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Causes of Leiomyosarcoma
written and compiled by doctordee
Search LMS site
Introduction - Sarcoma and Leiomyosarcoma

Soft tissue sarcoma (STS) accounts for approximately 1% of all cancers diagnosed annually in the United States. Population-based data from Connecticut covering the years 1935-1989 have shown an increasing incidence of STS in both genders, with a greater increase among men than women. The recent increase in acquired immune deficiency syndrome-related Kaposi's sarcoma does not explain the upward trend in STS, dating back decades. Excluding Kaposi's sarcoma, the incidence of soft tissue sarcoma has remained stable in Europe (3-4/100,000)

Fetch PMID: 9344316
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Soft tissue sarcomas are difficult to diagnose.
So one would expect there might be some fuzziness in sarcoma statistics, if there are some diagnostic difficulties.
Fetch PMID: 1932225

There are many different causes [etiologies] of sarcoma, which are reflected in the variations of sarcomas in site and cell type. Not all LMS risk factors are listed directly below, some are listed in the separate section they belong to, further down on this page.

Among the environmental exposures associated with STS are:

external radiation therapy (prevalence of radiation-induced sarcoma: 0.17-0.21%),
Thorotrast [a contrast Xray dye no longer used],
arsenical pesticides and medications,
phenoxy herbicides,
vinyl chloride,
immunosuppressive drugs,
alkylating agents,
androgen-anabolic steroids,
human immunodeficiency virus,
human herpes virus type 8 [Kaposi's sarcoma]
chronically edematous arms after radical mastectomy for breast cancer (Stewart-Treves syndrome)

Fetch PMID: 11441293
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Partly because of sarcoma rarity, scant attention has been given to their hereditary etiology. In one study the authors selected 10 sarcoma-prone families ... and focused on them.
These families displayed marked heterogeneity. In one of these families, 16 relatives had sarcomas, with 2 of the 16 each having 2 metachronous [at the same time] sarcomas; to our knowledge, this represents the greatest number of sarcomas reported in any family described to date. Two familial atypical multiple-mole melanoma syndrome kindreds with the CDKN2A mutation showed the association of sarcoma with malignant melanoma, whereas one family had several pancreatic carcinomas. Other families with sarcoma had hereditary nonpolyposis colorectal carcinoma with MSH2 mutation, hereditary breast carcinoma with BRCA1 mutation, and p53 mutation in a Li-Fraumeni syndrome.
Fetch PMID: 14584079

In addition, STS occurs excessively among persons with certain other heritable states. See the section on Hereditary LMS..
New syndromes are being discovered as the human genome is being interpreted.
Some cases of severe immunodeficiency [AIDS, transplant patients] show Epstein-Barr virus is sometimes implicated in LMS.
Sarcomas, including LMS, are associated with autoimmune thyroid disease, and associated with other autoimmune illnesses.
In some cases the genetic predisposition may have interacted with environmental determinants to produce particular tumors.
Fetch PMID: 281540
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Causes of sarcomas and leiomyosarcomas also include:
Post transplant immunosuppression.
thyroid disorders
autoimmune disease
hormonal factors [especially estrogen]
chronic repair processes

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These risk factors provide leads for further investigations into the genetic and environmental determinants of various forms of STS. Cancer is a genetic disease in which many factors including diet, smoking, chemicals, sunlight, hereditary factors, and viruses are thought to cause alterations or mutations in our genes. An alteration can result in a change of the DNA material within a gene or in excessive copies of a gene. When enough mutations accumulate, the normal processes inside the cell go awry, and tumors begin to grow.

It is quite clear that there are certain situations which cause certain damage which can result in LMS.
Why don't all the people who CAN get a cancer get it?

It's chance. It depends upon what the radiation photon, the virus, the antibody, actually attacks. Since most of the causal agents cause DNA damage, the sum of the exposures IS additive.

Much of the damage comes from free radicals. Antioxidants help prevent free radicals. So one way that people predisposed to cancer DON'T get the cancer, is lots of antioxidants in their foods. This has been illustrated with the epidemiological investigation of green tea drinkers and cancer incidence rates.

For exposure to be significant, it is usually noticeable. The one person I know who was exposed to that wood preservative, painted her deck and practically bathed in it. People who have had radiation therapy, or significant exposure to radiation know about it, usually. Cyclosphosphamide does not grow freely under trees.

Autoimmune disease, especially thyroid, seems to predispose to malignancy. Autoimmune disease relapses can be stress related. If there is less stress, there will be fewer autoimmune active spells, and fewer antibodies, and less chance of getting p53 DNA damage. Autoimmune disease itself probably develops from a combination of genetric susceptibility and possibly a viral trigger.

About smoking-- there was one study done that showed DNA repair took longer in cells of people who smoke.

In the words of a friend, it's mostly a crapshoot. BUT it is not completely a crapshoot. There are predisposing factors, and there are things you can do to counteract those factors...
Causes of Leiomyosarcoma PubMed Search
Causes of Sarcoma PubMed Search
How Cancer Starts [Carcinogenesis]

One Cell
Years before the cancer becomes a lump, it starts growing from one cell -- From a cell that has lost a number of vital control systems. The genes that control the vital control systems are on the strands of chromosomes that make up the cell's DNA, in the nucleus of the cell.

Genes and Mutation
If a gene is damaged or lost, that is called a mutation. Most mutations are "don't work" mutations. The damaged gene creates a protein/enzyme that "doesn't work", it doesn't do what it is supposed to do. A mutation may mean that too much protein is made. Or that a protein is not made at all.

Proteins Run the Cell
Proteins are the machinery, the driving forces that make the cell function. Some proteins act as 'on/off' switches that help to control how a cell behaves. For example, a hormone signal acts on a hormone receptor [a protein] in the cell or on the cell membrane. The protein then sends a signal down a chain of switches [other proteins]. This is a cascade of reactions, the final signal of which tells the cell to reproduce by dividing into two.

Mutations Prevent Proper Function
A mutation may mean that too much protein is made. Or that a protein is not made at all.
For example, a signalling protein may be permanently switched on. Other proteins, whose job is to control and limit cell division, may be permanently switched off.

Some genes encourage the cell to multiply or 'double'. Normally, this would not happen very often in most cells in adults. Many cells would only multiply to repair damage, for example after a wound or operation. If these genes become abnormal, they tell the cell to multiply all the time. Scientists call these genes oncogenes. This really means 'cancer genes.'

Tumour suppressor genes
Some genes are in the cell specifically to stop the cell multiplying or doubling. They act as the brake to the oncogene's accelerator. If one of these 'tumour suppressor genes' becomes damaged and stops working, then the cell may carry on and on multiplying.

Genes that repair other damaged genes
These genes normally repair any damage to the DNA that the cell's genes are made of. If these genes are damaged, then other mutations are not repaired and accumulation of mutations in the cell line might occur quickly. These genes have been found to be damaged in some human cancers, including colon (large bowel) cancer.

Carcinogens and Carcinogenesis
Something that damages a cell and makes it more likely to be cancerous is called a 'carcinogen'. There are carcinogens in cigarette smoke, and in barbecued or smoked food. Many other substances are known carcinogens, including heavy metals, estrogen, some organic solvents, as well as sunlight, chemotherapy agents, radiation and some viruses.
Carcinogenesis is the process of producing cancer.

How Cancer Starts [Carcinogenesis]
Mutations occur to the genes of cells by exposure to 'ionizing' radiation [like the sun's rays, radioactivity, Xrays], or chemical mutagens [like benzene and its derivatives] or viruses [which can introduce foreign DNA into the cell's DNA] or autoantibodies to DNA [created if a person has an autoimmune disease.] Other situations besides exposure to carcinogens can cause carcinogenesis. One is abnormal reproduction of the cell, with the result of two abnormal daughter cells, or mismatched DNA, or chromosomes stuck onto each other abnormally. Sometimes there are germline mutations, these are passed on in a family, and might consist of faulty guardian genes, or faulty repair genes, or specific mutations which create situations which predispose to development of specific cancers.

The usual mutation is one that causes a gene NOT to work. This means that the enzyme/protein that the gene produces [the gene product] does NOT work. For cancer to happen, a single cell needs to accumulate five or six different mutations. The usual probability of this happening is very very small.

So what makes it happen?
In every healthy normal cell, during reproduction there is a safety mechanism that checks that the DNA is intact and has no errors. The p53 gene is part of this safety mechanism. If the DNA is damaged, and cannot be repaired, then the p53 gene sets off a series of reactions that leads to apoptosis---the cell self-destructs. The p53 gene is called "the guardian of the genome" because it does not allow faulty DNA to exist, or to be passed on in the cell line. The "guardian of the genome" will cause a cascade of reactions that lead to apoptosis [cell suicide] in cells whose DNA is damaged and cannot be repaired. BUT What happens if the "the guardian of the genome" has a mutation?

If the Guardian Gene Doesn't Work
So a key mutation in the development of cancer would be damage to this p53 gene, or damage somewhere in its cascade of reactions. If the p53 cascade of reactions does not occur, then faulty DNA is passed on from the damaged cell to the cells that grow from the damaged cell [daughter cells]. Furthermore, the cell line with faulty p53 can now start collecting mutations. If the "caretaker gene" doesn't work, it allows defective-DNA daughter cells in the next generation. The defective daughter cells then accumulate their own additional mutations, which are ALSO passed to THEIR daughters. Who also accumulate some additional mutations. Which are ALSO passed to THEIR daughters. And so on...

Eventually, besides not being able to police its own DNA, there will be mutations involving reproduction and growth, invasiveness, and coherence to other cells. One or more mutation in each of these areas, about 5 or 6 mutations, are needed to develop a cancer cell.

When you have a cell that
*cannot destroy faulty DNA, [one mutation, often involving p53]
*which has ungovernable growth, [one mutation]
*which invades neighboring tissue, and [one or more mutations]
*which can separate itself from other tissue and [one or more mutations]
*journey via lymph or bloodstream to grow in a new place, [another mutation]
you have an invasive, metastasizing cancer.

So 'loss of function' mutations in these "caretaker genes" lead to an accumulation of mutations in the cell, and these mutations are carried through to subsequent cell generations. These cells are genetically unstable, as more and more mutations accumulate, and ARE PASSED ON to the next generation of cells. Inexorably, and inevitably, eventually, a cancerous cell will occur. The p53 gene is damaged or missing in the majority of human cancers.

It can take a long time before enough mutations happen for a cell to become cancerous. This is why many cancers are more common in older people. There has been more time to be exposed to carcinogens. And more time for accidents when cells reproduce.

Some people are said to have a 'genetic predisposition' to a type of cancer. This means they are more likely to develop that type of cancer than most people because they have been born with one of the mutations that makes a cell cancerous. They do not actually have the cancer because more than one mutation is necessary. But they are naturally further along the road towards getting cancer than people without that mutation.
For further discussion see the Scientific American Article
Untangling the Roots of Cancer--Scientific American Article

For some indication of the genetic changes in LMS tumors:
Fetch PMID: 11060455

A given mutation in a tumour may be specific to a particular carcinogen. However, the mutation that the carcinogen causes may differ depending on the species and the cell type. So a carcinogen will affect different types of tissues differently.
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For more information on gene alterations and cancer:
The National Cancer Institute - About Gene Alterations
The Doctor's Lounge - Cancer Biology FAQ's
NYAS - Genes and Cancer
NCI/CGAP - The Cancer Genome Anatomy Project
Molecular Pathology of Soft Tissue and Bone Tumors
OR use this link
Genetic alteration and gene expression modulation during cancer progression -- Molecular Cancer
Fetch Article


Cancer progresses through changes, as the cancer cells accumulate more and more mutations. The identification of the mutations and their expression in the cell, might provide new targets for treatment or treatment design, as well as tools for early diagnosis. .. see below:

Cancer progresses through a series of histopathological stages [dedifferentiation]. Progression is thought to be driven by the accumulation of genetic alterations and consequently gene expression pattern changes. The identification of genes and pathways involved will not only enhance our understanding of the biology of this process, it will also provide new targets for early diagnosis and facilitate treatment design. Gene approaches have proven to be effective in detecting chromosomal alterations and identifying genes disrupted in cancer...
See the rest of this article:
Chromosomal Instability in Cancer Causes and Consequences
Chromosomal Instability in Cancer

More than 100 cancer genes, each with its own blueprint for making a specific protein product, have already been identified -- about 80 oncogenes and 20 tumor suppressor genes. There are estimated at least an equal amount of cancer genes that have not been discovered yet.
The patterns of genes that are altered in individual tumors and specific cancers are yet to be defined. The more scientists learn about the molecular signature of a particular tumor or cancer, the easier it will be to make correct diagnoses, choices of therapy, and accurate predictions of outcomes.
National Cancer Institute: From "Gene Alterations and Cancer"

For more information about cancer, visit NCI's website.
NCI - gene alterations
NCI/CGAP - Cancer Genome Anatomy Project
Second and Multifocal Cancers

People with Soft Tissue Sarcomas [STS], of which Leiomyosarcoma is one, have a 7.5% chance of developing a second primary cancer [a higher chance than some other cancers have]. People with Soft Tissue Sarcomas are more than 12 times more likely [3.2 per 10,000] to develop another STS, than is the general population [4.0 per 100,000].

Multiple primary malignancies in association with 7.5% of soft tissue sarcomas [STS].

The phenomenon of two or three primary cancers developing in patients who had a STS occurs at a rate of 7.5%, a significantly higher rate than the occurrence of STS among the general cancer population (1%)... The follow up on patients with STS should include a search for a hidden second primary cancer. This is especially true in patients with primary malignant fibrous histiocytoma who demonstrate a risk for developing a renal cell carcinoma. STS was found approximately within +/- 27 years of the second primary cancer. For more information, see the abstract, and it might be possible to receive a copy of the paper by email from , the senior author.
Fetch PMID: 11283938

STS as second malignant lesion after therapy for Hodgkin's disease.

Report of two cases and review of the literature.
STS arose within the irradiated field within 21 years. A review of the pertinent literature is given and previous reports of malignant tumors and leukemias following therapy for Hodgkin's disease are summarized.
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STS as a second malignant neoplasm in children.

Although prior treatment may hinder the management of these patients, pediatric STS second malignancies can be cured using the same strategies used for de novo pediatric sarcomas. Long-term follow-up is mandatory given the risks of further malignancies and more severe, treatment-related side effects
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On the emergence of multifocal cancers synchronously [at the same time]

"Several tumors can exist as multiple lesions within a tissue. The lesions
may either arise independently, or they may be monoclonal. The importance of
multiple lesions for tumor staging, progression, and treatment is subject to
debate. Here we use mathematical models to analyze the emergence of
multiple, clonally related lesions within a single tissue. We refer to them
as multi-focal cancers. We find that multifocal cancers can arise through a
dynamical interplay between tumor promoting and inhibiting factors..."
Fetch PMID: 15461783

Multiple simultaneous primary soft tissue sarcomas.

"The synchronous or metachronous development of multiple primary soft tissue sarcomas (STS) of different histopathology has been reported only in isolated case reports. ...Representing 0.2% of all patients who were treated for STS [in the studied interval]. ... The incidence of second primary sarcomas in patients who were diagnosed previously with STS (4.0 per 10,000 population per year) was significantly greater than the incidence of primary STS in the general population (3.2 per 100,000 population per year; P < 0.01). CONCLUSIONS: Although it is an uncommon occurrence, patients who have a history of STS are at an increased risk for the development of a second primary STS."
Fetch PMID: 15494976

Search for the latest articles on Pubmed Search Engine
Put search terms in the search window.
for instance:
Sarcoma AND "Multiple Cancers"
Sarcoma AND "Second Primary"
OR enter the PMID for one of the papers, and click on Related Articles on the right hand side.
The Berwick Study

Dr. Berwick of MSKCC [Memorial Sloan Kettering Cancer Center] conducted a study of LMS patients a few years ago. Subjects submitted a swab of their saliva, and a separate swab from a spouse or other biologically unrelated person.

She found that LMS patients had more fragile/breakable DNA.

She also found, in an earlier study, that
"Patients with soft tissue sarcoma were 5.7 times more likely to be mutagen sensitive than controls (P = 0.01), as determined after dividing subjects into sensitive or not sensitive groups based on the median b/c among controls. As mutagen sensitivity has been shown to be associated with a number of cancers and appears to reflect genetic susceptibility, this assay may be an appropriate biomarker for radiation sensitivity or it may be a marker of susceptibility to soft tissue sarcoma."
Fetch PMID: 11746758

Etiology and Screening for Sarcomas
Excerpt from the NIH site

This article is well written. I recommend reading it.
NIH site

Screening for Sarcomas

"Given the rare incidence of sarcomas in the general population, no general screening is indicated beyond routine health care surveillance. However, it is important for physicians to be aware of the predisposing genetic tendencies and environmental exposures that might increase the risk of sarcoma development. Complete family history should reveal clues as to genetic predispositions, including a family history of polyposis, neurofibromatosis, retinoblastoma, any cancer at young age in first-degree relatives, or prior sarcomas. Genetic counseling would be appropriate to discuss issues relating to these predispositions. In appropriate patients, a more detailed clinical evaluation might be required at a lower threshold of intervention than one might use for general health care. Rapidly growing masses, especially symptomatic ones, in patients with neurofibromatosis should be considered for surgical removal to rule out the potential of sarcomatous transformation within a neurofibroma. Similarly, any superficial or deep abnormalities of skin or soft tissues in patients with a history of prior RT should be evaluated very thoroughly, given the known increased risk of sarcoma development. "

The above information is from the NIH site

Modifiable Risk Factors for Cancers

"Over 6 million people around the world die from cancer each year. Modifiable risk factors have been linked to a wide range of malignancies, including cancers of the oropharynx, oesophagus, larynx, lung, kidney, bladder, pancreas, skin, stomach, ovary, breast, cervix, uterus, prostate, and colon. Research indicates that over half of all cancers in developed countries could be prevented if we implemented population-wide measures to promote the following behaviours: reduce tobacco use, increase physical activity, control weight, improve diet, limit alcohol, utilise safer sex practices, get routine cancer screening tests, and avoid excess sun exposure."
Fetch PMID: 14735167
Uterine LMS

Leiomyosarcoma is a tumor derived from mutated smooth muscle cells. Smooth muscle is found in the skin, in the "goose bumps" raising muscles [pilor erectus], in the lining of blood vessels, in the gastrointestinal tract, and in the muscle layer of the uterus. I suspect that most LMS arises from the lining of blood vessels, except for some GI LMS, cutaneous LMS, and SOME uterine LMS. I think that is why true cutaneous LMS does not metastasize, as the subcutaneous type does.

I think Uterine LMS arises in three ways, all of which are possible, and probably all occur.

Firstly I think some uterine LMS arises from the lining of uterine blood vessels, not from the uterine muscle layer [myometrium].

Secondly I think that some of the uterine LMS arises from leiomyomata [leiomyomas] [uterine fibroids] that have undergone further mutation. That some LMS often occurs inside or adjacent to fibroids is very suspicious.

Thirdly I think that LMS occurs also de novo from the myometrium... from the smooth muscle tissue layer in the uterus.

There is no question that LMS can occur in the absence of fibroids, though it can be mistaken for one.

There is no question that leiomyomata have been harvested that show foci of LMS growing within them, as well.

All uterine cancers are related to estrogen levels. Estrogen tends to make uterine tissue proliferate. Proliferating tissue is more likely to have errors/mutations passed on.

LMS occurs about once every 30,000 fibroids.
However, for symptomatic fibroids--bleeding or painful ones-- the percentage of cancers found increases to ? about 2%.

So I would, myself, consider hysterectomy in the following cases, especially in peri- or postmenopausal women. In premenopausal women, careful consideration may need to be given to other factors.

1. Any fibroid in a woman whose family has a history of any kinds of cancer, but especially leiomyomatosis, LMS, or renal cell, or one of the inherited cancer promoting syndromes.
2. There is any FAST growth in a fibroid. {LMS is not the ONLY uterine
3. There is a foul smell vaginally, and no sexually transmitted disease.
4. There is bleeding that is not normal.
5. There is pain.
6. There is cramping.
7. There is a feeling of heaviness in the pelvis.
8. There are associated bladder or colon symptoms.
9. Degenerate or dishomogeneous fibroids.

Be aware, however, that many LMS tumors are without symptoms, and are a surprise finding on a pathology report.


Uterine Leiomyomata [leiomyomas, fibroids]

Uterine leiomyomas
, or fibroids, develop in the majority of American women and become symptomatic in one-third of these women. They are the most frequent indication for hysterectomy in the United States. Although the initiator or initiators of fibroids are unknown, several predisposing factors have been identified, including age (late reproductive years), African-American ethnicity, nulliparity, and obesity. Nonrandom cytogenetic abnormalities have been found in about 40% of tumors examined. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has only recently been explored.

PMID: 12826476
For more information about fibroids:
National Uterine Fibroids Foundation
(719) 633-3454
1 (877) 553-NUFF

Uterine Fibroids Mailing List at Yahoo

Estrogen Disruptors

"Endocrine-disrupting chemicals can undermine neurological and behavioral development and subsequent potential of individuals exposed. .. Some of the components and by-products of many manufactured organic compounds that interfere with the endocrine system are persistent and undergo biomagnification in the food web, which makes them of greater concern as endocrine disruptors. ... New technology has revealed that some man-made chemicals are ... [present] at concentrations which are biologically active. "

Pubmed Search for Estrogen Disruptors and Cancer

National Institute for Environmental Sciences. Read: Uterine Fibroid Growth Study
Fetch Study

World Wildlife Federation Read: Toxic Chemicals; Endocrine Disruptors
Fetch Article

Tamoxifen and Uterine Dysplasia and Cancers

Tamoxifen is an estrogen blocker used to block estrogen receptors in breast breast cancer patients. While Tamoxifen prevents stimulation of breast tissue by estrogen, it STIMULATES uterine estrogen receptors. Tamoxifen causes uterine dysplasia [abnormal growth of uterine tissue] and uterine cancers. Tamoxifen use is associated with the development of uterine leiomyosarcoma.

Search PubMed for Tamoxifen and Uterine Cancer

Search Pubmed for Tamoxifen and LMS

Diet and Uterine Myomas [Leiomyomas, Fibroids]

"Women with uterine myomas reported more frequent consumption of beef, other red meat, and ham and less frequent consumption of green vegetables, fruit, and fish. ...Myoma is associated with beef and ham consumption, whereas high intake of green vegetables seems to have a protective effect."

Fetch PMID: 10472866

Incidence of LMS in Women with Symptomatic Fibroids

The incidence in the GENERAL population of uterine fibroids that become cancerous is VERY low. However one study of a symptomatic population [symptoms being pain, bleeding, etc.] states that the presence of leiomyosarcoma in the hysterectomy specimens increased steadily from the fourth to seventh decades of age (0.2%, 0.9%, 1.4%, and 1.7%, respectively). The ages of these women ranged from 36 to 62 years. So a symptomatic woman in her 50's is in the 1.4% to 1.7% range. Note that a woman in her 50's is in her 6th decade.

Fetch PMID: 2327466

This link has statistics on Uterine LMS occurrence rates in relationship to generic fibroids.
Scroll to the bottom for combined uterine sarcoma statistics.

National Fibroid Foundation

Enlarged Uteri and Preoperative Diagnosis

One hundred and eighty two patients with symptomatic fibroids were sorted into 2 groups: those with uteri weighing more than 500g, and those with uteri weighing less. Of the patients with menorrhagia [abnormal bleeding], 21-30% did not undergo a preoperative biopsy. Biopsy failed to detect 2.75% of malignancies. All patients diagnosed postop with malignancy had complained of abnormal bleeding.
With complaints other than bleeding, a preoperative biopsy may be omitted. But "any menstrual complaints warrant an investigation of the endometrium even though the incidence of endometrial carcinoma in these larger uteri is only 1.1%."

Fetch PMID: 12611090

The management of uterine leiomyomas.

"English-language articles from MEDLINE, PubMed, and the Cochrane Database were reviewed from 1992 to 2002". "The level of evidence has been determined using the criteria described by the Canadian Task Force on the Periodic Health Examination. "

"BENEFITS, HARMS, AND COSTS: The majority of fibroids are asymptomatic and will not require intervention or further investigations. For the symptomatic fibroid, hysterectomy offers a definitive solution. However, it is not the preferred solution for women who wish to preserve their uterus. The predicted benefits of alternative therapies must be carefully weighed against the possible risks of these therapies. In the properly selected woman with symptomatic fibroids, the result from the selected treatment should be an improvement in the quality of life. The cost of the therapy to the health-care system and to women with fibroids must be interpreted in the context of the cost of untreated disease conditions and the cost of ongoing or repeat treatment modalities."

" RECOMMENDATIONS: 1. Medical management should be tailored to the needs of the woman presenting with uterine fibroids and geared to alleviating the symptoms. Cost and side effects of medical therapies may limit their long-term use. (III-C) 2. In women who do not wish to preserve fertility and who have been counselled regarding the alternatives and risks, hysterectomy may be offered as the definitive treatment for symptomatic uterine fibroids and is associated with a high level of satisfaction. (II-A) 3. Myomectomy is an option for women who wish to preserve their uterus, but women should be counselled regarding the risk of requiring further intervention. (II-B) 4. Hysteroscopic myomectomy should be considered as first-line conservative surgical therapy for the management of symptomatic intracavitary fibroids. (I-B) 5. It is important to monitor ongoing fluid balance carefully during hysteroscopic removal of fibroids. (I-B) 6. Laparoscopic myolysis may present an alternative to myomectomy or hysterectomy for selected women with symptomatic intramural or subserous fibroids who wish to preserve their uterus but do not desire future fertility. (II-B) 7. Uterine artery occlusion may be offered as an alternative to selected women with symptomatic uterine fibroids who wish to preserve their uterus. (I-C) 8. Women choosing uterine artery occlusion for the treatment of fibroids should be counselled regarding possible risks, and that long-term data regarding efficacy, fecundity, pregnancy outcomes, and patient satisfaction are lacking. (III-C) 9. Removal of fibroids that distort the uterine cavity may be indicated in infertile women, where no other factors have been identified, and in women about to undergo in vitro fertilization treatment. (III-C) 10. Concern of possible complications related to fibroids in pregnancy is not an indication for myomectomy, except in women who have experienced a previous pregnancy with complications related to these fibroids. (III-C) 11. Women who have fibroids detected in pregnancy may require additional fetal surveillance when the placenta is implanted over or in close proximity to hen the placenta is implanted over or in close proximity to a fibroid. (III-C) 12. In women who present with acute hemorrhage related to uterine fibroids, conservative management consisting of estrogens, hysteroscopy, or dilatation and curettage may be considered, but hysterectomy may become necessary in some cases. (III-C) 13. Hormone replacement therapy may cause myoma growth in postmenopausal women, but it does not appear to cause clinical symptoms. Postmenopausal bleeding and pain in women with fibroids should be investigated in the same way as in women without fibroids. (II-B) 14. There is currently no evidence to substantiate performing a hysterectomy for an asymptomatic leiomyoma for the sole purpose of alleviating the concern that it may be malignant. ..."

Fetch PMID: 12738981

Estrogen Levels and Development of Uterine Sarcomas

Uterine sarcomas studied here were leiomyosarcoma, mixed mullerian tumor, endometrial stromal sarcoma.
" We analyzed data from a population-based, multi-center, case-control study to determine whether the occurrence of histologic types of uterine sarcoma is related to exogenous hormone use and/or to two correlates of endogenous estrogens: excess weight and cigarette smoking."

"Use of oral contraceptives was positively associated with the risk of leiomyosarcoma ...primarily among women who last used these medications 15 or more years prior to diagnosis. Use of noncontraceptive estrogens was directly associated with the risk of mixed mullerian tumors, but only among recent and long-term users of these medications. Women in the highest quantile of body mass index ... one year prior to diagnosis were at increased risk of each type of uterine sarcoma .... Women who had ever smoked cigarettes were at reduced risk of leiomyosarcoma ... but the relationship was not more pronounced among heavy smokers; no association with smoking was observed with mixed mullerian tumors. CONCLUSIONS: Several of these findings parallel those from studies of endometrial carcinoma and may indicate a role for unopposed estrogen in the etiology of histologic types of uterine sarcoma."

[Smoking induces liver enzymes. These enzymes also metabolize estrogen. Estrogen levels in a group of women smokers will be less than estrogen levels in a group of women nonsmokers. Obese women make more estrogen in their fat tissue.
Increased estrogen levels are implicated in all uterine cancers, because the estrogen stimulates tissues to grow.]

Fetch PMID: 8616764

Endometrial Cancer after Antipsychotics Exposure

"Most endometrial cancers are related to hormonal imbalance, and antipsychotics are a common cause of hyperprolactinemia."
We investigated the possible relation between the use of antipsychotics and the risk of endometrial cancer. ... Use of antipsychotics, diabetes mellitus and obesity were identified as independent variables with risk ..Conclusions: Use of antipsychotics is a risk factor for endometrial cancer, and hyperprolactinemia associated with antipsychotics may impart the risk of endometrial cancer in premenopausal women."

Fetch PMID: 12566908

Some NON-causes of ULMS

If you are worried about the incidence of cancer with DDT, do the pubmed search:

Search Pubmed DDT and Cancer

I can tell you categorically that the induced labor drugs do not cause cancer. The yeast infection drugs like mycostatin and canesten are not implicated in the creation of cancer. Changing gynecologists does not cause cancer. The oral contraceptive pill actually reduces the rates of ovarian and uterine cancers. You can do pubmed searches on that, too.

Ovarian and uterine cancers in vitro fertilization patients

"Cancer cases in this large, well-defined cohort of IVF patients show a broad range of patient and tumor characteristics. We found an increased incidence of uterine sarcoma in women with a history of infertility. Increased ascertainment of preexisting cancers in the course of infertility investigations and management is to be expected."

Fetch PMID: 11426963

compiled by doctordee
December 2004
Autoimmune Causes of LMS

Autoimmune phenomena are involved with LMS in two ways...

1. As a causative agent, causing cancer.

Autoimmune diseases often have antibodies against the patient's DNA... anti-DNA antibodies... which can predispose toward DNA damage, and if against the p53 gene, can disable the guardian of the genome... so that mutations can accumulate.

2. Paraneoplastic syndromes. The cancer causes autoimmune phenomena.
These are collections of things that happen when people have cancer. My gluten enteropathy [an autoimmune problem] surfaced then, AFTER the cancer. Often a vasculitis [also an autoimmune problem] can occur after a cancer is diagnosed.


Malignancy in Autoimmune Diseases

Association between antecedent autoimmune diseases and malignancy, ... has been reported in generalized autoimmune diseases such as systemic lupus erythematosus, dermatomyositis, and rheumatoid arthritis, as well as in organ-specific autoimmune diseases such as Sjogren's syndrome and chronic thyroiditis.
..The activation of rheumatoid factor genes such as Humkv 325 and Vg was considered as one of the triggering factors to advance lympho-proliferative disorders (LPD), from the benign to malignant state.

A high amount of the bcl-2 protein expression was detected patients with SS, suggesting that the activation of this gene plays an important role in the progression of the lesion from benign to malignant...
Accumulation of many genetic abnormalities including bcl-2 and p53 genes by chronic stimulation of T and B cells at the site of the autoimmune reaction may be important in the high occurrence of LPD in patients with autoimmune diseases.
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p53 Autoantibodies in Patients with Autoimmune Disease

With few exceptions, autoantibodies directed against the gene product of the tumor suppressor gene p53 are only detected in cancer patients.

From 73 patients with various autoimmune diseases, we obtained 17 sera with elevated autoantibodies against the p53 protein comprising patients with SLE, Graves'disease, and immune vasculitis ... The overall prevalence (23%) of p53 autoantibodies was comparable to that in various cancers;

Patients with autoimmune diseases face an increased risk for malignancies. .
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p53 Antibodies in the sera of patients with various types of cancer

.. 130 papers published ... demonstrate that p53 antibodies (p53-Abs) are found predominantly in human cancer patients with a specificity of 96%. ...
It has been demonstrated that this immune response is due to a self-immunization process linked to the strong immunogenicity of the p53 protein. The clinical value of these antibodies remains subject to debate, but consistent results have been observed in breast, colon, oral, and gastric cancers, in which they have been associated with high-grade tumors and poor survival.
The finding of p53 Antibodies in the sera of individuals who are at high risk of cancer, such as exposed workers
or heavy smokers, indicates that they have promising potential in the early detection of cancer.
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Antinuclear antibodies (ANAs) reactive with a limited spectrum of nuclear antigens are characteristic of systemic lupus erythematosus (SLE) and other collagen vascular diseases, ...... our results imply that autoimmunity can be initiated by a "hit and run" mechanism in which the binding of a viral antigen to a self protein triggers an immune response that subsequently can be perpetuated by self antigen.
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Sarcoma and thyroid disorders

We have recently observed that many of our sarcoma patients presented also with thyroid disorders. Literature data are almost unavailable on this topic.

..analysis of files of patients with sarcoma and clinically overt thyroid disorders was carried out... 28 patients (4.6%) had an associated significant thyroid disorder.

The types of sarcoma were mainly liposarcoma followed by malignant fibrous histiocytoma, leiomyosarcoma and bone sarcoma. ... The interval between the diagnosis of the thyroid disorder and the sarcoma varied between -14 years (thyroid first) and +16.5 years (thyroid later) with a median of -0.2 years. Thyroid disorders included goiter, thyroiditis and carcinoma. There are both basic-science and clinical evidence to a possible common pathway that leads to the association between overt thyroid disorders and sarcomas of bone or soft tissues. Oncogene erbA activity is related to thyroid receptors to T3 and to development of sarcoma. .... The possible clinical implications are the need to screen patients with sarcoma to thyroid disorders, and patients with thyroid disorders for malignant diseases.
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Autoantibodies to p53 in sera of patients with autoimmune thyroid disease.

Mutations in the tumor suppressor gene, p53, lead to intracellular accumulation of abnormal p53 protein and are associated with p53 autoantibodies. p53 also accumulates in autoimmune diseases and Hashimoto's thyroiditis, but it is unknown if p53 autoantibodies occur in the latter.

We measured p53 autoantibodies in the sera of 93 patients with thyroid disease and 19 patients without thyroid disease. Anti-p53 antibodies were detected in the sera from 4.2% (2/48) of patients with autoimmune thyroid disease, including one patient with Hashimoto's thyroiditis (3.7%, 1/27) and one with Graves' disease (4.8%, 1/21).
A third patient with pseudohypoparathyroidism, but without thyroid disease, was also positive (1/19; 5.2%).

None of 19 patients with differentiated thyroid cancer had anti-p53 antibodies.

We conclude that anti-p53 antibodies can be detected in the sera from approximately 4% of patients with autoimmune thyroid
disease. This finding suggests that increased DNA damage and apoptosis may be associated with autoimmune thyroid disease.
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Programmed cell death (apoptosis)

Programmed cell death is a physiological, energy-consuming mechanism leading to suicide of the cell. Cell death is accomplished by the activation of endonucleases that fragment the cell's nuclear DNA. Some tumour cells remain susceptible to programmed death. These are hormone- and growth factor-dependent tumour cells. Hormone or growth factor deprivation induces signals leading to apoptosis. Other tumours gain strong resistance to apoptosis. ...

Loss of antioncogene p53 provides for resistance against programmed cell death.
Breakdown of resistance to apoptosis in tumour cells can be achieved by oncolytic viruses; generation of lymphotoxin and tumour necrosis factor; monoclonal antibodies; transfection with plasmid vectors carrying p53; gamma irradiation; and certain chemotherapeutic agents.
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autoimmune features in patients with malignancies.

Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of

generation of autoantibodies against various autoantigens, including oncoproteins ... tumour suppression genes (P53), proliferation associated antigens ... onconeural antigens ... cancer/testis antigens ..and rheumatic disease associated antigens...

The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role.

Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes ...

Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer.

Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy.

CONCLUSION: Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities.
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Neoplasia and the coeliac syndrome in adults.
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Celiac disease and malignancy.

Fifty-five patients with celiac disease and coexistent malignant disease (27 lymphoma, 28 other malignancies) are described.... The presentations of these malignancies were no different from their presentations in non-celiac patients, ...
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Myasthenia Gravis/thymectomy and malignancy.

Three hundred ninety patients who underwent thymectomy for myasthenia gravis (MG) were followed up to investigate the development of associated malignancies. There were 102 patients with thymoma and 288 without thymoma. ...Our findings suggest that the presence of thymoma facilitates the occurrence of extrathymic malignancy, and that thymectomy never enhances the occurrence of malignancy but possibly inhibits it.
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Chemical and Environmental Carcinogens


Considerable evidence supports a relationship between occupational chemicals as vinyl chloride, phenoxyacetic acid herbicides, chlorphenols, dioxin, arsenical pesticides and medications, medicinal measures as Thorotrast exposure , immunosuppressive drugs, alkylating agents, androgen-anabolic steroids, and cutting oil exposure , and the development of soft tissue sarcoma.
Statistical models identified different odds ratios across sarcoma subtypes for plywood exposure and exposure to wood and saw dust. Although exploratory, this analysis suggests that occupational risk factors for sarcoma are not uniform across subtypes.
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Although bone and soft tissue sarcomas are not common, a significant number of patients who develop these tumors will die with metastatic disease. Part of the reason is that many of the patients have advanced disease at diagnosis. Identification of an etiologic agent should allow for diagnosis at an earlier stage. ... The role of various chemical agents in the development of sarcomas needs further definition, as the literature is replete with conflicting reports. Problems exist in that we are dealing with a variety of agents with different levels of exposure, possibly resulting in different types of neoplasms. Additionally, many of the agents in question are not pure substances, but frequently are contaminated with other potentially carcinogenic agents. Finally, the majority of studies reported are from different countries. Thus, there may be unidentified operative genetic and environmental factors...
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Environmental causes probably account for well over half of all cancer cases. Most environmental risks are determined by lifestyle choices (smoking, diet, etc.), while the rest arise in community and workplace settings. The degree of cancer hazard posed by these voluntary and involuntary risks depends on the concentration or intensity of the carcinogen and the exposure dose a person received. In situations where high levels of carcinogens are present and where exposures are extensive, significant hazards may exist, but where concentrations are low and exposures limited, hazards are often negligible. When low-dose exposures persist over time they can represent significant public health hazards (for example, exposure to secondhand tobacco smoke).

Various chemicals (for example, benzene, asbestos, vinyl chloride, arsenic, aflatoxin) show definite evidence of human carcinogenicity; others are considered probable human carcinogens based on evidence from animal experiments (for example, chloroform, dichlorodiphenyl-trichloroethane [DDT], formaldehyde, polychlorinated biphenyls [PCBs], polycyclic aromatic hydrocarbons). Often in the past, direct evidence of human carcinogenicity has come from studies of workplace conditions involving sustained, high-dose exposures. Risks can be increased when particular exposures occur together (for example, asbestos exposure and cigarette smoking).

Occupational Cancer

Based on well-documented associations between occupational exposures and cancer, it is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.
Millions of U.S. workers are exposed to substances that have tested as carcinogens in animal studies.
Less than 2% of chemicals in commerce have been tested for carcinogenicity.

Cancer is a group of different diseases that have the same feature, the uncontrolled growth and spread of abnormal cells. Each different type of cancer may have its own set of causes. Many factors play a role in the development of cancer. The importance of these factors is different for different types of cancer. A person's risk of developing a particular cancer is influenced by a combination of factors that interact in ways that are not fully understood. Some of the factors include:

personal characteristics such as age, sex, and race
family history of cancer
diet and personal habits such as cigarette smoking and alcohol consumption,
the presence of certain medical conditions,
exposure to cancer-causing agents in the environment, and
exposure to cancer-causing agents in the workplace.
In many cases, these factors may act together or in sequence to cause cancer.

NIOSH National Istitute of Occupational Safety and Health
The NIOSH Web site features many different types of databases and information resources. They are categorized here by Chemical; Injury, Illness & Hazards Data and Information; Publications; Respirators and other Personal Protective Equipment; Agriculture; and Construction. The most popular databases include the International Chemical Safety Cards, NIOSH Pocket Guide to Chemical Hazards, and NIOSHTIC-2.
NIOSH and cancer

National Institute for Occupational Safety and Health
NIOSH site

US Dept of Labour OSHA site
Occupational Safety and Health Administration

OSHA site

Occupational and Environmental Epidemiology Branch, site
Occupational Exposure Articles

Cancer Causes and Risks,from
Fact Sheets

Artificial implants and soft tissue sarcomas.

The carcinogenic potential of artificial implants has been of concern in recent years. ... This paper examines a possible association between artificial implants and soft tissue sarcomas. J Clin Epidemiol. 1995
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Exposure to Agent Orange and occurrence of soft-tissue sarcomas

Agent Orange was the most common herbicide used in the Second Indochina War in the course of military operations in the former South Vietnam. Agent Orange is contaminated by the carcinogen 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in mean concentrations of 2 mg/kg. After much dispute of a causal association between exposure to herbicides containing TCDD and occurrence of soft-tissue sarcoma ... two simultaneous case-control studies were set up in Vietnam to examine possible relationships. ..
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An evaluation of dioxin/phenoxy herbicides/chlorophenols exposure and soft tissue sarcoma

A review of employment records and tissue specimens of seven workers, reported previously as having occupational dioxin exposure and soft tissue sarcomas, confirms that ... Methodological problems are discussed which must be addressed in the epidemiologic evaluation of the outcome of soft tissue sarcoma.
Other studies cited as well.
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Risk of soft tissue sarcomas and residence near incinerator of industrial wastes.

To investigate the association between occurrence of soft tissue sarcomas (STS) in Mantua and residence near an incinerator of industrial wastes.
.. CONCLUSION: The study shows a significant increase in risk of STS associated with residence within 2 km of an industrial waste incinerator; an aetiological role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be hypothesised. Occup Environ Med. 2003
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dioxin and sarcoma


Exposure to polymeric materials in vascular soft-tissue sarcomas.

..Since 1974, several reports have appeared on a distinct relationship between the exposure to vinyl chloride monomers and angiosarcomas of the liver. ...
..Among 21 adult cases of vascular sarcomas there were 4 patients with occupational exposure to vinyl chloride (VC) either alone or together with other artificial polymers. Seven other patients showed exposure to several plastics or resins other than VC. Altogether, 11 of 21 (52%) of the explored patients were found to have been exposed to artificial polymeric materials over a mean period of 18 years. ...

This study offers new evidence of the occurrence of vinyl-chloride-induced angiosarcomas outside the liver and confirms observations that have previously been published in case reports. Moreover, it may be suspected from this analysis that polyvinyl chloride and its monomers are not the only polymeric materials that may contribute to an induction of angiosarcomas in humans. Repeated occupational histories have to be taken from the patients to achieve data of the greatest value, since there are many professional activities that do not primarily lead to the assumption of specific exposure to polymeric materials.
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Vinyl chloride-specific mutations in humans and animals.

Vinyl chloride is a potent hepatocarcinogen which reacts with DNA to generate etheno bases. In order to determine whether mutational patterns in target genes in vivo are characteristic of vinyl chloride ... Two alterations were found which could be attributed to a direct effect of vinyl chloride: ... in human liver angiosarcomas, and lesions ...which lead to mutations in the p53 gene in human ...
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[The carcinogenic potential of biomaterials in hernia surgery]

... In conclusion, there are no data so far indicating a real risk for humans to develop malignant tumors due to implanted meshes. Therefore we further propagate the implantation of meshes in hernia repair in adult patients.
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EPA site for radiation exposure

Exposure to Tobacco Smoke
Tobacco Smoke

Environmental Exposures and Cancer

Majority of Cancers are Linked to the Environment

Breast Cancer and the Environment Studies
supported by NCI

Heavy metals are metals like lead, arsenic, cadmium. Lead is present in old paint, in some painted bowls, in leaded gasoline exposure.

Enhanced invasiveness of tumour cells after host exposure to heavy metals.

The invasiveness of tumour cells to heavy metal-exposed host cells or tissues was investigated....The results suggest that heavy metal-induced metallothioneins serve as a host-derived factor in malignant disease and closely relate to metastasis.
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Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats.

In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues.
..After lifetime observation, the incidence of soft tissue sarcomas increased significantly ... These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.
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Arsenic exposure and carcinogenesis.

Arsenic is well established as a human carcinogen,... Arsenic ...may act as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents.

.. Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic.

Occupational exposure to heavy metals:

DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected

Co-exposure to cadmium, cobalt, lead and other heavy metals occurs in many occupational settings, such as pigment and batteries production, galvanization and recycling of electric tools. However, little is known about interactions between several heavy metals. ...

.. In conclusion, the hazard due to cobalt exposure ... seems to be underestimated, especially when individuals are co-exposed to cadmium or lead. Co-exposure may cause genotoxic effects, even if the concentrations of individual heavy metals do not exceed TRK-values.
heavy metal co-exposures

Molecular and cellular mechanisms of cadmium carcinogenesis.

Cadmium is a heavy metal, which is widely used in industry, affecting human health through occupational and environmental exposure. In mammals, it exerts multiple toxic effects and has been classified as a human carcinogen by the International Agency for Research on Cancer.

Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. ... indirect mechanisms are implicated in the carcinogenicity of cadmium. In this review multiple mechanisms are discussed, ... The inhibition of DNA repair processes by cadmium represents a mechanism by which cadmium enhances the genotoxicity of other agents and may contribute to the tumor initiation by this metal. The disruption of E-cadherin-mediated cell-cell adhesion by cadmium probably further stimulates the development of tumors. It becomes clear that there exist multiple mechanisms which contribute to the carcinogenicity of cadmium, ...
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Hepatic angiosarcoma and heavy metal exposures

Hepatic angiosarcoma .... One fourth of the cases have demonstrated a relation with chemical carcinogens with the most frequent being thorium dioxide (thorotrast) and vinyl chloride. The case of an hepatic angiosarcoma which presented as an intraperitoneal hemorrhage in a patient who had undergone treatment with Neosalvarsan (dioxidiaminoarsenobenzol) 46 years beforehand is reported. The previous published reports include 6 cases of hepatic angiosarcoma related with treatment with arsenic salts and 4 cases in whom exposure was environmental.
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Corrosion products and their role in malignancy

We report a case of malignant fibrous histiocytoma of the bone that developed 20 years after a femoral fracture treated by plate-screw fixation.

Similar cases reported over the past fifteen years in the literature suggest the possible mechanisms of sarcomatous degeneration.

The possible carcinogenic effect of corrosion products is emphasized. ..[Analysis] of the tumor demonstrated the presence of chromium, iron and nickel at different concentrations. The association with other elements clearly demonstrates that the corrosion products were metabolized. The presence of metallic components in tumoral cells suggests a possible relationship between metallic implants and malignancy.

These observations emphasize the importance of creating a national, or even international, registry of malignant tumors that develop in contact with metallic implants in order to search for a possible cause and effect relationship.
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Cancer burden from arsenic in drinking water in Bangladesh.

Tissue studies of persons with intakes of the actinide elements: the U.S. Transuranium and Uranium Registries.

For more than three decades, the United States Transuranium and Uranium Registries (USTUR) have studied the biokinetics, dosimetry, and biological effects of plutonium, uranium, and americium through voluntary postmortem tissues from persons with known intakes. Radiochemical analyses of tissue obtained at autopsy have shown that plutonium and americium have different biokinetics and an appreciable deposition in the soft tissues of the body as well as the known depots in skeleton and liver. Studies of whole-body Thorotrast donors to the USTUR indicate that commonly accepted risk coefficients for alpha induction of bone sarcoma may be too high while those for leukemia are a factor of six too low. ,,,
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Risk of esophageal, ovarian, testicular, kidney and bladder cancers and leukemia among Finnish workers exposed to diesel or gasoline engine exhaust.
Engine Exhaust

Risk analysis of drinking water microbial contamination versus
disinfection by-products (DBPs)
Disinfection By-Products

Formaldehyde and Cancer


is an alpha-particle-emitting radiological contrast medium that caused chronic exposure to internal alpha-particle radiation when it was administered systemically. Cancer incidence in 432 Swedish patients exposed to Thorotrast was evaluated by computerized linkage of the cohort with the Swedish Cancer Register. Standardized incidence ratios (SIRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. A total of 170 cancers occurring in 152 individuals were reported, whereas only 57 cases were expected. The SIR was significantly increased for cancer at all sites (3.0), with the largest excesses noted for primary liver and gallbladder cancer (SIR = 39.2). Other significantly elevated risks were observed for liver cancer not specified as primary, small intestine cancer, stomach cancer, leukemia, kidney cancer, CNS tumors, and pancreatic cancer. Among women, there was a significantly increased risk for lung cancer, based on a small number. Our results show that cumulative radiation exposure is directly related to carcinogenesis in the liver and gallbladder, which is consistent with earlier findings. In addition, there may be a relationship between radiation exposure and the development of other solid tumors

Active Smoking

Our study provides evidence that active smoking may play a
role in breast cancer etiology and suggests that further research into
the connection is warranted, especially with respect to genetic
Active Smoking

Nickel-induced cancerous transformation ...

Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells...
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Angiosarcoma associated with foreign body material. A report of three cases.

The production of tumors through solid-state mechanisms has been demonstrated in experimental animals, but foreign body tumorigenesis has not been proven definitively in man. The authors report three patients with angiosarcoma that occurred in intimate association with foreign material retained for prolonged periods. ... Review of the literature disclosed six cases of angiosarcoma and 40 cases of sarcomas of other histologic types associated with foreign material, with latency periods of from 4 months to 63 years. Implanted foreign material thus should be considered capable of inducing virtually any form of sarcoma in humans.
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Neoplastic transformation of human cell lines by heavy metal-tungsten alloy particles.

Heavy metal-tungsten alloys (HMTAs) are dense heavy metal composite materials used primarily in military applications. HMTAs are composed of a mixture of tungsten (91-93%), nickel (3-5%) and either cobalt (2-4%) or iron (2-4%) particles. ...
Like the heavy metal depleted uranium (DU), the use of HMTAs in military munitions could result in their internalization in humans. Limited data exist, however, regarding the long-term health effects of internalized HMTAs in humans. ...This is the first report showing that HMTA mixtures of W, Ni and Co or Fe cause human cell transformation to the neoplastic phenotype. While additional studies are needed to determine if protracted HMTA exposure produces tumors in vivo, the implication from these ... results is that the risk of cancer ...from internalized HMTAs exposure may be comparable with the risk from other biologically reactive and insoluble carcinogenic heavy metal compounds (e.g. nickel subsulfide and nickel oxide).
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Increase in neoplasia in mice offspring after preconception exposure of parents to urethane or chromium(III)

...The present study examined the hypothesis that preconception carcinogenesis involves an increase in the rate of occurrence of neoplasms ...
.. Offspring (48-78/sex/group) were examined for all grossly apparent changes when moribund or at natural death, followed by histopathological diagnosis and statistical analysis.
Significant exposure-related changes occurred in multiple organs. Ten to 20 percent of offspring showed changes related to paternal exposure, including at least one sired by most treated males. ...
[list of lesions. ] Thus, preconception exposure of fathers to toxicants had a significant impact on both neoplastic and non-neoplastic changes in almost all tissues in which these lesions often occur naturally during the aging process. .
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Chemotherapy Agents

Leiomyosarcoma of urinary bladder following cyclophosphamide therapy

... We report two cases of [LMS of the urinary bladder] following cyclophosphamide therapy.

The first case is from a 53-year-old man ,,,treated for 6 years with cyclophosphamide. He presented with painless hematuria, ,,, A final diagnosis of leiomyosarcoma was made on radical cystoprostatectomy.

The second example is from a 21-year-old man who had received cyclophosphamide in early infancy for a bilateral retinoblastoma. He also presented with painless hematuria, and a bladder tumor was resected .. Cyclophosphamide, when used for a neoplastic or non-neoplastic condition, is associated with an increased risk of developing bladder cancer. ... A review of the literature shows an increased proportion of squamous cell carcinomas and sarcomas, especially leiomyosarcomas in cyclophosphamide exposed patients. Acrolein, a cytotoxic metabolite of cyclophosphamide excreted in urine, is regarded as the most likely causative agent.
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For more information, and further cases, see the
PubMed Search Related Articles

Testicular LMS after Androgenic Steroid Abuse

Intratesticular leiomyosarcoma in a young man after high dose doping with Oral-Turinabol: a case report.

..Androgenic anabolic steroids have been suspected of activity as carcinogens ... Although the proliferation of smooth muscle cells is stimulated by sexual steroids, to the authors' knowledge a possible relation between androgenic anabolic steroids and the development of leiomyosarcoma has not previously been reported in humans.

A 32-year-old man underwent right radical orchiectomy for a tumor ... of the right testicle.... The tumor was identified as an intratesticular leiomyosarcoma... The patient reported a 5-year history of systematic use of high dose Oral-Turinabol (4-chloro-1-dehydro-17alpha-methylteststerone) that began at age 18 years and stopped approximately 9 years before presentation.

.. The rarity of intratesticular leiomyosarcoma, the experimental induction of similar tumors in animals by androgens and estrogens, and the unusually young age at presentation of the patient in the current study support the hypothesis that high dose doping with androgenic anabolic steroids could have played a cocarcinogenic role ...
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Related Articles

Effects of androgenic-anabolic steroids in athletes.

Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone. They can exert strong effects on the human body that may be beneficial for athletic performance. A review of the literature revealed that most laboratory studies did not investigate the actual doses of AAS currently abused in the field. Therefore, those studies may not reflect the actual (adverse) effects of steroids. ...

The main untoward effects of short- and long-term AAS abuse that male athletes most often self-report are an increase in sexual drive, the occurrence of acne vulgaris, increased body hair and increment of aggressive behaviour. AAS administration will disturb the regular endogenous production of testosterone and gonadotrophins that may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including elevation of blood pressure and depression of serum high-density lipoprotein ... Psyche and behaviour seem to be strongly affected by AAS. Generally, AAS seem to induce increments of aggression and hostility. Mood disturbances (e.g. depression, [hypo-]mania, psychotic features) are likely to be dose and drug dependent. ...Many other adverse effects have been associated with AAS misuse, including disturbance of endocrine and immune function, alterations of sebaceous system and skin, changes of haemostatic system and urogenital tract. ..
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Mediterranean Diet May Reduce Mortality in Elderly

BMJ. Posted online April 8, 2005
The Mediterranean diet is characterized by a high intake of vegetables,
legumes, fruits, and cereals; a moderate to high intake of fish; a low
intake of saturated fats, with a high intake of unsaturated fats such as
olive oil; a low intake of dairy products (mainly cheese and yogurt) and
meat; and a modest intake of alcohol, mostly as wine. The modified
Mediterranean diet relies on plant foods and unsaturated fats. Studies have
demonstrated a protective effect of this diet on mortality,

Do preserved foods increase prostate cancer risk

Preserved foods have been found in some studies to be associated with increased cancer risks. The possible relationship between preserved foods and prostate cancer was investigated ... in southeast China during 2001-2002 ... The total amount of preserved food consumed was positively associated with cancer risk, the adjusted odds ratio being 7.05 ... for the highest relative to the lowest quartile of intake. In particular, the consumption of pickled vegetables, fermented soy products, salted fish and preserved meats was associated with a significant increase in prostate cancer risk, all with a significant dose-response relationship.
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Dietary antioxidant intake in patients at risk for second primary cancer.

..Twenty-four patients underwent three random, unscheduled, 24-hour dietary recalls over a 15-day period within 6 to 60 months after successful treatment for stage I or II oral cavity squamous cell carcinoma.

..The study sample had a lower mean daily dietary intake of fruits and vegetables and antioxidant nutrients, including vitamins A, C, E, and total carotenes than age- and sex-matched historic control subjects (all P <.05 except vitamin A). A positive linear correlation was noted between daily servings of F&V and dietary intake of vitamins A, C, E, and total carotenoids (all P <.05 except vitamin A). Compared to current recommendations, the study sample had lower mean daily dietary intake of vitamins A, C, and E (P =.81,.06, and <.01) and servings of fruits and vegetables (P <.01). When vitamin supplements were included in the analysis, mean daily intake exceeded recommended dietary allowance (RDA) for vitamins A, C, and E (all P <.05).

..This study suggests that patients treated for early-stage oral cavity carcinoma, at risk for second primary cancers, have a statistically significant deficiency in dietary (food) sources of antioxidant nutrients when compared with both historic control subjects and current recommendations. Vitamin supplementation significantly exceeded current RDAs. Because increased fruit and vegetable intake, but not vitamin supplementation exceeding RDA, is associated with reduced cancer risk, physicians may consider recommending at least five daily servings of fruits and vegetables as an alternative to vitamin supplementation.
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A wholly nutritional 'multifocal angiostatic therapy' for control of disseminated cancer.

A great deal of effort is now being devoted to the development of new drugs that hopefully will control the spread of inoperable cancer by safely inhibiting tumor-evoked angiogenesis.

However, there is growing evidence that certain practical nutritional measures have the potential to slow tumor angiogenesis, and it is reasonable to anticipate that, by combining several measures that work in distinct but complementary ways to impede the angiogenic process, a clinically useful 'multifocal angiostatic therapy' (MAT) might be devised.

Several measures which might reasonably be included in such a protocol are discussed below, and include:

a low-fat, low-glycemic index vegan diet, which may down-regulate the systemic IGF-I activity that supports angiogenesis;

supplemental omega-3-rich fish oil, which has been shown to inhibit endothelial expression of Flk-1, a functionally crucial receptor for VEGF, and also can suppress tumor production of pro-angiogenic eicosanoids;

high-dose selenium, which has recently been shown to inhibit tumor production of VEGF;

green tea polyphenols, which can suppress endothelial responsiveness to both VEGF and fibroblast growth factor;

and high-dose glycine, whose recently reported angiostatic activity may reflect inhibition of endothelial cell mitosis, possibly mediated by activation of glycine-gated chloride channels.

In light of evidence that tumor-evoked angiogenesis has a high requirement for copper, copper depletion may have exceptional potential as an angiostatic measure, and is most efficiently achieved with the copper-chelating drug tetrathiomolybdate. If logistical difficulties make it difficult to acquire this experimental drug, high-dose zinc supplementation can achieve a slower depletion of the body's copper pool, and in any case can be used as maintenance therapy to maintain an adequate level of copper depletion.

A provisional protocol is offered for a nutritionally based MAT entailing a vegan diet and supplemental intakes of fish oil, selenium, green tea polyphenols, glycine, and zinc.

Inasmuch as cox-2 is overexpressed in many cancers, and cAMP can boost tumor production of various angiogenic factors as well
as autogenous growth factors, adjunctive use of cox-2-specific NSAIDS may be warranted in some cases.
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Antigenotoxic potential of certain dietary constituents.

The human diet contains a variety of compounds that exhibit chemopreventive effects towards an array of xenobiotics. In the present study, the antigenotoxic potential of selected dietary constituents including Diallyl sulfide (DAS), Indole-3-carbinol (I3C), Curcumin (CUR), and Black tea polyphenols (BTP) has been evaluated ,,,

In addition, the ... effect of the above dietary constituents was identified towards Benzo(a)pyrene (BaP) and cyclophosphamide- (CP) induced cytogenetic damage in mouse bone marrow cells. The induction of BaP and CP induced chromosomal aberrations... were found to be inhibited in a dose-dependent manner by DAS, I3C, CUR, and BTP. Thus the study reveals the antimutagenic potential of these dietary compounds ...
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Diet and uterine myomas

To analyze the relation between selected dietary indicators and the risk of uterine myomas.

..Women with uterine myomas reported more frequent consumption of beef, other red meat, and ham and less frequent consumption of green vegetables, fruit, and fish. T... Myoma is associated with beef and ham consumption, whereas high intake of green vegetables seems to have a protective effect.
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Heterocyclic Amines in Cooked Meats

Research has shown that cooking certain meats at high temperatures creates chemicals that are not present in uncooked meats. A few of these chemicals may increase cancer risk.
..the study concluded that there were low levels of HCAs found in fast food meat products due to factors such as cooking temperature and time. The study suggested that greater exposure to HCAs stems from home cooking and cooking in non-fast-food restaurants where food may be cooked to order and where a larger amount of meat is consumed.

However, concerned individuals can reduce their exposure to HCAs by varying methods of cooking meats; microwaving meats more often, especially before frying, broiling, or barbecuing; and refraining from making gravy from meat drippings.
It is worthwhile to read the complete article. Fetch Article

Diets containing substantial amounts of red meat may increase the risk of various types of cancer.

The association with red meat intake may be due to a combination of factors, such as content of fat, protein, and iron, and/or meat preparation (e.g. cooking or preserving methods). Experimental studies have shown that meats cooked at high temperatures contain heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), which are mutagenic and carcinogenic in animals. To estimate intake of these meat-cooking mutagens a detailed meat cooking module within a Food Frequency Questionnaire in conjunction with a mutagen database was developed. Charred is a software application to estimate intake of the mutagenic compounds in cooked meats.

Some further discussion:

It is the burned organic material, the food or tobacco or wood, that comes into contact with high temperatures, that is transformed into possible carcinogens. There are also carcinogens in smoke [also organic material that has come into contact with high temperature.]

It is either Iceland, or Greenland that has a mountain range dividing the country. Because of this mountain range cutting off access to the fishing, half the country eats fresh fish, but the other half eats smoked fish. The incidence of stomach [gastric] cancer is much higher in the smoked fish area than the fresh fish area.

Japan has possibly the highest rate of stomach [gastric] cancer in the world. They thought it might be due to soy sauce, which is fermented strongly there. However, since helicobacter pylori was discovered, thinking has changed. Helicobacter pylori is a bacteria that lives in the mucous layer lining stomachs. It is responsible for most of the stomach ulcers in
the world, some of the bad breath, and its constant irritation of the stomach is carcinogenic. H. pylori is transmitted by poor food many chopsticks using the same central bowl, and its incidence was very high in Asian countries. Other poor hygiene practices are responsible for infections in the rest of the world.

ALSO: Organic doesn't always mean safe or uncontaminated. It just means some things WEREN"T done or added.

In a study on excessive nitrates present in foods, organic and normal carrots were compared. The organic carrots had a much higher concentration of nitrates from natural fertilizer, than did the normal carrots from commercial fertilizer.

Remember, not adding stuff doesn't mean that the Love Canal doesn't pollute your veggie patch. Your organic hens may be laying organic eggs while eating Chernobyl contaminated seeds.

above written by doctordee
Hereditary [Familial] LMS: Some Syndromes

.. STS occurs excessively among persons with certain heritable states including retinoblastoma, Li-Fraumeni syndrome, Gardner's syndrome, Werner's syndrome, nevoid basal cell carcinoma syndrome, neurofibromatosis type 1, and some immunodeficiency syndromes.
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Inherited syndromes usually have damaged DNA in the germline, which predisposes the people to certain cancers. Everyone who has more than one cancer, or anyone with a family with multiple members having cancer, should probably see a cancer geneticist for discussion of their family history, and possible testing. Some people with a cancer syndrome will have obvious signs of the syndrome [see way below], but others will be apparently normal except for cancers and chromosomal analysis.

A population-based study of familial soft tissue tumors.

We used the nationwide Swedish Family-Cancer Database to analyze the risk for soft tissue tumors in offspring by parental cancers and in siblings of soft tissue tumor probands. Additionally, risk for second cancer following soft tissue tumor was investigated.

In offspring, 1488 soft tissue tumors were diagnosed between years 1958 and 1996. Groups of offspring were compared by calculating standardized incidence ratios (SIRs) for soft tissue tumors.

Parental breast, prostate and connective tissue cancers were associated with offspring soft tissue tumors in sex- and age-specific groups. The SIRs were of borderline significance, suggesting a small etiological contribution by Li-Fraumeni syndrome.

Soft tissue tumors conveyed a high risk of second soft tissue tumor, probably partially due to recurrences. However, the observed risk for second nervous system cancer was consistent with Li-Fraumeni syndrome.

Other associations were unlikely to be due to Li-Fraumeni or other known syndromes, but they could be spurious findings arising from multiple comparisons. Among these, parental stomach cancer (SIR 3.19, 95% CI 1.69-5.17) and endocrine gland tumors (SIR 3.66, 95% CI 1.32-7.17), particularly parathyroid tumors (SIR 4.46, 95% CI 1.41-9.23), were associated with offspring fibrosarcoma, and parental breast cancers with offspring leiomyosarcoma (SIR 2.04, 95% CI 1.08-3.30).
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Cancer in twins: genetic and nongenetic familial risk factors

..Familial clustering has been observed for cancers that occur at specific sites. ...
The identification of familial effects for total cancer in this study is consistent with the idea that individuals may possess a genetic susceptibility to cancer in general
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Inherited Syndromes and Carcinogenesis

A syndrome is a group of symptoms that collectively characterize a disease, psychological disorder, or other abnormal condition. The syndromes below have been associated with LMS in one way or another. There are other syndromes which are no doubt waiting to be discovered. Finding a syndrome as a cause for LMS can sometimes alert the family to testing other members for the condition. And possibly instituting preventive measures.

A small percentage of all tumors have obvious familial clustering. The familial cancer syndrome is well defined for many cancers. Traits of familial tumors are sequentially inherited by offspring through gametes [eggs and sperm] in a Mendelian fashion, most commonly in an autosomal-dominant manner. People with these syndromes have inheritable faulty genes or mutations of genes in the germ line [in the DNA in the egg or sperm] that can be passed on to offspring.
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Carcinogenesis requires multiple genetic events. Some genes are closely related to the cell cycle and tumorigenesis; proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes. If these genes are faulty or mutated, they can cause transformation of normal cells to malignant cells. A normal cell is able to acquire the characteristics of a malignant cell under the influence of many factors: multiple environmental factors and a personal genetic factor.
Fetch PMID: 15375699
Related Articles: Carcinogenesis of Familial Tumors


Cancers result from the accumulation of inherited and somatic mutations in oncogenes and tumor suppressor genes. These genes encode proteins that function in growth regulatory and differentiation pathways. Mutations in those genes increase the net reproductive rate of cells.

Chromosomal instability (CIN) is a feature of most human cancers. Mutations in CIN genes increase the rate at which whole chromosomes or large parts of chromosomes are lost or gained during cell division. CIN causes an imbalance in chromosome number (aneuploidy) and an enhanced rate of loss of heterozygosity, which is an important mechanism of inactivating tumor suppressor genes. ...

Inactivation of both copies of a tumour suppressor gene is required for carcinogenesis, while germline deletion or inactivation of one copy results in an increase in the risk of cancer and is responsible for many of the known hereditary cancer syndromes.

In contrast, activation of only one copy of a proto-oncogene is required for carcinogenesis. [A proto-oncogene is a gene that when transformed into an oncogene, causes cancerous changes in the cell. This could be a gene that normally directs cell growth, but is altered to promote or allow uncontrolled cellular growth.]

Germline deletion or inactivation of one copy of a proto-oncogene halves the risk of activation at this locus....
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SOME syndromes that are associated with LMS or sarcoma are listed below, more are continually discovered both from human genome studies and from doctors coming into contact by chance with two or more people with symptoms that are similar, and who document these syndromes in the medical literature.

Beckwith-Wiedemann Syndrome
*Carney's Syndrome
Congenital Immune Deficiency Syndromes [associated with EBV virus]
Common Variable Immunodeficiency Syndrome
Congenital stenosis of the lower esophagus associated with leiomyoma and leiomyosarcoma of the gastrointestinal tract
*Cowden's Syndrome
*Familial ULMS,
Gardner's Syndrome
Hemihypertrophy Syndrome
*Leiomyomatosis & Renal Cell Cancer Syndrome
*Leiomyomatosis [Familial] Syndromes
*Li-Fraumeni Syndrome
Lynch II Syndrome
Nevoid Basal Cell Carcinoma Syndrome
Peutz-Jeghers Syndrome
Poland's Syndrome
*Retinoblastoma and LMS of the bladder syndrome
*Retinoblastoma predisposes to LMS
Rubinstein-Taybi Syndrome
Tuberous Sclerosis
Werner's Syndrome
Xeroderma Pigmentosum

*at least one member of the ACOR LMS list has been diagnosed with the asterisked syndromes.

Beckwith-Wiedemann Syndrome
A rare, overgrowth disorder in which babies are large at birth and may develop low blood sugar. Other common symptoms are a large tongue, large internal organs, and defects of the abdominal wall near the navel. Beckwith-Wiedemann syndrome increases the risk of developing certain cancers. Caused by DNA damage, or from imprinting errors. .
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*Carney's Syndrome, also called Carney"s Triad
Carney's syndrome, features gastrointestinal stromal tumors (GISTs), extra-adrenal paragangliomas, and pulmonary chondromas.
Fetch PMID: 15633134

Congenital Immune Deficiency Syndromes
Common Variable Immunodeficiency Syndrome
[associated with EBV virus. see Viral section.]

Congenital stenosis of the lower esophagus associated with leiomyoma and leiomyosarcoma of the gastrointestinal tract
Fetch PMID: 3052220

*Cowden's Syndrome
Cowden's syndrome is either familial [autosomal dominant] or sporadic and is associated with usually postpubertal development of a variety of cutaneous, stromal and visceral neoplasms. The syndrome is associated with mutations of the PTEN gene
Fetch PMID: 15920539

*Familial ULMS, no other identifiable symptoms.
We have had several pairs of sisters or mother and daughter that have had ULMS

Gardner's Syndrome
An inherited syndrome characterized by development of multiple tumors, including osteomas of the skull, epidermoid cysts, and fibromas before age 10 and of multiple polyposis predisposing to colon cancer.
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Hemihypertrophy Syndrome
Hemihyperplasia is characterized by asymmetric growth of cranium, face, trunk, limbs, and/or digits, with or without visceral involvement. It may be an isolated finding in an otherwise normal individual, or it may occur in several syndromes. Although isolated hemihyperplasia (IHH) is of unknown cause, it may represent one end of the clinical spectrum of the Wiedemann-Beckwith syndrome (WBS).
An association among many overgrowth syndromes and a predisposition to neoplasia is well recognized
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*Leiomyomatosis & Renal Cell Cancer Syndrome
Multiple fibroid tumors and renal cancer, can be associated with LMS.
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*Leiomyomatosis [Familial] Syndromes
Multiple fibroids in different places in the body. Sometimes undergo malignant transformation.
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*Li-Fraumeni Syndrome
Individuals are at risk for developing multiple cancers at unusually early ages. It may include cancers of the adrenal glands, brain, breast, bone, lung, melanoma skin cancer, pancreas, prostate, and germ cell ovarian and testicular cancer, as well as leukemia, lymphoma and soft tissue sarcomas. Additional cancer sites may include the larynx and stomach. Patients with this syndrome have a nearly 50% chance of developing an invasive cancer by age 30 (compared to 1% chance for general population). More than 90% of these patients will have cancer by age 70.
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Lynch II Syndrome
Hereditary non-polyposis colorectal cancer (HNPCC) (Lynch syndrome) It is the most common of the hereditary colorectal cancers and accounts for 5-10% of cases. This is characterized by development of predominantly proximal colon cancers. The Lynch type II patients have colon cancer as well as extra-colonic cancers.
Fetch PMID: 12075754 Free Full Text of Article is Available.

*Neurofibromatosis 1
NF1 is an autosomal dominant trait, but is also a sporadic mutation. NF1 is caused by abnormalities in one of the genes encoding a protein called neurofibromin. It causes unchecked growth of neurofibromatous tissue in nerves, skin and subcutaneous tissue, Malignant transformation of tumors occurs in approximately 5-10% of affected individuals.
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Nevoid Basal Cell Carcinoma Syndrome
Basal cell nevus syndrome is an autosomal dominant inherited set of multiple defects involving the skin, nervous system, eyes, endocrine glands, and bones. The condition causes an unusual facial appearance and a predisposition for skin cancers. Children with this disease have wide set eyes, a broad nasal saddle, and a heavy protruding brow. The hallmark of this disorder is the appearance of skin cancer (basal cell carcinoma) at or about puberty.
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Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome: An autosomal dominant inherited disorder characterized by freckle-like spots on the lips, mouth and fingers, and polyps in the intestines. Patients are at increased risk for developing cancer of the esophagus, stomach, colon, rectum, breast, ovary, testis and pancreas. The risk of cancer in the Peutz-Jeghers syndrome is very high. Among 210 patients with the symdrome, the risk of developing noncutaneous cancer between the ages of 15 to 64 was 93%.
Peutz-Jeghers syndrome is inherited in an autosomal dominant manner and is due to mutation in a gene on chromosome 19p13.3 called STK11 (serine/threonine-protein kinase 11) that appears to function as a tumor suppressor gene. Half of patients have an affected parent from whom they inherited an STK11 mutation and the other half have a new mutation in the STK11 gene.
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Poland's Syndrome
Poland's syndrome is characterized by a congenital defect of the pectoralis major [shoulder muscle] associated with various types of abnormalities of the arm of the same side. It has been associated with malignancies including LMS.
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*Retinoblastoma predisposes to LMS
Retinoblastoma is a malignant tumor which usually appears in infants or young children. The genetic cause is described as a "two-hit" process. Normally, individuals have two good copies of the retinoblastoma gene (RB-1) on chromosome 13. The disease develops in individuals in which mutation has occurred in both copies of RB-1.
The RB-1 gene carries the information for making a protein called pRB. This protein regulates cell division. When pRB is absent or defective due to defective copies of the gene, uncontrolled cell division occurs, and cancer results. pRB appears to be involved in many types of cancer besides retinoblastoma. [RB1 Loss of a single copy of chromosome 13 in the general region of the RB1 gene was found in around 35% of sarcomas. ed]
Genetic testing may be recommended to see if a defective gene has been inherited.
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*Retinoblastoma and LMS of the bladder syndrome
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Rubinstein-Taybi Syndrome
Rubinstein-Taybi syndrome is a condition characterized by short stature, moderate to severe mental retardation, distinctive facial features, and broad thumbs and first toes. Other features of the disorder vary. There is an increased risk of developing noncancerous and cancerous tumors.. It is inherited in an autosomal dominant pattern.
Fetch PMID: 7747773

Tuberous Sclerosis
Tuberous sclerosis is a rare genetic, neurological disorder in which benign tumors affect the brain, eyes, skin and internal organs. It is primarily characterized by seizures, mental retardation, and skin and eye lesions. Individuals with tuberous sclerosis may experience none or all of the symptoms with varying degrees of severity.
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Werner's Syndrome
Patients with Werner's Syndrome show a variety of the signs and symptoms of normal ageing at an early stage of their life; gray hair, alopecia, muscle atrophy, osteoporosis, cataracts, hypogonadism, diabetes mellitus, hyperlipidemia, atherosclerosis, malignancy, brain atrophy, and senile dementia. Werner's syndrome is a rare autosomal recessive disorder with chromosomal instability caused by the mutation of RecQ type DNA/RNA helicase.
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Xeroderma Pigmentosum
A hereditary disease with such extraordinary sensitivity to sunlight that it results in the development of skin cancer at a very early age. XP patients lack the normal capacity to repair the DNA damage inflicted by UV light. Damage to DNA is cumulative and cannot be reversed, and recurrent exposure can cause the rapid development of growths on the skin and eyes. 20% of XP patients also develop one or more of the following problems: blindness, deafness, mental retardation, poor coordination, spasticity, or retarded physical growth. XP is inherited as an autosomal recessive trait
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Inflammation as a Cause of Cancer

NSAID Use and Gastric Cancer Risk
..The relationship between the use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, and the risk of gastric cancer has not been well studied.... A fully recursive literature search to January 2003 was conducted in MEDLINE, PubMed, and CANCERLIT to identify potentially relevant case-control or cohort studies.... NSAID use was associated with a decreased risk of gastric cancer in a dose-dependent manner. This finding warrants proper clinical trials in populations with high risk of gastric cancer.
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Multicentric Extremity LMS
.. We report a 90 year-old male veteran who was found to have four leiomyosarcomas, one in right arm and the other three in right thigh. The patient sustained gunshot injuries over right thigh and right arm about 60 years ago in a war with severe wound sepsis .... These tumors happened to distribute in the vicinity of the old scars. It was speculated that these multicentric tumors were due to decreased immune surveillance caused by aging and induced by the previous trauma....
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LMS complicating chronic inflammation of the testis
..To report on a case of leiomyosarcoma of the testis that appeared to have arisen from a background of chronic testicular inflammation. ... A 65-year-old man with a 15-year history of diabetes mellitus and low-grade discomfort and swelling in the right testis presented as an emergency with exacerbation of the pain and swelling of the testis. Repeated ultrasound examination of the testis in the past 5 years had suggested a chronic testicular inflammatory disorder. Ultrasound during the current emergency case admission revealed a... a large heterogeneous solid mass ... in the right testis ... [After a] A right radical orchidectomy was performed. ...[the path report revealed a] primary leiomyosarcoma ...
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Carcinoma arising in the pleural cavity following pneumonectomy for hydatid disease.
We report a case of carcinoma following 42 years of chronic empyema [infection on the surface of the lung] in a patient who underwent surgery the age of 3. At the time of diagnosis, an esophageal fistula was observed and treated with cyanoacrylate. We hypothesize that chronic inflammation of the pleura, caused by decades of empyema, associated with the presence of ... a long-standing esophago-pleural fistula, led to neoplastic transformation.
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Angiosarcoma occurring with chronic osteomyelitis and residual foreign material: case report of a late World War II wound complication.
The case is reported of a World War II veteran who developed an angiosarcoma at the site of wounding 46 years previously. The wound was complicated by retained foreign material and chronic infection involving bone. ...There is slight but definite risk of tumour development in association with retained foreign material. This risk may be greater in older patients who have retained this foreign material for long periods and where the presence of the material is complicated by chronic infection.
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Lymphedema: an immunologically vulnerable site for development of neoplasms.
Lymphedema is the result of accumulation of protein-rich interstitial fluid (lymph stasis) caused by a failure of lymph drainage in the face of a normal capillary filtration. Whether the origin is congenital or acquired from infection, radiation, trauma, or surgery, chronic lymph stasis impairs local immune surveillance by disrupting trafficking of the immunocompetent cells in the lymphedematous district and stimulates vicarious angiogenesis by promoting development of a collateral lymphatic and hematic network in the lymphedematous district. When the local mechanisms of immune surveillance begin to fail, the lymphedematous region becomes an immunologically vulnerable area, predisposed to malignancy, chiefly vascular tumors such as Stewart-Treves syndrome and Kaposi's sarcoma, because of the continual angiogenic stimulus.
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Endemic Kaposi's sarcoma in Africa and local volcanic soils.
Endemic Kaposi's sarcoma (KS) in Africa, ... a chronic nodular condition predominantly affecting the feet and legs, is believed to arise in the lymphatic endothelium and is associated with chronic lymphoedema. As such, KS bears a resemblance to podoconiosis (non-filarial elephantiasis). ... The lymphatics and lymph nodes of patients with podoconiosis contain particulate alumino-silicates in macrophages consistent with the theory that ultrafine clay minerals are absorbed through the feet. The resulting chronic lymphatic irritation, inflammation, and collagenosis causes obstruction and lymphoedema. The geographical proximity of endemic KS to areas containing volcanic clay minerals, its lympho-endothelial origin, predilection for the feet and legs, and its prevalence among rural peasants and cultivators, suggest a common aetiology. Other features point to the participation of a low-grade, possibly sexually-transmitted, infective agent that becomes more pathogenic in the presence of immunosuppression. Damage to the dermal lymphatics of the feet and legs by absorbed clays could impair local immunity to such an agent. ...
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Stewart-Treves syndrome
..Stewart-Treves syndrome is an angiosarcoma associated with long-standing lymphoedema, most commonly seen as a rare complication of breast cancer treatment, and is associated with a poor outcome. ... ... Early diagnosis and treatment by radical ablative surgery confers a reasonable prognosis with this rare but aggressive disease. A nihilistic approach is unjustified.
In the world literature we can find about 400 cases of Stewart-Treves syndrome occurring after treatment for breast cancer. There are also occasional case reports of Stewart-Treves syndrome within chronically lymphoedematous upper extremity not related to breast cancer treatment and within chronically lymphoedematous leg. ...
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Inhibitory effect of medroxyprogesterone acetate on foreign body tumorigenesis in mice.
This paper reports on the investigation of the effect of medroxyprogesterone acetate (MPA) on foreign body tumorigenesis that resulted from sc implantation of a glass cylinder. Adult BALB/c mice of both sexes bearing the foreign body were separated into groups. Group 1 received 40 mg MPA sc every 2 months during 1 year, in the vicinity of the glass cylinder; group 2 received the same MPA treatment in the contralateral flank; and group 3 received no hormonal treatment. Sarcomas developed in 4 of 39, 9 of 41, and 17 of 39 mice, respectively. With the use of an evaluation based on the number of high-risk mice per time interval, the MPA inhibitory effect was found to be statistically significant in both groups: 26, 53, and 79% tumor incidence, respectively. A decrease in the rate of tumor development also was observed but only in mice treated with MPA in situ. An unexpected side effect of continuous MPA administration in females was the appearance of adenocarcinomas.
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Angiogenesis and prediction of sarcoma formation by plastic.
.. It is known that large plastic coverslips implanted s.c. in CBA mice produce sarcomas more rapidly and in a greater number than do small coverslips. We observed that within a few weeks after implantation the cells attached to the large coverslips showed an angiogenic capacity about 5-fold greater than that of the cells attached to the small coverslips. Months before a sarcoma was evident, angiogenesis induced by the cells attached to the large coverslips predicted the high risk of neoplastic transformation by large coverslips.
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Radiation Exposure

Post-irradiation Sarcomas

Identification of a causal agent should allow for diagnosis at an earlier stage. . This is particularly true of radiation-induced sarcomas because patients who develop this malignancy seem to have a poor prognosis. Radiation therapy has a prevalence of radiation-induced sarcoma of 0.17-0.21% As more patients survive their malignancies, we may see an increase in the incidence of postradiation sarcomas. Therefore, patients who receive radiation should be monitored closely, and a high index of suspicion should be maintained for complaints referable to the irradiated site. The development of sarcomas is a recognized complication of radiation therapy. Post-radiation sarcomas, while uncommon, are not rare. The imaging findings are not pathognomonic, but an appreciation of the expected latency period may help to suggest the diagnosis.
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Radiation-induced sarcomas can originate in either the irradiated bone or soft tissues. Most of these tumors are high-grade. The most common histologic subtypes are malignant fibrous histiocytoma (MFH) and osteosarcoma, although other histologies ... occur. Tumor size and grade are the two most important prognostic factors for soft tissue sarcomas, including those associated with radiation therapy.
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Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma.
..Numerous studies to date have suggested an association between radiation exposure and the development of soft tissue sarcoma after a latent period of several years. The current study was performed to quantify the risk of soft tissue sarcoma in the vicinity of previously irradiated anatomic regions in women with breast carcinoma... The risk of soft tissue sarcoma, especially angiosarcoma, was elevated after radiotherapy in women with breast carcinoma. Radiation-induced sarcomas are associated with poor overall prognosis. The treatment in most of the cases is late and ineffective, therefore careful follow-up is needed. There are still many uncertainties and questions about radiation-induced sarcomas.
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Clinicopathologic Assessment of Postradiation Sarcomas
KIT as a potential treatment target.
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Radiation-induced LMS as second primary tumors in the head and neck region: report of 2 cases.
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Development of primary LMS of the sternum postirradiation: report of a case.
We report herein the case of a 30-year-old man who developed a primary leiomyosarcoma (LMS) 11 years after undergoing a median sternotomy for mediastinal seminoma followed by 50 Gy radiotherapy. He was given two courses of chemotherapy, resulting in 90% tumor regression, after which resection of the tumor with adjacent chest wall structures was carried out. Reconstruction was performed using a methylmethacrylate prosthesis prepared preoperatively. Postoperatively, he received two additional courses of chemotherapy and has had no sign of recurrence for 45 months.
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Radiation induced sarcoma of the head and neck.
Radiation-induced sarcoma of the head and neck (RISHN) is a long-term complication of treatment. ...we have reviewed 69 cases reported in the English medical literature ...and pooled this information with our experience ...Surgery was the mainstay of treatment and follow-up ranged from 6 months to 15 years with a median of 48 months. The actuarial five-year disease free survival in these patients was 60%. ... There is at present little or no prospect for effective prevention of Radiation-induced sarcoma and therefore, a high index of suspicion based on the patient's symptoms assumes great importance in the outcome of these patients. Although surgical management of RISHN is challenging because of the close proximity of the tumour to important regional structures and the technical difficulties of operating in an irradiated area, complete surgical excision appears to offer the best means for palliation and the only realistic chance for long-term surviva
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Pelvic radiotherapy and LMS of the rectum
Leiomyosarcoma of the rectum is an uncommon malignancy; it accounts for less than 0.1% of all malignancies of the colon and rectum and only one case has been reported long-term following pelvic radiotherapy. We report a second case of leiomyosarcoma of the rectum after radiotherapy in an elderly women who received external radiation therapy eighteen years before, for endometrial carcinoma. We confirm that leiomyosarcoma may be a late uncommon effect of pelvic irradiation and suggest that close and long-term surveillance of irradiated patients is highly recommended.
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Radiation-induced LMS of the great vessels presenting as superior vena cava syndrome.
A patient with a pleomorphic intravascular leiomyosarcoma of the great vessels of the neck and mediastinum presented clinically with a superior vena cava syndrome. A latent period of 29 years elapsed between receiving orthovoltage radiation to the neck and right side of chest to treat recurrent ganglioneuroblastoma, and the appearance of a leiomyosarcoma and subsequent recurrences. ... This would appear to be the first reported case of radiation-induced intravascular leiomyosarcoma of the great vessels of the neck and mediastinum presenting as a superior vena cava syndrome.
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Dumb-bell sarcoma of the foramen jugulare with syringomyelia. A radio-induced tumour?
The clinicopathological findings of a 50-year-old man, who developed cervicothoracic syringomyelia at the age of 25 are presented. He was given radiation therapy at the age of 33. At the age of 57 he developed a foramen jugulare syndrome on the left, caused by a low grade leiomyosarcoma. Etiologically, the most attractive hypothesis appears to be that the tumour was induced by radiation therapy administered 24 years previously.
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Sarcomas arising after radiotherapy for peptic ulcer disease.
Therapeutic gastric irradiation has been used to reduce peptic juice secretion in patients with peptic ulcer disease. Between 1937 and 1968 a total of 2049 patients received such therapy at the University of Chicago. Three of these patients are known to have developed sarcomas in the field of radiation. Two gastric leiomyosarcomas of the stomach were diagnosed 26 and 14 years after treatment and a malignant fibrous histiocytoma of the anterior chest wall was removed six years after gastric irradiation. Of 743 peptic ulcer patients treated without irradiation and constituted as a control group for the study of therapeutic gastric radiation, none is known to have developed sarcoma. As the incidence of sarcoma in these patient groups is known only from the tumor registry of the University of Chicago, other cases of sarcoma may exist in the groups. While an increased incidence of sarcoma has not been proven to occur in patients who received therapeutic gastric irradiation for peptic ulcer disease, the possibility of such a risk should be borne in mind by physicians caring for such patients.
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In the Presence of Other Disease

Cancer incidence in patients with type 1 diabetes mellitus
Although patients with type 2 diabetes have elevated risks of liver, pancreatic, kidney, and endometrial cancer, little is known about the risk of cancer for patients with type 1 diabetes. We conducted a cohort study to examine cancer incidence among 29 187 patients in Sweden who were hospitalized for type 1 diabetes from 1965 through 1999. Relative risks of cancer were estimated by age-, sex- and calendar year of follow-up--adjusted standardized incidence ratios (SIRs), using data for the entire Swedish population as a reference. After excluding cancers diagnosed during the first year after hospital discharge, we observed 355 incident cases of cancer, which corresponded to a 20% increase in overall cancer incidence among type 1 diabetes patients ... Patients with type 1 diabetes had elevated risks of cancers of the stomach ... cervix ... and endometrium... Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.
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Full Text of Article

The Link with Thyroid Disease

There are a lot of people with thyroid problems on the ACOR LMS list, probably because of many reasons::

1. A shared faulty biochemical pathway that involves both thyroid disease and sarcomas.

2. Some thyroid disease is autoimmune. There is an increased occurrence of malignancy in autoimmune disease.

3. The treatment for cancer often involves chemotherapy. Chemotherapy can lead to the thyroid gland not working right, some of it might get destroyed.

4. The treatment for cancer often involves radiation. If the radiation field is aimed in the direction of the thyroid, a dose of radiation can cause problems in the gland.

So the treatment for cancer sometimes causes thyroid problems. [One study showed 16% of cancer patients had thyroid dysfunction of one type or another.]

5. Thyroid problems are somewhat common, anyway. Some of the thyroid problems might not be related.

6. Some people have cancer syndromes... that is they have faulty cancer suppressor genes. These people can get growths on their thyroid as well as tumors on their thyroid as well as their LMS.

7. Intrathyroid metastases.

8. There are second primary cancers, where the primary cancer could be either LMS or a thyroid cancer, and the second primary cancer being a thyroid cancer or LMS.

9. Probably there are other reasons too.

Thyroid Function

T3 and T4 are made by the thyroid gland. they are the thyroid hormones.

TSH is made by the pituitary gland. It is called Thyroid Stimulating Hormone. TSH stimulates the thyroid to make more T4 and T3.

The pituitary gland contains sensors that can tell what the levels of thyroid hormone are. If the thyroid hormone levels are low, more TSH is made to stimulate the thyroid gland to make more. If the thyroid hormone levels are high, less TSH is made to prevent the thyroid gland from making so much.

HyPOthyroidism means your T4 or T3 or both are low, and the TSH is high. This will make you sluggish, constipated, tired, sleep more, gain weight, lose hair, etc... Slows your system down.

HyPER thyroidism means either your T4 or T3 or both are high, and the TSH is low.This will make you insomniac, lose weight or eat prodigiously or both, have thick hair and fast nail growth, perhaps give you diarrhea... revs your system up.

If your pituitary is not working right, because of radiation or operation, the TSH will not be made. You will have a low TSH [it's not being made] and a low T4 as well, because the TSH is not stimulating the thyroid gland to make it. So hypothyroidism, can come from pituitary failure as well.

People who are very sick or very depressed or anorexic, sometimes have low TSH and low T4 as well. But they are not hypothyroid. This is called the sick euthyroid syndrome. [Eu thyroid is normal levels, not hypo or hyper].

Synthroid is manmade thyroid hormone. It is given as a pill for replacement if your thyroid hormone levels are too low.

Recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients.

Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. ... The recovery from this euthyroid sick syndrome is, at least in part, TSH-dependent, since the prolonged elevation of TSH values preceded and persisted during the normalization of T3 and the elevation of T4 levels. This biphasic pattern of induction of and recovery from the euthyroid sick syndrome may be a general feature of nonthyroidal disease. The euthyroid sick syndrome should be interpreted not only in relation to the presence of nonthyroidal diseases but also in relation to the recovery from these diseases.
Fetch PMID: 10094108

Reversible thyroid dysfunction during treatment with GM-CSF.
To investigate whether autoimmunity against thyroid antigens is induced or exacerbated by granulocyte-macrophage colony-stimulating factor, thyroid function and thyroid autoantibodies were studied in 14 patients with advanced breast cancer and 11 with soft-tissue sarcoma who received several cycles of doxorubicin and cyclophosphamide plus GM-CSF ... All patients had normal thyroid function before treatment. In 2 patients with pre-existing thyroid antibodies, thyroid dysfunction developed but disappeared after cessation of GM-CSF. No other autoimmune abnormalities appeared. Stimulation of antigen-presenting cells by GM-CSF may bring about this phenomenon.
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High-dose radiation and the emergence of thyroid nodular disease.
High-dose radiation (in excess of 2500 rads or centiGray) to the head and neck area is reputedly infrequently associated with the emergence of thyroid nodular disease. Thirty-three patients who underwent high-dose radiation and who developed thyroid nodular disease have been described....Consideration of radiation beam behavior showed that isodose curve, penumbra effect, back scatter, and special field resulted in the thyroid gland receiving a low dose, namely under 2500 rads.... It is apparent that for whatever reason and by whatever means and by whatever mechanism, high-dose radiation to the head and neck area can result in significant thyroid disease, and patients undergoing such radiation should be followed with this in mind...
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Thyroid carcinoma after successful treatment of osteosarcoma: a report of three patients.
We report three cases of papillary thyroid carcinoma occurring after successful treatment of osteosarcoma. Only one of the three patients received radiation therapy (to the chest) as part of the primary treatment of osteosarcoma. The onset of thyroid carcinoma occurred between 8 and 16 years from the cessation of osteosarcoma therapy. All patients are alive and disease-free from both malignancies. Whereas the association between osteosarcoma and thyroid carcinoma has not previously been recognized, there have been five case reports of these two entities occurring in the same patient. Three of these cases occurred in patients with Werner syndrome. None of the patients reported here had physical stigmata of Werner syndrome or a family history consistent with a hereditary cancer syndrome. Thyroid carcinoma occurs infrequently in patients with osteosarcoma, but in view of the rarity of these two disorders, this association may represent an inherited predisposition to these malignancies.
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Sarcoma and thyroid disorders: a common etiology?
We have recently observed that many of our sarcoma patients presented also with thyroid disorders. Literature data are almost unavailable on this topic. The relationship between the sarcoma and thyroid disorders is examined. Retrospective analysis of files of patients with sarcoma and clinically overt thyroid disorders was carried out. Of the 375 patients with soft tissue sarcomas (STS) and 235 with bone sarcoma (BS) ,,,(4.6%) had an associated significant thyroid disorder. The types of sarcoma were mainly liposarcoma followed by malignant fibrous histiocytoma, leiomyosarcoma and bone sarcoma. The primary sites were mainly limb and trunk. The interval between the diagnosis of the thyroid disorder and the sarcoma varied between -14 years (thyroid first) and +16.5 years (thyroid later) with a median of -0.2 years. Thyroid disorders included goiter, thyroiditis and carcinoma.

There are both basic-science and clinical evidence to a possible common pathway that leads to the association between overt thyroid disorders and sarcomas of bone or soft tissues. Oncogene erbA activity is related to thyroid receptors to T3 and to development of sarcoma. Cross talk of the sarcoma oncogene and the erbA might contribute to the development of sarcoma. The thyroid hormone receptor and the highly related viral oncoprotein v-erbA are found exclusively in the nucleus as stable constituents of chromatin. It has been shown that v-erbA can block the spontaneous differentiation in erythroid cells transformed by various retroviral oncogenes. V-erbA can alter the spectrum of neoplasia induced by the v-src oncogene, which
causes predominantly sarcomas and erythroblastosis in chicks. The erbA can cooperate with other oncogenes such as v-erbB or with v-fms, v-ras, and c-kit. Cooperation with v-myc may play a role in the development of rhabdomyosarcoma especially in thyroid hormone deficiency state.

The possible clinical implications are the need to screen patients with sarcoma to thyroid disorders, and patients with thyroid disorders for malignant diseases.
Fetch PMID: 12066223
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August 2005

Viral Causes of Cancer
Viral Causes

Sarcomas often occur in immunocompromised people, either with acquired or congenital immunodeficiency syndromes. Leiomyosrcoma, when it occurs as part of an immunocompromised syndrome, often involves Epstein-Barr Virus as part of the etiological picture. Epstein-Barr VIrus, which causes infectious mononucleosis, is implicated in several cancers. It is an oncogenic virus. It is a cause of Burkitt's lymphoma, is associated with nonHodgkins lymphomas, with nasopharyngeal carcinoma, and with LMS -- these seem to be either children with HIV or adults who are deliberately immunosuppressed because of a transplanted organ, or people with congenital immunodeficiency syndromes.

Epstein-Barr virus and cancer.
EBV was the first human virus to be directly implicated in carcinogenesis. It infects >90% of the world's population. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors.
Normal host populations can have vastly different susceptibility to EBV-related tumors as demonstrated by geographical and immunological variations in the prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has also been associated with epithelial malignancies arising in the gastric region and the breast, although some of this work remains in dispute. EBV uses its viral proteins, the actions of which mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs are beginning to show promise in the treatment of EBV-related disorders.
Epstein-Barr Virus and Cancer
Epstein-Barr Virus
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The complexity of the Epstein-Barr virus infection in humans.
The Epstein-Barr virus (EBV) was isolated 40 years ago from cultures of Burkitt lymphoma cells (BL). The tumor was encountered in Africa and exhibited characteristic geographical, clinical and pathological fatures. Serological studies revealed that the virus is ubiquitous in humans. The primary infection is often accompanied by the syndrome of acute infectious mononucleosis (IM). It can induce malignant proliferation of B lymphocytes in conditions of immunodeficiency. EBV
can immortalize B lymphocytes in culture. These cells carry the virus as isomes and express 9 virally encoded proteins. Their immunological recognition constitutes the surveillance which is responsible for the healthy virus carrier state. The main virus reservoir is represented by a low number of resting B lymphocyte which contain the viral genome but do not express its transformation proteins. The viral genome is detectable in all African BLs, in variable proportions of nasopharyngeal carcinoma, Hodgkin's disease, T cell lymphoma, lymphoepithelial like carcinoma, gastric carcinoma and leiomyosarcoma cases. The role of EBV in the genesis of these tumors is unknown.
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Characterization of natural Epstein-Barr virus infection and replication in smooth muscle cells from a leiomyosarcoma.
Cells from a leiomyosarcoma tumor (LMS-1) from a patient with the acquired immunodeficiency syndrome (AIDS) were ... cultured ... and studied ... The cultured cells harbored EBV, and infectious EBV continued to be detected by polymerase chain reaction and virus culture through several passages in vitro.
Several EBV antigens were expressed, .... Human umbilical cord lymphocytes that were transformed with virus isolated from cultured cells yielded immortalized cell lines that expressed EBV antigens similar to other EBV-transformed lymphocyte cell lines. These results confirm that EBV is capable of lytic infection of smooth muscle cells with expression of a repertoire of latent and replicative viral products and production of infectious virus. EBV infection of smooth muscle cells may contribute to the oncogenesis of leiomyosarcomas.
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Overview of the epidemiology of immunodeficiency-associated cancers.
Immunodeficiency, be it congenital, therapeutic, or infectious in origin, increases the risk of certain, but not all, types of cancer. A common feature of these cancers is that specific infectious agents appear to be important in their etiology, not only in immunodeficient subjects but also in the general population. People with acquired immunodeficiency syndrome (AIDS) are at an increased risk of Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, squamous cell carcinoma of the conjunctiva, and childhood leiomyosarcoma. It is striking that most of these cancers have been associated with specific human herpesvirus (HHV) infections: HHV-8 with Kaposi's sarcoma and the closely related Epstein-Barr virus with non-Hodgkin's lymphoma, Hodgkin's disease, and possibly also with childhood leiomyosarcoma. Moreover, similar associations between these viruses and cancer have been found, albeit inconsistently, in people who are not immunosuppressed. Further research is needed to establish whether the risk of other cancers is also increased in people with AIDS, although, if so, the cancers are likely to be rare or to have comparatively small associated relative risks. ... With the prospect of improved survival in people with AIDS, the effect of immunosuppression on cancer is likely to become an increasingly important issue.
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Laryngeal leiomyosarcoma.
We report one case of leiomyosarcoma (LMS) of the larynx occurring in a patient with a history of immunosuppressive therapy, and offer a critical review of the literature. Epstein-Barr virus (EBV) genome was not identified in the neoplastic cells.,,
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Primary leiomyosarcoma of brain in an adolescent with common variable immunodeficiency syndrome.
A 14-year-old girl with common variable immunodeficiency syndrome was found to have a low-grade malignant neoplasm arising in the left temporal lobe of the brain. Ultrastructural and immunohistochemical studies established a diagnosis of leiomyosarcoma, despite the rarity of this tumor in children. In situ hybridization with the EBER probe revealed essentially all of the neoplastic cells to be infected with Epstein-Barr virus (EBV). Children with the acquired immunodeficiency syndrome (AIDS) are known to exhibit an increased incidence of smooth muscle tumors associated with EBV. Similar tumors have been reported in EBV-infected patients undergoing therapeutic immunosuppression. This appears to be the first reported case of childhood leiomyosarcoma where the cause of the underlying immunodeficiency was a genetic rather than acquired disorder. The authors conclude that electron microscopy, immunohistochemistry, and other ancillary techniques are essential in the evaluation of unusual tumors in immunocompromised children, whether the cause is hereditary or acquired.
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Epstein-Barr virus-associated leiomyosarcomas in liver transplantation recipients. Origin from either donor or recipient tissue.
..Leiomyosarcoma, a mesenchymal malignancy with smooth muscle differentiation, is extremely rare in children. Immunosuppression, due to either antirejection medication in organ transplantation recipients or human immunodeficiency virus infection (HIV), appears to constitute a predisposition. ... Two cases of leiomyosarcoma in pediatric liver transplantation recipients were investigated ...for origin from donor or recipient tissue, and by EBER-1 in situ hybridization for evidence of latent Epstein-Barr virus (EBV) infection.
..A 9-year-old male developed a high grade, poorly differentiated leiomyosarcoma in his allografted liver 2 years after transplantation, and despite antineoplastic chemotherapy, he died of metastatic disease. The genotype of his tumor indicated an origin from donor tissue. A 12-year-old female had a low grade retroperitoneal leiomyosarcoma involving the superior mesenteric vein. After resection, she remained disease free without chemotherapy. The genotype of her tumor indicated an origin from native tissue. In both tumors, latent EBV infection was documented.
..Neoplastic smooth muscle proliferation in immunosuppressed ,,, transplantation recipients [involves]... transformation of either... donor tissue or recipient tissue elsewhere in the body, ... and [exhibits] ...evidence of latent EBV infection.
Fetch PMID: 8620427

Epstein-Barr virus-associated multicentric leiomyosarcoma in an adult patient after heart transplantation
Epstein-Barr virus (EBV)-associated smooth muscle tumors following solid organ transplantation are extremely rare, with only 12 cases reported in the literature thus far. The exact pathogenetic role of EBV infection in the oncogenesis of these soft tissue tumors in immunodeficient patients still unclear. We report a 26-year-old man in whom multiple smooth muscle tumors developed 36 to 51 months after heart transplantation. All tumors, two synchronous liver nodules, two subsequently occurring paravertebral tumors, and a single tumor in a vein at the left ankle were surgically resected. The tumor tissue was processed for routine histology and immunohistochemical (IHC) stains. Additionally, [tests] were used for EBV particle ...analysis. The histologic features and immunohistochemical profiles were consistent with leiomyosarcoma in all tumor nodules. EBV infection was detected in >95% of tumor cell nuclei by ...[EBV tests].

.. Under continuous antiviral therapy (famcyclovir) the patient currently shows no evidence of disease. Our data indicate that EBV infection plays a causal role in the development of smooth muscle tumors following organ transplantation. A latency type III, identical to EBV-associated posttransplant lymphoproliferative disorders, was identified and suggests a common pathogenetic mechanism in the development of these histogenetically distinct neoplasms. The fact that the patient currently shows no evidence of disease may be the result of the continuous administration of antiviral therapy because the soft tissue recurrences of the leiomyosarcoma occurred while the patient was not receiving antiviral prophylaxis.
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Estimation of risk of cancers before occurrence of acquired immunodeficiency syndrome in persons infected with human immunodeficiency virus.
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Epidemiology of AIDS-related malignancies an international perspective.
Patients with HIV infection are at increased risk for developing Kaposi's sarcoma, non-Hodgkin's lymphoma, and several other cancers. The relative risks for the most common epithelial cancers in the general population--lung, breast, colon/rectum, stomach, liver, and prostate--are not increased substantially in people with AIDS, however. Accumulating data suggest that HIV-infected patients also are at increased risk for developing Hodgkin's lymphoma, ..., leiomyosarcoma, ..
Notably, other viral infections have been implicated in the etiology of many of these conditions. The introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of AIDS-associated cancers in Western countries, but less than 1% of AIDS patients are receiving HAART in the HIV epicenter of sub-Saharan Africa. Further therapeutic advances that extend survival with HIV infection with varying reconstitution of immune competence may lead to additional alterations in cancer risk.
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Benign and malignant smooth muscle tumors containing Epstein-Barr virus in children with AIDS.
Smooth muscle tumors (leiomyosarcomas) are the second most prevalent malignancy of children with the acquired immunodeficiency syndrome (AIDS). We have investigated the tumors, plasma, and peripheral white blood cells of eight children with AIDS with smooth muscle tumors for evidence of tumor association with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). Very low levels of HIV were found in the tumors of the AIDS patients, probably resulting from blood-borne carriage of virus. These smooth muscle tumors had very high quantities of EBV in all the tumor cells by in situ hybridization, with an average of 4.5 EBV genomes per cell by quantitative polymerase chain reaction amplification. Increased amounts of EBV were found in the peripheral blood cells of two AIDS patients before the time of tumor diagnosis. EBV clonality studies demonstrated different monoclonal EBV infection of two separate colonic tumors from one patient, and dual or mixed monoclonal EBV infection in another patient. The muscle cells of leiomyomas and leiomyosarcomas of patients with AIDS demonstrated prominent staining with antibodies to the EBV receptor. The uniform distribution and striking amount of EBV in the tumor cells demonstrates that EBV is capable of infecting smooth muscle cells and that these cells support EBV replication. Clonal EBV proliferation suggests that EBV infection occurs at an early stage of tumor development. These findings indicate that EBV has a causal role in the oncogenesis of leiomyosarcomas of patients with AIDS.
Fetch PMID: 9402327

Cancer in human immunodeficiency virus-infected children:
a case series from the Children's Cancer Group and the National Cancer Institute.
..To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. ... WSixty-four children (39 boys, 25 girls) with 65 tumors were reported. ... Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. ... Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The ...After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates...
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Epstein-Barr virus-associated smooth muscle tumors in ataxia-telangiectasia.
Chromosomal breakage syndromes, including ataxia-telangiectasia (AT), are autosomal recessive disorders in which DNA repair mechanisms are defective resulting in chromosomal instability.
Affected individuals are at high risk for developing malignancy ... [One effect of AT,] severe immunosuppression, can permit virally mediated neoplasms to manifest, similar to those seen in acquired immunodeficiency syndrome (AIDS), congenital immune deficiency syndromes, and posttransplant populations. Epstein-Barr virus (EBV) is a common viral agent known to be associated with ... smooth muscle malignancies in such patients.
.. We present a case of EBV-associated laryngeal leiomyosarcoma and jejunal cellular leiomyoma in a child with AT. This case suggests that the development of neoplasia in patients with chromosomal breakage syndromes may be related to the immunosuppressive consequences of these diseases, and searching for infectious causes (such as EBV) is important.
Roughly one-third of patients with ataxia-telangiectasia (AT) develop malignant tumors.
Fetch PMID: 11823985
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compiled by doctordee
August 2005

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