BERKELEY, CA (UroToday.com) - At first sight, this is an unusual title for an article. After all, cancer is cancer. How can we possibly not call something that pathologists have for years diagnosed as malignant, cancer? The answer is that we have already been engaging in this change as to what we mean by ‘cancer’ in many solid organs, including prostate. Pathologists have gently but slowly changed the histological criteria for reporting cancer by recalibrating the assigned grade of a cancer against state-of-the-art epidemiological data on outcomes, with surveillance and after treatment. Gleason grade has shifted in this way a number of times over the last few years.
So, why should low-grade, low-volume, prostate lesions be redefined as something other than cancer? When you objectively evaluate these lesions against the hallmarks for malignancy set by Hanahan and Weinberg in their seminal paper in 2000, they do not have clear evidence of meeting the hallmarks.
First, cancer hallmark one states that cancers must have self-sufficiency in growth signals. Cancer cells can generate their own growth signals and reduce their dependence on stimulation from the surrounding normal tissue microenvironment. Gene expression profiles of individual prostate lesions show that growth-stimulatory factors are predominantly found in large high-grade lesions or lacking in small low grade lesions.
Second, cancer hallmark two states that cancer cells must be able to resist the normal anti-growth signals which normally direct them into a quiescent phase of the cell cycle or specific cell differentiation. Growth inhibitory factors, or those that promote them, are either lacking in large high tumours or prominent in low-volume, low-grade lesions.
Third, cancer hallmark three states that cancer cells must be able to resist cell death (apoptosis) in order to ensure continued growth and proliferation. Pro-apoptotic factors are up-regulated and anti-apoptotic factors down-regulated in small low-grade lesions.
Fourth, cancer hallmark four states that cancers must have unlimited replicative potential. Higher Gleason grade lesions exhibit decreased androgen signalling, similar to metastatic prostate cancer, which may reflect dedifferentiation and explain the clinical association of grade of the high-grade lesions with prognosis, whilst higher androgen signalling in low Gleason pattern lesions compared to high Gleason pattern lesions has been seen. Further, the TMPRSS2–ERG translocation results in over-expression of the ERG transcription factor, promoting proliferation – metastatic deposits in lymph nodes have been shown to share this rearrangement with just one lesion in the prostate and this lesion is almost always the index lesion – or secondary lesions with high grade components.
Fifth, cancer hallmark five states that cancer cells must be able to maintain and sustain angiogenesis, in order for tumors to break through the volume threshold of 1mm diameter, as tumors larger than this cannot rely upon the diffusion of oxygen from existing vessels. Microvessel density and pro-angiogenesis factors have been shown to be related to high-grade lesions in prostate cancer.
Finally, cancer hallmark six states that cancer cells, logically, should be able to invade local tissue and spread to distant tissues. Interestingly, many prostate ‘cancer’ lesions fail to exhibit either of these properties. Molecular biology evidence has shown that metastases usually arise from one lesion and this is likely to be the largest and highest grade. Epidemiological cohort data, as well as randomised controlled studies from watchful waiting, active surveillance, and radical prostatectomy, have shown that few if any men with Gleason 6 and low-volume disease die of their disease over 10-15 years.
The implications for clinical management are profound, if we accept that not all prostate cancer lesions are actually cancer. First, we would not need to chase every single millimetre of cancer when validating new ways of diagnosing prostate cancer. Second, not only do we not need to treat every millimetre of cancer, the reclassification could lead to active surveillance being unnecessary. Third, whilst at present prostate cancer is regarded as multifocal and an impediment to tissue-preserving focal therapy, focal therapy directed to the largest and highest-grade lesion (the two are strongly correlated in 95% of cases) could be a legitimate therapy compared to radical whole-gland treatments that cause significant morbidity. This would align prostate cancer management with almost all other solid organs.
Written by:
Hashim Uddin Ahmed, MRCS,[1, 2,*] Manit Arya, FRCS(Urol),[2, 3] Alex Freeman, FRC(Path),[4] and Mark Emberton, FRCS(Urol) (Full Professor)[1, 2] as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK
- Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK
- Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK
*Corresponding author:
Hashim Uddin Ahmed
Division of Surgery and Interventional Science
Charles Bell House
67 Riding House Street
University College London
London, UK
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Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? - Abstract
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