Nordic Testicular Cancer Mystery Prompts Chemicals Probe
Incidence of the usually uncommon malignancy is now almost 10 times the global average in Norway and Denmark, according to the International Agency for Research on Cancer in Lyon. Hundreds of chemicals, including drugs, pesticides and plastic materials, are being screened by scientists from Stockholm to Helsinki to find the cause.
The probe is focusing on compounds thought to interfere with hormone signaling called endocrine disrupters, which the United Nations said last month may be causing more diseases than previously thought. The European research may reveal why testicular cancer is increasing across the developed world.
“We don’t know what it is, but we know that it must be something in the environment causing the increase,” said Olof Akre, a cancer epidemiologist at Stockholm’s Karolinska Institute, in an interview. “When it happens, it’s really a crisis for these men.”
Malignant tumors of the testis are mostly picked up in men younger than 40. While earlier detection and better treatments have increased survival, curing the cancer often requires removal of the affected testicle, reducing fertility. Survivors also have a higher risk of developing metabolic conditions, such as diabetes, in later life.
“You might make some of these men totally infertile depending on the remaining ability to produce semen,” said Akre, who is part of a network of researchers in the Nordic region investigating the region’s testicular cancer epidemic.
Incidence last year was highest worldwide in Norway, with a rate of 12.7 cases per 100,000 men, and 12.5 per 100,000 in Denmark, according to IARC data. That compares with a rate of 1.5 globally, 5.8 across Europe and 5.1 in the U.S.
The American Cancer Society predicts there will be 7,920 new cases and 370 deaths in the U.S. this year. The five-year survival rate for men with testicular cancer that hasn’t spread to other parts of the body is 99 percent, and 96 percent if the cancer has spread to regional lymph nodes, according to the National Cancer Institute in Bethesda, Maryland.
Sweden’s rate of 7.2, much lower than that of Denmark and Norway, has been “constantly enigmatic,” said Akre.
“We are pretty close neighbors, yet we just don’t understand how we can have such big differences in the scope of testicular cancer,” he said. The nations’ agricultural systems “probably has had some consequences on what we eat and drink, but that’s where it stops. We have no more better ideas than this.”
Other Nordic countries may catch up. Cases in the region have been steadily rising for decades, increasing about 3 percent annually in Norway, 2.6 percent in Denmark, 3.2 percent in Sweden and 3.9 percent in Finland, Akre and colleagues found in a study published in 2004. The pace of growth matched rises in lung cancer and heart disease, he said.
“In all these countries, the trend is very similar,” said Jorma Toppari, professor in the departments of physiology and pediatrics at Finland’s University of Turku. “The same phenomenon is occurring in different countries with differences in time. It may be leveling off in those countries with the highest incidence.”
Testicular cancer also growing in other countries besides Nordic region. The incidence rate in the U.K. has more than doubled to 7 per 100,000 in the 33 years through 2008, according Cancer Research U.K. In the U.S., the rate grew 2.3 percent annually from 1975 to 1989, and 0.8 percent from 1989 to 2009, the National Cancer Institute said.
While testicular cancer is more common among Caucasians than Asians or Africans, studies on immigrants suggest environmental factors may be a more important driver of testicular cancer in the Nordic region compared with other malignancies, Toppari said.
People born outside Denmark who migrate there have a lower risk of testicular cancer than native-born Danes. That advantage is lost for children of migrants born in Denmark, according to research published in the Journal of the National Cancer Institute in 2008. A similar trend has been observed in Sweden.
“It matters where you were born and when you were born,” Toppari said.
Although testicular cancer is most commonly diagnosed in men in their 30s, the groundwork for it may be established in the first months of fetal development with abnormal growth, or dysgenesis, of the testis, said Niels Erik Skakkebaek, a professor in the department of growth and reproduction at the University of Copenhagen.
Almost all testicular cancers begin in sperm-making germ cells, according to the National Cancer Institute. The hypothesis is that in men with testicular cancer, development of the testes was distorted such that some of the embryonic stem cells that should have developed into germ cells didn’t differentiate properly and were maintained in the testes as stem cells, according to Skakkebaek, who was a member of a panel of experts that helped prepare last month’s report by the UN’s Environment Programme and the World Health Organization.
If the testes don’t properly develop in the womb, they may not produce sufficient testosterone and other chemical signals to trigger their natural descent from the abdomen to the scrotum before birth, he said. The idea is supported by experiments in animals, which have shown that testes are less likely to descend if they’re abnormal. A current hypothesis is that perturbations in testes development may be caused by exposure to chemicals, leading to undescended testis and endocrine disorders, Skakkebaek said in an interview.
That suggests testicular dysgenesis may be the result of a combination of environmental and predisposing genetic factors, Skakkebaek said, adding that more research in humans is needed to validate the finding.
The same interplay is probably also causing higher rates of cryptorchidism, the condition in which the testes fail to descend from the abdomen to the scrotum; hypospadias, an abnormality of the penis in which the urethra opening is in the wrong place; and reduced sperm concentration, Toppari said.
Several epidemiological studies have shown “weak” associations between cryptorchidism in sons and exposures of their mothers to drugs such as diethylstilbestrol, or DES, previously used for female hormone replacement therapy; the painkiller paracetamol; and mixtures of polybrominated diphenyl ethers, or PBDEs, used for flame retardant; and pesticide application, the UN report said.
Cryptorchidism at birth is associated with a fivefold increased risk of testicular cancer and also with impaired semen quality and sub-fecundity. A testicle remaining in the abdomen at puberty is a risk factor for testicular cancer, said the University of Copenhagen’s Skakkebaek.
In Denmark, cryptorchidism occurs in 9 percent of boys, four times higher than the rate in Finland and more than double the rate observed in 1961, a study published in 2004 found. In comparison, about 3 to 4 percent of full-term infants born in the U.S. have undescended testes, according to U.S. National Library of Medicine.
No studies have investigated a potential link between fetal exposure to endocrine-disrupter chemicals and the risk of testicular cancer decades later, the UN report said.
Researchers have so far only analyzed several hundred of the possibly thousand or so chemicals and chemical combinations that may be implicated, the University of Turku’s Toppari said.
“There is a big mixture of chemicals that may contribute,” he said.
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