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Pulmonary Lymphatic Pathology: Imaging, Genetics, and Beyond Jason Halpern MD, Thomas Egglin MD, Terrance Healey MD, Saurabh Agarwal MD, Scott Collins RTRCT Department of Diagnostic Imaging Alpert Medical School of Brown University Learning Objectives -Discuss the microscopic and macroscopic anatomy of the thoracic lymphatic system -Understand the indications for different imaging modalities used in the evaluation of lymphatic system pathology -Review various manifestations of lymphatic pathology in the chest through case-based learning -Highlight genetic syndromes and abnormalities associated with intra-thoracic lymphatic pathology Macroscopic lymphatic embryology and anatomy 2 Juguloaxillary 1 Cisterna Chyli 1 Mesenteric (retroperitoneal) 2 Inguinal (illiac) At gestational weeks 6-9, there are six primary lymph sacs. These sacs sprout endothelialized vessels (lymph vessels) which grow along the developing VENOUS system. The Cisterna Chyli is connected to jugular sacs by the THORACIC DUCT Macroscopic Anatomy - The thoracic duct ascends from the cisterna chyli (L1 or L2) then ascends through the diaphragmatic hiatus posterior to the esophagus. It usually lies to the right of the vertebral column between the aorta and azygos vein. At the level of T5, it then courses to the contralateral side where it passes posterior to the aortic arch and over the subclavian artery ultimately draining into the venous circulation of either the left jugular or subclavian vein. Microscopic lymphatic anatomy Secondary pulmonary lobule LYMPHATICS course along the peribronchovascular bundles and then divide to course with the pulmonary veins within the septal interstitium. Interlobular septal thickening can suggest processes involving the pulmonary venous or lymphatic system: Smooth septal thickening: Pulmonary edema, hemorrhage, amyloid, alveolar proteinosis Nodular septal thickening: Lymphangitic spread of malignancy, sarcoid, silicosis, CWP, LIP. Irregular septa thickening: Sarcoid, UIP, asbestosis, pleuroparenchymal elastosis. Imaging Modalities of the Lymphatic System 1. Radiography 2. Computed tomography 3. Lymphangiography 4. Nuclear lymphoscintigraphy 5. MR lymphography Imaging Modalities of the Lymphatic System Parenchymal disease Structural abnormalities 1. Radiography – Detection of abnormal airspace disease, associated findings (e.g., effusion in LAM) 2. Computed tomography –Mainstay of parenchymal imaging; evaluate interlobular septae, lymphadenopathy, masses/cyst, disease progression, treatment response. Imaging Modalities: Lymphangiography 1. Inguinal lymph node identified with US 2. Lipiodol injected into the bilateral inguinal nodes 3. Gradual progressive filling of the iliac chain lymphatic system. Imaging Modalities: Lymphangiography Leak Coils CC at L1 - Lymphangiography has the benefit of being therapeutic! - Cysterna Chyli is visualized at the L1 level. After direct cannulation, embolization coils are deployed below the level of the leak. Imaging Modalities: Lymphoscintigraphy - Intradermal injections of Tc-99 sulfur colloid - Allows anatomic and physiologic imaging - Less invasive than lymphangiography - Drawback: no potential for intervention
Imaging Modalities: MR Lymphography - Highly T2WI can help demonstrate CC and TD morphology - More recent work with intranodal Gd/subsequent dynamic imaging. - Useful for preoperative evaluation and surgical planning.
Lymphatic Cases Neoplastic/Systemic Lymphangitic carcinomatosis Kaposi Sarcoma Primary Pulmonary Diseases Lymphangioleiomyomatosis Lymphoid Interstitial Pneumonia Chylous effusion Congenital/Genetic Lymphangiectasis Lymphangioma Lymphangiomatosis Gorham's Disease Multifocal Lymphangioendotheliomatosis
Lymphangitic carcinomatosis Typical culprits: lung, breast, pancreatic, stomach, colon, prostate Nodular interlobular septal thickening
Lymphangitic carcinomatosis Nodular interlobular septal thickening 69F metastatic lung adenocarcinoma of right lung
Kaposi Sarcoma Most often AIDS-related with a low CD4 count. Can be idiopathic. Mid-lower lung zone predominant with ill-defined nodules with surrounding ground glass opacities. Additional findings are peribronchovascular and fissural nodularity. Adenopathy and effusions.
Lymphangioleiomyomatosis Rare ILD caused by proliferation of smooth muscle cells. Associated with Tuberous Sclerosis. Typically women age ~30. Diffuse thin-walled cysts, interlobular septal thickening, ground glass opacities. Can have lymphadenopathy Complicated by chylothoraxand pneumothorax.
Lymphoid interstitial pneumonia Diffuse infiltration of the alveolar septae by lymphocytes. Thin-walled cysts in a lower lobe predominant distribution, GGO, and centrilobular nodules, can have interlobular septal thickening. Associated with Sjogren’s in adults, and HIV in children, can be seen with other autoimmune diseases as well as immunocompromised individuals.
Lymphoid interstitial pneumonia Rare idiopathic condition often associated with Sjogren’s in adults, and HIV in children, and can be seen with other autoimmune diseases as well as immunocompromised individuals.
Lymphangioma Lymphangiomas are focal proliferation of well differentiated lymphatic tissues that usually are found within the first two years of life. However, lesions can often be slow growing and present in adulthood with symptoms of extrinsic airway compression, hemoptysis, Horner’s syndrome, dysphagia, SVC syndrome, or secondary infection. Or, can be incidental findings like in this case, found on abdominal CT of a 30 year old male with abdominal pain!
Lymphangioma MRI demonstrates a T2 bright/T1 dark mass with intralesional septations and no post-contrast enhancement (not shown).
Lymphangioma Can also be secondary as a result of surgery, chronic infection, radiation, or trauma. 70 yo F Breast CA s/p radiation (note skin thickening and bx clip), slowly enlarging right paraspinal lesion; biopsy proven lymphangioma, likely secondary to radiation therapy.
Lymphangiomatosis Rare condition with multiple lymphangiomas in different organ systems often associated with other lymphatic abnormalities. Case: 34 year old female presents with cough and fever. The patients CT is shown on the next slide.
Lymphangiomatosis Large low-attenuation anterior mediastinal cystic mass with thin internal septations without significant post contrast enhancement. The patient has multi-organ involvement with cystic lesion noted within the liver, spleen, and bones. Some authors placed this entity and “Ghoram’s” disease on a spectrum.
Gorham’s Disease Rare condition where there is uncontrolled proliferation of lymphatic/vascular structures within bone causing resorption and cystic replacement. Most common locations of involvement are shoulder, spine and ribs.
Gorham’s Disease T2 bright lesions within this patients cervical spine cause cystic replacement of bone, findings which are compatible with cystic replacement by lymphatic malformations. This patient had a prior biopsy proven lymphatic malformation of her left shoulder and neck.
Multifocal Lymphangioendotheliomatosis with thrombocytopenia Very rare disorder characterized by multiple benign lymphangioendotheliomas in a cutaneous, gastrointestinal and multi-organ distribution. The lymphatic malformations cause a consumptive coagulopathy leading to thrombocytopenia. Patients are often born with multiple skin lesions, thrombocytopenia, which can predispose to gastrointestinal hemorrhage as a result of GI involvement. This patient was born with innumerable hemangiomas and presented with bloody emesis and stools. Chest radiograph reveals multiple pulmonary nodules.
Multifocal Lymphangioendotheliomatosis with thrombocytopenia A CT scan substantiates these findings and demonstrates multiple rounded pulmonary nodules without lobar predilection. After histopathologic diagnosis the patient was started on the antiangiogenic agent sirolimus.
Chylous Effusion Causes - Trauma: Iatrogenic (thoracic surgery) >> non-iatrogenic - Malignant: Lymphoma/Leukemia, metastatic disease - Non-Malignant: Castleman’s, Kaposi’s, TB, Histoplasmosis, MM, Waldenstroms, irradiation. - Syndromic: Noonan and Turner syndromes, yellow nail, Gorham’s disease, POEMS - Idiopathic: Often linked to occult malignancy.
Chylothorax case 1 58 F post mediastinoscopy for staging a RLL lung neoplasm. Fluid collection in the region of the superior mediastinum and thoracic inlet. Triglyceride level of the aspirate: 580 mg/d
Chylothorax case 1 58 F post mediastinoscopy for staging a RLL lung neoplasm. The patient goes on to lymphangiography where a thoracic duct leak is located. S/P glue and coil embolization
Chylothorax case 2 61 M Post RLL segmentectomy with post operative high output chylous fluid. Nodal lymphangiography demonstrates leak. Post-op: small right effusion s/p n-BCA embolization
Advances in Genetics The genetics of lymphatic anomalies have only recently become the target of investigation. In particular, disease that involve lymphedema, whether primary or secondary, are chronic and often difficult to treat. For example, the VEGF-C/VEGFR-3 signaling pathway is being investigated as a target in possible autologous graft in combination with adenoviral expression of VEGF-C. In preclinical trials this seems to increase lymphangiogenesis around implanted lymph nodes suggesting future utility in lymphatic system repair. Additionally, another study demonstrated that injecting a plasmid containing HGF, in rat and mouse models which simulated breast cancer related lymphedema, prevented overt development of lymphedema. The PI3K/AKT signaling pathway is upregulated in a number of syndromic pathways where mTOR inhibitors have been shown to be useful for decreasing lymphedema. An example of an mTOR inhibitor is sirolimus, the medication our patient with multifocal lymphangioendotheliomatosis is currently taking! Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest. 2014;124(3):898-904.
Genetics of Syndromes Involving the Lymphatic System A wide variety of both germline and post-zygotic mutations have been identified and are associated with sporadic and familial lymphatic abnormalities. Disease Inheritance Gene Mutation (protein) Lymphatic phenotype features Primary congenital lymphedema / Nonne-Milroy lymphedema AD/AR/de novo FLT4 (VEGFR-3) Lymphedema Milroy-like disease AD VEGFC lymphedema Tuberous sclerosis AD TS1, TS2 LAM, Chylothorax Noonan Syndrome AD PTPN11/KRAS/SOS1/RAF1 Lymphedema, chylothorax,lymphagiectasia Turner Syndrome Sex linked MonosomyX Cystic hygroma,lymphangioma, lymphedema Yellow Nail Syndrome /Primary lymphedema with yellow nails and pleural effusions AD FOXC2 Pleural effusions, lymphedema, dystrophic nails Hennekam lymphagiectasia-lymphedema syndrome AR CCBE1 Lymphedema,lymphangiectasia, MR Klippel-Trenaunay-Weber Syndrome Possible translocation at t(8;14)(q22.3;q13) --(VG5Q) Lymphatic malformations, lymphedema Gorham’s Disease–phantom bone disease Unknown Proliferation of lymphatic channels in bone causing replacement Proteus Syndrome (Wiedemann syndrome) AD,de novo PTEN, AKT1 Lymphaticmalformations CLOVES, Klipple-Trenaunay-Weber syndrome Somatic PIK3CA Lymphatic malformations
Conclusion Having a general idea of the microscopic and macroscopic anatomy of the lymphatic system will help to understand pathogenesis of lymphatic disease processes. Understanding the various imaging modalities of the lymphatic system and multiplicity of pathologies helps referring clinicians provide optimal care for their patients. Research into the genetics of the lymphatics will likely create additional therapeutic options for lymphatic processes which may ultimately make imaging the lymphatic system more relevant.
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