ABSTRACT
Maximum standard uptake value (SUVmax) of F-18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) is reportedly useful for evaluating regional lymph nodes (RLNs) of non-small-cell lung cancer (NSCLC) to predict malignancy. However, it is difficult for clinicians to measure SUVmax (mSUVmax) as calculated by a workstation.We assessed the utility of simplified SUVmax (sSUVmax) in screening RLNs for pathologic malignancy. The highest color was visually defined in the region of interest. The resulting color can be quantified using the color bar, and interpreted as sSUVmax. Patients in respiratory medicine and surgery who underwent both contrast-enhanced CT and FDG-PET/CT within 3 months before radical lobectomy were evaluated retrospectively. The correlation was examined by regression analysis and receiver operating characteristic (ROC) curve analyses.Participants comprised 69 patients with NSCLC treated between May 2009 and April 2016. Medical group comprised 22 patients from respiratory medicine. The prediction model could be written as a linear relationship (mSUVmaxâ=â1.019â×âsSUVmax; Râ=â0.930). A total of 316 RLNs resected by surgery in total cohort were pathologically determined. From ROC curves, area under curve for sSUVmax was 0.72 (95% confidence interval, 0.61-0.83; Pâ<â.0002). The cutoff sSUVmax was 2.42 (sensitivity, 52%; specificity, 88%; accuracy, 85%).The sSUVmax allows quantification of colors from FDG-PET/CT and shows a close correlation to mSUVmax. This value may have potential in screening for RLNs, and thoracic clinicians can readily determine the value. These findings may facilitate better planning of therapeutic strategy in the real world.
Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Lung Neoplasms/diagnostic imaging , Lymph Nodes/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Aged , Aged, 80 and over , Databases, Factual , Early Detection of Cancer/methods , Female , Fluorodeoxyglucose F18 , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Middle Aged , ROC Curve , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Early-onset pulmonary emphysema is uncommon and its pathogenesis is poorly defined. A 30-year-old man was admitted to our intensive care unit with severe respiratory failure. Besides smoking heavily since the 14 years of age, he had habitually inhaled organic solvents, such as toluene, in his adolescence. High-resolution computed tomography showed evident pulmonary emphysema throughout the lung fields. Based on the findings of right heart catheterization, he was diagnosed with an acute exacerbation of chronic obstructive pulmonary disease complicated with pulmonary hypertension. Heavy smoking from a young age and exposure to toluene were the suspected causes of the patient's severe pulmonary emphysema.
Subject(s)
Hypertension, Pulmonary/chemically induced , Lung/pathology , Pulmonary Disease, Chronic Obstructive/chemically induced , Respiratory Insufficiency/etiology , Smoking/adverse effects , Toluene/adverse effects , Adult , Humans , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/drug therapy , Male , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/drug therapy , Respiratory Insufficiency/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Spontaneous pneumothorax is a major and frequently recurrent complication of lymphangioleiomyomatosis (LAM). Despite the customary use of pleurodesis to manage pnenumothorax, the recurrence rate remains high, and accompanying pleural adhesions cause serious bleeding during subsequent lung transplantation. Therefore, we have developed a technique of total pleural covering (TPC) for LAM to wrap the entire visceral pleura with sheets of oxidized regenerated cellulose (ORC) mesh, thereby reinforcing the affected visceral pleura and preventing recurrence. METHODS: Since January 2003, TPC has been applied during video-assisted thoracoscopic surgery for the treatment of LAM. The medical records of LAM patients who had TPC since that time and until August 2014 are reviewed. RESULTS: TPC was performed in 43 LAM patients (54 hemithoraces), 11 of whom required TPC bilaterally. Pneumothorax recurred in 14 hemithoraces (25.9%) from 11 patients (25.6%) after TPC. Kaplan-Meier estimates of recurrence-free hemithorax were 80.8% at 2.5 years, 71.7% at 5 years, 71.7% at 7.5 years, and 61.4% at 9 years. The recurrence-free probability was significantly better when 10 or more sheets of ORC mesh were utilized for TPC (P = 0.0018). TPC significantly reduced the frequency of pneumothorax: 0.544 ± 0.606 episode/month (mean ± SD) before TPC vs. 0.008 ± 0.019 after TPC (P<0.0001). Grade IIIa postoperative complications were found in 13 TPC surgeries (24.1%). CONCLUSIONS: TPC successfully prevented the recurrence of pneumothorax in LAM, was minimally invasive and rarely caused restrictive ventilatory impairment.
ABSTRACT
Leakage of fluid from blood vessels, leading to oedema, is a key feature of many diseases including hyperoxic acute lung injury (HALI), which can occur when patients are ventilated with high concentrations of oxygen (hyperoxia). The molecular mechanisms driving vascular leak and oedema in HALI are poorly understood. VEGF-D is a protein that promotes blood vessel leak and oedema when overexpressed in tissues, but the role of endogenous VEGF-D in pathological oedema was unknown. To address these issues, we exposed Vegfd-deficient mice to hyperoxia. The resulting pulmonary oedema in Vegfd-deficient mice was substantially reduced compared to wild-type, as was the protein content of bronchoalveolar lavage fluid, consistent with reduced vascular leak. Vegf-d and its receptor Vegfr-3 were more highly expressed in lungs of hyperoxic, versus normoxic, wild-type mice, indicating that components of the Vegf-d signalling pathway are up-regulated in hyperoxia. Importantly, VEGF-D and its receptors were co-localized on blood vessels in clinical samples of human lungs exposed to hyperoxia; hence, VEGF-D may act directly on blood vessels to promote fluid leak. Our studies show that Vegf-d promotes oedema in response to hyperoxia in mice and support the hypothesis that VEGF-D signalling promotes vascular leak in human HALI. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Subject(s)
Acute Lung Injury/complications , Hyperoxia/complications , Pulmonary Edema/etiology , Signal Transduction , Vascular Endothelial Growth Factor D/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolism , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Bronchoalveolar Lavage Fluid , Cell Line, Tumor , Female , Humans , Hyperoxia/metabolism , Hyperoxia/pathology , Lung/metabolism , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Oxygen/metabolism , Pulmonary Edema/complications , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , Vascular Endothelial Growth Factor D/administration & dosage , Vascular Endothelial Growth Factor D/genetics , Vascular Endothelial Growth Factor Receptor-3/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease caused by dysregulated activation of the mammalian target of rapamycin (mTOR). Sirolimus, an inhibitor of mTOR, has been reported to decrease the size of angiomyolipomas and stabilize pulmonary function in patients with LAM. However, the optimal dose for the treatment of LAM remains unclear. METHODS: We conducted a retrospective, observational study of 15 patients with LAM who underwent sirolimus therapy for more than 6 months. The efficacy was evaluated by reviewing the patients' clinical courses, pulmonary function and chest radiologic findings before and after the initiation of sirolimus treatment. RESULTS: All patients had blood trough levels of sirolimus lower than 5ng/mL. Sirolimus treatment improved the annual rates of change in FVC and FEV1 in the 9 patients who were free from chylous effusion (FVC, -101.0 vs. +190.0mL/y, p=0.046 and FEV1, -115.4 vs. +127.8mL/y, p=0.015). The remaining 7 patients had chylous effusion at the start of sirolimus treatment; the chylothorax resolved completely within 1-5 months of treatment in 6 of these cases. These results resembled those of previous studies in which blood trough levels of sirolimus ranged from 5 to 15ng/mL. CONCLUSIONS: Low-dose sirolimus (trough level, 5ng/mL or less) performed as well as the higher doses used previously for improving pulmonary function and decreasing chylous effusion in patients with LAM.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Lung Neoplasms/drug therapy , Lymphangiomyoma/drug therapy , Sirolimus/administration & dosage , Adult , Chylothorax/drug therapy , Chylothorax/etiology , Female , Forced Expiratory Volume , Humans , Lung Neoplasms/complications , Lung Neoplasms/genetics , Lung Neoplasms/physiopathology , Lymphangiomyoma/complications , Lymphangiomyoma/genetics , Lymphangiomyoma/physiopathology , Male , Middle Aged , Molecular Targeted Therapy , Pleural Effusion, Malignant/drug therapy , Pleural Effusion, Malignant/etiology , Retrospective Studies , Sirolimus/blood , TOR Serine-Threonine Kinases , Treatment Outcome , Vital CapacityABSTRACT
Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm(2)) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.
Subject(s)
Lymphangiogenesis/physiology , Signal Transduction/physiology , Vascular Endothelial Growth Factor Receptor-3/physiology , Animals , Cell Line, Tumor , Female , Humans , Lymphatic Metastasis , Lymphatic Vessels/pathology , Mice , Mice, SCID , Neovascularization, Physiologic , Vascular Endothelial Growth Factor D/physiology , Vascular Endothelial Growth Factor Receptor-2/physiologyABSTRACT
VEGF-D is an angiogenic and lymphangiogenic glycoprotein that can be proteolytically processed generating various forms differing in subunit composition due to the presence or absence of N- and C-terminal propeptides. These propeptides flank the central VEGF homology domain, that contains the binding sites for VEGF receptors (VEGFRs), but their biological functions were unclear. Characterization of propeptide function will be important to clarify which forms of VEGF-D are biologically active and therefore clinically relevant. Here we use VEGF-D mutants deficient in either propeptide, and in the capacity to process the remaining propeptide, to monitor the functions of these domains. We report for the first time that VEGF-D binds heparin, and that the C-terminal propeptide significantly enhances this interaction (removal of this propeptide from full-length VEGF-D completely prevents heparin binding). We also show that removal of either the N- or C-terminal propeptide is required for VEGF-D to drive formation of VEGFR-2/VEGFR-3 heterodimers which have recently been shown to positively regulate angiogenic sprouting. The mature form of VEGF-D, lacking both propeptides, can also promote formation of these receptor heterodimers. In a mouse tumor model, removal of only the C-terminal propeptide from full-length VEGF-D was sufficient to enhance angiogenesis and tumor growth. In contrast, removal of both propeptides is required for high rates of lymph node metastasis. The findings reported here show that the propeptides profoundly influence molecular interactions of VEGF-D with VEGF receptors, co-receptors, and heparin, and its effects on tumor biology.
Subject(s)
Heparin/chemistry , Vascular Endothelial Growth Factor D/physiology , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolism , Animals , Cell Line , Chromatography, Affinity , Endothelial Cells/metabolism , Female , Humans , Lymphangiogenesis , Lymphatic Metastasis , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/pathology , Neovascularization, Pathologic/metabolism , Neuropilins/metabolism , Protein Binding , Protein Multimerization , Protein Precursors/chemistry , Protein Precursors/genetics , Protein Precursors/metabolism , Protein Precursors/physiology , Protein Structure, Tertiary , Sequence Deletion , Vascular Endothelial Growth Factor D/chemistry , Vascular Endothelial Growth Factor D/genetics , Vascular Endothelial Growth Factor D/metabolism , Vascular Endothelial Growth Factor Receptor-2/chemistry , Vascular Endothelial Growth Factor Receptor-3/chemistryABSTRACT
The lymphatic vasculature is important for skin biology as it maintains dermal fluid homeostasis. However, the molecular determinants of the form and function of the lymphatic vasculature in skin are poorly understood. Here, we explore the role of vascular endothelial growth factor-d (Vegf-d), a lymphangiogenic glycoprotein, in determining the form and function of the dermal lymphatic network, using Vegf-d-deficient mice. Initial lymphatic vessels in adult Vegf-d-deficient mice were significantly smaller than wild-type but collecting lymphatics were unaltered. The uptake/transport of dextran in initial lymphatics of Vegf-d-deficient mice was far less efficient, indicating compromised function of these vessels. The role of Vegf-d in modulating initial lymphatics was further supported by delivery of Vegf-d in skin of wild-type mice, which promoted enlargement of these vessels. Vegf-d-deficient mice were subjected to cutaneous wounding to challenge lymphatic function: the resulting wound epithelium was highly edematous and thicker, reflecting inadequate lymphatic drainage. Unexpectedly, myofibroblasts were more abundant in Vegf-d-deficient wounds leading to faster wound closure, but resorption of granulation tissue was compromised suggesting poorer-quality healing. Our findings demonstrate that Vegf-d deficiency alters the caliber of initial lymphatics in the dermis leading to reduced functional capacity.
Subject(s)
Dermis/physiology , Lymphatic Vessels/abnormalities , Lymphatic Vessels/physiology , Vascular Endothelial Growth Factor D/physiology , Wound Healing/physiology , Age Factors , Animals , Body Fluids/metabolism , Dermis/blood supply , Dermis/injuries , Female , Granulation Tissue/physiology , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Vascular Endothelial Growth Factor D/deficiency , Vascular Endothelial Growth Factor D/geneticsABSTRACT
VEGF-D is a mitogen for endothelial cells that promotes tumor growth and metastatic spread in animal models, and expression of which correlates with lymph node metastasis in some human cancers. It is secreted from the cell as a full-length form with propeptides flanking a central region containing binding sites for VEGFR-2 and VEGFR-3, receptors that signal for angiogenesis and lymphangiogenesis. The propeptides can be cleaved from VEGF-D, enhancing affinity for VEGFR-2 and VEGFR-3 in vitro; however, the importance of this processing in cancer is unclear. To explore the necessity of processing for the effects of VEGF-D in cancer, we use a mutant full-length form that cannot be processed, and show that, in contrast to full-length VEGF-D that is processed, this mutant does not promote tumor growth and lymph node metastasis in a mouse tumor model. Processing of VEGF-D is required for tumor angiogenesis, lymphangiogenesis, and recruitment of tumor-associated macrophages. These observations may be explained by the requirement of processing for VEGF-D to bind neuropilin receptors and activate VEGFR-2. Our results indicate that proteolytic processing is necessary for VEGF-D to promote the growth and spread of cancer, and suggest that enzymes catalyzing this processing could be targets for antimetastatic therapeutics.
Subject(s)
Neoplasm Metastasis/pathology , Neoplasm Metastasis/physiopathology , Vascular Endothelial Growth Factor D/metabolism , Animals , Cell Line, Tumor , Female , Humans , Lymphangiogenesis/physiology , Macrophages/pathology , Macrophages/physiology , Mice , Mice, Inbred NOD , Mice, SCID , Mutant Proteins/genetics , Mutant Proteins/metabolism , Mutant Proteins/physiology , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/pathology , Neoplasms, Experimental/physiopathology , Neovascularization, Pathologic/physiopathology , Neuropilins/metabolism , Protein Processing, Post-Translational , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Transplantation, Heterologous , Vascular Endothelial Growth Factor D/genetics , Vascular Endothelial Growth Factor D/physiologyABSTRACT
INTRODUCTION: The optimal treatment for patients older than 80 years with small cell lung cancer (SCLC) is unknown. METHODS: A retrospective chart review was conducted for 45 patients aged 80 years or older with SCLC, and therapeutic indices and toxicities of anticancer treatment were compared with those of 38 patients aged 70 to 79 years. Subgroup analyses according to the levels of performance status (PS) and comorbidity were also performed. RESULTS: Twenty-four (53%) of the 45 patients underwent combination chemotherapy and/or thoracic radiotherapy, which resulted in significant survival benefit compared with those left untreated (p < 0.01). The main reasons for not administrating anticancer treatments were advanced age (>85 years), poor PS, and severe comorbidities. The average total chemotherapy dose delivered was 60% of the intended protocol dose. Median survival time and 1-year survival of the treated patients were 13.0 months and 57% for limited disease and 10.3 months and 40% for extensive disease, respectively. Despite a lower chemotherapy dose being administered, survival indices were similar to those of patients aged 70 to 79 years. Survival benefit was observed even in the treated patients with PS 2 to 3 or a moderate degree of comorbidity compared with those left untreated. The frequency of grade 3 to 4 hematologic toxicities was not significantly different between the two age groups. CONCLUSIONS: The standard chemotherapy regimen with or without thoracic radiotherapy seems to be feasible for patients older than 80 years with SCLC, even for those with PS 2 to 3 and/or moderate comorbidity, although frequent dose adjustment is necessary.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Aged , Aged, 80 and over , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Retrospective Studies , Small Cell Lung Carcinoma/pathology , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease in which abnormal smooth muscle-like cells (LAM cells) proliferate in the lungs and along the axial lymphatic systems, including the lymph nodes and thoracic ducts. LAM cells are transformed due to loss-of-function type mutations of either the TSC1 or TSC2 tumor suppressor genes. The pathological features include the proliferation of benign-looking LAM cells and the existence of abundant lymphatic vessels that are associated with clinical conditions such as chyle leakage. LAM cells produce potent lymphangiogenic growth factors (VEGF-C and VEGF-D) and the lymphatic vessel density within LAM lesions correlates with the histologic severity of LAM. The serum VEGF-D level increases in LAM, especially in patients with lymphatic involvement. LAM cell clusters (LCCs), which are postulated pathologically to be generated by lymphangiogenesis-mediated fragmentation and subsequent shedding into the lymphatic circulation, are observed in both chylous effusion and LAM-associated lymphatics within LAM tissue specimens. The identification of LCCs in chylous effusion together with the characteristic clinical manifestations can therefore be an alternative for a lung biopsy if LAM patients are complicated with chylous effusion. CONCLUSION: LAM appears to be a disease involving a dysfunction of the lymphatic system and a fascinating model of tumor dissemination that is exclusively lymphangitic. LAM-associated lymphangiogenesis that mediates the shedding of LCCs seems to play a central role in the dissemination of LAM cells and progression in LAM and it may also be a potential therapeutic target as well as the dysregulated mTOR signaling pathway.
Subject(s)
Lymphangioleiomyomatosis/metabolism , Lymphatic System/metabolism , Neoplasm Proteins/metabolism , Animals , Humans , Lymphangioleiomyomatosis/pathologyABSTRACT
A 30-year-old Japanese woman with lymphangioleiomyomatosis (LAM) developed a left chylothorax and chylous ascites. A pleuro-peritoneal communication was confirmed by a scintigram with (99)mTc-labeled macroaggregated-albumin injected into the peritoneal cavity. Video-assisted thoracic surgery revealed a protruding papillary lesion on the left diaphragm. Chyle was oozing into the pleural cavity through this lesion. Histopathological analyses demonstrated that the protrusion was a diaphragmatic LAM lesion and that LAM-associated lymphangiogenesis enabled communication between the pleural and peritoneal cavities through lymphatic vessels. This case demonstrated a new mechanism for chylous pleural effusion in LAM and illustrates the significance of LAM-associated lymphangiogenesis.
Subject(s)
Diaphragm , Lymphangioleiomyomatosis/complications , Muscle Neoplasms/complications , Peritoneal Cavity/physiopathology , Pleural Cavity/physiopathology , Adult , Chylothorax/etiology , Chylous Ascites/etiology , Female , Humans , Lymphangioleiomyomatosis/surgery , Lymphatic Vessels/diagnostic imaging , Lymphatic Vessels/physiopathology , Muscle Neoplasms/surgery , Peritoneal Cavity/diagnostic imaging , Pleural Cavity/diagnostic imaging , Radionuclide ImagingABSTRACT
A 53-year-old woman was admitted to our hospital due to a severe respiratory condition and malnutrition. Radiological and electrophysiological findings suggested the existence of inexplicable cor pulmonale. Although we commenced to determine the causes of her severe condition, she suddenly died 3 days after admission. Postmortem autopsy revealed tumor cell microemboli in the small pulmonary arteries due to gastric cancer. Such a case of cor pulmonale as the first clinical manifestation is exceptionally rare. Occult malignancy should be considered as a differential diagnosis when one encounters a patient with subacutely aggravated respiratory condition and inexplicable cor pulmonale.
Subject(s)
Lung Neoplasms/complications , Pulmonary Embolism/complications , Pulmonary Embolism/etiology , Pulmonary Heart Disease/diagnosis , Pulmonary Heart Disease/etiology , Stomach Neoplasms/complications , Diagnosis, Differential , Fatal Outcome , Female , Humans , Middle Aged , Pulmonary Artery/pathologyABSTRACT
RATIONALE: Birt-Hogg-Dubé (BHD) syndrome, a rare inherited autosomal genodermatosis first recognised in 1977, is characterised by fibrofolliculomas of the skin, an increased risk of renal tumours and multiple lung cysts with spontaneous pneumothorax. The BHD gene, a tumour suppressor gene located at chromosome 17p11.2, has recently been shown to be defective. Recent genetic studies revealed that clinical pictures of the disease may be variable and may not always present the full expression of the phenotypes. OBJECTIVES: We hypothesised that mutations of the BHD gene are responsible for patients who have multiple lung cysts of which the underlying causes have not yet been elucidated. METHODS: We studied eight patients with lung cysts, without skin and renal disease; seven of these patients have a history of spontaneous pneumothorax and five have a family history of pneumothorax. The BHD gene was examined using PCR, denaturing high-performance liquid chromatography and direct sequencing. MAIN RESULTS: We found that five of the eight patients had a BHD germline mutation. All mutations were unique and four of them were novel, including three different deletions or insertions detected in exons 6, 12 and 13, respectively and one splice acceptor site mutation in intron 5 resulting in an in-frame deletion of exon 6. CONCLUSIONS: We found that germline mutations of the BHD gene are involved in some patients with multiple lung cysts and pneumothorax. Pulmonologists should be aware that BHD syndrome can occur as an isolated phenotype with pulmonary involvement.
Subject(s)
Cysts/genetics , Germ-Line Mutation , Lung Diseases/genetics , Pneumothorax/genetics , Proteins/genetics , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Aged , Exons/genetics , Female , Genetic Heterogeneity , Humans , Introns/genetics , Kidney Neoplasms/genetics , Male , Middle Aged , Mutagenesis, Insertional/genetics , Neoplastic Syndromes, Hereditary/genetics , Organ Specificity , Pedigree , Phenotype , Proto-Oncogene Proteins/deficiency , RNA Splice Sites/genetics , Recurrence , Sequence Deletion/genetics , Tumor Suppressor Proteins/deficiencyABSTRACT
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by an abnormal proliferation of smooth muscle-like cells (LAM cells) in the lung and along the axial lymphatics. LAM demonstrates a heterogeneous clinical course, but there is no serum surrogate marker available for assessing the disease severity or predicting the disease progression. Since the authors have recently demonstrated the extensive LAM-associated lymphangiogenesis and its potential role in progression and metastasis of LAM cells, they hypothesized that serum levels of lymphangiogenic growth factors might be increased in LAM and become a surrogate marker for disease severity. METHODS AND RESULTS: VEGF-A, VEGF-C, and VEGF-D in serum of 44 patients with LAM were measured by enzyme-linked immunosorbant assay. Only VEGF-D was significantly increased in LAM patients as compared with age- and gender-matched healthy volunteers (n=24) (LAM vs. control, geometric mean 95% CI; 1069.3 pg/mL (809.4 approximately 1412.6) vs. 295.9 pg/mL (262.6 approximately 333.5), p<0.0001). Serum VEGF-D levels negatively correlated with variables of pulmonary function tests, FEV1/FVC (forced expiratory volume in one second/forced vital capacity) (r=-0.365, p<0.05) and %DLco/VA (the percentage of diffusing capacity for carbon monoxide/alveolar volume to the predicted value) (r=-0.560, p<0.001). As expected, the group who received hormone therapy showed more deteriorated pulmonary function with higher serum VEGF-D levels than the group who was just observed without hormone therapy. Immunohistochemical examination of lung specimens demonstrated the positive immunoreactivity of LAM cells for VEGF-D. CONCLUSION: Serum VEGF-D levels may be a valuable surrogate marker for evaluating the disease severity in LAM.
Subject(s)
Lymphangioleiomyomatosis/blood , Vascular Endothelial Growth Factor D/blood , Adult , Female , Forced Expiratory Volume/drug effects , Forced Expiratory Volume/physiology , Hormones/pharmacology , Hormones/therapeutic use , Humans , Leiomyoma/metabolism , Lymphangioleiomyomatosis/drug therapy , Lymphangioleiomyomatosis/physiopathology , Middle Aged , Myocytes, Smooth Muscle/metabolism , Respiratory Function Tests , Uterine Neoplasms/metabolism , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor C/blood , Vascular Endothelial Growth Factor D/metabolism , Vital Capacity/drug effects , Vital Capacity/physiologyABSTRACT
Lymphangioleiomyomatosis (LAM) affects exclusively women of reproductive age, involves the lungs and axial lymphatic system, and is frequently complicated with renal angiomyolipomas. LAM lesions are generated by the proliferation of LAM cells with mutations of one of the tuberous sclerosis complex (TSC) genes. Recent studies indicate that LAM cells can migrate or metastasize to form new lesions in multiple organs, although they show a morphologically benign appearance. In the previous study, we reported LAM-associated lymphangiogenesis and implicated its role in the progression of LAM. In this study, we further focused on the lymphatic abnormalities in LAM: LAM-associated chylous fluid (5 pleural effusion and 2 ascites), surgically resected diaphragm (1 patient), and axial lymphatic system including the thoracic duct, lymph nodes at various regions, and diaphragmatic lymphatic system (5 autopsy cases). We demonstrated that LAM cell clusters enveloped by lymphatic endothelial cells (LCC) in all chylous fluid examined. We identified LAM lesion in the diaphragm (2 of 5 autopy cases and one surgical specimen), thoracic duct (5 of 5), and lymph nodes (retroperitoneal (5 of 5), mediastinal (4 of 5), left venous angle (5 of 5) with total positive rate of 68% to 88% at each region of the lymph node, but less frequent or none at remote lymph nodes located away from the axial lymph trunk (cervical [1 of 5] and axillary [0 of 5]). LCCs were identified in intra-LAM lesional lymphatic channels where LAM cells proliferate along lymphatic system. In in vitro culture system, LCC can fragment into each proliferating LAM cell. These findings suggest that LAM-associated lymphangiogenesis demarcates LAM lesion into bundle- or fascicle-like structure and eventually shed LCC into the lymphatic circulation and that LCCs play a central role in the dissemination of LAM lesion.
Subject(s)
Endothelial Cells/pathology , Lymphangiogenesis , Lymphangioleiomyomatosis/pathology , Neoplasm Metastasis/pathology , Neoplastic Cells, Circulating/pathology , Adult , Chylous Ascites/etiology , Female , Humans , Immunohistochemistry , Lymphangioleiomyomatosis/complications , Thoracic Duct/pathologyABSTRACT
Lymphangioleiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lungs, lymph nodes, and/or other organs. We examined lymphangiogenesis using immunohistochemistry for Flt-4 (VEGFR-3), a new specific marker for lymphatic endothelial cells, as well as the expression of vascular endothelial growth factor (VEGF)-C in LAM. Specimens were obtained from 6 autopsy cases, a single lung transplant case, and 8 surgical cases for analyses. We demonstrated that lymphatics were extremely abundant in both pulmonary and extrapulmonary LAM and that lymphatic endothelial cells not only proliferated encompassing LAM foci but also infiltrated the intra-LAM foci, and that in advanced LAM, lymphangiogenesis involved vascular walls and interstitium surrounding the area where LAM cells proliferate. In contrast, angiogenesis, confirmed with CD31 immunostaining, was observed less in the LAM foci. LAM cells demonstrated positive reactivity against anti-VEGF-C antibody at varying intensities. Significant correlation (P < 0.001) was noted between the degree of lymphangiogenesis in LAM or VEGF-C expression on LAM cells and lymphagioleiomyomatosis histologic score (LHS), which represents the histologic severity of pulmonary LAM and has been reported to have prognostic significance. Our study is likely to provide a novel point of view on the pathophysiologic significance of lymphangiogenesis in LAM.
Subject(s)
Lung Neoplasms/pathology , Lymphangiogenesis , Lymphangioleiomyomatosis/pathology , Lymphatic Vessels/pathology , Neovascularization, Pathologic , Adult , Aged , Aged, 80 and over , Biomarkers/analysis , Female , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Lymphangioleiomyomatosis/metabolism , Prognosis , Tumor Cells, Cultured , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolismABSTRACT
Pulmonary lymphangioleiomyomatosis (LAM) is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells (LAM cells) in the lungs. Pulmonary LAM can occur as an isolated form (sporadic LAM) or in association with tuberous sclerosis complex (TSC) (TSC-LAM), a genetic disorder with autosomal dominant inheritance with various expressivity resulting from mutations of either the TSC1 or TSC2 gene. We examined mutations of both TSC genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified six unique and novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of 6 patients with TSC-LAM and TSC1 germline mutation in 1 (4.5%) of 22 sporadic LAM patients. In accordance with the tumor-suppressor model, loss of heterozygosity (LOH) was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or two identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting LAM cells can spread from one lesion to another. Our results from Japanese patients with LAM confirmed the current concept of pathogenesis of LAM: TSC-LAM has a germline mutation but sporadic LAM does not; sporadic LAM is a TSC2 disease with two somatic mutations; and a variety of TSC mutations causes LAM. However, our study indicates that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even for patients with sporadic LAM.