Introduction to the lymphoproliferative disorders
- DOI:
- 10.1093/med/9780199204854.003.220402_update_001
Essentials
Lymphoproliferative disorders occur when the normal mechanisms of control of proliferation of lymphocytes break down, resulting in autonomous, uncontrolled proliferation of lymphoid cells and typically leading to lymphocytosis and/or lymphadenopathy, and sometimes to involvement of extranodal sites, e.g. bone marrow.
Causes of lymphoproliferative disorder
These include (1) malignant—clonal in nature, resulting from the uncontrolled proliferation of a single transformed cell, e.g. lymphoma; (2) nonmalignant—polyclonal lymphoproliferative disorders may result from conditions including (a) infections—lymphocytosis is commonly caused by viral infections, e.g. Epsitein–Barr virus (EBV); lymphadenopathy is a common feature of a very wide variety of infections, (b) reactive—conditions such as systemic lupous erythematosus (SLE) and sarcoidosis frequently cause lymphadenopathy.
Clinical approach
Distinguishing among the lymphoproliferative disorders clinically and pathologically is not always easy.
Clinical assessment—when eliciting the history of a patient with suspected lymphoproliferation, particular note should be taken of their general health, the type and duration of any constitutional symptoms, and any episodes of recent infection/exposure to drugs/travel. Thorough examination of all lymph node sites is required, as is careful examination of the oropharynx, tonsils, skin, spleen, and liver.
Investigation—whenever a lymphoproliferative disorder is suspected, the key initial investigation is the full blood count and examination of the blood film, sometimes augmented by immunocytochemistry and flow cytometry. Depending on clinical context, other investigations may include (1) serological studies for viral pathogens; (2) serological studies for rheumatological disease; (3) imaging for mediastinal and intra-abdominal lymphadenopathy; (4) bone marrow examination; and—if no diagnosis is apparent—(5) lymph node biopsy. However, there are many pitfalls in morphological interpretation of lymph node histology, which is a matter for the specialist, who will often draw on supplementary information from flow cytometry, cytogenetics, and immunoglobulin/TCR gene rearrangement studies to demonstrate the clonal nature of malignant disease and provide data with prognostic and therapeutic significance, or to identify the presence of specific viruses such as EBV and human herpes virus 8.
The human immune system has the capacity to identify and respond specifically to invading pathogens. It can also ‘remember’ the exposure, such that subsequent exposure to the same pathogen results in a more rapid and potent immune response. Lymphocytes play the key role in the adaptive immune response, mediating both specificity and memory.
Lymphocytes
The lymphocytes can be divided into two morphologically indistinguishable types, which play different and complementary roles in the immune system. Both are derived from lymphohaemopoietic stem cells that reside in fetal liver and in adult bone marrow. B cells develop in the marrow (the human equivalent of the avian bursa of Fabricius) and their principal role is to generate immunoglobulin (antibodies). B cells represent about 20% of the lymphocyte population in peripheral blood. T cells, which mature within the thymus, orchestrate the immune response: they are capable of cell-mediated cytotoxicity, they generate inflammatory cytokines, and they provide help for B-cell function. T cells account for approximately 80% of the lymphocytes in the peripheral circulation. A much smaller population of lymphoid-appearing cells express neither B-cell nor T-cell markers. These null cells, also known as natural killer (NK) cells and large granular lymphocytes (LGLs), are capable of cell-mediated cytotoxicity, especially against tumour cells and virally infected cells. NK cells are a component of the innate immune response, as they do not demonstrate immunological memory.
Lymph nodes
In their role in infection surveillance, lymphocytes circulate through the body via a network of lymphatic and blood vessels. At strategic locations, lymphoid cells are organized to allow direct interaction among lymphocytes and other specialized cells of the immune system.
These interactions permit the production of specific, functional effector cells. The network includes approximately 500 to 600 discrete lymph nodes, lymphoid populations in the oropharynx (Waldeyer’s ring), bronchial tree, and gut, as well as in the thymus, the bone marrow, and the spleen.
Within lymph nodes, lymphocytes are arranged in a central medulla surrounded by an outer cortex contained within a connective tissue capsule (Fig. 22.4.2.1). Afferent lymphatics penetrate the cortex and lymphocyte-rich fluid filters toward the medullary sinusoids and the efferent lymphatics at the hilum of the node. The vascular supply to the lymph node includes specialized postcapillary venules that allow the passage of peripheral blood lymphocytes into the node. Lymphocytes are ultimately returned to the bloodstream via the thoracic duct.
(From Arno J (1980). Atlas of lymph node pathology, with permission.)
Roughly spherical follicles are found in the lymph node cortex and predominantly comprise B cells. Primary follicles contain clusters of naive, unstimulated B cells. Secondary follicles, with pale ‘germinal centres’ surrounded by a darker ‘mantle’ zone, represent foci of B cells proliferating and differentiating in the presence of antigen-bearing dendritic cells and activated ‘helper’ T cells (Th cells). The interfollicular and paracortical zones of the lymph node are densely populated by T cells. Macrophages, follicular dendritic cells, and interdigitating reticulum cells all process and present antigen to the lymphocytes within the node.
The design of the lymph node facilitates the process whereby the subpopulation of lymphocytes capable of responding to a specific antigen is expanded. Antigens are delivered to the subcapsular sinus of the node via afferent lymphatics, and are taken up by reticulum cells and presented on their surface in the context of the major histocompatibility complex (MHC) proteins. Specific T-lymphocyte responses require that peptide antigens, which are derived from ‘foreign’ proteins, appear on the surface of antigen-presenting cells in close association with a ‘self’ MHC molecule. B cells, on the other hand, are capable of responding to some antigens in solution. Optimal B-cell responses require the ‘help’ of T cells both via direct cell–cell contact and in response to cytokines secreted by T cells. Only those T cells and B cells that have been genetically preprogrammed to interact with a specific antigen will proliferate and differentiate in response to it.
Antigen receptors
Both B and T cells express transmembrane receptors on their cell surfaces. These proteins bind antigen and define the antigenic specificity of the cell. In the case of B cells, the immunoglobulin molecule serves as the B-cell receptor (Fig. 22.4.2.2). Each immunoglobulin molecule is a bivalent tetramer comprising a pair of heavy chains bound to two light chains (of either κ or λ type). Genetic recombination of approximately 400 immunoglobulin gene segments (located on chromosomes 2, 14, and 22), generates about 1015 distinct antibody specificities. The expression of recombination activating genes (RAG1 and RAG2) early in B-cell development mediates the random rearrangement of variable (V), diversity (D), and joining (J) gene segments. Terminal deoxyribonucleotidyl transferase (TdT) contributes to the diversity of immunoglobulin molecules by inserting additional nucleotides during the splicing of gene segments. This process gives rise to a vast repertoire of antibody molecules, each with a unique antigen-binding cleft. All of the progeny cells of a B cell that has rearranged its immunoglobulin genes have the same antigenic specificity and are referred to as a clone. Most protein antigens are complex and contain many different epitopes (structures capable of binding an antigen receptor). Therefore, most pathogens stimulate many lymphocyte clones to proliferate: that is to say, they result in polyclonal responses. As B-cell clones mature, the isotype of the antibodies they produce ‘switches’ from IgM/IgD to IgG, IgA, or IgE.
In an analogous fashion, T-cell precursors rearrange the T-cell receptor (TCR) genes. The TCR consists of a heterodimer of α and β chains, or γ and δ chains in a minority of T cells. The α and β genes are encoded on chromosomes 14 and 7, respectively, while the γ and δ chains are on chromosomes 7 and 14, respectively. T-cell precursors randomly assemble variable, joining, and diversity gene segments to generate a vastly diverse array of antigen-specific T-cell clones. When the T cell encounters antigen to which it can productively bind, the cell undergoes clonal expansion, and generates both activated effector cells and long-lived memory cells.
Lymphocyte ontogeny
As lymphocytes develop and mature from multipotent progenitors to terminally differentiated effector cells, they express a sequential pattern of surface proteins. Some of these cell-surface molecules subserve known, critical functions in the cells that bear them. Others are of less clear biological significance, but are useful markers of cell type and status of differentiation and activation. Malignant lymphomas and lymphoid leukaemias are frequently classified and understood on the basis of their expression of cell-surface markers (Fig. 22.4.2.3) In some cases, the stage of differentiation at which malignant transformation occurred can be inferred from the pattern of the surface antigens expressed by the malignant cells.
Lymphocytes develop from bone marrow-derived haemopoietic stem cells. Although the surface characteristics of these elusive cells are not well understood, it is likely that human stem cells express the cell-surface glycoprotein CD34. The first recognizable sign of commitment to the B-lymphoid lineage is the expression of TdT and the rearrangement of the immunoglobulin heavy chain. As differentiation progresses, B-cell progenitors turn on the expression of class II MHC molecules (HLA DR) as well as CD19 and then CD10 (the latter is also known as the ‘common acute lymphoblastic leukaemia antigen’, CALLA). The immunoglobulin light chain is rearranged and the cells (now termed pre-B cells) express the µ heavy chain within their cytoplasm. As the cells progress to the early B-cell stage, CD34, TdT, and CD10 expression are extinguished, and CD19, CD20, and CD21, as well as IgM, are expressed on the cells’ surface. Mature B cells express surface IgM and/or IgD, in addition to CD19 and CD20. Plasma cells, the end result of B-cell differentiation, produce cytoplasmic as well as secreted immunoglobulin, but do not express surface immunoglobulin. They lack CD19 and CD20 expression.
Similarly, as T cells mature they progress through an orderly cascade of genetic and cell-surface events. CD34-positive progenitors that are destined for a T-lymphoid fate migrate from the marrow to the thymus and express TdT as well as CD7. Next, the cells express the CD2 molecule, which, among other things, mediates the binding of T cells to sheep erythrocytes. The T-cell receptor genes are then rearranged and subsequently expressed on the surface of the thymocyte in association with the CD3 molecule. Distinct populations of mature thymocytes emerge: those that express CD4 and function as cytokine-secreting ‘helper’ cells and those that express CD8 and function as cytotoxic ‘killer’ cells. Rare ‘double-positives’ (CD4+CD8+) and ‘double-negatives’ (CD4–CD8–) also exist. The CD4 molecule mediates the binding of T cells to MHC class II molecules, whereas CD8 binds MHC class I proteins.
The third descendant of the lymphoid stem cell, the NK cell, is characterized by its expression of CD7, CD2, CD16, and CD56, in addition to other surface proteins. NK cells are distinguished from T cells by the fact they do not express CD3 (and therefore the T-cell receptor).
Lymphoproliferative disorders
A variety of conditions spanning the spectrum of benign, reactive processes to frank malignant transformation results in the expansion of lymphocyte populations. The lymphoproliferative disorders are a loosely defined group of malignant and nonmalignant entities characterized by the autonomous, poorly controlled proliferation of lymphoid cells. Lymphoproliferation is typically manifested by lymphocytosis and/or lymphadenopathy. In addition, lymphoproliferation may involve extranodal sites, including bone marrow, liver, skin and soft tissues. Distinguishing among the lymphoproliferative disorders clinically and pathologically is not always easy. Malignant tumours are clonal in nature; they result from the uncontrolled proliferation of a single transformed cell. In contrast, nonmalignant lymphoproliferation contains polyclonal lymphocyte populations. Lymphoproliferative disorders may result from chronic antigenic stimulation, certain viral infections, or from an imbalance among interacting lymphocyte populations, as may occur in congenital or acquired immunodeficiency syndromes. In addition, lymphocytes are prone to the acquisition of chromosomal translocations, particularly involving the immunoglobulin and T-cell receptor genes, and such changes may contribute to malignant transformation (see Table 22.4.2.1).
Table 22.4.2.1 Causes of lymphadenopathy
Clinical features |
Histological characteristics |
|
|---|---|---|
Infectious |
||
Bacterial |
Regional, often tender |
Suppurative |
Mycobacterial (tuberculosis, leprosy) |
Regional or generalized |
Suppurative granulomas |
Viral (EBV, CMV, HIV) |
Often generalized |
Follicular hyperplasia |
Fungal (Histoplasma, Coccidioides spp.) |
Often hilar |
Suppurative granulomas |
Parasitic (Toxoplasma, Chlamydia spp.) |
Usually regional(cervical, inguinal) |
Suppurative granulomas |
Reactive |
||
Rheumatological conditions (SLE, RA) |
Often generalized |
Follicular hyperplasia |
Sarcoidosis |
Especially hilar |
Epithelioid granulomas |
Drugs (e.g. phenytoin) |
Generalized |
Paracortical expansion |
Castleman’s disease |
Localized/multicentric |
Follicular hyperplasia (hyaline vascular or plasma cell) |
Rosai–Dorfman disease |
Usually cervical |
Sinus hyperplasia |
Neoplastic |
||
Leukaemia/lymphoma |
Often generalized, ‘rubbery’ |
Effacement of nodal architecture |
Metastatic (carcinoma, melanoma) |
Regional, rock hard |
Subcapsular expansion, effacement of nodal architecture |
Other |
||
Storage diseases (e.g. Gaucher’s) |
Generalized |
Paracortical or sinusoidal lipogranulomas |
EBV, Epstein–Barr virus; CMV, cytomegalovirus; HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis.
Lymphocytosis
Normal peripheral blood usually contains approximately 1000 to 5000 lymphocytes/µl, accounting for approximately 40% of the circulating leucocytes. Infants and young children typically have higher absolute lymphocyte counts. Increased numbers of circulating lymphocytes (lymphocytosis) and/or the appearance of abnormal (or atypical) lymphocytes in the blood are usually caused by either viral infection or lymphoid malignancy. The appearance of the circulating lymphocytes on a peripheral blood smear may provide clues to the pathogenesis of the elevated lymphocyte count. For example, infectious mononucleosis results from primary infection with the Epstein–Barr virus (EBV), and gives rise to large numbers of ‘atypical’ lymphocytes with abundant cytoplasm in the peripheral blood. Chronic lymphocytic leukaemia (CLL) leads to an increase in circulating normal-appearing ‘mature’ lymphocytes. CLL is also frequently associated with the appearance of ‘smudge’ cells in the peripheral smear, a preparation artefact caused by the destruction of the fragile CLL cells. Follicular lymphoma may be associated with the circulation of characteristic cells with a cleaved nucleus.
Lymphadenopathy
Enlargement of one or more lymph nodes (lymphadenopathy) is an extremely common clinical finding. With the exception of inguinal nodes, normal lymph nodes are non-palpable. Nodes that are palpable and/or exceed approximately 1 × 1 cm on imaging studies are considered pathological. Lymph node enlargement often results from the body’s normal and adaptive response to an immunological challenge; however, it may signify a pathological inflammatory or malignant disease. The causes of lymphadenopathy fall into three main categories: infectious, inflammatory (reactive), and neoplastic (see Table 22.4.2.1) Younger patients, especially children, are more likely to develop adenopathy as a result of infection, while the likelihood of haematological or metastatic malignancy increases with age.
Approach to the patient with suspected lymphoproliferation
The evaluation of the patient with a suspected lymphoproliferative disorder should take into account the age and general health of the patient, the duration of the adenopathy, the coexistence of fever, weight loss, night sweats, pruritus, and cough, as well as any recent infections, medications, travel, and animal exposures. The physical examination should make note of the location (generalized vs regional), the texture (hard vs rubbery), and the mobility (fixed vs mobile) of the lymph nodes, and the presence or absence of associated signs of inflammation (warmth, tenderness, erythema). The skin and oropharynx should be examined and the size of the liver and spleen should be assessed. Additional screening studies may include a complete blood count, measurement of the erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP). The level of lactate dehydrogenase (LDH) may be elevated. Serological studies for certain viral pathogens and for rheumatological diseases can be helpful. Radiographs of the chest should be obtained if mediastinal adenopathy is suspected. Ultrasound of enlarged nodes may demonstrate central suppuration, which is characteristic of acute lymphadenitis. Axial imaging, e.g. CT, is required to diagnose intra-abdominal adenopathy.
Biopsy
When a lymphoproliferative disorder is suspected, pathologic analysis of involved tissue is necessary to determine the specific diagnosis. In some cases, analysis of peripheral blood and/or bone marrow may yield a diagnosis. However, lymph node biopsy is often needed. Before proceeding to biopsy, a trial of observation with or without empirical antibiotics (usually an antistaphylococcal agent) may be appropriate in some patients with lymphadenopathy. However, empirical treatment with steroids should be avoided because it may undermine the diagnosis and proper therapy of lymphoid malignancy. If the lymphadenopathy does not improve within 2 weeks, then a lymph node biopsy should be strongly considered. The largest accessible node is most often selected for biopsy. A fine-needle aspiration of lymph nodes is adequate for diagnosis in a restricted set of clinical circumstances: for example, diagnosis of recurrent disease or metastatic carcinoma or melanoma. Culture of a lymph node aspirate may yield a microbiological diagnosis in infective lymphadenitis. Most pathologists prefer an excisional biopsy, when possible, because nodal architecture is preserved. A portion of the sample should be reserved fresh (i.e. not fixed in formalin) for flow cytometry and cytogenetic studies, if indicated.
Histological examination of lymph nodes is the mainstay of diagnostic studies, however nondiagnostic or nonspecific inflammatory findings are frequently encountered. Reactive lymph nodes demonstrate characteristic, but by no means specific, histological patterns that involve the three functional domains of the lymph node: the follicles, the paracortex, and the medullary sinuses.
An increase in the size and/or number of lymphoid follicles (which contain proliferating B cells,) is termed ‘follicular hyperplasia’. The specific cause is rarely identified. This pattern of lymph node reactivity is characteristic of rheumatological conditions and of HIV infection and Castleman’s disease. Castleman’s disease is a rare and poorly understood non-neoplastic cause of lymphadenopathy that occurs in localized and multicentric forms. The multicentric form is a systemic illness without defined therapy that is associated with infection with human herpesvirus-8 (HHV-8, also known as Kaposi’s sarcoma herpesvirus).
Paracortical expansion accompanies T-cell proliferation and is characteristic of certain viral causes of lymphadenopathy, such as EBV infection. Paracortical expansion with granuloma formation is typical of mycobacterial infections and sarcoidosis. In Kikuchi’s disease and Kawasaki’s disease (mucocutaneous lymph node syndrome), paracortical necrosis is seen in involved lymph nodes.
Sinus hyperplasia is caused by an increased number of histiocytes in the medullary sinuses. This pattern of lymph node reactivity is seen in the histiocytic syndromes and in storage diseases. A rare condition known as sinus histiocytosis with massive lymphadenopathy or Rosai–Dorfman disease is characterized by an extreme polyclonal proliferation of macrophages. This entity often involves the cervical lymph nodes, but may occur in virtually any nodal or extranodal site and is usually, but not always, self-limited.
Involvement by a malignant lymphoma leads to effacement of the lymph node structure to a greater or lesser degree. Histology correlates with clinical behaviour and will be described in subsequent sections focused on the classification of lymphoma. Histology alone may be inadequate to distinguish the malignant from the non-malignant lymphoproliferative disorders. Supplemental information from flow cytometry, cytogenetics, and immunoglobulin/TCR gene rearrangement studies demonstrate the clonal nature of malignant disease and provide data with prognostic and therapeutic significance.
Immunohistochemistry and flow cytometry
Immunohistochemistry is used to characterize the pattern of surface marker expression in fixed or frozen tissue samples. Flow cytometry is performed on cells in suspension, such as peripheral blood or bone marrow, or on cell suspensions prepared from a lymph node or other solid tumour. For flow cytometry, solid specimens should not be fixed or frozen but kept refrigerated until processing. Both techniques detect the binding of monoclonal antibodies of known specificity to the clinical sample. Using a panel of antibodies, these studies demonstrate the types of cells present in the sample. Nonhaemopoietic metastatic tumours can be identified. The lineage of lymphoid malignancies can be revealed, e.g. B cell vs T cell vs NK cell. In the case of B-cell lymphoproliferation, the relative expression of κ and λ light chains can be measured. As described above, B cells express either the κ or the λ light chain, but not both. Predominant expression of either the κ or λ light chain by a population of B cells, a phenomenon known as light-chain restriction, suggests a clonal process. Using flow cytometry, lymphoid neoplasms can be placed within the hierarchy of normal lymphocyte ontogeny, and clinical behaviour, such as response to cytotoxic therapy, can often be predicted. These studies may be used to demonstrate the presence of a surface antigen to which monoclonal antibody-based therapy has been developed (e.g. CD20 and rituxumab). Sometimes, malignant cells demonstrate lineage infidelity, with expression of a pattern of surface markers that does not correspond to a normal cellular counterpart. This may fortuitously provide an immunophenotypical fingerprint to detect small amounts of disease, early relapse, or minimal residual disease after therapy.
Genetic studies
The high proliferative rate of lymphocytes and the genetic events that occur within them, set the stage for the development of chromosomal translocations that are aetiologically linked to malignant transformation. Increasingly, haemopoietic cancers are being defined genetically by the presence of specific, nonrandom chromosomal translocations. The detection and study of these translocations has increased diagnostic precision, has provided insights into the molecular mechanisms of oncogenesis, and has revealed molecular targets for rational therapeutic design. Chromosomal translocations can be demonstrated using classical cytogenetic techniques. Additionally, specific gene rearrangements may be detected using the polymerase chain reaction (PCR) and/or fluorescence in situ hybridization (FISH). As experience with these specialized studies in lymphoproliferative disorders has accumulated, certain genetic abnormalities have become highly associated with specific clinical entities. For example, rearrangement of the c-MYC oncogene on chromosome 8 is detected in the majority of patients with Burkitt’s lymphoma and its presence may be used to support this diagnosis. Other examples are discussed in detail in subsequent chapters in this text. In some circumstances, these techniques are applied to the detection of minimal residual disease during and after therapy. In addition, molecular methods may be used to identify the presence of specific viral sequences, such as those encoded by EBV and HHV-8.
As described above, the hallmark of lymphocyte differentiation is the somatic rearrangement of the antigen-receptor genes, immunoglobulin in the case of B cells and the TCR in the case of T cells. Each lymphocyte clone has a unique arrangement of the components of the antigen-receptor genes, while cells of nonlymphocyte lineage preserve the germ-line structure of these genes. Lymphoproliferative malignancies are composed of clonal proliferations arising from a single cell with a rearranged antigen-receptor locus. The pattern of gene rearrangement helps to characterize the lineage and stage of differentiation of the tumour. For example, pre-B-cell acute lymphoblastic leukaemia cells usually contain rearranged heavy-chain genes with germ-line light-chain genes, whereas B-CLL cells usually have a rearrangement of both heavy- and light-chain genes and express surface immunoglobulin. Furthermore, since clonal populations of lymphocytes all contain the same antigen–receptor rearrangement, these cells possess a ‘molecular signature’ that is unique to the malignant clone.
Consequently, antigen-receptor rearrangements have become the target of DNA diagnostic techniques for diagnosing and following lymphoproliferative malignancies. Antigen–receptor rearrangements can be detected by several methods including Southern blot and PCR-based techniques. The genetic detection of clonal B-cell populations was first achieved using Southern blotting. While Southern blotting is still the ‘gold standard’ for determining B-lymphoid clonality of confusing lymphoproliferations, PCR-based techniques have largely supplanted it for the detection of MRD. For these studies, PCR is performed using oligonucleotide primers based on conserved sequences within the immunoglobulin heavy-chain locus; approximately 70 to 90% of rearrangements can be detected by this approach. To detect MRD with maximal sensitivity, such rearrangements are then subjected to sequence analysis to determine the antigen-specific sequences unique to the tumour rearrangement. An allele-specific oligonucleotide can then be synthesized and used in a PCR analysis that can detect residual clonal populations representing as few as 1 in 105 cells.
Further reading
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Look A (1997). Oncogenic transcription factors in human acute leukemias. Science, 278, 1059–64.Find this resource:
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Powell LD, Chung P, Baum LG (2013). Overview and compartmentalization of the immune system. In: Hoffman R, et al. (eds) Hematology: Basic Principles and Practice. Elsevier (Saunders), Canada.Find this resource:
Rose MG, Degar BA, Berliner N. (2004). Molecular Diagnostics of Malignant Disorders. Clinical Advances in Hematology & Oncology, 2, 650–660.Find this resource:
Sell S (1996). Immunology, immunopathology, and immunity. Appleton & Lange, Stamford, CT.Find this resource:
Strauchen J (1998). Diagnostic histopathology of the lymph node. Oxford University Press, New York.Find this resource:
Wickremasinghe R, Hoftbrand A (1999). Biochemical and genetic control of apoptosis: relevance to normal hematopoiesis and hematological malignancies. Blood, 93, 3587–600.Find this resource:
