ABSTRACT
Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize their distribution as focal or multifocal versus diffuse. Focal cavitary lesions are often caused by inflammatory, infectious, or neoplastic processes in contrast to diffuse cystic lung diseases. An algorithmic approach to diffuse cystic lung disease can help narrow the differential diagnosis, and additional testing such as skin biopsy, serum biomarkers, and genetic testing can be confirmatory. An accurate diagnosis is essential for the management and disease surveillance of extrapulmonary complications.
Subject(s)
Birt-Hogg-Dube Syndrome , Cysts , Histiocytosis, Langerhans-Cell , Lung Diseases , Lymphangioleiomyomatosis , Humans , Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/therapy , Histiocytosis, Langerhans-Cell/complications , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/pathology , Birt-Hogg-Dube Syndrome/complications , Birt-Hogg-Dube Syndrome/diagnosis , Birt-Hogg-Dube Syndrome/pathology , Tomography, X-Ray Computed/methods , Lung Diseases/diagnosis , Lung Diseases/etiology , Lung/pathology , Cysts/diagnosis , Cysts/complications , Cysts/pathology , Diagnosis, DifferentialABSTRACT
INTRODUCTION: Tuberous sclerosis complex is an inherited multisystemic disorder with manifestations in various organ systems as a result of a mutation of 1 of 2 tumor suppressor genes, tuberous sclerosis complex-1 or tuberous sclerosis complex-2. Perivascular epithelioid cell tumors have been shown to be associated with these gene mutations and include a variety of tumors such as angiomyolipomas and lymphangioleiomyomatosis. PATIENT CONCERNS: In this report, we present a case of a 28-year-old woman presenting with symptoms of severe abdominal pain and nausea with a medical history of cardiac rhabdomyoma, adenoma sebaceum, Ash leaf spots, bilateral renal angiomyolipomas, and retinal hamartoma, which are manifestations of tuberous sclerosis complex. The patient was operated twice for colonic perforations in the rectosigmoid and ileocecal regions where the pathologic examination revealed multiple tumoral lesions in both specimens. DIAGNOSIS: The tumor consisted of a myomatous component where the nodules were composed of spindle cells with fascicular array, and a lymphangiomatous component where epithelioid cells could be observed. Immunohistochemically, smooth muscle markers (desmin and SMA) were positive and the epithelioid component showed HMB-45 positivity. A diagnosis of leiomyomatosis-like lymphangioleiomyomatosis was established due to its morphological and immunohistochemical features, the presence of the tumor in multiple foci, and widespread lymphovascular invasion. INTERVENTIONS: The patient had a perforation in her bowel twice during the hospital stay and underwent Hartmann operation and ileocecal resection in 2 different surgical operations. OUTCOMES: After the second operation the patient developed fever and was diagnosed with SARS-CoV-2 infection. No other complication was observed during her stay and the patient's follow-up was unremarkable. CONCLUSION: Perivascular epithelioid cell tumors are associated with tuberous sclerosis and can rarely appear in the colon. Therefore, lymphangioleiomyomatosis should be in the differential diagnosis in a tuberous sclerosis patient presenting with a colonic tumor.
Subject(s)
Angiomyolipoma , Leiomyomatosis , Lymphangioleiomyomatosis , Perivascular Epithelioid Cell Neoplasms , Tuberous Sclerosis , Adult , Angiomyolipoma/diagnosis , Angiomyolipoma/etiology , Angiomyolipoma/surgery , COVID-19 , Colon , Female , Humans , Leiomyomatosis/diagnosis , Leiomyomatosis/surgery , Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/surgery , Tuberous Sclerosis/complications , Tuberous Sclerosis/diagnosisABSTRACT
Lymphangioleiomyomatosis (LAM) is a slowly progressive, low-grade, metastasising neoplasm of women, characterised by infiltration of the lung parenchyma with abnormal smooth muscle-like cells, resulting in cystic lung destruction. The invading cell in LAM arises from an unknown source and harbours mutations in tuberous sclerosis complex (TSC) genes that result in constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, dysregulated cellular proliferation, and a programme of frustrated lymphangiogenesis, culminating in disordered lung remodelling and respiratory failure. Over the past two decades, all facets of LAM basic and clinical science have seen important advances, including improved understanding of molecular mechanisms, novel diagnostic and prognostic biomarkers, effective treatment strategies, and comprehensive clinical practice guidelines. Further research is needed to better understand the natural history of LAM; develop more powerful diagnostic, prognostic, and predictive biomarkers; optimise the use of inhibitors of mTOR complex 1 in the treatment of LAM; and explore novel approaches to the development of remission-inducing therapies.
Subject(s)
Lung Neoplasms , Lymphangioleiomyomatosis , Female , Humans , Lung/pathology , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/genetics , Mutation , Sirolimus/therapeutic useABSTRACT
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.
Subject(s)
Lung Neoplasms/diagnosis , Lung/diagnostic imaging , Lymphangioleiomyomatosis/diagnosis , Tuberous Sclerosis/complications , Adult , Aged , Female , Humans , Lung Neoplasms/etiology , Lymphangioleiomyomatosis/etiology , Male , Middle Aged , Retrospective Studies , Tomography, X-Ray Computed , Young AdultABSTRACT
Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In lymphangioleiomyomatosis, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high-throughput screen utilizing the "Repurposing" library at the Broad Institute of MIT and Harvard (Cambridge, MA), with or without the autophagy inhibitor chloroquine. Ritanserin, an inhibitor of diacylglycerol kinase alpha (DGKA), was identified as a selective inhibitor of proliferation of Tsc2-/- mouse embryonic fibroblasts (MEF), with no impact on Tsc2+/+ MEFs. DGKA is a lipid kinase that metabolizes diacylglycerol to phosphatidic acid, a key component of plasma membranes. Phosphatidic acid levels were increased 5-fold in Tsc2-/- MEFs compared with Tsc2+/+ MEFs, and treatment of Tsc2-/- MEFs with ritanserin led to depletion of phosphatidic acid as well as rewiring of phospholipid metabolism. Macropinocytosis is known to be upregulated in TSC2-deficient cells. Ritanserin decreased macropinocytic uptake of albumin, limited the number of lysosomes, and reduced lysosomal activity in Tsc2-/- MEFs. In a mouse model of TSC, ritanserin treatment decreased cyst frequency and volume, and in a mouse model of lymphangioleiomyomatosis, genetic downregulation of DGKA prevented alveolar destruction and airspace enlargement. Collectively, these data indicate that DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis and promote proliferation. Targeting macropinocytosis with ritanserin may represent a novel therapeutic approach for the treatment of TSC and lymphangioleiomyomatosis. SIGNIFICANCE: This study identifies macropinocytosis and phospholipid metabolism as novel mechanisms of metabolic homeostasis in mTORC1-hyperactive cells and suggest ritanserin as a novel therapeutic strategy for use in mTORC1-hyperactive tumors, including pancreatic cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2086/F1.large.jpg.
Subject(s)
Diacylglycerol Kinase/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lymphangioleiomyomatosis/drug therapy , Pinocytosis/drug effects , Ritanserin/pharmacology , Tuberous Sclerosis Complex 2 Protein/deficiency , Tuberous Sclerosis/drug therapy , Angiolipoma/genetics , Animals , Autophagy/drug effects , Cell Proliferation , Chloroquine/pharmacology , Diacylglycerol Kinase/genetics , Diacylglycerol Kinase/metabolism , Down-Regulation , Drug Synergism , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression , Kidney Neoplasms/genetics , Lung Neoplasms/etiology , Lung Neoplasms/pathology , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/pathology , Lysosomes/drug effects , Lysosomes/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Nude , Nutrients/metabolism , Phosphatidic Acids/metabolism , Phospholipids/metabolism , Pinocytosis/physiology , Tuberous Sclerosis/complicationsABSTRACT
Lymphangioleiomyiomatosis (LAM) is a rare disease affecting women in childbearing age. A sporadic form (S-LAM) affecting previously healthy women, and a form associated with Tuberous Sclerosis Complex (TSC-LAM) are described. Some data suggested that TSC-LAM could be a milder disease compared to S-LAM. To investigate whether the different disease behavior is real or due to overdiagnosis of screened TSC women, we compared the natural history of S-LAM and TSC-LAM in patients with incidental diagnosis. Clinical, and functional data from 52 patients (23 with S-LAM and 29 with TSC-LAM) were analysed. At diagnosis functional impairment was mild without differences between groups [FEV1 % pred was 97% (88-105) and 94% (82-106) in TSC-LAM and S-LAM, respectively, p = 0.125]. Patients with S-LAM had less renal angiomyolipoma, and lower VEGF-D serum levels than TSC-LAM. There was no difference in the baseline extent of pulmonary cysts on CT scan and no difference in yearly rate of functional decline between TSC-LAM, and S-LAM patients [e.g. yearly rate of decline of FEV1 % pred was -0.51 (-1.59-2.24) and -0.90 (-1.92--0.42) in TSC-LAM and S-LAM, respectively, p = 0.265]. In conclusion, the natural history of TSC-LAM and S-LAM, when a potential selection bias due to screening in the latter group is balanced, is similar. Our study suggests that the prevalence of S-LAM can be significantly underestimated due to a tendency to diagnosis more frequently patients with more severe impairment, without identifying several ones with asymptomatic disease.
Subject(s)
Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/etiology , Tuberous Sclerosis/diagnosis , Tuberous Sclerosis/etiology , Adult , Female , Forced Expiratory Volume , Humans , Lymphangioleiomyomatosis/epidemiology , Lymphangioleiomyomatosis/physiopathology , Male , Middle Aged , Prevalence , Rare Diseases , Severity of Illness Index , Tuberous Sclerosis/epidemiology , Tuberous Sclerosis/physiopathologySubject(s)
Lung Neoplasms/mortality , Lymphangioleiomyomatosis/mortality , Tuberous Sclerosis/complications , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Female , Humans , Lung Neoplasms/etiology , Lymphangioleiomyomatosis/etiology , Male , Middle Aged , Ohio , Sex Factors , Survival Analysis , Young AdultABSTRACT
Although lymphangioleiomyomatosis is often observed with tuberous sclerosis, uterine lymphangioleiomyomatosis is rare. Our patient was 36 years old (gravida 0, para 0). She had a history of tuberous sclerosis, and many myometrial cystic lesions were identified during assisted reproductive therapy. Although we administered a gonadotropin-releasing hormone analog, myometrial cystic lesions increased in size. Therefore, simple hysterectomy, bilateral salpingo-oophorectomy and pelvic lymph node biopsy were performed. Postoperative histology showed lymphangioleiomyomatosis and myometrial abscess. For uterine lesions in young women with tuberous sclerosis, the possibility of uterine lymphangioleiomyomatosis should also be considered.
Subject(s)
Lymphangioleiomyomatosis , Myometrium , Peritonitis , Tuberous Sclerosis/complications , Uterine Diseases , Adult , Female , Humans , Hysterectomy , Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/surgery , Myometrium/pathology , Myometrium/surgery , Peritonitis/diagnosis , Peritonitis/etiology , Peritonitis/surgery , Salpingo-oophorectomy , Uterine Diseases/diagnosis , Uterine Diseases/etiology , Uterine Diseases/surgeryABSTRACT
Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. It commonly causes several types of cystic disease and benign tumors (angiomyolipomata) in the kidneys that can both lead to significant premature loss of glomerular filtration rate. The main risks of angiomyolipomata, severe bleeding, loss of renal function, and pulmonary lymphangioleiomyomatosis, can be ameliorated by active surveillance and preemptive therapy with mTOR inhibitors. The cystogenic mechanism may involve primary cilia, but also appears to also involve a majority of normal tubular cells and may be driven by a minority of cells with mutations inactivating both their TSC1 or TSC2 genes. Malignant tumors are rare.
Subject(s)
Kidney Neoplasms/etiology , Renal Insufficiency, Chronic/therapy , Tuberous Sclerosis/etiology , Angiomyolipoma/etiology , Animals , Humans , Hypertension/drug therapy , Hypertension/etiology , Kidney Diseases, Cystic/etiology , Lymphangioleiomyomatosis/etiology , Mutation , Renal Insufficiency, Chronic/etiology , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/geneticsABSTRACT
PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the TSC1 or TSC2 gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin-positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder (TSC1/TSC2 somatic mutations). Biomarkers of whole-body tumor burden/activity and response to rapalogs or other therapies remain needed in TSC/LAM. EXPERIMENTAL DESIGN: These preclinical studies aimed to assess feasibility of [18F]fluorocholine (FCH) and [18F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers. RESULTS: We previously reported that TSC2-deficient cells enhance phosphatidylcholine synthesis via the Kennedy pathway. Here, we show that TSC2-deficient cells exhibit rapid uptake of [18F]FCH in vivo and can be visualized by PET imaging in preclinical models of TSC/LAM, including subcutaneous tumors and pulmonary nodules. Treatment with rapamycin (72 hours) suppressed [18F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [18F]FCH-PET imaging of TSC2-deficient xenografts in ovariectomized mice also showed a significant decrease in tumor SUV. Finally, we found rapamycin-insensitive uptake of FACE by TSC2-deficient cells in vitro and in vivo, reflecting its mitochondrial accumulation via inhibition of aconitase, a TCA cycle enzyme. CONCLUSIONS: Preclinical models of TSC2 deficiency represent informative platforms to identify tracers of potential clinical interest. Our findings provide mechanistic evidence for testing the potential of [18F]FCH and [18F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors.
Subject(s)
Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/metabolism , Mitochondria/metabolism , Phosphatidylcholines/metabolism , Positron-Emission Tomography , Tuberous Sclerosis/diagnosis , Tuberous Sclerosis/metabolism , Aged , Animals , Biomarkers , Choline/analogs & derivatives , Disease Models, Animal , Female , Fluoroacetates , Heterografts , Humans , Image Processing, Computer-Assisted , Immunohistochemistry , Lipid Metabolism , Lymphangioleiomyomatosis/etiology , Male , Mice , Mice, Transgenic , Mitochondria/genetics , Oxygen Consumption , Positron-Emission Tomography/methods , Rats , Tuberous Sclerosis/etiologyABSTRACT
Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.
Subject(s)
Lung Neoplasms/etiology , Lung/pathology , Lymphangioleiomyomatosis/etiology , Multiple Pulmonary Nodules/pathology , Tuberous Sclerosis/etiology , Animals , Female , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/drug therapy , Lymphangioleiomyomatosis/pathology , Mice , Multiple Pulmonary Nodules/genetics , Pneumothorax/etiology , Prognosis , Sirolimus/therapeutic use , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 2 Protein/geneticsABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous condition that predisposes to numerous proliferative lesions, including perivascular epithelioid cell tumors (PEComas), such as lymphangioleiomyomatosis (LAM) and angiomyolipomas, and rare neuroendocrine neoplasms. We describe herein a TSC2-harboring tuberous sclerosis patient manifesting with a synchronous well-differentiated L-cell rectal neuroendocrine tumor and leiomyomatosis-like LAM of the rectum. The background large bowel wall was thickened by confluent nodular areas comprising vessels and spindle-to-epithelioid cells, which are immunoreactive for myoid (smooth muscle actin, muscle specific actin, and desmin) and melanocytic markers (HMB45, Melan-A, microphthalmia transcription factor, and CD117). With the exception of TSC-related pancreatic neuroendocrine tumors, the association between tuberous sclerosis and neuroendocrine neoplasms remains largely unknown in the gastrointestinal tract. Neuroendocrine tumorigenesis in tuberous sclerosis is often linked to inactivating mutations of TSC2 leading to aberrant activation of mammalian target of rapamycin (mTOR) pathway. In this report, we document, for the first time, two foci of L-cell rectal neuroendocrine tumor arising in the setting of tuberous sclerosis, thus broadening the spectrum of TSC-associated endocrine disorders. Moreover, to our knowledge, this is only the second documented case of gastrointestinal leiomyomatosis-like LAM in a patient with tuberous sclerosis. The current case provides further evidence that, similar to pancreatic neuroendocrine tumors, neuroendocrine tumors of the luminal gastrointestinal tract may also be a feature of tuberous sclerosis and can be seen in association with PEComas.
Subject(s)
Neuroendocrine Tumors/pathology , Perivascular Epithelioid Cell Neoplasms/pathology , Rectal Neoplasms/pathology , Tuberous Sclerosis/pathology , Adolescent , Female , Humans , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/pathology , Neuroendocrine Tumors/etiology , Perivascular Epithelioid Cell Neoplasms/etiology , Rectal Neoplasms/etiology , Tuberous Sclerosis/complicationsABSTRACT
A 34-year-old male with frequent recurrence of right pneumothorax was admitted to our hospital. He was a current smoker and outwardly male without genital aplasia. He was diagnosed as tuberous sclerosis complex (TSC) at 2 year-old and underwent transcatheter arterial embolization for right renal hemorrhage due to renal tumor 2 years ago. Chest Computed Tomography showed that he had multiple tiny round cystic lesions with thin wall in both lungs. The recurrent pneumothorax was expected to be associated with TSC-Lymphangioleiomyomatosis (LAM). Video-assisted thoracic surgery was successfully performed. The operative and histological findings revealed that the bullae were classified into two groups; emphysematous bullae and bullae due to LAM. His postoperative course was uneventful. TSC-LAM is extremely rare, but in some cases the clinical recognition might be escaped due to subtle findings of bullae in early LAM, resulting in diagnosis as spontaneous pneumothorax.
Subject(s)
Blister/etiology , Lymphangioleiomyomatosis/etiology , Pulmonary Emphysema/etiology , Smoking/adverse effects , Tuberous Sclerosis/complications , Adult , Biopsy , Blister/diagnostic imaging , Blister/surgery , Humans , Immunohistochemistry , Lymphangioleiomyomatosis/diagnostic imaging , Lymphangioleiomyomatosis/surgery , Male , Pneumothorax/etiology , Pulmonary Emphysema/diagnostic imaging , Pulmonary Emphysema/surgery , Recurrence , Thoracic Surgery, Video-Assisted , Tomography, X-Ray Computed , Treatment Outcome , Tuberous Sclerosis/diagnosisSubject(s)
Tuberous Sclerosis/diagnosis , Adolescent , Adult , Angiomyolipoma/diagnostic imaging , Angiomyolipoma/etiology , Female , Gingival Hypertrophy/etiology , Heart Neoplasms/diagnostic imaging , Heart Neoplasms/etiology , Humans , Hydrocephalus/etiology , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/etiology , Lymphangioleiomyomatosis/diagnostic imaging , Lymphangioleiomyomatosis/etiology , Mothers , Optic Atrophies, Hereditary/etiology , Rhabdomyoma/diagnostic imaging , Rhabdomyoma/etiologyABSTRACT
Lymphangioleiomyomatosis (LAM) is a devastating rare lung disease affecting primarily childbearing age women in which tumors consisting of abnormal smooth-muscle-like cells grow within the lungs and progressively lead to loss of pulmonary function. LAM cells metastasize to the lungs, predominantly through the lymphatics; however, the source of the LAM cell is still unknown. LAM cells contain inactivating mutations in genes encoding tuberous sclerosis 1 or 2, proteins that normally limit cell growth through suppression of mammalian target of rapamycin complex 1. As of today, sirolimus (an mammalian target of rapamycin complex 1 inhibitor) is the only treatment, available for LAM patients that is approved by the Food and Drug Administration; however, this drug and others in its class provide stabilization but not remission of LAM. One of the biggest problems in treating LAM is that both the origin of the LAM cells and the mechanism of the sexual dimorphism in LAM are still not understood. LAM cells express estrogen and progesterone receptors, and lung function declines during periods of high circulating estrogen levels. Moreover, numerous basic research studies find that estrogen is a key driving force in LAM cell proliferation, migration, and metastasis. In this review, we highlight recent insights regarding the role of steroid hormones in LAM and discuss possible explanations for the profound female sexual dimorphism of LAM.
Subject(s)
Estrogens/metabolism , Lymphangioleiomyomatosis/etiology , Progesterone/metabolism , Cathepsin K/metabolism , Female , Humans , Leiomyoma/pathology , Leukocyte Elastase/metabolism , Lung/pathology , Lymphangioleiomyomatosis/genetics , Lymphangioleiomyomatosis/metabolism , Lymphangioleiomyomatosis/pathology , Lymphatic Metastasis , Matrix Metalloproteinases/metabolism , Selective Estrogen Receptor Modulators , Sex Characteristics , Uterine Neoplasms/pathology , Uterus/pathologyABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.
Subject(s)
Tuberous Sclerosis/complications , Tuberous Sclerosis/physiopathology , Angiomyolipoma/etiology , Brain/pathology , Brain/physiopathology , Epilepsy/etiology , Humans , Kidney/pathology , Kidney/physiopathology , Lung/pathology , Lung/physiopathology , Lymphangioleiomyomatosis/etiology , Skin/pathology , Skin/physiopathology , Tomography, X-Ray Computed/methods , Tuberous Sclerosis/epidemiology , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/analysis , Tumor Suppressor Proteins/geneticsABSTRACT
INTRODUCTION: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease affecting mainly young women. BACKGROUND: The respiratory manifestations are characterized by a progressive cystic destruction of the lung parenchyma. Extrapulmonary involvement includes benign renal tumours called angiomyolipomas and abdominal lymphatic masses called lymphangioleiomyomas. At the pathological level, the cellular proliferation found in LAM is in part due to the presence of mutations in the tumour suppressor genes TSC1 and TSC2 (Tuberous Sclerosis Complex). These mutations lead to the activation of the mTOR pathway, which is currently the main therapeutic target. mTOR inhibitors such as sirolimus or everolimus have shown a beneficial effect on the decline in pulmonary function and a reduction of angiomyolipoma size, but are necessary in only some patients. PERSPECTIVES: LAM cells have migratory properties mediated by the formation of new lymphatic vessels. They are also able to secrete metalloproteases, which enhance their invasiveness. Moreover, the expression of estrogen and progesterone receptors by LAM cells suggests a possible role for sex hormones in the pathogenesis of the disease. CONCLUSION: A better understanding of mTOR-independent mechanisms would allow the development of novel therapeutic approaches.
Subject(s)
Lung Neoplasms , Lymphangioleiomyomatosis , Adult , Female , History, 20th Century , History, 21st Century , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/epidemiology , Lung Neoplasms/etiology , Lung Neoplasms/therapy , Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/epidemiology , Lymphangioleiomyomatosis/etiology , Lymphangioleiomyomatosis/therapyABSTRACT
Lymphangioleiomyomatosis (LAM) is associated with dysfunction of the tuberous sclerosis complex (TSC) leading to enhanced cell proliferation and migration. This study aims to examine whether doxycycline, a tetracycline antibiotic, can inhibit the enhanced migration of TSC2-deficient cells, identify signalling pathways through which doxycycline works and to assess the effectiveness of combining doxycycline with rapamycin (mammalian target of rapamycin complex 1 inhibitor) in controlling cell migration, proliferation and wound closure. TSC2-positive and TSC2-negative mouse embryonic fibroblasts (MEF), 323-TSC2-positive and 323-TSC2-null MEF and Eker rat uterine leiomyoma (ELT3) cells were treated with doxycycline or rapamycin alone, or in combination. Migration, wound closure and proliferation were assessed using a transwell migration assay, time-lapse microscopy and manual cell counts respectively. RhoA-GTPase activity, phosphorylation of p70S6 kinase (p70S6K) and focal adhesion kinase (FAK) in TSC2-negative MEF treated with doxycycline were examined using ELISA and immunoblotting techniques. The enhanced migration of TSC2-null cells was reduced by doxycycline at concentrations as low as 20 pM, while the rate of wound closure was reduced at 2-59 µM. Doxycycline decreased RhoA-GTPase activity and phosphorylation of FAK in these cells but had no effect on the phosphorylation of p70S6K, ERK1/2 or AKT. Combining doxycycline with rapamycin significantly reduced the rate of wound closure at lower concentrations than achieved with either drug alone. This study shows that doxycycline inhibits TSC2-null cell migration. Thus doxycycline has potential as an anti-migratory agent in the treatment of diseases with TSC2 dysfunction.
Subject(s)
Doxycycline/therapeutic use , Focal Adhesion Kinase 2/drug effects , Lymphangioleiomyomatosis/etiology , Sirolimus/therapeutic use , Tuberous Sclerosis/drug therapy , rho-Associated Kinases/drug effects , Animals , Doxycycline/administration & dosage , Lymphangioleiomyomatosis/drug therapy , Mice , RatsABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease with high phenotypic variability. The incidence is approximately one in 5000-10,000 births. TSC is characterized by widespread hamartomas and benign or rarely malignant neoplasms affecting various organs, most commonly the brain, skin, retinas, kidneys, heart, and lungs. The wide range of organs affected reflects the roles of TSC1 and TSC2 genes in the regulation of cell proliferation and differentiation. Clinical diagnostic criteria are important because genetic testing does not identify the mutation in up to 25% of patients. Imaging is pivotal, as it allows a presumptive diagnosis of TSC and definition of the extent of the disease. Common manifestations of TSC include cortical tubers, subependymal nodules, white matter abnormalities, retinal abnormalities, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), renal angiomyolipoma, and skin lesions. Pulmonary involvement consists of LAM and, less commonly, multifocal micronodular pneumocyte hyperplasia (MMPH), which causes cystic and nodular diseases, respectively. Recent reports indicate that pulmonary LAM is found by computed tomography in up to 35% of the female patients with TSC. MMPH is rare and may be associated with LAM or, less frequently, occurs as an isolated pulmonary manifestation in women with TSC. Dyspnea and pneumothorax are common clinical presentations of LAM, whereas MMPH is usually asymptomatic. The aim of this review is to describe the main clinical, imaging, and pathological aspects of TSC, with a focus on pulmonary involvement.