Clinical Laboratory Strategies: December 13, 2007

Diagnosing Prostate Cancer in Obese Men
Higher Blood Volume Dilutes PSA Values
By Phil Kibak

Excluding basal and squamous cell skin cancers, the American Cancer Society reports that prostate cancer is the most common type of cancer found in American men with an estimated 219,000 new cases detected in 2007. New research proposes an explanation for the finding that a high body mass index (BMI), a measure of obesity, may make it harder to detect prostate cancer with PSA and lead to delayed diagnosis and increased risk of mortality. This issue of Strategies examines a recent study suggesting that PSA findings in obese men need to be adjusted to enhance their clinical interpretation.

A decision to conduct more specific diagnostic tests for prostate cancer often is based on a PSA blood test. But a recent study suggests that obesity may make it harder to identify prostate cancer with the PSA test. New research led by Stephen J. Freedland, MD, Assistant Professor of Urology and Pathology at Duke University School of Medicine (Durham, N.C.) found evidence that higher blood volumes in obese men result in a hemodilution effect that decreases PSA concentrations and leads to false-low interpretations. The widely-reported study was published November 21, 2007 in the Journal of the American Medical Association (JAMA 2007; 298:19, 2275–2280).

Missed Cancer in Obese Men

“Our study showed that blood PSA concentrations can be diluted due to the fact that obese men with prostate cancer have greater blood volumes compared with normal weight men with the disease,” said Lionel Bañez, MD, a research fellow at Duke University Medical Center and first author of the study. “The importance of this new finding is that we may be missing cancers in obese men because the low PSA values do not meet the cutoff that would prompt a physician to go to the next level and perform a prostate biopsy.”

The scientists compared the records of almost 14,000 men who had undergone radical prostatectomy surgery between 1986 and 2006 at the Duke University Prostate Center, the Brady Urological Institute at the Johns Hopkins Hospital (Baltimore, Md.), or at one of five Veterans Affairs hospitals—in Durham, N.C.; Augusta, Ga.; Los Angeles; San Francisco; and Palo Alto, Calif.—comprising the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. They calculated pre-operative BMI and analyzed the relationship between BMI and PSA values. Other study factors included PSA mass—total PSA protein in circulation—and estimated body surface area and total plasma volume. The researchers  also adjusted for cancer-related variables that might have affected PSA concentration, such as Gleason score, the presence or absence of extracapsular extension, the absence or presence of positive surgical margins, and seminal vesicle invasion.

Men were categorized by BMI into four groups—normal weight, BMI less than 25; overweight, BMI between 25 and 29.9; mildly obese, BMI between 30 and 34.9; and moderately to severely obese, with BMI equal to or greater than 35. The researchers observed that increasing BMI was associated with lower PSA concentrations in all three cohorts. Men with a BMI of 35 or greater had 21% to 23% larger plasma volumes relative to normal-weight men. Men in the most obese group had serum PSA concentrations that were 11% to 21% lower than those of normal-weight men.

Other Factors Play a Role

Lower PSA values may mean that underlying disease is not being detected. Because cancer is generally a progressive process, some of these undetected cancers will continue to grow and may present at a later point, when they are larger and more difficult to treat. “These findings suggest that it would be reasonable to adjust PSA results in obese men by lowering the cutoff the institution uses to prompt a biopsy by 15 to 20 percent,” said Bañez. “And, as the prevalence of obesity seems to be rising in the United States this may be something that affects an increasing number of American men.”

But the PSA test does have limitations—approximately one-third of prostate cancers detected at a PSA level at or above 4 ng/mL have already spread to the prostate capsule or beyond, and approximately 15% of men with a PSA level less than 4 ng/mL have prostate cancer that is detectable by needle biopsy. Although the finding from this new study is an important consideration, hemodilution may not be the most significant factor to consider when assessing PSA and prostate disease, said Herbert A. Fritsche, PhD, chief of clinical chemistry at M.D. Anderson Cancer Center (Houston, Texas), citing research he and his colleagues conducted (Urology 2005 October; 66(4):819-23). “Our study was different in that we looked at men who had higher than normal levels of PSA but were biopsy negative for prostate cancer. We tried to correlate different factors including body surface area, BMI, weight, height, and age, among others,” he said. “But of all the variables we tested, we observed that prostate volume most significantly correlated with increased PSA.”

“How to better use the PSA test is on everyone’s mind and if physicians need to perform some kind of factor adjustment, that would be ideal,” Fritsche added. “But this is an extremely complex issue and there seem to be other variables that come into play.”

Hemodilution also may be related to other markers and other diseases, noted Bañez, and may not be specific to prostate cancer. “With regard to this phenomenon, our research may have far-reaching consequences into other blood markers that are used to diagnose disease.”

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