Onward and Upward for the Blue Books

Few diseases receive more attention or are more thoroughly studied than cancer. We, as pathologists, are uniquely placed to understand cancer and, as a result, to develop logical, evidence-based classifications for the disease. The classification of cancer is not only an important academic exercise in its own right, but it also underpins the diagnosis and treatment of individual patients, as well as informing research into new therapies and prevention strategies. The World Health Organization (WHO)’s International Agency for Research on Cancer (IARC) is responsible for the Classification of Tumors – a series of reference books known colloquially as the “Blue Books,” which collate key information on cancer for those who study, diagnose, monitor, or treat the disease.

The Blue Books provide both an internationally recognized classification and the standards against which cancers and benign tumors are diagnosed. These standards include not only diagnostic criteria, but also images that pathologists can compare with individual patient tumors to arrive at a diagnosis. Such information underpins all cancer diagnosis, treatment and research; without the correct diagnosis, appropriate patient management is impossible, and without the ability to refer to correctly diagnosed tumors, cancer research is also impossible – whether it be comparison of cancers of one diagnostic group with controls, drug trials, or epidemiological investigations.

In the past, the books were developed by histopathologists with expertise in the features of the disease – but now, as genetics and other disciplines become increasingly important to the classification and diagnosis of cancer, things are changing. As radiology advances and methods such as liquid biopsy become more sophisticated, it is quite likely that many patients will no longer need a solid tissue biopsy. This is a challenge for cancer registries in particular, as they require diagnostic information drawn largely from pathology reports. It is also a challenge for the books as we seek to incorporate more information and yet keep them concise.

The key concept remains the classification of cancers on the basis of shared characteristics, but because those are no longer limited to histology, we need to involve other disciplines in putting together the official classification. The WHO Blue Books are well-known to pathologists, but one of the things I’m keen to do is bring the books to a wider audience, including those in cancer registration and epidemiology, those in basic or applied research, and those in clinical roles who need to better understand cancer diagnosis. I very much hope that they will use the Blue Books too, of course!

About the Blue Books

Each series of Blue Books has had up to 11 volumes covering all systems of the body. They are comprehensive and definitive, at the expense of being very slow to produce; the current (fourth) series has taken 12 years, and two volumes - Skin and Eye - are still not quite there (though they will be available in the summer of 2018). The challenge for the fifth series will be to meet the need for more rapid updates and, simultaneously, to improve quality by assessing evidence more rigorously.

Obviously, cancer classification must be updated regularly. We’ve set ambitious targets for the new series, aiming to produce three books a year. If we manage that, the entire set can be revised approximately every four years, which I believe is optimal. However, we are dependent on volunteer contributors – about 150 for each book – all of whom give freely of their time and expertise to ensure that the information is as good and as reliable as possible. The Blue Books wouldn’t exist at all without such support, and that of the editors who coordinate the whole effort on behalf of the profession as a whole.

The WHO Blue Books have a very distinguished past, and certainly a bright future as well. One way we’re moving ahead is that we intend to set up an online facility for those who prefer it. There will still be physical books as well, of course, but this should allow us to offer a more cost-effective option and to include additional content. I’m particularly keen, for instance, to see whole slide images of tumors online, suitably annotated with the diagnostic features, and – ideally – a set of such images showing the variation one can expect within a single entity. Others may want more molecular information, or interactive tools to assist with diagnosis. All of this is possible, and by exploring those options, we’re looking forward to making the Blue Books more necessary and relevant than ever.

My job as Head of the WHO Classification of Tumors Group is to lead the whole process. At the moment, we’re working hard on our infrastructure, including improving the online submission system contributors use to deliver text and figures and speeding up the production process that results in a completed book. We also hope to grow the team in Lyon, where the group is based, to ensure that we can support the books’ contributors and editors as much as possible. How can pathologists help? I’d like them to engage with us. Most will already know of the WHO Blue Books, though perhaps not all use them regularly. I’d like to know how we might continue to improve their impact and meet the evolving needs of diagnostic professionals across the board.

Changing classifications

As we move into a precision medicine-based future, it’s inevitable that there will be some reclassification of cancers. The problem with histopathology is that, in the past, evidence has been of the lowest level – essentially opinion, usually based on pattern recognition. The advent of molecular analysis, initially by immunohistochemistry and now by an array of technologies, such as next generation sequencing, is changing our understanding of cancer classification and providing hard data. To be clear, I’m not saying that histology is not evidence-based medicine; digital pathology is here to stay, and we can measure diagnostic features in H&E slides as accurately as clinical chemistry labs can estimate a sodium level!

Scientific advances will change things – sometimes in obvious ways, but sometimes unpredictably. We have to be ready to change our classification of disease accordingly. One such advance is the rise of the liquid biopsy, which is changing the diagnostic landscape. And though there is a temptation to start writing and publishing classification changes in accordance with molecular findings, cancer classification has to be somewhat conservative – we don’t want to publish an official change now that we later have to reverse.  This causes headaches for epidemiologists, oncologists, and others who need to know that a tumor’s incidence has not changed simply due to a revised classification. We need to think very seriously about what is required, what is desirable, and what is probably neither relevant nor useful in making a diagnosis. 

We also need to take advantage of multiple modalities – tissue, genetics, imaging – and have some form of integration between them to change the face of cancer classification by moving beyond histopathology alone. Why is that so exciting? Because it really takes us back to our roots. Pathology is simply the study of disease, and the more angles from which we can investigate disease, the more we can learn – and the more we can help our patients.

The books don’t only contain classification information, though. They also offer written descriptions of the cancers and a selection of characteristic illustrations that pathologists can use to work out whether the tumor they have in front of them matches the one in the book. I consider those images and descriptions to be the “standards” against which we diagnose cancers. Just as a clinical biochemist would use a commercially available standard to determine whether or not a test is working, so we use “histopathology standards” to provide additional confidence in our diagnoses. By increasing our use of online systems, we can provide more images and information to pathologists than is possible in a physical volume, which lets us be thorough without sacrificing one of the best characteristics of the Blue Books: brevity. The content of the hard copies is restricted to what is essential for diagnosis, and we work hard to maintain that.

New content for a new world

The inclusion of digital resources to the Blue Books offers obvious advantages when it comes to referencing, but I think we will also see some huge advantages in terms of the tools pathologists can use to examine and manipulate those images. Although some of the complex computational science can be a little scary at the moment, the software itself is much less complicated because all of the “thinking” goes on behind the scenes. A tool may be as simple as a pathologist selecting an area on the slide and pressing a button – an easy way to yield an answer that helps with the grading or staging of a tumor!

Another change is the adoption of the International System of Units (SI), the international standard for measurement, in the Blue Books. Pathologists have been rather slow to embrace SI units – we still talk, for instance, about high-power fields, which can differ substantially between different microscopes. In extreme cases, one pathologist might call something malignant whereas another would call it benign on the basis of the mitoses per high-power field! In the forthcoming book on skin tumors, we’ve already transitioned from high-power fields to millimeters squared. We’re also making sure that, wherever necessary, the books adhere to international standards such as the Human Genome Variation Society notation for mutations.

It’s vital for us to consider what tools we include in the Blue Books – not just in terms of new technologies, but also older and more accessible ones. The WHO and IARC are United Nations organizations, so it’s vital that we also consider the provision of tools for low- and middle-income countries with fewer resources. No doubt there will be plenty of debate about what information is and is not important for particular cancer types. I look forward to many such informative and enjoyable discussions around the Blue Books. Above all, we must remember that the classification we use for diagnosis is the basis of everything else in cancer research and treatment. The Blue Books are a daunting job from that point of view – they define the classification, and so inform every decision we make.

There is no doubt that the work that goes into the classification of tumors and produces the WHO Blue Books is an incredibly worthwhile effort that directly helps patients, doctors, and cancer researchers. We are very grateful to all those involved at every stage. The work will continue to grow and adapt to changing times, taking advantage of new developments and ensuring that new information is properly evaluated. I look forward to a bright future for cancer classification.