Non - Hodgkin

lymphoma
 Introduction
• These are a large group of clonal lymphoid tumours, about 85% of B
cell and 15% of T or NK (natural killer) cell origin.
• Their clinical presentation and natural history are more variable than
in Hodgkin lymphoma.
• They are characterized by an irregular pattern of spread.
• Significant proportion of patients develop extra nodal disease.
• Their frequency has increased markedly over the last 50 years and
with an incidence of approximately 17 in 100 000
• they now represent the fifth most common malignancy in some
developed countries
 Aetiology
• In the majority of cases of NHL, the cause is not identified,
although several factors are known to play a role in
lymphomagenesis.
• A small number of lymphomas originate from chronic antigenic
stimulation
• Helicobacter pylori infection appears to be a possible causative
agent for the development of gastric mucosa - associated
lymphoid tissue (MALT) lymphoma.
• Similarly, infection with Campylobacter jejuni has been
suggested recently to be associated with the development of
immunoproliferative small intestinal disease.
 Viruses
• Epstein – Barr virus (EBV) was fi st thought to be associated
with lymphomagenesis following its isolation from endemic
Burkitt lymphoma tissue
• EBV is also associated with the development of the endemic
(African) type of Burkitt lymphoma (BL), in which it is expressed
by 98%
• Adult T - cell leukaemia lymphoma (ATLL) is a T – cell
malignancy that occurs after a 40 - to 60 - year period of clinical
latency in about 3– 5% of Human T - c ell l eukaemia/ l
ymphoma v irus t ype I (HTLV - I-) infected individuals.
 Viruses
• Human herpesvirus (HHV) - 8 is the causative agent of both
Kaposi sarcoma (KS) and primary effusion lymphoma
• Hepatitis C virus (HCV) infection is associated with the
development of essential mixed cryoglobulinaemia, a low -
grade lymphoproliferative disorder that can progress to NHL
• HIV
 Clinical features of non - Hodgkin
lymphomas
• Superficial lymphadenopathy. asymmetric painless enlargement of lymph
nodes in one or more peripheral lymph node regions.
• Constitutional symptoms Fever, night sweats and weight loss occur less
frequently than in Hodgkin lymphoma and their presence is usually
associated with disseminated disease.
• Oropharyngeal involvement In 5 – 10% of patients there is disease of the
oropharyngeal ‘ sore throat”
• infections due to neutropenia or purpura with thrombocytopenia may be
presenting features in patients with diff use bone marrow disease.
• The liver and spleen are often enlarged and involvement of retroperitoneal
or mesenteric nodes is frequent.
 Laboratory investigations
• biopsy (e.g. bone marrow or extra nodal tissue) is the definitive
investigation
• Morphological examination is assisted by immunophenotypic and,
in some cases, genetic analysis
• For B - cell lymphomas, expression of either κ or λ light chains
confirms clonality and distinguishes the disease from a reactive
Node.
• A fine needle aspiration may be performed to exclude another
cause of lymphadenopathy (e.g. tuberculosis, carcinoma) but is
not useful in establishing a diagnosis of lymphoma
 Laboratory investigations
• Lymphoma cells (e.g. mantle zone cells, ‘ cleaved follicular
lymphoma ’ or ‘ blast in the peripheral blood in some patients
• HIV should be tested for in all patients.
• Trephine biopsy of marrow is valuable
• The serum lactate dehydrogenase (LDH) level is raised in
more rapidly proliferating and extensive disease and is used
as a prognostic marker
• Elevation of serum uric acid may occur
• Immunoglobulin electrophoresis may reveal a paraprotein
 Cell of origin
• B - cell lymphomas tend to mimic normal B cells at different
stages of development
• They can be divided into those resembling precursor (bone
marrow) B cells, those resembling germinal centre (GC) cells
and those post – GC cells in lymph nodes.
• T - cell lymphomas resemble precursor T cells in bone
marrow or thymus, or peripheral mature T cells.
 Proposed cellular origin of B -
lymphoid malignancies
• The cellular origin of the different lymphoid malignancies can be
inferred from immunoglobulin gene rearrangement status and
membrane phenotype.
• Mantle cell lymphoma and a proportion of B – cell chronic lymphocytic
lymphoma (B - CLL) cases have unmutated immunoglobulin genes
• marginal zone lymphoma, diffuse large cell lymphoma, follicle cell
lymphoma, lymphoplasmacytoid lymphoma and some B – CLL cases
have mutated immunoglobulin genes.
Specific subtypes of non -
Hodgkin
lymphoma
 Low - grade non - Hodgkin
lymphoma
Specific subtypes
• Small Lymphocytic Lymphoma
• Lymphoplasmacytoid lymphoma
• Marginal zone lymphomas
• Follicular lymphoma
• Mantle cell lymphoma
• Heavy - chain diseases
 Small
Lymphocytic Lymphoma
• the same morphology, immunophenotype and cytogenetics as chronic
lymphocytic lymphoma (CLL),
• Most of the patients are elderly and often no treatment is required
(watch and wait)
• Mature B-cell disorder with an indolent course
• predominance of small lymphoid cells, usually with dense,
hypermature nuclei and little cytoplasm, and smudge cell are
frequently seen
• Bone marrow shows decreased M:E ratio because of elevated
lymphoid cells.
• Flow cytometry is positive for CD5, CD19, CD20, CD23
 Lymphoplasmacytoid lymphoma
(Waldenström’s
macroglobulinaemia)
• This is an uncommon condition, seen most frequently in men over 50
years of age.
• The disease produces a monoclonal IgM paraprotein,
lymphoplasmacytoid lymphoma (LPL) may be termed Waldenström ’s
macroglobulinaemia.
• The cell of origin appears to be a post - germinal centre B cell with the
characteristics of an IgM - bearing memory B cell
• Hyperviscosity syndrome is a common complication as IgM
paraprotein (a pentameter) increases blood viscosity more than
equivalent concentrations of IgG or IgA.
Lymphoplasmacytoid
lymphoma

Lymphoplasmacytoid
lymphoma associated with
Waldenström’s macroglobulinaemia.
Bone marrow shows cells
with features of lymphocytes and
plasma cells.
 Marginal zone lymphomas
• Marginal zone lymphomas are low - grade lymphomas that
arise from the marginal zone of B - cell germinal follicles
• It is thought that lymphoid hyperplasia initially occurs in
response to antigen or inflammation and then cells acquire
secondary genetic damage that leads to lymphoma
• They are classified according the anatomical site at which they
arise, such as the spleen, mucosa (MALT) or lymph node
(nodal).
• Mucosa - associated lymphoid tissue (MALT) lymphomas
usually arise in the stomach or thyroid
 Follicular lymphoma
• This represents around 25% of NHL with a median age of onset of
60 years. It is associated with the t(14; 18) translocation in the
great majority of cases
• The translocation leads to constitutive expression of the BCL - 2
gene with increased survival of cells because of reduced apoptosis
• Presentation is usually with painless lymphadenopathy, often
widespread
• sudden transformation may occur at a rate of about 3% a year to
aggressive diff use tumourssometimes associated with a leukaemic
phase
 Mantle cell lymphoma
• Mantle cell lymphoma is derived from pre – germinal centre cells
localized in the primary follicles or in the mantle region of secondary
follicles.
• It has a characteristic phenotype of CD19 + and CD5 + (like CLL)
• but in contrast to CLL is CD22 + and CD23 − .
• A specifi c t(11; 14) translocation juxtaposes the cyclin D1 gene to the
immunoglobulin heavy – chain gene, and leads to increased
expression of cyclin D1.
• Presence of this translocation is required for diagnosis.
• Clinical presentation is typically with lymphadenopathy and often
there is bone marrow infiltration
 High - grade non - Hodgkin
lymphoma
Specific subtypes
• Diffuse large B - c ell lymphomas (DLBCL)
• Burkitt lymphoma
• Lymphoblastic lymphomas
• Primary central nervous system l ymphoma
 Diffuse large B - cell lymphomas (DLBCL)
• DLBCL are a heterogeneous group of disorders representing the
classic ‘ high - grade ’ lymphomas.
• As such they typically present with rapidly progressive
lymphadenopathy associated with a fast rate of cellular
proliferation.
• Progressive infiltration may affect the bone marrow, gastrointestinal
tract, brain , spinal cord, the kidneys or other organs.
• The most common cytogenetic changes involve the BCL - 6 gene at
chromosome 3q27; and translocation of the BCL – 2 gene, occurs in
20%.
 Burkitt lymphoma
• Burkitt lymphoma occurs in endemic or sporadic forms.
• Endemic (African) Burkitt lymphoma is seen in areas with chronic
malaria exposure and is associated with Epstein – Barr virus (EBV)
infection.
• In virtually all cases the MYC oncogene is over-expressed because it is
translocated to an immunoglobulin gene, usually the heavy - chain
locus t(8;14)
• Typically the patient, usually a child, presents with massive
lymphadenopathy, often of the jaw
• There is an increased incidence in HIV infection
T -cell lymphomas
 Specific subtypes
Peripheral T - cell non - Hodgkin lymphoma, unspecified
• These derive from post - thymic T cells at various stages of diff
erentiation
Angioimmunoblastic lymphadenopathy
• occurs in elderly patients with lymphadenopathy, hepatosplenomegaly,
skin rashes and a polyclonal increase in serum IgG.
Mycosis f ungoides
• chronic cutaneous T – cell lymphoma that presents with severe
pruritus and psoriasis - like lesions
 Specific subtypes
Sézary syndrome
• In Sézary syndrome there is dermatitis, erythroderma, generalized
lymphadenopathy and circulating T - lymphoma cells
Adult T - cell leukaemia/ lymphoma
• This is associated with human T - cell leukaemia/ lymphoma virus type
1 (HTLV - 1) infection
Anaplastic large cell lymphoma
• Anaplastic large cell lymphoma is particularly common in children and
is usually of T - cell phenotype.
• The disease is CD30 + and usually associated with the t(2; 5) (p23; q35)
translocation