Lymph nodes and extranodal lymphoid tissue, spleen and thymus

Cortex

Germinal centres of lymph node follicles are the principal sites of B-cell activation in response to antigenic challenge. Antigen–antibody complexes entering the lymph node through afferent lymphatics are captured, via their fraction complement-binding (Fc) receptors, onto surface projections of specialised antigen-presenting cells called follicular dendritic cells (FDC). These are mesenchymal cells that are normally restricted to primary follicles and germinal centres. They have long cytoplasmic processes linked by desmosomes to form a network throughout the germinal centre. Antigen on FDC surfaces is presented to ‘naïve’ B lymphocytes in the presence of T-helper cells; these B cells subsequently undergo morphological and functional changes to become antibody-producing effector cells or memory cells. After antigenic challenge, the initial step in B-cell transformation in the germinal centre is production of a centroblast , a rapidly dividing cell responsible for expanding the antigen-reactive B-cell clone, followed by selection and differentiation into centrocytes . During this germinal centre reaction, B-cell immunoglobulin genes undergo somatic hypermutation to produce higher-affinity immunoglobulin molecules. B cells in which hypermutation does not achieve this undergo apoptosis. The number of B cells that act as progenitors for a fully mature germinal centre is remarkably small; abundant centroblasts and centrocytes arise by extensive proliferation of only a few antigen-stimulated progenitor cells. The function of germinal centres is to generate immunoglobulin-secreting plasma cells and memory B cells in response to antigenic challenge.

A fully formed germinal centre is seen histologically as a round, pale structure in the cortex ( Fig. 22.1 ), surrounded by a rim of small lymphocytes termed the mantle zone . Distinct zonation may be seen within the germinal centre. A pale zone, facing towards the subcapsular sinus, is rich in centrocytes and T cells (specifically, T-follicular helper, or T _FH , cells) and contains the greatest density of FDC. Facing towards the medulla is a darker zone rich in rapidly dividing centroblasts admixed with tingible body macrophages. The latter phagocytose debris from apoptosis of B cells following unsuccessful immunoglobulin gene hypermutation.

B cells enter and leave the germinal centre through its mantle zone. In some lymph node reactions, and in reactive lymphoid tissue at extranodal sites, a population of post­germinal centre B cells may also accumulate outside the mantle zone; these are marginal zone B cells.

Paracortex

This is the main lymph node region for generating T-cell reactions and it therefore contains large numbers of T lymphocytes. There is a predominance of the helper/inducer T-cell subset expressing cluster of differentiation (CD) 4 antigen. As in the germinal centre, specialised antigen-presenting cells are present; these are interdigitating reticulum cells (IDRC) and they differ morphologically and functionally from FDC. They are derived from macrophages and possess abundant cytoplasm, with complex processes which interdigitate with neighbouring T cells. Large amounts of class II human leukocyte antigen (HLA) molecules are expressed on IDRC surfaces and this is important for interactions with immune cells, especially antigen presentation to CD4+ T cells. The paracortex also contains specialised blood vessels, termed high endothelial venules (HEV), which provide a specific route for T cells to leave the node.

Medulla

Lymph drains to the hilum through sinuses that converge in the medulla. These sinuses are lined by macrophages which phagocytose particles from lymphatic fluid. Between the sinuses lie medullary cords containing numerous antibody-secreting plasma cells. Many of the latter mature here from postgerminal centre B cells after their transit through mantle zones; medullary cords are a major site of antibody secretion.

Granulomatous lymphadenitis

Granulomatous lymphadenitis can occur in a variety of clinical settings, such as mycobacterial infection, sarcoidosis and Crohn disease, which are described elsewhere ( Ch. 14 ) and will not be discussed further here.

Toxoplasmosis — infection with Toxoplasma gondii , a protozoal organism — in an immunocompetent individual produces a short, flu-like illness and localised lymphadenopathy, usually occipital or cervical, which persists for several weeks. Affected lymph nodes are enlarged with germinal centre hyperplasia and formation of adjacent ill-defined granulomas. In addition, there is florid marginal zone B-cell hyperplasia characterised by accumulation of medium-sized, monomorphic B cells adjacent to follicles and lymph node sinuses. This triad of follicular hyperplasia, follicle-associated granulomas and marginal zone B-cell hyperplasia ( Fig. 22.2 ) strongly suggests toxoplasmic lymphadenitis; the diagnosis is confirmed serologically.

Lymph nodes associated with lymphatics draining tumours occasionally show a granulomatous reaction in the absence of metastatic involvement, possibly a reaction to tumour antigens. Lymph nodes may also develop granulomas in response to foreign particles, for example, silicone compounds used in plastic surgery and joint replacement. Ink pigments are found commonly within paracortical macrophages in individuals who have heavy skin tattooing but these cells rarely aggregate to form granulomas.

Necrotising lymphadenitis

A variety of infections may cause necrosis within lymph nodes. Examples are lymphogranuloma venereum and cat-scratch disease . Lymphogranuloma venereum is a sexually transmitted chlamydial disease and most commonly affects inguinal lymph nodes. Cat-scratch disease follows a bite or scratch from an infected cat; days to weeks later, tender cervical or axillary lymphadenopathy develops; inguinal nodes are less commonly affected. Two organisms have been shown to be responsible for cat-scratch disease; Bartonella henselae causes up to 75% of cases while Afipia felis is less common. In immunosuppressed patients, particularly those with HIV/AIDS, infection with B. henselae may cause an unusual vascular proliferation termed bacillary angiomatosis . Lymphogranuloma venereum and cat-scratch disease show histological similarities, with stellate abscesses surrounded by palisaded macrophages ( Fig. 22.3 ).

A rare form of necrotising lymphadenitis is Kikuchi disease , in which tender cervical or occipital lymphadenopathy develops, most commonly in young adult Asian women. The cause is unknown and its pathology is more accurately attributed to extensive, confluent apoptosis within the lymph node rather than true necrosis, since absence of neutrophils from the necrotic tissue is striking. A florid macrophage and T-cell reaction occurs that may be mistaken for lymphoma. Systemic lupus erythematosus occasionally causes autoimmune lymphadenitis with very similar histology.

Sinus histiocytosis

This is a very common reaction in lymph nodes, particularly those associated with lymphatics draining neoplasms; its features have been described above ( p. 528 ). Sinus histiocytosis with massive lymphadenopathy (SHML or Rosai–Dorfman syndrome) is a rare condition of unknown cause that presents typically with bulky cervical lymphadenopathy in the first and second decades of life and may persist for several years. It may, however, affect individuals of any age and involve other tissues. Lymph node sinuses are distended by large, distinctive macrophages admixed with lymphocytes and plasma cells. Many lymphocytes and plasma cells appear to lie within macrophage cytoplasm because they pass through it in membrane-lined channels, a process termed emperipolesis . Molecular genetic analysis of SHML has shown it to be a polyclonal disorder; it usually follows a benign course and may regress spontaneously. However, in some patients with extensive disease the course is aggressive and fatalities have occurred.

Paracortical hyperplasia

Paracortical hyperplasia is prominent in many cases of lymphadenopathy. Two entities deserve special mention: dermatopathic lymphadenopathy and infectious mononucleosis (glandular fever).

Patients with chronic inflammatory skin conditions (e.g. severe eczema or psoriasis) and others with cutaneous T-cell lymphomas (CTCL) commonly develop enlarged inguinal and axillary lymph nodes; a condition known as dermatopathic lymphadenopathy . The enlarged lymph nodes may have yellow or buff-coloured cut surfaces and, microscopically, the paracortex is expanded by nodular collections of pale histiocytes admixed with small T lymphocytes. The histiocytes are predominantly IDRC, sometimes accompanied by conventional macrophages with visible intracytoplasmic lipid or skin-derived melanin.

Infectious mononucleosis is due to acute infection by Epstein–Barr virus (EBV). After an initial sore throat and flu-like illness, this causes widespread lymphadenopathy and is characterised, at least in later stages if lymph node enlargement persists, by paracortical expansion including numerous, large, activated B and T cells. This histological picture may be mistaken for lymphoma.