Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis

Lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) produce cystic and nodular disease, respectively, in the lungs of patients with tuberous sclerosis. The objective of this study was to prospectively characterize the prevalence, clinical presentation, and genetic basis of lung disease in TSC. We performed genotyping and computerized tomographic (CT) scanning of the chest on 23 asymptomatic women with tuberous sclerosis complex (TSC). Cystic pulmonary parenchymal changes consistent with LAM were found in nine patients (39%). These patients tended to be older than cyst-negative patients (31.9 +/- 7.6 yr versus 24.8 +/- 11.6 yr, p = 0.09). There was no correlation between presence of cysts and tobacco use, age at menarche, history of pregnancy, or estrogen-containing medications. Three of the cyst-positive patients had a prior history of pneumothorax. Pulmonary function studies revealed evidence of gas trapping but normal spirometric indices in the cyst-positive group. All nine cyst-positive patients had angiomyolipomas (AML), which were larger (p < 0.05) and more frequently required intervention (p = 0.08) than cyst-negative patients (8 of 14 with AMLs, p < 0.05). Ten patients (43%) had pulmonary parenchymal nodules. Pulmonary nodules were more common in women with cysts (78% versus 21%, p < 0.05), and 52% of all patients had either cystic or nodular changes. TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease. Correlation of the mutational and radiographic data revealed one pair of sisters who were discordant for cystic disease, two mother- daughter pairs who were discordant for nodular disease, and no clear association between cyst development and a specific mutational type. This prospective analysis demonstrates that cystic and nodular pulmonary changes consistent with LAM and MMPH are common in women with TSC.     

Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex. Renal angiomyolipomas, which are found in most tuberous sclerosis patients, also occur in 60% of sporadic LAM patients. We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis. In this study, we report the identification of somatic TSC2 mutations in five of seven angiomyolipomas from sporadic LAM patients. In all four patients from whom lung tissue was available, the same mutation found in the angiomyolipoma was present in the abnormal pulmonary smooth muscle cells. In no case was the mutation present in normal kidney, morphologically normal lung, or lymphoblastoid cells. Our data demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas and pulmonary LAM cells of women with sporadic LAM, strongly supporting a direct role of TSC2 in the pathogenesis of this disease.     

Lymphangioleiomyomatosis and Tuberous Sclerosis Complex

Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease of women of child-bearing age and affects mainly the lungs, promoting cystic destruction of lung parenchyma or leading to abdominal tumor formation (e.g., angiomyolipomas, lymphangioleiomyomas). LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. A substantial body of evidence has now been gathered suggesting that the two diseases share a common genetic origin. TSC is caused by mutations in two genes, TSC1 on chromosome 9q34 and TSC2 on 16p13. Both of these genes are tumor suppressor genes encoding hamartin (TSC1) and tuberin (TSC2). Sporadic LAM is correlated with a mutation in the TSC2 gene and tuberin appears to play a central role in the pathogenesis of the disease. A TSC2 loss or mutation leads to disruption of the tuberin-hamartin heteromer and dysregulation of S6K1 activation leading to aberrant cell proliferation seen in LAM disease. The extremely diverse clinical and radiologic features of the disease and the complex therapeutic approach are reviewed in detail. Although new therapeutic agents have been tested, to date no effective treatment has been proposed and the prognosis of patients with LAM remains poor. As long as newer therapeutic agents do not change this picture, lung transplantation remains the last hope for patients with respiratory failure at the advanced stage of the disease.     

A patient with TSC1 germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis (LAM) can occur as in isolated form (sporadic LAM) or as a pulmonary manifestation of tuberous sclerosis complex (TSC) (TSC-associated LAM). Recent studies, however, revealed that both forms of LAM are genetically related but that sporadic LAM is a distinct clinical entity caused by somatic mutations of TSC2 (not TSC1) rather than a forme fruste of TSC carrying either of the TSC1 or TSC2 germline mutations. METHOD: Case presentation and in-depth molecular and histopathological examinations. A 34-year-old Japanese woman was diagnosed as having pulmonary lymphangioleiomyomatosis (LAM) when bilateral pneumothoraces were surgically treated in 1992. Although slowly progressive renal disfunction was observed due to bilateral multiple renal cysts during the past 4 years, she had no other clinical features of TSC and was diagnosed as having sporadic LAM with multiple renal cysts of undetermined aetiology. Her subsequent clinical course was complicated by an endobrochial carcinoid tumour, which eventually resulted in her death in June 1999 due to massive haemoptysis. RESULTS: Postmortem examination revealed the presence of LAM lesions in the lungs, mediastinal lymph nodes, kidneys and uterus. Diffuse renal LAM lesions are presumed to generate multiple renal cysts by constricting the nephron rather than epithelial hyperplasia obstructing lumina, which is analysis of the TSC genes demonstrated that she did not have TSC2/PKD1 contiguous gene syndrome but had a TSC1 germline mutation (Sato T et al. J Hum Genet 2002; 47: 20-8) that had occured de novo. CONCLUSION: This patient therefore illustrates that clinical manifestations of TSC are sufficiently diverse as to allow a forme fruste of TSC that mimics sporadic LAM and that TSC1 mutation can cause multiple renal cysts resulting in renal failure.     

The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis

Lymphangiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex (TSC). Because only a minority of women with TSC develops symptomatic LAM, we hypothesized that a relationship might exist between the type of germline TSC1 or TSC2 gene mutation and the risk of developing LAM. We examined all 41 exons of the TSC2 gene and 21 coding exons of the TSC1 gene for mutations in a group of 14 women with both TSC and LAM using single-strand conformation polymorphism analysis. Seven mutations were found in TSC2 and one in TSC1. Of the seven patients with TSC2 mutations, two had the same in-frame exon 40 deletion and one had an exon 41 missense change. We conclude that germline mutations in the extreme carboxy-terminus of tuberin can result in LAM. Further studies will be required to determine whether mutations in exons 40 and 41 are associated with an increased incidence and/or severity of LAM in women with TSC.     

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had TSC2 LOH in 33 of 60 (55%) LAM patients. Cells with TSC2 LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.     

Smooth muscle-like cells in pulmonary lymphangioleiomyomatosis

Proliferation, migration, and differentiation of smooth muscle (SM)-like lymphangioleiomyomatosis (LAM) cells in the lungs are pathologic manifestations of pulmonary LAM, a rare lung disease predominantly afflicting women and exacerbated by pregnancy. LAM cells form nodules throughout the lung without any predominant localization, but can also form small cell clusters dispersed within lung parenchyma. LAM cells have the appearance of "immature" SM-like cells, irregularly distributed within the nodule in contrast to organized SM cell layers in airways and vasculature. Progressive growth of LAM cells leads to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. Pathogenetically, LAM occurs from somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2. The TSC1/TSC2 protein complex is an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy. The observation that the TSC1/TSC2 functions as a negative regulator of the mammalian target of rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling pathway yielded the first rapamycin clinical trial for LAM. Although LAM is a rare lung disease, the elucidation of disease-relevant mechanisms of LAM will provide a better understanding of not only SM-like cell growth, migration, and differentiation in LAM but may also offer insights into other metabolic diseases such as cardiovascular diseases, diabetes, and cancer. In this article, we will summarize the progress made in our understanding of LAM, and we will focus on how dysregulation of TSC1/TSC2 signaling results in abnormal proliferation and migration of SM-like LAM cells.     

Lymphangioleiomyomatosis and tuberous sclerosis

Tuberous sclerosis (TSC) is an inherited disorder best known for its association with severe learning difficulties, epilepsy, behavioural problems, skin and renal pathology Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of parenchyma, occurs as an infrequent symptomatic pulmonary complication in TSC and as a very rare sporadic disease in those without signs of TSC. Considered a generalized and progressive cystic lung disease that is difficult to treat with a poor prognosis, it has been reported almost exclusively in women, most commonly presenting with dyspnoea and pneumothorax in those of childbearing age.We investigated the clinical features and prognosis of LAM in patients with TSC including the effects of treatment, stratified by the method of diagnosis of LAM (i.e. histological or radiological).We found histological proof of diagnosis in 10 of 21 patients with TSC and symptomatic lung disease, onset in childhood in four, three males with LAM, individuals with apparently focal disease, great variation in clinical course and no clear treatment benefit. In those with TSC, symptomatic LAM is infrequent but causes a significant morbidity and mortality It was not possible to detect predisposing factors, other than being female. Males with apparent LAM should be rigorously investigated.     

Lymphangioleiomyomatosis: a review of the literature

Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of lung parenchyma, can occur as a rare sporadic disease or as a complication of tuberous sclerosis (TSC). It is a cystic lung disease, usually generalized and progressive, may be extremely difficult to treat and has been considered to have a poor prognosis. It has almost exclusively been reported to present in women of childbearing age, most commonly with dyspnoea and pneumothorax. We reviewed the English literature from 1939 to 1997 for cases of LAM both with and without TSC, in order to document the prevalence, clinical features, investigations, treatment and outcome within and between these two groups. No study has yet determined the prevalence of LAM symptomatically within the general population, but it probably affects 1-3% of the TSC population. Patients with TSC often present with an insidious onset of dyspnoea whilst non-TSC patients present more commonly with acute breathlessness secondary to pneumothorax. Patients with TSC are also less likely to suffer from chylothorax. The age of onset of symptoms and of diagnosis are similar. LAM is rare in children and even less common in males in both groups. The natural course of LAM remains unclear and effect of treatment variable. Although symptomatic LAM is uncommon it causes a significant amount of morbidity and mortality both in the TSC and general population, but asymptomatic LAM is not uncommon in TSC. Further research is required to determine the natural history of this condition and to evaluate current treatment regimes.     

Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism

Lymphangiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells and cystic degeneration of the lung. LAM affects almost exclusively young women. Although lung transplantation provides effective therapy for end-stage LAM, there are reports of LAM recurrence after lung transplantation. Whether these recurrent LAM cells arise from the patient or the lung transplant donor is an area of controversy. We used microsatellite marker fingerprinting and TSC2 gene mutational analysis to study a patient with recurrent LAM after single-lung transplantation. The DNA microsatellite marker pattern indicated the presence of patient-derived LAM cells in the allograft. A somatic one base pair deletion in exon 18 of the TSC2 gene was identified in pulmonary and lymph node LAM cells before transplantation. The same mutation was in the recurrent LAM, demonstrating that the recurrent LAM was derived from the patient. Fluorescence in situ hybridization revealed that cells immunoreactive with the monoclonal antibody HMB-45 did not contain a Y chromosome. These data indicate that histologically benign LAM cells can migrate or metastasize in vivo to the transplanted lung. In addition, the patient had no evidence of a renal angiomyolipoma at autopsy and therefore demonstrated for the first time that somatic TSC2 mutations cause LAM in patients without angiomyolipomas.     

Lymphangioleiomyomatosis: A review

Lymphangioleiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without evidence of other disease (sporadic LAM) or in conjunction with tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. LAM commonly presents with progressive breathlessness or with recurrent pneumothorax, chylothorax, or sudden abdominal hemorrhage. Computed tomography (CT) scans show numerous thin-walled cysts throughout the lungs, abdominal angiomyolipomas, and lymphangioleiomyomas. No effective treatment currently exists for this progressive disorder. The prevalence of lymphangioleiomyomatosis is probably underestimated based on its clinical latency and the absence of specific laboratory tests. With the utilization of international LAM data registries the "classical" picture of the disorder appears to be evolving as a larger number of patients are evaluated. An increased awareness of LAM and its common clinical presentation may advance the development of new therapeutic strategies and reduce the number of mistakenly diagnosed patients.     

Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan

BackgroundLymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes.MethodsUsing cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations.ResultsFour clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required.ConclusionsHierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.     

Current aspects of lymphangioleiomyomatosis

Lymphoangioleiomyomatosis (LAM) is a characteristic diffuse proliferation of abnormal smooth muscle fibers predominantly developing in the lung and leading to cystic destruction. An almost totally specific marker, HMB45, is available. This monoclonal antibody labels cells of the melanocyte line, LAM cells and renal angiomyolipoma cells. The antigen carried by all these cell lines is probably gp-100 involved in melanogenesis. Two gene loci are formally implicated in the pathogenesis of Bourneville tuberous sclerosis (BTS): TSC1 (9q 34.3) and TSC2 (16p 13.3). The TSC2 locus could be implicated in the pathogenesis of pulmonary LAM. LAM and BTS have similar clinical and histological features and could be two different phenotypic forms, distinguished strictly on a nosological basis, of the same disease. The hormone-dependence theory is suggested on the basis of purely clinical arguments, particularly the almost exclusive female predominance, generally during the period of genital activity. Certain counter arguments have also been put forward and consequently, since no in vitro cell culture model or animal model of LAM is available, it is not really possible to verify the hypothesis. Epidemiological data have been recently acquired in France with the constitution of the GERM"O"P registry of LAM cases in France. Recent technological progress in imaging techniques has also been helpful for earlier, more precise diagnosis. HMB45 immunolabeling improves diagnostic sensitivity on small tissue fragments obtained with transbronchial biopsies. The course of LAM appears to be different in certain patient subgroups. Certain patients develop rapidly fatal disease in months or years while in the majority of patients the disease is much less aggressive for years. A minority of patients also have very slowly evolving disease sometimes diagnosed after menopause. Lung transplantation remains the ultimate treatment in case of life-threatening prognosis.     

Lymphangioleiomyomatosis: a clinical update

Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that is associated with mutations in tuberous sclerosis genes, renal angiomyolipomas, lymphatic spread, and remarkable female gender restriction. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections. Lung function declines at approximately twofold to threefold times the rate of healthy subjects, based on an annual drop in FEV1 of 75 to 120 mL in reported series. The diagnosis of pulmonary LAM can be made on high-resolution CT (HRCT) scan with reasonable certainty by expert radiologists, but generally requires a lung biopsy in cases in which tuberous sclerosis complex, angiomyolipomata, or chylous effusions are absent. The currently available treatment strategies are based on the antagonism of estrogen action, and are empiric and unproven. A trial of bronchodilators is warranted in patients with reversible airflow obstruction seen on pulmonary function testing. Pleurodesis should be performed with the initial pneumothorax, because the rate of recurrence is high. Angiomyolipomas that exceed 4 cm in size are more likely to bleed and should be evaluated for embolization. Air travel is well-tolerated by most patients with LAM. Lung transplantation is an important option for LAM patients, and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis in most patients. Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo HRCT scan screening for LAM. Multicenter clinical trials based on several well-defined molecular targets are currently underway in the United States and Europe.     

Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis

Rationale: Lymphangioleiomyomatosis (LAM) is characterized by exercise performance impairment. Although airflow limitation is common, no previous studies have evaluated the prevalence and impact of dynamic hyperinflation (DH) in LAM. Objectives: To investigate the dynamic responses during maximal exercise and the prevalence, predictors, and repercussions of DH in LAM. Methods: Forty-two patients with LAM performed symptom-limited incremental cycle exercise and pulmonary functions tests (PFTs) and were compared with 10 age-matched healthy women. Dyspnea intensity, inspiratory capacity, oxygen saturation, and cardiac, metabolic, and respiratory variables were assessed during exercise. Patients with LAM also performed a 6-minute walk test (6MWT). Measurements and Main Results: Patients with LAM had higher baseline dyspnea, poorer quality of life, obstructive pattern, air trapping, and reduced diffusing capacity of carbon monoxide in PFTs. Although they had the same level of regular physical activity, their maximal exercise performance was reduced and was associated with ventilatory limitation, greater desaturation, and dyspnea. The prevalence of DH was high in LAM (55%), even in patients with mild spirometric abnormalities, and was correlated with airflow obstruction, air trapping, and diffusing capacity of carbon monoxide. Compared with the non-DH subgroup, the patients who developed DH had a ventilatory limitation contributing to exercise cessation on cycling and higher desaturation and dyspnea intensity during the 6MWT. Conclusions: Ventilatory limitation and gas exchange impairment are important causes of exercise limitation in LAM. DH is frequent in LAM, even in patients with mild spirometric abnormalities. DH was associated with the severity of disease, higher dyspnea, and lower oxygen saturation. In the 6MWT, desaturation and dyspnea were greater in patients with DH.     

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease categorized by an overgrowth of atypical smooth muscle cells (LAM cells) in the lungs and axial lymphatics, which is associated with the mesenchymal tumor angiomyolipoma. The disease occurs in women generally in their mid thirties with a prevalence approximately 1 per million in the general population but is much more frequent in women with tuberous sclerosis complex (TSC). LAM is categorized by airflow obstruction, lung cysts, recurrent pneumothorax, and pleural and abdominal chylous collections. The disease is progressive, generally resulting in respiratory failure and death. The TSC-2 gene is abnormal in LAM cells and may be responsible for their disordered growth. These cells are of an unusual phenotype, expressing smooth muscle proteins, melanoma proteins, estrogen and progesterone receptors. Although at present of unknown significance these are useful in diagnosis. Treatment is largely supportive, being directed at airflow obstruction, pneumothorax, chylous complications, and bleeding from angiomyolipomas. In patients with rapidly progressive disease, hormone manipulation is frequently tried in the form of progesterone or antiestrogen therapies although no firm evidence of their efficacy exists.     

Bone mineral density in lymphangioleiomyomatosis

Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM), a disorder affecting women that is characterized by cystic lung lesions, is frequently treated with antiestrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether antiestrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD was found in 70% of the patients and correlated with severity of lung disease and age. Greater severity of lung disease, menopause, and oophorectomy were associated with greater decline in BMD. After adjusting for differences in initial lung function and BMD, we found similar rates of BMD decline in progesterone-treated (n = 122) and untreated patients (n = 89). After similar adjustments, we found that bisphosphonate-treated patients (n = 98) had lower rates of decline in lumbar spine BMD (-0.004 +/- 0.003 vs. -0.015 +/- 0.003 gm/cm(2), p = 0.036) and T-scores (-0.050 +/- 0.041 vs. -0.191 +/- 0.041, p < 0.001) than untreated patients (n = 113). We conclude that abnormal BMD was frequent in LAM. Progesterone therapy was not associated with changes in BMD; bisphosphonate therapy was associated with lower rates of bone loss. We recommend systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.     

Unilateral lymphangioleiomyomatosis

Pulmonary involvement in tuberous sclerosis complex (TSC) resembles lymphangioleiomyomatosis (LAM) in its clinical, radiologic, and histopathological features. Typical high-resolution computed tomography (HRCT) findings are of bilateral thin-walled cysts symmetrically throughout both lungs, with associated increase in lung volumes. Atypical cases have been described; and we report a case of biopsy proven, focal unilateral disease. The presence of nodules has been reported in association with TSC that histologically are composed of proliferated type II pneumocytes. We discuss other atypical cases of TSC and sporadic LAM and review current concepts of the pathogenesis of the 2 diseases, with reference to our case.     

A case of bronchostenosis in the allograft after lung transplantation in pulmonary lymphangioleiomyomatosis]

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease characterized by hamartomatous proliferation of abnormal smooth muscle cells in the lungs. Recently, severe LAM has been listed as an indicated disease for lung transplantation. A 34-yr-old woman with severe pulmonary cystic changes in a chest CT scan was diagnosed as having an isolated form of pulmonary LAM without genetic disorders. Despite intensive progesterone treatment, her pulmonary functions deteriorated rapidly. In January 2001, a left single-lung transplantation was performed from a cadaveric donor. The total operating time was 8 hours and 47 minutes. Total ischemic time was 5 hours and 59 minutes, which was within the permitted time limit. Except for right pneumothorax, the postoperative course was fairly good without any sign of rejection or infection in the allograft. For about two months after transplantation, bronchostenosis occurred in the left lower lobe bronchus, and necessitated a stent placement. During the following three months, stenosis of the bronchi in the anastomotic and peripheral sites occurred repeatedly, which also necessitated stent placement or balloon dilations on each occasion. Despite all the intensive treatment, the bronchostenosis of the peripheral sites still remains and improvement of her pulmonary functions has been poor. Moreover, a recent chest CT scan revealed a progression of the disease in the native lung. Consequently, we registered her as a candidate for transplantation of the right lung. Bronchostenosis should be kept in mind as a complication of lung transplantation.     

Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM), a disease that occurs primarily in women, is characterized by cystic lung lesions causing respiratory failure, which may require lung transplantation. Lung diffusion (DLCO) and/or FEV1 are decreased, but frequently not in parallel with each other. Because cardiopulmonary exercise testing (CPET) provides information that is not obtainable from resting cardiopulmonary tests, we performed CPET in 217 LAM patients and correlated exercise data with clinical markers of severity, computed tomography scans, lung function, and histology. VO2max was decreased in 162 patients, of whom 28 did not reach anaerobic threshold; 29 had low oxygen uptake at anaerobic threshold, and 54 developed hypoxemia. Hypoxemia occurred even in patients with near normal DLCO and FEV1. VO2max decreased with an increasing score of histologic LAM severity and was correlated with computed tomography scans, the use of oxygen, and resting PaO2. DLCO and FEV1, however, were the only significant predictors of VO2max. We conclude that CPET uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements in patients with LAM.