How to detect testicular cancer

Testicular cancer tends to be a young man's disease. In 1993, U.S. physicians diagnosed some 6,600 cases, accounting for about 1 out of every 91 new malignancies in men. Though relatively rare, it nevertheless is the most common cancer in American males age 15 to 35.

Over the past several decades, the incidence of this disease has increased worldwide. Moreover, risk of the cancer varies dramatically between populations. For instance, at 7.8 new cases per 100,000 males in the population, the testicular cancer risk faced by Danish men is more than five times that faced by men in neighboring Finland. In the United States, where the incidence falls about midway between the rates of these two groups, there is a sharp polarity by race. Whites are about seven times as likely to develop the cancer as blacks.

While the overwhelming majority of people with testicular cancer survive -- typically 90 percent or more -- balancing a young man's desire to maintain his fertility against the risk of a cancer recurrence presents physicians and patients with a dilemma.

At issue is whether to actively look for signs of quiescent disease -- by taking a biopsy of the second testicle -- when the first testicle and its tumor are removed.

Most U.S. physicians recommend a wait-and-see approach. If a second cancer occurs, the remaining testicle is removed.

In several European countries, however, the trend is toward recommending immediate biopsy. A growing body of studies indicates that in most cases, the small percentage of men who will go on to develop a tumor in the second testicle (typically 2 to 5 percent) already possess characteristic cellular abnormalities -- essentially, localized seeds of cancer -- that can be identified in a sample of testicular tissue.

When physicians find signs of this precancerous condition, they offer to irradiate the second testicle. This kills the precancerous cells while sparing the organ, which produces the male sex hormone testosterone. However, radiation treatment also kills the testicle's sperm-producing cells, rendering the man infertile.

These two tacks toward cancer follow-up reflect differences in attitudes about risk management. They also could have legal repercussions. Doctors who do not offer to biopsy the second testicle may find themselves vulnerable to litigation if another cancer develops -- especially if it's a lethal one.

Patients, too, face difficult tradeoffs. Those electing biopsy must balance the peace of mind that comes from knowing their cancer status against the risk of a positive finding -- and a call for treatment that guarantees infertility. Patients who opt not to undergo biopsy may prolong fertility, but at the risk of later castration.

No one knows what causes testicular cancer. However, in 1972, Danish endocrinologist Niels E. Skakkebaek published a paper describing unusual cells in the testes of men who later developed the disease. Because he suspected the cancer evolved from these abnormal cells, Skakkebaek termed the apparent cancer precursors "carcinoma in situ" (CIS).

When initially presented with this hypothesis, "most people didn't believe it," recalls pathologist Ivan Damjanov of Jefferson Medical College in Philadelphia. "But it's not controversial anymore," he says, adding that the potential of testicular CIS to transform into a cancer has been well accepted since about the mid1980s. And because visual examination cannot distinguish which CIS cells may develop into an invasive tumor, he observes, "we therefore treat all of them as if they will."

Moreover, he notes, visual clues offer no indication of how quickly such a transformation might occur. "So we don't know whether we have to take it [the CIS] out tomorrow or can leave it for 2 weeks, even 2 years."

Like fetal germ cells, the noninvasive CIS cells lack the mature structure that characterizes the sperm-making or sperm-nurturing cells into which they were supposed to have evolved. CIS cells also produce several biochemical signatures of fetal cells -- such as an enzyme present in embryonic cells migrating from the yolk sac to the genital regions.

But to the trained eye, Damjanov notes, CIS cells don't look like normal fetal cells: "They look like cancer." Moreover, Skakkebaek adds, they bear an abnormal genetic signature. With 60 to 70 chromosomes each, these cells possess a dozen or two too many.

Over the past 20 years, Skakkebaek, now chief of the Department of Growth and Reproduction at University Hospital (Rigshospitalet) in Copenhagen, has observed CIS cells in adults as well as young boys. Initially, he observed them in testicular biopsies from infertile men who went on to develop testicular cancer. Later, his group found CIS cells in a 10-year-old boy undergoing surgery to correct his cryptorchidism (undescended testes); within 10 years, the boy had developed testicular cancer.

More recently, Skakkebaek's team has biopsied young boys with other conditions that have been linked to testicular cancer -- for example, hypospadia, a partially unfused penis, or intersex, a condition in which some of a boy's cells lack the male, or Y, chromosome. At least one Danish researcher has even observed CIS cells in a fetal testis.

The similarity of CIS cells to fetal cells and their appearance even in young children suggests that these testicular antecedents of cancer probably form during fetal life, then lie dormant for decades, Skakkebaek now believes.

"We think hormones that become active in puberty may play a role in the proliferation of these cells," he says. "When a child is born, he may have just a few. With age, [the cells] may proliferate."

Physicians confirm a testicular tumor by examining a suspicious gonad after its removal, according to the National Cancer Institute. This is because biopsying a tumor-bearing testicle runs the risk of dislodging any cancer cells that may have turned metastatic -- gained the ability to seed new cancers throughout the body. Because CIS cells are not invasive, biopsying them does not pose a similar risk.

If a pathologist observes invasive disease in the excised gland, doctors will conduct further tests to gauge whether and how much the malignancy has spread -- thereby assessing the need for follow-up surgery and for postsurgical radiation therapy, chemotherapy, or both.

In the United States, most doctors then advise patients to perform monthly self-examinations (sound advice for all men) and to report suspicious signs -- such as a hard lump, testicular enlargement, or buildup of fluid in the scrotal sac. If signs point to a second cancer, the remaining testicle is removed.

Losing one testicle should not prevent a man from fathering a child. Infertility and other problems typically arise when doctors must take the second gonad. Loss of both testes also leaves a man vulnerable to "a sort of male menopause," notes urologist Timothy B. Hargreave of Western General Hospital in Edinburgh.

Insufficient testosterone can lead to a softening of bones, hot flashes, lethargy, and a waning interest in sex. Though doctors can prescribe lifelong administration of testosterone to head off such symptoms, the hormone isn't well absorbed through the intestine. So the most effective treatments usually involve weekly injections or longer-duration implants of the hormone under the skin, Hargreave notes. Over a lifetime, this can prove "a bother for everybody concerned," he says, explaining why many European physicians seek to preserve the endogenous source of the hormone -- the remaining testicle.

Moreover, Skakkebaek observes, men who lose both testicles often develop psychological problems that hormone-replacement therapy cannot address.

Full castration "is really a pity," he says. "And in our clinic, we consider it a failure when we have to remove the second testis."

A different risk-benefit calculation prevails west of the Atlantic, as john P. Donohue outlined 15 months ago during a workshop in Copenhagen. "My current practice has been to adopt a passive approach to the question [of biopsying the second testicle]," said Donohue of Indiana University Medical Center (IUMC) in Indianapolis. In general, he added, U.S. urologists "have had a similar philosophy."

In the absence of tumors, CIS cells have not been associated with metastases. As a result, Donohue says, "we have not felt any great urgency to detect [their] presence." Moreover, he notes, because no more than 1 in 20 survivors of testicular cancer will ever develop a second malignancy, "we have not felt that this risk factor was sufficient to justify a biopsy in every case." Exceptions to this rule are patients believed to be at especially high risk, such as those born with one or more undescended testicles or those with a history of infertility.