Lymph Node PDF

LYMPH NODE Dr Nadia Halib (BSc., Phd, UKM) Department of Basic Sciences & Oral Biology, Faculty of Dentistry, Universiti Sains Islam  Lymph nodes – widely distributed and easily accessible lymphoid tissue. Examined for diagnostic purposes. They are discrete encapsulated structures, contain...

LYMPH NODE Dr Nadia Halib (BSc., Phd, UKM) Department of Basic Sciences & Oral Biology, Faculty of Dentistry, Universiti Sains Islam  Lymph nodes – widely distributed and easily accessible lymphoid tissue. Examined for diagnostic purposes. They are discrete encapsulated structures, contain B-cell and T-cell zones – invested with phagocytes and antigen-presenting cells (Fig. 6-8). Activation of resident immune cells leads to morphologic changes in lymph nodes. Several days of antigenic stimulation – the primary follicles enlarge and develop pale-staining germinal centres, in which B cells acquire to make high-affinity antibodies against specific antigens. Paracortical T-cell zones may also undergo hyperplasia. Trivial injuries and infections induce subtle changes; more significant infections produce nodal enlargement and sometimes leave residual scarring. For this reason, lymph nodes in adults are almost never “normal” or “resting,” and it is often necessary to distinguish morphologic changes secondary to past experience from those related to present disease. Infections and inflammatory stimuli often elicit regional or systemic immune reactions within lymph nodes. Lymphadenitis Acute Nonspecific Lymphadenitis Acute lymphadenitis in cervical region – due to drainage of microbes or microbial products from infections of the teeth or tonsils. In the axillary or inguinal regions – caused by infections in the extremities. In mesenteric lymph nodes – draining acute appendicitis. Self- limited infections – also cause acute mesenteric adenitis and induce symptoms mimicking acute appendicitis, (a differential diagnosis that plagues the surgeon). Acute generalized lymphadenopathy – due to systemic viral infections (particularly in children) and bacteraemia Nodes involved by acute lymphadenitis are enlarged and painful. Extensive abscess formation – cause the nodes become fluctuant. Suppurative infections may penetrate through the capsule of the node and track to the skin to produce draining sinuses – thus overlying skin is red  healing of such lesions is associated with scarring. MORPHOLOGY The nodes are swollen, grey-red, and engorged. Microscopically – prominence of large reactive germinal centres containing mitotic figures. Macrophages often contain particulate debris derived from dead bacteria or necrotic cells. When pyogenic organisms are the cause – neutrophils are prominent & the centres of the follicles may undergo necrosis  sometimes the entire node is converted to a bag of pus. With less severe reactions – scattered neutrophils infiltrate the follicles and accumulate within the lymphoid sinuses. The endothelial cells of the sinuses undergo hyperplasia. Follicular hyperplasia Caused by stimuli that activate humoral immune responses. Defined by the presence of large oblong germinal centres (secondary follicles) – which are surrounded by a collar of small resting naive B cells (the mantle zone) (Fig. 13-3). Germinal centres are polarized – consisting 2 distinct regions: (1) a dark zone containing proliferating blast like B cells (centroblasts) & (2) a light zone composed of B cells with irregular or cleaved nuclear contours (centrocytes). Interspersed between the germinal B centres – is inconspicuous network of antigen-presenting follicular dendritic cells and macrophages (often referred to as tingible-body macrophages) – containing nuclear debris of B cells (which undergo apoptosis if they fail to produce an antibody with a high affinity for antigen).  Causes of follicular hyperplasia include : rheumatoid arthritis toxoplasmosis early stages of infection with HIV. This hyperplasia is morphologically similar to follicular lymphoma. Features of a reactive (nonneoplastic) hyperplasia include : 1) preservation of the lymph node architecture, including the interfollicular T-cell zones and the sinusoids; 2) marked variation in the shape and size of the follicles; and 3) the presence of frequent mitotic figures, phagocytic macrophages, and recognizable light and dark zones, *all of which tend to be absent from neoplastic follicles. Paracortical hyperplasia Caused by stimuli that trigger T-cell–mediated immune responses – such as acute viral infections (e.g., infectious mononucleosis). The T-cell regions – contain immunoblasts, activated T cells (3 @ 4 times the size of resting lymphocytes that have round nuclei), open chromatin, prominent nucleoli, and moderate amounts of pale cytoplasm. The expanded T-cell zones encroach on and efface the B-cell follicles. In such cases immunoblasts is numerous (special studies needed to exclude a lymphoid neoplasm). In addition, there is often a hypertrophy of sinusoidal and vascular endothelial cells, accompanied by infiltrating macrophages and eosinophils. Sinus histiocytosis Also called reticular hyperplasia. Refers to an increase in number and size of cells that line lymphatic sinusoids. This hyperplasia may be prominent in lymph nodes draining cancers such as carcinoma of the breast. The lining lymphatic endothelial cells are hypertrophied and macrophages are greatly increased in numbers  resulting in the expansion and distension of the sinuses. Chronic Nonspecific Lymphadenitis Lymph nodes in chronic reactions – are nontender, as nodal enlargement occurs slowly over time (and acute inflammation with tissue damage is absent). Chronic lymphadenitis – is common in inguinal and axillary nodes, (which drain areas of the body and stimulated by immune reactions to trivial injuries and infections of the extremities). Chronic immune reactions – can promote the appearance of immune cells in nonlymphoid tissues. These collections are called tertiary lymphoid organs. Example – chronic gastritis caused by Helicobacter pylori, in which aggregates of mucosal lymphocytes are seen that simulate the appearance of Peyer patches. In rheumatoid arthritis – which B-cell follicles appear in the inflamed synovium. Lymphotoxin, a cytokine required for the formation of normal Peyer patches, is involved in the establishment of these “extranodal” inflammation-induced lymphoid cells. Cat-Scratch Disease Cat-scratch disease – is a self-limited lymphadenitis caused by the bacterium Bartonella henselae. It is a disease of childhood; 90% of the patients are < 18 years of age. It manifests with regional lymphadenopathy, most frequently in the axilla and the neck. The nodal enlargement appears 2 weeks after a feline scratch or, less commonly, after a splinter or thorn injury. An inflammatory nodule, vesicle, or eschar is sometimes visible at the site of the skin injury. In most patients the lymph node enlargement regresses during a period of 2 to 4 months. Rarely, encephalitis, osteomyelitis, or thrombo- cytopenia may develop in patients. Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) is a reactive condition – marked by cytopenias and signs and symptoms of systemic inflammation related to macrophage activation. For this reason, it is also sometimes referred to as macrophage activation syndrome. Some forms are familial and may appear early in life, even in infants, while other forms are sporadic and may affect people of any age. Pathogenesis. The common feature of all forms of HLH is systemic activation of macrophages and CD8+ cytotoxic T cells. The activated macrophages – phagocytose blood cell progenitors in the marrow and formed elements in the peripheral tissues Mediators released from macrophages and lymphocytes suppress – haematopoiesis and produce symptoms of systemic inflammation. These effects lead to cytopenia and a shock-like picture – referred to as “cytokine storm” or the systemic inflammatory response syndrome.  Familial forms of HLH are associated with several different mutations – which impact the ability of cytotoxic T cells and NK to form cytotoxic granules. These defects is based on the premise that cytotoxic T cells keep immune responses by lysing antigen-bearing dendritic cells or activated macrophages If this regulatory mechanism fails – hyperactivation of the immune system and the clinical syndrome of HLH ensue. Unbridled HLH is associated with high levels of inflammatory mediators such as interferon-γ, TNFα, IL-6, and IL-12, soluble IL-2 receptor. “Sporadic” cases in adults also prove to have mutations in the same set of genes The most common trigger for HLH is infection with Epstein-Barr virus (EBV). Clinical Features. Patients present with an acute febrile illness associated with splenomegaly and hepatomegaly. Heamophagocytosis - is seen on bone marrow examination but is not sufficient to make the diagnosis. Laboratory studies – reveal anaemia, thrombocytopenia & high levels of plasma ferritin + soluble IL-2 receptor (indicative of severe inflammation) As well as elevated liver function tests and triglyceride levels, both related to hepatitis. Coagulation studies – show disseminated intravascular coagulation  which can progress to multiorgan failure, shock, and death.  Treatment – immunosuppressive drugs and “mild” chemotherapy. Patients with germline mutations that cause HLH or who have persistent/resistant disease are candidates for hematopoietic stem cell transplantation. Without treatment, those with familial forms has poor prognosis – typically survive for less than 2 months. With prompt treatment – roughly half of patients survive, though many do so with significant sequelae (such as renal damage in adults and growth and mental retardation in children). Lymphoid Neoplasms Definitions and Classifications Confusing between terms lymphocytic leukaemia Vs lymphoma. Leukaemia – is used for neoplasms that present with wide-spread involvement of the bone marrow and the peripheral blood. Lymphoma – is used for proliferations that arise as discrete tissue masses. “Lymphoma” occasionally have leukemic presentations, and evolution to “leukaemia” is common during the progression of incurable “lymphomas.” Conversely – tumours identical to “leukaemia” sometimes arise as soft- tissue masses without detectable bone marrow disease. Hence, when applied to particular neoplasms, the terms leukaemia and lymphoma merely reflect the usual tissue distribution of each disease at presentation.  Within the large group of lymphomas, Hodgkin lymphoma is segregated from all other forms, which constitute the non-Hodgkin lymphomas (NHLs). Hodgkin lymphoma – has distinctive pathologic features and is treated differently. Another special group of B cell tumours, (which differs from most lymphomas) – is the plasma cell neoplasms. These most often arise in the bone marrow and rarely involve lymph nodes or the peripheral blood. The clinical presentation of the various lymphoid neoplasms – is determined by the anatomic distribution of disease. Two thirds of NHLs and all Hodgkin lymphomas – present as enlarged nontender lymph nodes (often > 2 cm). The remaining 1/3 of NHLs – present with symptoms related to the involvement of extranodal sites (e.g., skin, stomach, or brain).  The lymphocytic leukaemia – come to attention because of signs and symptoms related to the suppression of normal haematopoiesis by tumour cells in the bone marrow. Finally, the most common plasma cell neoplasm, multiple myeloma – causes bony destruction of the skeleton with pain due to pathologic fractures. Other symptoms – caused by proteins secreted from the tumour cells or from immune cells that are responding to the tumour. Examples : plasma cell tumours related to the secretion of whole antibodies or Ig fragments Hodgkin lymphoma (which associated with fever) – related to the release of cytokines from inflammatory cells responding to the tumour cells; and peripheral T-cell lymphomas Tumors of functional T cells that often release a number of inflammatory cytokines and chemokines.  The current World Health Organization (WHO) classification scheme – uses morphologic, immunophenotypic, genotypic, and clinical features to sort the lymphoid neoplasms into 5 broad categories, which are separated according to the cell of origin: 1) Precursor B-cell neoplasms (neoplasms of immature B cells) 2) Peripheral B-cell neoplasms (neoplasms of mature B cells) 3) Precursor T-cell neoplasms (neoplasms of immature T cells) 4) Peripheral T-cell and NK-cell neoplasms (neoplasms of mature T cells and NK cells) 5) Hodgkin lymphoma (neoplasms of Reed-Sternberg cells and variants) PRECURSOR B- AND T- CELL NEOPLASMS Acute Lymphoblastic Leukaemia/Lymphoma Acute lymphoblastic leukemia/lymphomas (ALLs) – are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts. 85% are B-ALLs – typically manifest as childhood acute “leukemias”. Less common T-ALLs –present in adolescent males as thymic “lymphomas.” ALL is the most common cancer of children. B-ALL peaks in the age of 3 – because the number of normal bone marrow pre-B cells (the cell of origin) is greatest very early in life. Similarly, the peak incidence of T-ALL is in adolescence - the age when the thymus reaches maximum size. B- and T-ALL also occur less frequently in adults of all ages. Pathogenesis. 70% of T-ALLs – mutations in NOTCH1, a gene that is essential for T-cell development. B-ALLs – mutations in genes PAX5, E2A, and EBF, ETV6 and RUNX1 (genes needed in hematopoietic precursors). 90% of ALLs have numerical or structural chromosomal changes – hyperploidy (>50 chromosomes). Hyperdiploidy and hypodiploidy are seen only in B-ALL. In addition, B- and T-ALL are associated with completely different sets of translocations, indicating that they are pathogenetically distinct. Immunophenotype B-ALLs – express the pan B-cell marker CD19 and the transcription factor PAX5, CD10. Very immature B-ALLs – CD10 is negative. More mature “late pre-B” ALLs – express CD10, CD19, CD20, and cytoplasmic IgM heavy chain (μ chain). T-ALLs – are positive for CD1, CD2, CD5, and CD7. More immature tumours are usually NEGATIVE for surface CD3, CD4, and CD8, Whereas “late” pre–T-cell tumours are POSITIVE for these markers. Clinical Features. Genetically and immunophenotypically distinct BUT they are clinically similar. In both – the accumulation of neoplastic “blasts” in the bone marrow suppresses normal haematopoiesis by physical crowding, competition for growth factors. The common features : Abrupt stormy onset within days to a few weeks of the first symptoms Symptoms related to depression of marrow function, e.g fatigue due to anaemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia Mass effects caused by neoplastic infiltration – including bone pain resulting from marrow expansion and infiltration of the subperiosteum; generalized lymphadenopathy, splenomegaly, and hepatomegaly; testicular enlargement; In T-ALL, complications related to compression of large vessels and airways in the mediastinum Central nervous system manifestations such as headache, vomiting, and nerve palsies resulting from meningeal spread, all of which are also more common in ALL Prognosis. With aggressive chemotherapy about 95% of children with ALL obtain a complete remission, and 75% to 85% are cured. Only 35% to 40% of adults are cured. Factors are associated with a worse prognosis: 1) age < 2 years – because of the strong association of infantile ALL with translocations involving the MLL gene; 2) presentation in adolescence or adulthood 3) peripheral blood blast counts > than 100,000, which reflects a high tumour burden.  Favourable prognostic markers include: 1) age between 2 and 10 years, 2) a low white cell count, 3) hyperdiploidy, 4) trisomy of chromosomes 4, 7, and 10 5) the presence of a t(12;21). Notably, the molecular detection of residual disease after therapy is predictive of a worse outcome in both B- and T-ALL and is being used to guide new clinical trials. PERIPHERAL B-CELL NEOPLASMS Chronic Lymphocytic Leukaemia, Small Lymphocytic Lymphoma Chronic Lymphocytic Leukaemia, Small Lymphocytic Lymphoma Chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) differ only in the degree of peripheral blood lymphocytosis. CLL is the most common leukaemia of adults in the Western world. There are about 15,000 new cases of CLL each year in the United States – median age at diagnosis is 60 years & there is a 2:1 male predominance. CLL/SLL is much less common in Japan and other Asian countries than in the West. Pathogenesis The most common genetic anomalies are deletions of 13q14.3, 11q, and 17p, and trisomy 12q. Molecular characterization of the region deleted on chromosome 13 has implicated two microRNAs, miR-15a and miR-16-1, as possible tumour suppressor genes. The cell of origin may be either a post-germinal centre memory B cell or a naive B cell. Deep sequencing of CLL genomes – revealed gain-of-function mutations involving the NOTCH1 receptor in 10% to 18% of tumours, as well as frequent mutations in genes that regulate RNA splicing. Immunophenotype. CLL/SLL cells – express the pan B-cell markers CD19 and CD20, CD23 and CD5 The latter a marker that is found on a small subset of normal B cells. Low-level expression of surface Ig (usually IgM or IgM and IgD) is also typical. Clinical Features. Patients are often asymptomatic at diagnosis. When symptoms appear, they are nonspecific and include easy fatigability, weight loss, and anorexia. Generalized lymphadenopathy and hepatosplenomegaly are present in 50% to 60% of symptomatic patients. Leukopenia in individuals with SLL and marrow involvement, while counts in excess of 200,000/mm3 are seen in CLL patients with heavy tumour burdens. Hypogammaglobulinemia is common – contributes to an increased susceptibility to infections caused by bacteria 10% to 15% of patients develop haemolytic anaemia or thrombocytopenia due to autoantibodies made by non- neoplastic B cells  Another factor influence patient survival is the tendency of CLL/SLL to transform to a more aggressive tumour. Most common – transformation to diffuse large B-cell lymphoma, so-called Richter syndrome (approximately 5% to 10% of patients). Transformation to diffuse large B-cell lymphoma – is heralded by rapidly enlarging mass within a lymph node or the spleen. Transformation due to mutations that increase growth. Large-cell transformation is an ominous event, with most patients surviving less than 1 year. Follicular Lymphoma Pathogenesis. Follicular lymphoma arises from germinal centre B cells and is strongly associated with chromosomal translocations involving BCL2 – leads to overexpression of BCL2 (see Fig. 13-12). BCL2 antagonizes apoptosis and promotes the survival of follicular lymphoma cells. Early in the disease – follicular lymphoma cells growing in lymph nodes are found within a reactive follicular dendritic cells admixed with macrophages and T cells. Expression profiling studies have shown that differences in the genes expressed by these reactive cells are predictive of outcome, implying that the response of follicular lymphoma cells to therapy is influenced by the surrounding microenvironment. Immunophenotype. The neoplastic cells closely resemble normal germinal centre B cells, expressing CD19, CD20, CD10, surface Ig, and BCL6. Unlike CLL/SLL and mantle cell lymphoma, CD5 is not expressed. BCL2 is expressed in more than 90% of cases, in distinction to normal follicular centre B cells, which are BCL2-negative (Fig. 13-12). Clinical Features. Follicular lymphoma – present with painless, generalized lymphadenopathy. Involvement of extranodal sites, such as the gastrointestinal tract, central nervous system, or testis, is relatively uncommon. Survival (median, 7 to 9 years) is not improved by aggressive therapy; Hence, the usual approach is to palliate patients with low-dose chemotherapy or immunotherapy (e.g., anti-CD20 antibody) when they become symptomatic. Histologic transformation occurs in 30% to 50% of follicular lymphomas - commonly to diffuse large B-cell lymphoma. Less common – tumours resembling Burkitt lymphoma emerge that are associated with chromosomal translocations involving MYC. Like normal germinal centre B cells, follicular lymphomas have ongoing somatic hyper- mutation, which may promote transformation by causing point mutations or chromosomal aberrations. The median survival is less than 1 year after transformation. Diffuse Large B-Cell Lymphoma Pathogenesis. Frequent pathogenic event – is dysregulation of BCL6, a DNA-binding zinc- finger transcriptional repressor (required for the formation of normal germinal centres). About 30% of DLBCLs contain various translocations that have in common a breakpoint in BCL6 at chromosome 3q27. BCL6 represses the expression of factors that normally serve to promote germinal centre B-cell differentiation, growth arrest, and apoptosis, and each of these effects is believed to contribute to the development of DLBCL. Mutations similar to those found in BCL6 are also seen in multiple other oncogenes Immunophenotype. These mature B-cell tumours – express CD19 and CD20 and show variable expression of germinal centre B-cell markers such as CD10 and BCL6. Most have surface Ig. Special Subtypes. Several subtypes of DLBCL : Immunodeficiency-associated large B-cell lymphoma – occurs in the setting of severe T-cell immunodeficiency (e.g., advanced HIV infection and allogeneic bone marrow transplantation). Restoration of T-cell immunity may lead to regression of these proliferations. Primary effusion lymphoma – presents in patients with advanced HIV infection or older adults. The tumour cells are often anaplastic in appearance and fail to express surface B- or T-cell markers. Clinical Features. DLBCL – presents as a rapidly enlarging mass at a nodal or extranodal site. It can arise anywhere in the body. Waldeyer ring, the oropharyngeal lymphoid tissue that includes the tonsils and adenoids, is commonly involved. Primary or secondary involvement of the liver and spleen may take the form of large destructive masses (Fig. 13-14). Extranodal sites include the gastrointestinal tract, skin, bone, brain, and other tissues. Bone marrow involvement – occurs late in the course. DLBCLs are aggressive tumours that are rapidly fatal without treatment. Burkitt Lymphoma Category Category of Burkitt Lymphoma : 1) African (endemic) Burkitt lymphoma, 2) Sporadic (nonendemic) Burkitt lymphoma, and 3) a subset of aggressive lymphomas occurring in individuals infected with HIV. Burkitt lymphomas occurring in each of these settings are histologically identical but differ in some clinical, genotypic, and virologic characteristics. Pathogenesis. All forms of Burkitt lymphoma are associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels. MYC is a master transcriptional regulator that increases the expression of genes, required for aerobic glycolysis, the so-called Warburg effect. When nutrients such as glucose and glutamine are available, Warburg metabolism allow cells to biosynthesize all of the building blocks— nucleotides, lipids, proteins—that are needed for growth and cell division. Burkitt lymphoma is the fastest growing human tumour. The translocation partner for MYC is usually the IgH locus [t(8;14)] but may also be the Ig κ [t(2;8)] or λ [t(8;22)] light chain loci.  Essentially all endemic Burkitt lymphomas are latently infected with EBV, which is also present in about 25% of HIV-associated tumours and 15% to 20% of sporadic cases. The configuration of the EBV DNA is identical in all tumour cells within individual cases, indicating that infection precedes transformation. Although this places EBV at the “scene of the crime,” its precise role in the genesis of Burkitt lymphoma remains poorly understood. Immunophenotype. These are tumours of mature B cells – that express surface IgM, CD19, CD20, CD10, and BCL6. Burkitt lymphoma do not express the antiapoptotic protein BCL2. Clinical Features. Both endemic and sporadic Burkitt lymphomas are found mainly in children or young adults Most tumours manifest at extranodal sites. Endemic Burkitt lymphoma often presents as a mass involving the mandible and involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal glands. In contrast, sporadic Burkitt lymphoma – often appears as a mass involving the ileocecum and peritoneum. Involvement of the bone marrow and peripheral blood is uncommon. Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy. Most children and young adults can be cured. Plasma Cell Neoplasms and Related Disorders Multiple Myeloma Multiple myeloma – is the most common lymphoid malignancies. The median age at diagnosis is 70 years, and more common in males and in people of African origin. It principally involves the bone marrow and associated with lytic lesions throughout the skeletal system. The most frequent M protein produced by myeloma cells is IgG (60%), followed by IgA (20%–25%); rarely are IgM, IgD, or IgE M proteins observed. In the remaining cases, the plasma cells produce only κ or λ light chains. Because free light chains are small in size, they are also excreted in the urine, where they are referred to as Bence Jones proteins. Pathogenesis Myeloma often has chromosomal translocations that fuse the IgH locus on chromosome 14 to oncogenes such as the cyclin D1 and cyclin D3 genes. Dysregulation of D cyclins is common in multiple myeloma and is believed to contribute to increases in cell proliferation. Proliferation of myeloma cells also is supported by the cytokine interleukin 6 (IL-6), which is produced by fibroblasts and macrophages in the bone marrow stroma. Late in the course, translocations involving MYC are sometimes observed, particularly in patients with aggressive disease. Multiple myeloma has effects on the skeleton, the immune system, and the kidney, all of which contribute to morbidity and mortality Clinical Features. Clinical findings stem mainly from (1) the effects of plasma cells on the skeleton; (2) the production of excessive immunoglobulins, and (3) the suppression of humoral immunity. Bone resorption often leads to pathologic fractures and chronic pain. The hypercalcemia can give rise to neurologic manifestations, such as confusion, weakness, and lethargy, and contributes to renal dysfunction. Decreased production of normal immunoglobulins – sets recurrent bacterial infections. Renal insufficiency, which trails only infections as a cause of death. Renal failure (50% of patients) – is associated with the presence of Bence Jones proteinuria  The diagnosis rests on radiologic and laboratory findings. It can be strongly suspected when imaging studies show typical bone lesions But definitive diagnosis requires a bone marrow examination. Marrow involvement often gives rise to a normocytic normochromic anaemia, sometimes accompanied by moderate leukopenia and thrombocytopenia. Lymphoplasmacytic Lymphoma. Lymphoplasmacytic lymphoma is a B-cell neoplasm bearing a superficial resemblance to CLL/SLL, it differs in that a substantial fraction of the tumour cells undergo terminal differentiation to plasma cells. Most commonly, the plasma cell component secretes monoclonal IgM, often in amounts sufficient to cause a hyperviscosity syndrome known as Waldenström macroglobulinemia. Unlike multiple myeloma, complications stemming from the secretion of free light chains (e.g., renal failure and amyloidosis) are relatively rare and bone destruction does not occur. Pathogenesis. Lymphoplasmacytic lymphoma are associated with acquired mutations in MYD88. The MYD88 gene encodes an adaptor protein that participates in signaling events that activate NF-κB and also augment signals downstream of the B-cell receptor (Ig) complex, both of which may promote the growth and survival of the tumour cells. Immunophenotype. The lymphoid component expresses B-cell markers such as CD20 and surface Ig, whereas the plasma cell component secretes the same Ig that is expressed on the surface of the lymphoid cells. This is usually IgM but can also be IgG or IgA. Clinical Features. The dominant presenting complaints are nonspecific and include weakness, fatigue, and weight loss. Approximately half the patients have lymphadenopathy, hepatomegaly, and splenomegaly. Anaemia caused by marrow infiltration is common. About 10% of patients have autoimmune haemolysis caused by cold agglutinins, IgM antibodies that bind to red cells at temperatures of less than 37°C.  Patients with IgM-secreting tumours have large size, high concentrations IgM – greatly increases the viscosity of the blood, giving rise to a hyperviscosity syndrome characterized by the following: Visual impairment associated with venous congestion, which is reflected by striking tortuosity and distention of retinal veins; retinal haemorrhages and exudates can also contribute to the visual problems Neurologic problems such as headaches, dizziness, deafness, and stupor, all stemming from sluggish blood flow and sludging Bleeding related to the formation of complexes between macroglobulins and clotting factors as well as interference with platelet functions Cryoglobulinemia resulting from the precipitation of macroglobulins at low temperatures, which produces symptoms such as Raynaud phenomenon and cold urticaria Tumour growth can be controlled with low doses of chemotherapeutic drugs and immunotherapy with anti-CD20 antibody. Transformation to large-cell lymphoma occurs but is uncommon - Median survival is about 4 years. Hodgkin Lymphoma Hodgkin lymphoma encompasses a distinctive group of neoplasms that are characterized by the presence of a tumour giant cell, the RS cell. Unlike most NHLs, Hodgkin lymphomas arise in a single lymph node or chain of lymph nodes and typically spread in a stepwise fashion to anatomically contiguous nodes. Although the Hodgkin lymphomas are now understood to be unusual tumours of B cell origin, they are distinguished from the NHLs by their unusual pathologic and clinical features. Classification Five subtypes of Hodgkin lymphoma are recognized: 1) nodular sclerosis, 2) mixed cellularity, 3) lymphocyte rich, 4) lymphocyte depletion, and 5) lymphocyte predominant. In the first four subtypes the RS cells share morphologic and immunophenotypic features  lump together these entities under the rubric classical Hodgkin lymphoma. The lymphocyte predominant type is set apart by the expression of germinal centre B cell markers by the RS cells. This subtype and the two most common forms - the nodular sclerosis and mixed- cellularity types Pathogenesis Hodgkin lymphoma is a neoplasm that arises from germinal centre B cells. Another clue into the aetiology of Hodgkin lymphoma stems from the frequent involvement of EBV. EBV is present in the RS cells in as many as 70% of cases of the mixed- cellularity subtype. The structure of the EBV genome is identical in all RS cells in a given case – indicating that infection precedes (and therefore may be related to) transformation and clonal expansion. Thus, EBV infection probably is one of several steps contributing to tumour development, particularly of the mixed-cellularity subtype.  The characteristic nonneoplastic, inflammatory cell infiltrate is generated by a number of cytokines – including IL-5, a chemoattractant for eosinophils; transforming growth factor-β, a fibrogenic factor; and IL-13, which may stimulate RS cell growth through an autocrine mechanism. Hodgkin lymphoma is a cardinal example of a tumour that escapes from the host immune response by expressing proteins that inhibit T cell function. The RS cells of classical Hodgkin lymphoma express high levels of PD ligands, factors that antagonize T cell responses. In many tumours the region on chromosome 9 containing the genes encoding the two PD ligands, PD-L1 and PD-L2, is amplified, an alteration that appears to contribute to their overexpression. Clinical Features Manifests as painless lymphadenopathy. Definitive distinction from NHL can be made only by examination of a tissue biopsy Younger patients with more favorable subtypes tend to present with stage I or stage II disease and usually are free of so-called “B symptoms” (fever, weight loss, night sweats). Patients with advanced disease (stages III and IV) are more likely to exhibit B symptoms as well as pruritus and anaemia. Because of the long-term complications of radiotherapy, patients are now treated with systemic chemotherapy.  More advanced disease is treated with chemotherapy, together with field radiotherapy. The 5-year survival rate for patients with stage I-A or II-A disease is more than 90%. Even with advanced disease (stage IV-A or IV-B), the overall 5-year disease- free survival rate is around 50%. Among long-term survivors treated with radiotherapy, a higher risk of certain malignancies, including lung cancer and breast cancer, as well as cardiovascular disease, has been reported. These sobering results have spurred development of new regimens that minimize the use of radiotherapy and use less toxic chemotherapy. Thank you