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Last update: 06/13/2016

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TOPIC SEARCH: PubMed | SearchMedica

What Caused My Lymphoma?

NCI: "Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk."  Continue to Overview below.
 


Overview

2013:  Experts on risk factors for acquiring lymphoma and how it's diagnosed  

There are many factors associated with the increased risk of developing a lymphoma, but no definitive causes have been identified, with the exception of of H pylori infection, which has a causal role in the development of some mucosa-associated lymphatic tissue lymphomas (MALT). 

To many observers, the increase in incidence rates of lymphomas over the past 20 years, and the higher incidence rates in industrialized countries, suggests that environmental factors play a role.  However, with prosperity comes improvement in health care, which can increase the median age of the population (a risk factor) and also the ability to diagnose lymphomas. 

Consider also what experts call the problem of confounding variables in epidemiological research.  For example, an elevated risk associated with exposure to a specific drug, may be from the drug, or from the underlying condition the drug is given to treat.  Environmental confounding variables are particularly complex as no two individuals breath the same air, have the same diets, drink the same water, or have exposures to the same infection or chemicals.   

There could be many contributing factors that lead to the development of a lymphoma over time, such as advancing age, chronic infection, inherited disposition, exposures to chemicals or radiation, and chance. 

"Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer."    Cancer.gov

Regarding suspected environmental factors, scientists often study groups that are exposed in the workplace (because these exposures are higher and can be estimated with greater assurance), to see if the incidence rates of disease in the persons exposed to workplace toxins are significantly higher compared to the general population.

Regarding immune suppression as a risk factor?

Immune suppression is associated with an elevated risk of lymphoma – such as in transplant recipients where high doses of immune suppressing drugs on a daily basis are needed to prevent organ rejection.

Chronic inflammation (from autoimmune conditions) that are often treated with immune suppressing drugs (such as steroids) are also associated with increased risk of lymphoma – therefore, arguably, judicious use of anti-inflammatory drugs (steroids, NSAIDS) may decrease the net risk of lymphoma despite the association in people with autoimmune disease.

When the commercial says: “cases of lymphoma have been reported,” it does not mean that the drug caused it – only that the reported cases of lymphoma for those taking the drug appear to be higher than for the general population.

The factors that might have contributed to the lymphomas in this cohort include: chronic inflammation, shared predisposition to lymphoma and autoimmune disease, the long term use of steroids, or some other unknown factor.

In short, association is not evidence of causation.

An example: people who wear helmets when participating in sport have more brain injuries than the general population. Thus, helmets are associated with brain injury … But in this simple example it’s clear that the activity causes brain injury and that there would be more injuries in the sport without the helmet.

Regarding the risk of relapse – and just a lay person’s impression: Lymphomas take many years to present and multiple insults to the DNA are needed to cause it. It seems to me that the judicious use of steroids is very unlikely to increase the risk of lymphoma or of a relapse. More important would be the efficacy of the treatment for the lymphoma. Did it get all of the cells or not?

Full text reports:

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Science Daily: Type 2 Diabetes Linked to Increased Blood Cancer Risk
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Environmental Health News: Research links pesticides -
The results strengthen an argument for an environmental
link to increased risk for human NHL that is linked to higher
levels of organochlorine pollutants.
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Epidemiology of adult non-Hodgkin lymphoma http://bit.ly/qdokmY
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Etiologic heterogeneity (risk factor variation) among NHL subtypes,
Blood.
2008 http://bit.ly/bUDXZw
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Occupation and malignant lymphoma: a population based case control
study in Germany, Occup Environ Med 2006 http://bit.ly/btSkWn
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Environmental and Occupational Causes of Cancer New Evidence, 2005–2007,
Rev Environ Health 2009 http://bit.ly/afBT4S 
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Patterns of autoimmunity and subsequent CLL in Nordic countries,
Blood.
2006  http://bit.ly/d95BDm
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Inherited predisposition to CLL, http://bit.ly/a7dfp8
Expert Rev Hematol.
2008  


Factors
associated with an increase risk of developing a lymphoma:  

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Chemical exposures - chronic exposures to dioxins, PCBs, pesticides, solvents, and fertilizers 
 

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Chronic infections - H pylori is strongly associated with MALT
 

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Depressed immunity - such as caused by immune-suppressing drugs used to prevent
rejection of organ transplants. 

Lay comment It may be that depressed immunity is a common underlying risk factor.  
For example, chemical exposures, increasing age, and chronic and viral infection may depress or modify immunity in ways that favor the development of a lymphoma.
 

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Family history - genes and/or shared environmental determinants are associated with increased risk
 

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Genotypes - normal genetic variations that regulate immunity or cellular defense mechanisms 
may predispose some individuals to developing a lymphomas or other cancers.
 

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Viral exposures - Epstein Barr, Hepatitis C, and SV-40 are associated with some kinds of lymphomas.
 

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Age  - increasing age is a known risk factor for developing lymphomas and other cancers.
The median age for the development of NHL is about 65 years. 
 

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Chance - Genetic copy errors can take place within cells when they divide, leading to 
abnormal growth and survival controls of the cells.  Such chance errors may become more 
common, or inadequately addressed by repair mechanisms, when combined with factors listed above.

"It is likely that most blood cancers are the result of cellular misadventures in blood-forming cells 
or lymphocytes, aberrations of normal cell processes, such as spontaneous mutations 
resulting in oncogene formation and inadequacies of DNA repair mechanisms."  http://theoncologist.alphamedpress.org/cgi/content/full/13/2/126 

NOTES: It's difficult to identify factors that may cause lymphoma, and
many of the items within are classified as associations, and not as validated risk factors. 

An association is an observation that one event or condition occurs more commonly with another. But associations do not mean one thing caused another. See also Associations 

A cancer occurs when cells develop mutations that lead to loss of growth and survival controls - leading to so-called malignant behavior of that cell and all of its descendents.  It should be noted that avoidance of risk factors after the fact (following a diagnosis) will not undo or reverse the genetic defects in cancer cells... no more than putting away a match will put out a previously set fire.

Related Items about risk factors ... in the News:

 
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Not specific to lymphoma:

Red meat cancer link explained | UTSanDiego http://bit.ly/1Bdkok0

when people consume beef, pork, lamb and bison, a sugar molecule called Neu5Gc from those meats gets fully incorporated into human tissue. The immune system then attacks that substance, leading to tissue inflammation and a higher lifetime risk of cancer.

Most cancers are due to chance - random mutations.  However, about 1/3 are associated with environmental factors, such as smoking and diet.  This article very nicely explains an important research finding.  The study validated the role of a sugar molecule in meat, that finds its way into the cells of our body ... which can elicit an immune response leading to chronic inflammation, leading to an increased risk of cancer. 

Source study: pnas.org

A related article: 
Most cancer is bad luck: Study | UTSanDiego http://bit.ly/14hH2LZ

Source report:
Bad Luck of Random Mutations Plays Predominant Role in Cancer, Study Shows - 01/01/2015 http://bit.ly/1DaNhg9

 


What caused my Lymphoma?

There's a strong consensus that the development of a lymphoma is the result of many factors over a very long period of time - and not one cause.  That is, for a normal lymphocyte to become a lymphoma requires multiple mutations to key genes (so-called oncogenes) - such as to a gene that corrects cellular errors, or that initiates cell death when defects in the cell are detected, or to genes responsible for proliferation - that get stuck in the ON position.

You might imagine a single cell that by chance develops a mutation of a type that is not sufficient to initiate self-destruction ... perhaps it's a random error that can happen among the billions of cell divisions that take place in a day. (A chronic infection increasing the odds that copy error will occur during cell division.)

... This abnormal cell then divides and creates a family of atypical cells that are not yet malignant ... and, over time, only a handful continue on (perhaps stimulated to survive past their prime by infection?), which then acquire, by chance, or by exposure to chemicals or virus - another mutation ... and so on, and so on, for years.

(Years? Probably yes. Consider how long the latency is for melanoma, a skin cancer - presenting in adulthood but linked to sunburns in childhood. What accounts for the delay? Most likely, the requirement for additional mutations and damage to occur to specific genes within the sun-damaged cells.)

Also, as we age the built-in cellular and immune defenses against abnormal cells may weaken - an error "picked up" by our cells in our twenties is left unrepaired when we are sixty.

So ... age, chance, toxins, maybe in some cases a normal genetic predisposition, a chronic infection ... could all play a part in the path from normal lymphocyte to a lymphoma - defined as blood cells that has lost the ability to regulate their growth and survival.

So the question what caused my lymphoma seems impossible to determine in any single case - and it's proven elusive overall because there are multiple contributing factors - not the least of which are bad luck and aging. There are likely very different causes for any two survivors with the same diagnosis - a reason so many associations have been detected as suspected risk factors, but very few if any smoking guns.

~ Karl S.
 


In the News:

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Medscape 2015: (free registration / login required)
Does This Cause Cancer? http://bit.ly/1aLYxHk


Experts discuss evidence for and against BPA, Cell Phones, Artificial Sweeteners, Pesticides, Power Lines ... then give interesting verdicts

 
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Geographic clustering for cutaneous t-cell lymphoma - PubMed - NCBI http://1.usa.gov/1F0MFMT
* Clin Gastroenterol Hepatol,  2014
Risks of Lymphoma with anti-tumor necrosis factor for IBD  http://1.usa.gov/1iEMJsN
* Leuk Lymph 2013:
Body mass index, height and risk of lymphoid neoplasms in a large United States cohort. http://1.usa.gov/1cL4uOl
* FHCRC 2013:
Study finds link between allergies and increased risk of blood cancers in women http://bit.ly/J2zxgT
* Medscape 2013:
Allergies and Hematologic Cancer Risk: Is There a Link? http://bit.ly/1eqN8ca
* Medical xpress 2013: Cancer:
Lymphoma-linked risk factor identified http://bit.ly/16IKPw2
* Cancer Research UK 2013:
Huge genetic analysis points to cancer-causing culprits http://bit.ly/1cDCTnL

Intriguing

* 2012, Shuangge , Associate Professor of Biostatistics, Yale University:
Risk factors for the etiology and prognosis of follicular lymphoma

 


Resources: On the Causes of Lymphomas and other Cancers

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Battling the Hematological Malignancies: The 200 Years' War  theoncologist.alphamedpress.org
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Overview on causes of cancers Cancerhelp.org
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Infection-Driven Lymphomas:  The List Grows thehematologist 2004
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NIH 11th report on carcinogens  NIH.gov | Lymphoma-specific
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Update on Epidemiology and Therapeutics for Non-Hodgkin’s Lymphoma 
Julie M. Vose, Brian C.-H. Chiu, Bruce D. Cheson, Janet Dancey and John Wright  
(Posted Nov_28_02)  Abstract   asheducationbook.org
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Viral Origins of Lymphoma  MD Anderson Cancer Center
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Do you live in a high risk area?  MAP on NCI website
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Occupation and risk of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. 
J Occup Environ Med. 2002 May;44(5):469-74. PMID: 12024692 PubMed abstract
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Risk factors, overviews  MSKCC  
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Roswell Park Cancer Institute  Journal updates
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Some aspects of the etiology of non-Hodgkin's lymphoma NIH.gov


Allergies

 
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* FHCRC 2013:
Study finds link between allergies and increased risk of blood cancers in women: Gender may play a role in the association of chronic immune stimulation and development of hematologic cancers http://bit.ly/J2zxgT
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Allergies and risk of non-Hodgkin's lymphoma by subtype. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):401-7. PMID: 11927501  PubMed
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Case-control study of non-Hodgkin's lymphoma among women and heterosexual men in the San Francisco Bay Area, California. Am J Epidemiol. 1999 Aug 15;150(4):375-89. PMID: 10453814  PubMed


Aspirin and Other Pain Killers

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Acetaminophen tied to blood cancers http://reut.rs/jc93zU

This article could be used as a model for how to explain such findings.
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Regular use of aspirin or acetaminophen and risk of non-Hodgkin lymphoma. http://www.ncbi.nlm.nih.gov/pubmed/15947882  2005 Apr;16(3):301-8.
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Regular use of aspirin, but not other nonsteroidal anti-inflammatory drugs (NSAIDs), is associated with a significant reduction in risk of Hodgkin's lymphoma  docguide.com
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Aspirin may help prevent Hodgkin's disease- study 18 Feb 2004  cnn.com


Autoimmune
disease

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Immune-Related and Inflammatory Conditions and Risk of Lymphoplasmacytic Lymphoma or Waldenström Macroglobulinemia http://1.usa.gov/1H0m01C

We used Swedish population-based registries to identify 2470 case patients with LPL-WM, 9698 matched control subjects, and almost 30 000 first-degree relatives of either case patients or control subjects. We evaluated a wide range of autoimmune, infectious, allergic, and inflammatory conditions. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each condition by use of logistic regression.

An increased risk of LPL-WM was associated with a personal history of the following autoimmune diseases:
systemic sclerosis (OR = 4.7, 95% CI = 1.4 to 15.3),
Sjögren syndrome (OR =
12.1, 95% CI = 3.3 to 45.0),
autoimmune hemolytic anemia (OR = 24.2, 95% CI = 5.4 to 108.2),
polymyalgia rheumatica (OR = 2.9, 95% CI = 1.6 to 5.2), and
giant cell arteritis (OR = 8.3, 95% CI = 2.1 to 33.1).


An increased risk of LPL-WM was associated with a personal history of the following infectious diseases:
pneumonia (OR = 1.4, 95% CI = 1.1 to 1.7),
septicemia (OR = 2.4, 95% CI = 1.2 to 4.3),
pyelonephritis (OR = 1.7, 95% CI = 1.1 to 2.5),
sinusitis (OR = 2.7, 95% CI = 1.4 to 4.9),
herpes zoster (OR = 3.4, 95% CI = 2.0 to 5.6), and
influenza (OR = 2.9, 95% CI = 1.7 to 5.0).

An increased risk of LPL-WM was associated with a family history of the following autoimmune or infectious diseases:
Sjögren syndrome (OR = 5.0, 95% CI = 2.1 to 12.0),
autoimmune hemolytic anemia (OR = 3.8, 95% CI = 1.1 to 13.2),
Guillain–Barré syndrome (OR =
4.1, 95% CI = 1.8 to 9.4),
cytomegalovirus (OR = 2.7, 95% CI = 1.4 to 5.3),
gingivitis and periodontitis (OR = 1.9, 95% CI = 1.3 to 2.7), and
chronic prostatitis (OR = 4.3, 95% CI = 1.7 to 11.1).
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Autoimmune disease in individuals and close family members and susceptibility to non-Hodgkin's lymphoma - Mellemkjaer - 2008 - Arthritis & Rheumatism - Wiley Online Library http://bit.ly/1CRTL68

A personal history of systemic autoimmune diseases (RA, SLE, Sjögren's syndrome, systemic sclerosis) was clearly linked with NHL risk, both for individual conditions (hierarchical odds ratios [ORh] ranged from 1.6 to 5.4) and as a group (ORh 2.64 [95% confidence interval (95% CI) 1.72–4.07]).

In contrast, a family history of systemic autoimmune diseases was modestly and non-significantly associated with NHL (ORh 1.31 [95% CI 0.85–2.03]). An increased risk of NHL was found for a personal history of 5 non-systemic autoimmune conditions (autoimmune hemolytic anemia, Hashimoto thyroiditis, Crohn's disease, psoriasis, and sarcoidosis) (ORh ranged from 1.5 to 2.6) of 27 conditions examined.
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Autoimmune diseases associated with non-Hodgkin ly... [Ann Oncol. 2014] - PubMed NCBI http://1.usa.gov/1rdOrFK

Many of 33 studied ADs (except for ankylosing spondylitis, diabetes type I graves/hyperthyroidism, multiple sclerosis, chorea minor, and pernicious anemia), especially when diagnosed at younger ages, were associated with higher risk of NHL. However, the absolute risk of NHL in many ADs is still small.
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Autoimmune and Chronic Inflammatory Disorders and Risk of Non-Hodgkin Lymphoma by Subtype http://bit.ly/1uC9WAC

Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.
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Autoimmune Disease Is a Risk Factor for the Development of Non-Hodgkin's Lymphoma  rheum.com



Bacteria
H pylori risk

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Clear association has been made, and treatment of H pylori can lead to sustained remissions of H pylori + MALT lymphoma.

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Regression of gastric high grade MALT lymphoma after Helicobacter pylori eradication



Benzene

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"Exposure to benzene, an important industrial chemical and component of 
gasoline, is a widely recognized cause of leukemia, but its association with 
non-Hodgkin lymphoma (NHL) is less clear."

full text: http://cebp.aacrjournals.org/cgi/content/full/16/3/385 

"Potential mechanisms include immunotoxicity and the induction of
double-strand breaks with subsequent chromosome damage resulting in
translocations and deletions. We conclude that, overall, the evidence
supports an association between occupational benzene exposure and NHL."



Blood
transfusions

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"The findings in this study suggest that occupational exposure to specific chemicals plays an important role in the development of NHL in Canada."



Chemicals 
(PCBs), 
associations

(occupational)

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"The findings in this study suggest that occupational exposure to specific chemicals plays an important role in the development of NHL in Canada."

Comment:  The evidence regarding the causal effects of herbicides and pesticides in lymphomas appears thin (even if plausible).  However,  I found the precautionary principle described in the report below to be very compelling ... and grounded in common sense. ~ KarlS

The Dose Makes the Poison—Or Does It?

INVOKING THE PRECAUTIONARY PRINCIPLE

You may have heard of the Precautionary Principle, an approach that developed in Europe to protect human health and the environment in the face of the many unanswered and answerable questions related to environmental and human health. The principle calls for implementation of preventative measures to protect environmental quality and public health in spite of scientific uncertainties.

 www.actionbioscience.org
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Agent Orange - Fast Track for VA Claims
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Understanding Population and Individual Risk Assessment: The Case of Polychlorinated Biphenyls and Lymphoma cebp.aacrjournals.org

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A Cross-Sectional Study of Occupational Exposure to Trichloroethylene (TCE), Chromosomal Aberrations, and Related Biomarkers in Guangdong, China  ClinicalTrials.gov  

Comment:  We are often asked if it would be useful to poll support list members to help identify common life style factors and exposures that may have led to developing lymphomas. 

It's very  difficult to find reliable answers to questions like this by using surveys because there are just too many factors to consider, and it's virtually impossible to quantify the exposures  (concentrations, time, confounding factors) ... many of which can happen without our knowledge.  Do we know, for example, what's in our drinking water, air, and foods?

For this reason, epidemiologists focus research on occupational groups so that the exposures of suspected agents can be more reliably estimated. But even with this approach there have been many suspects identified, but no conclusive information. Nobody to prosecute and lock up.

But, an important new investigational tool may help cement causal environmental factors that lead to increased risk of lymphomas. In the study below, molecular profiling will be done on persons exposed to TCE in the workplace who have developed a lymphoma, and who have not yet received treatment. With this tool it may be possible to identify specific "chromosomal aberrations that have been associated with NHL and related hematological malignancies."

It's one thing to say you have lymphoma and you were exposed to TCE, and another to say: TCE is known to cause specific chromosome damage to lymphocytes in animals and people. These individuals have lymphoma, were exposed to significant levels of TCE, and the malignant cells have this specific abnormality.

If the study determines this, we will have a much higher level of confidence about the risk of TCE specific to lymphoma ... a smoking gun - a biomarker. The link above describes a study with this goal that is recruiting patients. It's an NCI study. The center is in Maryland.
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Persistent organochlorine (PCB) chemicals in plasma and risk of non-Hodgkin's lymphoma. Cancer Res. 2005 Dec 1;65(23):11214-26. PMID: 16322272 | Related articles
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PCBs, furans may factor in risk of non-Hodgkin lymphoma  eurekalert.org

Scientists have found some additional evidence that environmental exposure to polychlorinated biphenyls (PCBs) may be associated with non-Hodgkin lymphoma, according to a study published in the December 1 issue of Cancer Research.
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Report Supports Association Between Agent Orange and CLL
  
"A re-evaluation of evidence now supports an association between exposure to herbicides used during the Vietnam War and the development of a specific form of leukemia in veterans"  IOM  protectingourhealth.org
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Blood Levels of Organochlorines before and after Chemotherapy among Non-Hodgkin’s Lymphoma Patients  cebp.aacrjournals.org
 
" Several small studies suggest a link between environmental exposure to organochlorine compounds and risk of non Hodgkin’s lymphoma (NHL). Because NHL is uncommon, studies of the topic often use a population-based case-control design, in which cases generally are enrolled after treatment has begun.  If chemotherapy affects blood levels of organochlorines, exposure will be misclassified and findings distorted. "
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Case-control study on concentrations of organohalogen compounds and titers of antibodies to Epstein-Barr virus antigens in the etiology of non-Hodgkin lymphoma   safe2use.com
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A nested case-control study of non-Hodgkin lymphoma and serum organochlorine residues.
Lancet. 1997 Jul 26;350(9073):240-4. PMID: 9242800  PubMed
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NHL and occupational exposure to chemicals in Canada. Canadian Cancer Registries Epidemiology Research Group  PubMed



Diet and risk of lymphoma

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Diet and nutrient intakes and risk of non-Hodgkin's lymphoma in Connecticut women.
Am J Epidemiol. 2004 Mar 1;159(5):454-66. PMID: 14977641 

Risk of NHL associated with diet and nutrient intakes appeared to vary based on NHL subtype. An association between dietary intake and NHL risk is biologically plausible because diets high in protein and fat may lead to altered immunocompetence, resulting in an increased risk of NHL. The antioxidant or inhibiting nitrosation reaction properties of vegetables and fruits may result in a reduced risk.
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Obesity and risk of non-Hodgkin's lymphoma: A meta-analysis.
Int J Cancer. 2007 Apr 18;  PMID: 17443495 

These findings indicate that excess body weight is associated with an increased risk of non-Hodgkin's lymphoma, especially of diffuse large B-cell lymphoma.



Dioxin
exposures

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Understanding Population and Individual Risk Assessment: The Case of Polychlorinated Biphenyls and Lymphoma http://cebp.aacrjournals.org/content/15/5/830.full 
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Dioxin emissions from a solid waste incinerator and risk of non-Hodgkin lymphoma. Epidemiology. 2003 Jul;14(4):392-8. PMID: 12843761 | Abstracts



Drugs

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There have been reported associations between certain drugs and an increased risk of developing a lymphoma. 

TOPIC SEARCH: PubMed

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Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006 Mar;54(3):692-701. PMID: 16508929 
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Should arthritis patients fear the side effects of Enbrel, Remicade, and Humira? about.com    
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Remission of lymphoma after drug withdrawal in rheumatoid arthritis  eMJA
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Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf. 1999 Jun;20(6):475-87. Review. PMID: 10392665  PubMed



Familial or Genes and risk of developing lymphomas

Familial describes a trait or disease that is observed with higher frequency within the same family, whether the etiology [cause] is genetic or environmental, or a combination of the two.  Where a hereditary disease is one that is caused by a genetic trait.

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TOPIC SEARCH: PubMed | Medscape | Web

There may be inherited factors (susceptibilities) increasing the risk of developing a lymphoma, but a family history of lymphoma alone does not mean you have a high probability of developing a lymphoma.  It appears that other factors must contribute - including random copy errors (bad luck), chronic infection, increasing age, immune suppression, or common exposures to environmental toxins.   

New Item

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Best Practice Res Clinical Haematol. 2011:
Host genetics in follicular lymphoma http://1.usa.gov/XvKteN

Given an estimated lifetime risk of NHL of 1 in 48 (2.1%) in the United States [1] and a RR of 1.5 for the risk of NHL in first degree family members [13], then the absolute lifetime risk of NHL is 3.2% in first degree relatives of an NHL patient.

For FL, the estimated lifetime risk is 1 in 278 (0.36%) [1], and using a RR of 4.0 for the risk of FL in first degree family members [8], then the absolute lifetime risk of FL is 1.4% among first degree relatives of FL patients.

The clinical significance of the absolute increased risk to relatives of patients with FL is not trivial, although the relatively low incidence of FL, the modest familial risk, and the lack of a screening test/clinical intervention all argue against clinical surveillance of families of FL patients at this time. Results of candidate gene studies of risk are too preliminary to move to the clinic, and even replicated loci are too few that they are not useful in identifying individuals at high risk of FL.

Comment: regarding familial risks (incidence among relatives of patients with FL) shared environmental exposures cannot be ruled out as a contributing factor.

 

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Genetic Susceptibility to Lymphoma - Technical review ncbi.nlm.nih.gov

"The risk of lymphoma among siblings of lymphoma probands (family members through whom a family's medical history comes to light.) was over 2.5-fold that of the general population and lower among other family members." [1]  

However, common environmental exposures have not been ruled out: "Lymphomas may also cluster within families, not because of an inherited genetic susceptibility, but because of shared environmental determinants." B. Cheson  Source: asheducationbook.org

  1. The incidence of lymphoma in first-degree relatives of patients with Hodgkin disease and non-Hodgkin lymphoma: results and limitations of a registry-linked study.

    Cancer. 2000 May 15;88(10):2357-66. PMID: 10820359  PubMed
  2. Familial aggregation of hematopoietic malignancies and risk of non-Hodgkin's lymphoma.

    Cancer Res. 1992 Oct 1;52(19 Suppl):5468s-5473s. Review. PMID: 1394155  PubMed
  3. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.

    Blood. 2001 Jul 1;98(1):194-200. PMID: 11418480  PubMed
  4. CLL: Scientists find new leukemia gene risk factors
     
  • Risk of Non-Hodgkin's Lymphoma and Family History of Lymphatic, Hematologic, and Other Cancers - Vol. 13, 1415-1421, September 2004   aacrjournals.org
  • The role of genes in the development of non-Hodgkin's lymphoma  news-medical.net 

    "... variations of individual DNA building blocks in genes encoding for the cellular signaling molecules tumor necrosis factor (TNF) and interleukin 10 (IL-10) increase the risk of developing non-Hodgkin's lymphoma."
  • Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database  bloodjournal.org/cgi/content/full/106/2/668  Blood, 15 July 2005, Vol. 106, No. 2, pp. 668-672.

    "The present findings give evidence for a strong familial association of NHL, with little differences in the magnitude of risks for various histopathologic subtypes. The patterns of risks in parents and siblings support the hypothesis of an autosomal-dominant component for diffuse large B-cell NHL and a recessive one for follicular NHL."
  • Anticipation in families with Hodgkin's and non-Hodgkin's lymphoma in their pedigree.
    Leuk Lymphoma. 2006 Oct;47(10):2115-27. PMID: 17071485 

    "Anticipation" is an earlier onset and/or increasing severity [of disease] in successive generations.  ... These data suggest that anticipation occurs in families that exhibit both HL and NHL and that both neoplasms may have a common genetic basis.
  • Family history of hematopoietic cancer increases non-Hodgkin lymphoma risk  cancerpage.com  2007

    "Because family history represents the interaction between shared environmental exposures, behaviors, and genetic susceptibility, a full understanding of NHL heritability can provide clues regarding underlying disease mechanisms, particularly as it relates to disease and subtype-specific heterogeneity," the investigators explain.

    "Future efforts in sib-pair or twin studies may further our understanding of the sibling relationships, particularly for the male- and female-specific associations for family history of NHL and leukemia, respectively," the researchers add.
  • Highly increased familial risks for specific lymphoma subtypes. 
    Goldin LR, Björkholm M, Kristinsson SY, Turesson I, Landgren O. Br J Haematol. 2009 May 4. PMID: 19438470

    Relatives were at the highest risk for developing the same lymphoma subtype as the case. DLBCL was increased 10-fold among relatives of DLBCL patients, FL was increased fourfold among relatives of FL patients and HL was increased fourfold among relatives of HL patients. These results imply that germline susceptibility genes are specific to lymphoma subtype.


  • ... Genetic Susceptibilities

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    Polymorphisms are normal genetic variations that influence biological processes ... each variation may have both strengths (protective aspects) and weaknesses (susceptibilities). Just as being tall or short can provide advantages and disadvantages.

    We already know that normal genetic variations are what account for differences in how patients metabolize the same drugs, just one example - but also data is emerging that polymorphisms influence susceptibility to disease.

    Get used to seeing polymorphisms in the news, and SNP, pronounced "snips," which stands for Single Strand Polymorphisms.

    Polymorphisms may explain why persons exposed to the same toxins do not all come down with cancers. But susceptibility does not mean causing ... for example, other  triggers may be required, such as environmental exposures.

    (KS 2/08)

    News Items

    bullet
    Genetic Susceptibility to Lymphoma - Technical review ncbi.nlm.nih.gov
    bullet See SNPs fact sheet ornl.gov



    Fats
    (saturated, trans)
    and some meats

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    TOPIC SEARCH: PubMed 

    "Intake of beef, pork, or lamb as a main dish was associated with a statistically significantly increased risk of NHL. Higher intake of trans unsaturated fat was also statistically significantly associated with an increased risk of the disease." [1]

    1. Dietary fat and protein in relation to risk of NHL among women  - Full Text
    2. Diet and risk of non-Hodgkin lymphoma in older women.
      JAMA. 1996 May 1;275(17):1315-21. PMID: 8614116 | Related articles
    3. Dietary factors and non-Hodgkin's lymphoma in Nebraska (United States).
      Cancer Causes Control. 1994 Sep;5(5):422-32. PMID: 799996



    Fluoride

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    "The percentage of people supplied with "optimally" fluoridated drinking water (FD) obtained from the Fluoridation Census 1985, U.S.A. were used for regression analysis of incidence rates of cancers at thirty six sites (ICD-WHO, 1957)." [1]

    1. Regression analysis of cancer incidence rates and water fluoride in the U.S.A. based on IACR/IARC (WHO) data (1978-1992). International Agency for Research on Cancer.
      J Epidemiol. 2001 Jul;11(4):170-9. PMID: 11512573  PubMed
    2. Correlation of incidence rates for selected cancers in 29 census sub-divisions of Alberta, Canada, 1961-1981. Ecol Dis. 1983;2(2):129-33. PMID: 6332009  PubMed




    Life Style 
    Sunlight / Diet

    Also see Fats

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    "Higher intake of vegetables, particularly cruciferous vegetables, may reduce the risk of non-Hodgkin's lymphoma among women." [1]

    1. Higher intake of fruits and vegetables associated with lower risk of NHL  Harvard.edu 
    2. Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER Case-Control Study. Blood. 2006 Nov 21;  PMID: 17119116 

      lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism.
    3. Sun exposure, vitamin D receptor gene polymorphisms and risk of non-Hodgkin lymphoma. Abstract

      "Recent findings suggest that ultraviolet (UV) radiation exposure may reduce risk of developing non-Hodgkin lymphoma (NHL), but the biologic basis for this relationship remains unclear."
    4. Green tea consumption and hematologic malignancies in Japan: the Ohsaki study



    Gasoline exposure and associated risk

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    bullet
    Occupational Exposures and Non-Hodgkin’s Lymphoma in Southern Sweden  PDF

    Eric Dryver, MD, Lars Brandt, MD, PHD, Timo Kauppinen, PHD, Hakan Olsson, MD, PHD

    "Exposures to gasoline (OR 1.92; CI 1.20, 3.08), solvents (OR 1.59; CI 1.11, 2.28), and other oil products (OR 1.54; 1.01, 2.36) for more than five years were associated with increased risks of NHL (Table 2). The occupations of automobile mechanic (OR 1.82; CI 1.18, 2.81) and painter (OR 1.77; CI 1.13, 2.76) were also related to increased NHL risks."

    See for meaning of OR 



    Hair Dye

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    ... experimental animal studies and other epidemiologic studies provides little convincing evidence linking non-Hodgkin's lymphoma with normal use of hair-color products in humans." [1]
    1. Hair-color products and risk for non-Hodgkin's lymphoma: a population-based study in the San Francisco bay area. Am J Public Health. 1998 Dec;88(12):1767-73. PMID: 9842372  PubMed


    Inflammation, chronic

     

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    See autoimmune and Viral infection



    Hormone Replacement Therapy

     

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    Immune-Related and Inflammatory Conditions and Risk of Lymphoplasmacytic Lymphoma or Waldenström Macroglobulinemia http://1.usa.gov/1H0m01C



    For menopausal hormone therapy use, overall associations between NHL and unopposed estrogen and estrogen plus progestin were null, with the potential exception of an inverse association (RR = 0.49, 95% CI, 0.25-0.96) between use of unopposed estrogen and diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype, among women with a hysterectomy. These data do not support an important role for reproductive factors or exogenous hormones in modulating lymphomagenesis. 2
     
    1. Hormone Replacement Therapy and Risk of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia1 PuMed  | full text
    2. Reproductive factors, exogenous hormone use and risk of lymphoid neoplasms among women in the National Institutes of Health-AARP Diet and Health Study Cohort. http://bit.ly/1gEc3z  

      n -= 134,074 women.



    Magnetic Fields

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    "Lymphoma Promotion Studies -- Studies conducted in two strains of transgenic mice [PIM mice carrying the pim-1 oncogene and TSG-p53 mice, in which the tumor suppressor gene, p53, has been deleted] revealed no activity of 60 Hz magnetic field exposure as a promoter of hematopoieticneoplasia." [1]
     
    1. Studies to Evaluate the Toxicity and Potential Carcinogenicity of 60 Hz Magnetic Fields in Laboratory Animals  infoventures.com



    Melanoma

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    It is prudent to check for melanoma often if you have NHL.

    An association between cutaneous melanoma and non-Hodgkin's lymphoma: pooled analysis of published data with a review oxfordjournals
    1. See for more detail and ABCD image chart 

     

    Metals

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    1. Listing Occupational Carcinogens
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1247606/?tool=pmcentrez
       
    2. Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and
      Cocarcinogenesis: Nickel, Arsenic and Chromium
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602826/?tool=pmcentrez


    Mothballs

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    1. Mothballs linked to increase risk of lymphoma in women  ehp.niehs.nih.gov | abstract


    Nitrates in
    drinking water

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    "These findings indicate that long-term exposure to elevated nitrate levels in drinking water may contribute to the risk of NHL." [1]

    1. Drinking water nitrate and the risk of non-Hodgkin's lymphoma - NCI



    Immune suppression/Organ Transplants/HIV/AIDS

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    A depressed or malfunctioning immune system is associated with increased risk of developing Lymphomas.
     
    bullet
    *Am J Hem 2014:
    Risk of diffuse large B-cell lymphoma after solid organ transplantation in the United States. http://1.usa.gov/QLuJR9
     
    bullet
    Meta-analysis of risk for lymphoma with immunomodulators for inflammatory bowel disease  http://bit.ly/aFd4kp
    bullet
    Risk of Lymphoma Following Exposure to Calcineurin Inhibitors and Topical Steroids in Patients with Atopic Dermatitis. J Invest Dermatol. 2006 Nov 9;  PMID: 17096020 
    bullet
    Cancer risk from arthritis drugs overstated-study  alertnet.org 

    The new analysis showed the cancer risk was 2.4 times greater among patients who used the drugs, and the risk of infectious disease was 1.8 times greater.
    bullet
    Immunomodulators for Inflammatory Bowel Disease Raise Lymphoma Risk  oncolink

    "Treating inflammatory bowel disease (IBD) with azathioprine or 6-mercaptopurine (6-MP) increases the risk of lymphoma by about fourfold, according to a report in the August issue of Gut. Still, the absolute risk of this malignancy is small and, for most patients, the benefits of these agents outweigh the risks."
    bullet
    Primary Immune Deficiency (Hyper-IgM Syndrome)  Immune Deficiency Foundation
    bullet
    Lymphoma risks in populations with altered immunity--a search for mechanism.  Cancer Res 1992 Oct 1;52
    bullet
    HIV/AIDS: Update: cancer risk in persons with HIV/AIDS in the era of combination antiretroviral therapy.  AIDS Read 2000 Jun;10(6):341-6
    bullet
    The role of immunosuppression in lymphoma.  Recent Results Cancer Res 2002;159:55-66



    Pesticides

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    bullet
    Lancet 2015:
    Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate http://bit.ly/1HrIt9W
    bullet
    Pesticides Research Report: Do Pesticides Cause Lymphoma?
    bullet
    A nested case-control study of non-Hodgkin lymphoma and serum organochlorine residues.
    Lancet. 1997 Jul 26;350(9073):240-4. PMID: 9242800  PubMed
    bullet
    Pesticides and childhood lymphoma: "A newly published study has found that children exposed to pesticides in the home may be three to seven times more likely to develop non-Hodgkin's lymphoma (NHL), compared to unexposed children." article - CNN  abstract - Cancer 2000 Dec 1;89(11):2315-21
    bullet
    Published studies showing pesticides increase risk:
    Cancer Epidemiol Biomarkers Prev 2001 Nov;10(11):1155-63
    Cancer 1999 Mar 15;85(6):1353-60
    bullet
    Environmental epidemiology of non-Hodgkin's lymphoma in eastern Nebraska.  Am J Ind Med 1990;18(3):303-5



    Radon exposure

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    bullet
    Study Links Residential Radon Exposure to Increased Risk of Hematologic Malignancies in Women - The ASCO Post http://bit.ly/1PaLGfi
    bullet
    Interactive map:
    US Radon Levels Map http://bit.ly/1XOB6mV
     



    Rheumatoid
    Arthritis

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    "Disease processes at work in patients with rheumatoid arthritis appear to increase their risk of developing lymphoma, a form of cancer that affects lymph tissue, according to Swedish researchers."

    bullet
    Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature.

    http://www.ncbi.nlm.nih.gov/pubmed/18501101 
    bullet
    Should arthritis patients fear the side effects of Enbrel, Remicade, and Humira? about.com  
    bullet
    Remission of lymphoma after drug withdrawal in rheumatoid arthritis  eMJA
    bullet
    Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf. 1999 Jun;20(6):475-87. Review. PMID: 10392665  PubMed
    bullet
    Rheumatoid Arthritis & Lymphoma  PersonalMD.com

    Psoriasis

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    Patients with psoriasis are at increased risk for developing lymphoma. But additional studies are necessary to determine if the increased rate of lymphoma is related to psoriasis severity, psoriasis treatment, or an interaction between these risk factors. 
     
    bullet
    Lymphoma Rates Are Low but Increased in Patients With Psoriasis: Results From a Population-Based Cohort Study in the United Kingdom. 
    Arch Dermatol. 2003 Nov;139(11):1425-1429.  PMID: 14623702 | Related abstracts
    bullet
    Researchers Link Psoriasis to Increased Lymphoma Rate  psoriasis.org 

    They also commented that it is not clear whether the increased rate was due to psoriasis severity or treatment, or whether the results apply to younger patients.



    Sjogren’s
    Syndrome

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    bullet
    Malignant lymphoma in primary Sjogren's syndrome.  Isr Med Assoc J 2001 Oct;3(10):761-6

    "A low grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the commonest lymphoid neoplasia in Sjogren's syndrome."
    bullet
    See Sjögren's Syndrome for details about this condition and its associations with lymphomas.


    Smoking

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    bullet
    Expression of DNA mismatch repair proteins in transformed non-Hodgkin's lymphoma: Relationship to smoking. Leuk Lymphoma. 2006 Sep;47(9):1806-12. PMID: 17064992 

    We found that the relative risk of negative immunostaining for either MLH1 or MSH2 was 2.2 times higher in smokers than non-smokers (relative risk = 2.2041, 95% confidence interval: 0.89714, 5.41491). No direct correlation was found between smoking and the mutations in the p53 gene. These results suggest that cigarette smoking may play a role in the development of transformed lymphomas through defective mismatch repair.
    bullet
    Tobacco and alcohol consumption and risk of lymphoma: Results of a population-based case-control study in Germany. Int J Cancer. 2005 Aug 3; PMID: 16080191 
    bullet
    Italian Study Links Tobacco Use to Development of [follicular] Non-Hodgkin’s Lymphoma  cancerconsultants.com 
     
    "They reported a 50 percent increased risk for 16-33 pack-years and an 80 percent increased risk with 34 pack years or greater. There was no increased risk for the other NHL subtypes. In the second study, data on over 6,500 cases of NHL showed only an increase incidence of follicular NHL and not other cell types."
    bullet
    Smoking AND lymphoma  Related PubMed abstracts
    bullet
    Cigarette Smoking in Women Increases Risk for Follicular Lymphoma.
    United States Researchers from Yale University have reported that long-term cigarette smoking in women increases the risk of developing follicular lymphoma.  cancerconsultants.com



    Stress?

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    In the News

    bullet
    AACR: Risk of Infection-Related Cancers after the Loss of a Child: A Follow-up Study in Sweden http://bit.ly/V3BH2z

    Because stress is such a common part of life it's exceedingly difficult if not impossible to measure objectively, or to link it to this or any disease conclusively.

    Stress could play a role in immune suppression, so I think epidemiologists have looked for extreme cases of stress - loss of a child, divorce, etc., to see if there's an increased incidence of lymphoma in such populations.

    See for one report: http://bit.ly/6Z50M4 but note that confounders exist, such as possible shared genetic determinants and environmental exposures (ie., virus/other), and that the increased risk is small - as in not definitive - could be from unrelated factors.

    Most experts say that the development of any cancer is not determined by one, but by multiple factors and that for a normal cell to become a cancer requires multiple "hits" on DNA within the cell. So even if stress plays a small part in some cases, it's probably not the main player.

    KarlS

    bullet
    Query "psychological stress" AND risk of lymphoma? PubMed 
    bullet
    Stressful life experiences and risk of relapse of breast cancer: observational cohort study  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC115851/
    bullet
    Cancer survival in parents who lost a child: a nationwide study in Denmark  http://www.nature.com/bjc/journal/v88/n11/full/6600948a.html
    bullet
    Stress spectrum disorders in oncology ncbi.nlm.nih.gov
    bullet
    Psychological stress in oncology: the role of glucocorticoids - ncbi.nlm.nih.gov
    bullet
    Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. ncbi.nlm.nih.gov



    Viral
    Associations

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    EBV | HCV | Mouse virus | SV40 virus

    A type of virus that can cause cancer (which are uncommon) is called an oncovirus: See for discussion: http://en.wikipedia.org/wiki/Oncovirus

    Epstein Barr Virus (EBV)
     

    bullet
    About EBV - CVC
    bullet
    Epstein-Barr virus (EBV) associated lymphomas   Related abstracts

    The three main types of EBV-associated lymphomas are

    Burkitt lymphoma,
    Hodgkin lymphoma and
    post-transplant lymphomas
     
    bullet
    NEJM: Characteristics of Hodgkin's Lymphoma after Infectious Mononucleosis  nejm.org

    snips:

    "We estimated that the median incubation period for Hodgkin's lymphoma attributable to infectious mononucleosis–related EBV infection was 4.1 years, with a peak in risk 2.4 years after infection.

    These estimates are in accordance with those of a large case–control study of Hodgkin's lymphoma in which the median interval between infectious mononucleosis and Hodgkin's lymphoma was five years.17

    ...

    We emphasize that in absolute terms, the risk of Hodgkin's lymphoma after infectious mononucleosis is only on the order of 1 case per 1000 persons.5  Consequently, other cofactors acting in concert with infectious mononucleosis–related EBV infection presumably must be present for the infection to give rise to Hodgkin's lymphoma.16
    bullet
    Case-control study on concentrations of organohalogen compounds and titers of antibodies to Epstein-Barr virus antigens in the etiology of non-Hodgkin lymphoma   safe2use.com 

    HCV

    "Accumulating evidence support a role for hepatitis C virus (HCV) in the pathogenesis of human lymphoproliferative disorders." 

    bullet
    Treatment of Hepatitis C Reduces Incidence of Non-Hodgkin’s Lymphoma cancerconsultants.com

    Researchers from Japan have reported that viral elimination in hepatitis C virus (HCV) infected patients reduces the incidence of non-Hodgkin’s lymphoma (NHL). The details of this study appeared in the December, 2007 issue of the American Journal of Medicine.
    bullet
    Hepatitis C infection increases lymphoma risk   aidsmap.com

    "Although the risk of developing lymphomas is small, our research suggests that screening of HCV-infected individuals could identify conditions which may lead to cancer. It might then be possible to prevent progression to lymphoma," commented investigator Eric A. Engels, adding, "more research is needed to further clarify the relationship between HCV infection and lymphoma."
    bullet
    The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B-cell malignancy. Semin Liver Dis. 2000;20(2):143-57. Review. PMID: 10946420 

    It can be postulated that HCV is the stimulus not only for the apparent benign lymphoproliferative process underlying a wide spectrum of clinical features, but also for the progression to frank lymphoid malignancy in a subgroup of patients. Current data indicate a higher prevalence of overt B-cell non-Hodgkin's lymphoma in HCV-infected patients, especially in some geographic areas.
    bullet
    Hepatitis C virus infection and non-hodgkin lymphoma: Results of the NCI-seer multi-center case-control study. Int J Cancer. 2004 Aug 10;111(1):76-80. PMID: 15185346 | Related Articles
    bullet
    Association between hepatitis C virus and NHL, and effects of viral infection on histologic subtype and clinical cours
    bullet
    Hepatitis C virus, B-cell proliferation and lymphomas.
    Leuk Lymphoma. 2002 Apr;43(4):747-51. PMID: 12153160  PubMed
    bullet
    Viral Origins of Lymphoma  MD Anderson Oncology

    Mouse Virus
    (common to breast cancer and NHL)

    bullet

    Clonal Isolation of Different Strains of Mouse Mammary Tumor Virus-Like DNA Sequences from Both the Breast Tumors and NHL of Individual Patients Diagnosed with Both Malignancies
    http://clincancerres.aacrjournals.org/content/10/17/5656.full

    The study brought to our attention by Liz (nhl-INFO) certainly fits with widely held theory that chronic infection is a risk factor for lymphoma – and a theory I just learned of regarding a possible viral cause for some types of breast cancer. Viral infections may contribute in more direct ways than other forms of infection because they/it hijacks DNA in order to replicate and may modify gene expression in ways that favor evolution of the infected cells to a malignancy.

    From Discussion:  “Numerous reports have suggested a relationship between human breast cancer and non-Hodgkin’s lymphoma (1, 2, 3, 4, 5, 6) .

    Our results that indicate the presence of Mouse Mammary Tumor Virus-Like -like envelope and LTR sequences in both the breast tumors and non-Hodgkin’s lymphomas of 6 patients suffering from both malignancies suggest that a viral etiology may exist in certain cases of patients suffering from both malignancies."

    SV40 virus

    bullet

    See SV40 Issues for recent updates and details.

     

     
    Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
    professional medical advice or to replace your relationship with a physician.
    For all medical concerns,  you should always consult your doctor. 
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