About Lymphoma > Lymphoma simplified

Last update: 02/06/2016

Condensed overview of Cancer

A cancer develops from genomic damage (mutations) to cells that lead to abnormal growth and persistence of the cells (malignant behavior). 

The mutations can lead to epigenomic changes that turn on or off specialized genes that would protect the cell from becoming a cancer or being detected by the immune system. 

* Lymphomas are highly sensitive to standard chemotherapy and radiotherapy, which work by damaging the DNA of rapidly dividing cells causing the cells to initiate programmed cell death.

Targeted approaches to treating cancer include:

1) by inhibiting the pathways in the cell that are activated by the mutations that drive the malignant behavior

2) by activating genes that have been silenced, or by turning off overactive genes - so called epigenetic treatments

4) by targeting cell surface antigens that are expressed only on lymphocytes, such as cd20 (Rituxan), cd19, cd22, cd30 ...

5) by inhibiting how the cancer cells corrupt or hijack the host system, such as the immune system or the blood supply.

Why Lymphoma is generally more treatment sensitive than other cancers

Lymphoma arises from infection-fighting immune cells called lymphocytes. Normal lymphocytes replicate and increase in number in response to an infection. We feel bad during infections because of this activity and the inflammation that arises. When the job is done, the infection knocked out, the lymphocytes die off so as not to interfere with organ function – and we start to feel better too.

Lymphoma is similar to a normal reaction to an infection – but a reaction that does not get turned off. The defective immune cells continue to persist and divide even when no infection is driving it. (With some notable exceptions, such as h-pylori positive MALT)

A reason lymphoma is highly sensitive to chemotherapy and radiotherapy is that the normal cells of this kind have an inherently short lifespan … they are built for fast replication but also for fast dying.

Immune cells of this type are inherently chemo- and radiation-sensitive … as evidence by how our normal lymphocytes counts nose-dive during chemotherapy – unlike most other types of cells in our body. Importantly, these important cells emerge again from stem cells that divide infrequently and are not adversely affected by standard kinds and doses of chemotherapy or radiation. Within a few weeks or more, the normal lymphocytes needed to protect us from infection rebound to normal levels.

In the News:

The Hallmarks of Cancer - click the Figure tabs to walk through this comprehensive presentation http://bit.ly/14MtLK3

TOPIC SEARCH: PubMed

What is cancer?

What is lymphoma?

How does it start?

What determines its clinical behavior?

Lymphoma Overview

"Lymphoma is a blood cell cancer.  The effected cells are called lymphocytes, a type of white blood cell that helps protect us from infection."

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Cancer begins with damage to DNA in the cell nucleus. These "hits" can result from random errors, or by exposures to chemicals or radiation:

But the cell has defenses: 

It can initiate cell death (suicide) when a defect is detected (so-called apoptosis),  or it can repair the error and become a normal cell.

If these defenses fail, an atypical cell is formed.

But multiple "hits" on the DNA are required to cause a cancer.

A third line of defense is your immune system.  For example,   T-cells or Natural Killer cells can detect abnormal cells and kill them.  Tumor cells may develop ways to shut down the immune system and avoid attack, such as by immune checkpoint signaling.

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Additional Reading

	Dr. Sharman's CLL & Lymphoma Blog: Making sense of all the different lymphomas
	Lymphoma in more detail
	Risk factors associated with developing lymphoma
	Lymphoma classifications
	Lymphoma statistics
	Lymphoma symptoms

     Outside resources

	Lymphoma simplified: cancerhelp.org.uk
	History of Cancer  Cancer.gov
	Cancer 101 Webcast
	Understanding cancer series nci.nih.gov

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Defining Cancer

In normal tissues, the rates of new cell growth and old cell death are kept in balance. 
 
In cancer, this balance is disrupted. This disruption can result from uncontrolled cell growth or loss of a cell's ability to undergo "apoptosis."
 
 Apoptosis, or "cell suicide," is the mechanism by which old or damaged cells normally self-destruct."

Source: http://press2.nci.nih.gov

Lymphomas are often very sensitive and responsive to different treatments. 

Aggressive lymphomas are often cured, and indolent lymphomas are often  managed well when treatment is indicated. 

Importantly, recent advances in the understanding of lymphoma have led to effective new therapies.

World Health Organization Classification of Neoplastic Diseases

WHO Classification of B-cell Lymphoid Neoplasms 

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Lymphoma Simplified -  how it begins

Our body is made of countless cells of many types.  Cells have specialized jobs and names, such as skin, nerve, heart, lung, blood, immune cells, and so on. For the human body to function normally, each organ must have a certain number of cells.

By design, the cells in most organs have a short lifespan.  Therefore, to continue functioning the body needs to replace these lost cells by the process of cell division. 

Cell division and cell death are controlled by genes that are located in the cell nucleus. Genes function like an instruction manual telling the cell what proteins to make.  These proteins in turn control the behavior of the cell.

Some proteins direct the cell to divide; others how long it will live; and others begin cell death - a normal process by which the body rids itself of old, unneeded, or damaged cells. 

Under normal conditions there is a balance in which new cells replace old, and each cell carries out tasks specific to its kind:  Heart cells pump, stomach cells produce acids, immune cells recognize invaders and kill them, and so on.  The balance ensures that the organs and systems function properly and serve the needs of the body.

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The beginning of cancer

In any cell the genetic code can get damaged so that the instructions in the "manual" are altered in ways that produce abnormal types and amounts of proteins that can lead to abnormal behavior of the cell. 

... Instead of resting, the cells may continue dividing; instead of dying the cells stay alive.  Mutations may also turn off genes that can repair damaged DNA, or that can induce cell death when mutations in the cell are detected.  See also tumor suppressor genes

 Lymphocytes are very active cells, which undergo  many normal  transformations in their life cycle and many more cell divisions than most other cell types.   They are designed to divide rapidly to address infections, but also to die off fast when the infection is under control.

Cell division, being a highly complex process, is prone to mistakes.  Mistakes may not be "picked up" or may often be inconsequential.   The defective or atypical cell will not necessarily lead to a cancer, however ... additional errors must occur.  Before it becomes a cancer the parent cell divides many times, passing on the defects that have malignant potential to the children cells.  Additional "hits" on the atypical cells may result from chemical exposures,  viral infections, oxidation, random errors ... 

For example: An atypical (slightly defective) lymphocyte  may be kept active longer because of chronic stimulation by a bug or virus (chronic infection being associated with higher risk of acquiring lymphoma) - making  additional random copy errors more likely to occur. 

... The first cell to lose normal growth control is called the cell of origin. When the cell of origin divides, the new cells inherit the genetic defects of the parent cell. Thus, in cancer, the descendants of the cell of origin are clones of this cell.

A hallmark of cancer cells is that they have growth and survival advantages over normal cells. Their cell division is not balanced by cell death. The abnormal cells may eventually form lumps called tumors. 

The word tumor simply means a mass of cells. Tumors can be either benign or malignant. Benign tumors are not a threat to life or long-term health, while malignant tumors are. The word malignant means 'showing great malevolence and being disposed to do evil.' One way that pathologists identify a tumor as being malignant is if the cells within it are clonal - all identical to the cell of origin. In contrast, benign tumors are made up of related but different cells. 

The hallmarks of cancer cells include:

	Limitless potential to divide and grow
	Resisting cell death (resisting apoptosis - normal programmed cell death)
	Evasion of detection by the immune system
	Inhibition of immune action (immune checkpoint blockade)
	Development of a sustaining blood supply (angiogenesis)
	Self sufficiency in growth signals
	Insensitive to anti-growth signals
	Tissue invasion and metastasis (spreading beyond the organ of origin)
	Reprogramming of energy metabolism
	Recruitment of normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment."* Note: Lymphomas are considered systemic cancers, because both normal and abnormal lymphocytes (the cell of origin) have the capacity to migrate anywhere in the body to fight infection.  Thus, finding lymphoma cells in the bone marrow or spleen is not unusual, and not considered a metastasis.
	Update: Hallmarks of cancer: the next generation. This report has added emerging hallmarks: 1) reprogramming of energy metabolism and 2) evading immune destruction.

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Lymphoma is a kind of blood cancer

Blood is a fluid made up of plasma and many types of blood cells, such as red blood cells (erythrocytes), white blood cells (leukocytes) and platelets. Blood circulates through the heart, arteries and veins. It carries "nourishment, hormones, vitamins, antibodies, heat and oxygen to the body's tissues." labtestsonline.org

 B-cell Cancers by Cell Maturation Stage - Click to enlarge

Lymphoma is a cancer that affects a type of white blood cells called lymphocytes – immune cells that normally protect you from illness. About 85% of lymphomas are of b-cell origin, and 15% of t-cell origin.  

B-cells originate and mature (differentiate) in the bone marrow. 

T-cells also start out in the bone marrow, but they differentiate and mature in the thymus gland. 

Natural Killer cells are a third kind of lymphocyte. They specialize in killing foreign cells and possibly signaling to alert other immune cells of invaders.

 

 
Leukocytes - Click to enlarge

The different types of lymphoma are determined according to what type of lymphocyte has become cancerous, and the stage of development. Click b-cell cancers by cell development to enlarge the illustration shown above.

As with other cancers, the root cause of lymphomas is damage to genes that leads to abnormal (deregulated) growth controls in the cell. 

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Lymphomas are a Family of Related Cancers.  

The cell of origin determines the subtype of lymphoma, and influences its  clinical behavior - growth rate and sensitivity to treatments.

The cell of origin, such as T-cell, B-cell, and NK cell, and the stage of maturation of that cell determines the type of lymphoma. This is often referred to as the cell type or diagnosis, such as follicular small cleaved lymphoma.

When a lymphocyte becomes malignant, its biologic behavior is arrested at that stage. This stage of development influencing its location tendencies and growth rate and other cellular behaviors. 

Analogy: Consider that just as children grow faster than adults, cells at earlier stages of development tend to grow faster than they do at mature stages. 

The malignant cells then may accumulate to form tumors that enlarge the lymph nodes or spread to other areas of the lymphatic system, such as the spleen or bone marrow, or outside the lymphatic system to the skin, or mucosal linings of the stomach. 

How widespread the lymphoma is, is summarized by the stage. Staging is the process of determining where the lymphoma is located by imaging and other methods. 

NOTE:  It's common for the lymphoma to be at stage IV at diagnosis. But, advanced stage of disease does not mean the treatments will not be effective. 

About growth rate. The cell of origin will also influence how fast or slow the lymphoma cells will tend to grow.  The growth tendency of the lymphoma is also called the grade.

Aggressive grade lymphomas divide and grow rapidly, and therefore prompt and aggressive treatment is indicated. 

Indolent grade lymphomas may not divide faster than normal lymphocytes. Here the malignant behavior can be resistance to cell death - a failure to "erase" itself after it's normal functions have been completed.  This results in a slow buildup of excess cancer cells causing tumors to form, but more slowly. 

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Mutations also influence the clinical behavior

The specific damage to DNA - and the gene expression - is likely to be variable for patients who have the same diagnosis. 

These differences may explain, in part, why patients with the same diagnosis can have lymphomas that develop at different rates, and respond differently to the same treatments. 

Recall that genes expression determine what proteins the cells express and this determines behavior. Response to treatment is also cell behavior.  For example, cells detecting damage to DNA - induced by treatment - will initiate cell death, but only if the genes that can activate the cell-death program are functioning or activated by the treatment.   

 "Ultimately, it may well be that the optimal treatment will be determined by patient clinical and biological characteristics." ~ Dr. Bruce Cheson - Advances in the Treatment of Non-Hodgkin's Lymphoma - Medscape (free login)

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Your Lymphoma is Unique

Factors that may account for clinical differences in lymphomas:

	The cell type: T-cell, B-cell, NK-cell, and subtypes of each;
	The stage of development of the cell of origin;
	Slight differences in stage of development;
	Specific damage to the genes;
	Different patterns of gene expression - silent versus active genes;
	Differences in the health, strength and characteristics of the immune systems;
	Differences in the microenvironment in the tumors, which are made up of  malignant and normal cells. Here the interactions among the cells in the tumor may be promoting or stabilizing; See also Immune signatures in follicular Lymphoma
	The presence or absence of antigen stimulation inside the body. An antigen is defined as a molecule that is recognized by the immune system as something that does not belong in the body.   Activation of lymphoma cells, like normal lymphocytes, may be promoted by an antigen, such as a bacteria, virus, ... or normal molecules the immune system mistakes to be foreign (as in an autoimmune response).    For example, a bacteria (the antigen) may trigger the cancerous lymphocyte to activate and divide, thus promoting the growth of the lymphocyte tumors.  MALT is a subtype of lymphoma that develops in the mucosal linings.  This lymphoma can resolve in many cases by treating a bacterial infection called H-pylori.

Notable Quote: "As we move to consider these tumors by their genetic abnormality (genotype) rather than their cellular appearance (phenotype), one converts the generalities of leukemia, lymphoma, and myeloma into hundreds of diseases with distinct genetic causes, clinical manifestations, and drug responsiveness."  ^Source

Encouraging Developments:  New technologies, particularly microarrays, can help to characterize gene expression in malignant cells, allowing scientists to see what is wrong, and compare one person's cancer to another's. For the first time in history we can begin to see what we are trying to fix at a fundamental level, and this is likely to lead to rationale selection of cancer therapies, as well as faster drug development and testing.  See NBN for more details.

Additional reading

Understanding cancer series  nci.nih.gov   An exceptional educational series provided by the National Cancer Institute: Cancer The Immune System Cancer Genomics Molecular Diagnostics Angiogenesis Blood Stem Cell Transplants Genetic Variation (SNPs) Gene Testing Cancer Genome Project Nanodevices Cancer and the Environment