Lymph nodes, thymus and spleen

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Chapter 22 Lymph nodes, thymus and spleen

Common clinical problems from disease of the lymph nodes, thymus and spleen 597
Pathological basis of signs and symptoms attributable to the lymphoreticular system 597
Normal structure and function 598
Lymph node enlargement 599
Normal structure and function 613
Normal structure and function 615
Commonly confused conditions and entities relating to the lymph nodes, thymus and spleen 619




Pathological basis of signs and symptoms attributable to the lymphoreticular system

Sign or symptom Pathological basis
Enlarged lymph nodes
Neoplastic infiltration

primary (lymphoma)
secondary (metastases)
Specific infections (e.g. tuberculosis, toxoplasmosis, infectious mononucleosis) Reactive hyperplasia

Enlarged spleen

Congestion (heart failure, portal hypertension)
Storage disorder
Neoplastic infiltration (leukaemia, lymphoma)

Susceptibility to infection

Immune deficiency

acquired (lymphoma, leukaemia, AIDS, iatrogenic)

Weight loss/pyrexiaInterleukins produced by inflammatory or lymphomatous (i.e. type B symptoms) tissue acting on thermoregulatory centre in hypothalamusMuscle weakness (myasthenia gravis)Thymic hyperplasia or neoplasiaHowell–Jolly inclusions in red cellsPersistence of DNA fragments in red cells due to splenic atrophy



Lymph nodes are discrete encapsulated structures, usually ovoid and ranging in diameter from a few millimetres to several centimetres. They are situated along the course of lymphatic vessels and are more numerous where these vessels converge (e.g. roots of limbs, neck, pelvis and mediastinum).

Micro-architecture and functional anatomy

Lymph nodes are surrounded by a connective tissue capsule, with trabeculae that extend into the substance of the node and provide a framework for the contained cellular elements. Beneath the capsule is a slit-like space, the subcapsular sinus, into which the afferent lymphatics drain after penetrating the capsule. Lymph from the subcapsular sinus passes via the medullary cords to the hilum of the lymph node from which the efferent lymphatic drains.

Three distinct micro-anatomical regions can be recognised within normal lymph nodes (Ch. 9). These regions are:

the cortex, which contains nodules of B-lymphocytes either as primary follicles or as germinal centres
the paracortex or deep cortex, which is the T-cell-dependent region of the lymph node
the medulla, containing the medullary cords and sinuses which drain into the hilum.

The micro-anatomical regions of the lymph nodes are populated by a variety of specialised cells with different functional characteristics.

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.

Table 22.1 Characteristics and nomenclature (Kiel scheme) of follicle centre cells and therefore B-cell lymphomas derived therefrom

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

Fig. 22.1 Morphological changes of the germinal centre B-cell. Hypothetical follicle centre B-cell transformation. The virgin B-lymphocyte has two activation pathways. The first involves direct transformation to an immunoblast following exposure to an antigen, with subsequent differentiation to an immunoglobulin-secreting plasma cell; this pathway is independent of the germinal centre. The second pathway occurs within the germinal centre and involves the generation of a centroblast as the initial reaction to antigen exposure, with subsequent differentiation to a centrocyte.

The function of germinal centres is to generate immunoglobulin-secreting plasma cells in response to antigenic challenge. Within the lymph node, plasma cells are located principally within the medullary cords.

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.


Fig. 22.2 Lymph node germinal centre. image Normal germinal centre showing distinct zoning, the lower half containing closely packed and rapidly dividing centroblasts. image A germinal centre stained with monoclonal antibody to proliferating cells (Ki-67). Numerous dividing cells (brown nuclei) are seen in the lower, centroblast-rich, region of the germinal centre. image High-power view of phagocytic or ‘tingible body’ macrophage (arrowed) engulfing apoptotic lymphoid cells. These are concentrated in the most proliferative part of the germinal centre.


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).


Lymph enters the marginal sinus of the node and drains to the hilum through sinuses that converge in the medullary region. The sinuses are lined by macrophages which phagocytose particulate material within the lymph. Between the sinuses in the medulla lie the medullary cords, which contain numerous plasma cells and are one of the main sites of antibody secretion within the lymph node.


image Localised or generalised
image Diagnosis often requires lymph node biopsy
image May be due to inflammatory, reactive or neoplastic disorders
image Neoplastic disorders may be primary (e.g. lymphoma) or secondary (e.g. metastatic carcinoma)

Lymph node enlargement (lymphadenopathy) may be localised or widespread and is a common clinical problem that frequently requires a biopsy to establish a diagnosis. The causes of lymphadenopathy are varied and include:

infection (both local and systemic)
autoimmune disorders
neoplasms (either primary or metastatic).


Lymph nodes respond to a wide variety of inflammatory stimuli by cellular proliferation which leads to node enlargement. The cell type that proliferates is dependent upon the antigenic stimulus, which may elicit:

a predominantly B-cell response with germinal centre hyperplasia which may be associated with marginal zone hyperplasia
a predominantly T-cell response with paracortical expansion
a macrophage response which is associated with sinus hyperplasia
most commonly, a mixed response in which all the cellular elements of the lymph node are activated and proliferate.

Non-specific reactive hyperplasia

The pattern of cellular proliferation within a lymph node may give some clue to the aetiology of the lymphadenopathy (see below); however, in many instances these clues are absent and the features are termed non-specific reactive hyperplasia. On occasions the node enlargement may reach a considerable size and be difficult to distinguish clinically and macroscopically from neoplastic disorders. Microscopically, numerous enlarged germinal centres are seen; these may be present throughout the node and are not restricted to the outer cortex as in the normal state. The germinal centres are active, with a predominance of large blast cells, a high mitotic rate, and often contain numerous tingible body macrophages. There may be an expanded marginal zone which may form a thick rim around the germinal centre. The paracortex usually shows some degree of hyperplasia characterised by the presence of transformed, large lymphoid cells and vessels lined by large endothelial cells (high endothelial venules). The sinuses often show hyperplasia of the lining macrophages, termed sinus histiocytosis.

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

Some types of non-neoplastic lymphadenopathy exhibit histological features that allow the pathologist to make an exact diagnosis. These may be grouped into the following categories:

granulomatous lymphadenitis
necrotising lymphadenitis
sinus histiocytosis
paracortical hyperplasia.

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).


Fig. 22.3 Toxoplasmic lymphadenitis. There is follicular hyperplasia with epithelioid granulomas (arrowed) adjacent to germinal centres. A perifollicular proliferation of uniform B-cells, termed marginal zone B-cells, is also present.

Lymph nodes draining tumours occasionally show a granulomatous reaction in the absence of metastatic involvement, possibly a reaction to tumour antigens. It is particularly common in Hodgkin’s lymphoma. Lymph nodes may develop a granulomatous response to foreign particulate material; this most often occurs as a response to silicone compounds used in plastic surgery and joint replacement.

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).


Fig. 22.4 Cat scratch disease. Lymph node showing central abscess formation surrounded by palisaded histiocytes.

A rare form of necrotising lymphadenitis is Kikuchi’s disease, in which tender cervical or occipital lymphadenopathy develops, most commonly in young adult women. The aetiology is unknown. Systemic lupus erythematosus may cause a necrotising lymphadenitis which is histologically very similar to Kikuchi’s disease.

Sinus histiocytosis

Sinus histiocytosis with massive lymphadenopathy (SHML or Rosai–Dorfman syndrome) is a rare condition of unknown aetiology which is more common in black populations than in others. It presents typically with bulky cervical lymphadenopathy in the first and second decades of life and may persist for several years. SHML may, however, affect any age and any organ. Histologically, the lymph node sinuses are grossly distended by an infiltrate of large histiocytic cells whose morphology is quite distinctive; admixed with these cells are lymphocytes and plasma cells, which are often seen in the cytoplasm of the histiocytes. Molecular analysis of SHML has shown it to be a polyclonal disorder. The disease often follows a benign course and may regress spontaneously. Some patients with extensive nodal and extranodal disease have pursued an aggressive course and fatalities due to SHML have occurred.

Langerhans’ cell histiocytosis (histiocytosis X) may affect lymph nodes and characteristically involves the sinuses initially, where clusters of typical, pale Langerhans’ cells with folded nuclei may be seen among giant cells and eosinophils. Langerhans’ cell histiocytosis is a clonal neoplastic disease which may present as a variety of clinical syndromes with uni- or multi-focal disease.

Paracortical hyperplasia

Paracortical hyperplasia is a prominent feature in many cases of lymphadenopathy. Two entities deserve special mention: dermatopathic lymphadenopathy and infectious mononucleosis.

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.

Infectious mononucleosis is due to Epstein–Barr virus. This causes widespread lymphadenopathy and is characterised, certainly in the later stages, by paracortical hyperplasia with numerous, large, transformed T-cells. The histological picture may be mistaken for high-grade non-Hodgkin’s lymphoma or Hodgkin’s lymphoma by the unwary pathologist.

Human immunodeficiency virus infection

The human immunodeficiency virus (HIV) specifically binds to the cluster of differentiation (CD) 4 antigen, which is expressed by helper/inducer T-cells and by cells of the mononuclear phagocytic system, and to a member of the chemokine receptor family CXCR4. The destruction of cells bearing the CD4 antigen causes a severe immune dysregulation, which ultimately leads to a profound immunodeficiency state called the acquired immune deficiency syndrome (AIDS).

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).


Lymph node biopsies from patients infected with HIV show a spectrum of appearances that, although not absolutely specific, are virtually diagnostic in the appropriate clinical setting. Initially the follicles are hyperplastic and often markedly irregular in shape. Ultrastructurally, a proliferation of dendritic reticulum cells is observed, with complex branching of their processes. In between the DRC processes, retroviral particles can be identified. In some follicles there is focal destruction of the follicular dendritic cell (FDC) meshwork. This is associated with an infiltrate of small CD8+ T-lymphocytes and focal haemorrhage into the germinal centres (‘follicular lysis’). The paracortical reaction is usually disproportionately less than the degree of follicular activation and only scattered immunoblasts and transformed lymphocytes are observed. There is also a reversal of the normal CD4:CD8 ratio of T-cells, often with a preponderance of CD8+ cells. The sinuses may be filled with marginal zone B-cells.

In the later stages of HIV infection, involutional changes are apparent. There is loss of germinal centre B-cells and depletion of paracortical T-cells; sinus histiocytosis may be prominent. These involutional changes are a poor prognostic sign and portend the development of AIDS.


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.


Fig. 22.5 Mycobacterial infection of a lymph node in AIDS. image Aggregates of large histiocytes with foamy cytoplasm. image A similar area stained for acid-fast bacilli (Ziehl–Neelsen stain), demonstrating numerous mycobacteria (stained red; arrowed).


Neoplastic lymph node enlargement may occur in:

malignancies of the immune system (Hodgkin’s lymphoma and the non-Hodgkin’s lymphomas)
metastatic spread of solid tumours and involvement by leukaemia.

Hodgkin’s lymphoma

The first detailed account of the pathology of Hodgkin’s lymphoma was given by Thomas Hodgkin in 1832 in which he described the morbid anatomical appearances of lymph nodes. Earlier descriptions of a similar disease process exist but these lack sufficient detail to categorise them as a distinctive clinicopathological entity. The eponymous term Hodgkin’s disease was generously applied by Wilks in 1865 after he had discovered Hodgkin’s original paper. Hodgkin’s observations were based purely on the macroscopic appearances of the disease at postmortem and it was some years before microscopic studies were undertaken. Over the ensuing decade a gradual awareness of the histopathological features of Hodgkin’s lymphoma emerged with descriptions of the typical giant cell by Sternberg and Reed.

Many attempts were made to classify Hodgkin’s disease into clinically meaningful groups, the most successful of which was proposed by Lukes and Butler in 1966. This classification was felt to be too complicated for clinical use and was simplified at the Rye Conference. The essential concept of the Lukes and Butler classification was that nodular sclerosis was a distinctive entity and separate from other types of Hodgkin’s disease and that lymphocyte predominant, mixed cellularity and lymphocyte depleted represented a spectrum of disease of varying clinical aggressiveness which was reflected in the histopathological picture.

More recent studies have demonstrated that lymphocyte predominant nodular Hodgkin’s lymphoma is distinctive and that nodular sclerosis and mixed cellularity are closely related. This view is reflected in the World Health Organization classification, which clearly separates nodular lymphocyte predominant from other forms of Hodgkin’s lymphoma, which are collectively termed ‘classical Hodgkin’s lymphoma’:

classical Hodgkin’s lymphoma

nodular sclerosis grades 1 and 2
mixed cellularity
lymphocyte-rich classical Hodgkin’s lymphoma
lymphocyte depleted
nodular lymphocyte predominant 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.

Nodular lymphocyte predominant Hodgkin’s lymphoma differs from classical Hodgkin’s lymphoma in having intact immunoglobulin transcription factors and an absence of crippling mutations. This form of Hodgkin’s lymphoma also shows the presence of ongoing immunoglobulin gene hypermutation in an identical form to that seen in the follicle centre cell non-Hodgkin’s lymphoma and again emphasises the difference between lymphocyte predominant and classical Hodgkin’s lymphoma.

The clear demonstration of a lymphoid cell of origin for classical Hodgkin’s lymphoma as well as the nodular lymphocyte predominant type has prompted replacement of the term Hodgkin’s disease with Hodgkin’s lymphoma.

Classical Hodgkin’s lymphoma

Clinical features

Hodgkin’s lymphoma shows a peak incidence in the third and fourth decades and is relatively rare in childhood and old age.

The commonest clinical presentation is one of lymphadenopathy, most often in the upper half of the body, with involvement of cervical and/or axillary lymph nodes. The enlarged nodes are typically rubbery, discrete and mobile, and may achieve a considerable size. Radiological evidence of mediastinal involvement is present in over half of patients and on occasion may be massive, causing respiratory embarrassment. A third of patients with Hodgkin’s lymphoma have systemic symptoms (weight loss greater than 10%, unexplained pyrexia of 39°C or more, and drenching night sweats) and in a small proportion the clinical picture will be dominated by these symptoms. Classical Hodgkin’s lymphoma appears to arise in lymph nodes or the thymus, and spreads, certainly in its early stages, via the lymphatics in a contiguous and predictable fashion. Involvement of the liver and bone marrow is rarely seen in the absence of splenic involvement and thus the spleen appears to be the key to haematogenous dissemination.

Stage is an important determinant in the treatment and prognosis of patients with Hodgkin’s lymphoma; the staging system currently used is that proposed at the Ann Arbor workshop in 1971 and modified at the Cotswolds meeting in 1989.

Stage I. Involvement of a single lymph node region.
Stage II. Involvement of two or more lymph node regions on the same side of the diaphragm.
Stage III. Involvement of lymph node regions on both sides of the diaphragm (III), subdivided into III1 = upper abdominal disease (splenic, hilar, coeliac or portal disease) and III2 = lower abdominal disease (para-aortic, iliac and mesenteric disease).
Stage IV. Disseminated involvement of one or more extralymphatic organs such as liver, lung and bone marrow, with or without lymph node involvement.

The absence or presence of the systemic symptoms described above is indicated by the suffix A or B respectively; E indicates involvement of a single extranodal site contiguous with or proximal to a known nodal site; X denotes the presence of bulky disease, > one-third widening of the mediastinum at T5–6 or >10cm maximum dimension of a nodal mass. The survival of patients declines with advancing stage, bulky disease (X) and the presence of systemic (B) symptoms.

Classical Hodgkin’s lymphoma is also associated with a variety of haematological and biochemical abnormalities such as anaemia, lymphocytopenia, a raised erythrocyte sedimentation rate (ESR) and a low serum albumin. These abnormalities are also indicators of a reduced survival.


Classical Hodgkin’s lymphoma is principally a disease of lymph nodes. A lymph node biopsy is usually done to establish the diagnosis.

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.

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