For GI cancer, a digital and molecular reset

The WHO Blue Books are designed to be used by pathologists in an array of settings, Dr. Klimstra says. “Whether you are talking about a major academic center in the U.S. or Europe or a small hospital in a developing country, it’s intended to be used throughout the entire world.” Some countries have developed parallel classifications over the years and continue to reference them, but all pathology practices in the world are aware of the WHO Classification of Tumours Series and can access a printed copy or the online version.

Historically, the printed version of Digestive System Tumours has been a major reference produced once a decade, based on a series of meetings and input from experts who redraft the text and figures and illustrations. “Although it is technically not an atlas, in the sense of providing exhaustive illustration of every different variant of tumor that arises in every organ, it is well illustrated in the text version,” Dr. Klimstra says. “But when you are dealing with printed documents, it’s clunky. You can’t make minor updates when you need to achieve a consensus of experts.” So having the online version “will provide a simpler way for modifications to incorporate new data that will augment our understanding.”

Pathologists learn so much from their exposure to illustrations, he says, and high-quality graphics have always been a feature of the WHO Blue Books. “When you collect world experts together and they all have their archives of gross photographs and microscopic slides, you can produce the best examples and most classic illustrations of the features.”

Now, the incorporation of digital slides will allow an interactive experience for the reader, who will be able to look at not just a single snapshot, such as would appear in a book, but also different magnifications that can be examined more comprehensively. This capability has become practical only in the past few years, Dr. Klimstra says. The WHO has learned from the experience of PathPresenter, which has created an educational portal for digital slides that is now an entirely new feature of the WHO series.

The new descriptions of tumors by molecular phenotypes will be helpful in supporting diagnosis, he says. “Over the past decade, we have been doing a lot more molecular analysis of every cancer type and we understand there are certain key alterations, whether they are mutations, gene fusions, or other alterations, that are highly characteristic of certain tumor types. In some instances, the old classification system did not mesh perfectly with the new information we are getting from genomics.”

The editorial board’s decisions about which terms to recommend changing and which to leave alone, Dr. Klimstra says, were driven by several factors. “To some extent, how we name tumors is a matter of personal preference. Terminology can be fraught with various implications. Some people think the designations ‘tumor,’ ‘carcinoma,’ and ‘neoplasm’ all mean the same thing, but others say no, they have different implications. Over time, we’ve developed a lexicon that is in general usage and that most pathologists, and hopefully most treating physicians, understand.”

When you get a consensus group together, he adds, it’s natural to look at improving existing classifications. “The group may decide to make changes because of a subtle linguistic preference for one term over another. But the principle was that we shouldn’t make changes just because we can, but only because there is a rationale, hopefully based on data.” For example, “we realized that a variant of intraductal pancreatic neoplasm that had been regarded as related to a broader category of tumors is actually genetically different and should stand on its own as a separate entity. So that fed into the terminology change and classification change in this case.”

One challenge for the editorial team was how to clarify the often ambiguous lines between benign and malignant tumors. “There is ambiguity in certain circumstances where the pathologic findings don’t fully account for the malignant potential of a tumor,” Dr. Klimstra says. “For example, tumors of the appendix have been problematic for years because some look very benign and it is hard to predict if they will behave aggressively, but nonetheless patients develop abdominal dissemination from these appendix neoplasms.”

The editors chose a change in approach for a number of different neoplasm types to not strictly categorize things as benign or malignant. “We have the concept of a neoplasm of undetermined or uncertain malignant potential. That category persists because we simply don’t have rigid criteria for benign or malignant. Some of it has been resolved by talking about risk stratification. That is, we recognize a spectrum of biology from essentially benign on one end to fully malignant on the other end. Within this continuum, there are key pathology findings that can tell you how close you are to one end of the spectrum.”

Development of the WHO Blue Books is ongoing, says editorial board member Alexander J. Lazar, MD, PhD, professor of pathology and genomic medicine at the University of Texas MD Anderson Cancer Center. There are three books at various stages of editing and production at any one time under the direction of the standing editorial board and the 12- to 15-person boards of specific subject matter experts from around the world. Since the June publication of Digestive System Tumours, the breast tumor book became available online in August and was formally announced at the European Congress of Pathology in Nice, France. Writing is complete for the fifth edition of Tumours of Soft Tissue and Bone, which will be published next and followed by the gynecologic tumor and lung tumor books.

Dr. Lazar is enthusiastic about the online availability of the new books. “The website will be something we hope people will adopt and find as a good way to access this information as well. This website is very different from what was available previously, which was basically a giant PDF of the book. This was hundreds of pages, and while you could read it on a computer screen, it had no other type of functionality in terms of a user interface. The resolution was limited, and you were not able to magnify the photomicrographs significantly, have access to whole-slide images, or do complex word searching.”

The transition to online availability does, however, take the series into unknown territory, he says. “We are in the very early days for this, so what the uptake will be for the Web-based version versus print I don’t think we know yet. The number of books that are being printed and the rate at which the digestive book is selling are consistent with what we have experienced with the WHO books in the past.” In addition to the whole-slide images, the online version’s searchability will be much faster than consulting an index in a traditional book for every occurrence of a particular word or concept, he notes.

The price of the printed books—in the $130 to $150 range—is modest. The pricing model for the Web-based version of the books is still in flux, but Dr. Lazar expects it to be an annual individual user or site license fee to access all of the books that are online—which includes some books from the fourth edition and will eventually include all fifth-edition books as they appear over the next three to four years. The WHO pricing model takes into account the ability to pay in developed countries versus developing countries, and the Web platform will probably do so also, Dr. Lazar says.

The editorial board consensus on changing established, day-to-day terms in pathology was conservative: no change unless there was strong evidence and rationale for the change. But, Dr. Lazar says, a few such changes were made in the new edition. “The example that people notice the most is where part of the characterization of the tumor involves looking at counting mitoses per a particular defined area.”

“A very common terminology used to characterize mitotic activity is a certain number of mitoses per high-power field. However, this terminology turns out to be quite imprecise because on different people’s microscopes, depending on how they are set up, a high-power field could mean very different things. In recognition of this, mitotic counts are given per defined amounts in an area—in most cases mitoses per millimeter squared—as opposed to using ‘10 high-power fields’ without a definition of what a high-power field is.”

Since the same tumor may be present across multiple organ systems, another priority was to make sure each book in the WHO series discussed the tumor in a way that is consistent with the other books. “A benign tumor such as schwannoma, for example, will characteristically involve multiple different organ systems and may be in as many as eight or more of the different books. Each book may describe slight differences in the way the tumor presents or looks in the different organ systems, but we want to make sure all the essential definitions are consistent with one another.”

The accelerated publishing schedule in this edition of the WHO series—with all books produced over six years from start to finish as opposed to over 10 years or more—is partly aimed at helping provide this consistency in definitions as well as in style and format, Dr. Lazar says. In addition, “we think the accelerated schedule is appropriate because our knowledge is expanding so rapidly; it is important to do interval updates frequently and efficiently.”

The WHO editorial board and expert panels walk a fine line in handling the wide range of technical sophistication of their worldwide readership, editorial board members agree. It’s a big challenge, Dr. Klimstra says. “You want to be applicable in all practice scenarios, but as molecular findings have been incorporated into cancer diagnosis, in practice settings without access to molecular findings you may not be able to apply classifications effectively. There’s an inevitable disconnect between highly technical practices, where there is enough sophistication and, frankly, monetary resources, versus others, where you have a microscope with stained slides and you have to do the best you can.”

There may not be an elegant way to resolve this issue. “On the one hand, we don’t want a classification system that can’t be used by three quarters of the planet,” Dr. Klimstra says. “On the other hand, we cannot ignore the importance of data from novel technologies. The mutational analysis of KRAS and EGFR in lung cancer is standard care in industrialized countries but not readily available in the entire world. These are things in a global community we have to struggle with. But the WHO is trying to find the most effective classification with the least demand for highly sophisticated and esoteric testing.”

In the coming years, the question of how to incorporate molecular features into the basic classifications of tumors is likely to remain one of the most frequent topics of discussion by the WHO editorial board, Dr. Washington says. “Do we stick with the histology-based classification with an overlay from the molecular, or will it be more important to start with a molecular basis? That will be the big challenge.”

For now, the new Digestive System Tumours is an important milestone in pathology. “This book is the most up-to-date accumulation of knowledge about all of the different factors that go into classifying and predicting the outcome and the right treatment for cancers of the digestive system,” Dr. Klimstra says. “It has brought in expert knowledge from around the world and condensed in one place essentially everything you need to know to accurately diagnose this broad array of cancers. This has been a hallmark of the WHO classification for years, and it remains a vibrant part of how we understand the pathology of cancer. In that regard it is a singular effort in the world.”

Anne Paxton is a writer and attorney in Seattle. The WHO Classification of Tumours Online can be accessed at https://tumourclassification.iarc.who.int/welcome and includes the six most recent volumes from the fourth and fifth editions. For a limited time, the annual subscription fee of €160 is reduced to €100.