologic and molecular analyses showed that the recurrent tumors in three patients originated from the recipients of the transplants.
Conclusions Lung transplantation for bronchioloalveolar carcinoma is technically feasible, but recurrence of the original tumor within the donor lungs up to four years after transplantation was common.
There is limited but convincing evidence that bronchioloalveolar carcinoma is distinct from typical adenocarcinoma of the lung. A National Cancer Institute survey of 2382 patients with bronchioloalveolar carcinoma found a substantially higher five-year survival rate among patients with all stages of the variant than among patients with typical adenocarcinoma.4 The distribution of metastases in the two neoplasms also differs. As compared with typical adenocarcinoma, bronchioloalveolar carcinoma has a higher incidence of metastasis within the lung7 and a lower incidence of brain metastasis.8
We studied the outcome of treatment of seven patients with stage IV bronchioloalveolar carcinoma who underwent lung transplantation.
Methods
Study Design
This study was approved by the institutional review board of the University of Alabama at Birmingham. Candidates for the procedure were required to have biopsy-proved bronchioloalveolar carcinoma and no evidence of extrapulmonary disease. At surgery, one or both of the patient's lungs were removed and replaced by one or both lungs from a cadaveric donor by conventional methods of lung transplantation.9 Post-transplantation care was identical to that of other patients undergoing lung transplantation at the institution. Recurrences were detected radiographically, with histologic confirmation in large surgical biopsy specimens, although one case (in Patient 7) was detected incidentally during a transbronchial biopsy performed for routine surveillance.
Genetic Analysis of Original and Recurrent Bronchioloalveolar Carcinoma
To determine the origin of the recurrences, amplification of polymorphic dinucleotide repeats of the genome ("microsatellite" DNA) from the original and recurrent tumors was performed in three of the patients (Figure 1). Tissue from the tumors was obtained from rehydrated tissue sections; regions of the sections that contained only tumor were identified and specifically excised. The tissue was incubated in 50 mM TRIS–hydrochloric acid (pH, 8.3), 1 mM ethylenediaminetetraacetic acid, 0.5 percent polyoxyethylenesorbitan monolaurate, and 500 µg of proteinase K per milliliter; the nucleic acid fraction was extracted by standard techniques. Microsatellite primer set D1S1728 (Research Genetics, Huntsville, Ala.) was mixed with the DNA-containing template from the slides in a mixture that contained Taq polymerase-chain-reaction buffer, 2 mM magnesium chloride, 1 mM deoxyadenosine triphosphate, 1 mM deoxyguanosine triphosphate 1 mM deoxythymidine triphosphate, 0.5 mM deoxycytosine triphosphate, and 0.5 µl of [
-33P]deoxycytosine triphosphate (1000 to 3000 Ci per millimole; Dupont/NEN, Wilmington, Del.) in a total volume of 25 µl. The amplified fragments were size-fractionated by electrophoresis on a 4 percent Sequel gel (American Bioanalytical, Natick, Mass.) and then autoradiographed.
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Seven patients with bronchioloalveolar carcinoma received transplants of one or two cadaveric lungs (Table 1). Four patients had undergone surgical resection of the original tumor with intention to cure, but in all four patients, recurrences appeared 4 to 17 months later. The remaining three patients had stage IV disease at the time of presentation and were not candidates for conventional surgical resection. Four of the recipients of transplants were free of disease for more than 38 months. At this writing, two of these patients (Patients 2 and 4) are alive 62 and 50 months, respectively, after transplantation and have no evidence of recurrence.
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A histologic analysis of the recurrent tumors within the transplanted lungs showed that these tumors were similar to the original tumors in the first three patients to have recurrence. Patients 3 and 5 had mucin-positive bronchioloalveolar carcinoma, and the recurrent tumors that appeared in them were also mucin-positive. In Patient 1, both the original tumor and the recurrent tumor were mucin-negative.
To study the original and recurrent tumors from Patients 1, 3, and 5, we used the polymerase chain reaction to amplify highly polymorphic dinucleotide repeats (microsatellite DNA).10 In all three patients, the microsatellite fragments found in DNA from the donor lung were clearly different from those in DNA from the original tumor. By contrast, in Patients 1 and 3, the fragments amplified in the recurrent tumors were almost identical to those in the original tumors. Although some differences between the original and recurrent tumors in Patient 5 were discernible, the recurrent tumor was clearly more similar to the original tumor than to the donor lung. These results support the notion that the recurrent bronchioloalveolar carcinoma found in the donor lungs originated in the recipients.
Discussion
For four of seven patients, lung transplantation for stage IV bronchioloalveolar carcinoma limited to the lungs was followed by a lengthy period of disease-free survival. Two of the seven patients are alive with no evidence of disease 62 and 50 months after transplantation. The survival rate for patients with stage IV bronchioloalveolar carcinoma rarely exceeds five years.4,8 In four of the seven patients, there were recurrences in the donor lungs at various times after transplantation. Histologic and molecular analyses of these recurrent tumors in three patients strongly suggested that the recurrences arose from the original bronchioloalveolar carcinoma in the native lungs of the patients.
In all four of these cases, the recurrences were limited to the donor lungs. In the case of Patient 5, who died of pulmonary complications of the recurrent tumor, an autopsy revealed extensive intrapulmonary bronchioloalveolar carcinoma without any microscopical evidence of extrapulmonary bronchioloalveolar carcinoma.
The site from which the recurrent bronchioloalveolar carcinoma arose within the donor lungs is unclear. Because the trachea and proximal mainstem bronchi were preserved in all of these patients as a requirement for transplantation of the donor lungs, it is possible that some bronchioloalveolar-carcinoma cells were present in these structures and were "washed" back into the transplanted lungs. If this was the case, the bronchioloalveolar-carcinoma cells must have remained dormant within the transplanted lungs for several years in Patients 1 and 3 before developing into clinically detectable disease. It is also possible that before transplantation, bronchioloalveolar-carcinoma cells disseminated to extrapulmonary sites, where they remained dormant, and later migrated back to the lung transplants. In support of this possibility, several groups have presented evidence that there are neoplastic cells in the blood or bone marrow of patients with non–small-cell lung cancer, even in early stages of the disease.11,12,13,14,15,16
Because all the recurrences appear to have originated from microscopic disease extant at the time of transplantation, it is interesting that suppression of the cell-mediated immunity required for allograft survival did not clearly enhance the spread or growth of extrapulmonary foci of bronchioloalveolar carcinoma. Further examination of the tumor genotypes, particularly in the context of genes commonly mutated in lung cancers, may help define differences that are associated with the variable clinical course of these patients after transplantation.
Supported in part by a Veterans Affairs Merit Review (to Dr. Garver) and by the Department of Surgery, University of Alabama at Birmingham.
We are indebted to the lung-transplantation coordinators, Drs. Mark Forshag and Jane Parks, for their help in the care of the patients; to Drs. Dianna Milewicz and Liz Putnam (University of Texas–Houston) for helpful advice on the analysis of microsatellite DNA; and to Dr. Ralph Crowe of the Department of Pathology, University of Alabama at Birmingham, who assisted in the interpretation of some histologic studies.
Source Information
From the Departments of Medicine (R.I.G., X.W., K.R.Y.), Surgery (G.L.Z., D.C.M.), and Pathology (N.B.P.), University of Alabama at Birmingham; and the Lung Transplant Program (G.L.Z., D.C.M., K.R.Y.) and Lung Cancer Program (R.I.G., G.L.Z.), UAB Hospital, Birmingham, Ala.
Address reprint requests to Dr. Garver at the School of Medicine, University of Alabama at Birmingham, 701 South 19th St./LHRB 339, Birmingham, AL 35294, or at robgarver{at}sprintmail.com.
References
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