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Editorials and Perspectives: Clinical Transplantation

Lung Transplantation for Lymphangioleiomyomatosis: The French Experience

Reynaud-Gaubert, Martine1,10; Mornex, Jean-François2; Mal, Hervé3; Treilhaud, Michèle4; Dromer, Claire5; Quétant, Sébastien6; Leroy-Ladurie, François7; Guillemain, Romain8; Philit, François2; Dauriat, Gaëlle3; Grenet, Dominique9; Stern, Marc9

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doi: 10.1097/TP.0b013e31817c15df
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Lymphangioleiomyomatosis (LAM) is a rare disorder of unknown origin first described in 1937 (1). Lymphangioleiomyomatosis exclusively affects women in their child bearing years, with an onset in the fourth decade. It is characterized by respiratory symptoms such as dyspnea, cough, hemoptysis, but complications such as pneumothoraces or chylous effusions and ascitis can reveal the disease (2, 3). Lymphangioleiomyomatosis has a variable and unpredictable rate of progression and eventually leads to respiratory failure. Nowadays, medical therapeutic interventions are limited and consist mainly in the management of complications. Although the recent published results of therapy with the mammalian target of rapamycin (mTOR) inhibitor, sirolimus hold promise especially as a treatment of angiomyolipoma (AML) (4), enthusiasm about the pulmonary function results should be tempered (5) and justify the need for larger clinical trials using such therapies. Indeed, lung transplantation (LT) has emerged as a potential treatment option in patients affected with end-stage respiratory insufficiency. In the International Registry, LAM accounts for approximately 1% of all of the transplanted patients (6). Thus, limited clinical experience on LT in this disease is nowadays available (7–12). We therefore conducted a national survey to obtain more information on presurgical status and postoperative outcome after LT for LAM.


In September 2006, a standardized questionnaire was sent to each transplant centers in France to collect all cases of patients who underwent lung or heart-LT for LAM. In all cases, the diagnosis of pulmonary LAM has been confirmed on histological examination of the explanted lung. The questionnaire focused on several issues: demographic and pretransplant characteristics of patients, modalities of the diagnosis of LAM, type of surgery, perioperative management and postoperative results, including survival, incidence of acute rejection and infections, freedom from bronchiolitis obliterans syndrome (BOS), incidence of recurrence of LAM, complications arising from the native lung in case of single-lung transplantation (SLT), and incidence of malignancy.

Statistical Analysis

Descriptive statistics were used to analyze recipient characteristics. Unless otherwise indicated, data were obtained on every item for all of the patients. Normally distributed continuous data were expressed as mean±SD. Actuarial survival data were expressed as Kaplan-Meier survival estimates.


From 1988 to 2006, 45 lung transplant procedures were performed in 44 women for end-stage LAM at 9 of the 11 active transplant centers in France; a total of 1798 LTs have been performed in France during the same period. Thirty-four patients underwent SLT with 21 right SLT and 13 left SLT, and 11 patients experienced bilateral lung transplantation (BLT). One patient was retransplanted (BLT) for BOS 5 years after the initial procedure (left SLT). The age at diagnosis was 36±9.8 years and the age at transplantation was 41±10 years.

The characteristics of the 44 patients are summarized in Table 1. Extrapulmonary manifestations of LAM consisted of renal AML which were identified in 16 patients (eight unilateral, eight bilateral) among them five giant lesions were treated by selective arterial embolization and two required a unilateral nephrectomy, pelvic and abdominal AML in 15 patients, with a chylous ascites in one case. In four patients, pulmonary LAM developed in the context of tuberous sclerosis. Thirty-nine patients (88.6%) underwent previous thoracic surgery which consisted of an open lung biopsy performed in the majority of patients (70%) to make the diagnosis of LAM, pleurodesis (22 patients), and pleurectomy (10 patients).

Baseline characteristics of the patients with LAM (n=44)

The main abnormalities of the latest preoperative pulmonary functional assessment are summarized in Table 2. The functional disorders were mainly obstructive defects in 30 patients (66.6%) and combined obstructive and restrictive pattern in 15 patients (33.3%). The mean forced expiratory volume in 1 second (FEV1) of the whole transplanted population was 22.8% of predicted. All the studies for carbon monoxide diffusing capacity (n=19) had a decreased diffusing capacity of carbon monoxide per alveolar volume (mean value: 27.2±8.8% of predicted). All patients presented with resting arterial hypoxemia on room air and 47.6% presented with hypercapnia (mean PaCO2: 42.6±9.8 mm Hg). Almost all the patients (93%) required oxygen and three patients required noninvasive ventilation before transplantation. The results of right cardiac catheterization were obtained preoperatively for only 20 patients. Pulmonary hypertension (PAPm >25 mm Hg) was noted in 9 (45%). The mean PAPm was 33±8.3 mm Hg and the highest PAPm recorded was 47 mm Hg.

Pulmonary function at the late evaluation before lung transplantation (n=45)

Operative and perioperative details of transplant procedures are given in Table 3. The main intraoperative complications were related to previous pleural procedures. About half the patients had moderate-to-severe pleural adhesions responsible of moderate or severe hemorrhage, requiring repeated thoracotomy in 10 patients (22%). No surgically intraoperative procedure was performed to decrease the rate of LAM related complications such as pneumothorax or chylothorax after lung transplant. For example, pleurodesis or ligation of the thoracic duct.

Operative and perioperative details of transplant procedure for LAM (n=45)

The mean duration of follow-up was 53±50 months (median 37 months, range, 3-188 months). Survival of the 44 transplanted patients was 79.6% at 1 year, 74.4% at 2 years, 64.7% at 5 years, and 52.4% at 10 years (Fig. 1). There was no difference in survival according to the type of procedure and to the presence of AML. Twenty-five patients (56.8%) were alive at 62.6±52 months (median 60.8 months; range, 3-188 months).

Kaplan-Meier survival after LT estimates for 44 patients with LAM.

The best functional test values were obtained 12.6±11.4 months after surgery. The mean postoperative FEV1 was 1.41±0.35 L, that is, 54%±14% of the predicted value (median 1.45 L, i.e., 55%, range, 21%-81%) and 2.21±0.85 L, that is, 76%±26% of the predicted value (median 1.92 L, i.e., 74%, range, 54-129) for the single transplant and the bilateral transplant recipients, respectively. Eighteen patients experienced at least one episode of acute rejection (14/18 histologically proven). The mean number of episode per patient was 1.72±0.88 (range, 1-4). The first episode of acute rejection occurred at a mean of 34±27 days (median 18 days, range, 7-137) after transplantation. Bronchiolitis obliterans syndrome was diagnosed in 15 patients (34%) at a mean±SD of 41.7±35.1 months (median 24.8 months; range, 10.9-108 months), including four BOS stage 1,six BOS stage 2, five BOS stage 3.

In five SLT recipients, pneumothorax arose from the native lung. One case of bilateral pneumothorax was observed after a BLT. In four SLT recipients, chylothoraces occurred in the native lung (n=2) and in the transplanted side (n=2), and there were bilateral recurrent chylothorax in two BLT recipients. In one of the 16 patients affected with AML, there was a late postoperative hemorrhage which has been successfully treated by embolization. Renal insufficiency occurred in three patients and one patient required renal transplantation 3 years after LT.

Malignant neoplasm was observed in seven cases. Three patients developed a lymphoproliferative disease, two uterine carcinoma, one breast carcinoma, and one basocellular skin cancer. Two cases of recurrence of LAM were observed, one on the transplanted lung (with specific radiological and histological findings) and the other on mediastinal and retroperitoneal lymph nodes (Table 4).

Postoperative complication after lung transplantation for LAM (n=44)


Lung transplantation for the treatment of respiratory failure in LAM is nowadays admitted. The first successful transplantation in LAM, a combined heart-lung procedure has been reported by Estenne and al. (7) in 1984. Because LAM is a rare disorder, there are few data in the literature on transplanted LAM. Except the retrospective multicenter series published in1996 by Boehler et al. (8) and the review of 14 patients who underwent LT for LAM in Washington University (10), the other published data on the topic have limitations largely because of the limitations of the registries (11, 12). Between January, 1995 and June, 2006, 175 LT for LAM were recorded in the International Registry of Heart and Lung Transplantation (6). Although LAM accounts for only 1% of all lung-transplanted recipients (and 2% of LT in the French registry), specific guidelines exist for referral and for transplantation in LAM (13). However, the physicians treating LAM patients often have difficulties in assessing the prognosis of the disease and in deciding to refer patients to a transplant team. Factors associated with a poor prognosis comprised a reduction in FEV1/ forced vital capacity, an increase in percentage TLC, and predominantly cystic LAM lesions than smooth muscle proliferation on histologic examination of the lung (14–16). Our study gave us the opportunity to assess lung function before transplantation, data not reported by the registries (11, 12). In accordance with a previous series (8), almost all of our LAM patients had a severe obstructive deficiency, with an important decrease in carbon monoxide diffusing capacity leading to a hypoxemia and subsequent supplemental oxygen at rest for all of the transplant candidates.

The patients evaluated in this series had a typical preoperative clinical course, with the average age of 41 years at transplantation, similar to that described in other series of transplanted LAM (8, 10, 11). About 75% of the patients underwent SLT. Both unilateral and bilateral procedures, and more rarely, heart-LT have been performed successfully in LAM. In the 2007 registry of ISHLT (6), there were mostly bilateral procedures in LAM patients (59 SLT vs. 116 BLT). The choice of the type of procedure depends in part on the surgical team and on the country. Indeed, SLT is predominant in the cohort of Boehler et al. (8), whereas there were more BLT (74%) in the United Network for Organ Sharing (UNOS) between 1998 and 2002 (11). However, the type of transplant did not seem to affect survival in the largest patient cohort from data collected by the UNOS (11). Because of elevated specific LAM-related complication developing from the native lung after SLT (8, 11) and the potential risk of recurrence of the disease, BLT have been favored over SLT for LAM several years ago (10, 11). Finally, as we found in our cohort, despite there were demonstrably better pulmonary function test results in double lung transplant recipients (8, 17), there would be no differences in subjective measures of function using the Functional Performance Inventory scores between single and double lung recipients (17).

Pleural interventions such as pleurodesis and pleurectomy are often performed to manage recurrent pneumothorax and chylothorax in patients with LAM (18, 19). Several years ago, a previous intrapleural procedure causing extensive pleural adhesions would have been considered as a contraindication to LT. Because experience with transplantation increased previous intrapleural interventions causing complexity of the operative dissection, and consecutive pleural-related perioperative bleeding became a relative than an absolute contraindication (8, 10, 18, 20). However, in few series, hemorrhage frequently led to repeated surgery or death (8–10, 15) and the use of cardiopulmonary bypass has been associated with significantly increased morbidity and mortality (20). Dusmet et al. (21), did not found any significant increase in the operating time, blood loss, transfusion requirements, time of intubation, and intensive care unit stay in the study population (not affected with LAM) with a previous intrapleural procedure (n=18) when compared with controls without any previous surgery (n=18). In our population, there were a high percentage of women with a history of pneumothorax and chylothorax, which was responsible for previous surgery in nearly 90% of cases. This could explain the frequent use of cardiopulmonary bypass (29%) and repeat thoracotomy requirement (22%).

Although the perioperative and postoperative periods are fraught with specific related LAM complications, in agreement with the other series (8, 10, 11, 20, 21), prevalence of major morbidity, incidence of acute rejection episodes and BOS, rate of infection or short-term mortality in LAM were similar when compared with what is observed after LT for other indications (6). In accordance with the UNOS database and St Louis’ experience, long-term survival in patients transplanted for LAM is better than seen in other recipients (65% vs. 53% at 5 years) (6), even if the difference did not reach statistical significance. We observed some cases of postoperative pneumothorax and chylothorax. In the literature, the risk of pneumothorax occurring from the native lung after SLT and the occurrence of chylous effusions, sometimes recurrent and refractory chylothoraces, were also underlined in patients with LAM (8, 10, 15, 18, 19, 22).

The recognition of the association of renal AML and LAM is important preoperatively, as the risk of bleeding associated with a large AML is well-known. In the series of Collins et al. (15), 5 of 13 transplanted patients (38%) had renal AML and 4 (31%) had complications related to renal AML, including retroperitoneal hemorrhage, renal colic, and renal failure, requiring a nephrectomy in two. We observed the same incidence of preoperative AML (35%) with only one case of postoperative hemorrhage and three cases of renal insufficiency requiring a renal transplantation in one at 3 years posttransplant. However, the outcome of AML in patients who received lung transplants is limited in the literature and the median follow-up time of our cohort is too short to investigate long-term renal complications. A successful case of nephron-sparing nephrectomy after selective embolization for giant AML has been reported in a LAM transplanted women (23). In our series, five patients had selective arterial embolization for bleeding before transplantation. The impact of such a procedure before the transplantation on the postoperative renal events necessitates to be evaluated.

Like other systemic diseases such as Langerhans’ cell histiocytosis (24) and sarcoidosis (25), LAM could recur in the allograft but the recurrence rate seems to be much lower than for the other mentioned diseases. We observed a recurrence of LAM in two of our transplanted recipients (4.5%). Recurrent LAM is a rare event, and so, there are only few reports (case reports) of allograft recurrence. In such cases, pulmonary recurrence did not affect survival and prognosis of the graft and has been generally identified incidentally in asymptomatic patients at postmortem examination (8, 10, 11, 26–30).Therefore, the clinical significance of recurrence of LAM remains unclear, and larger series of recurrent LAM on the allograft would be needed. There have been several theories proposed to explain the mechanism of recurrence in the allograft. Recent genetic analysis of these cases indicated that benign LAM cells migrate by metastatic mechanism to form new lesions in multiple organs and in the allograft (29). Indeed, analysis of microsatellite markers revealed that foci of recurrent LAM in the allograft contain recipient-derived cells and that the same TCS2 gene mutation present in the native LAM cells was also found in the recurrent LAM cells, demonstrating that recurrent LAM foci did not represent neoformation of the transplanted lung itself (28, 29).

Our patients received a standard triple immunosuppressive regimen including anticalcineurin agents. There are no specific data on the topic of immunosuppression in such patients, and transplanted LAM patients received the same immunosuppressive regimen than in other indications (10, 25). The morbidity resulting from long-term immunosuppression seems similar between the LAM and non-LAM recipients (10), but renal outcome was not specially evaluated. However, the recent molecular-genetic advances of signaling pathways involved in cell growth and proliferation improved knowledge in the physiopathology of LAM. It has been showed that mutations in tuberous sclerosis genes could result in constitutive activation of the mTOR and that drug sirolimus (also called rapamycin), in suppressing mTOR signaling, might constitute an ameliorative therapy (4, 5). There is no data available on the use of mTOR inhibitors, as part of many transplant immunosuppression regimens, in transplanted LAM. We can hypothesize that such drugs could constitute a useful alternative immunosuppressant agents to prevent or delay the recurrence of LAM after transplantation and might need further investigations.

In summary, despite the high prevalence of perioperative events because of previous pleural procedures and thoracic surgery and postoperative specific LAM related complications, the posttransplant respiratory function and survival are satisfactory. Our survey demonstrates that LT can be performed successfully in patients who had previous thoracic surgical procedures and constitutes a valuable therapeutic option of end-stage failure from LAM. Nevertheless, LAM patients potentially candidates to a future LT should be probably usefully referred to experienced transplantation centers to manage pleural complications.


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Lung transplantation; Lymphangioleiomyomatosis; Tuberous sclerosis

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