Lymphadenopathy
Functions of lymphatic system:
One way system returns lymph fluid to the cardiovascular system via vessels.
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Responsible for the removal of interstitial fluid from tissues returning it back to
blood
Absorbs and transports fatty acids and fats as chyle from the digestive system
Transports white blood cells to and from the lymph nodes into the bones
The lymph transports antigen-presenting cells (APCs), such as dendritic cells, to the
lymph nodes where an immune response is stimulated.
Lymph:
Fluid derived from blood plasma.
Pushed out through the capillary wall by pressure exerted by the heart or by osmotic
pressure at the cellular level.
Contains nutrients, oxygen, and hormones, as well as toxins and cellular waste products
generated by the cells.
Lacteals are lymph vessels that transport intestinal fat and are localized to the GI tract.
Lymphatic vessels: Blind-ended tubes with thin endothelial walls (only a single cell in
thickness).
Primary lymphoid organs = Thymus and bone marrow (generate lymphocytes from
immature progenitor cells)
Secondary lymphoid organs = Maintain mature naive lymphocytes and initiate an adaptive
immune response. Site of antigen activation of lymphocytes e.g peyers patches, spleen,
adenoids (Mucosal-associated lymphatic tissue MALT)
The spleen:
Surrounded by a connective tissue capsule that extends inward to divide the organ into
lobules. 2 types of tissue known as red and white pulp: Red pulp consists of venous sinuses
filled with blood and cords of lymphocytes and macrophages; white pulp is lymphatic tissue
consisting of lymphocytes around the arteries. Lymphocytes are densely packed within the
cortex of the spleen.
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It serves as a reservoir of lymphocytes for the body
It filters blood
It plays an important role in red blood cell and iron metabolism through macrophage
phagocytosis of old and damaged red blood cells
It recycles iron by sending it to the liver
It serves as a storage reservoir for blood
It contains T lymphocytes and B lymphocytes for immunologic response
Immunity
The immune system is typically divided into two categories--innate and adaptive--although
these distinctions are not mutually exclusive.
Innate immunity
Innate immunity refers to nonspecific defense mechanisms that come into play immediately
or within hours of an antigen's appearance in the body. These mechanisms include physical
barriers such as skin, chemicals in the blood, and immune system cells that attack foreign
cells in the body. The innate immune response is activated by chemical properties of the
antigen.
Adaptive immunity
Adaptive immunity refers to antigen-specific immune response. The adaptive immune
response is more complex than the innate. The antigen first must be processed and
recognized. Once an antigen has been recognized, the adaptive immune system creates an
army of immune cells specifically designed to attack that antigen. Adaptive immunity also
includes a "memory" that makes future responses against a specific antigen more efficient.
Adaptive Immunity: Humoral and Cell mediated
Humoral Immunity
The principal functions of B-cells are to make antibodies (immunoglobulins)
against antigens, to perform the role of antigen-presenting cells (APCs), and to develop into
memory B cells after activation by antigen interaction.
The human body makes millions of different types of B cells each day that circulate in
the blood and lymphatic system performing the role of immune surveillance.
They do not produce antibodies until they become fully activated.
Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its
surface that will bind to one particular antigen. The BCR is a membranebound immunoglobulin, and it is this molecule that allows the distinction of B cells from
other types of lymphocyte, as well as being the main protein involved in B cell activation.
Once a B cell encounters its cognate antigen and receives an additional signal from a T
helper cell, it can further differentiate into one of the two types of B cells (plasma B
cells and memory B cells)
Cell-mediated immunity
Most effective in removing virus-infected cells, but also participates in defending
against fungi, protozoans, cancers, and intracellular bacteria. It also plays a major role
in transplant rejection.
Activation of phagocytes, natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes,
and the release of various cytokines in response to an antigen.
CD4 cells or helper T cells provide protection against different pathogens.
T Cells mature in the Thymus
Cytotoxic T cells cause death by apoptosis without using cytokines, therefore in cell
mediated immunity cytokines are not always present.
Cellular immunity protects the body by:
1. activating antigen-specific cytotoxic T-lymphocytes that are able to
induce apoptosis in body cells displaying epitopes of foreign antigen on their
surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells
displaying tumor antigens;
2. activating macrophages and natural killer cells, enabling them to destroy pathogens;
and
3. stimulating cells to secrete a variety of cytokines that influence the function of other
cells involved in adaptive immune responses and innate immune responses.
Cell-mediated immunity is directed primarily at microbes that survive
in phagocytes and microbes that infect non-phagocytic cells. It is
Characteristic
% Ig in plasma
Location
IgG
80
Inta/extravasc
ular
IgM
6
Intravascular
IgA
13
Secretions/int
ravascular
IgD
<1
B-cell surface
Structure
Protein
subunits
Half-life
(days)
Special
features
Monomeric
Non
Pentameric
J
Dimeric
J and S
Monomeric
None
IgE
<1
Mast cells,
basophils,
secretion
Monomeric
None
23
5
6
3
2
Placental
passage
Primary
antibody
produced
Present in
milk and
secretions
B cell receptor
Mediates
atopy
Localised
Local infection
Pyogenic e.g tonsillitis
TB
Lymphoma
Secondary carcinoma
Generalised
Infection
EBV
CMV
Toxoplasma sp.
TB
HIV infection
Lymphoma
Leukaemia
Systemic disease
SLE
Sarcoidosis
Rheumatoid arthritis
Drug reaction e.g. phenytoin
Causes of lymphadenopathy
Differential diagnosis
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Subcutaneous lesions, eg lipoma, abscess
Hernia
Skin lesions, eg sebaceous cyst
Neck: branchial cleft cysts, cystic hygromas, salivary glands, thyroglossal duct cysts
(usually in midline)
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In the absence of obvious infection or any other underlying disorder, or if there is any
suspicion of malignancy - refer.
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Localised lymphadenopathy should prompt a search for an adjacent precipitating
lesion and an examination of other nodal areas to rule out generalised
lymphadenopathy.
Lymph nodes greater than 1 cm in diameter are generally considered to be
abnormal.
History of malaise and weight loss may be associated with malignancy or certain
infections, eg HIV, TB.
Painful, tender lymph nodes are usually associated with infection.
Firm or hard, painless nodes are often associated with malignancy.
Full examination is essential and may reveal associated bruising (eg leukaemia)
orhepatosplenomegaly (eg lymphoma).
Lymphadenopathy in the neck may cause superior vena cava obstruction.
Investigations
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Full blood count: white cell count raised in infection or malignancy, blood film for
leukaemia
Acute phase reactants, eg ESR and CRP, often raised in infection or malignancy
Liver function tests: liver infiltration
Infection:
Swabs from primary infection site for culture and sensitivities
Viral titres, eg Epstein-Barr virus, HIV, hepatitis
Investigations for TB
Syphilis serology
Toxoplasma screen
Blood cultures
Autoantibody screen: SLE, rheumatoid arthritis
Chest X-ray: sarcoidosis, TB, primary or secondary malignancy
CT scan: nodal distribution, staging of lymphoma
Fine needle aspiration or biopsy (ideally excisional biopsy) of lymph node may be
required; some patients, particularly children, remain undiagnosed after biopsy
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Sentinel node biopsy:
The sentinel node is the first node identified or the node with the highest
radioactivity count.
Sentinel node biopsy can avoid the need for block dissection of lymph nodes.
It is often used in the preoperative assessment of breast cancer and melanoma and
may have benefits in other cancers.
The sentinel node can be identified either by local injection of blue dye and
following its path, or by gamma camera imaging following injection of 99mTc
Leukaemia
Malignant neoplasm of haematopoietic stem cells, characterised by diffuse replacement of the bone
marrow by neoplastic cells.
In most cases cells spill over into blood where they can be seen in large numbers.
Cells may also infiltrate liver, spleen, lymph nodes and other tissues.
Overall incidence 10/100,000
Leukaemia can be divided on the basis of the speed of evolution of the disease (acute or chronic)
and further subdivided upon cell type
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Acute myeloid leukaemia (AML)
Acute lymphoblastic leukaemia (ALL)
Chronic myeloid leukaemia (CML)
Chronic lymphocytic leukaemia (CLL)
Aetiology
Most cases unknown.
Genetic:
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More common in some chromosomal disorders (e.g. downs)
Philadelphia chromosome. Found in 95% CML and some ALL. Long arm of chromosome 22
shortered by reciprocal translocation to long arm of chromosome 9 (t(9,22))
Environmental:
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Chemicals e.g. benzene compunds in industry
Drugs e.g AML after treatment with alkylating agents e.g. mephalan
Radiation exposue. Can iduce genetic damage to haematopeitic precursors, increased
incidence of Nagasaki and Hiroshima survivors and patients treated with ionising radiation.
Acute leukaemia
Clonal proliferation of myeloid or lymphoid precursors. Reduced capacity to differentiate into
mature cellular elements.
↑Leukaemic cells in bone marrow, peripheral blood and other tissues.
↓ Red cells, platelets and neutrophils
Epidemiology
Both types can occur at any age but generally:
AML Middle aged-elderly
ALL  Childhood
Clinical features
Anaemia
Bleeding
Infection (e.g. pneumonia)
Peripheral lymphadenopathy
Splenomegaly
Investigations
Peripheral blood film and bone marrow aspirate
FBC: anaemia and thrombocytopaenia (NB WCC usually raised but may be normal or low)
If fever: Chest xray and blood cultures
Bone marrow: Increased cellularity, high % abnormal lymphoid or myeloid blast cells
AML
1. AML with recurrent cytogenic abnormalities (includes acute polymyelocytic leukaemia with
t(15;17) or variants
2. AML with multilineage dysplasia
3. AML and MDS, therapy related, occurring after chemotherapy or radiotherapy
4. AML-not otherwise categorised
ALL
1. Precursor B cell ALL
2. Burkitt cell leukaemia
3. Precursor T cell ALL
MDS, myelodysplastic syndromes
Management
Induction chemotherapy (returns blood film and bonemarrow to normal)
Risk of failure based on cytogenic pattern
Successful remission induction followed by further treatment (consolidation)
Supportive care:
Blood transfusion and platelets.
Treat infection with IV antibiotics.
Prevent acute tumour lysis syndrome
(massive and rapid breakdown tumour cells leads to increased urate, potassium phosphate and
hypocalcaemia. AKI due to deposition in renal tubules. Prevent and treat with allopurinol, urate
oxidase and high IV fluids)
Treatment of AML
Treat with curative intent (<60years)
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Low risk of failure (based on cytogenic pattern)
o IV chemo. E.g. cytabarbine and danorubicin
Intermediate risk
o Consolidating chemotherapy to induce remission
o Bone marrow transplant (sibling matched, allogenic)
High risk
o Only curable with allonegnic transplant. NB. High risk associated with advanced age,
when toxicity of treatment increases.
Prognosis:
30% cure rate
Complete remission in 75% of under 60 year olds.
50% of those entering remission will be cured.
Long survival after recurrence rarely achieved without allogenic transplant.
Treatment of ALL
Remission induction with combination chemo e.g. vincristine, dexamethasone, asparginase and
danorubicin.
Propensity to involve CNS, so prophylactic intrathecal drugs e.g. methotrexate
Prognosis:
Good, 80% alive and disease free at 5 years, almost all achieve remission. Worsens with age.
Chronic myeloid leukaemia
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Middle age
Philadelphia chromosome
Insidious onset:
Fever
Weight loss
Sweating
Symptoms of anaemia
Splenomegaly
Untreated chronic phase lasts 3-4 years. Followed by blast transformation with development of
acute leukaemia (usually AML) and commonly, death.
Investigations
FBC: Anaemia + raised WCC (NB> platelets may be low, normal or raised)
Bone marrow aspirate: hypercellular marrow with increase in myeloid progenitors.
Philadelphia chromosome and BCR-ABL oncogene shpwn by cytogenics and reverse transcriptase
PCR.
Management
Imatinib, for chronic phase. Blocks anzymatic action of BCR-ABL fusion protein.
Complete haematological response in 95%.
In acute phase: chemotherapy, as of acute leukaemia to attempt to induce a second chronic phase.
Chronic lymphocytic leukaemia
Incurable disease of older people. Characterised by uncontrolled proliferation and accumulation of B
lymphocytes (although T cell CLL does occur)
Clinical features
Early asymptomatic .
Symptoms of bone marrow failure: anaemia, bleeding, infection.
Autoimmune haemolysis in some patients
Lymphademopathy
Hepatosplenomegaly
Investigations
FBC: Raised WCC and lymphoctyosis (+anaemia, thormobocytopaemia)
Blood film: Small lymphocytes of mature appearance (smear/smudge cells-an arterfact of cell
rupture while film being made)
Bone marrow: Lymphocyte infiltration
Immunophenotyping: Excludes reactive lymphocytosis and other lymphoid neoplasms
Management
Early stage: Expectant
Indictaions for treatment=advanced stage or symptoms e.g. anaemia, infections, splenic discomfort
Oral chlorambucil(+/- prednisolone) palliates.
Fludarabine, cyclophosphamide and/or rituximab has an impact on bone marrow and can induce
remission.
Prognosis
Median survival variable. Patients with 11q or 17p deletions (sites of two tumour suppressor genes)
at high risk of not responding to treatment.
Lymphoma
Neoplastic transformations of normal T or B cells which reside predominantly in lymphoid tissues.
Commoner than leukaemia.
Histological appearance classifies into Hodgkins and Non-Hodgkins
Hodgkins lymphoma
Primarily disease of young adults
Previous EBV infection may have a role in pathogenesis
Clinical features
Painless lymphnode enlargement (cervical)
‘rubbery’ consistency
Hepatosplenomegaly
Systemic ‘B’ symptoms= fever, drenching night sweats, weight loss (>10% 6 months)
Other=pruritis, fatigue, anorexia, alcohol induced pain at site of enlarged lymph nodes
Invetsigations
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FBC: May have normocytic, normochromic anaemia
Raised ESR
LFTs
LDH is an adverse prognostic marker
CXR- mediastinal widening from enlarged nodes
Lymphnode biopsy: REED-STEINBERG CELLS (malignant B lymphocytes in a background of
benign small lymphocytes and histiocytes)
CT-disease staging
Management
Stage 1 – Single lymph node region or single extra
lymphatic organ or site
Stage 2 - 2 or more groups of lymph nodes affected.
same side of diaphragm
Stage 3 – Lymph nodes affected on both sides of the
diaphragm
Stage 4 – Diffuse or disseminated involvement of one
or more extra lymphatic organs or tissues, with or
without associated lymph node involvement