Lymphoid tissues are collections of lymphocytes strategically located at potential sites of infection. They can be classified as either primary lymphoid organs (bone marrow and thymus) where de novo synthesis and maturation of lymphocytes occur; or secondary lymphoid organs where activation of lymphocytes occur. Lymph nodes are secondary lymphoid organs widely distributed throughout the body.
They are strategically located at areas that are open to foreign microorganisms (e.g. the oral cavity). For the sake of completeness, other secondary lymphoid organs include (but are not limited to) the spleen, mucosa-associated lymphoid tissue (MALT), tonsils, and Peyer’s patches. The average young adult has about 450 lymph nodes throughout the body; most of which are in the abdominopelvic region, then the thorax and the remainder in the head and neck.
This article will focus on the anatomy and histology of lymph nodes, their various locations and clinically relevant points.
Lymph nodes are bean-shaped structures about 0.1 – 2.5 cm in length. The node is enclosed in a capsule and has an indentation on one surface (along one of its long axes) known as the hilum. The hilum is the point at which arteries carrying nutrients and lymphocytes enter the lymph node and veins leave it. Afferent lymphatic vessels enter the lymph node through the capsule peripherally and efferent lymphatic vessels leave the node via the hilum. The former takes lymph from peripheral sites to the node, while the latter takes processed lymph from the nodes back to the venous circulation.
A horizontal section through the lymph node reveals that the dense connective tissue capsule (composed of elastin, collagen and fibroblasts) projects trabeculae interiorly; giving the lymph node a lobular appearance, while carrying major blood vessels of the lymph node. Additionally, there is a pericapsular adipose tissue layer that surrounds the connective tissue capsule. This layer contains arterioles and venules that supply the lymph node. The lymph node is divided into an outer cortex and an inner medulla. Histological staining of the node reveals that the cortex stains darker than the medulla with hematoxylin and eosin (H&E) due to its higher cell content. The cortex contains lymphoid nodules, which are non-encapsulated, spherical collections of lymphocytes. Beneath the fibrous capsule is the subcapsular sinus. The subcapsular sinus receives afferent lymphatic ducts at intervals that deposit lymphatic fluid in the space. The subcapsular sinus communicates with the cortical sinuses that travel parallel to the capsular trabeculation. They carry lymph to the medullary sinus.
Within the cortex are regions of lymphocyte aggregation (primarily B-cells and some supporting T-cells) and specialized follicular dendritic cells that form the lymphoid follicles or lymphatic nodules. These can either be primary or secondary follicles depending on their cellular population. Primary lymphoid follicles contain small, dormant lymphocytes, while secondary lymphoid follicles contain a lighter staining area of active lymphocyte proliferation known as a germinal centre. The germinal centre supports affinity maturation (high affinity antibody production) of B-cells. It is subdivided into a dark zone, light zone and a mantle zone. The B-cells of the dark zone are known as centroblasts. They rapidly replicate, resulting in hypermutation of their antibody molecules. Centroblasts migrate to the light zone, where they are referred to as centrocytes. Here they compete for binding with the unprocessed antigens presented on the surface of follicular dendritic cells. Those centrocytes that successfully bind to the follicular dendritic cells will survive, while the others will die. Small, quiescent cells are peripherally marginalized due to the rapid proliferation of the central cells. These cells form the mantle zone of the germinal centre.
Deep to the cortical layer and superficial to the medulla is the paracortex. This region contains mostly T-cells of the CD4 (cluster of differentiation) and CD8 subsets. Migrating dendritic cell lines (such as Langerhans cells) found in this area present processed antigen to the T-cells.
The lymphocytes of the medulla are less organized and form irregular medullary cords. The cords also contain plasma cells, small lymphocytes and macrophages. The medullary sinuses drain the lymph coming from the cortical sinuses to the efferent lymphatic vessel via the hilum.
The hilum of the lymph nodes is the primary point of entry for arteries and exit for veins. Once they enter the hilum, they give off straight branches that pass through the medulla. The arteries form bundles of anastomosing arterioles and capillaries in the cortex that return to similarly branched venules and veins. In the paracortical zone, there are large numbers of postcapillary high endothelial veins that act as a point where blood-borne lymphocytes leave the blood vessels and enter the lymph nodes.
The lymphatic vasculature is comprised of lymphatic capillaries and lymphatic vessels. They are valvular channels responsible for taking lymph to and from the lymph nodes and back to the main systemic circulation. The valves of the lymphatic vessels ensure that lymph flows in a unidirectional manner: from afferent lymphatic vessels to efferent lymphatic vessels. They have very thin walls and their valves can be appreciated histologically when the vessel is cut along its longitudinal axis. Unlike arteries and veins, which are open at both ends, lymphatic vessels begin as blind-ended (closed at one end) channels in the interstitium of specific organs. Their thin endothelial walls permit passive movement of excess interstitial fluid into the lumen of the vessels, which is subsequently returned to the venous circulation.
Regional Lymph Nodes
As stated above, lymph nodes are strategically located throughout the body at points susceptible to foreign microorganisms. The following is an overview of these lymph node regions and their subdivisions.
It is a long held concept that the brain is the only region of the body devoid of a lymphatic system. The idea was that resident microglia were totally responsible for maintaining immunity within the region. However, the method by which these macrophages entered the central nervous system was still unclear. It has been recently proposed by Louveau et al. (2015) that lymphatic channels line the dural sinuses located between the two layers of dura and drain their contents to the deep group of cervical lymph nodes.
CervicalThe cervical lymph nodes can be subdivided into two major groups. Those superficial to the sternocleidomastoid muscle are known as the superficial cervical nodes, while those deep to the same muscle are the deep cervical nodes. The superficial cervical nodes are further subdivided into the pre-auricular or parotid nodes (anterior to the external ear), mastoid nodes (posterior to the external ear), and the occipital nodes. The deep cervical nodes are located in relation to the internal jugular vein. The superior deep cervical nodes are adjacent to the upper part of the internal jugular vein, while the inferior deep cervical nodes are adjacent to the lower part of the same vein.
Waldeyer's ringThe nasal and oral passages are two of the major ports of entry that pathogens use to access the human body. The region is guarded by a collection of lymphatic tissue known as Waldeyer’s ring. This circular collection of lymphoid tissue is formed by the pharyngeal tonsils (adenoids) located in the fossa of Rosenmüller, the tubal tonsils of Gerlach in the torus tubaris, the palatine tonsils between the palatoglossal and palatopharyngeal folds, the lingual tonsils at the posterior region of the tongue and mucosa-associated lymphatic tissue lining the oropharyngeal wall.
AxillaryThe axillary lymph nodes were previously divided into three groups by pectoralis minor. Level one nodes are inferior to the muscle, level two nodes are posterior to the muscle and level three nodes are superior to the muscle. Subsequently, axillary nodes have been divided into five groups, viz. apical, central (in the fat of the axilla), posterior (subscapular), anterior (pectoral) and lateral (medial to the axillary vein) nodes.
Epitrochlear or supratrochlear nodes are located superficial to the deep fascia of the arm and medial to the basilic vein and proximal to the medial epicondyle.
hilum of the lungs, the juxta-oesophageal nodes, and superior and inferior tracheobronchial nodes. There are also posterior mediastinal nodes. The thymus, which is a primary lymphatic organ, is also found in the anterior mediastinum.Mediastinal lymph nodes are divided into nine stations. They include those found in the
Throughout the abdominopelvic region there are numerous groups of nodes associated with specific viscera and adjacent to the main vascular structures within the region. Those associated with the vascular structures include the para-aortic and mesenteric (superior and inferior) nodes, common, internal and external iliac nodes, and the superior and middle rectal nodes.
InguinalThe inguinal lymph nodes are defined as superficial or deep based on their relationship to the fascia lata of the thigh. The group of nodes superficial to the fascia lata are the superficial inguinal nodes. They are further subdivided into inferior, superolateral and superomedial nodes. Those nodes deep to the fascia are the deep inguinal nodes. The largest and most superior of the deep nodes is the deep inguinal node of Cloquet. It is located in the femoral ring.
As a secondary lymphatic organ, lymph nodes are the site of activation of lymphocytes. When the immune system is activated, the primary lymphoid follicles begin to actively proliferate and develop germinal centres. As a result, enlarged lymph nodes palpated during clinical examination give an indication of the source of inflammation based on the regions the nodes drain.
Excess proliferation can result in enlarged and painful lymph nodes or lymphadenopathy. Lymphadenopathy is a common feature of infectious (HIV, infectious mononucleosis, tonsillitis) and metastatic diseases. Lymph nodes are often excised and biopsied in order to stage non-benign lesions.
Congenital or iatrogenic insult to the lymphatic channels may result in subcutaneous collection of high-protein lymphatic fluid. This process, known as lymphedema, is usually observed in the peripheries. There have been cases of upper limb lymphedema secondary to radical mastectomies (removal of breast tissue and axillary lymph nodes).
Although cancerous lesions are the product of unregulated cell proliferation, the metastatic process usually follows a particular pattern. For carcinomas that disseminate by way of the lymphatic system, they most often come in contact with regional nodes (i.e. those nodes that are closest to the origin of the tumor) before moving on to the next tier of nodes in the series. Therefore, these immediate regional nodes are referred to as sentinel lymph nodes.
While classically the word sentinel referred to a soldier who stands guard at a post, from a medical perspective, sentinels are one of the first concrete indicators of disease. This concept contributes to the notion that if cancer is indeed present, then it is more likely to be first found in a sentinel node than other lymph nodes. As a result, clinicians are more inclined to perform a sentinel lymph node biopsy in order to help diagnose and stage individuals suspected to have cancer.
If a sentinel node is biopsied and no evidence of cancer is observed, then it is unlikely that the patient has cancer. On the other hand, if there is evidence of cancer cells found on a sentinel lymph node biopsy, then the patient has cancer and it is also likely that the cancer has spread to nearby nodes. This information will assist with staging of the cancer and the mode of therapy that will be employed.