Since I began working in pathology in the late 1970s I’ve seen some amazing changes in the understanding of cancer. For patients in particular, the results have been nothing short of spectacular: improved diagnostic methods and tools have produced improvements in cancer treatment and survival. And these developments aren’t slowing down; if anything, the pace of change is increasing.
In the 1970s, when Leslie Sobin was producing the first World Health Organization (WHO) Classification of Tumours – the ‘WHO blue books’ – histopathology was based on the use of microscopes and stained slides to study cells. Computers were large and a lot less powerful than a smartphone of today. They could be used to measure the size of cancer cells, or how many were expressing a given enzyme, but only with difficulty.
However, biochemical methods were already being used to assess the role of proteins, particularly enzymes, and the world within the cell was accessible using the electron microscope. That meant we could diagnose cancers, but otherwise not give much help to oncologists and surgeons.
The revolution didn’t start in cancer science, but in immunology, thanks to a couple of brilliant cell biologists in Cambridge – Kohler and Milstein – who were exploring cell fusion (at the time, a little known and poorly funded branch of research of no great significance). They fused a fibroblast, which is easy to grow, with a plasma cell, a factory for antibodies. This meant that the fused cells would grow and produce a clone of cells, all producing a single type of antibody. The monoclonal antibody reagents produced were famously thought by the government agency responsible to be ‘of no commercial value’. Unsurprisingly, they then went on to form the basis of the multi-trillion-pound biomedical industry.
Geneticists also relied largely on stained slides to look at the structure of chromosomes. However, another backwater of biology, the study of thermophilic bacteria, lead to another breakthrough: polymerase chain reaction (PCR). The DNA polymerase in these bacteria only works at high temperatures, so the reaction can be stopped and started by cycling the temperature. This has formed the basis of most DNA sequencing and mutation detection technology, and has transformed our understanding of cancer, which is usually the result of acquired changes (often mutations) in DNA.
We had to wait around 40 years, but pathologists are now using scanned images to make cancer diagnoses without microscopes. They’re being assisted by powerful image-analysis programs, and even artificial intelligence tools to improve diagnostic accuracy. Indeed, DNA sequencing has now reached the stage that the entire human genome can be sequenced in a few days, for less than £500 (just ten years ago it would have cost around £1m). Monoclonal antibodies underpin the diagnosis of cancer by aiding the detection of individual proteins in blood and tissues. Some are now also important drugs: Herceptin for breast cancer is an example, as is the new class of immunotherapy drugs transforming cancer care.
The level of technology available today allows the molecular – and not just the cellular – basis of cancers to be investigated and used for diagnosis to an unparalleled degree. Individualised treatment is standard for cancer patients and relies on tests targeting the building blocks of life – DNA, RNA and proteins. There are certainly still challenges for the pathologist though, such as in integrating the information from a biopsy and deciding the priorities. The complexity of investigation makes the pathologist’s job harder and more interesting than ever before.
Given the pace of change in cancer diagnosis and treatment, the future may well see more incredible discoveries. Radiological information will likely provide resolution at cellular level (it already does in the eye, for instance), so the biopsy sample, taken by fine needle, may only be required to provide additional information to guide cancer treatment.
Staying in touch with recent advances is difficult too, and the degree of information overload is such that advances that should reach patients don’t. This is where the WHO blue books are even more relevant than before. They synthesise evidence to provide the standards and criteria that pathologists around the world use to diagnose tumours. This consistency is important for patients, who need an accurate diagnosis, but also to epidemiologists and cancer researchers who need the diagnosis before they enter a patient into a registry, study, or clinical trial. Increasingly, histopathology alone can’t provide enough information, so the classification summarises the clinical, radiological, genetic and molecular criteria required and desirable for tumour diagnosis.
Given the pace of change in cancer diagnosis and treatment, the future may well see more incredible discoveries. Radiological information will likely provide resolution at cellular level (it already does in the eye, for instance), so the biopsy sample, taken by fine needle, may only be required to provide additional information to guide cancer treatment. Sequencers will attach to mobile phones (some do already), and artificial intelligence will do most of the heavy lifting. This may mean that the current roles of geneticists and bioinformaticians will evolve dramatically again, as they did with the introduction of next-generation DNA sequencing.
The histopathologist will still have a dedicated workstation, akin perhaps to an airline seat, with a screen, a trackball in one arm, and a self-refilling coffee cup on the other. Yet their job will be to make sure that the computers know what they are doing, that they do it efficiently and accurately, and that the right diagnostic information is given to the clinical team.
The backwaters of biology, like the ones that gave rise to monoclonal antibodies and PCR – and more recently individualised therapy (which I was told firmly was a daft idea and a waste of time) – will all have been mapped. If you want to prove me wrong – and I hope you can – find one of those backwaters and come up with something that will transform the understanding of disease. to prove the value of human pathologists.
And finally, what of the WHO blue books? Well, we’re finally putting the classification onto a website, yes, but there will still be books for those that want them, and they will still be blue. Some things do stand the test of time.