Incidence of Primary Neoplasms in Explanted Lungs: Long-Term Follow-Up From 214 Lung Transplant Patients N.A. Abrahams, M. Meziane, P. Ramalingam, A. Mehta, M. DeCamp, and C.F. Farver ABSTRACT Background. Undetected neoplasms in explanted lungs at transplantation are an unusual occurrence that may significantly complicate both the short- and long-term outcome of these patients. The incidence and survival of undetected primary neoplasms in explanted lungs with clinical and radiologic correlation have not been studied in a large cohort of patients. Methods. We reviewed the files of 214 consecutive lung transplants from the Transplant Center at the Cleveland Clinic Foundation from 1991 to 2000. Data collected included age, gender, pathology of explanted lung, and survival. Retrospective review of all imaging studies was performed in those cases where a primary neoplasm was detected after transplant. Results. One hundred thirteen males and 101 females underwent lung transplantation for the following diagnoses: emphysema, 118; cystic fibrosis, 35; primary pulmonary hypertension, 27; usual interstitial pneumonia, 26; lymphangioleiomyomatosis, 4; sarcoidosis, 2; and pneumoconiosis, 2. Four neoplasms were found in the explanted lungs, representing a 2% incidence. All four neoplasms were bronchogenic carcinomas, including three adenocarcinomas and one squamous cell carcinoma. Three of four neoplasms were found in the setting of emphysema and were detected at an early stage (stage I), and the fourth presented as stage IV in the setting of usual interstitial fibrosis. No recurrence of tumor was seen in the stage I cases. The stage IV case died in the perioperative period. Retrospective review of the imaging studies showed that, in all four cases, a portable chest radiograph performed immediately before transplant failed to identify the lesions. A chest computerized tomogram was performed in all four cases from 3 to 27 months prior to transplantation and revealed a suspicious lesion in one of the four. Conclusions. Undetected neoplasms in explanted lungs at transplantation are uncommon, with an incidence of 2% at our institution. Adenocarcinoma was the most common cell type. In long-term survivors, no recurrences were found. The 3-year survival was 50% and this approaches the 3-year survival of transplant recipients without lung tumors (58.8%) at our institution. Chest radiographs appear to have a very low sensitivity for the detection of small lesions suspicious for a neoplasm. Chest computerized tomograms performed immediately prior to transplantation may be of benefit in detecting these neoplasms.
L
UNG TRANSPLANTATION is increasingly used as treatment for many end-stage pulmonary diseases. However, due the limited availability of donor lungs1 compared with the large numbers of end-stage patients, the selection criteria for lung transplantation recipients are strict.2,3 The detection of a malignancy in a potential recipient is an absolute contraindication for transplanta-
tion.4 Despite this, a small number of undetected malignancies in explanted lungs have been reported.5 The effect on From the Department of Anatomy and Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA. Address reprint requests to Dr Carol F. Farver, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail:
[email protected]
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.10.014
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 36, 2808 –2811 (2004)
PRIMARY NEOPLASMS IN TX LUNGS
survival of a clinically undetected primary lung neoplasm found at transplantation has not been well studied in a large cohort of transplant recipients. This study evaluates the incidence and long-term survival of lung transplant patients with primary undetected neoplasms in explanted lungs at our institution and compares it to the overall survival of patients who have undergone lung transplantation at the Cleveland Clinic Foundation. In addition, preoperative chest imaging studies in patients with undetected neoplasms are evaluated to ascertain the effectiveness of these studies in finding unsuspected lung neoplasms. METHODS Clinical Two hundred fourteen consecutive patients who underwent singleor double-lung transplantation at the Transplant Center of the Cleveland Clinic Foundation between January 1991 and December 2001 were included in the study. Patients who had undergone heart and lung transplantation were excluded from the study. Clinical information collected from the Transplant Center Database on all 214 patients included: age at time of transplant; gender; underlying pulmonary disease; history of smoking; and survival. The surgical pathology reports for these cases were reviewed, including macroscopic and microscopic features and final diagnoses pertaining to the type and stage of malignancy present in the explanted lung and the underlying pulmonary pathology. All imaging studies on patients with undetected malignancies at the time of transplant were retrospectively reviewed and the pretransplant findings were compared with the reviewed findings. The incidence of undetected malignancies was calculated. The survival of the patients with bronchogenic carcinoma found at the time of transplantation was calculated and compared with the overall survival of patients who have undergone lung transplantation at the Cleveland Clinic Foundation. The study was approved by the Institutional Review Board of the Cleveland Clinic Foundation and informed consent was obtained from all patients.
Pathology A pulmonary pathologist reviewed all explanted lungs at the time of surgery and appropriate sections from all lobes and any abnormal areas were submitted for microscopic evaluation. This assessment included at least two sections from each lobe, a peripheral section and a perihilar section. Dissection of the large airways was performed and a thorough search for mass lesions was carried out on all specimens. Routine hematoxylin– eosin-stained sections were prepared from paraffin-embedded sections. For all transplant cases, the clinical diagnoses made prior to transplant were confirmed on the explanted material.
RESULTS
A total of 113 males and 101 females underwent lung transplantation. The entire cohort had a mean age at the time of transplant of 45 years (range 6 to 67 years). No discrepancies were noted between the clinical diagnosis prior to transplant and the pathologic diagnoses after transplant, except for the four cases of undetected malignancy noted in what follows. The pulmonary diseases found in the explanted lung are presented in Table 1. The overall
2809 Table 1. Pulmonary Pathology in 214 Transplant Patients Pulmonary pathology
Emphysema Cystic fibrosis Primary pulmonary hypertension UIP Lymphangioleiomyomatosis Sarcoidosis Pneumoconiosis
Number of cases
Percentage
118 35 27 26 4 2 2
55% 16% 13% 12% 2% 1% 1%
incidence of undetected malignancies in explanted lungs was calculated at 2% in this series (4 of 214 cases). Four clinically undetected neoplasms were found in the explanted lungs at the time of gross dissection. Three of the cases were adenocarcinomas and the fourth case was a squamous cell carcinoma. Two adenocarcinomas and one squamous cell carcinoma were detected at an early stage (stage I). The fourth neoplasm was an adenocarcinoma that presented as stage IV in the setting of usual interstitial fibrosis (Fig 1). One patient was a smoker (45-year smoking history), and one patient had quit smoking 6 years prior to undergoing transplant; two patients were nonsmokers. Cell type; pathologic stage, and survival are presented in Table 2. Three- and 5-year survival for the group with undetected malignancy was 50% and 25%, respectively, with survival for the lung transplant recipients without malignancy at 58.8% and 40.6%, respectively. The radiologic interpretation of the imaging studies, upon review, remained unchanged in three of the four cases due to the small tumor size. In the remaining case of adenocarcinoma arising with UIP (case 1), small areas of possible scar (8.0 mm) were noted on a CT imaging that had been performed 14 months before transplant, which were too small to characterize further (Fig 2). No follow-up CT scan was performed immediately prior to transplant (Table 3). The overall incidence of undetected malignancies in explanted lungs was calculated at 2% in this series (4 of 214 cases).
DISCUSSION
Although much is known and has been reported with regard to the development of malignancies after transplantation,6 little has been revealed concerning the detection of neoplasms prior to transplantation. Furthermore, the effect of a clinically undetected malignancy in the explanted lung on the short- and long-term survival of these patients has not been studied in a large cohort of transplant recipients. Two case reports have documented primary undetected malignancies in explanted lungs.5,7 In the two cases reported by Svendsen et al, both tumors were well-differentiated adenocarcinomas of the lung, ⬍1.0 cm in size.5 In only one of these cases was follow-up noted. That patient was diseasefree at 34 months. In a large review of 183 explanted lungs performed by Stewart and colleagues in the UK, only one adenocarcinoma of the lung was found; however, the sur-
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ABRAHAMS, MEZIANE, RAMALINGAM ET AL
Fig 2. Chest computerized tomogram of case 1 at 14 months prior to transplantation showing a small (8-mm) nodule (arrow), too small to characterize further.
Fig 1. Usual interstitial pneumonitis. (A) (hematoxylin– eosin stain; original magnification 20⫻) with a well-differentiated adenocarcinoma (B) (hematoxylin– eosin stain; original magnification 400⫻).
vival and management of this one patient was not discussed.7 Our results indicate marginal differences in survival between those with an undetected malignancy (50%) and those without (58.8%) at 3 years. However, a larger difference was noted at 5 years, where the group with an undetected malignancy had a survival of 25% compared to the group without malignancy (40.6%). There are no reported guidelines for the clinical management of lung transplant patients with malignancies detected in the explanted lungs, due to the rarity with which they
present. Radiographic review seems to indicate that the tumors are usually ⬍1.5 cm in size, as in both cases presented by Svendsen et al and in two of the cases from our series (Table 3), which hinders radiographic detection. In the two previous cases of undetected malignancies reported by Svendsen et al, a high-resolution CT scan was performed 1 year prior to transplant. However, immediately prior to transplantation, a chest radiograph was the only imaging study performed.5 Similarly, our results emphasize the need for shorter interval times between chest CT scan and transplantation (range 3 to 27 months), at the same time highlighting the low sensitivity of portable chest radiographs performed immediately prior to transplantation. Chest CT, because of the cross-sectional capability, is the most sensitive method to detect neoplasms that are missed by conventional radiographic exams because of their small size and/or difficult locations. Furthermore, chest CT may allow differentiating between benign and malignant lesions. However, advanced lung disease may obscure small neoplasms, especially in end-stage fibrotic lungs. When small lesions are detected but remain too small to characterize by chest CT criteria, or cannot be biopsied, then one has to assure their stability over time. If no prior imaging study is available for comparison, these patients should undergo chest CT immediately before transplantation to assure that the neoplasm has not changed. In our series, it is possible that the majority of the neoplasms could have been sus-
Table 2. Cell Type, Pathologic Stage of Neoplasms, and Patient Survival Case no.
Diagnosis
1 2 3 4
UIP Emphysema Emphysema Emphysema
Age (y)
54 58 58 59
Gender
Cell type
M F M F
Adenocarcinoma Adenocarcinoma Adenocarcinoma Squamous cell carcinoma
Stage
Stage Stage Stage Stage
IV T4N1M1 IA T1N0M0 IB T2N0M0 IA T1N0M0
Recurrence
Survival
N/A No No No
Dead: 1 week Dead: 2 years Dead: 3 years Alive: 6 years
PRIMARY NEOPLASMS IN TX LUNGS
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Table 3. Radiologic Review of Patients With Clinically Undetected Malignancies at Time of Transplant Tumor size in explanted lung
Types of chest imaging studies prior to transplantation
CT scan (14 months before surgery), portable chest radiograph CT scan (3 months before surgery)
Portable chest radiograph
2
0.5–2.0 cm multifocal 1.1 cm
3 4
2.0 cm 0.9 cm
CT scan (27 months before surgery) CT scan (5 months before surgery)
Portable chest radiograph Portable chest radiograph
Case no.
1
Chest imaging study immediately prior to transplant*
Portable chest radiograph
Review of preoperative CT scan
Small 8.00 mm nodules detected, too small to characterize Small scattered areas of nonspecific scar tissue No lesion detected on CT Scan Small scattered areas of nonspecific scar tissue
*Within 24 hours prior to transplantation.
pected or detected if a chest CT had been repeated immediately prior to surgery. In one case, 8.0-mm nodules were present on a CT scan performed 14 months prior to transplantation and pathologic evaluation showed interval growth of the lesions. In the other three cases, imaging studies were inadequate, because only portable one-view chest radiographs were obtained and their poor quality could not demonstrate suspicious lesions even after retrospective review. In one case with a 2.0-cm lesion, the most recent chest CT was obtained 27 months prior to surgery, a time interval during which a fast-growing malignancy could develop. With the remaining two cases, in which the neoplasms were roughly 1.0 cm in size, retrospective review of the CT scan obtained 3 and 5 months before surgery revealed no detectable malignancy. With an ever-increasing pool of potential candidates for transplant and a limited number of donors, it is imperative that those patients who are most likely to benefit from transplant be selected. The pretransplant clinical work-up includes a number of analytical tests and imaging techniques as defined by published guidelines.2 Our results indicate that, even when an appropriate pretransplant clinical work-up is used, there is still a 2% incidence of undetected malignancies. The present cohort of 214 patients offers the opportunity to appreciate the real incidence and survival of undetected malignancies in explanted lungs. Although the incidence is
only 2%, a primary lung tumor should be kept in mind, and sought, at the time of evaluation of a candidate for transplant. When an undetected malignancy is detected at the time of transplant and is staged as a T1N0M0/T2N0M0, we believe that short-term survival (3 years) is not significantly different from that of transplant patients without a malignancy. Strict adherence to pretransplant selection criteria as well as clinical transplant protocols that require a highresolution CT scan immediately (less than 24 hours) prior to transplant may also help to decrease the incidence of undetected primary malignancies in explanted lungs. REFERENCES 1. Hosenpud JD, Bennett LE, Keck BM, et al: J Heart Lung Transplant 17:656, 1998 2. Morrison DL, Maurer JR, Grossman RF: Clin Chest Med 11:207, 1990 3. Trulock EP: Annu Rev Med 43:1, 1992 4. Ginns LD, Wain JC: Transplantation. In: Ginns LC, Benedict Cosimi A, Morris PJ (eds): Transplantation. Oxford: Blackwell; 1999, p 490 5. Svendsen CA, Bengtson RB, Park SJ, et al: Transplantation 66:1108, 1998 6. Penn I: Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 12 (Suppl):S328, 1993 7. Stewart S, McNeil K, Nashef SA, et al: Audit of referral and explant diagnoses in lung transplantation: a pathologic study of lungs removed for parenchymal disease. J Heart Lung Transplant 14:1173, 1995