Blood Simple – Pathologist Michael Misialek encourages men’s health checkups as the PSA era heads toward Gene Tests and the Prostate Health Index

June is Men’s Health Month in the USA and the third Sunday of June is celebrated as Father's Day. So in addition to Prostate Cancer Awareness Month in September and "Movember" (grow or wear a mustache in November to show you're "committed to changing the face of men’s health") June is a good time for health organizations to stand up for men. The College of American Pathologists (CAP) does so in an advisory, "5 Things to Know About Your PSA Test."

Michael J. Misialek, MD, Pathologist.

The pathologists' organization suggests that if you're a man "heeding the advice of your wife, girlfriend or significant other," you may have decided this June "to schedule yourself for that routine physical that you've been putting off. One aspect of your visit to the doctor’s office might be a PSA test."

"Your Prostate Specific Antigen screening test," CAP says, "will be studied and evaluated by a pathologist like Michael J. Misialek, MD, FCAP. Dr. Misialek says there’s a lot you need to understand about this test." Dr. Misialek, associate chair, Department of Pathology, Newton-Wellesley Hospital, and a clinical assistant professor in pathology, Tufts University School of Medicine in Massachusetts, wants men to understand the following points:

1. The test is simple, but the explanation isn’t.

The level of Prostate Specific Antigen is measured by analyzing the same type of blood sample that might be collected to check your cholesterol or blood sugar levels. Some doctors do not routinely include the PSA test in an annual physical exam.

As with other types of cancer screening, Dr. Misialek notes, your doctor must fully explain what the results might show and prepare you to think about the options that would be considered if the PSA levels are elevated

2. There is no consensus about the right age to should start PSA screening.

“If you look at published guidelines, PSA screening is a moving target,” says Dr. Misialek. “Criticism of early PSA screening often focuses on a cost-benefit analysis,” he says. “Early screening could result in unnecessary testing and costly treatment of a cancer that may not be aggressive.” Recently, the American College of Physicians’ High Value Care Task Force published new guidelines based on an analysis of the recommendations of several medical groups. Their conclusion: Americans are getting far too many cancer screening tests.

3. Elevated PSA doesn’t always mean you have cancer.

BPH (enlarged prostate) and inflammation can raise PSA in the absence of cancer, though about 80 percent of cancers will have an elevated PSA. “It’s still the best test we have for now,” says Dr. Misialek.

4. Newer tests in the pipeline might be more effective.

5. Genetic testing may be appropriate for prostate cancer.

New research has shown that mutations of such genes as BRCA1 and BRCA2 may be linked to early onset prostate cancer. These are the same genes known to play roles in some breast and ovarian cancers.

These tips are highly relevant and accurate except, perhaps, for a comment under  "Newer Tests in the Pipeline" about the Prostate Health Index (PHI).

A new test called PHI (Prostate Health Index)—now in early clinical trials—shows promise that it may be more accurate in finding cancers than the PSA test, says Dr. Misialek.

First off, tequipment and technology for the Prostate Health Index (PHI) are  FDA approved and already in use. PHI is recommended by the National Comprehensive Cancer Network (NCCN). PHI has been proven more accurate at finding prostate cancers under certain conditions.  The proviso is that PHI (made up of three tests including PSA) has not been endorsed as a test most men might receive (or even require) during a walk-in annual checkup.

Men well plugged in to health info are already benefiting from the Prostate Health Index.  I think it  will be unfortunate if men less plugged in who may benefit from this test -- and do fall into the group for which FDA and  NCCN recommend it -- were to suppose that it is not yet available, or not for them.

With this in mind I want to look a bit closer at the Prostate Health Index. And I may as well mention upfront, if used for the designated groups of patients, PHI does not raise costs, it lowers costs.

Prostate Health Index combines  three Beckman Coulter assays:

  • PSA
  • free PSA
  • p2PSA

"Free" PSA, discovered in the early 1990s, is a form of PSA associated with absence of prostate cancer.  The higher the "free" PSA level in ratio to the total PSA, the lower the risk of prostate cancer. Free PSA is an "inactive" form of PSA "and for this reason . . . not complexed with protease inhibitors. An important part of the discovery of free PSA was its correlation with benign prostate disease. That is, free PSA is generally lower in prostate cancer than in benign prostate enlargement" (Gabriela De Angelis, MD et al, "... PSA: From Prostate Antigen to Tumor Marker, 2007).

The "free" PSA test has been used in the USA for over a decade as followup for men with a PSA in a "gray" zone between  4 and 10 ng/mL.  One main value of the fPSA test lies in its power to help reduce unnecessary biopsies. But it is not specific for prostate cancer. A healthy-looking high ratio of fPSA to total PSA may prove a "false negative" concealing the presence of prostate cancer.

 Next came p2PSA, a precursor form of PSA also known as serum proPSA. It is associated with presence of prostate cancer. Higher levels are found in the blood and tissue of prostate cancer patients. p2PSA,  Italian urologists reported in a 2011 study , "significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml" (Eur Urol. 2011 Aug).

In the USA, the p2PSA test has been available since June 2012, when FDA approved the assay and a specific device, called Access Immunoassay Systems, for processing the results.

The Prostate Health Index runs all 3 tests - PSA + fPSA + p2PSA - on blood from a single draw and analyzes the result.  PHI runs on a single bench-top device, Beckman Coulter's Access 2 Immunoassay System, with built-in refrigeration and push-button  computerized algorithms (find video here) . with this equipment, technicians can process "over 50 available immunoassay diagnostic assays" (i.e for up to 50 different health conditions) at a rate of over 100 an hour.

With rapid-throughput complex processing, a single blood draw can yield numbers representing a high-probability prediction of whether a man does or does not have aggressive prostate cancer. How much is this information worth?  What harm -- if any -- can it do potentially? And how much good? This is one point at which people who infleunence men's health decision differ.

As Daniel Pendick at Harvard Men's Health Watch  reported July 2, 2012 (Harvard expert urges caution for use of new prostate cancer test),  "According to clinical data that Beckman Coulter submitted to the FDA, using the PHI score could prevent about one in seven unnecessary biopsies while still detecting 95% of cancers. In comparison, use of free PSA testing alone could prevent one in ten unnecessary biopsies."

"In men with PSA levels in the 4.0 to 10 range," Pendick writes, "biopsy confirms cancer about 25% of the time."  Heading for a track well-worn by objectors to the  plain old PSA test,  Pendick states that PHI "needlessly exposes the remaining 75% of men to discomfort, anxiety, and the risk of infection and/or bleeding." Dr. Mark Garnick, a Harvard MedicalSchool expert in prostate cancer and editor in chief of, warned Harvard Men's Health Watch that "doctors must take care not to allow use of the PHI test to worsen the existing overdiagnosis and overtreatment of low-risk cancers."

FDA has set limits on PHI by approving Beckman Coulter's system "for use as an aid in distinguishing prostate cancer from benign prostatic conditions, for prostate cancer detection in men aged 50 years and older with total PSA >4.0 to <10.0 ng/mL, and with digital rectal examination findings that are not suspicious for cancer." They add: "Prostatic biopsy is required for diagnosis of cancer."

In other words, FDA has not approved PHI as a first-line early detection test for primary care doctors to  offer to men arriving during Men's Health Month. Some doctors and health insurers may need convincing of the company's second claim, that PHI "Lowers Healthcare Costs." Time will tell, but a study out of USC Los Angeles estimated in 2012 that "Over 25 annual screening cycles, the strategy of PSA plus phi dominated the PSA-only strategy using both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL, and was estimated to save $1199 or $443, with an expected gain of 0.08 or 0.03 quality adjusted life years, respectively" (Cost-effectiveness of Prostate Health Index for prostate cancer detection, Nichol MB et al, BJU Int. 2012).

Currently, clinical trials of PHI are under way in Ireland and other parts of the world (Foley RW et al, Improving multivariable prostate cancer risk assessment using the Prostate Health Index  BJU Int. 2015 Apr 3).

The College of American Pathologists (CAP) is a professional organization representing more than 18,000 board-certified pathologists. The College of American Pathologists (CAP) serves patients, pathologists, and the public by "fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide." CAP’s Laboratory Improvement Programs, founded 65 years ago, serves customers "in more than 100 countries, accrediting 7, 700 laboratories and providing proficiency testing to 20,000 laboratories worldwide." Follow CAP on Twitter: @pathologists.

Photo credit: JBLM PAO. "MAY 2010: Arthur Thompson winces as Pfc. Shama Serratt, MAMC Dept. of Pathology, draws blood for cholesterol screening at the annual Retiree Appreciation Day May 14, 2010 at American Lake Community Center. Various veterans' organizations, military staff agencies and medical assistance teams were on hand to answer questions and provided substantial on-site services."

Posted by Jacqueline Strax, June 11, 2015.