What is the basic structure of a lymph node. How do lymph nodes contribute to immune function. What are the clinical implications of lymph node disorders. What is the embryological origin of lymph nodes. How is lymph node histology related to immune responses.

Anatomy and Structure of Lymph Nodes

Lymph nodes are small, bean-shaped structures that play a crucial role in our immune system. Typically measuring 0.1 to 2.5 cm in size, these glandular organs are strategically positioned throughout the body, with 400-450 nodes in an average human. They are particularly abundant in areas vulnerable to pathogen entry, such as the cervical, axillary, inguinal, perihilar, and intra-abdominal regions.

The structure of a lymph node is designed to optimize its immune surveillance function:

• A convex surface penetrated by afferent lymph vessels
• A concave side (hilum) where the efferent lymphatic vessels exit, along with blood vessels and nerves
• An outer capsule of dense connective tissue
• Internal compartments divided by trabeculae

Key Anatomical Features

How is a lymph node organized internally? The internal structure of a lymph node can be divided into three main regions:

1. Outer cortex
2. Paracortex
3. Medulla

This organization allows for efficient filtering of lymph and interaction between immune cells and potential pathogens.

Histological Architecture of Lymph Nodes

The histological structure of lymph nodes is complex and highly specialized to support their immune functions. Let’s examine each region in detail:

Outer Cortex

The outer cortex is the first line of defense within the lymph node. It contains:

• Subcapsular sinus: The initial space where afferent lymph enters
• Cortical sinuses: Branches of the subcapsular sinus
• Lymphoid nodules: Aggregates of B and T lymphocytes

Why is the endothelium of cortical sinuses perforated? This structural feature allows antigen-presenting cells, circulating antigens, and lymphocytes to access the lymphatic tissue, facilitating immune responses.

Paracortex

The paracortex, located deeper within the node, is primarily populated by T lymphocytes. This region is crucial for T cell-mediated immune responses and interaction with dendritic cells.

Medulla

The innermost region of the lymph node, the medulla, contains:

• Medullary cords: Strings of lymphoid tissue
• Medullary sinuses: Channels for lymph drainage

This area is rich in plasma cells and macrophages, playing a vital role in antibody production and antigen clearance.

Lymph Node Function in Immune Surveillance

Lymph nodes serve as critical checkpoints in the body’s defense against pathogens. Their primary functions include:

• Filtering lymph fluid to trap pathogens and foreign particles
• Providing a site for lymphocytes to interact with antigens
• Facilitating the activation and proliferation of B and T lymphocytes
• Supporting the production of antibodies by plasma cells

How do lymph nodes enhance immune responses? By concentrating antigens and immune cells in a confined space, lymph nodes dramatically increase the efficiency of immune recognition and response.

Embryological Development of Lymph Nodes

The embryological origin of lymph nodes is a fascinating process that begins early in fetal development. Lymph nodes arise from lymph sacs, which are outgrowths of the venous system. This process typically starts around the 8th week of gestation.

Key stages in lymph node development include:

1. Formation of lymph sacs from endothelial outgrowths
2. Invasion of mesenchymal cells into the lymph sacs
3. Development of the node’s internal structure
4. Colonization by lymphoid progenitor cells

Why is understanding lymph node embryology important? Knowledge of this process can provide insights into lymphatic system disorders and potential therapeutic approaches.

Clinical Significance of Lymph Nodes

Lymph nodes are not only crucial for normal immune function but also play a significant role in various clinical conditions:

Lymphadenopathy

Lymphadenopathy refers to the enlargement of lymph nodes. It can be localized or generalized and may indicate various conditions:

• Infections (bacterial, viral, fungal, or parasitic)
• Autoimmune disorders
• Malignancies (lymphoma, metastatic cancer)

How can lymphadenopathy aid in diagnosis? The pattern and characteristics of enlarged lymph nodes can provide valuable clues about underlying diseases, guiding further diagnostic procedures.

Lymphadenectomy

Lymphadenectomy is the surgical removal of lymph nodes, often performed in cancer treatment. It serves two primary purposes:

1. Staging: Determining the extent of cancer spread
2. Treatment: Removing potentially cancerous tissue

While crucial in many cancer treatments, lymphadenectomy can lead to complications such as lymphedema.

Lymphedema

Lymphedema is a condition characterized by tissue swelling due to impaired lymphatic drainage. It can occur as a complication of lymphadenectomy or radiation therapy, significantly impacting a patient’s quality of life.

What are the management strategies for lymphedema? Treatment often involves a combination of compression therapy, exercise, and specialized massage techniques to promote lymph drainage.

Lymph Node Histology and Immune Responses

The histological appearance of lymph nodes is dynamic and closely related to immune activity. Key features include:

• Primary follicles: Dormant B cell aggregates
• Secondary follicles: Activated B cell clusters with germinal centers
• Paracortical expansion: Indicative of T cell activation

How does lymph node histology reflect immune status? The presence and characteristics of these structures can provide valuable information about ongoing immune responses and potential pathological conditions.

Advanced Techniques in Lymph Node Analysis

Modern medical science has developed sophisticated methods for analyzing lymph nodes, enhancing our understanding of immune function and disease processes:

Immunohistochemistry

Immunohistochemistry allows for specific identification of cell types and markers within lymph node tissue. This technique is invaluable in diagnosing lymphomas and assessing immune responses.

Flow Cytometry

Flow cytometry enables rapid analysis of large numbers of cells, providing detailed information about lymphocyte populations and their activation states.

Molecular Techniques

PCR and gene sequencing can detect specific genetic abnormalities or pathogen presence in lymph node samples, aiding in precise diagnosis and treatment planning.

How have these advanced techniques impacted clinical practice? They have revolutionized the diagnosis and classification of lymphoid malignancies, allowing for more targeted and effective treatments.

Future Directions in Lymph Node Research

As our understanding of lymph node biology continues to evolve, several exciting areas of research are emerging:

• Engineered lymph nodes for immunotherapy
• Nanotechnology-based lymph node targeting for drug delivery
• Artificial intelligence in lymph node image analysis
• Lymph node organoids for disease modeling and drug testing

What potential breakthroughs might these research areas yield? They could lead to more effective cancer treatments, improved management of autoimmune disorders, and novel approaches to enhancing immune responses against pathogens.

In conclusion, lymph nodes are fascinatingly complex structures that play a pivotal role in our immune system. Their intricate histology reflects their crucial function in immune surveillance and response. As medical science advances, our understanding of lymph node biology continues to deepen, opening new avenues for diagnosis, treatment, and prevention of a wide range of diseases. From their embryological origins to their clinical significance in various pathological conditions, lymph nodes remain a subject of intense scientific interest and medical importance.

Lymph nodes: Histology | Kenhub

Author:
Lorenzo Crumbie MBBS, BSc
•
Reviewer:
Jerome Goffin

Last reviewed: July 13, 2023

Reading time: 22 minutes

Lymph node (histological slide)

The presence of foreign organisms within the blood stream can trigger a massive cascade of events that will disrupt many homeostatic microenvironments within the body. Therefore, the immune system carries out detailed surveillance of the blood in order to detect these pathogens. One method of screening takes place at the level of the lymph nodes. These are secondary lymphoid organs that are widely distributed throughout the body. Apart from its role in immune regulation, the lymphatic system is also important for immune regulation and fat absorption.

Between 400 and 450 lymph nodes are scattered throughout the average human body. They are found along the lymphatic vessels, which carry fluid from the interstitial space into the main circulation. They are particularly abundant in the cervical, axillary, inguinal, perihilar, and intra-abdominal areas. These locations are vulnerable points of entry of pathogens into the host’s intrinsic environment. As a result, it is important that surveillance is maximized in these areas. This article will review the embryology and gross anatomy of lymph nodes. However, the primary focus will be on the histological composition of these structures as well as clinically relevant points regarding lymph node function.

Contents

1. Gross anatomy
2. Histological architecture
   1. Outer cortex
   2. Paracortex
   3. Medulla
3. Blood Supply
4. Embryology
5. Clinical notes
   1. Lymphadenopathy
   2. Lymphadenectomy
   3. Lymphedema
6. Sources

+ Show all

Gross anatomy

At approximately 0.1 by 2.5 cm, the lymph node is a relatively small glandular structure that resembles a kidney-bean. It has a convexed surface that is penetrated by afferent lymph vessels. On the opposing side, there is a concavity that is penetrated by the supplying artery, vein and nerve and also allows exit of efferent lymphatic vessels. This concavity is known as the hilum of the lymph node. They are suspended in loose connective tissue that follows the large vasculature.

[Active lymph node. Stain: hematoxylin and eosin. Medium magnification.]

Histological architecture

Lymph nodes are encapsulated by dense connective tissue comprised of elastin and collagen fibres along with interspersed fibroblasts. The convexed surface of the lymph node is pierced by numerous afferent lymph vessels. They extend to the deeper areas of the lymph node by way of the trabecular extensions of the cortex. As the trabeculae penetrate the lymph node, they continue as reticulin fibrils (type III collagen) that offer additional structural support to the gland.

Trabeculae (histological slide)

Cross sectional analysis of a lymph node reveals that it is subdivided into three regions:

Outer cortex

The outermost layer is the cortex. It is made up of a subcapsular sinus, cortical sinus and lymphoid nodules. The subcapsular sinus is the first space that lymph fluid from the afferent channels enters within the node. The fluid then travels from here to the cortical sinuses; which are branches of the subcapsular sinus. The cortical sinuses are also known as trabecular sinuses because they travel along the trabecular network within the lymph node.

Cortex (histological slide)

The endothelium of the trabecular sinuses are perforated by dendritic processes as well as reticulin fibres. Antigen presenting cells (APCs), circulating antigen, and lymphocytes flowing within the lymph can access the lymphatic tissue within the nodes through the disrupted endothelium. The cortical layer also has relatively large aggregates of helper T – lymphocytes and rapidly dividing B – lymphocytes in the peripheral part of the lymph nodes. Although both T cells and B cells are present in the cortex, B cells are more abundant than T cells are in this region. These lymphoid nodules are situated around the branched, interlacing extensions of the follicular dendritic cells (FDCs). The nodules may or may not have a germinal centre depending on if it is a primary or secondary follicle.

Primary follicle (histological slide)

Histological staining of lymph node samples are strongly influenced by the amount of antigen the cells of the lymph node are exposed to. Additionally, the number of cells within the node as well as the distinct separation of the cords is also influenced by antigenic exposure. As a result, the primary follicle is comprised of small dormant lymphocytes throughout, while the secondary follicle has a heterogeneous collection of large B lymphocytes that have already been activated by inciting antigens. Primary follicles absorb less histological stains then secondary follicles. This is likely due to fewer cells in the primary follicle when compared to the secondary follicle.

Secondary follicle (histological slide)

The germinal centre can be further subdivided into a dark zone, light zone and a mantle zone. Each zone facilitates different aspects of B cell affinity maturation. In the peripherally aspect of the germinal centre, quiescent B cells are found in the mantle zone. These cells are characterized by intense basophilic staining, small cytoplasmic volume and a heterochromatic nucleus. Other cells in the mantle zone include follicular dendritic cells as well as the occasional helper T lymphocyte and macrophages. The fate of B cells in the mantle zone can go one of two ways. These cells either remain in the lymph node and mature into antibody secreting plasma cells and remain in the lymph node, or they transform into memory B cells that re-enter the systemic circulation.

Germinal center (histological slide)

The other two zones of the germinal centre are the light zone and dark zone. The light zone contains centrocytes that interact with follicular dendritic cells that express intact antigen on their surface. Centrocytes with high affinity binding to the follicular dendritic cell antigen will persist, while those with weak binding undergoes apoptosis. While resident macrophages help to clean up apoptotic B cells, helper T cells support the remaining B cells and foster the class switching phase of the cellular maturity.

Centrocytes (histological slide)

In the dark zone of the germinal centre, the centroblasts are highly mitotic and have a strong likelihood of producing mutated antibodies. These are the source cells for the light zone.

Centroblasts (histological slide)

Paracortex

Deep to the cortical layer is the paracortex. Its margins blend with the superficial cortex and deep medulla. The principal distinguishing features are the absence of lymphoid nodules and the large number of T lymphocytes (both cluster of differentiation 4 and 8 positive T cells [CD4+ and CD8+]) within the stroma of the paracortex.

Paracortex (histological slide)

The paracortex also has unique venules known as high endothelial venules (HEVs). Most of the lymphocytes that enter the lymph node do so via these channels. They are made up of cuboidal endothelium that is fitted apically with integrins and glycoproteins. Both these surface markers allow unimpeded passage of lymphocytes (i.e. diapedesis) from the percolating blood into the lymph node. These specialized vessels are also present in the mucosa associated lymphatic tissue distributed throughout the gastrointestinal tract. However, they are at their highest level of development within the lymph nodes.

Medulla

The deepest layer of the lymph node is the medulla. It is subdivided functionally and histologically into two other regions; which are the medullary cords and sinuses. The cords are populated by plasma cells, as well as B – cells and T – cells. The cells are arranged in cord-like projections extending centrally from the paracortex.

Medulla (histological slide)

Interlacing between the cords are distended areas lined by discontinuous endothelium. The luminal surface of the sinuses also contains a vast network of reticular cell processes. They act as the final point of filtration of circulating lymph. The medullary sinuses are the terminal continuations of the peripherally located cortical sinuses. They eventually culminate at the hilum of the lymph node to form efferent lymphatic vessels.

Medullary sinuses (histological slide)

Lymph vessels are lined by a single layer of squamous endothelium. They are fitted with valves that promotes unidirectional flow of lymph from the afferent lymph vessels to the lymph node and then to the efferent lymph vessels. The afferent lymph channels bring lymph with either free floating or complement bound antigen into the subcapsular space. Of note, the subcapsular space extends around the entire lymph node except at the hilum. The lymph then flows through the cortical sinuses.

Efferent lymphatic vessels (histological slide)

Blood Supply

The arterial supply of the lymph nodes is derived from the vessels they encircle within their respective regions. For example, the axillary lymph nodes are perfused by arterial branches of the axillary artery. Each lymphatic artery gains access to the node by way of the hilum. As the vessel penetrates this area, it gives off a myriad of straight branches within the medulla that also arborize to supply areas that are distal to the vessels.

Hilum of the lymph node (histological slide)

In the cortex, the straight arteries branch off into arterioles that form tightly packed anastomosing networks. The capillaries are more commonly seen around the germinal centres, where there are usually less arterioles. Capillaries also become more numerous when there is antigenic stimulation of the lymph node. The arterioles and capillaries then return to similarly numerous anastomosing networks of venules and veins. They tend to follow the course of the arteries and arterioles in the opposite direction. Eventually the veins leave the node via the same point of entrance of the arteries (the hilum).

Embryology

A few weeks after the initiation of cardiovascular development (third week of gestation), the lymphatic system begins to take shape (sixth week of gestation). Numerous studies dating from 1995 to 2002 identified vascular endothelial growth factor receptor 3 (VEGFR 3), vascular endothelial growth factor C (VEGF C) and prospero homebox 1 (PROX1) as integral components in the development of lymphatic vessels. While VEGFR 3 and VEGF C are essential for vascular differentiation from mesenchyme, the presence of PROX1 is imperative for lymphatic endothelial cell differentiation. Definitive confirmation of the venous derivative theory postulated in 1902 was recently confirmed in 2007.

One theory proposed that outpouchings of the venous endothelium (i.e. diverticulae) result in the formation of lymphatic sacs. Another school of thought proposes that the lymphatic system, like the rest of the vascular network, originates from cells arising from the mesenchymal layer and develops separately from the veins. The former theory, proposed in 1909, is the most widely accepted concept.

The lymph sacs develop adjacent to the primitive venous network. The lymph sacs identified at the early stage of development are paired (jugular and posterior lymph sacs) and unpaired lymph sacs (retroperitoneal and cisterna chyli). Jugular lymphatic sacs form around the superior cardinal veins (precursors to the jugular veins). There are axillary lymphatic sacs that develop around the right subclavian vein. On the left side, the thoracic duct forms on either side of the left brachiocephalic vein. There are also lumbar and iliac sacs forming caudally. The lumbo-iliac, jugular and axillary sacs are bilateral structures.

Cisterna chyli

The deep cervical nodes are the first to develop from its lymphatic sac. It is followed by the axillary, parasternal, and mediastinal lymph nodes; which also arise from their respective lymphatic sacs. The retroperitoneal, lumbo-iliac and inguinal nodes are derived from the lumbo-iliac lymphatic sacs. The differentiation from sac to nodes occurs when the sacs are invaded and segmented by adjacent mesenchymal cells.

Axillary lymph nodes

The mesenchyme also forms the lymph node capsule and connective tissue stroma. More specifically, it gives rise to the fibroblastic reticular cells that produce the connective tissue stroma as well as its extracellular matrix. Eventually lymphoid tissue inducer cells that promote the development of lymphoid tissue within the lymph node are formed. There is subsequent invasion of the lymph nodes by thymic lymphocytes either shortly before, or during the antenatal period,. These T lymphocytes tend to migrate into the deeper cortex while the B lymphocytes migrate to the outer cortex of the lymphatic nodules.

Now that you’ve learned about the structure of a lymph node, test your knowledge with the following quiz.

Clinical notes

Lymphadenopathy

Certain groups of lymph nodes are responsible for draining lymph from particular regions of the body. For example, lymphatic fluid from the lower limbs and perineal area will drain to the inguinal lymph nodes. Keep in mind that this lymph may contain pathogenic antigen from potential invaders. This antigenic stimulation can result in local enlargement of lymph nodes draining that particular region. The antigenic stimulation may also lead to changes not only in the size of the nodes, but also their consistency. This process is known as lymphadenopathy; it is also applicable to any disease process that affects the reticuloendothelial system. Lymph node enlargement is considered significant based on how large the nodes get. A general rule of thumb states that any enlargement greater than 1 cm of more than one lymph node is considered lymphadenopathy. However, some clinicians say that enlargement should be related to the region the nodes are located in. In other words:

• Cervical lymph nodes greater than 2 cm are considered significant
• Axillary lymph nodes greater than 1 cm are considered significant
• Inguinal lymph nodes greater than 1.5 cm are considered significant

Lymphadenopathy can be further classified as local or generalized. If swollen nodes are only seen in one region (i.e. cervical or axillary) then it is local. But if swollen nodes are found in more than one areas (i.e. epitrochlear and cervical) then it is generalized. Typically, swollen lymph nodes are reflective of self-limiting viral or bacterial infections in children. However, there are other non-benign conditions that may also result in lymphadenopathy. Furthermore, in adults, it is unlikely for lymph nodes to be found in a quiescent state as past exposure may incite long standing morphological changes within the nodes. Therefore it is important to differentiate between an ongoing disease process and a past exposure. Nevertheless, the swollen glands should not be ignored.

Lymphadenopathy should not be confused with lymphadenitis. The latter refers to an acute inflammatory process within the lymph node. While this condition also presents with lymph node enlargement, it is characterized by painful, indurated lymph nodes. This is in contrast to lymphadenopathy where the lymph nodes are painless on palpation and are not erythematous.

Clinicians can use clues from lymph node enlargement to determine where the underlying insult is occurring. Palpating lymph nodes is a clinical skill that is relatively easy to master and should not be neglected. Palpation of lymph nodes is particularly important during the general examination of a patient, as well as during examination of specific systems such as the respiratory system and abdominal exam. Common areas to palpate include the epitrochlear, axillary, cervical, pre and postauricular, occipital, submandibular and submental nodes. Inguinal nodes may also be palpated but the popliteal nodes are difficult to appreciate. In addition to the size and location of the nodes, the clinician should also note whether or not these nodes are tender, indurated and febrile as this points to a clinical diagnosis of lymphadenitis. Lymph nodes that are immobile, clumped together, and firm are more than likely (but not exclusively) a sign of malignancy than those that were described earlier.

The list of aetiological factors leading to lymphadenopathy is quite eclectic. The can be generally classified based on whether or not the lymphadenopathy is generalized (systemic) or regional (localized). Below is a truncated list of the causes of lymphadenopathy:

• 
  Generalized
  
  • Infections
    • Viral
    • Bacterial
    • Parasitic

  • Autoimmune & Hypersensitivity disorders
    • Systemic lupus erythematosus
    • Drug reactions

  • Storage disorders
    • Gaucher disease

  • Neoplasms
    • Leukaemias
    • Lymphomas

• 
  Regional (specifically those that are palpable)
  • Cervical
    • Upper respiratory tract infections
    • Infectious mononucleosis
    • Leukaemias
    • Lymphomas

  • Submaxillary and Submental
    • Oral infection

  • Occipital
    • Tinea capitis
    • Rubella
    • Roseola

  • Pre-auricular
    • Cutaneous infection
    • Catscratch disease

  • Supraclavicular
    • Tuberculosis
    • Lymphoma

  • Axillary
    • Immunization reaction
    • Non-neoplastic lesions of the breast
    • Mastitis
    • Brucellosis
    • Lymphoma

  • Inguinal
    • Insect bites
    • Sexually transmitted infections

Lymphadenectomy

In cases where lymphadenopathy is believed to be a result of a non-benign process, then surgical excision of the node may be warranted. Lymphadenectomy is a diagnostic and therapeutic approach to managing patients with malignancies. It is often done in addition to removing a primary tumor. Recall that a hallmark feature of cancers is their ability to metastasize. If these malignant cells gain access to the circulating lymph then they can spread throughout the body and become lodged in the lymph nodes. This will result in the formation of a secondary site from which these nodes can spread. Therefore, clinicians use this information as a part of staging the malignancy. The stage of the malignancy also influences the mode of treatment that would be best for the patient.

Lymphedema

Lymphedema is a disorder of the lymphatic system characterized by swelling of the limbs as a result of disrupted lymphatic pathways. The etiology of lymphedema can be primary due to lymphatic hypoplasia which is inherited, or secondary due to obstruction or disruption of lymphatic vessels. Symptoms and signs of this condition are brawny, fibrous, nonpitting edema in one or more limbs diagnosed by physical examination.

Primary lymphedema is uncommon and occurs as a result of hypoplastic lymphatic channels. The clinical presentation can vary in phenotype and patient age. There are also associations with lymphedema and other genetic disorders such as Turner syndrome.

The causes of secondary lymphedema are more common and very often misdiagnosed. They are multicausal and can occur after surgery including lymph node dissection (typically breast cancer), radiation therapy, after trauma, lymphatic obstruction by a tumor, venous insufficiency, or infectious diseases such as lymphatic filariasis. Other than swelling, these patients may develop skin changes that include hyperkeratosis or hyperpigmentation. Further complications may lead to the development of elephantiasis (extreme hyperkeratosis that looks like elephant skin) or lymphangitis (acute bacterial infection of lymphatic vessels).

Lymphedema is diagnosed by a good physical examination and additional tests with CT and MRI. The treatment of primary lymphedema is surgical including reconstruction while the treatment of secondary lymphedema means management of the cause. To mobilize fluid in lymphedema, physicians/patients may employ complex decongestive physiotherapy (CDPT). This involves a specific massage technique, skincare, and carefully fitted elastic compression garments. When applied correctly, CDPT dramatically increases lymphatic transport, delays the development of interstitial fibrosis, and improves symptoms.

Sources

All content published on Kenhub is reviewed by medical and anatomy experts. The information we provide is grounded on academic literature and peer-reviewed research. Kenhub does not provide medical advice. You can learn more about our content creation and review standards by reading our content quality guidelines.

References:

• 
  Bailey, R. and Weiss, L. (1975). Light and electron microscopic studies of postcapillary venules in developing human fetal lymph nodes. American Journal of Anatomy, 143(1), pp.43-57.
• 
  Butler, M., Isogai, S. and Weinstein, B. (2009). Lymphatic development. Birth Defects Research Part C: Embryo Today: Reviews, 87(3), pp.222-231.
• 
  Dhar, A. (2017). Lymphadenitis – Dermatologic Disorders – MSD Manual Professional Edition. [online] MSD Manual Professional Edition. Available at: http://www.msdmanuals.com/professional/dermatologic-disorders/bacterial-skin-infections/lymphadenitis [Accessed 12 Sep. 2017].
• 
  Douketis, J. (2017). Lymphadenopathy – Cardiovascular Disorders – MSD Manual Professional Edition. [online] MSD Manual Professional Edition. Available at: http://www.msdmanuals.com/professional/cardiovascular-disorders/lymphatic-disorders/lymphadenopathy [Accessed 12 Sep. 2017].
• 
  Gray, H. and Standring, S. (2009). Gray’s anatomy. 40th ed. [Edinburgh u.a.]: Churchill Livingstone Elsevier.
• 
  Kanwar, V. and Sills, R. (2017). Lymphadenopathy: Background, Pathophysiology, Epidemiology. [online] Emedicine.medscape.com. Available at: http://emedicine.medscape.com/article/956340-overview#a4 [Accessed 12 Sep. 2017].
• 
  Kumar, V., Abbas, A. and Aster, J. (2015). Robbins and Cotran pathologic basis of disease. 9th ed. Philadelphia, PA: Elsevier Saunders.
• 
  Mescher, A. and Junqueira, L. (2013). Junqueira’s Basic Histology. 13th ed. McGaw-Hill.
• 
  James D. Douketis, MD (2017). Lymphedema – Cardiovascular Disorders – MSD Manual Professional Edition. [online] Available at: http://www.msdmanuals.com/professional/cardiovascular-disorders/lymphatic-disorders/lymphedema [Accessed 12 Sep. 2017].
• 
  Pansky, B. (1982). Review of medical embryology. New York: Macmillan.
• 
  Vondenhoff, M., van de Pavert, S., Dillard, M., Greuter, M., Goverse, G., Oliver, G. and Mebius, R. (2008). Lymph sacs are not required for the initiation of lymph node formation. Development, 136(1), pp.29-34.

Author, review and layout:

• Lorenzo Crumbie
• Uruj Zehra
• Adrian Rad

Illustrators:

• Lymph node (histological slide) – Smart In Media
• Cisterna chyli – Begoña Rodriguez
• Axillary lymph nodes – Begoña Rodriguez
• Trabeculae (histological slide) – Smart In Media
• Cortex (histological slide) – Smart In Media
• Primary follicle (histological slide) – Smart In Media
• Secondary follicle (histological slide) – Smart In Media
• Germinal center (histological slide) – Smart In Media
• Centrocytes (histological slide) – Smart In Media
• Centroblasts (histological slide) – Smart In Media
• Paracortex (histological slide) – Smart In Media
• Medulla (histological slide) – Smart In Media
• Medullary sinuses (histological slide) – Smart In Media
• Efferent lymphatic vessels (histological slide) – Smart In Media
• Hilum of the lymph node (histological slide) – Smart In Media

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Lymphatic System and Immune System

Medical Terminology for Cancer

© Copyright 1996-2013

9: The Lymphatic and Immune Systems

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Contents

Functions of the lymphatic system
Components of the lymphatic system
Circulation of tissue fluids
The Immune System
Cancer Focus
Roots, suffixes, and prefixes
Related Abbreviations and Acronyms
Further Resources

Functions of the lymphatic system

The key functions of the lymphatic system:

• Drains excess fluids and proteins from tissues all around the body and returns them back into the bloodstream.
• Removes waste products produced by cells.
• Fights infections.
• Absorbs fats and fat-soluble vitamins from the digestive system and transports these into the bloodstream.

Components of the lymphatic system

The major (encapsulated) lymphatic organs are the lymph nodes, thymus and spleen. In addition the lymphoid tissues include:

Mucosa-associated lymphoid tissue (MALT)

These are bundles of lymphatic cells, called lymphatic nodules, located within the mucus membranes that line the gastrointestinal, respiratory, reproductive, and urinary tracts. These nodules contain lymphocytes and macrophages which defend against invading bacteria and other pathogens that enter these passages along with food, air, or urine. These nodules can be solitary or grouped together in clusters.

Major clusters of lymphatic nodules include:

• Tonsils: these are clusters of lymphatic tissue under the mucous membrane lining of the nose, mouth, and throat. Lymphocytes and macrophages in the tonsils provide protection against foreign substances and pathogens that enter the body through the nose or mouth.
• Adenoids: A cluster of lymphatic tissue that hangs from the upper part of the back of the nasal cavity. Adenoids get bigger after birth but usually stop growing by the age of 7. Like the Tonsils, they can be removed without significantly increased risk of infections.
• Peyer’s patches: these are clusters of lymphatic nodules in the mucosa that lines the ileum of the small intestine. They play an important role in defending against the large number of pathogens that enter the gastrointestinal system.

Circulation of tissue fluids

Fluid in the spaces between tissues is called interstitial fluid, or ’tissue fluid’. This provides the cells of the body with nutrients (via the blood supply) and a means of waste removal. Lymph is formed when the interstitial fluid is collected through tiny lymph capillaries (see diagram), which are located throughout the body. It is then transported through lymph vessels to lymph nodes, which clean and filter it. Lymph then flows on to the lymphatic ducts, before emptying into the right or the left subclavian vein, where it mixes back with blood.

Blood is enriched with oxygen (by the respiratory system) and nutrients (by the digestive system), which are circulated all around the body (by the cardiovascular system). Some fluid (blood plasma) leaks out into the tissues via tiny capillaries, contributing to interstitial fluid, which eventually drains back into the lymphatic system.

The Immune System

The immune system includes a variety of defenses against viruses, bacteria, fungal infections, and parasites (such as thread worms). The lympatic system is part of the broader Immune System.

Innate immune system

This are the non-specific, unchanging lines of defenses which include:

• Physical and chemical barriers to pathogens.
• Producing cytokines and other chemical factors to recruit immune cells to sites of infection.
• Activates the complement cascade to identify bacteria, activate cells and to promote clearance of dead cells or antibody complexes.
• Identifies and removes foreign substances present in organs, tissues, the blood and lymph, by specialised white blood cells.
• Activation of the adaptive immune system, through a process known as antigen presentation.

Adaptive immune system

Adaptive (or acquired) immunity is where immunological memory is made after an initial response to a new pathogen, leading to an enhanced response to future exposure to that same pathogen. This process of acquired immunity is the basis of vaccination. This is essential because bacteria and viruses are continually adapting and evolving in an ‘arms race’ with our immune systems. Features of the adaptive immune system include:

• Recognition of specific “non-self” antigens, during the process of antigen presentation.
• The generation of responses tailored to destroy specific pathogens or pathogen-infected cells.
• Development of immunological memory, in which each pathogen is “remembered” by signature antibodies or T cell receptors. These memory cells can be called upon to quickly eliminate a pathogen should subsequent infections occur.

Cells of the Immune System

There are many different cell types and sub-types involved in the immune system. Some of the main types include:

• Lymphocytes: are white cells which circulate between blood and lymph. They play an important role in fighting infection. There are many kinds of lymphocytes; the main types are T cells, B cells and natural killer cells. Lymphocytes initially develop in the bone marrow. Some migrate to the thymus, where they mature into T cells ; others mature in the bone marrow as B cells.
• Neutrophils: are the most abundant type of white blood cells and are an important part of the innate immune system. Neutrophils are a type of phagocyte (cells which engulf and then digest, cellular debris and pathogens). They are normally found in the blood stream, but are quickly recruited to the site of injury or infection following chemical signals such as Interleukin-8.
• Macrophages: are another type of phagocyte and have a role in both the innate and adaptive immune systems. They attack foreign substances, infectious microbes and cancer cells. Macrophages also stimulate lymphocytes and other immune cells to respond to pathogens.
• Dendritic cells: are antigen-presenting cells which act as messengers between the innate and adaptive immune systems. They are usually located in tissues in contact with the external environment such as the skin, linings of the nose, lungs, stomach and intestines. In response to pathogens they migrate to the lymph nodes where they interact with T cells and B cells to initiate the adaptive immune response.

Antigens and Antibodies

Antibodies (also known as an immunoglobulins) are Y-shaped proteins produced by B-cells,that bind to specific antigens on the surface of foreign objects such as bacteria and viruses. This identifies and ‘tags’ the foreign object as ‘non-self’, signalling other immune cells to attack them.

Hormones and the Immune System

There are several hormones generated by the immune system. These hormones are generally known as lymphokines. Steroids and corticosteroids (components of adrenaline) suppress the immune system.

Cancer Focus

Metastatic spread of cancer via the lymph nodes

Lymph nodes close to the primary tumor are often the first site of metastases (spread of cancer). Lymph node metastases are rarely life threatening, but their detection is a prognostic factor for many types of cancer as it shows the tumor has developed the ability to spread. Tumor cells may travel via the lymphatic system and spread to to lymph nodes and distant organs.

Sentinel Lymph Node Biopsy

A dye is injected near the primary tumor to identify the position of the sentinel lymph node (the first lymph node to which cancer cells are most likely to spread as the lympatic system drains fluid away from the tumor). The sentinel node is surgically removed and a pathologist checks for the presence of cancer cells. SLNB is most frequently used to help stage breast cancer and melanoma. It is a less extensive operation compared to standard lymph node surgery.

Immunosuppression

This is reduced activity or efficiency of the immune system and its ability to fight infections and other diseases. Certain diseases such as AIDS or lymphoma can cause immunosuppression. It is also a common side-effect of anticancer chemotherapy, leading to cancer patients having an increased risk of infections during treatment.

Lymphoma

A general term form for malignant disease of the lymphatic tissue characterized by abnormal, uncontrolled cell growth. There are a number of types of lymphoma, including Hodgkin Lymphoma, with most other types classed together as Non-Hodgkin Lymphoma.

Hodgkin Lymphoma

A malignancy of the lymphatic tissue that occurs most often in males, and the peak incidence is between ages 15 and 35. It is characterised by progressive, painless enlargement of the lymph nodes, spleen, and general lymph tissue. In Hodgkin Lymphoma Reed-Sternberg cells (a specific type of lymphocyte) become abnormal and grow in an uncontrolled way.

Internet Resources for Hodgkin Lymphoma

Non Hodgkin Lymphoma (NHL)

NHL is cancer of the lymphatic tissue, that does not involve abnormal Reed-Sternberg cells (a specific type of lymphocyte). There are many different types of NHL. Some grow very slowly, whilst others grow quickly and need aggressive treatment.

Internet Resources for NHL

AIDS related lymphoma

Incidence of non-Hodgkin’s lymphoma has increased in parallel with the AIDS epidemic. Lymphomas affecting HIV infected people are mostly of the aggressive B-cell types (diffuse large cell, B-immunoblastic, or small non-cleaved Burkitt’s / Burkitt’s like lymphoma) which are less common in non-HIV infected lymphoma patients. The HIV virus is not thought to a direct cause of lymphoma, rather it weakens the body’s defences and may increase susceptibility to other infections such as the Epstein-Barr and HHV-8 viruses which are associated with these types of lymphomas.

Internet Resources for AIDS related Lymphoma

Waldenstrom’s Macroglobulinemia

This is a rare malignant condition, involving an excess of beta-lymphocytes (a type of cell in the immune system) which secrete immunoglobulins (a type of antibody). WM usually occurs in people over sixty, but has been detected in younger adults.

Internet Resources for Waldenstrom’s Macroglobulinemia

Cancer Immunotherapy

This is treatment to stimulate the patient’s own immune system to attack the cancer cells. Different approaches include: 1) cancer vaccination to train the immune system to recognise the cancer cells as targets to be destroyed, 2) giving therapeutic antibodies to recruit immune system cells to destroy tumor cells, and 3) cell based immunotherapy which is either transfusing immune cells (such as Natural killer Cells) or by administering cytokines (such as Interleukins) which activate the immune cells.

HPV Vaccination and Cervical Cancer

Human papillomavirus (HPV) is a common cause of infection. There are over 100 different sub-types of HPV. HPV types 16 and 18 cause 70% of cervical cancers and are also linked to cancers of the anus, vulva, vagina, penis, as well as the mouth and throat. Over time these can cause cells in the cervix to change, leading to precancerous conditions – cervical intraepithelial neoplasia (CIN), with a higher risk of developing cancer. Vaccination against HPV 16, 18 and other ‘high risk’ types of HPV reduces the risk of developing cervical and other HPV-related cancers.

Internet Resources for HPV Vaccination and Cervical Cancer

Lymphedema

Lymphedma is an abnormal build up of interstitial fluid due to problems in the lymphatic system. It can have many causes. In the context of cancer it is often a result of obstruction by a tumor or enlarged lymph nodes. It can also be a side effect of radiotherapy or surgery, which has damaged the lymph vessels.

Roots, suffixes, and prefixes

Most medical terms are comprised of a root word plus a suffix (word ending) and/or a prefix (beginning of the word). Here are some examples related to the Lymphatic and Immune systems. For more details see Chapter 4: Understanding the Components of Medical Terminology

component	meaning	example
aden(o)-	gland	Lymphadenopathy – disease of, or swelling/enlarged lymph nodes
immun(o)-	Immunity	Immunosuppression = reduced activation or efficacy of the immune system
lymph(o)-	Lymph	Lymphoma = tumour of lymphoid cells
lymphaden(o)-	lymph node	Lymphadenectomy = surgical removal of lymph node(s)
lymphangi(o)-	lymphatic vessels	Lymphangitis = inflammation or infection of the lymphatic vessels
splen(o)-	spleen	Splenomegaly = enlargement of the spleen
thym(o)-	thymus	Thymectomy = surgical removal of the thymus
tox(o)-	poison	Immunotoxicity = adverse effects on immune system function resulting from exposure to chemical substances.

Related Abbreviations and Acronyms

Further Resources (9 links)

 Immune System

National Cancer Institute
Detailed presentation and notes.

 Introduction to the Lymphatic System

SEER, National Cancer Institute
Part of a SEER training module for cancer registry staff.

 Lymphatic System – Self Test questions

WebAnatomy, University of Minnesota
Test your anatomy knowledge with these interactive questions. Includes different question types and answers.

 Mechanism of lymph node metastasis in prostate cancer

Future Oncol. 2010 May;6(5):823-36
Datta K, Muders M, Zhang H, Tindall DJ. Mechanism of lymph node metastasis in prostate cancer. Future Oncol. 2010 May; 6(5): 823-836. (full article available free on PubMed Central)

 Sentinel Lymph Node Biopsy

National Cancer Institute
Factsheet in the form of questions and answers, with references.

 The components of the immune system

National Library of Medicine
A section, with diagrams from: Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

Paul Andersen
Paul Andersen explains how your body protects itself from invading viruses and bacteria. He starts by describing the nonspecific immune responses of skin and inflammation. He then explains how we use antibodies to disrupt the function of antigens and mark them for destruction. He then explains both the homoral and cell-mediated immune response highlighting the importance of B and T lymphocytes. He finally describes the process of long term immunity.

 The Lymphatic System

Cancer Research UK
Short overview, with diagrams.

UCSF
Dr. Katherine Gundling, Professor, Division of Allergy and Immunology at UCSF presents an overview of the immune system, how it functions and what can go wrong.

This guide by Simon Cotterill

First created 4th March 1996
Last modified: 1st February 2014

Lymphatic System Anatomy–Lymphosurgery Center

The lymphatic system is an important part of the human cardiovascular system and complements it.

Unlike the circulatory system, the lymphatic system does not have its own pump and is open. The lymph circulating in it moves slowly and under little pressure. Lymph is a fluid that is constantly formed by drainage of interstitial fluid into the lymphatic capillaries.

The structure of the lymphatic system includes:

• lymphatic capillaries
• lymphatic vessels
• lymph nodes
• lymphatic trunks and ducts

subclavian trunks; on the right into the right lymphatic duct, right jugular and right subclavian trunks. The ducts and trunks flow into the large veins of the neck, and then into the superior vena cava. In this way, lymph is transferred from the interstitial spaces back into the blood.

Lymphatic vessels pass through the lymph nodes. They are combined into several groups and are located along the vessels. Many afferent vessels carry lymph to the node, and it flows out from there only through one or two efferent vessels. Lymph nodes are small formations of a round, oval, bean-shaped, less often ribbon-shaped form up to 2 cm long. Here, lymph is filtered, foreign matter is separated and destroyed, and lymphocytes are produced here to fight infection. Lymph nodes that perform a barrier and immune role.

Main functions of the lymphatic system:

• Transport function – carrying lymph, metabolic products from tissues to the venous bed.

• Drainage function – the return of proteins, water, salts, toxins and metabolites from tissues to the blood. Removal of fluid, pus, effusion from the wound, cavities. Stability of the “capillary lymphatic pump”

• Lymphocytopoiesis, hematopoietic function – formation, maturation, differentiation of lymphocytes involved in immune reactions.

• Immune, protective functions – formation of the body’s immune defense, neutralization of foreign particles, bacteria, viruses, fungi, protozoa that enter the body. filtration from impurities, tumor particles and cells.

Any failure or blockage of the lymphatic vessels or nodes entails swelling or swelling of the tissues, lymphadenitis, erysipelas, lymphostasis occur. Experts, not without reason, believe that the lymph could tell about what the blood is “silent about”, because many of the waste products of the cells first enter the lymph, and then into the blood.

If most doctors can help us in the fight against many diseases, then only individual doctors – lymphologists – can diagnose and treat disorders in the lymphatic system.

According to the statistics of doctors themselves, in the CIS there are only a few lymphologists – specialists in the lymphatic system.

Lymphologists say: Your health is the purity of your lymphatic system!

Be healthy and happy!

where they are located, what functions they perform, in which diseases 9 increase0001

Inflammation and enlargement of the lymph nodes usually causes discomfort and pain. As a rule, this indicates that an inflammatory process is underway in the body.

What are lymph nodes

Lymph nodes are the most important organs that perform a barrier-filtration function ¹ . Their main function is the biological filter of lymph – a colorless liquid that washes all the tissues and cells of the body. It consists of plasma and formed elements. Interestingly, lymph plasma has an almost similar chemical structure to blood plasma, but contains fewer proteins ² .

Useful information about lymph nodes

Where are the lymph nodes

Lymph nodes are found almost everywhere. They are arranged in such a way as to become an obstacle in the way of various “garbage”: toxins, viruses, bacteria, parasites, fungi, cancer cells.

Most lymph nodes are located deep under the skin and even near internal organs where they cannot be felt. But some lymph nodes – under the jaw, in the armpits, in the groin – can be palpated even in a healthy, non-inflamed state.

Photo: Shutterstock

Functions of the lymph nodes

As mentioned earlier, the main function of the lymph nodes is barrier-protective function. In these organs of the lymphatic system, protective cells of the body are formed, such as lymphocytes, antibodies, phagocytes. Lymph nodes protect against the penetration of infections, and also prevent the reproduction of malignant tumor cells and play a role in the immune response to substances foreign to the body.

The lymph nodes also perform the following functions:

• hematopoietic – after the lymph nodes, lymph enriched with lymphocytes gets into the blood;
• drainage – promote the outflow of excess fluid;
• depository (reserve) – lymph node is a temporary storage of lymphocytes and lymph. The latter lingers in the lymph node in order to ensure the unloading of the bloodstream in “emergency” situations, for example, during venous congestion;
• metabolic – lymph nodes are involved in the metabolism of fats, proteins, carbohydrates and other substances.

Causes of swollen lymph nodes

Lymph nodes have their own diseases, and most often their inflammation is a reaction to some other disease or condition. Completely different reasons can lead to an increase in lymph nodes (lymphadenopathy). Consider the most common of them.

Local infections

Infection is one of the most common causes of swollen lymph nodes.

— For example, it can be acute respiratory diseases, leading to an increase in regional lymph nodes associated with the area in which inflammation occurs, says general practitioner Oksana Khamitseva.

As a rule, the focus of the disease is located near enlarged lymph nodes. So, with infections of the upper respiratory tract, the lymph nodes in the neck become inflamed, with a sexual infection – in the groin.

Generalized viral and bacterial infections

If only one category of lymph nodes is affected, then they speak of local inflammation. If the nodes that are not adjacent to each other increase, then we are talking about a generalized inflammation of the lymph nodes.

This widespread inflammation can be caused by infections – bacterial, viral, fungal, which affect the entire body. It can be tuberculosis, some infectious skin diseases, rubella, chickenpox, cytomegalovirus, mononucleosis, HIV and others.

Autoimmune diseases

Autoimmune connective tissue diseases such as arthritis and systemic lupus erythematosus can also lead to swollen lymph nodes. In such diseases, the body begins to attack its own cells. Due to the increasing load on the lymph nodes, their inflammation occurs.

Tumor processes

Swollen lymph nodes can also signal tumor processes in the body. As we wrote above, lymph nodes prevent the reproduction of cancer cells, but in some cases, tumor cells can get stuck in them and multiply. Tumor processes can lead to the development of leukemia, lymphogranulomatosis, lymphoma.

Hypersensitivity of the body

Allergic reactions can also provoke inflammation of the lymph nodes. In addition, their increase may be associated with hypersensitivity to certain drugs.

How lymph nodes are treated

The treatment of lymphadenopathy is varied and always depends on its cause. An increase in lymph nodes is a signal of inflammation, so you need to look for its source.

Most often, inflammation of the lymph nodes occurs as a secondary process, that is, a reaction to another disease:

• if this is associated with acute respiratory infections, then it is necessary to treat the respiratory tract infection itself, be it a bacterium or a virus;
• if it is associated with a generalized infection (mononucleosis, HIV), then long-term specific therapy is selected here;
• cat-scratch disease (felinosis) is treated with special antibiotics;
• Sepsis is controlled only in the hospital by intravenous administration of various drugs, including antibiotics, and ionic solutions.
• autoimmune diseases (systemic lupus erythematosus, Kawasaki disease, etc.) are treated by a rheumatologist, prescribing hormones or cytostatics for long courses under constant supervision.

Lymphadenopathy can also be caused by cancer. Conventionally, they can be divided into 3 sections:

1. leukemia, when the primary malignant focus is in the bone marrow;
2. lymphomas, when the foci are located directly in the lymph nodes;
3. metastases, when the focus is located in the internal organ, and cancer cells affect the lymph nodes in the path of lymph outflow.

— In the case of leukemia, a bone marrow transplant is possible. With lymphoma, it is useless to do this, you can only use various options for radiation, chemotherapy, genetic engineering methods. And if lymphadenopathy is caused by metastases, then, as a rule, the tumor of the corresponding organ is removed, entering healthy tissues and capturing the “package” of affected lymph nodes, says our expert Oksana Khamitseva.

How to maintain the health of the lymphatic system at home

According to physician Oksana Khamitseva, the health of the lymphatic system primarily depends on two components: good lymphatic drainage and normal functioning of the immune system. This is not difficult to achieve:

• regular physical activity;
• avoid tight, constricting clothing;
• smoking and alcohol cessation;
• courses of multivitamins 2 times a year;
• food high in protein and fiber in the diet;
• adequate fluid intake.

Popular questions and answers

General practitioner Oksana Khamitseva answers popular questions about lymph nodes.

Which lymph node is responsible for what?

– Each internal organ is supplied with lymph nodes, arteries and veins. If we talk about those lymph nodes that we can feel:

• Submandibular: increase with rhinitis, pharyngitis, tonsillitis, inflammation of the teeth and gums.
• Cervical: inflamed with acute respiratory infections, conjunctivitis, otitis media.
• Parotid: react to otitis media, acute respiratory infections.
• Occipital: increased with head and neck infections, acute tonsillitis, infectious mononucleosis.
• Axillary: may also be associated with mononucleosis, mastitis, breast cancer, HIV, cat scratch disease.
• Elbows: felinosis, HIV.
• Inguinal: mumps, generalized infections, inflammation of the urogenital organs.

What to do if the lymph nodes are inflamed?

— If you have lymphadenitis, you need to see a doctor, because you don’t know what it can be connected with. If you notice an increase in lymph nodes in the head and neck, there are signs of acute respiratory infections (runny nose, sore throat, cough, fever), then you can independently start taking vitamins, antiviral drugs, NSAIDs, symptomatic treatments for colds.

If you notice an increase in lymph nodes, which is objectively not related to the infectious process, then doing something without a doctor’s recommendation can be dangerous. Even taking vitamins, if the process is autoimmune, will spur the immune system to even more aggressive inflammation.

Why is inflammation of the lymph nodes dangerous?

— Complications of lymphadenitis include:

• transfer of infection to nearby tissues: bones, subcutaneous fat, skin;
• blockage by blood clots of veins adjacent to inflamed lymph nodes;
• violation of lymphatic drainage, edema, “elephantiasis” of the limbs.

What can not be done with enlarged lymph nodes?

– If you notice an increase in lymph nodes, then it is strongly not recommended to ignore it, heat or apply ice, make lotions without the permission of a doctor. Also, do not smear with anti-inflammatory ointments (you will reduce one lymph node and decide that you are cured, and if it is an oncology?), squeeze and massage the lymph node.

The patient does not know in which direction the lymph flows from this or that lymph node, and if you make the wrong movements, stagnation can be provoked.

Which doctor treats lymph nodes?

— All roads lead to a therapist. After examination and examination, a specialist can identify what lymphadenitis is associated with, treat acute respiratory infections or refer to an ENT doctor, an infectious disease specialist if an infectious process is detected. If an autoimmune disease is detected, your doctor is a rheumatologist, and in case of suspicion of leukemia or lymphoma, an oncologist.

Sources:

1. Semioshko N.V. Lymph nodes adjacent to the celiac trunk // BBC 28.706 Ya431 V 38. – 2014. – P. 111. http://sno.grsmu.by/conference/mk47.pdf#page=111
2. Pogrelchuk O.E., Danko E.S. Blood and lymph. Hematopoiesis // In the world of scientific discoveries. – 2018. – S. 219-221. https://www.elibrary.ru/download/elibrary_36443065_39723184.pdf
3. Dvoretsky L.I. Differential diagnosis in lymphadenopathy // Handbook of a polyclinic doctor. – 2005. – no. 2.