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(Radiology. 2001;219:503-509.)
© RSNA, 2001

Thoracic Imaging

Frequency and CT Findings of Recurrent Disease after Lung Transplantation1

Jannette Collins, MD, MEd, Michael J. Hartman, MD, Thomas F. Warner, MD, Nestor L. Müller, MD, PhD, Ella A. Kazerooni, MD, H. Page McAdams, MD, Richard M. Slone, MD and Leonard A. Parker, MD

1 From the Departments of Radiology (J.C., M.J.H.) and Pathology (T.F.W.), University of Wisconsin Hospital and Clinics, E3/311 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-3252; and the Departments of Radiology at the University of British Columbia Centre for Health Sciences, Vancouver, Canada (N.L.M.); University of Michigan School of Medicine, Ann Arbor (E.A.K.); Duke University Medical Center, Durham, NC (H.P.M.); Washington University School of Medicine, St Louis, Mo (R.M.S.); and University of North Carolina School of Medicine, Chapel Hill (L.A.P.). Received August 19, 2000; revision requested September 26; revision received October 24; accepted November 1. Address correspondence to J.C. (e-mail: jcollin4@facstaff.wisc.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the frequency and computed tomographic (CT) findings of recurrence of the primary disease after lung transplantation at six North American lung transplantation centers.

MATERIALS AND METHODS: Medical records of 1,394 lung transplant recipients were reviewed to identify patients with recurrent primary disease. Their CT scans and pathologic specimens were reviewed.

RESULTS: The frequency of disease recurrence in the six transplantation centers was 1% (15 of 1,394 patients), including six previously reported cases. Sarcoidosis recurred in nine (35%) of 26 transplants and was the most common disease to recur. Three (33%) of nine patients with recurrent sarcoidosis had correlative findings at CT. When present, CT findings were usually different at recurrence compared with pretransplantation CT findings.

CONCLUSION: A relatively small percentage of patients are at risk for recurrence of primary disease following lung transplantation. Sarcoidosis is the most common disease to recur.

Index terms: Bronchiolitis obliterans, 60.2191 • Histiocytosis, 60.66 • Lung, CT, 60.1211 • Lung, transplantation, 60.458 • Lymphangiomyomatosis, 99.829 • Proteinosis, pulmonary alveolar, 60.791 • Sarcoidosis • Talc, 60.775


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
As of March 18, 1999, the Registry of the International Society for Heart and Lung Transplantation has recorded 2,510 heart-lung transplantations from 124 programs and 5,347 single and 3,751 double lung transplantations from 153 lung transplantation programs (1). The number of heart-lung transplantation procedures peaked in 1989 and has declined thereafter; now it accounts for only 10% of the total procedures in the Western hemisphere (1). While the number of lung transplantations increased continuously through 1993, the lack of available donors has resulted in a plateau of approximately 1,000 procedures performed each year worldwide (1). The most common indications for adult lung transplantation are chronic obstructive pulmonary disease (the most common indication for single lung transplantation), cystic fibrosis (the most common indication for bilateral lung transplantation), idiopathic pulmonary fibrosis, and primary pulmonary hypertension (1). The total lung transplantation actuarial survival rate during 1988–1999 is approximately 70% at 1 year and 45% at 5 years (1).

Infection and obliterative bronchiolitis are the most common causes of death after heart-lung or lung transplantation (1). Other important causes include acute rejection, lymphoproliferative disease, and other malignancies. Numerous case reports (2–30) have described recurrence of primary disease as a complication of lung transplantation, in some cases leading to patient death. The purpose of this study was to determine the frequency and computed tomographic (CT) findings of recurrence of the primary disease after lung transplantation at six North American lung transplantation centers.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Medical records of all patients (n = 1,394) who underwent single (n = 638), bilateral (n = 719), and heart-lung (n = 37) transplantation at the University of Wisconsin (n = 169), Madison; University of British Columbia (n = 84), Vancouver, Canada; University of Michigan (n = 188), Ann Arbor; Duke University Medical Center (n = 263), Durham, NC; Washington University (n = 515), St Louis, Mo; and University of North Carolina (n = 175), Chapel Hill, between 1988 and 2000 were reviewed to identify cases of recurrent primary disease. CT scans obtained near the time of diagnosis of recurrence were reviewed for the presence of abnormalities associated with the diseases that lead to the transplantation: emphysema, honeycombing, lymphadenopathy, nodules, consolidation, ground-glass opacification, cysts, bronchiectasis, bronchiolectasis, bronchial wall thickening, and tree-in-bud opacities. Final interpretation of all CT scans was determined by consensus between radiologists (N.L.M., H.P.M., R.M.S., L.A.P., E.A.K.) from the home institution and one other radiologist (J.C.). Pathologic specimens were reviewed by a pathologist at the home institution. Patient history, including age at recurrence, primary disease leading to transplantation, and method of diagnosis of recurrent disease, was obtained from medical records.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The study group included 15 patients with recurrence of the primary disease (four from the University of Wisconsin, one from the University of British Columbia, five from the University of Michigan, two from Duke University Medical Center, two from Washington University, and one from the University of North Carolina) who underwent single lung (n = 5), bilateral lung (n = 9), or heart-lung (n = 1) transplantation. Six diseases recurred (Table). The frequency of disease recurrence among the six centers was 1% (15 of 1,394 transplants).


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  		Patient Demographics, CT and Pathologic Findings, and Frequency of Disease Recurrence after Lung Transplantation at Six Centers

 
Patients ranged in age from 21 to 59 years (mean age, 45 years) at the time of diagnosis of disease recurrence. Six (40%) patients were women, and nine (60%) were men. The underlying pulmonary diseases leading to transplantation were sarcoidosis (n = 9) (Figs 1, 2), LAM (n = 2) (Fig 3), LCH (n = 1) (Fig 4), talc granulomatosis (n = 1) (Fig 5), diffuse panbronchiolitis (n = 1) (Fig 6), and pulmonary alveolar proteinosis (n = 1). Disease recurrence was pathologically proved in all cases with transbronchial lung biopsy (n = 12), open lung biopsy (n = 1), fine-needle lung aspiration (n = 1), or autopsy (n = 1).



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  		Figure 1. Recurrent sarcoidosis. Transverse high-resolution CT scan obtained in a 43-year-old woman 2 years after bilateral lung transplantation shows numerous miliary nodules (arrows) in the upper lungs bilaterally. Transbronchial lung biopsy showed noncaseating granulomas.

 


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  		Figure 2a. Recurrent sarcoidosis. (a) Transverse high-resolution CT scan obtained in a 46-year-old asymptomatic man 32 months after bilateral lung transplantation shows an irregular nodule (arrow) in the right lower lobe. (b) Photomicrograph of a histologic specimen obtained from CT-guided fine-needle aspiration of the nodule in a shows noncaseating granulomatous lesions (G), which had an appearance similar to that found at pretransplantation histologic examination, with no evidence of infection or malignancy. (Hematoxylin-eosin stain; original magnification, x100.)

 


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  		Figure 2b. Recurrent sarcoidosis. (a) Transverse high-resolution CT scan obtained in a 46-year-old asymptomatic man 32 months after bilateral lung transplantation shows an irregular nodule (arrow) in the right lower lobe. (b) Photomicrograph of a histologic specimen obtained from CT-guided fine-needle aspiration of the nodule in a shows noncaseating granulomatous lesions (G), which had an appearance similar to that found at pretransplantation histologic examination, with no evidence of infection or malignancy. (Hematoxylin-eosin stain; original magnification, x100.)

 


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  		Figure 3. Recurrent LAM. Transverse CT scan obtained in a 49-year-old woman 5 years after bilateral lung transplantation shows enlargement of a right retrocrural node (arrow). Fine-needle aspiration of the node showed groups of oval to spindle-shaped cells arranged in a large cohesive aggregate. The individual cells were monomorphic and small, with blunt-ended cigar-shaped nuclei. (Reprinted, with permission, from reference 31.)

 


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  		Figure 4a. Recurrent LCH. (a) Transverse high-resolution CT scan obtained in a 20-year-old man 7 months after bilateral lung transplantation shows an irregular nodule in the right upper lobe (arrow). The man had no history of cigarette smoking. (b) Photomicrograph of a CT-guided biopsy specimen of the nodule in a shows large clusters of brown CD1a-positive cells (arrow). (Immunoperoxidase stain; original magnification, x100.)

 


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  		Figure 4b. Recurrent LCH. (a) Transverse high-resolution CT scan obtained in a 20-year-old man 7 months after bilateral lung transplantation shows an irregular nodule in the right upper lobe (arrow). The man had no history of cigarette smoking. (b) Photomicrograph of a CT-guided biopsy specimen of the nodule in a shows large clusters of brown CD1a-positive cells (arrow). (Immunoperoxidase stain; original magnification, x100.)

 


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  		Figure 5a. Recurrent talc granulomatosis. (a) Transverse high-resolution CT scan obtained in a 49-year-old woman 18 months after right lung transplantation shows no acute disease in either lung. There is emphysema of the native left lung related to a history of methylphenidate hydrochloride abuse and 40-pack-year cigarette smoking; its appearance was unchanged compared with its appearance on the pretransplantation CT scan. (b) Photomicrograph of a transbronchial biopsy specimen of the right lung obtained 18 months after transplantation shows talc particles (arrows), which have a pale yellow color. (Hematoxylin-eosin stain; original magnification, x100.) (c) Photomicrograph of the same specimen as in b imaged with partially polarized light shows birefringent plates (arrows) formed by the talc particles. (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 5b. Recurrent talc granulomatosis. (a) Transverse high-resolution CT scan obtained in a 49-year-old woman 18 months after right lung transplantation shows no acute disease in either lung. There is emphysema of the native left lung related to a history of methylphenidate hydrochloride abuse and 40-pack-year cigarette smoking; its appearance was unchanged compared with its appearance on the pretransplantation CT scan. (b) Photomicrograph of a transbronchial biopsy specimen of the right lung obtained 18 months after transplantation shows talc particles (arrows), which have a pale yellow color. (Hematoxylin-eosin stain; original magnification, x100.) (c) Photomicrograph of the same specimen as in b imaged with partially polarized light shows birefringent plates (arrows) formed by the talc particles. (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 5c. Recurrent talc granulomatosis. (a) Transverse high-resolution CT scan obtained in a 49-year-old woman 18 months after right lung transplantation shows no acute disease in either lung. There is emphysema of the native left lung related to a history of methylphenidate hydrochloride abuse and 40-pack-year cigarette smoking; its appearance was unchanged compared with its appearance on the pretransplantation CT scan. (b) Photomicrograph of a transbronchial biopsy specimen of the right lung obtained 18 months after transplantation shows talc particles (arrows), which have a pale yellow color. (Hematoxylin-eosin stain; original magnification, x100.) (c) Photomicrograph of the same specimen as in b imaged with partially polarized light shows birefringent plates (arrows) formed by the talc particles. (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 6a. Recurrent diffuse panbronchiolitis. (a) Posteroanterior chest radiograph in a 41-year-old man obtained 22 months prior to lung transplantation shows hyperinflation and diffuse bronchiectasis. (b) Gross specimen of a coronal section of explanted left lung shows cystic spaces (arrows) representing bronchiectasis and bronchiolectasis with focal areas of consolidation. (c) Posteroanterior chest radiograph obtained 2 months after bilateral lung transplantation shows clear lungs bilaterally. (d) Posteroanterior chest radiograph obtained 69 months after image in c (78 months after transplantation) shows severe bilateral bronchiectasis and areas of consolidation. (e) Transverse high-resolution CT scan obtained 38 months after transplantation shows bilateral bronchiectasis (large arrow), bronchiolectasis (small arrow), thickening of airway walls (arrowheads), and areas of consolidation in the lower lungs. (f) Photomicrograph of a histologic section of transplanted lung shows bronchiectasis (long straight arrows), bronchiolization of air spaces (short straight arrow), and interstitial foamy macrophages (curved arrow). (Hematoxylin-eosin stain; original magnification, x100.) (Images courtesy of Victor L. Roggli, MD, Durham, NC.)

 


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  		Figure 6b. Recurrent diffuse panbronchiolitis. (a) Posteroanterior chest radiograph in a 41-year-old man obtained 22 months prior to lung transplantation shows hyperinflation and diffuse bronchiectasis. (b) Gross specimen of a coronal section of explanted left lung shows cystic spaces (arrows) representing bronchiectasis and bronchiolectasis with focal areas of consolidation. (c) Posteroanterior chest radiograph obtained 2 months after bilateral lung transplantation shows clear lungs bilaterally. (d) Posteroanterior chest radiograph obtained 69 months after image in c (78 months after transplantation) shows severe bilateral bronchiectasis and areas of consolidation. (e) Transverse high-resolution CT scan obtained 38 months after transplantation shows bilateral bronchiectasis (large arrow), bronchiolectasis (small arrow), thickening of airway walls (arrowheads), and areas of consolidation in the lower lungs. (f) Photomicrograph of a histologic section of transplanted lung shows bronchiectasis (long straight arrows), bronchiolization of air spaces (short straight arrow), and interstitial foamy macrophages (curved arrow). (Hematoxylin-eosin stain; original magnification, x100.) (Images courtesy of Victor L. Roggli, MD, Durham, NC.)

 


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  		Figure 6c. Recurrent diffuse panbronchiolitis. (a) Posteroanterior chest radiograph in a 41-year-old man obtained 22 months prior to lung transplantation shows hyperinflation and diffuse bronchiectasis. (b) Gross specimen of a coronal section of explanted left lung shows cystic spaces (arrows) representing bronchiectasis and bronchiolectasis with focal areas of consolidation. (c) Posteroanterior chest radiograph obtained 2 months after bilateral lung transplantation shows clear lungs bilaterally. (d) Posteroanterior chest radiograph obtained 69 months after image in c (78 months after transplantation) shows severe bilateral bronchiectasis and areas of consolidation. (e) Transverse high-resolution CT scan obtained 38 months after transplantation shows bilateral bronchiectasis (large arrow), bronchiolectasis (small arrow), thickening of airway walls (arrowheads), and areas of consolidation in the lower lungs. (f) Photomicrograph of a histologic section of transplanted lung shows bronchiectasis (long straight arrows), bronchiolization of air spaces (short straight arrow), and interstitial foamy macrophages (curved arrow). (Hematoxylin-eosin stain; original magnification, x100.) (Images courtesy of Victor L. Roggli, MD, Durham, NC.)

 


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  		Figure 6d. Recurrent diffuse panbronchiolitis. (a) Posteroanterior chest radiograph in a 41-year-old man obtained 22 months prior to lung transplantation shows hyperinflation and diffuse bronchiectasis. (b) Gross specimen of a coronal section of explanted left lung shows cystic spaces (arrows) representing bronchiectasis and bronchiolectasis with focal areas of consolidation. (c) Posteroanterior chest radiograph obtained 2 months after bilateral lung transplantation shows clear lungs bilaterally. (d) Posteroanterior chest radiograph obtained 69 months after image in c (78 months after transplantation) shows severe bilateral bronchiectasis and areas of consolidation. (e) Transverse high-resolution CT scan obtained 38 months after transplantation shows bilateral bronchiectasis (large arrow), bronchiolectasis (small arrow), thickening of airway walls (arrowheads), and areas of consolidation in the lower lungs. (f) Photomicrograph of a histologic section of transplanted lung shows bronchiectasis (long straight arrows), bronchiolization of air spaces (short straight arrow), and interstitial foamy macrophages (curved arrow). (Hematoxylin-eosin stain; original magnification, x100.) (Images courtesy of Victor L. Roggli, MD, Durham, NC.)

 


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  		Figure 6e. Recurrent diffuse panbronchiolitis. (a) Posteroanterior chest radiograph in a 41-year-old man obtained 22 months prior to lung transplantation shows hyperinflation and diffuse bronchiectasis. (b) Gross specimen of a coronal section of explanted left lung shows cystic spaces (arrows) representing bronchiectasis and bronchiolectasis with focal areas of consolidation. (c) Posteroanterior chest radiograph obtained 2 months after bilateral lung transplantation shows clear lungs bilaterally. (d) Posteroanterior chest radiograph obtained 69 months after image in c (78 months after transplantation) shows severe bilateral bronchiectasis and areas of consolidation. (e) Transverse high-resolution CT scan obtained 38 months after transplantation shows bilateral bronchiectasis (large arrow), bronchiolectasis (small arrow), thickening of airway walls (arrowheads), and areas of consolidation in the lower lungs. (f) Photomicrograph of a histologic section of transplanted lung shows bronchiectasis (long straight arrows), bronchiolization of air spaces (short straight arrow), and interstitial foamy macrophages (curved arrow). (Hematoxylin-eosin stain; original magnification, x100.) (Images courtesy of Victor L. Roggli, MD, Durham, NC.)

 


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  		Figure 6f. Recurrent diffuse panbronchiolitis. (a) Posteroanterior chest radiograph in a 41-year-old man obtained 22 months prior to lung transplantation shows hyperinflation and diffuse bronchiectasis. (b) Gross specimen of a coronal section of explanted left lung shows cystic spaces (arrows) representing bronchiectasis and bronchiolectasis with focal areas of consolidation. (c) Posteroanterior chest radiograph obtained 2 months after bilateral lung transplantation shows clear lungs bilaterally. (d) Posteroanterior chest radiograph obtained 69 months after image in c (78 months after transplantation) shows severe bilateral bronchiectasis and areas of consolidation. (e) Transverse high-resolution CT scan obtained 38 months after transplantation shows bilateral bronchiectasis (large arrow), bronchiolectasis (small arrow), thickening of airway walls (arrowheads), and areas of consolidation in the lower lungs. (f) Photomicrograph of a histologic section of transplanted lung shows bronchiectasis (long straight arrows), bronchiolization of air spaces (short straight arrow), and interstitial foamy macrophages (curved arrow). (Hematoxylin-eosin stain; original magnification, x100.) (Images courtesy of Victor L. Roggli, MD, Durham, NC.)

 
Among the six centers, CT findings were present in recurrent sarcoidosis, LAM, LCH, and diffuse panbronchiolitis. Recurrent sarcoidosis manifested as either a solitary pulmonary nodule or numerous miliary nodules. Recurrence of LAM was seen as an enlarged retrocrural lymph node. A solitary pulmonary nodule was seen in the case of recurrent LCH. Findings of bronchiectasis, bronchiolectasis, bronchial wall thickening, and tree-in-bud opacities were seen with recurrent diffuse panbronchiolitis. At the time of diagnosis of recurrence, no CT scans showed consolidation, ground-glass opacification, or cysts. Emphysema and honeycombing were seen in only the nontransplanted lungs in patients with single lung transplants, and its appearance was unchanged compared with its appearance on CT scans obtained prior to the diagnosis of disease recurrence.

Frequency of specific diseases was 35% for sarcoidosis (nine recurrences in 26 transplants), 10% for LAM (two recurrences in 21 transplants), 25% for LCH (one recurrence in four transplants), 50% for pulmonary alveolar proteinosis (one recurrence in two transplants), and 100% for diffuse panbronchiolitis and talc granulomatosis (one recurrence in one transplant for both). The frequency of recurrence for these six diseases was 27% (15 of 55 transplants).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A computer search of the literature identified 26 articles that reported the recurrence of pulmonary disease after lung transplantation. Review of bibliographies revealed three additional articles. These 29 articles report on 35 cases of recurrence of pulmonary disease after lung transplantation and include six of the 15 cases identified in the current study. The 35 previously reported cases of recurrent disease include sarcoidosis (n = 14) (2–11), LCH (n = 5) (12–14), LAM (n = 4) (15–18), bronchioloalveolar cell carcinoma (n = 4) (19), desquamative interstitial pneumonitis (n = 3) (20–23), pulmonary alveolar proteinosis (n = 1) (24), giant cell interstitial pneumonitis (n = 1) (25), diffuse panbronchiolitis (n = 1) (26), talc granulomatosis (n = 1) (27), and bronchiectasis secondary to aspiration (n = 1) (28). Two additional articles (29,30) reported on recurrence of sarcoidosis but not on the number of cases. These cases were not included in the total number of recurrences.

The 35 published cases and our nine previously unreported cases result in 44 cases of recurrence of primary disease after lung transplantation, representing 10 diseases. According to the International Society for Heart and Lung Transplantation (1), diseases leading to single or bilateral lung transplantation include emphysema (45.1% or 19.4%, respectively), cystic fibrosis (2.0% or 32.8%, respectively), idiopathic pulmonary fibrosis (21.9% or 7.3%, respectively), miscellaneous (12.8% or 17.9%, respectively), {alpha}1-antitrypsin deficiency (10.7% for both), primary pulmonary hypertension (4.7% or 9.9%, respectively), and retransplantation (2.8% or 2.2%, respectively). Of these, only miscellaneous diseases are included in the list of recurrences derived from our multi-institutional review and review of the literature. A relatively small percentage of patients treated with lung transplantation are therefore at risk for recurrence of disease.

Sarcoidosis, a multisystem disorder of unknown cause principally characterized by granulomatous lesions of the respiratory tract and other organs, is the most commonly reported disease to recur. The frequency of recurrence among the six centers was 35% (nine of 26 transplants). That this disease recurs is not surprising since it is characterized by an augmented immune response, with activated lymphocytes and mononuclear phagocytes at sites of disease activity. It has been hypothesized (6) that acute allograft rejection and evolution of sarcoid granulomas may share common immunopathogenetic mechanisms. Although the incidence of acute rejection does not differ between patients with and those without sarcoidosis, histologic grades of rejection are substantially more severe among patients with sarcoidosis (4).

Fourteen cases of recurrent sarcoidosis have been reported (in addition to two additional reports of an undocumented number of recurrences), and we describe seven previously unreported cases. Recurrence of sarcoidosis has been reported as early as 2 weeks after transplantation (4), despite maintenance on a regimen intended to inhibit or minimize T-cell responses, and as late as 2 years after transplantation (7,10). In most cases, recurrence is diagnosed as an incidental finding at transbronchial lung biopsy and is unrelated to clinical or radiologic abnormalities. CT scans have shown subtle interstitial opacities (7) and miliary nodules (2,3,6). One of our previously unreported cases of recurrent sarcoidosis was associated with the CT finding of a solitary nodule.

Transbronchial biopsy of recurrent sarcoidosis shows multiple noncaseating giant cell epithelioid granulomas. Because granulomas can also be seen with mycobacterial or fungal infection, it is important to exclude these diagnoses. In addition, a negative transbronchial lung biopsy finding does not exclude recurrent sarcoidosis, due to the patchy nature of the disease (9).

LCH is a disorder of unknown cause characterized by focal interstitial proliferation of Langerhans cells that surround the terminal bronchioles and alveolar ducts. The frequency of recurrence of LCH among the six centers was 25% (one of four transplants). Five cases of recurrence of LCH after lung transplantation have been reported, and we describe one previously unreported case. Three patients were symptomatic and three were not. Asymptomatic patients require no therapy other than observation and advice to stop smoking. Recurrence occurs as early as 7 months (our unreported case) and as late as 4 years (12) after transplantation. Although the disease is said to be more common in cigarette smokers, both our case and one of the cases reported by Gabbay et al (13) involved lifelong nonsmokers. In one case of recurrence, a patient had been a smoker but stopped smoking after transplantation (12).

CT scans in patients with recurrent LCH show one or more of the following: diffuse thin-walled cysts, diffuse nodular opacities, and interstitial fibrosis (12–14). The disease typically affects the upper and middle lung zones and spares the costophrenic angles. However, in one patient, the radiologic changes were most prominent in the lower lobes, both initially and with recurrence (12). In our previously unreported case, CT scans showed a nodule in the right upper lobe.

At histologic examination, LCH is diagnosed with the presence of bronchiolocentric nodules formed of focal collections of Langerhans cells interspersed with eosinophils and small lymphocytes (12). Langerhans cells are normally present in the human lung and are seen with interstitial pneumonitis and other lung diseases, but it is the formation of large aggregates that distinguishes LCH and leads to lung destruction. In the transplanted lung, donor Langerhans cells, initially present in the grafted lung, are progressively replaced with Langerhans cells derived from the recipient’s bone marrow. It has been hypothesized that the pathogenesis in two patients with relapse was due to the repopulation of the transplanted lung with abnormally reactive Langerhans cells from the recipient (supporting a systemic process) in addition to exogenous stimulation with tobacco smoke (14).

LAM is a rare disorder of abnormal smooth muscle cell proliferation that can lead to end-stage pulmonary disease; it affects predominantly white women of childbearing age. Patients often have spontaneous pneumothorax, chylothorax, hemoptysis, and slowly progressive dyspnea. Compared with all lung transplant recipients, patients who have undergone lung transplantation for LAM have increased morbidity and mortality due to complications related to their underlying disease (native lung pneumothorax, chylous pleural effusions and ascites, hemorrhagic renal angiomyolipomas, and recurrence of disease) (31). Four cases of recurrent LAM have been reported (15–18), all as incidental diagnoses from 1 year (15) to 5 years (18) after transplantation. We report an additional case of recurrent LAM diagnosed incidentally at autopsy 2 years after single lung transplantation.

Because the diagnoses were made incidentally, either at autopsy in patients who died of a cause unrelated to LAM or during routine biopsy, CT findings of recurrent LAM in the lung were not reported. In one case, incidental enlargement of a retrocrural lymph node at CT was proved to represent recurrence of LAM with fine-needle aspiration (18). Pretransplantation CT scans typiczally show thin-walled cysts randomly scattered throughout the lungs, with normal intervening lung parenchyma.

Histologic findings of LAM include diffuse abnormal proliferation of short fascicles of immature smooth muscle cells, with obliteration of the normal pulmonary architecture, that results in large dilated lymphatic and vascular channels and air spaces. Immature smooth muscle cells can be seen surrounding blood vessels, bronchioles, and lymphatic channels.

The recurrence of LAM raises interesting questions regarding its cause. Because it occurs almost exclusively in women, one might expect the use of male donors to preclude the development of recurrence. However, LAM has been reported (32) in a man, and three of the four reported cases of recurrence involved a male donor. Bilateral lung transplantation does not prevent recurrence due to nodal involvement.

Bronchioloalveolar carcinoma is a type of bronchogenic adenocarcinoma histologically characterized by well-differentiated adenocarcinoma cells lining the alveolar walls and by the preservation of interstitial structures. Bronchioloalveolar carcinoma tends to metastasize widely throughout the lungs but less commonly elsewhere. Garver et al (19) treated seven patients with intrapulmonary metastatic bronchioloalveolar carcinoma with unilateral (n = 2) or bilateral (n = 5) lung transplantation. Four of the seven patients had recurrent bronchioloalveolar carcinoma limited to the donor lungs 10–48 months after transplantation. Histologic and molecular analyses showed that the recurrent tumors in three patients originated from the recipients of the transplants. In 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 were reportedly alive with no evidence of disease 62 and 50 months after transplantation; overall survival for stage IV bronchioloalveolar carcinoma rarely exceeds 5 years (33,34). Radiologic findings in the four cases of recurrent bronchioloalveolar carcinoma were not described.

Desquamative interstitial pneumonitis was described in 1965 by Liebow et al (35) as a unique form of interstitial lung disease of unknown cause with distinctive histologic findings and a characteristic clinical course that was generally believed to be more favorable than that of most forms of interstitial fibrosis. Three cases of recurrent desquamative interstitial pneumonitis have been reported (20–22); these occurred between 1 month (21) and 1 year (20) after transplantation. Two of the three patients were symptomatic. Two patients smoked cigarettes prior to transplantation.

High-resolution CT findings were normal in one case (21) and showed ground-glass opacities in the lower lobe of the transplanted lung in a second case (20). The most frequently described (36) high-resolution CT finding in patients with desquamative interstitial pneumonitis is ground-glass opacification involving mainly the lower lobes.

The most striking histologic feature of desquamative interstitial pneumonitis is intraalveolar accumulation of clumps of cells. The term "desquamative" was coined because these cells were originally thought to be alveolar type II cells that had sloughed from the epithelial surface. We now know that most of these cells are histiocytes. Recurrence of disease may be due to a systemic process or may be related to a process mediated by surface characteristics of the native lung.

One case each of recurrent pulmonary alveolar proteinosis (24), giant cell interstitial pneumonia (25), diffuse panbronchiolitis (26), talc granulomatosis (27), and bronchiectasis secondary to aspiration (28) has been reported to occur 3 years, 2 years, 10 weeks, 18 months, and an unspecified time after lung transplantation, respectively. Possible factors related to recurrence of pulmonary alveolar proteinosis include inhaled agents, altered immunity, locally produced toxic agents, overproduction of surfactant-like material by type 2 pneumocytes, or defective clearance of the material by alveolar macrophages due to an underlying defect in circulating monocytes (24). In the one reported case of recurrent pulmonary alveolar proteinosis, the chest radiograph showed diffuse air-space opacities in both lungs. At histologic examination, intraalveolar proteinaceous material was present and stained intensively with periodic acid-Schiff digest stains.

Giant cell interstitial pneumonia is a unique form of pulmonary fibrosis attributed to cobalt exposure, usually in the form of hard metal. Diagnosis of recurrence was made at histologic examination on the basis of the presence of interstitial lymphocytic infiltrates and fibrosis, multinucleated giant cells attached to alveolar septa or free in the intraalveolar spaces, and large numbers of histiocytes in the transplanted lung (25). Radiologic findings were not reported. The cause of recurrence may be a result of residual hard metal particles in the native lung spilling into the transplanted lung, but this is unlikely, as this could not be confirmed at autopsy. An immune-mediated process is possible, with hard metal in the native lung affecting the transplanted lung.

Diffuse panbronchiolitis is a disease characterized by chronic inflammation of the sinuses and respiratory bronchioles, most commonly affecting the Asian population, although the reported case of recurrence occurred in an African American patient (26). In this case, histologic examination showed an accumulation of foamy cells in the walls of respiratory bronchioles and adjacent alveolar ducts. Pre- and posttransplantation high-resolution CT performed at the time of recurrence showed the same findings: bronchiectasis, bronchial wall thickening, and small nodular and linear branching opacities in a bronchiolar distribution. The rapid symptomatic recurrence of diffuse panbronchiolitis in the allograft suggests the presence of a systemic disorder.

Recurrent talc granulomatosis occurred as an unusual consequence of the intravenous injection of methylphenidate hydrochloride. While the patient had a 20-year history of intravenous drug abuse, no drug use was reported during the 7 years prior to transplantation. At the time recurrence was diagnosed, the patient admitted recurrent drug abuse. Histologic findings in the transplanted lung showed numerous, small, birefringent particles lying within the alveolar capillary lumina, with a poorly formed histiocytic response. High-resolution CT scans showed severe panacinar emphysema in the native lung and absence of acute disease in the transplanted lung. The reported (37,38) high-resolution CT findings of talc granulomatosis are ground-glass opacities or small nodules throughout the lungs, which can progress to larger nodules and conglomerate masses in the upper lobes with compensatory overinflation of the lower lobes. In patients with a history of intravenous methylphenidate hydrochloride abuse, a relatively common finding at high-resolution CT is the presence of bilateral primarily panacinar emphysema (39).

In summary, 35 cases of recurrent disease have been reported after lung transplantation, and we report nine additional cases. These 44 cases represent 10 diseases, none of which are common indications for lung transplantation. Sarcoidosis is the most commonly reported disease to recur, with 21 cases now reported in the literature and with a 35% incidence of recurrence among our six centers. Recurrence of the primary disease for which transplantation was performed is often discovered incidentally and can be considered in patients with or without new pulmonary symptoms, new abnormal findings at pulmonary function testing, or new findings at chest radiography or CT. Although no patient died as a direct result of disease recurrence (except in the cases of recurrent bronchioloalveolar carcinoma), recurrence can become a more serious complication if the incidences of infection and obliterative bronchiolitis decrease.


   FOOTNOTES
 
Abbreviations: LCH = Langerhans cell histiocytosis, LAM = lymphangioleiomyomatosis

Author contributions: Guarantor of integrity of entire study, J.C.; study concepts, J.C., R.M.S.; study design, J.C., N.L.M.; literature research, J.C.; clinical studies, all authors; data acquisition, all authors; data analysis/interpretation, J.C.; statistical analysis, J.C.; manuscript preparation and definition of intellectual content, J.C.; manuscript editing, revision/review, and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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