Lymphoid and haematopoietic systems

Functions of the lymphoreticular system

The lymphoreticular system is composed of various organs and tissues which facilitate the interaction of lymphocytes with cells of monocyte–macrophage lineage in the generation of immune responses. The main organs and tissues of the system are the thymus ( E-Fig. 16.1 ), spleen ( E-Fig. 16.2 ), lymph nodes, bone marrow and mucosa- associated lymphoid tissue (MALT), such as tonsils ( E-Fig. 16.3 ) and Peyer’s patches of the gut ( E-Fig. 16.4 ).

Lymphocytes are produced in the bone marrow. Their number is selectively expanded, mainly in lymph nodes ( E-Fig. 16.5 ), in response to specific immunological requirements. Many lymphoid cells circulate through peripheral tissues via blood and lymphatic vessels in a constant search for antigens.

The monocyte–macrophage system includes tissue macrophages (histiocytes), which are found in virtually every organ. These become activated following tissue damage and, together with monocytes recruited from the blood, act as phagocytic cells in the process of organisation (see Ch. 2 ). These cells also process antigen for presentation to T lymphocytes. Some tissues include a population of specialised dendritic antigen-presenting cells that have a role in initiating specific immune responses.

We will consider disorders affecting some of the main organs of the haematolymphoid system as follows:

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  Lymph nodes

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    reactive processes

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    metastatic tumours

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    primary tumours (lymphoma).

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  Bone marrow

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    abnormalities of haematopoiesis

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    metastatic tumours

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    myeloma

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    leukaemia and lymphoma

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    myeloproliferative and myelodysplastic processes.

Reactive disorders of lymph nodes

The lymphoreticular system is remarkably labile and quickly responds to the presence of infective agents or foreign material in the activation of an immune response. There are two main patterns of immune response:

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  The cell-mediated response : This involves the activity of T lymphocytes that are either directly or indirectly cytotoxic.

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  The humoral response : This involves the activation of B lymphocytes, which differentiate into antibody-secreting plasma cells; interaction of antibody with antigen leads to destruction or inactivation of the antigen.

Lymphadenopathy (lymph node enlargement) is a common consequence of infection and other immune reactions. Various different histological appearances can occur. These are determined by the nature of the immune stimulus and the patient’s capacity to mount an immune response. In broad terms, three main patterns of non-specific lymphadenopathy are recognised which reflect reaction and expansion of different constituent areas of the lymph node ( Fig. 16.1 ):

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  follicular hyperplasia

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  paracortical hyperplasia

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  sinus hyperplasia/sinus histiocytosis.

Some infections and other immune stimuli give rise to more specific patterns of lymphadenopathy which can allow the pathologist to suggest a particular aetiology. Examples include the finding of multiple minute granulomas in cases of toxoplasmosis, granulomatous lymphadenitis with caseous necrosis in tuberculosis (see Ch. 5 ) and follicular lysis in HIV infection (see Ch. 5 ).

Malignant disorders of the lymphoid system

This is less common than reactive lymphadenopathy, but is also a frequent finding in clinical practice. Although primary malignant tumours of the lymphoid system are the main focus of this section, it is important to recognise that metastatic spread of other tumours such as carcinoma and malignant melanoma ( E-Fig. 16.6 ) to lymph nodes is a regular occurrence (see Fig. 7.13 and Fig. 16.2 ), and this possibility must therefore always be considered before suggesting a diagnosis of lymphoma.

Lymphoma is a primary tumour of lymphoid tissue. This group of disorders is divided into two broad categories on the basis of the cell types present:

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  Non-Hodgkin lymphoma (NHL) may be derived from B or T lymphocytes.

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  Hodgkin lymphoma (HL), previously known as Hodgkin’s disease, is characterised by the presence of Reed–Sternberg cells.

Lymphoma usually presents with involvement of a group of lymph nodes and may then spread to involve multiple nodal groups, as well as other haematolymphoid organs such as bone marrow and spleen. NHL may arise in other organs or tissues such as skin, gut, thyroid, brain, salivary gland, lung and testis. Classification of lymphoma is complex and will be considered in the next section.

Other constituent cells of the lymph node may rarely proliferate and so give rise to lymphadenopathy. One example is a group of disorders known as Langerhans’ cell histiocytosis . This condition has previously been known as histiocytosis X and by a range of eponymous designations, reflecting different patterns and severities of disease ( Letterer–Siwe , Hand–Schüller–Christian disease , etc.). It is characterised by proliferation of histiocytic cells, which resemble the Langerhans’ antigen-presenting cells found in normal skin and lymph nodes. There is a spectrum of severity, ranging from benign and localised to disseminated and rapidly fatal disease, which can involve skin, viscera, bone marrow and lymph nodes.

Lymphoma classification

Division of lymphomas into non-Hodgkin and Hodgkin types reflects important differences in both clinical behaviour and tumour morphology.

Non-Hodgkin lymphomas (NHLs ) form a large and diverse group of diseases, all of which are malignant, despite the suffix -oma. The main features common to this group are listed below:

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  Presentation is usually with painless lymphadenopathy.

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  Disease may appear to be localised to one nodal group or may be widely disseminated, with generalised lymphadenopathy and involvement of other organs.

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  Biopsy is usually performed to establish the diagnosis and to allow classification.

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  Definitive classification involves assessment of cell morphology, immunophenotype and molecular/ cytogenetic features.

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  A number of forms of NHL show characteristic chromosomal abnormalities that are useful in diagnosis and, in some instances, in assessing prognosis.

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  Most tumours are derived from a clonal proliferation of B or T lymphocytes and may be broadly divided into low- and high-grade types.

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  B-cell lymphomas are considerably more common than T-cell types.

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  B-cell lymphomas may arise at extranodal sites, most commonly within mucosa-associated lymphoid tissue (MALT), and these behave differently from nodal lymphomas.

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  T-cell lymphomas most frequently occur in skin and may present as a disease termed mycosis fungoides.

Hodgkin lymphoma (HL) is less common ( Fig. 16.13 )

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  Whilst most cases of NHL are widespread at the time of diagnosis, HL may be localised to a single nodal group.

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  Spread is predictable, usually by involvement of contiguous nodal groups and with dissemination to liver, spleen and bone marrow only late in disease.

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  The neoplastic cells (Reed–Sternberg cells and variants) often form only a small proportion of the mass, with a prominent reactive haematolymphoid cell population forming the bulk.

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  Extranodal involvement is uncommon.

Various systems have been devised for the classification of haematolymphoid tumours. Classification of tumours is necessary to allow recognition of those that have similar features and facilitates improved prediction of behaviour, prognosis and response to treatment. Most earlier systems were based primarily upon the morphological appearances of the tumour cells, dividing lymphomas on the basis of architecture into diffuse (sheets of cells with no pattern of organisation) versus follicula r (arranged in nodules resembling the follicles of a normal node), on the basis of cell size into small cell and large cell types (broadly reflecting low-grade or high-grade behaviour), or on the basis of similarities to normal constituent cells within the lymph node (e.g. centrocytes, centroblasts, immunoblasts, etc). Although these classification systems were useful in allowing certain subtypes of lymphoma to be described and identified, it is now recognised that morphology alone is imperfect and is insufficient to allow reliable separation of some entities that appear histologically similar but behave differently.

The development of immunohistochemical staining methods and of newer molecular techniques has revolutionised the practice of haematolymphoid pathology. The most recent internationally recognised system of classification is that of the World Health Organization (WHO) . This system uses a combination of clinical, morphological, immunohistochemical and molecular techniques to recognise sub-groups of lymphoma with shared characteristics. The WHO classification includes a very large number of entities, but only those that are common or that illustrate an important pathophysiological concept will be considered here ( Fig. 16.3 ).

FLOAT NOT FOUND

An approach to lymph node examination in clinical practice

In clinical practice, the diagnostic pathologist first considers the architecture of the involved lymph node and notes the cytological features of the constituent cells, including cell size, nuclear shape, the presence, type and position of nucleoli and the amount and distribution of cytoplasm. This initial assessment guides the selection of appropriate immunohistochemical stains which can identify whether the tumour is of B or T cell lineage, as well as other markers which characterise specific subtypes of lymphoma (see Fig. 16.10 ).

This examination is often sufficient to achieve a diagnosis but may be supplemented, particularly in difficult cases, by molecular investigations . Molecular studies can confirm clonality of the cell population where there is uncertainty about whether a lymphoid cell population is reactive or neoplastic (by showing that all tumour cells have the same immunoglobulin or T cell receptor gene rearrangement) or can be used to look for non-random chromosomal translocations that characterise a particular tumour type, e.g. a t(8;14) translocation is typically present in cases of Burkitt lymphoma.

All of these findings should then be correlated with the clinical and radiological information so that an appropriate plan can be formulated for optimal patient management. From the pathologist’s point of view, this may involve further staging of the tumour by sampling of tissue from other sites, e.g. bone marrow biopsy, or by the assessment of subsequent biopsies for residual disease following treatment. Some newer therapies use specific molecular targeting systems and in some instances, pathological examination to look for immunopositivity within the tumour is needed to predict whether a certain drug will be effective, e.g. rituximab targets the CD20 antigen of B cell tumours and so will lack efficacy in CD20 negative tumours. In addition to their diagnostic value, some markers also provide important prognostic information. For example, high grade B cell NHL may be divided into distinct prognostic and therapeutic groups using a combination of immunohistochemical and molecular methods (see clinical box ‘WHO classification of lymphoid neoplasms’).

Who Classification of Lymphoid Neoplasms

The most recent revision of this classification emphasises the importance of combining clinical, histological, immunohistochemical and genetic features to allow reliable recognition and diagnosis of disease. This is essential so that all pathologists use the same, reproducible criteria to diagnose disease and therefore we know that we can make meaningful observations regarding how different groups of tumours behave and respond to treatment. Advances in molecular diagnostic methods have been used to refine and subclassify some tumour groups, aiming to give better prognostic information and guide treatment. An example of this is seen in the revised classification of high grade B cell non-Hodgkin lymphomas, where rearrangements of the MYC, BLC2 and BLC6 genes are now used diagnostically to define aggressive ‘double hit’ and ‘triple hit’ subtypes of the disease.

B cell non-Hodgkin lymphoma

T-cell non-Hodgkin lymphoma

Hodgkin lymphoma

Bone marrow disease

The bone marrow spaces between the trabeculae of spongy bone are occupied by adipose tissue with intervening collections of haematopoietic cells which are responsible for the production of red blood cells, white blood cells and platelets ( E-Fig. 16.8 ). These cell lines are derived from a reservoir of haematopoietic stem cells , which differentiate into the various specialised cell lines in response to specific growth factors. The bone marrow is able to respond rapidly to increased demands for the various blood cells by increased proliferative activity of the precursor and stem cells.

The main diseases involving the bone marrow are:

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  abnormalities of haematopoiesis

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  metastatic tumours

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  myeloma

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  leukaemia and lymphoma

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  myeloproliferative and myelodysplastic processes.

Multiple myeloma

This group of disorders falls within the WHO category of mature B-cell neoplasms but is considered here because its most frequent presentation is as a disseminated disease, characterised by widespread bone marrow involvement. Myeloma is a neoplastic proliferation of terminally differentiated B cells that have developed the features of plasma cells and so can produce large amounts of immunoglobulin. The features of myeloma are diverse and are a product of various interrelated processes, including displacement of normal haematopoietic elements by the tumour (leading to anaemia, thrombocytopenia and immune dysfunction), bone destruction ( E-Fig. 16.9 ) (causing pain, lytic lesions on X-ray and increased risk of fracture), renal disease and hypercalcaemia, with its associated metabolic consequences. In some patients, the excess immunoglobulin molecules produced may be deposited in the tissues in the form of amyloid , an abnormal fibrillar protein with a ß-pleated sheet configuration (see Ch. 15 and E-Fig. 16.10 ). These insoluble deposits may cause end-organ damage, particularly in the kidney.

Leukaemias

Leukaemias are characterised by neoplastic proliferation of white cells within the bone marrow, which then circulate within the peripheral blood. General characteristics of leukaemias include:

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  neoplastic proliferation of marrow derived cells, forming one or more neoplastic cell lines

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  circulation of the neoplastic cells in the peripheral blood

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  suppression of normal haematopoietic activity by the expanding leukaemic cell population.

Because the neoplastic leukaemic cells circulate in the blood, the cells are usually deposited in other tissues and organs, particularly lymph nodes, liver and spleen. Leukaemias are classified according to the cell of origin, but a useful general division is into two main types: chronic leukaemias and acute leukaemias.

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  Chronic leukaemias are characterised by neoplastic proliferation of relatively mature white cells. Typically, the clinical course is indolent, with a long natural history. Although the neoplastic cells predominate in the marrow, other haematopoietic cells can survive alongside and adequate numbers of red cells and platelets are produced. Chronic leukaemias are mainly seen in adults over the age of 40 years, but some may eventually transform into a more aggressive acute leukaemia.

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  Acute leukaemias are characterised by neoplastic proliferation of very immature white cells ( blast cells ). The course of the disease is very rapid, with destruction of all other haematopoietic cell lines in the marrow. Without treatment, acute leukaemias are rapidly fatal.

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  Chronic lymphocytic leukaemia (CLL) is considered in the previous section owing to its overlap with small lymphocytic lymphoma ( Fig. 16.5 ), but its appearance in the bone marrow is illustrated here ( Fig. 16.16 ).

  

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  Chronic myeloid leukaemia (CML) is a neoplastic proliferation of the more mature precursors of neutrophils (for example myelocytes and metamyelocytes) and occurs most commonly in adults.

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  Acute lymphoblastic leukaemia (ALL) is a tumour of immature lymphocyte precursors (lymphoblasts), and occurs most commonly in children (see also clinical box ‘Clinical features of some T-cell non-Hodgkin lymphomas’).

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  Acute myeloid leukaemia (AML) is a tumour of immature precursor cells in the myeloid series (mainly myeloblasts) and is most common in adults ( Fig. 16.17 ). It is the most common of a group of acute leukaemias derived from various myeloid precursors, collectively called acute non- lymphoblastic leukaemias.

  

Some lymphomas that originate in lymph nodes may also eventually spread to involve bone marrow and there may be enough circulating lymphoma cells in the blood to be detected in a blood film, highlighting again that there are areas of overlap between leukaemia and lymphoma.