PSA testing ‘dilemma’: A pathologist’s perspective

Filip Vukasin

14/10/2022 3:53:47 PM

Prostate cancer screening guidelines are typically debated by urologists and GPs, but a pathologist’s perspective  adds extra nuance to a discussion often seen as black and white.

Pathologist at the lab
There can be substantial variation in PSA results depending on which laboratory receives the sample.

The case
A 67-year-old male had 70 mL of blood collected in a single sitting and serum was sent out as genuine referred samples requesting prostate-specific antigen (PSA) testing to 14 laboratories in Queensland, New South Wales and Victoria. All were privately billed.
These included two large private laboratories, a major state health laboratory, not-for-profit laboratories operating in each of Queensland, NSW and Victoria, as well as two private laboratories operating across the three states.
The result
The resulting PSA values ranged from a low of 2.6 to a high of 3.6, with the majority not providing an exact same result.
For Dr John Appleton, chemical pathologist and Head of Biochemistry at QML Pathology, this was concerning.
‘I was alarmed by the variation in the results,’ he told newsGP.
‘The subject of the study was of course myself. [It] avoided any ethical questions and I fitted the criteria nicely.
‘We in the labs all know this exists from the monthly quality assurance surveys run by [the Royal College of Pathologists of Australasia] and the Australasian Association for Clinical Biochemistry (AACB).
‘But it is only when you actually see the variations of results from a single sample that you realise what a dilemma this creates for anyone supporting a single clinical cut-off.’
The discussion
Dr Appleton is referring to the 2016 prostate cancer guidelines that recommend offering ‘further investigation if total PSA is greater than 3.0 ng/mL’. The guidelines do not recommend digital rectal examination or tracking the rise of PSA.
What prompted him to conduct this small survey was a conversation he had with a prominent urologist who believes GPs and pathologists are not following the guidelines.
‘I had been in discussion with a urologist on several occasions and he was applying a large amount of pressure on me to have the whole of the Healius group of labs change over to reporting a cut-off of three only, as opposed to reporting to age-related reference intervals,’ Dr Appleton said.
‘Healius includes QML Pathology in Queensland, Tasmanian Medical Laboratory, Laverty Pathology in NSW and the ACT, Dorevitch Pathology in Victoria, Abbott Pathology in South Australia and Western Diagnostics in Western Australia and Northern Territory.
‘He told me that the CEO of Sullivan and Nicolaides [the Queensland branch of Sonic] had changed all Sonic labs over to reporting to the guideline, and I doubted that, so I set up [the] small trial.’
Dr Appleton found that only two labs reported quoting the clinical cut-off of 3.0 ng/mL, with one quoting age-related reference intervals (RI) in the serial graphical report. All other 12 laboratories reported age-related RIs with two referring to the 2016 guidelines in the body of the report.
 This contrasted with what the urologist thought was happening. 
‘It is all very well to call and ask the lab how it reports, but until you actually see the report, you do not know what else they may put in the report,’ Dr Appleton said.
‘We didn’t go to a cut-off of three because we knew assays had varying results. We are reliant on kit suppliers for reference intervals and all manufacturers are overseas. Age-related RIs are also based on the suppliers, although some labs could develop their own reference intervals.
‘I was uncomfortable to changing to a cut-off of three after speaking to my whole team. [The urologist] thought all of Sonic had changed over to the cut-off and was surprised to find that they hadn’t.’
The issue of varying PSA results between laboratories and the recommendation of a single cut-off of three instead of reporting them for age-related RIs is a part of the prostate cancer screening discussion that does not get a lot of attention.
Most of the controversy is whether to have prostate cancer screening or not and there are many articles celebrating the high profile lives saved by men having PSA tests, including actor Ben Stiller, footballer Sam Newman and rugby player Terry Campese.
But sometimes their advice goes against recommendations.
Adjunct Associate Professor David Smith, epidemiologist and group lead of the prostate cancer stream at the Daffodil Centre, told newsGP he has concerns with this.
‘Locally we have seen a number of regional-based campaigns that encourage non-evidence-based approaches to prostate cancer testing. Some of these use men well below the recommended ages for testing as spokesmen to non-evidenced-based messages,’ he said.
Stories that quote 37-year-old ex-footballers encouraging all men to have a yearly test can be counterproductive when there is no guideline recommendation of clear evidence of benefit.’

Adjunct Associate Professor David Smith believes the 2016 prostate cancer guidelines are out of date.

GP Dr Brett Montgomery also recently pointed out that the current NHMRC and RACGP Red Book guidelines align in offering widespread PSA screening only to those ‘who have been informed of the benefits and harms’.
‘I thought this article and the comments from Dr Montgomery were useful additions to the discussion,’ Associate Professor Smith said.
‘The Australian guidelines do need a diligent and systematic review and update.’
According to the epidemiologist, ‘things have moved on’ in the more than five years since the 2016 guidelines were drafted.
‘Diagnostic approaches and management options have changed. Guidelines should reflect this and should be kept current,’ he said.
‘The differences between the [Cancer Council Australia] guide and the Red Book appear to be overstated in a number of sectors, particularly those who feel that every man should get tested.’
And while acknowledging that prostate cancer remains the second largest cause of cancer death among men, with around 3500 fatalities annually, Associate Professor Smith points out that mortality rates have fallen ‘significantly’ over the past two decades.
‘The challenge is to accelerate this mortality decline,’ he said.
‘And we need to ensure that all stakeholders – consumers, primary care, specialists, researchers, politicians and policy makers – are driven by the evidence and not anecdote.’
Meanwhile, for Dr Appleton, the difference between a PSA of 2.6 or 3.6 from the same blood sample provides a conundrum.
According to guidelines, a result of 2.6 would not necessarily need further investigation. However, a result of 3.6 would commence a cascade of events that could include repeat testing, MRI or biopsy.
‘We all know that all labs vary in results. This is a test-by-test phenomenon [and] the discrepancies are all within acceptable method variation,’ he said.
‘If I had moved house or state, the sudden jump would be alarming, and I’d probably be seeing a urologist quickly and having further investigation.
‘If my PSA result can be as high as around 3.6 or as low as 2.6 on the same sample but from different labs, I argue that we need either method-specific cut-off values, or international standardisation of all assays in current use.’
He also believes several conclusions ‘must be drawn’ from his experiment.
‘For ongoing management, it is essential that a patient attends the same laboratory for each test,’ Dr Appleton said.
‘Also, it is highly questionable to use a single clinical decision cut-off across the board in the light of inter-method variation.
‘Finally, the 2016 guidelines are not commonly used by laboratories in PSA reporting and require revision in view of not only this, but also the emergence of new radiological investigations.’
Dr Appleton’s interest in PSA for prostate cancer screening was heightened by his own non-malignant medical condition and he continues to have it monitored.
He, better than most, understands that each result is not as black and white as the text it is printed on.
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Dr Peter James Strickland   15/10/2022 1:23:54 PM

All these problems have originated from the urologists NOT recommending PSAs as often as ethically required in my opinion. We have a tumour as common as breast cancer, and if there is a PSA of 3.6 --do NOT do an DRE, but repeat it within 3-6 months --fiddling with tumours metastasizes them. If the PSA is rising then go for further investigation, but don't leave it for 5 years in anyone aged over 50 yrs! Over 50 years of practice, and seeing guys dying in agony from a preventable outcome from prostate ca., it is NOT appropriate to leave PSA testing now for many years--if one does a DRE and the prostate feels firm, then investigate--it is a no-brainer. If I see nipple retraction in a breast, and can feel no lump , and especially a lump, I recommend MRI, and NOT mammography for women to reduce the chance of micro-metastasises from severe compression of any lump found --DO NO HARM is our philosophy, isn/t it?

Dr Siva Kumar Raju Muppala   15/10/2022 4:22:19 PM

Lab variable results are significant not only for PSA but for other tests like TSH, INR and for many as well.

Bel   16/10/2022 3:47:05 AM

INR is supposed to be standardised across labs. It literally stands for "international normalised ratio" and is just the prothrombin time in a standardised ratio.

It definitely would be nice if there was a standardisation between assays for PSA.

In terms of how that was created for INR the WHO Expert Committee on Biological Standardization worked on it back in the 1980s, and they had an internationally accredited reference agent, and then all commercial products had their "international sensitivity index (ISI)" in comparison to that reference agent analysed - with the ISI of each product used in the calculation of the INR.

A quick google search show that the WHO Expert Committee on Biological Standardization does seem to have an internationally accredited reference agent for PSA.... do they not use these to standardise PSA assays when manufacturers develop them??