Lymphoreticular system

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24.2 The thymus258
24.3 The spleen259

Self-assessment: questions262
Self-assessment: answers264

Basic principles

The cells which circulate in the peripheral blood can be classified simply into those that are non-nucleated (erythrocytes and platelets) and those that are nucleated (leucocytes or white blood cells). White blood cells can be further subclassified into three main cell types:

• granulocytes
• monocytes
• lymphocytes.
The main function of these cells is to protect against infection. Lymphocytes and monocytes circulate around the body in blood vessels and lymphatic vessels, but they also accumulate in organised masses called lymphoid tissues. These organised masses together are known as the lymphoreticular system and the main components of this system are the lymph nodes, thymus, spleen, tonsils, adenoids, and the Peyer patches. The latter three tissues are known as mucosa-associated lymphoid tissue (MALT).

24.1. Lymph nodes

Learning objectives
You should:

• understand the structure and function of lymph nodes
• know the causes of lymphadenopathy
• have a basic understanding of the lymphoid neoplasms.

Structure and function

Lymph nodes are ovoid, encapsulated structures, which range in size from a few millimetres to a few centimetres. They are situated along the course of lymphatic vessels and tend to occur in groups where these vessels converge (e.g. the axilla, groin, neck and mediastinum). Lymph is essentially interstitial fluid containing proteins that need to return to the bloodstream, but which are prevented from doing so within the tissues because of overwhelming hydrostatic pressure. Lymph is therefore carried away from the tissues in small peripheral lymphatic vessels, which converge to form larger vessels, until eventually a single large lymphatic vessel called the thoracic duct ultimately drains the lymph into the bloodstream at the root of the neck. Before the lymph enters the bloodstream, it must pass through one or more lymph nodes. Within the lymph nodes, foreign agents and unwanted materials, which have gained access to the tissues, are entrapped and an immune response is mounted.
Each lymph node is divided into three main regions: the cortex, the paracortex and the medulla (Figure 66).
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Figure 66

The cortex

The cortex is the area just beneath the capsule, and it contains spherical aggregations of B lymphocytes (B cells). These aggregations are called primary follicles. B cells are involved in humoral immunity and the primary follicle is the principal site of B cell activation in response to antigenic stimulation. Antigens that enter the lymph node are presented to the B cells in the primary follicle. Activated B cells enlarge and undergo a series of changes, resulting ultimately in the production of immunoglobulin-secreting plasma cells. Hence, after antigenic stimulation, the primary follicle enlarges and develops a pale-staining germinal centre that contains large, activated B cells. The germinal centre is surrounded by a rim of small unchallenged B cells called the mantle zone.

The paracortex

The paracortex is the area between the follicles and is rich in T lymphocytes (T cells). T cells are involved in cell-mediated immunity. Scattered histiocytic cells are also present.

The medulla

The medulla contains the medullary cords and sinuses. The sinuses are lined by macrophages, which phagocytose particulate material within the lymph. The medullary cords contain numerous plasma cells, which secrete immunoglobulins (antibodies).
Lymph enters the lymph node via multiple afferent lymphatic vessels, which perforate the fibrous capsule and empty into a slit-like space just beneath the capsule called the subcapsular sinus. From there, the lymph enters the cortex via multiple, small cortical sinuses, which penetrate into the node. In the medulla, these sinuses begin to converge into larger sinuses (the medullary sinuses) and, in turn, the medullary sinuses join to form a single efferent lymphatic vessel.


When there is a pathological process affecting a lymph node, it usually becomes enlarged. Lymphadenopathy is a term used to denote lymph node enlargement. Lymphadenopathy may be localised or widespread. There are two main causes:

• non-neoplastic (reactive) lymphadenopathy
• neoplastic lymphadenopathy.
Neoplasms of the lymph nodes can be divided into primary (lymphoma) or secondary (metastases).

Non-neoplastic (reactive) lymphadenopathy

Reactive lymph nodes enlarge because there is proliferation of one or more cell types within them. The various antigenic stimuli evoke the reactive proliferation of particular cell types within the lymph node, and may induce other changes. In many cases, the morphological changes induced by these aetiological agents are non-specific, such that precise diagnosis of the causal agent is not possible on histological grounds alone (blood tests may be needed). In other cases, the reactive changes are entity specific, such that the pathologist is able to make an exact diagnosis.

Non-specific reactive changes

Lymph nodes may react in one of five different ways to antigenic stimulation. Often, a combination of one or more of these patterns is seen.
Acute non-specific lymphadenitis This occurs when there is direct drainage of pyogenic infectious microbes into a lymph node, causing a localised acute inflammatory response. Affected lymph nodes become enlarged and tender. Microscopically, there is lymph node oedema and hyperaemia, and neutrophil polymorphs migrate from the vasculature into the nodal parenchyma. There may be progression to abscess formation.
Follicular hyperplasia This occurs when there is a B cell response, and is characterised by marked enlargement and prominence of the germinal centres.
Paracortical hyperplasia This is the result of a T cell response. The paracortex expands and encroaches on the follicles. This pattern is often encountered in reactions induced by drugs and acute viral infections.
Sinus histiocytosis This is seen if there is a marked proliferation of histiocytic cells, which normally occupy the sinuses. The sinuses become dilated and engorged with numerous histiocytes.
Granulomatous lymphadenitis This term refers to the formation of granulomas within a lymph node. A granuloma is a collection of macrophages. Causes include:

• tuberculosis
• sarcoidosis
• cat scratch disease
• Crohn’s disease
• toxoplasmosis
• reaction to foreign material.

Entity-specific reactive changes

A number of reactive conditions affecting lymph nodes induce morphological appearances which, although often complex, may be distinctive enough to enable the pathologist to make an exact diagnosis. Such conditions include certain infections (e.g. toxoplasmosis, human immunodeficiency virus (HIV) infection, Epstein–Barr virus infection), some connective tissue diseases (e.g. systemic lupus erythematosus), reactions to types of foreign material (e.g. silicone), certain drug reactions (e.g. some anticonvulsants) and conditions of uncertain aetiology (e.g. Castleman disease).

Neoplastic lymphadenopathy


Lymphomas are classified into subtypes according to histological appearance and immunophenotype (i.e. the staining patterns on immunohistochemistry). Different subtypes behave differently, have different prognoses, and require different treatments. Hence, classification of lymphoma is the means by which pathologists convey meaningful information to the clinicians. There have been a number of classification systems in the past (e.g. Kiel classification, Working Formulation for Clinical Usage), all of which have had their merits. However, many entities went by different names in the different classification systems, and this was a source of confusion for both pathologists and clinicians. In addition, there have been major advances in our knowledge and understanding of lymphoid neoplasms since the 1980s, and many new entities have now been recognised. To overcome these problems, a new unifying lymphoma classification system was devised and published by the International Lymphoma Study Group in 1994, and it was called the ‘Revised European-American Classification of Lymphoid Neoplasms’ (REAL). A few years later, when the World Health Organization (WHO) was developing a new classification system for neoplastic diseases of the haematopoietic and lymphoid tissues, it adopted the REAL classification, making only a few modifications. It is the 2001 WHO Lymphoma Classification System that is currently used in clinical practice.
There are two main types of lymphoma – Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. They are considered separate for two main reasons:

• Hodgkin’s lymphoma is characterised morphologically by the presence of unique neoplastic cells called Reed–Sternberg cells
• Hodgkin’s lymphoma may be associated with certain clinical symptoms.

Hodgkin’s lymphoma

Hodgkin’s lymphoma is differentiated from the other types of lymphoma by the presence of distinctive and diagnostic tumour cells called Reed–Sternberg cells (RS cells), although for the diagnosis of Hodgkin’s lymphoma to be made, the RS cells must be associated with the appropriate cellular background. Classically, the RS cell is large with a pale, bilobed nucleus and large, prominent, eosinophilic nucleoli. The nucleoli are bounded by a clear zone, giving the cell a characteristic ‘owl-eye’ appearance. The various subtypes of Hodgkin’s lymphoma are shown in Table 57.
Table 57 The WHO lymphoma classification system
*Within the non-Hodgkin’s group, only the most common subtypes are shown.
The subtypes which constitute the majority of lymphoid neoplasms in adults.
§The subtypes most common in children.
Hodgkin’s lymphoma • Nodular lymphocyte-predominant Hodgkin’s lymphoma
• Classical Hodgkin’s lymphoma
• Nodular sclerosing Hodgkin’s lymphoma
• Lymphocyte-rich classical Hodgkin’s lymphoma
• Mixed-cellularity Hodgkin’s lymphoma
• Lymphocytedepleted Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma* • B cell neoplasms
• Precursor B cell neoplasms
• Mature B cell neoplasms
• Precursor B lymphocytic leukaemia/lymphoma§
• B cell chronic lymphocytic leukaemia/ small lymphocytic lymphoma
• Plasma cell myeloma
• Extranodal marginal zone B cell lymphoma of MALT type
• Follicular lymphoma
• Mantle cell lymphoma
• Diffuse large B cell lymphoma
• Burkitt’s lymphoma§
• T/NK cell neoplasms
• Precursor T cell neoplasms
• Mature T cell neoplasms
• Precursor T lymphoblastic lymphoma§
• Mycosis fungoides/Sézary syndrome
• Peripheral T cell lymphoma
• Angioimmunoblastic T cell lymphoma
• Anaplastic large-cell lymphoma
Clinical features Typical patients are young adults, the peak incidence being in the third and fourth decades of life. Patients usually present with painless lymphadenopathy, which typically affects the upper half of the body. The enlarged lymph nodes are discrete, mobile, and rubbery in consistency. Patients may also present with systemic symptoms (unexplained pyrexia, drenching night sweats, unexplained weight loss).

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