Leukemia (Blood Cancer)

 

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 a 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 antibodies 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 extra-nodal sites, and have distinctive Reed-Sternberg cells. The second category is non-Hodgkin lymphomas which tend to spread non-contiguously, can involve extra-nodal 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 extra-nodal 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. The second type of B cell lymphoma is follicular lymphoma, and it’s 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 chromosomes with each other.

As a result and the BCL2 gene from chromosome 18 is placed after the immunoglobulin heavy chain promoter on chromosome 14, and that results in over-expression of BCL-2. Bcl-2 normally blocks cell death or apoptosis, so over-expression of the BCL-2 gene prevents the cell from dying. The third type of B cell lymphoma is Burkitt lymphoma, and it’s a highly aggressive lymphoma. Burkitt lymphoma can also result from chromosomal translocation. In this case, the Myc gene is translocated from chromosome 8 where it ends up adjacent to the promoter on chromosome 14 and again that up-regulates 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 extra-nodal involvement of the jaw and is often associated with Epstein Barr virus infection. In contrast, in individuals outside Africa, Burkitt lymphoma classically causes extra-nodal 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. There are a few “tangible bodies” that 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 as the night sky. The fourth type of B cell lymphoma is mantle cell lymphoma, and this one’s an aggressive lymphoma.

Mantle cell lymphoma can also result from chromosomal translocation. In this case, the BCL1 gene from chromosome 11 ends up next to the immunoglobulin promoter on chromosome 14, which again up-regulates its expression. The BCL1 gene encodes the protein cyclin D1, which stimulates cell growth, so once again the translocation results in increased cell division. The 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 extra-nodal - mostly happening in the lining of the stomach among individuals with chronic inflammation, like those with Helicobacter pylori infection, bacteria that cause chronic gastritis. There’s also nodal marginal zone lymphoma, which happens within lymph nodes, and splenic marginal zone lymphoma which happens in the spleen. The 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 produce 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 is the T cell lymphomas. The first T cell lymphoma is adult T-cell lymphoma, but it’s sometimes referred to as 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 extra-nodal involvement of the gastrointestinal tract, it can cause bowel obstruction. If there’s extra-nodal involvement of the bone marrow, it can cause fatigue, easy bruising, or recurrent infections. And if there’s extra-nodal 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 extra-nodal involvement. And finally, a lymph node biopsy is required for diagnosis. Treatment options for non-Hodgkin lymphoma mainly consist 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.