Sporadic Lymphangioleiomyomatosis Research Articles

Lymphangioleiomyomatosis as a potent lung cancer risk factor: Insights from a Japanese large cohort study.

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease. We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available. Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS. Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM.

Chylous pleural effusion as an unusual presentation of a sporadic lymphangioleiomyomatosis: A case report

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Probability of sporadic lymphangioleiomyomatosis in women presenting with spontaneous pneumothorax

BackgroundSporadic lymphangioleiomyomatosis (S-LAM) is a rare low-grade neoplasm of young women characterized by multiple pulmonary cysts leading to progressive dyspnea and recurrent spontaneous pneumothorax (SP). The diagnosis of S-LAM may be delayed by several years. To reduce this delay, chest computed tomography (CT) screening has been proposed to uncover cystic lung disease in women presenting with SP. However, the probability to discover S-LAM in this population has not been determined precisely. The aim of this study was to calculate the probability of finding S-LAM in women presenting with (a) SP, and (b) apparent primary SP (PSP) as first manifestation of S-LAM.MethodsCalculations were made by applying the Bayes theorem to published epidemiological data on S-LAM, SP and PSP. Each term of the Bayes equation was determined by meta-analysis, and included: (1) the prevalence of S-LAM in the general female population, (2) the incidence rate of SP and PSP in the general female population, and (3) the incidence rate of SP and apparent PSP in women with S-LAM.ResultsThe prevalence of S-LAM in the general female population was 3.03 per million (95% confidence interval 2.48, 3.62). The incidence rate of SP in the general female population was 9.54 (8.15, 11.17) per 100,000 person-years (p-y). The incidence rate of SP in women with S-LAM was 0.13 (0.08, 0.20). By combining these data in the Bayes theorem, the probability of finding S-LAM in women presenting with SP was 0.0036 (0.0025, 0.0051). For PSP, the incidence rate in the general female population was 2.70 (1.95, 3.74) per 100,000 p-y. The incidence rate of apparent PSP in women with S-LAM was 0.041 (0.030, 0.055). With the Bayes theorem, the probability of finding S-LAM in women presenting with apparent PSP as first disease manifestation was 0.0030 (0.0020, 0.0046). The number of CT scans to perform in women to find one case of S-LAM was 279 for SP and 331 for PSP.ConclusionThe probability of discovering S-LAM at chest CT in women presenting with apparent PSP as first disease manifestation was low (0.3%). Recommending chest CT screening in this population should be reconsidered.

Lymphangioleiomyomatosis: diagnosis of a rare cystic lung disease in a clinical case

Sporadic lymphangioleiomyomatosis (LAM) is an orphan disease that primarily affects women of childbearing age. Increasing awareness of this disease among physicians can contribute to its timely diagnosis and treatment.The aim of this work was to present a case of a young woman with a rare cystic lung disease. At the first visit to the clinic, the patient showed pronounced clinical, radiological and functional changes in the bronchopulmonary system, and a rare pathology was suspected. Establishing the definitive diagnosis in the shortest possible time was essential because pathogenetic therapy with an mTOR inhibitor had to be initiated as soon as the diagnosis of LAM had been clarified. Until 2010, a definitive diagnosis of LAM was made only by surgical lung biopsy. However, there is currently a shift in practice toward less invasive diagnostic methods that eliminate the need for surgical intervention in most patients.Conclusion. An algorithm for making a definitive diagnosis (sporadic LAM) without morphologic examination of the lung is demonstrated.

Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring.

The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with R 2 values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD.

Metabolic signatures of lymphangioleiomyomatosis in biofluids: nuclear magnetic resonance (NMR)-based metabonomics of blood plasma: a case-control study.

Our aim was to analyze and compare the characteristics and differences of blood metabolites between lymphangioleiomyomatosis (LAM) patients and healthy controls, in order to find biomarkers that can be used for the diagnosis and classification of LAM. Between January 2020 to January 2022, 61 eligible LAM patients [51 sporadic LAM (S-LAM) and 10 tuberous sclerosis complex LAM (TSC-LAM)] from the First Affiliated Hospital of Guangzhou Medical University and 30 healthy controls were enrolled. Blood samples were taken for nuclear magnetic resonance (NMR) detection. Data analysis was performed by the umbrella program, and Wilcoxon analysis was used for comparisons between groups. The difference indicators were modeled by logistic regression. Diagnostic accuracy of the best predictive parameters was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and the sensitivity and specificity were calculated. The indexes differed between LAM patients and healthy controls, S-LAM patients and healthy controls, and between TSC-LAM patients and healthy controls. There were two different metabolic indexes between S-LAM and TSC-LAM patients. After logistic regression modeling and ROC analysis, methionine (AUC =0.929, sensitivity =73.8%, specificity =100%, cut-off value =0.011 mmol/L) and acetic acid (AUC =0.966, sensitivity =95.1%, specificity =90%, cut-off value =0.006 mmol/L) had the highest diagnostic efficiency in LAM patients, and could be used to distinguish between affected and healthy people. Methionine was significantly associated with pneumothorax (P<0.05), and creatinine was significantly correlated with hysteromyoma (P<0.05). Methionine and acetic acid in the plasma of LAM patients are potential biomarkers. Methionine was also associated with pneumothorax in LAM patients. Also, acetone and creatinine were promising metabolic markers to distinguish S-LAM from TSC-LAM. NMR as a new non-invasive diagnostic method had a good discriminatory power for LAM.

Clinical features and outcomes of male patients with lymphangioleiomyomatosis: A review.

Lymphangioleiomyomatosis (LAM) is a rare disease involving multiple systems, which is divided into sporadic LAM (S-LAM) and tuberous sclerosis complex-LAM, mostly affecting women who are in childbearing age stage. Data on male patients are limited and scattered. Therefore, it is necessary to conduct a systematic review to investigate the clinical features, diagnosis, treatment, and outcomes of LAM in male. We performed a literature review by searching for all the published reported cases of LAM in male during the past 35 years (April 1986-October 2021). 36 male patients described in 26 references were included in this article. The median age of onset was 34 years (interquartile range: 1-79). The most common initial manifestations were cough, dyspnea, respite, and hemoptysis, with pulmonary complications such as pneumothorax and chylothorax. Five patients (13.9%) were asymptomatic at admission. Nearly half of the 36 male patients had thin-walled air-filled cysts that were visible throughout both lungs. Considering the abovementioned atypical clinical features, misdiagnosis was committed in 8 patients (22.2%). In addition, patients with tuberous sclerosis complex lymphangioleiomyomatosis often have no pulmonary manifestations at onset but present multiple extrapulmonary manifestations and have higher rates of renal angiomyolipomas than patients with S-LAM (P < 0.01). Eventually, 4 patients with S-LAM eventually died. Physicians should increase the awareness of LAM in male. Early monitoring of various systems should be recommended to ensure early management and active follow-up. Tuberous sclerosis complex patients should immediately be tracked for the onset of LAM disease to improve prognosis.

Gene mutations in sporadic lymphangioleiomyomatosis and genotype–phenotype correlation analysis

BackgroundSporadic lymphangioleiomyomatosis (S-LAM) is a rare neoplasm with heterogeneous clinical features that is conventionally considered to be related to TSC2. This study serves to elucidate the mutation landscape and potential correlation between S-LAM genomic profiles and clinical phenotypes.MethodsGenomic profiles of 22 S-LAM patients were obtained by sequencing genomic DNA and cell-free DNA from various specimens using an NGS (next-generation sequencing)-based tumor-driver gene panel. Detected mutations were summarized. Symptoms, serum vascular endothelial growth factor D (VEGF-D) values, pulmonary function, and six-minute walk distance (6MWD) were compared among groups with different TSC2 status and genotypes to analyze genotype–phenotype correlations.Results67 Variants in 43 genes were detected, with a TSC2 mutation detection rate of 68.2%. The TSC2 detection rate was similar in specimens obtained either through transbronchial lung biopsy (TBLB) or surgical lung biopsy (70.0% vs. 69.2%, p > 0.05). A novel mutation in VEZF1 (c.A659G) was detected in four participants and may represent a mild disease state. TSC2 mutation was significantly related to a shorter 6MWD (p < 0.05), and a higher percentage of VEGF-D over 800 pg/mL (p < 0.05); stop-gain mutation was significantly related to a higher prevalence of pneumothorax.ConclusionsTumor-driver mutations in genes other than TSC2 may have a role in S-LAM, and TBLB specimens are practical alternatives for genomic analysis. TSC2 mutation detectability and types are related to the disease severity and phenotypes of S-LAM.

Lymphangioleiomyomatosis – case series

Abstract We describe a series of five cases of sporadic lymphangioleiomyomatosis (LAM) diagnosed in a 2-year period and followed for at least 6 months. All cases describe women aged between 37 years and 67 years (median at 44), mostly non-smokers, either with symptomatic presentations, complications at debut or incidental imagistic diagnosis. The cystic lesions were unanimous, but two cases had atypical patterns. Spirometric parameters were normal in two cases, the rest presenting obstruction with hyperinflation ± bronchodilator positive response. The diffusing capacity of lung for carbon monoxide (DLCO) varied between 79.8% and 29.5%. Two cases had histopathological confirmation, one of which was really unexpected considering its imagistic pattern. The therapeutic intervention consisted of sirolimus and/or bronchodilator. The evolution was stationary for four cases and unfavourable for one. This case series ranges from textbook to atypical LAM and has the aim to raise awareness regarding this rare disease.

Tuberous sclerosis complex: a complex case.

Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms’ tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.

Sirolimus Suppresses Phosphorylation of Cofilin and Reduces Interstitial Septal Thickness in Sporadic Lymphangioleiomyomatosis.

Sporadic lymphangioleiomyomatosis (S-LAM) is a rare lung disease characterized by the proliferation of smooth muscle-like LAM cells and progressive cystic destruction. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has a proven efficacy in patients with LAM. However, the therapeutic mechanisms of sirolimus in LAM remain unclear. We aimed to evaluate sirolimus-related lung parenchymal changes and the potential effect in LAM cells and modulating pathological cystic destruction. Lung specimens were examined for histopathological changes by HMB45 staining and compared the LAM patients treated with and without sirolimus. We detected the overexpression of mTOR, HMB45, and phosphorylation of cofilin (p-cofilin) in LAM patients. Sirolimus showed efficacy in patients with LAM, who exhibited a reduced expression of mTOR and p-cofilin as well as reduced interstitial septal thickness. In addition, sirolimus suppresses mTOR and p-cofilin, thus suppressing the migration and proliferation of LAM cells isolated from the patient’s lung tissue. This study demonstrates that interstitial septal thickness, as determined by histological structural analysis. Sirolimus effectively reduced the expression of p-cofilin and interstitial septal thickness, which may be a novel mechanism by sirolimus. Moreover, we develop a new method to isolate and culture the LAM cell, which can test the possibility of medication in vitro and impact this current study has on the LAM field. The development of approaches to interfere with mTOR-cofilin1-actin signaling may result in an option for S-LAM therapy.

Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study.

Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM.Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls.Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively.Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.

The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

Uncommon radiologic computed tomography appearances of the chest in patients with lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts. The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so uncommon HRCT appearances present challenges to establishing the proper LAM diagnosis. The objective of this study is to accrue uncommon chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients. 311 females referred to our hospital, including 272 S-LAM patients (mean age 39.2 years) and 39 TSC-LAM patients (mean age 38.3 years), were retrospectively evaluated. We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and uncommon findings in addition to cysts. We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction. The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules. It is important to be aware of various radiologic findings that make HRCT cystic appearance atypical of LAM.

Improved Exercise Tolerance and Lung Function in Women with LAM Following Three Months of Exercise Training

Rationale: While exercise has been shown to improve respiratory symptoms, exercise tolerance, and bone mineral density in many populations, no supervised exercise training interventions have been undertaken in patients with lymphangioleiomyomatosis (LAM). Objectives: To assess the effects of a supervised exercise intervention on exercise tolerance, pulmonary function, and bone mineral density in patients with LAM. Methods: subjects with LAM (Sporadic LAM n=7; TS-LAM n=1) enrolled in the study. Subjects participated in two weekly supervised aerobic exercise training (50-60 minutes) at 80-85% heart rate max for 12 weeks. Heart rate and oxygen saturation levels were monitored throughout the intervention. Treadmill ergometry (VO2peak), spirometry (FEV1, FVC, FEV1/FVC, FEV1 predicted, peak flow), and bone mineral density assessments were performed prior to and 12 weeks after initiation of intervention. Measurements and Main Results: After 12 weeks of supervised aerobic exercise training, group mean improvements were seen in all outcomes including VO2peak, FEV1, FVC, FEV1/FVC, FEV1 predicted, peak flow, and whole body bone mineral density. Conclusions: Results from this study indicate that supervised exercise training can improve exercise tolerance, pulmonary function, and bone mineral density in patients with lymphangioleiomyomatosis. Further research is needed, including longitudinal studies with larger sample sizes, to determine long-term effects and consistency of these findings. Aerobic exercise may offer a viable alternative to, or work in conjunction with, pharmacological intervention in the treatment of lymphangioleiomyomatosis.

A Case of Sporadic Lymphangioleiomyomatosis Diagnosed by Transbronchial Lung Cryobiopsy

A Case of Sporadic Lymphangioleiomyomatosis Diagnosed by Transbronchial Lung Cryobiopsy

A RARE TWIST: LYMPHANGIOLEIOMYOMATOSIS PLUS DIFFUSE LARGE B-CELL LYMPHOMA

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare systemic disease resulting in cystic lung destruction, recurrent pneumothoraces, chylous pleural effusions, and abdominal tumors. This multisystem disease most commonly affects women of childbearing age, resulting in stepwise decline in pulmonary function, with clinically apparent hypoxemia developing in most patients within a decade after onset of symptoms. Here we present a rare case of late-onset LAM with concurrent high grade B-cell lymphoma. CASE PRESENTATION: The patient is a 62-year-old female nonsmoker with a remote history of spontaneous pneumothorax who presented due to pleuritic chest pain at rest. Chest CT revealed innumerable pulmonary cysts up to 15 mm, few solid noncalcified pulmonary nodules, multiple complex mediastinal lesions, and a 30% left anterior pneumothorax. Chest tube was placed; the patient was admitted. A nontender swelling was noted on the skull which the patient attributed to a work injury several months prior. MRI showed a 5 cm lytic lesion involving the left frontal bone and subgaleal space with hypercellular diffusion pattern. Craniectomy with resection was performed; pathology revealed high-grade B cell lymphoma. CT abdomen revealed a 4x4 cm right-sided irregular exophytic renal mass. The patient had VEGF-D level of 1382 pg/mL, which, combined with diffuse cystic lung disease, was consistent with a diagnosis of LAM. The patient was discharged and underwent chemotherapy and radiation in the outpatient setting. Two months later, she was readmitted with recurrent left pneumothorax. She failed doxycycline chemical pleurodesis (as there was a nation-wide talc shortage) and went for VATS decortication, pleurectomy, LLL wedge resection, and mechanical pleurodesis. Immunohistochemistry studies on lung pathology confirmed LAM (Table 1). DISCUSSION: LAM may develop sporadically, or may arise in a patient with preexisting tuberous sclerosis complex. The clinical presentation varies and may include cough, dyspnea, recurrent pneumothorax, pleural effusion, or respiratory failure. Overall, the patient’s family history and clinical presentation was not consistent with tuberous sclerosis complex. This is a case of likely sporadic LAM in a patient with recurrent pneumothorax, the first being 5 years prior to this presentation. The concurrent diffuse large B cell lymphoma of the skull adds an interesting twist, as there have only been case reports of LAM occurring with malignant lymphoma. CONCLUSIONS: Although LAM is diagnosed at a median age of 35, more women are being diagnosed at an older age. Pleurodesis after the first occurrence of pneumothorax should be considered due to the high rate of recurrence, as seen in this patient who had multiple pneumothoraces and failed chemical pleurodesis. Sirolimus is also recommended for LAM but this patient’s concurrent treatment for lymphoma complicates her treatment options. Reference #1: McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med. 2016;194(6):748-761. doi:10.1164/rccm.201607-1384ST Reference #2: Park S, Lee EJ. Diagnosis and treatment of cystic lung disease. Korean J Intern Med. 2017 Mar;32(2):229-238. doi: 10.3904/kjim.2016.242. Epub 2017 Feb 28. Reference #3: Jawad H, Walker CM, Wu CC, Chung JH. Cystic interstitial lung diseases: recognizing the common and uncommon entities. Curr Probl Diagn Radiol. 2014 May-Jun;43(3):115-27. doi: 10.1067/j.cpradiol.2014.01.001. DISCLOSURES: No relevant relationships by Helen Li Mitchell, source=Web Response No relevant relationships by Sushant Soni, source=Web Response No relevant relationships by Justin Thomas, source=Web Response No relevant relationships by Shawnt Tosonian, source=Web Response

Rare association: sporadic lymphangioleiomyomatosis and Pi-SZ alpha-1-antitrypsin deficiency

We present a case of a 32-year-old Caucasian woman with Pi-SZ alpha-1-antitrypsin deficiency and sporadic lymphangioleiomyomatosis (LAM). The patient is a lifelong non-smoker with no exposure history. She has no...

Continuation of mTOR Inhibition in LAM Patients Listed for Lung Transplant is Safe

Use of mammalian target of rapamycin (mTOR) inhibitors in lymphangioleiomyomatosis (LAM) is now standard of care.1 However, in LAM patients listed for lung transplant (LTX), mTOR inhibitors are often held, as sirolimus has been associated with anastomotic dehiscence2,3. This hold can lead to accelerated respiratory failure. In a survey of LTX programs, 35.4% did not allow patients to remain on mTOR therapy while on the wait list4. We sought to collect a case series of patients who remained on mTOR inhibitors while on the waitlist and describe their outcomes after LTX. Pulmonologists who had managed LAM patients with LTX and continued mTOR inhibitor were contacted. Information was collected from those providers, pertaining to mTOR inhibitor use, airway complications, and transplant outcomes. Eight LAM patients were identified as having been on mTOR inhibitor up until call-in for LTX. Average ages at diagnosis and at LTX were 38.5 years and 48.2 years, respectively. The mTOR inhibitor was started 46.8 months before LTX, with a mean time between listing and LTX of 10.5 months. Seven patients had sporadic LAM, and one had tuberous sclerosis complex-associated LAM. mTOR inhibitor was continued at time of listing in all patients. Three were on sirolimus prior to listing; in two of those patients, sirolimus was switched to everolimus at time of listing. After LTX, mTOR inhibition was resumed in 4 of 8 patients, at a mean of 0.85 years after LTX. One patient had a significant airway complication, a partial right mainstem dehiscence with subsequent stenosis requiring stenting, and recurrent bronchopulmonary infections. She remains alive at 11.3 months after transplant at time of survey. No other patients had wound healing issues. All were alive at time of survey, at a median of 34.9 months after LTX (range, 11.3 to 115.0 months). While controversy abounds regarding the use of mTOR inhibitors during while listed for LTX in LAM patients, this case series suggest that continuation of mTOR inhibitor during waitlist phase before LTX is reasonable and safe. Programs should consider allowance of mTOR inhibition in LAM patients on the LTX waitlist.

SUN-446 RENAL ANGIOMYOLYPOMAS IN SPORADIC LYMPHANGIOLEIOMYOMATOSIS

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease that mostly afflicts young women. The average age at presentation is typically between the mid-thirties and mid-forties but can extend to eighties. Sporadic LAM is used for patients with LAM not associated with tuberous sclerosis complex (TSC). A 46 year old female initial presentation with shortness of breath at age of 43. Part of her evaluation for dyspnea included CT Chest which showed multiple thin-walled cysts and some reticular changes, which were compatible with Lymphangioleiomyomatosis and chronic interstitial lung disease, pulmonary function test revealed an obstructive pattern. CT and MRI abdomen done for surveillance showed multiple hepatic hemangiomas with bilateral renal masses represents angiomyolipoma. She had no other pulmonary complications. Patient denied personal of family history of seizure disorders, no skin lesions apart from the chronic idiopathic urticaria. There is no family history of Tuberos sclerosis. Her renal function was normal through out her follow up period. started initially on tamoxifen but she was shifted to sirolimus due to side effects. Follow up imaging showed stable renal masses. Clinical presentation: Pulmonary manifestations include fatigue, progressive dyspnea, spontaneous pneumothorax, pleural effusion which is most likely due to chylothorax and occurs in 10-30 % of patients in LAM. Exertional dyspnea is the most common presenting symptom and 1/3 of women with LAM have reversible airflow obstruction, which is confused with other obstructive lung diseases. Non pulmonary manifestations include Renal angiomyolipomas (AMLs) which are benign masses that contain blood vessels, muscle tissue, and fat. They occur in approximately 30% of patients with sporadic LAM & usually asymptomatic unless lesions are >4 cm it may present with abdominal pain due to hemorrhage specially if the mass contains aneurysm. Tuberous sclerosis is suspected if lesions are large, bilateral and multiple or if there is renal impairment. usually it is incidentally discovered on CT abdomen but Ct chest should be considered in case of large, bilateral lesions are present,11 % of patients with sporadic AMLs have cystic changes in the lung consistent with LAM. Renal AMLs are typically diagnosed by the presence of fat within a renal tumor on non contrast-enhanced CT. Fat-free or fat-poor AMLs can also occur, and must be distinguished from renal cell carcinomas, oncocytomas, or other more aggressive neoplasms, which can rarely complicate TSC and sporadic LAM.MRI can be more sensitive for detecting fat density. Vascular endothelial growth factor-D, VEGF-D levels are measured in the serum of patients with suspected LAM, in whom typical thin-walled cysts are found on chest CT and it is diagnostic for LAM if the level is greater than or equal to 800 pg/mL. The primary histopathologic abnormality is the proliferation of atypical smooth muscle like cells (LAM cells). Sirolimus, mTOR inhibitor, is a supportive but not curative medication. Lung function goes back to pretreatment function upon discontinuation of the medication,. Most renal angiomyolipomas do not require specific treatment unless big or hemorrhagic. Big tumors can be treated with embolization, radiofrequency ablation or partial nephrectomy if not responding to mTOR therapy.