nodes, thymus and spleen

Chapter 22 Lymph nodes, thymus and spleen





LYMPH NODES




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 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


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.







NON-NEOPLASTIC LYMPHADENOPATHY


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:








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


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).



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).



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.





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).






NEOPLASTIC LYMPHADENOPATHY


Neoplastic lymph node enlargement may occur in:





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’:




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.






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.


Jun 16, 2017 | Posted by in GENERAL SURGERY | Comments Off on nodes, thymus and spleen

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