The lymphatic system and sentinel lymph nodes: conduit for cancer metastasis

AbstractThe lymphatic system is a complicated system consisting of the lymphatic vessels and lymph nodes draining the extracellular fluid containing cellular debris, excess water and toxins to the circulatory system. The lymph nodes serve as a filter, thus, when the lymph fluid returns to the heart, it is completely sterile. In addition, the lymphatic system includes the mucosa-associated lymphoid tissue, such as tonsils, adenoids, Peyers patches in the small bowel and even the appendix. Taking advantage of the drainage system of the lymphatics, cancer cells enter the lymphatic vessels and then the lymph nodes. In general, the lymph nodes may serve as a gateway in the majority of cases in early cancer. Occasionally, the cancer cells may enter the blood vessels. This review article emphasizes the structural integrity of the lymphatic system through which cancer cells may spread. Using melanoma and breast cancer sentinel lymph node model systems, the spread of early cancer through the lymphatic system is progressive in a majority of cases. The lymphatic systems of the internal organs are much more complicated and difficult to study. Knowledge from melanoma and breast cancer spread to the sentinel lymph node may establish the basic principles of cancer metastasis. The goal of this review article is to emphasize the complexity of the lymphatic system. To date, the molecular mechanisms of cancer spread from the cancer microenvironment to the sentinel lymph node and distant sites are still poorly understood and their elucidation should take major priority in cancer metastasis research.

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Lymphangiogenesis in development and disease

Thrombosis and Haemostasis ◽

10.1160/th07-04-0238 ◽

2007 ◽

Vol 98 (08) ◽

pp. 304-310 ◽

Cited By ~ 27

Author(s):

Ruediger Liersch ◽

Michael Detmar

Keyword(s):

Lymph Nodes ◽

Cancer Metastasis ◽

Lymphatic System ◽

Vascular System ◽

Malignant Tumors ◽

Inflammatory Diseases ◽

Transplant Rejection ◽

Lymphatic Vessels ◽

Lipid Uptake ◽

Molecular Control

SummaryThe lymphatic vascular system plays an important role in the maintenance of fluid homeostasis, in the afferent immune response, in the intestinal lipid uptake and in the metastatic spread of malignant cells. The recent discovery of specific markers and growth factors for lymphatic endothelium and the establishment of genetic mouse models with impairment of lymphatic function have provided novel insights into the molecular control of the lymphatic system in physiology and in embryonic development. They have also identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Moreover, the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Importantly, malignant tumors can directly promote lymphangiogenesis within the primary tumor and in draining lymph nodes, leading to enhanced cancer metastasis to lymph nodes and beyond. Based upon these findings, novel therapeutic strategies are currently being developed that aim at inhibiting or promoting the formation and function of lymphatic vessels in disease.

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Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis

Experimental Biology and Medicine ◽

10.1177/15353702211021022 ◽

2021 ◽

pp. 153537022110210

Author(s):

Chu-An Wang ◽

Shaw-Jenq Tsai

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Lymphatic Metastasis ◽

Lymphatic Vessel ◽

Cancer Metastasis ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Extracellular Vesicle ◽

Tissue Fluid ◽

Vessel Infiltration

Metastasis is not only one of the hallmarks of cancer but, unfortunately, it also is the most accurate biomarker for poor prognosis. Cancer cells metastasize through two different but eventually merged routes, the vasculature and lymphatic systems. The processes of cancer metastasis through blood vessel have been extensively studied and are well documented in the literature. In contrast, metastasis through the lymphatic system is less studied. Most people believe that cancer cells metastasize through lymphatic vessel are passive because the lymphatic system is thought to be a sewage draining system that collects whatever appears in the tissue fluid. It was recently found that cancer cells disseminated from lymphatic vessels are protected from being destroyed by our body’s defense system. Furthermore, some cancer cells or cancer-associated immune cells secrete lymphangiogenic factors to recruit lymphatic vessel infiltration to the tumor region, a process known as lymphangiogenesis. To ensure the efficiency of lymphangiogenesis, the lymphangiogenic mediators are carried or packed by nanometer-sized particles named extracellular vesicles. Extracellular vesicles are lipid bilayer particles released from eventually every single cell, including bacterium, with diameters ranging from 30 nm (exosome) to several micrometers (apoptotic body). Components carried by extracellular vesicles include but are not limited to DNA, RNA, protein, fatty acid, and other metabolites. Recent studies suggest that cancer cells not only secrete more extracellular vesicles but also upload critical mediators required for lymphatic metastasis onto extracellular vesicles. This review will summarize recent advances in cancer lymphatic metastasis and how cancer cells regulate this process via extracellular vesicle-dependent lymphangiogenesis.

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Sentinel lymph node biopsy in breast cancer surgery

Reviews in Health Care ◽

10.7175/rhc.v2i2.26 ◽

2011 ◽

Vol 2 (2) ◽

pp. 101-112

Author(s):

Mario Taffurelli

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Sentinel Lymph Node ◽

Lymph Nodes ◽

Lymphatic System ◽

Cancer Surgery ◽

Breast Cancer Surgery ◽

Axillary Lymph Nodes ◽

Axillary Lymph

Axillary lymph node status is one of the most reliable prognostic factors of long-term survival in breast cancer surgery. Metastatic involvement of the axillary lymph nodes is also crucial in the decision making of potentially useful adjuvant treatment. Until the last decade, Axillary Lymph Nodes Dissection (ALND) was performed in order to obtain the regional lymphatic system staging. In case of non-metastatic spread, that kind of surgery was limited only to this purpose; no further oncological benefits were obtained and the patients were exposed to several comorbidities affecting this type of surgery. Complications after ALND are reported in 15-30% of cases. They are well known and range from early bleeding, infection, symptomatic nerve damage, and longstanding limb lymph-edema with an incredible impairment of the quality of life.The Sentinel Lymph Node (SLN) theory holds that the SLNs are the first nodes draining lymph from an anatomic region (i.e. the breast) where metastatic disease will most likely to be found. If that node is found to be cancer free, the entire lymphatic system is likely to be cancer free; if it is metastatic, there is an elevated chance of finding more metastatic nodes. Thanks to the application of this hypothesis, several patients over the last 10-15 years have avoided unnecessary major demolitive surgery. To obtain accurate evaluation of the SLN a multidisciplinary dedicated team is necessary. This procedure has been internationally validated and the false negative rate is nowadays less than 5% when performed by expert hands. Dedicated breast surgeons working in a high-volume centres are necessary to reach satisfactory confidence in performing this very specialised procedure in order to obtain an accurate staging. The number of women presenting to the breast oncology units is continuously increasing and the implementation of screening programs has been crucial in detecting numerous patients (more than 75%) with early disease and non-metastatic axillary lymph nodes. The practice of the SLN is clearly able to offer those patients an accurate staging with low comorbidities, preserving their quality of life.

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Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection

Nature Communications ◽

10.1038/s41467-020-18454-0 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Matthew K. Siggins ◽

Nicola N. Lynskey ◽

Lucy E. Lamb ◽

Louise A. Johnson ◽

Kristin K. Huse ◽

...

Keyword(s):

Lymph Nodes ◽

Cancer Cells ◽

Streptococcus Pyogenes ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Systemic Infection ◽

Intracellular Pathogen ◽

Infection Site ◽

Local Infection ◽

Draining Lymph Nodes

Abstract Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.

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Scanning electron microscopy of freeze-fractured prescapular lymph node of caprine

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100111331 ◽

1984 ◽

Vol 42 ◽

pp. 244-245

Author(s):

O. Faroon ◽

F. Al-Bagdadi ◽

T. G. Snider ◽

C. Titkemeyer

Keyword(s):

Lymph Node ◽

Lymph Nodes ◽

Lymphatic System ◽

Three Dimensional ◽

Meat Products ◽

The Body ◽

Morphological Data ◽

The World ◽

Cellular Constituent ◽

Scanning Electron

The lymphatic system is very important in the immunological activities of the body. Clinicians confirm the diagnosis of infectious diseases by palpating the involved cutaneous lymph node for changes in size, heat, and consistency. Clinical pathologists diagnose systemic diseases through biopsies of superficial lymph nodes. In many parts of the world the goat is considered as an important source of milk and meat products.The lymphatic system has been studied extensively. These studies lack precise information on the natural morphology of the lymph nodes and their vascular and cellular constituent. This is due to using improper technique for such studies. A few studies used the SEM, conducted by cutting the lymph node with a blade. The morphological data collected by this method are artificial and do not reflect the normal three dimensional surface of the examined area of the lymph node. SEM has been used to study the lymph vessels and lymph nodes of different animals. No information on the cutaneous lymph nodes of the goat has ever been collected using the scanning electron microscope.

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Infrared fluorescence lymphography in experimental and clinical practice

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2018-17-2-84-91 ◽

2018 ◽

Vol 17 (2) ◽

pp. 84-91 ◽

Cited By ~ 1

Author(s):

G. V. Papayan ◽

A. L. Akopov ◽

P. A. Antonyan ◽

A. A. Ilin ◽

N. N. Petrishchev

Keyword(s):

Lymph Nodes ◽

Near Infrared ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Diagnostic System ◽

Biological Tissues ◽

Peritumoral Injection ◽

Intradermal Administration ◽

Nir Fluorescence ◽

Real Time Visualization

Introduction. Near infrared (NIR) fluorescent diagnostics is promising due to a deeper penetration into biological tissues. Material and methods. In experiments on rabbits and in clinical studies evaluation the lymphatic system with the use of the instrument complex FLUM-808 was analysed. Results. For visualization of the lymphatic vessels of the skin, the intradermal administration of ICG, dissolved in 20 % albumin in the order of 0.02 mg/ml, is optimal. Peritumoral injection of ICG allows visualizing sentinel lymph nodes in patients with lung cancer. Conclusions. The developed NIR fluorescence diagnostic system FLUM-808 allows to real time visualization of lymphatic vessels and lymph nodes.

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BIOPSY OF THE SIGNALING LYMPH NODES IN GASTRIC CANCER - CURRENT STATUS OF THE PROBLEM AND PROSPECTS

Problems in oncology ◽

10.37469/0507-3758-2018-64-3-335-344 ◽

2018 ◽

Vol 64 (3) ◽

pp. 335-344

Author(s):

Aleksey Karachun ◽

Yuriy Pelipas ◽

Oleg Tkachenko ◽

D. Asadchaya

Keyword(s):

Gastric Cancer ◽

Lymph Node ◽

Sentinel Lymph Node ◽

Lymph Nodes ◽

Stomach Cancer ◽

Current Status ◽

Regional Lymph Nodes ◽

Systematic Analysis ◽

Tumor Spread ◽

Special Value

The concept of biopsy of sentinel lymph node as the first lymph node in the pathway of lymphogenous tumor spread has been actively discussed over the past decades and has already taken its rightful place in breast and melanoma surgery. The goal of this method is to exclude vain lymphadenectomy in patients without solid tumor metastases in regional lymph nodes. In the era of minimally invasive and organ-saving operations interventions it seems obvious an idea to introduce a biopsy of sentinel lymph node in surgery of early gastric cancer. Meanwhile the complexity of lymphatic system of the stomach and the presence of so-called skip metastases are factors limiting the introduction of a biopsy of sentinel lymph node in stomach cancer. This article presents a systematic analysis of biopsy technology of signaling lymph node as well as its safety and oncological adequacy. Based on literature data it seems to us that the special value of biopsy of sentinel lymph nodes in the future will be in the selection of personalized surgical tactics for stomach cancer.

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Overcoming physiological barriers by nanoparticles for intravenous drug delivery to the lymph nodes

Experimental Biology and Medicine ◽

10.1177/15353702211010762 ◽

2021 ◽

pp. 153537022110107

Author(s):

Noah Trac ◽

Eun Ji Chung

Keyword(s):

Drug Delivery ◽

Lymph Node ◽

Lymph Nodes ◽

Cancer Metastasis ◽

Subcutaneous Administration ◽

Mononuclear Phagocyte ◽

Intravenous Drug ◽

Rapid Clearance ◽

Nanoparticle Design ◽

Lymph Node Targeting

The lymph nodes are major sites of cancer metastasis and immune activity, and thus represent important clinical targets. Although not as well-studied compared to subcutaneous administration, intravenous drug delivery is advantageous for lymph node delivery as it is commonly practiced in the clinic and has the potential to deliver therapeutics systemically to all lymph nodes. However, rapid clearance by the mononuclear phagocyte system, tight junctions of the blood vascular endothelium, and the collagenous matrix of the interstitium can limit the efficiency of lymph node drug delivery, which has prompted research into the design of nanoparticle-based drug delivery systems. In this mini review, we describe the physiological and biological barriers to lymph node targeting, how they inform nanoparticle design, and discuss the future outlook of lymph node targeting.

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Cytologic Features of Lipogranulomatous Reaction in an Axillary Sentinel Lymph Node

Acta Cytologica ◽

10.1159/000513982 ◽

2021 ◽

pp. 1-4

Author(s):

Jose Antonio Jimenez-Heffernan ◽

Mariel Valdivia-Mazeyra ◽

Patricia Muñoz-Hernández ◽

Consuelo López-Elzaurdia

Keyword(s):

Lymph Node ◽

Sentinel Lymph Node ◽

Sentinel Lymph Node Biopsy ◽

Lymph Nodes ◽

Breast Biopsy ◽

Lymph Node Biopsy ◽

Sentinel Lymph Nodes ◽

Fat Necrosis ◽

Histologic Analysis ◽

Node Biopsy

Introduction: Multinucleated giant cells (MGC) are a rare finding when evaluating axillary sentinel lymph nodes. Some are described as foreign body-type MGC accompanied by foamy macrophages. They have been rarely reported in nodes from patients in which a previous breast biopsy was performed. The tissue damage induced by biopsy results in secondary changes including fat necrosis and hemorrhage that can migrate to axillary nodes. In this report, we illustrate a lipogranulomatous reaction in cytologic samples obtained during a sentinel lymph node examination of a woman previously biopsied because of breast carcinoma. We have found no previous cytologic descriptions and consider it an interesting finding that should be known to avoid diagnostic misinterpretations. Case: A 51-year-old woman underwent mastectomy of the right breast with a sentinel lymph node biopsy at our medical center. One month before, a control mammography revealed suspicious microcalcifications and a vacuum-assisted breast biopsy resulted in a diagnosis of high-grade intraductal carcinoma with comedonecrosis. Surgery with a sentinel lymph node biopsy was performed. The sentinel node was processed as an intraoperative consultation. Frozen sections and air-dried Diff-Quik stained samples were obtained. They showed abundant lymphocytes with MGC and tumoral cells. MGC showed ample cytoplasm with evident vacuoles of variable size. Occasional hemosiderin-laden macrophages were also present. The complete histologic analysis and immunohistochemical studies revealed no malignant cells. Histologic analysis showed, in subcapsular location, occasional MGC phagocyting lipid droplets. Hemosiderin-laden macrophages were a common finding. Conclusion: Lipogranulomas may appear at axillary sentinel lymph nodes because of fat necrosis induced by previous breast biopsy. The most important consideration is not confounding MGC with epithelial cell clusters. This can occur with not well-processed samples, especially if unmounted.

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