Pulmonary Lymphangiomyomatosis Research Articles

Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation. Knockdown of SPHK1 showed reduced viability, migration and invasion in TSC2-deficient cells. Selective SPHK1 antagonist PF543 potently suppressed the viability of TSC2-deficient cells and induced autophagy-mediated cell death. Meanwhile, the cognate receptor S1PR3 was identified to mediating the tumorigenic effects of sphingosine-1-phosphate (S1P). Treatment with TY52156, a selective antagonist for S1PR3, or genetic silencing using S1PR3-siRNA suppressed the viability of TSC2-deficient cells. Both SPHK1 and S1PR3 inhibitors markedly exhibited antitumor effect in a xenograft model of TSC2-null cells, restored autophagy level, and triggered cell death. Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1/S1P/S1PR3 signaling may have potent therapeutic benefit for patients with TSC/LAM or other hyperactive mTOR neoplasms with autophagy inhibition.

Diagnostic value and safety of medical thoracoscopy under local anesthesia for unexplained diffuse interstitial lung disease: A retrospective study.

ObjectiveWe aimed to explore the safety and diagnostic value of medical thoracoscopic lung biopsy in patients with unexplained diffuse interstitial lung disease (ILD) in a single center pilot study.MethodWe retrospectively analyzed clinical and pathological diagnostic data from 52 patients with diffuse ILD undergoing medical thoracoscopic lung biopsy.ResultsForty-four cases of diffuse ILD were confirmed pathologically, giving a diagnostic rate of 84.6%. Among these 44 patients, 11 patients were diagnosed with cancer, including eight patients with lung adenocarcinoma, three patients with metastases; two from a gastrointestinal malignancy, and one from a granulosa cell tumor of the ovary. There were 17 cases of idiopathic interstitial pneumonia, including nine cases of usual interstitial pneumonia (UIP), four cases of non-specific interstitial pneumonia (NSIP), three cases of cryptogenic organizing pneumonia (COP), and one case of acute interstitial pneumonia (AIP). There were 12 cases of rare interstitial pneumonias, which included six cases of pulmonary alveolar proteinosis, one case each of pulmonary Langerhans cell histiocytosis (LCH) and pulmonary lymphangiomyomatosis, two cases of nodular sarcoidosis, and two cases of chronic eosinophilic pneumonia. We recorded various complications, including bleeding, infection, and pneumothorax. A total of 28 patients (53.8%) experienced at least one of the above complications, but there were no deaths associated with biopsy.ConclusionsMedical thoracoscopic lung biopsy appears a safe and effective method for diagnosing diffuse ILD of unknown cause but further prospective studies, with larger numbers, including comparison with other established techniques are required.

Video Assisted Thoracoscopic Surgery (VATS) of Lymphangiomyomatosis (LAM) with Multiple Pulmonary Bullae in a Woman: A Case Report and Literature Review

Background: Pulmonary lymphangiomyomatosis is relatively rare disease and it is a systemic disease with an unknown etiology. The abnormal proliferation of smooth muscle leads to the obstruction of bronchi, lymphatic vessels and small blood vessels. At present, there are not many clinical reports on the treatment of LAM thoracoscopic surgery. So this article reports a case of LAM in a middle-aged woman and reviews of the relevant literature.

Birt\u2013Hogg\u2013Dub\xe9 syndrome: a literature review and case study of a Chinese woman presenting a novel FLCN mutation

BackgroundThe Birt–Hogg–Dubé (BHD) syndrome is a very rare autosomal dominant form of genodermatosis caused by germline mutations in the folliculin (FLCN) gene, which is mapped to the p11.2 region in chromosome 17. BHD commonly presents cutaneous fibrofolliculomas, pulmonary cysts, renal cell carcinoma, and recurrent pneumothoraxes. The disease is easily ignored or misdiagnosed as pneumothorax, pulmonary lymphangiomyomatosis (LAM), or emphysema. Follow-up and guidelines for managing recurrent pneumothoraxes in these patients are lacking.Case presentationWe reported the case of a 56-year-old Chinese woman who presented skin lesions, multiple lung bubblae, recurrent pneumothoraxes, thyroid nodules, and pulmonary inflammatory pseudotumors (PITs). The patient had a family history of pneumothoraxes and renal tumor. The BHD diagnosis was confirmed by genetic testing, which revealed a novel FLCN mutation in exon 14. Furthermore, the patient underwent a bullectomy because of recurrent pneumothorax 6 years ago.ConclusionTo our knowledge, the novel mutation in exon 14 and the manifestation of PIT in the present case have never been reported for BHD. The patient underwent a bullectomy previously with no relapse at the last follow-up before the preparation of this report, thereby suggesting that thoracotomy with bullectomy may be a possible therapeutic approach for some BHD patients with recurrent pneumothorax.

RETINAL ASTROCYTIC HAMARTOMA: Optical Coherence Tomography Classification and Correlation With Tuberous Sclerosis Complex.

To propose a classification of retinal astrocytic hamartoma based on spectral domain optical coherence tomography and correlate each class with systemic manifestations of tuberous sclerosis complex. Retrospective chart review conducted at four international referral medical retina centers. There were 43 consecutive patients with an established diagnosis of tuberous sclerosis complex based on presence of at least 2 major or 1 major and 2 minor features of the diagnostic criteria. Clinical and spectral domain optical coherence tomography features regarding retinal astrocytic hamartoma were documented. The mean patient age at presentation was 16.2 years. The retinal astrocytic hamartoma was classified as Type I (n = 41), Type II (n = 25), Type III (n = 20), or Type IV (n = 12). Patients with Type II showed greater number of cutaneous fibrous plaques (odds ratio = 64.8; 92% confidence interval: 64.2-65; P < 0.001); those with Type III displayed higher incidence of subependymal giant-cell astrocytomas (odds ratio = 43.2; 95% confidence interval: 43.0-43.3; P < 0.001); and those with Type IV showed higher incidence of pulmonary lymphangiomyomatosis (odds ratio = 126; 95% confidence interval: 122-128; P < 0.001). Retinal astrocytic hamartoma can be classified into four morphologic groups, based on spectral domain optical coherence tomography. There are important systemic tuberous sclerosis complex correlations with each class.

围绝经期肺淋巴管平滑肌瘤病1例及临床分析

目的：提高对围绝经期妇女肺淋巴管平滑肌瘤病(PLAM)的认识并引起对该病的重视与思考。方法：对我院2013年收治的1例PLAM患者的临床资料进行分析，并复习文献，以提高对本病的认识和诊断水平。结果：PLAM是一种持续发展的弥漫性肺间质疾病，多见于育龄期妇女，但同时也发生于围绝经期患者。结论：对围绝经期妇女发生渐进性呼吸困难不能缓解，类似肺气肿的临床表现及X线胸部阴影，并出现反复气胸或乳糜胸水时同样应考虑为PLAM可能，最好能以肺组织活检明确诊断。该病预后差，目前无有效的预防和治疗方法。 Objective: To improve awareness and attention of pulmonary lymphangiomyomatosis (PLAM) in perimenopausal women. Method: A perimenopausal woman suffered from PLAM was analyzed in our department. Result: PLAM is a rare cystic interstitial lung disease that exclusively affects women of child-bearing age. We report a case of perimenopausal female with PLAM. Conclusion: PLAM has been seen in perimenopausal woman and should be considered in patients presenting progressive exertional dyspnea, chronic non-productive cough, spontaneous pneumothorax, chy-lothorax and a plain X-ray chest which shows a hyperinflated lung with reticular or reticulonodular pattern. Lung biopsy should be considered when there is doubt about the diagnosis. The disease prognosis is poor, and currently there are no effective prevention and treatment methods.

Association between the growth rate of renal cysts/angiomyolipomas and age in the patients with tuberous sclerosis complex

Renal manifestations of tuberous sclerosis complex (TSC) occur with a high frequency and a wide range of severity. The onset and complications of each affected organ depend on the age. This study aimed to investigate the associations between comorbidities, frequency, and size of cysts/angiomyolipomas of TSC and the patients in the different ages. We performed a systematic evaluation of patients with TSC at integrated clinics for TSC. The patients were diagnosed with TSC according to Roach's clinical diagnostic criteria. All the patients underwent a systematic evaluation with a medical history review, recording of cutaneous manifestations, magnetic resonance imaging of the brain, chest computed tomography scan, and cardiac echography. Each patient was routinely evaluated with renal magnetic resonance imaging. Of the 57 patients with TSC, renal lesions or manifestations were observed in 38.5 % at preschool-age group (<6 years) that increased to 75.0, 85.7, and 100 % in school-age group (6-18 years), young adulthood group (18-30 years), and middle-aged group >30 years, respectively. Renal complications or interventions were found in 72.7 % of patients >30 years. There was a strongly positive association between the size of renal lesions and age (p < 0.001). Comorbidities of TSC were significantly correlated with pulmonary lymphangiomyomatosis (p < 0.001) and seizure remission (p = 0.018). The results indicate a positive association of progressively growing renal lesions in patients with TSC with increasing age. It is mandatory for clinicians that monitor the high-risk patients to minimize and prevent renal complications in the future.

Clinical analysis of tuberous sclerosis complex complicated with renal angiomyolipoma: a report of 22 cases

To explore the diagnosis and treatment of tuberous sclerosis complex complicated with renal angiomyolipoma. The clinical data of 22 patients with tuberous sclerosis complex complicated with renal angiomyolipoma were analyzed retrospectively. There were 12 males and 10 females with a mean age of 23 (1-46) years. All of them had bilateral multiple renal angiomyolipomas. The mean tumor size was 8.5 (0.7-18.0) cm in diameter. The presence or absence of clinical symptoms showed a significant correlation with tumor size.Eight patients with angiomyolipoma under 4 cm in diameter were continuously monitored at an outpatient clinic. There were 8 patients with lesions of 4-10 cm.Five of them underwent nephron-sparing surgeries and another 3 monitored at an outpatient clinic. There were 6 patients with tumor over 10 cm. Three of them underwent transcatheter arterial embolization and one case took rapamycin after embolization.One patient with concurrent renal cell carcinoma underwent partial nephrectomy. Chronic renal failure occurred in one case dying of pulmonary lymphangiomyomatosis with serious hemoptysis. During a mean follow-up of 25 months, neither severe renal hemorrhage nor symptomatic aggravation was found.In the case of rapamycin, there was 10% reduction in the size of angiomyolipoma. Most cases of tuberous sclerosis complex are complicated with bilateral multiple renal angiomyolipoma. The small lesions under 4 cm in diameter may be monitored at an outpatient clinic.For those larger (>4 cm) or symptomatic ones, medication, embolization or surgery is necessary.

Topical rapamycin (sirolimus) for facial angiofibromas

Rapamycin (sirolimus) is a fungal fermentation product that inhibits the proper functioning of a serine/threonine protein kinase in mammalian cells eponymously named mammalian target of rapamycin, or mTOR. Rapamycin is a novel class of anticancer and immunosuppressant drugs targeting the proteins at molecular level. Rapamycin (sirolimus) is routinely incorporated in drug-eluting stents used for cardiac angioplasty. In recent years, rapamycin was found to be efficacious in managing the symptom complex of tuberous sclerosis, i.e. renal angiomyolipoma, giant cell astrocytoma and pulmonary lymphangiomyomatosis. Various investigators have also proved that topically applied rapamycin causes regression of facial angiofibromas, giving better cosmetic results.

Treatment of pulmonary and retroperitoneal lymphangioleiomyomatosis with rapamycin: a case presentation and literature review

To improve the diagnosis and treatment of pulmonary lymphangiomyomatosis, clinical data for the first successfully treated case of pulmonary and retroperitoneal lymphangiomyomatosis in our hospital has been comprehensively analyzed, and the relevant literature has been reviewed. A 45-year-old Han Chinese woman initially presented six months ago with increasing shortness of breath on exertion and was admitted to our hospital after four days of chest pain. Admission examination revealed chylothorax, interstitial lung disease, and enlarged retroperitoneal lymph nodes. The patient was finally diagnosed with pulmonary and retroperitoneal lymphangiomyomatosis based on laparotomy examination and biopsy of the retroperitoneal lymph nodes. After six months of rapamycin treatment, the symptoms - lung function, arterial blood gas, and imaging of the patient- were improved significantly. Pulmonary lymphangiomyomatosis clinically manifests as progressive dyspnea, recurrent pneumothorax, and chylothorax, and can be diagnosed by its characteristic features in high-resolution computed tomographic images or pathological examination. The successful treatment of pulmonary lymphangiomyomatosis with rapamycin brings new hope to those afflicted with this disease.

Cystic lung disease is not uncommon in men with tuberous sclerosis complex

To assess the frequency of cystic lung disease suggestive of pulmonary lymphangiomyomatosis in men with tuberous sclerosis complex. Retrospective review of CT scans of the chest and abdomen on 29 men with tuberous sclerosis complex encountered during a 13-year period, 1998 to 2010. Cystic lung disease (defined as ≥4 cysts) was seen in 11 of 29 men (38%) with tuberous sclerosis complex. The mean age of those with cystic lung disease was 46.3±19.1 years. None of the patients had experienced pneumothorax or chylothorax and none had undergone a lung biopsy for evaluation of cystic lung disease. Lymphangiomyomatosis had been diagnosed in two of 11 patients with cystic lung disease. Renal angiomyolipomas were demonstrated in 14 of 25 patients (56%) with renal imaging available; all 14 had multiple bilateral renal involvement. In this limited cohort of patients, the presence of cystic lung disease did not correlate with age, smoking exposure or the presence of renal AMLs. We conclude that tuberous sclerosis complex -related lymphangiomyomatosis may not be rare in men but is milder in severity.

Lymphangiomyomatosis discovered by massive hemoptysis during general anesthesia -A case report-

Lymphangiomyomatosis (LAM) is a rare lung disease that is characterized by the progressive proliferation of atypical smooth muscle-like cells, which leads to severe respiratory impairment and death. Dyspnea, cough, recurrent pneumothorax, and hemoptysis are the most common clinical symptoms of LAM. We report a 29-year-old female patient with massive hemoptysis during laparoscopic gynecologic surgery under general anesthesia, who was diagnosed with pulmonary LAM.

Tuberous sclerosis complex - a case report / Kompleks tuberozne skleroze – prikaz slučaja

Abstract Tuberous sclerosis complex is a multisystem, autosomal dominant disorder affecting children and adults, which results from mutations in either of two genes, TSC1 (encoding hamartin) or TSC2 (encoding tuberin). Tuberous sclerosis complex often causes disabling neurologic disorders, including epilepsy, mental retardation, and autism. Major features of the disease include dermatologic manifestations, such as facial angiofibromas, renal angiomyolipomas, and pulmonary lymphangiomyomatosis. We report a 20-year-old woman with epilepsy and subnormal intelligence, who was admitted for evaluation of multiple facial papules that have gradually increased in number over the past 15 years. She had been previously diagnosed with tuberous sclerosis complex based on findings of cardiac ventricular rhabdomyomas, tuberosclerotic nodules of glial proliferation in the cerebral cortex, and renal angiomyolipoma. The facial papules were angiofibromas, confirming the clinical presentation of tuberous sclerosis complex. Detailed examination of the skin and mucosa revealed Shagreen patches, nontraumatic subungual and gingival fibroma, all features of tuberous sclerosis complex. A multidisciplinary team approach was used for diagnosis and medical care of tuberous sclerosis complex in order to treat many organ systems affected by tuberous sclerosis in our patient. The patient received antiepileptic medications, while rapamycin was recommended.

Giant renal angiomyolipomatosis in association with pulmonary lymphangiomyomatosis

Giant renal angiomyolipomatosis in association with pulmonary lymphangiomyomatosis

Endoscopic Ultrasound Images of Thoracic Lymphangiomyomatosis

Purpose: We report the first endoscopic ultrasound (EUS) images of Thoracic Lymphangiomyomatosis. Methods: Lymphangiomyomatosis is a rare hereditary disease characterized by smooth muscle proliferation in the lymphatic tissues and organs leading to formation of multiple cysts. It usually involves the lungs. Diagnosis is usually based on histopathology consisting of large cystic spaces lined by lymphangiomyomatous walls. We describe a 22-year-old woman with a prior diagnosis of Pulmonary Lymphangiomyomatosis who presented with hemoptysis & a new large mediastinal mass on CT. We used endoscopic ultrasound to localize the mass and biopsy it. Histopathology was consistent with progression of Lymphangiomyomatosis with extension from the lungs into the posterior mediastinum. She was treated with pulse IV Interferon-alpha & is currently doing well with no recurrence of hemoptysis. Results: These are the first endoscopic ultrasound (EUS) images of Lymphangiomyomatosis. Notable features on EUS are multiple thin walled cystic spaces within the soft tissue mass. Conclusion: Till now, the diagnosis of Lymphangiomyomatosis was based on histopathology. We believe that with improving fidelity & expanding indications for EUS, providers need to be aware of the sonographic morphology of different pathologic conditions in the thorax. EUS may offer a presumptive diagnosis of Lymphangiomyomatosis even prior to histopathology because of the peculiar sonographic appearance.Figure: Soft tissue density encasing distal esophagus on CTFigure: Multiple Cystic spaces in periesophageal space on EUS.Figure: Close up view of cystic spaces – seen at top of screen.

Sclérose tubéreuse de Bourneville révélée par des pneumothorax à répétition

Tuberous sclerosis complex (TSC) is an autosomal dominant phacomatosis. We report a 29-year-old woman who presented with recurrent pneumothorax in whom the diagnosis of TSC relied on the existence of family history (child with cardiac rhabdomyome), skin lesions, pulmonary lymphangiomyomatosis, hepatic lipomas, renal angiomyolipomas, uterine myomas and cerebral lesions on MRI. The diagnostic of TSC might be difficult as it could mimic pulmonary lymphangiomyomatosis.

Identification of the Benign Mesenchymal Tumor Gene HMGA2 in Lymphangiomyomatosis

The normal expression pattern of HMGA2, an architectural transcription factor, is primarily restricted to cells of the developing mesenchyme before their overt differentiation during organogenesis. A detailed in situ hybridization analysis showed that the undifferentiated mesoderm of the embryonic lung expressed Hmga2 but it was not expressed in the newborn or adult lung. Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. Here, we show that HMGA2 is misexpressed in pulmonary lymphangiomyomatosis (LAM), a severe disorder of unknown etiology consisting of lymphatic smooth muscle cell proliferation that results in the obstruction of airways, lymphatics, and vessels. Immunohistochemistry was done with antibodies to HMGA2 and revealed expression in lung tissue samples obtained from 21 patients with LAM. In contrast, HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation. In vivo studies in transgenic mice show that misexpression of HMGA2 in smooth muscle cells resulted in increased proliferation of these cells in the lung surrounding the epithelial cells. Therefore, similar to the other mesenchymal neoplasms, HMGA2 misexpression in the smooth muscle cell leads to abnormal proliferation and LAM tumorigenesis. These results suggest that HMGA2 plays a central role in the pathogenesis of LAM and is a potential candidate as a therapeutic target.

Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease

The most exciting advances in the tuberous sclerosis complex (TSC) field occurred in 1993 and 1997 with the cloning of the TSC2 and TSC1 genes, respectively, and in 2003 with the identification of Rheb as the target of tuberin's (TSC2) GTPase activating protein (GAP) domain. Rheb has a dual role: it activates mTOR and inactivates B-Raf. Activation of mTOR leads to increased protein synthesis through phosphorylation of p70S6K and 4E-BP1. Upon insulin or growth factor stimulation, tuberin is phosphorylated by several kinases, including AKT/PKB, thereby suppressing its GAP activity and activating mTOR. Phosphorylation of hamartin (TSC1) by CDK1 also negatively regulates the activity of the hamartin/tuberin complex. Despite these biochemical advances, exactly how mutations in TSC1 or TSC2 lead to the clinical manifestations of TSC is far from being understood. Two of the most unusual phenotypes in TSC are the apparent metastasis of benign cells carrying TSC1 and TSC2 mutations, resulting in pulmonary lymphangiomyomatosis, and the ability of cells with TSC1 or TSC2 mutations to differentiate into the separate components of renal angiomyolipomas (vessels, smooth muscle and fat). We will discuss how the TSC signaling pathways are affected by mutations in TSC1 or TSC2, focusing on how these mutations may lead to the renal and pulmonary manifestations of TSC.

The Role of Tuberin in Cellular Differentiation: Are B‐Raf and MAPK Involved?

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). This review focuses on the genetic and biochemical basis of the renal and pulmonary manifestations of TSC, angiomyolipomas, and lymphangiomyomatosis, respectively. Genetic analyses of sporadic angiomyolipomas revealed that all three components (smooth muscle, vessels, and fat) derive from a common progenitor cell, indicating the ability of cells lacking tuberin to differentiate into multiple lineages. Other genetic studies showed that the benign smooth muscle cells of pulmonary lymphangiomyomatosis have the ability to migrate to other organs. These findings suggest that tuberin and hamartin play a role in the regulation of cellular migration and differentiation. We have found that tuberin activates B-Raf kinase and p42/44 MAPK and that cells lacking tuberin have low levels of B-Raf activity. We hypothesize that aberrant B-Raf activity in angiomyolipomas leads to abnormal cellular differentiation and migration.

Abdominal CT findings of 7 patients with pulmonary lymphgiomyomatosis

目的 探讨肺淋巴管平滑肌增生症腹部病变的CT表现.方法回顾性分析7例经病理证实的肺淋巴管平滑肌增生症,7例均作腹部CT扫描,对其腹部CT表现进行研究分析.结果7例患者中6例有腹部阳性表现:肾血管平滑肌脂肪瘤2例,其中1例合并胸导管增大、胸腔积液; 腹膜后淋巴结肿大2例,合并腹水、胸腔积液1例;肝脏血管平滑肌脂肪瘤1例;腹膜后淋巴管肌瘤合并子宫肌瘤1例. 结论肺淋巴管平滑肌增生症可并发腹部多脏器病变,CT扫描对发现和诊断其腹部病变具有重要意义。