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  • Related to cancers in general and breast cancer in particular
  • Lymphadenopathy is enlargement of lymph nodes by disease. Usually the lymph nodes become clinically palpable. "Adeno" in the name comes from the old name "lymph gland"
  • Lymph nodes are part of a distributed phagocytic mechanism and also part of the lymphocytic system
  • Many of the cells in lymph nodes recirculate, so each individual lymph node is linked to every other lymph node in the system.
  • Lymphoid aggregates: tonsils, adenoids, airways, peyer's patches, appendix.
    • Spleen and thymus play important roles.
    • Spleen = effector.
    • Thymus = major maturation site (not effector).
    • Bone marrow = origin
    • Liver is also a major part of the phagocytic response (via Kupffer cells: hence enlarged lymph nodes may also be linked to hepatomegaly and splenomegaly)
  • Hence enlarged lymph nodes isn't diagnostic of anything in particular. Need to work out whether the pattern is localised or generalised
  • Lymph nodes are essentially filters: phagocytic and immunological response functions.
  • T cells arrive in lymph nodes via blood after circulating in tissues

Causes of lymphadenopathy

  • Antigenic stimulation (reactive hyperplasia):
    • may be dominantly of B cells (follicular), T cells (interfollicular, diffuse) or macrophages (sinus histiocytosis)
    • localised reactive hyperplasia common with infections in drainage area (usually follicular) and neoplasms (sinus histiocytosis)
    • generalised reactive hyperplasia occurs with systemic antigenic stimulation due to circulating micro-organisms (e.g. HIV, hepatitis B, infective endocarditis), circulating immune complexes (e.g. rheumatoid disease, SLE), drug reactions or (rarely) storage diseases
  • Inflammation (lymphadenitis; where the lymph node itself is infected/inflamed):
    • localised acute suppurative lymphadenitis may follow spread of pyogenic bacteria from infection in drainage area; other infections may cause non-suppurative lesions e.g. TB (cat scratch disease = mixture granulomatous and acute inflammation).
      • acutely enlarged, painful, tender LNs, unlike reactive hyperplasia, usually localised; painless, localised, nontender LNs = TB. Extrapulmonary TB most commonly occurs in lymph nodes; remember to include it in differential diagnosis.
    • generalised lymphadenitis associated with a variety of systemic infections e.g. infectious mononucleosis, CMV, brucellosis, secondary syphilis, disseminated TB, various fungi, Toxoplasma and other parasitic infestations, as well as non-infective causes e.g. sarcoidosis
  • Metastatic malignancies: (much more common than LN primaries)
    • usually localised, usually carcinomas
    • may be generalised involvement in spread of leukaemias
    • Very common in epithelial malignancies. Sequential drainage = sequential spread of tumour in LNs. They appear white, with many areas of necrosis. Microscopic: aggregates of non-LN tissue (e.g. glandular = adenocarcinoma). Use LN involvement to assess patients who present early (later on, just use TNM system).
      • Look for the first lymph node to which the site drains (sentinel lymph node: gatekeeper; same principle applies to other cancers). You inject a marker (dye/radioisotope) into the primary tumour or into the overlying skin and see which LN the lymph nodes drains to first. Hence instead of removing all the lymph nodes in the area, just pick out the sentinel lymph node. The sentinel lymph node can be sectioned thoroughly to look for evidence of spread. This allows you to look for micro-metastases (cytokeratins in epithelial cells that lymphoid cells don't have: use immunostaining to pick out aggregations of tumour cells). You don't know whether these cells will survive and form metastases. Answer: yes - micrometastases and presence of only a few tumour cells result in worse outcomes with no adjuvant provided
    • Leukaemia causes generalised lymphadenopathy (not a metastasis as these cells were circulating in the first place)
  • Primary malignancies (lymphomas - 4% of reportable malignancies in Australia):
    • lymphoma = primary malignancies of lymphoid tissue or non-lymphoid sites. Do not count within lymphoma tumours that arise in bone marrow. Due to spread, the boundary between leukaemia and lymphoma is blurred. Unlike metastatic epithelial cells, which don't belong in LNs, which induce stroma, making the LN hard and sticky (matted together), lymphomas give you large lymph nodes that are firm, rubbery and discrete (not hard and matted). Despite their size, there isn't much evidence of necrosis (metastases in their home territory).
    • heterogeneous group of neoplasms, customarily subdivided into non-Hodgkin and Hodgkin lymphomas
    • Non-Hodgkin lymphomas include numerous distinct neoplasms, may present with localised or generalised lymphadenopathy or with extra- nodal involvement, varies with histopathological type
    • Hodgkin lymphoma usually produces localised lymphadenopathy initially, with subsequent spread to contiguous groups of lymph nodes

Structure of lymph node

  • Cortex:
    • Follicles, made of B lymphocytes
      • Pale area at middle = germinal centre = active B cells with a larger cytoplasm, secreting antibody. Gene rearrangement that allows the production of the most specific antibody possible (clonal expansion and diversification)
    • Interfollicular area, made of T cells
  • Medulla:
    • B cells, often matured to plasma cells
    • Sinuses, containing lots of macrophages (become prominent in infection)
  • Depending on the stimulus, you'll get:
    • B cell response (follicular hyperplasia)
    • T cell response (interfollicular pattern of hyperplasia, obscuring follicular visibility)
    • Particulate stimulus (phagocytic role of fixed-tissue macrophages (a.k.a. histiocytes); sinusoidal). Macrophages are in sinuses, then many T cells around it.
    • Mixed patterns (not mutually exclusive)

Lymphomas

  • Looking at other tumours: type, grade (differentiation), stage (how far it's spread; good at predicting behaviour; using TNM). For lymphomas, T is important, grading isn't important (type is grade), and staging depends on which type of tumour it is.
  • Two types of lymphoma:
    1. Hodgkin's lymphoma (10%)
    2. Non-Hodgkin's lymphoma (90% of them). Most Non-Hodgkin's lymphoma belong to two groups.

Non-Hodgkin's lymphoma

  • Most belong to B lymphocytes; sometimes form follicular aggregates of cell (if not too undifferentiated). If undifferentiated, they look like immunoblastic cells (at centre of follicle)
    1. Diffuse (40%) - replicating immunoblasts of centre of germinal centre
    2. Follicular (40%) - look a little like follicles, but at high power: loose nuclei, lots of cytoplasm, mitotic figures, appear to be proliferating. These are relatively better differentiated tumours.
  • Most of our chemotherapy is targeted at rapidly growing cells (so 1 has a better prognosis than 2).
  • Other = 10%
    • Also including T cell tumours

Hodgkin's lymphoma

  • Not homogeneous
  • Hodgkin's lymphoma starts in one group of nodes early on (or one extranodal site), then spreads to another site then to another site (so you can use staging based on extent of spread - due to sequential pattern of spread).
    • Hence staging is a critical part of the assessment and determines prognostic outcome and treatment
    1. Nodular sclerosing (most common): Lymph node has nodules within it and bands of connective tissue
    2. Other varieties = war between tumour cells and host (lymphocytes). 3 regions: lymphocyte proliferation, mixed cellularity and lymphocyte depletion
  • Systemic constitutional manifestation: fever, weight loss due to accelerated cytokine release (even without infection). More constitutional symptoms = poorer prognosis (included in staging).
  • Pattern of tumour cells
    • Arise from B cells
    • Highly mutated cells, with very few B cell markers (determined as B cells using genotype)
    • Multiple large cells, some of which are binucleate. All have prominent nucleoli
    • Lots of lymphocytes
    • Reed-Sternberg cell: Large, binucleate cell, relatively symmetrical, large nucleoli
      • Not actually that common in the nodular sclerosing (most common) variant
      • More commonly see the uninucleate cells
      • Also use markers
    • Distinct cell type, pattern of growth and constitutional stages, all of which are assessed to determine prognosis and treatment


  • Other than patients with reactive hyperplasia and lymphadenitis, the only way to work out what is happening in the lymph nodes is to get a biopsy. Presentation of lymphoma vs TB can be the same (need biopsy).

Approach to diagnosis

  • Clinical features:
    • age
    • distribution of enlarged nodes
    • size, consistency, inflammatory changes, fixation
    • abnormalities in region of drainage
    • associated features
      • constitutional manifestations
      • hepatosplenomegaly
      • skin rashes
  • Investigations:
    • full blood count, clinical chemistry
    • serology for specific infections (antibodies for infections that might cause enlargement)
    • imaging studies
      • X-ray or CT
      • nuclear medicine scan
    • biopsy
      • fine needle aspiration (cytology, less invasive, no histo; most of the time, it's enough)
      • excision (gives you lymph node architecture; especially important in sentinel nodes)