Restoring Pathology to its Former Glory

The face of pathology is changing as fast as its disciples can keep up. With molecular techniques rocketing to the forefront and digital pathology becoming an increasingly significant part of the laboratory professional’s workload, it’s obvious that the word “pathology” no longer means what it did just a few short years ago. What hasn’t changed, though, is pathology’s status as a key component of medical research – so how can we restore it to its former glory and bring it back to the center of the biomedical sciences?

The genome generation

When I first took up pathology in 1986, I was immediately fascinated by the possibility of combining research and clinical diagnostics. It was a time of discovery for many oncogenes and genomic defects driving oncogenesis. Personally, I was following up the (incorrect) hypothesis that ras oncogene activation might also arise from amplification and translocation, and for that project, I was trying to establish Southern blotting in the pathology department at the University of Aachen in Germany, where I worked. That’s when I realized my complete ignorance of practical science – a lack of knowledge I needed to remedy to be an effective pathologist. As a result, I spent almost four years as postdoctoral scientist, splitting my time between the University of Munich’s Gene Center and the University of Texas MD Anderson Cancer Center. After my sojourn in the United States, I returned to Germany much better educated and ready to take on new challenges: first a pathology residency at the University of Regensburg, and then the establishment of my own research group in molecular pathology. Ever since, I have been trying to understand the molecular basis of morphology and oncogenesis – a curiosity that has led my laboratory to successfully pioneer the cloning of a number of homeobox genes and receptors.

After establishing a collaborative research group investigating mechanisms of cell death funded by the DGF (German Research Society), I was appointed full professor of pathology at the University of Aachen in 1999 and then, two years later, became chair of the pathology department at the University of Bonn. But around 2010, it became clear to me that next generation sequencing and comprehensive cancer genotyping held tremendous promise for pathology, so I decided to move to the University of Cologne, where I saw a chance to turn that promise into reality. My colleagues and collaborators there shared my strong vision for molecular medicine, and the Comprehensive Cancer Center CIO Cologne was – and still is – Germany’s best place for translational cancer research. Molecular pathology plays a huge role and, ever since I started work here, the hospital’s CEOs have massively supported new initiatives. For instance, along with oncologist Jürgen Wolf and molecular geneticist Roman Thomas, I founded the Genomic Medicine Network (Netzwerk Genomische Medizin, www.ngm-cancer.com), now by far Germany’s largest initiative for comprehensive cancer profiling. Over the last five years, the Network has analyzed more than 20,000 cancer genomes in order to funnel patients into appropriate targeted therapies. That’s a lot of patient benefit!

I think that collaboration with genetics is crucial for diagnostic pathology’s ongoing development. Discovering the genomic basis of pathological changes in tissues has become a reality in daily practice. To that end, my colleagues and I have allied with genetics to create a special Center for Familial Cancers. By analyzing the mutations that occur in our patients’ tumors, we frequently find that they suffer from predispositions to cancer – and as a result, we funnel a number of patients into the Center for further evaluation and treatment. This kind of collaboration is not only good for those patients, but also great for scientific advancement, so I hope we see much more of it going forward. In fact, we regularly host guest pathologists and scientists from all over the world. I invite every pathologist who wishes to share our philosophy to spend some time with us, learn how we run our department, and take home any knowledge they find useful!

Making pathology important and profitable

I think our most important accomplishment is that we have brought pathology back to the center of clinical medicine, at least in oncology. No patient at the University Hospital is treated without in-depth pathology analysis and discussion in a multidisciplinary tumor board. If a pathologist is not present, the board will not make decisions. We’ve also reinstated pathology as one of the most scientifically productive departments at the hospital – and we’re productive in other ways as well; I believe that the Genomic Medicine Network now serves as a blueprint for molecular oncology, and will eventually guide the formation of a national network for cancer patients.

I never think about balancing scientific productivity with the business of pathology – I just listen to my instincts and curiosity. I feel that if you’re always thinking about business and profits, you’re going to lose your spirit. Somehow, despite its casual nature, my approach has been the basis for both economic and scientific success, making pathology one of the most profitable departments at our hospital. To give you an example, in 2014, we were running out of resources for multiplex cancer genome profiling due to the end of a grant. We decided to continue testing without reimbursement because we had great faith in it, both scientifically and for the sake of our patients. As a result, by the end of the year, profits in my department had fallen by €1 million and our administration was getting increasingly nervous. Luckily, many German insurance companies eventually realized the benefits of what we were doing – they asked for an expert opinion and came to the conclusion that reflex testing of multiple oncogenic alterations in lung cancer by NGS is economically more efficient than sequential single biomarker testing and also beneficial for patient outcome. And we started to receive regular reimbursement from an integrated care contract (a specific contract reimbursing a health service selectively for a group of healthcare providers, in our case Pathology, at our University together with hundreds of lung oncologists in Germany), providing substantial revenue for the hospital. It has always been our philosophy to do the things we believe in. We owe thanks to our administration for their continuous support in whatever we choose to pursue, but as you can see, the results have been great so far.

The system by which molecular biology services are reimbursed in Germany is changing right now. At the moment, there are still problems with it; new therapies are being introduced without reimbursement of the biomarkers. The integrated care contract I mentioned earlier, established within the Genomic Medicine Network, provides a convenient solution, which is why I’m so happy that other German university hospitals are now joining a similar national network. With the help of the German Cancer Aid, the plan is that 16 other molecular pathology platforms in Germany will be enabled to perform multiplex NGS diagnostics and serve interdisciplinary, genomically-informed tumor boards for innovative and targeted therapies.

I strongly believe that university departments are true drivers in molecular medicine. However, as pathology is now more involved than ever in clinical decision-making, it’s also needed in regional hospitals farther from universities. We’ve established a model for combining local presence and connecting local units to big centers, which we follow in our own hospital; our department is connected to a wide variety of regional departments in a 110-kilometer radius from Siegen to Luxembourg. For some, we provide the entire anatomical pathology service, including staffing. In other cases, we serve as preferred collaborators and receive histology slides and perform molecular services.

Encouraging healthy competition

There’s clear competition between Germany’s major universities in terms of scientific performance. For example, part of our scientific funding from the Ministry of Science and Technology is based on our performance in comparison to other university hospitals, and part of the funding provided by the medical faculty is based on scientific output in comparison to other departments. But that’s not the only source of rivalry these days; there is also severe competition between university, regional and private hospitals for patients and services. Pathology is no longer purely scientific – it’s economic now as well, and we regularly analyze our department’s performance with a team of financial controllers.

We also go outside the standard scope of our work by providing extensive pathology services in Luxembourg. It’s a very small country that lacks a university hospital, and – like so many other places – it has a hard time attracting enough medical students to the field of pathology. Cologne has a long tradition of supporting Luxembourg (a few places at our medical school, for instance, are always reserved for students from Luxembourg), so we help out with pathology at the Labaratoire National de Santé (LNS). The LNS is now under the direction of Fernando Schmitt, a good friend and visionary pathologist and cytologist, who shares our philosophy with regard to molecular pathology and is eager to collaborate with us. At the moment, we’re establishing direct links between our patient information systems so that we can work together even more closely and effectively.

The pathology of the future

At my institute, we have recently moved to very comprehensive hybrid capture gene panels in molecular diagnostics. For hereditary cancer patients, whole exome sequencing will also be an appealing option in the future. Genomic and proteomic technologies are taking their place next to histology as crucial techniques for the pathology lab – so it’s increasingly important for pathologists to receive appropriate training in molecular pathology, so that they understand these analyses.

Digital pathology is another incoming revolution. We will be able to steer our workflow much better, work outside the lab whenever necessary, and see a trend toward more quantitative work on digital slides. As pathology becomes entirely digital, I anticipate a wide range of new capabilities – things like three-dimensional organ reconstruction from slides, or merged morphologies generated by overlaying histology, molecular data, radiological images and functional imaging. All of these are fascinating possibilities, but they’ll require large datasets, and pathologists will need a more robust understanding of electronic data handling than ever before.

I think that, a decade from now, the average pathologist will need both a strong science background and solid training across almost all areas of medicine. They’ll be working in teams rather than alone, and they will spend a lot of time in interdisciplinary clinical boards. I also anticipate that pathology will return to its former place as a central discipline for medical research – and pathologists themselves will become key collaborators with scientists of all kinds.