Taking Charge of Your Health

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.

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