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Diagnostics Oncology, Training and education, Profession, Biochemistry and molecular biology

Uro Star

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What inspired you to specialize in uropathology?

Actually, I made that decision because of the high frequency of bladder cancer in Spain. As I was interested in developing a research-based career, I thought bladder cancer would be a good model to learn about the field of cancer in general.

What is the most groundbreaking research in your field in recent memory?

Major advances in uropathology include the definition of the urothelial carcinoma-related molecular pathways. Three primary genetic alterations are associated with the pathogenesis pathway of non-muscle invasive bladder cancer (the Ras-MAPK and PI3K-AKT pathway alterations, and mutations in upstream tyrosine kinase receptor FGFR3), all of which are responsible for promoting cell growth in urothelial neoplasia. On the other hand, muscle-invasive urothelial carcinoma primarily involves alterations in tumor suppressor genes related to cell cycle control.

Understanding the pathogenesis of kidney cancer (from VHL mutation to up-regulation of hypoxia-inducible factor and the consequent stimulus of neovascularization, cell proliferation, energy supply, and metastasis) clearly represents an important breakthrough. And it has modified the way we approach the pathology of renal cell carcinoma.

Major advances in pathology of prostate cancer include the discovery of the TMPRSS2-ERG rearrangement, which once again significantly improves our molecular understanding of the disease.

What do those advances mean for you and pathology in general?

Our new molecular understanding – together with the refinement of classic histopathology approaches to these tumors – offers a translational approach to urologic cancer, making uropathology an important discipline in uro-oncology practice and research. How have these advances modified the practice of anatomic pathology? Well, the answer is a little disappointing – no major molecular breakthrough has been incorporated in practice. I guess the integration of knowledge gained on the molecular level remains challenging, but should at least motivate uropathologists to find the right balance between classic histopathology and the molecular approach to uro-oncology practice.

What current research initiatives hold most promise – and why?

Diagnosis of bladder cancer via urine biomarker detection is really promising and could be put into practice in the coming years. And using FGFR3 tyrosine-kinase alterations to target non-muscle invasive bladder cancer is another major field of research. Finally, there are a few good examples of how the uropathology field might evolve in the future; for instance, rationalizing therapy of prostate cancer based on TMPRSS2-ERG rearrangement. The general consensus is that translational research will be incorporated in practice via novel tests that ultimately select the patients who can benefit from upcoming new therapies.

What about your own research?

Over the last decade, we have observed that cyclin D3 (cell cycle regulator, CCND3) is altered in bladder cancer and seems to be detected in aggressive tumors. We have subsequently developed models to use CCND3, either alone or in combination with FGFR3, as a potential predictive biomarker of response to immunotherapy in high-grade urothelial bladder cancer – an aggressive form of the disease. We have hypothesized that CCND3 and FGFR3 protein alterations could form the basis of a urine detection test of recurrent bladder cancer after therapy. Our data, which is currently at prepublication stage, appears to match information from more conventional invasive clinical approaches, such as cystoscopy, and so holds promise.

Is any area of uropathology neglected by research?

When looking at the resources dedicated to cancer research in the USA and Europe, I notice that uropathology projects are somewhat limited compared with “popular” cancers. So I feel the whole field is somewhat neglected. This trend is particularly true with bladder cancer research funding – and that must change. For instance, an organ pathology like bladder cancer, which is considered the most expensive single solid tumor in the USA and Europe, needs more attention.

Is uropathology a growing field or struggling to attract new talent?

Uropathology is a relatively new field in practicing pathology, mainly stemming from the complexity of prostate pathology and its correlation with different therapeutic modalities. In this context, it’s relatively easy to get new pathologists and residents interested. In fact, the large number and lower age of current uropathologists attending scientific activities clearly reflects an increasing interest. That’s great because it will help improve research in urologic oncology and it will also support implementation of future translational tests that can modulate the therapy of urologic tumors – a flourishing area of modern uropathology.

What do you like most about your job?

I guess my diagnostics and counseling help guide proper treatment of patients with urologic disease – I really love that aspect of my job. The opportunity to teach junior pathologists from an academic perspective is also very rewarding.

I have to say that there is something special about signing out cases on the microscope – I enjoy that very much. And the fact that I learn something new, curious – or both – every day keeps me professionally happy.

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About the Author
Antonio López Beltrán

Antonio López Beltrán is a Professor at the University of Cordoba, Spain, and Director of Anatomic Pathology at the Champalimaud Cancer Center, Lisbon, Portugal.

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