A Case Study Of Pulmonary Lymphangiomyomatosis

Part 1:Clinical characteristics of pulmonary lymphangioleiomyomatosis Background: Pulmonary lymphangiomyomatosis(PLAM)is a rare low-grade malignant tumor disease,which occurs in women of childbearing age and is characterized by diffuse cystic lesions in the lungs.The main clinical manifestations are recurrent pneumothorax and aggravated dyspnea,which would be likely to bemisdiagnosed with chronic obstructive pulmonary disease or pulmonary bullae.The research of PLAMl in China started late,the recognition level of the disease is low,the rate of misdiagnosis is high,and the effective treatment is lacking.Most of the domestic literatures are case reports or retrospective large sample literature case summary,and few cases of pulmonary lymphangiomyomatosis are directly observed.In most parts of China,the knowledge of PLAM is limited,misdiagnosis and missed diagnosis are common,and effective treatment is limited.Most of the previous studies in China are case reports in the literature,and there is a lack of direct observational studies on pulmonary lymphangioleiomyomatosis.Objective: To investigate the clinical features of pulmonary lymphangioleiomyomatosis(PLAM)and improve the diagnosis and treatment level of PLAM.Methods: Collect the clinical data of patients diagnosed with pulmonary lymphangioleiomyomatosis from December 2016 to February 2019 in the Department of Respiratory and Critical Care Medicine,Anhui Provincial Hospital,the First Affiliated Hospital of University of Science and Technology of China,establish a datadatabase,and conduct follow-up through telephone,WeChat follow-up,outpatient or hospital check-up to investigate the clinical features of pulmonary lymphangioleiomyomatosis and compare the similarities and differences with domestic and foreign PLAM studies.Results: All 16 patients with PLAM were female,3 of them were diagnosed with lymphangiomyomatosis with tuberous sclerosis(TSC-LAM),and the remaining 13 were sporadic lymphangiomyomatosis(S-LAM);1)Age characteristics: The average age of onset of PLAM was 35.0 ± 10.8 years,the average age of diagnosis was 37.1 ±11.4 years..There was no difference in the age of onset of S-LAM and TSC-LAM.2)Clinical features: The most common clinical symptoms in this group were dyspnea on exertion(100%),cough and expectoration(38%)and pneumothorax(38%).The most common first symptom is dyspnea on exertion(44%),the incidence of first low back pain was higher in TSC-LAM than in S-LAM.3)Imaging and complication features:Typical pulmonary imaging features are thin-walled vesicles(100%)of various sizes and diffuse distribution in the whole lung,followed by pneumothorax(38%)and pleural effusion(38%).The most common extrapulmonary imaging findings were angiomyolipoma(69%)and enlarged retroperitoneal lymph nodes(44%),in which TSC-LAM was often accompanied by bilateral angiomyolipoma and intracranial calcified nodules.4)Pulmonary function and blood gas analysis characteristics: The most common dysfunction in pulmonary function test of PLAM was decreased diffusion function(50%),while 43% of patients had normal ventilation function and obstructive ventilation dysfunction.Hypoxemia was present in 25% of patients.5)The main pathological findings were spindle smooth muscle-like cells distributed along the lymphatic vessels,blood vessels and around the cyst wall.The positive rate of SMA and HMB45 by immunohistochemistry was high,and some of them could be positive for ER and PR.6)Diagnosis: 16 patients with PLAM were consistent with the clinical history and typical pulmonary diffuse thin-walled cystic manifestations;10 patientswith PLAM were confirmed by pathology,4 patients with PLAM were diagnosed by serum endothelial growth factor VEGF-D levels greater than 800 pg/mL,and 2patients with PLAM were confirmed by the presence of nodular sclerosis signs and renal angiomyolipomas confirmed by imaging.7)The mean misdiagnosis time of PLAM was 13 months.It was often misdiagnosed as bullae(50%),renal maligmancy(31%)and spontaneous pneumothorax(19%).8)Treatment and follow-up: 11 cases received sirolimus treatment,of which 6 cases were stable or improved,3 cases were still aggravated,2 cases only took medicine for 1 month,chest tightness symptoms were temporarily stable;1 case who treated with Chinese traditional medicine for 1month was temporarily stable;1 case with post-transplantation condition was improved;the remaining 3 patients did not receive any related treatments,1 case aggravated,the two others was on stable condition.Conclusion: PLAM mainly occurs in women of childbearing age.The most common first symptom is dyspnea on exercise The diagnosis mainly depends on characteristic imaging and pathological findings.Elevated serum VEGF-D level is also helpful for diagnosis.Sirolimus treatment should be recommended for patients with significant symptoms,poor lung function,and renal angiomyolipoma,early pleural intervention would be recommended for pneumothorax,and lung transplantation treatment may be considered for patients with advanced stage of PLAM.Part 2: Efficacy and Safety of Sirolimus in Treatment of Pulmonary LymphangiomyomatosisBackground: With the deepening understanding of PLAM,its pathogenesis has been confirmed to be related to the inactivation of tumor suppressor gene TSC1/TSC2.TSC gene can negatively regulate mammalian target of rapamycin(m TOR),thereby regulating the abnormal proliferation of cells.As a specific inhibitor of m TOR,Sirolimus(also known as rapamycin)has been confirmed by a number of foreign studies that Sirolimus can significantly improve the clinical symptoms of pulmonary lymphangioleiomyomatosis,slow or stabilize the rate of decline of lung function,reduce the level of serum endothelial growth factor VEGF-D,and also has a good effect on chylous pleural effusion and renal angiomyolipoma.The guidelines for diagnosis and treatment of LAM issued in 2016 clearly recommend the use of Sirolimus in the treatment of PLAM patients with impaired pulmonary function,obvious symptoms and renal involvement.The Food and Drug Administration Departments of the United States and Japan have approved the clinical use of PLAM of Sirolimus,but China has not yet obtained the clinical approval of this drug.Domestic Sirolimus is only applicable to the anti-rejection reaction of graft,while the treatment of PLAM belongs to off-label drug use.At present,there are few detailed literature reports on the use of sirolimus in the treatment of pulmonary lymphangioleiomyomatosis PLAM in China.There is lack of large cohort studies.Some case reports only supply the use of sirolimus in the treatment regimen,but are lack of the subsequent evaluation of symptoms,pulmonary function,blood gas,activity tolerance and imaging.In addition,insufficient attention has been paid to the initial safe dose,maintenance trough concentration,and adverse effects of sirolimus in China.Objective: Through dynamic observation and analysis of sirolimus intervention in the treatment of pulmonary lymphangioleiomyomatosis and the incidence of adverse events,especially the impact on lung function,to provide good diagnosis and treatment experience for sirolimus intervention in pulmonary lymphangioleiomyomatosis,improve the quality of diagnosis and treatment of PLAM.Methods: This study collected clinical data of PLAM patients diagnosed as pulmonary lymphangiomyomatosis from December 2016 to February 2019 in the Department of Respiratory and Critical Care Medicine,First Affiliated Hospital of China University of Science and Technology and Anhui Provincial Hospital.In this study,female patients with PLAM treated with sirolimus were selected as the study subjects,and the patients were followed up dynamically.The clinical follow-up data of all patients were collected through this way,and the corresponding indicators of each clinical data were compared to evaluate the efficacy and safety of sirolimus.Efficacy assessments included clinical symptoms,pulmonary function,arterial blood gases,radiographic changes,activity tolerance or six-minute walk distance,and serum VEGF-D levels.Adverse events occurring during medication were also recorded.Results: 1)Efficacy: Among of 11 patients with pulmonary lymphangioleiomyomatosis treated with sirolimus,6 patients showed improvement in pneumothorax and dyspnea after activity,and 3 patients gradually worsened.In 5 patients complicated with angiomyolipoma or retroperitoneal enlarged lymph nodes,the lesions shrank or disappeared after 3-24 months of sirolimus intervention(5/6,83%).The 6MVW of 5patients with PLAMincreased after treatment(5/6,83%)Among 4 patients,serum VEGF-D levels decreased by 1450.6pg/ml from the previous baseline.The monthly FEV1 and FEV1/ estimated values of PLAM patients increased by 3ml and 0.24% after taking the drug.2)Safety: 8 patients developed adverse reactions of hyperlipidemia(46%),oral ulcer(36%),menstrual disorder(18%),bronchial infection(9%),neutropenia(9%),liver dysfunction(9%),diarrhea(9%)and rash(9%)during the sirolimus treatment,most of which were mild and improved after symptomatic treatment.Conclusion: Sirolimus can improve clinical symptoms and pulmonary function,increase activity tolerance,reduce the size of renal angiomyolipoma or retroperitoneal enlarged lymph nodes,and decrease VEGF-D levels in most patients with PLAM.Common adverse effects of sirolimus are oral ulcers,hyperlipidemia and menstrual abnormalities which usually do not affect its treatment.