The term non-Hodgkin lymphoma, sometimes called NHL, can be broken down.
Lymph- refers to lymphocytes and oma- refers to a tumor.
“Non-Hodgkin” refers to the absence of a key cell that’s seen in Hodgkin lymphoma,
the Reed-Sternberg cell.
So, non-Hodgkin lymphoma is a tumor derived from lymphocytes - specifically B-cells and
T-cells, which mainly live in the lymph nodes and move through the blood and lymphatic system.
Now, B-cell development begins in the bone marrow, which is a primary lymphoid organ.
That’s where young precursor B-cells mature into naive B-cells.
The naive B cells then leave the bone marrow and circulate in the blood and eventually
settle down in lymph nodes.
Humans have hundreds of lymph nodes, scattered throughout the body, and they’re considered
secondary lymphoid organs.
Each lymph node has B-cells which group together in follicles in the cortex or outer part of
the lymph node, along with T-cells in the paracortex just below the cortex.
B-cells differentiate into plasma cells, which are found in the medulla or center of the
lymph node.
Plasma cells release antibodies or immunoglobulins.
Antibodies bind to pathogens like viruses and bacteria, to help destroy or remove them.
Various immune cells, including B-cells have surface proteins or markers that are called
CD, short for cluster of differentiation, along with a number - like CD19 or CD21.
In fact, the combination of surface proteins that are on an immune cell works a bit like
an ID card.
Now, a B cell is activated when it encounters an antigen that binds just perfectly to its
surface immunoglobulin.
Some of these activated B-cells mature directly into plasma cells and produce IgM antibodies.
Other activated B-cells go to the center of a primary follicle in the lymph node and they
differentiate into B-cells called centroblasts and start to proliferate or divide.
These proliferating centroblasts form a germinal center, located in the center of the follicle
of the lymph node.
These centroblasts have a rearrangement of their immunoglobulin genes, and some of them
undergo a class switch where they change from producing IgM antibodies to producing IgG
or IgA antibodies.
Within the germinal center, centroblasts mature into centrocytes; and the centrocytes that
make antibody with high affinity for the antigen, differentiate into either plasma cells which
go to the medulla or memory B-cells which circulate in the blood and reside in lymph
nodes, spleen, and mucosa-associated lymphoid tissue, also called MALT.
Now, T-cell development starts in the thymus from precursors that arise in the bone marrow.
In the thymus, these precursor T-cells mature and express either CD4 on helper T-cells or
CD8 on cytotoxic T-cells sometimes known as suppressor T cells.
Mature T-cells circulate in the blood and are found in the paracortex of the lymph nodes.
Generally speaking, lymphomas are grouped into two categories.
The first category is Hodgkin lymphomas which tend to spread in a contiguous manner, rarely
involve extranodal sites, and have distinctive Reed-Sternberg cells.
The second category is non-Hodgkin lymphomas which tend to spread non-contiguously, can
involve extranodal sites like the skin, gastrointestinal tract, and the brain, and don’t usually
contain Reed-Sternberg cells.
In non Hodgkin lymphoma, there is usually a genetic mutation in a lymphocyte - either
a B cell or a T cell.
When something like that happens, cells are supposed to undergo apoptosis - or programmed
cell death, but instead the lymphocyte starts to divide uncontrollably - becoming a neoplastic
cell.
Usually, lymphomas develop in lymph nodes and they’re called nodal lymphomas.
Lymphomas can happen anywhere in the body, though, and when they develop in other tissues
or organs - like the stomach or skin - they’re called extranodal lymphomas.
Lymphoma cells can also get into the blood and can spread to other parts of the body.
If lymphoma cells get into the gastrointestinal tract they can grow and cause bowel obstruction.
If they go to the bone marrow, they can crowd out normal bone marrow progenitor cells and
decrease the number of healthy red blood cells, white blood cells and platelets.
If they go to the spinal cord they can cause spinal cord compression.
Now, the two main groups of Non-Hodgkin lymphomas are B cell and T cell lymphomas.
B cell lymphomas are more common and the neoplastic B cells usually express CD20 on their surface.
And there are various types of B cell lymphomas and an important feature is how quickly each
one grows- they can be indolent or slow to grow, aggressive, or highly aggressive.
The first type of B cell lymphoma is a diffuse large B cell lymphoma, this type is the most
common and it’s an aggressive lymphoma.
A second type of B cell lymphoma is a follicular lymphoma, and it’s an indolent lymphoma.
One known mechanism for how a follicular lymphoma develops, is a chromosomal translocation between
chromosome 14 and chromosome 18.
In the translocation, the two chromosomes swap large pieces of chromosome with each
other.
As a result an the BCL2 gene from chromosome 18 is placed after the immunoglobulin heavy
chain promoter on chromosome 14, and that results in overexpression of bcl-2.
Bcl-2 normally blocks cell death, or apoptosis, so overexpression of the bcl-2 gene prevents
the cell from dying.
A third type of B cell lymphoma is Burkitt lymphoma, and it’s a highly aggressive lymphoma.
Burkitt lymphoma can also result from a chromosomal translocation.
In this case, the Myc gene is translocated from chromosome 8 where it ends up adjacent
to IgH promoter on chromosome 14 and again that upregulates its expression.
The Myc gene stimulates cell growth and metabolism, so the translocation results in increased
cell division.
In individuals in Africa, Burkitt lymphoma classically causes extranodal involvement
of the jaw and is often associated with Epstein Barr virus infection.
In contrast, in individuals outside Africa, Burkitt lymphoma classically causes extranodal
involvement of the abdomen - most often at the ileocecal junction - and is less frequently
associated with Epstein Barr virus infection.
Epstein Barr virus infects lymphocytes and can incorporate its DNA into a host cell’s
DNA, but exactly how that leads to lymphoma is still unclear.
Under the microscope, Burkitt lymphoma is said to have a "starry sky” appearance.
That’s because there are a few “tingible bodies” which are macrophages that have
eaten up dead neoplastic cells that look like little stars.
And these are scattered among lots of neoplastic lymphocytes that look dark like the night
sky.
A fourth type of B cell lymphoma is mantle cell lymphoma, and this one’s an aggressive
lymphoma.
Mantle cell lymphoma can also result from a chromosomal translocation.
In this case, the BCL1 gene from chromosome 11 ends up next to the immunoglobulin promoter
on chromosome 14, which again upregulates its expression.
The BCL1 gene encodes the protein cyclin D1, which stimulates cell growth, so once again
the translocation results in increased cell division.
A fifth type of B cell lymphoma is marginal zone lymphoma, and it’s an indolent lymphoma.
The most common type is marginal zone lymphoma of mucosa-associated lymphoid tissue or MALT.
This type is extranodal - mostly happening in the lining of the stomach among individuals
with chronic inflammation, like those with Helicobacter pylori infection, a bacteria
that causes chronic gastritis.
There’s also nodal marginal zone lymphoma, which happens within lymph nodes, and splenic
marginal zone lymphoma which happens in the spleen.
A sixth type of B cell lymphoma is lymphoplasmacytic lymphoma, and this one’s also an indolent
lymphoma.
This form of lymphoma often involves the bone marrow, lymph nodes, and spleen, and the neoplastic
cells sometimes produces immunoglobulins, called “M proteins,” that are found at
high levels in the blood.
When this happens, the additional proteins in the blood cause the blood to be more thick
and viscous and the condition is called Waldenstrom macroglobulinemia.
The other group of non Hodgkin lymphomas are the T cell lymphomas.
The first T cell lymphoma is adult T-cell lymphoma, but it’s sometimes referred to
as a leukemia because the abnormal white blood cells or leukocytes often get into the bloodstream.
Adult T-cell lymphoma is thought to be caused by the human T-lymphotropic virus or HTLV,
which spreads through body fluids and infects T cells.
HTLV incorporates its DNA into T cell DNA and causes a genetic mutation in the process,
and that leads to adult T-cell lymphoma.
The second T cell lymphoma is mycosis fungoides which is a T cell lymphoma of the skin that
causes patches on the skin that looks a bit like a fungal infection.
The neoplastic cell in mycosis fungoides is a CD4+ helper T-cell, and under a microscope
it has a distinctive “cerebriform” nucleus because it looks like a brain.
If these neoplastic CD4+ helper T-cells start to circulate in the blood, they can cause
Sezary syndrome, which is when there’s a generalized red rash called erythroderma or
itchy skin.
For symptoms, Individuals with non-Hodgkin lymphoma usually develop painless lymphadenopathy.
The release of cytokines causes symptoms like fever, drenching night sweats, and weight
loss.
If there’s extranodal involvement of the gastrointestinal tract, it can cause bowel
obstruction.
If there’s extranodal involvement of the bone marrow, it can cause fatigue, easy bruising,
or recurrent infections.
And if there’s extranodal involvement of the spinal cord, it can cause weakness and
a loss of sensation - usually in the legs.
Identifying non Hodgkin lymphoma often begins with imaging studies, like a CT scan, which
can help establish the stage of the lymphoma.
The staging is based on the extent of nodal and extranodal involvement.
And finally a lymph node biopsy is required for diagnosis.
Treatment options for non-Hodgkin lymphoma mainly consists of chemotherapy and radiation
therapy, and depend on things like the lymphoma subtype, whether it’s indolent, aggressive,
or highly aggressive, and how far it has spread.
If the lymphoma has CD20-positive B-cells, Rituximab can also be used.
Rituximab is a monoclonal antibody that binds CD20 and induces complement-mediated lysis,
as well as direct cytotoxicity and apoptosis.
All right, as a quick recap, non-Hodgkin refers to the absence of “Reed-sternberg cells”
which are characteristic of hodgkin lymphoma.
Non-hodgkin lymphomas can originate from B cells or T cells, though they most commonly
arise from B cells.
Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma among
adults, and follicular lymphoma is the most common indolent or slow-growing non-hodgkin
lymphoma.
T cell lymphomas include adult T-cell lymphoma, which is sometimes referred to as leukemia,
as well as mycosis fungoides.