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Breaking Up Is Hard to Do

November 18, 2022

December 2022

Pathologists and clinicians came together to help classify hematologic neoplasms, split, and now many hope they can reunite.

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

For the first time in more than two decades, hematologists and hematopathologists have more than one classification system available to them that attempt to provide a framework for the recognition of disease entities in the field of hematologic neoplasms.

Beta versions of the fifth edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours were published in July 2022 and are available at tumourclassification.iarc.who.int/, and final versions of the International Consensus Classification (ICC) of mature lymphoid neoplasms, myeloid neoplasms, and acute leukemia from the Clinical Advisory Committees (CACs) of the Society of Hematopathology (SH) and the European Association for Haematopathology (EAHP) were published in September 2022.1-4

The goal of these classification systems in hematologic malignancies or solid tumors is to get global acceptance of a classification system that is relevant and has everyone using the same criteria, according to Daniel Arber, MD, the Donald West and Mary Elizabeth King Professor and chair of pathology at the University of Chicago.

“It helps when you get a diagnosis that you know is the same diagnosis everywhere,” Dr. Arber said. “You can have a disease name, but if everyone is using different disease criteria it could mean a different thing.”

ASH Clinical News spoke with Dr. Arber and other experts about the history of collaboration between the WHO’s International Agency for Research on Cancer (IARC) and the CACs of the SH and EAHP, reasons that they split, and how the current situation might affect practicing hematologists.

In the Beginning

The IARC was created in 1965 as a specialized agency under the WHO. Among its assignments, the IARC was tasked with creating a histopathological and clinical classification and grading of human tumors.5 The WHO classification of human tumors – often referred to as “blue books” – began with first (1967-1981) and second (1982-2002) editions edited by Leslie Sobin, MD. These editions were essentially pamphlets, according to Dr. Arber, were based on histological typing, and were not widely used by hematopathologists.

In 1994, the Revised European-American Lymphoma (REAL) Classification of Lymphoid Neoplasms, proposed by the International Lymphoma Study Group, was published.6 Led by Nancy L. Harris, MD, then at the Massachusetts General Hospital in Boston, Harald Stein, MD, then at Free University of Berlin, and Elaine S. Jaffe, MD, of the National Institutes of Health, and colleagues, this classification system defined each disease type by morphology, immunophenotype, and genetic and clinical features.

The REAL classification was a big step forward and was the first large effort at getting an international classification system accepted, according to James Cook, MD, PhD, professor of pathology at the Cleveland Clinic Lerner College of Medicine.

“After that was published, Dr. Sobin at IARC reached out to Dr. Jaffe, who was president of SH at the time, and invited her to have SH organize the classification of lymphoma and myeloid neoplasms for what was going to be the third edition of the WHO classification,” Dr. Cook said. “The SH agreed and also extended that invitation to the EAHP to get broad international input.”

Bringing in Clinician Input

Beginning with the third edition, the WHO classification system for hematolymphoid tumors was a collaboration between SH, EAHP, and IARC.

“The classifications have always been led by pathologists, but in the field of hematolymphoid cancers there is a close codependence between pathology data and clinical data when it comes to classifying leukemias and lymphomas,” explained Joseph Khoury, MD, Stokes-Shackleford Professor and chair in the Department of Pathology and Microbiology at University of Nebraska Medical Center. “Those leaders had a vision to engage a group of leading clinicians who focused on leukemias and lymphomas to seek their input into the classification. It was widely accepted and supported.”

This clinical input was gathered during a CAC meeting that included many international experts in hematology.

“The prior WHO blue books were almost entirely pathology written, but with the CAC process, a pathologist would raise a point about a proposed change and clinicians could weigh in on whether they thought it was a good idea or a bad idea,” Dr. Arber said. “There was a back and forth. If every clinician didn’t entirely agree, they at least had input and could possibly modify things to provide understanding of the clinical impact of what was proposed.”

In a report of the CAC meeting in 1997, Dr. Jaffe and colleagues wrote, “The experience of developing the WHO Classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.”7

This endeavor was completed with the publication of the third edition in 2001.8 The model was repeated for the fourth edition (2008) and the revised fourth edition (2017).

Signs of Discord

In 2016, the World Health Assembly ratified a Framework of Engagement with Non-State Actors (FENSA) that applied to all United Nations entities, including the WHO. This framework “endeavors to strengthen WHO engagement with non-State actors (NGOs [nongovernmental organizations], private sector entities, philanthropic foundations, and academic institutions) while protecting its work from potential risks such as conflict of interest, reputational risks, and undue influence.”9 All partnerships and collaborations with non-State actors are evaluated by IARC/WHO against an established set of rules.

“The framework set a minimum level of governance, equitability, and transparency,” Dr. Khoury said. “As a result, leadership of the WHO Classification of Tumours had to find a new mechanism to procure input into the classification, and the old CAC structure – which lacked transparent governance – was no longer permissible.”

Instead, Dr. Khoury clarified, multidisciplinary collaboration (pathologists, hematologists, oncologists, geneticists, etc.) was built into the fabric of the editorial board and author selection for the fifth edition.

In 2017, a new head of the WHO Classification of Tumours, Ian Cree, FRCPath, set up an independent editorial board with standing members nominated by major international societies of pathology, meeting the requirements set forth in the framework.10 (There was a published response to Dr. Cree’s letter from members of the ICC that disputes some of the details therein.11)

According to Dr. Khoury, there was a discussion of working with several key opinion leaders who had contributed to prior volumes, but doing so within the constraints of the new framework and without making exceptions for just this organ system.

Dr. Cook said that as preparations began for the fifth edition, IARC approached the two pathology societies and expressed that it would no longer participate in the CAC collaboration.

In Dr. Cook’s view, an approach without the CAC eliminated the clinical consensus and consensus guidelines that came out of the CAC, which were critical to the success of prior classifications.

“We felt it was important for that to continue, even if it had to be independent of what WHO was doing,” Dr. Cook said.

This led to the organization of the CAC meetings in September 2021 and the subsequent ICC classification publications. According to an editorial introducing the classifications, it represented “a major revision of previous classifications and is a significant step forward, further recognizing molecular heterogeneity as an integral component.”12

The combined CAC on which the ICC classifications are based involved 138 participants (some in-person and some remote) from 23 countries and five continents. It was organized by clinical and pathology co-chairs.

The ICC declined to let anyone participating in the IARC process be involved in the CAC to ensure the ICC participants received recognition for their work, according to Dr. Arber.

Similarly, according to Dr. Cook, IARC had already refused to work with the current and prior leaders of the CAC.

The WHO classification took the effort of 420 participants from 31 countries and five continents. The framework of the classification adhered to a hierarchical structure that underpinned the classification of cancers in other organ systems.13 Careful deliberation between experts from various disciplines resulted in a balanced approach that was forward-looking while remaining tethered in established practice, Dr. Khoury clarified.

“At the inception of the 11th volume in the current fifth edition, I asked both the current presidents of the SH and EAHP to join the editorial board,” Dr. Cree said in an e-mailed statement. “Dr. Cook accepted but later resigned. . . . There were many members of both societies involved, including Dr. Reiner Siebert, who was an editor in the fourth edition, and many senior authors from that volume.”

Overlap and Differences

The groups are not in agreement on the details behind the split, and this article is not attempting to reconcile the differing accounts. Regardless, there are some areas of overlap and differentiation between the classification systems that clinicians and pathologists should be aware of. The existence of two separate classification systems means that clinicians have to decide how they apply the systems when diagnosing certain diseases, and pathology reports should include diagnoses from both systems – that is, until there is a reunification, if there is one.

“There is over 90% overlap between the WHO and ICC classifications,” Dr. Khoury said. “The areas where there is a difference is typically because the data are not clear and decisions had to be based on consensus. It is important to flag these as areas where additional data are needed to inform future classifications, and we need to work on research and producing data to support clearer decisions on how to bridge some of the gaps.”

Dr. Cook mostly agreed, saying, “Both are working from the revised fourth edition classification and doing any updates from there. There are many entities that did not change.”

On the myeloid side, the ICC classification calls cases of myelodysplastic syndromes (MDS) with 10% to 19% myeloblasts MDS/acute myeloid leukemia (AML), “reflecting the diagnostic continuum between AML and MDS and the clinical and genetic heterogeneity among individual patients with these lower blast counts.”4

“This means there could be some patients classified as having AML by the ICC classification but who would be classified as having MDS by the WHO system,” Dr. Cook said.

Dr. Arber noted that several molecular categories were added to the ICC classification for acute lymphoblastic leukemia, as well, but that these should only drive additional testing and will not change the diagnosis much.

On the lymphoid side, the WHO classification eliminated the diagnosis of post-transplant lymphoproliferative disorders as a distinct entity, Dr. Cook said.

“WHO has a new classification system for immune-deficiency-associated disorders, whereas ICC clinicians felt that the post-transplant lymphoproliferative disorders were well-established as a clinical entity and wanted to retain them as their own diagnosis,” Dr. Cook said.

Elias Campo, MD, PhD, of Hospital Clinic of the University of Barcelona, also pointed out that the ICC maintained cytological grades for follicular lymphoma (FL). In contrast, the WHO classification states that grading FL into grades 1-2 and 3A is no longer mandatory.

Dr. Campo added that the ICC considered that multiple myeloma should be classified based on basic genetic features. These classifications are not currently included in the IARC WHO classification, he said.

Dr. Cook noted that the final IARC classifications have not yet been published.

“I don’t know if we can expect many major changes in what is ultimately published, but, in theory, they could still adjust some things,” Dr. Cook said.

The Effect on Clinical Practice

Just exactly how the existence of two classification systems will affect the field is unknown, according to Dr. Campo.

“My hope is that it won’t influence much because the terms in the classifications, with some exceptions, are the same,” Dr. Campo said. “For instance, we have a category for [FL] in the WHO classification, in the ICC classification, and in [the Surveillance, Epidemiology, and End Results (SEER) database]. Therefore, databases and International Classification for Diseases (ICD) codes will have the same category; the problem is that within this category the criteria to classify things might have changed.”

According to Dr. Cook, the SEER database has largely been using the 2008 WHO classification and has not yet fully updated to the 2017 classification.

“My hope is that databases would allow sufficient flexibility to specify which classification schema was used,” Dr. Cook said. “That will obviously be up to each database organization to decide.”

Dr. Khoury agreed that it is up to the purview of the tumor registrars, who base their determinations on guidelines from standards-setting organizations.

Moving forward, pathologists may have to give diagnoses in both systems, Dr. Arber said, which is what was done more than 20 years ago when there were multiple classification systems.

“If we are using one, we will have to be clear which we are using,” Dr. Arber said. “If there is a difference between systems, we will have to call it out so that treating physicians understand that.”

Although this may be challenging, Dr. Arber said it is not an entirely bad thing.

“If you look at publications now, people don’t always use the WHO classifications,” Dr. Arber said. “Sometimes older systems are still used. It adds another layer of complexity to things, but I don’t think it is going to be a disaster.”

Dr. Khoury, who was involved with the WHO classification, said he believes the ICC was an effort to put a stamp on how some people in the field thought the classification should proceed. As to which system will emerge as being more widely accepted, he has a firm opinion.

“We should be clear. There is only one WHO classification, and that is true for all cancer types and organ systems,” Dr. Khoury said. “That is also true for leukemias and lymphomas.”

“My assumption is that payers will be basing their decision primarily on the WHO classification because that is the standard that is followed throughout the world for cancer diagnosis,” Dr. Khoury added. “If people choose to use the ICC system or choose to be confused by the fact that there is something other than what WHO has proposed, that is unfortunate.”

Dr. Cree echoed this view and said that he does not think the publication of the two classification systems will affect things much.

“What happens in the U.S. is up to the U.S., and SEER runs its own ship, but it tends to take the WHO books as a template for everything,” Dr. Cree said. “One of the perspectives that is somewhat lost at times is that there is a lot more to [the WHO classifications] than just hematopathology. This is just one of 14 volumes in the classification.”

In an editorial published prior to the ICC classification, William R. Macon, MD, of Mayo Clinic, who participated in the WHO/IARC classification, wrote that he supported the SH/EAHP-endorsed CAC meeting but expressed a hope that those participating in the meeting would not publish a classification until they could review the final WHO product. Dr. Macon worried that “a different and competing classification that causes loss of global consensus may turn out to be an example of perfection being the enemy of good.”14

Breaking Up or on a Break?

With the final publication of the fifth edition still awaited as of the end of October 2022, it is unknown what exactly the future holds for the relationship between IARC and ICC, their classification systems, and practicing hematologists and hematopathologists.

“It is going to be a challenge as for how this will play out,” Dr. Cook said. “Hematopathologists and hematologists will have to be familiar with both systems, but I think ultimately one approach or the other will end up being favored and more widely accepted.”

There seems to be general agreement that a united classification system can once again be possible in the near future.

“With new leadership at IARC, everyone wants there to be a unified classification again,” Dr. Arber said. “I think things will merge again with the sixth edition.”

The ICC has acknowledged the importance of the WHO blue books for “standardizing the categorization and nomenclature of hematologic neoplasms” but outlined a vision for future revisions that increasingly refine prognostication and information personalized therapy.12

In an introduction published with the ICC classifications, Mario Cazzola, MD, of Fondazione IRCCS Policlinico San Matteo and University of Pavia in Italy, and Laurie H. Sehn, MD, of the University of British Columbia, wrote that this type of dynamic update will “require ongoing close collaboration among pathologists, hematologists, oncologists, genomics scientists, bioinformaticians, and clinical trialists,” and suggested the formation of an international working group that could collaborate with the WHO. Members of this proposed group would be selected based on merit and have staggered, limited terms.

Dr. Arber acknowledged that this split has caused a rift in the community, with greater effect in some places than others, but he is still hopeful that the breakup won’t be forever.

It’s also unclear whether there will be further divide or not. “Everyone involved with the ICC would like to see a return to collaboration and a more unified approach,” Dr. Cook said.

Dr. Cree agreed, saying, “We would like to have the entire community using a single classification. There is no reason why they shouldn’t.”

References

  1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720-1748.
  2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719.
  3. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140(11):1229-1253.
  4. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228.
  5. Sohier R, Sutherland AGB. The Origin of the International Agency for Research on Cancer. IARC Technical Report No. 6. Lyon. 2015. Accessed September 21, 2022. https://publications.iarc.fr/Book-And-Report-Series/Iarc-Technical-Publications/The-Origin-Of-The-International-Agency-For-Research-On-Cancer-2015.
  6. Harris NL, Jaffe ES, Stein H, et al. A Revised European-American Classification of Lymphoid Neoplasms: A Proposal From the International Lymphoma Study Group. Blood. 1994;84(5):1361-1392.
  7. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. 1999;10(12):1419-1432.
  8. Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, France; 2001.
  9. World Health Organization. WHO’s engagement with non-State actors. May 28, 2016. Accessed September 22, 2022. https://www.who.int/about/collaboration/non-state-actors.
  10. Cree IA. The WHO Classification of Haematolymphoid Tumours. 2022;36:1701-1702.
  11. Swerdlow SH, Campo E, Arber DA, et al. Response to “The WHO classification of haematolymphoid tumours” (Editorial) [published online, 2022 Aug 27]. Leukemia. doi: 10.1038/s41375-022-01689-9.
  12. Cazzola M, Sehn LH. Developing a classification of hematologic neoplasms in the era of precision medicine. Blood. 2022;140(11):1193-1199.
  13. World Health Organization. International Agency for Research on Cancer. WHO Classification of Tumours. Accessed September 22, 2022. https://whobluebooks.iarc.fr/structures/haematolymphoid/.
  14. Macon WR. What, how, and when for the WHO: will the clock be turned back for the next hematolymphoid tumor classification? J Hematopathol. 2021;14:185-186.

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