Chapter 22 Lymph nodes, thymus and spleen
COMMON CLINICAL PROBLEMS FROM DISEASE OF THE LYMPH NODES, THYMUS AND SPLEEN
Sign or symptom | Pathological basis |
---|---|
Enlarged lymph nodes | |
Enlarged spleen | |
Susceptibility to infection | |
Weight loss/pyrexia | Interleukins produced by inflammatory or lymphomatous (i.e. type B symptoms) tissue acting on thermoregulatory centre in hypothalamus |
Muscle weakness (myasthenia gravis) | Thymic hyperplasia or neoplasia |
Howell–Jolly inclusions in red cells | Persistence of DNA fragments in red cells due to splenic atrophy |
LYMPH NODES
Micro-architecture and functional anatomy
Three distinct micro-anatomical regions can be recognised within normal lymph nodes (Ch. 9). These regions are:
Germinal centres
The germinal centre is the principal site of B-cell activation in response to antigenic challenge. Antigen, bound to antibody, entering the lymph node via the afferent lymphatics is trapped upon the surface of specialised antigen-presenting cells called dendritic reticulum cells (DRCs) by their Fc receptors. DRCs are restricted to primary follicles and germinal centres and are binucleate cells with long cytoplasmic processes linked by desmosomes which form a network throughout the germinal centre. Antigen trapped on the surface of the DRC is presented to ‘virgin’ B-lymphocytes in the presence of T-helper cells (T-cell co-operation) and these B-cells subsequently undergo a series of morphological and functional changes (Table 22.1). After antigenic challenge, the initial step in B-cell transformation is the formation of the centroblast, which is a rapidly dividing cell that is responsible for expansion of the antigen-reactive B-cell clone; this then develops into a centrocyte (Fig. 22.1). During the germinal centre reaction the B-cell immunoglobulin genes undergo 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 the fully mature germinal centre is remarkably small and the mass of the germinal centre B-cell population is made up by the extensive proliferative activity of a small number of progenitor cells.
Cell features | Nomenclature |
---|---|
Small lymphocyte with round nucleus | Lymphocyte |
Small or large cell with indented nucleus | Centrocyte |
Large cell with round nucleus and usually multiple nucleoli | Centroblast |
Large cell with round nucleus and large nucleolus | Immunoblast |
The fully formed germinal centre is seen histologically as a rounded, pale structure in the cortex of the lymph node, surrounded by a rim of small, round lymphocytes termed the mantle zone. Distinct zonation may be seen within the germinal centre: a pale zone faces towards the subcapsular sinus, is rich in centrocytes and T-cells, and contains the greatest density of DRCs; at the opposite pole of the germinal centre is a dark zone rich in rapidly dividing centroblasts mixed with tingible body macrophages which phagocytose the cellular debris generated by apoptosis of B-cells secondary to unsuccessful immunoglobulin gene hypermutation (Fig. 22.2). In florid B-cell reactions a population of post-germinal centre B-cells may accumulate adjacent to the mantle zone; these are termed marginal zone B-cells.
Paracortex
The paracortex is the T-cell-dependent region of the lymph node and accordingly contains large numbers of T-lymphocytes with a predominance of the helper/inducer subset (CD4+). The cluster of differentiation (CD) 4 antigen is expressed by helper/inducer T-cells. As in the germinal centre, specialised antigen-presenting cells are present in the paracortex; these are called interdigitating reticulum cells (IDCs) and are different morphologically and functionally from the DRCs. IDCs possess abundant cytoplasm with complex membrane profiles which interdigitate with surrounding T-cells. Large amounts of class II human leukocyte antigen (HLA) substances are expressed on the surface of the IDC and this is important for interactions between immune cells, especially in antigen presentation to T-cells (particularly the helper T-cells).
NON-NEOPLASTIC LYMPHADENOPATHY
Non-specific reactive hyperplasia
Non-specific reactive hyperplasia may occur in lymph nodes draining sites of infection and, in some cases, pathogenic organisms may cause inflammatory changes within the substance of the node, termed lymphadenitis, which may progress to abscess formation.
Specific disorders
Granulomatous lymphadenitis
Granulomatous lymphadenitis can occur in a variety of clinical settings such as mycobacterial infection (Ch. 14), sarcoidosis (Ch. 14) and Crohn’s disease (Ch. 15). These are described elsewhere and will not be detailed here.
Infection with Toxoplasma gondii, a protozoal organism, in the immunocompetent host produces a flu-like illness of short duration and localised lymphadenopathy, usually occipital or high cervical, which persists for some weeks. The affected lymph node is enlarged and shows germinal centre hyperplasia with formation of ill-defined granulomas adjacent to them. In addition, there is florid marginal zone B-cell hyperplasia characterised by a proliferation of medium-sized, monomorphic B-cells. This histological triad of follicular hyperplasia with adjacent granulomas and marginal zone B-cell hyperplasia suggests a diagnosis of toxoplasmic lymphadenitis which should be confirmed serologically (Fig. 22.3).
Necrotising lymphadenitis
A variety of diseases caused by infectious agents may lead to necrosis within lymph nodes. Examples are lymphogranuloma venereum and cat scratch disease. Lymphogranuloma venereum is a sexually transmitted chlamydial disease and most commonly affects the groin nodes. Cat scratch disease follows a bite or scratch from an infected cat. Days to weeks later, tender lymphadenopathy develops in the cervical or axillary regions; the groin is less commonly affected. Two organisms have been shown to be responsible for cat scratch disease: both are extracellular, pleomorphic coccobacilli. The commoner is Bartonella henselae, which causes up to 75% of cases; less common is Afipia felis. In immunosuppressed patients, particularly those with AIDS, infection with B. henselae may cause an unusual vascular proliferation termed bacillary angiomatosis. This may affect lymph nodes or extranodal sites. Lymphogranuloma venereum and cat scratch disease show histological similarities, with formation of stellate abscesses within the lymph node, surrounded by palisaded histiocytes (Fig. 22.4).
Paracortical hyperplasia
Patients with exfoliative chronic skin conditions such as severe eczema or psoriasis, and patients with cutaneous T-cell lymphoma, quite commonly develop enlarged lymph nodes in the groin and axilla. This condition is dermatopathic lymphadenopathy. The enlarged lymph nodes may have a yellow or brown cut surface and, microscopically, the paracortex is expanded by pale histiocytes with the cytological features of interdigitating reticulum cells and Langerhans’ cells; lipid droplets and melanin pigment may also be apparent.
Human immunodeficiency virus infection
Lymphadenopathy is extremely common in HIV infection and may be observed in association with systemic symptoms in the AIDS-related complex (Ch. 9) and in the persistent generalised lymphadenopathy (PGL) syndrome (defined as persistent, extra-inguinal lymphadenopathy, in two or more non-contiguous sites, of greater than 3 months’ duration and of no known aetiology other than HIV infection).
Complications
Lymphadenopathy in HIV infection may not be due solely to immune dysregulation and aberrant lymphocyte proliferation; a variety of neoplastic and infective conditions may also affect the lymph node. Lymphadenopathic Kaposi’s sarcoma and high-grade B-cell non-Hodgkin’s lymphoma (often with Burkitt-like morphology) are common. A wide variety of infectious agents may cause lymph node enlargement, of which atypical mycobacterial infection is frequently encountered (Fig. 22.5). Pneumocystis jiroveci may also be encountered in the lymph nodes of severely immunosuppressed patients.
NEOPLASTIC LYMPHADENOPATHY
Neoplastic lymph node enlargement may occur in:
Hodgkin’s lymphoma
The malignant cell of Hodgkin’s lymphoma forms only a small percentage of the cellular population within affected lymph nodes, the bulk of the tissue being made up of reactive lymphocytes, macrophages, plasma cells and eosinophils attracted into the cellular milieu by a variety of cytokines secreted by the Hodgkin’s and Reed–Sternberg (H-RS) cells. The relative paucity of the H-RS cell population has hampered efforts to define its origin. Many cell lineages have been postulated for the H-RS cell, including macrophages, follicular dendritic cells, interdigitating reticulum cells and, most recently, lymphocytes. Elegant microdissection studies have isolated single H-RS cells which have then been subjected to molecular biological analysis; this has shown that, in the vast majority of cases studied, the H-RS cells have a clonal immunoglobulin gene rearrangement, indicating that they are derived from B-lymphocytes. In addition, there is evidence of somatic hypermutation of the immunoglobulin genes which indicates that the cells are of germinal centre origin. The majority of cases of classical Hodgkin’s lymphoma have defects in the critical transcription factors required for immunoglobulin production, either OCT 2 or BOB 1 or both. Approximately 25% of patients with classical Hodgkin’s lymphoma acquire crippling mutations in their immunoglobulin genes. Both the lack of transcription factors and crippling mutations in the immunoglobulin genes prevent the production of a functional immunoglobulin molecule.
Classical Hodgkin’s lymphoma
Clinical features
Morphology
Macroscopically, affected lymph nodes are enlarged, with a smooth surface. Classical Hodgkin’s lymphoma, unlike the non-Hodgkin’s lymphomas, rarely breaches the lymph node capsule, a fact that accounts for the discrete nature of the lymphadenopathy upon palpation. The cut surface is usually homogeneously white (Fig. 22.6), although in some histological subtypes a nodular or fibrotic appearance may be present.