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WHO Lymphoma Classification Update in Progress, but Is It ‘Too Complicated’?

Fuerst, Mark L.

doi: 10.1097/01.COT.0000470188.70502.d4
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NEW YORK—An update to the Fourth Edition of the World Health Organization (WHO) Classification of Hematopoietic and Lymphoid tissues is in progress. Nancy Lee Harris, MD, Professor of Pathology at Massachusetts General Hospital and Harvard Medical School, discussed the changes here at the “Modern Radiation for Lymphoma: Updated Role and New Rules” meeting at Memorial Sloan Kettering Cancer Center.

“The fourth edition is now six years old, but WHO will not begin work on a fifth edition until all volumes of the fourth edition are published,” she said. “WHO has now agreed to an update,” which is expected to be available in about a year.

Harris noted that multiple meetings of the editors were held between 2012 and 2014, with senior advisors added in genetics and myeloid diseases. Clinical Advisory Committees (Lymphoid and Myeloid) met in March 2014. “No one gets everything he or she wants in this collaborative effort, but we do try to arrive at a consensus that benefits our patients.”

In an interview, elaborating on remarks he made at the meeting, Saul Rosenberg, MD, Professor of Medicine and Radiation Oncology Emeritus at Stanford University School of Medicine, said, “WHO classification is based on good science and ideas, but the new update is very complicated and extremely complex. It may overestimate the clinician's ability to handle it. We only have a limited number of treatments that work. I worry that every patient will be given a different diagnosis.”

NANCY LEE HARRIS, MD. NANCY LEE HARRIS, MD: “We are not inventing new diseases, we are discovering new diseases. It is no different from astronomy or genetics or microbiology. You do not hear people complaining when a new planet or gene or microbe is discovered.”

Harris responded: “In the 1990s, when we published the REAL [Revised European American Lymphoma] classification, we were advised by clinicians to simplify the classification for community oncologists. At a CME meeting where this was being discussed, one of the participants said to me during a break, ‘I'm a community oncologist, and I get this! You don't have to simplify it for me!’ I believe that when we identify distinct diseases, with distinctive pathological and clinical features, it is easier both for pathologists to make a diagnosis and for clinicians to understand what their patients have and to individualize treatment. Precision medicine requires precise diagnoses.”

She added: “We are not inventing new diseases, we are discovering new diseases. It is no different from astronomy or genetics or microbiology. You do not hear people complaining when a new planet or gene or microbe is discovered.”

Harris noted that after the exchange of views between herself and Rosenberg at the meeting, a radiation oncologist approached her at lunch and said, “I think I recognized a patient of mine in one of the new entities you described: a young man in his early 20s who presented with a large neck mass.

It was completely resected, and the pathologist called it ‘follicular lymphoma grade 3B with diffuse large B-cell lymphoma.’ The patient had no other sites of disease, but had no insurance and couldn't afford further treatment. One year later, he returned with upper airway obstruction and had a large mass of the ipsilateral tonsil, which was recurrent lymphoma. At this time he had insurance, so he was treated with chemotherapy and it resolved.

“We are considering local radiation, but the medical oncologist says that because it is follicular lymphoma, he is recommending maintenance rituximab. If this is the new entity you described, diffuse large B-cell lymphoma and follicular lymphoma grade 3B with IRF4 rearrangements, it sounds like this has nothing to do with conventional follicular lymphoma, and the patient should have a good outcome without maintenance rituximab.”

The radiation oncologist was absolutely right, Harris said.

A Brief History of Lymphoma Classification

In the 1970s, there were multiple lymphoma classifications in use, Harris related. “An international study, led by exasperated clinicians, failed to result in a consensus on the ‘best’ classification, and led to the development of the Working Formulation, which was designed to translate between classifications. It included broad prognostic groups based on the survival of patients in the study, and these groups became more important than specific pathological categories, which were designed to be broad and heterogeneous, so that all entities in all classifications could be covered.”

In the 1980s to the 1990s, the problem of classification persisted. The Working Formulation became the major American classification, but the Kiel Classification was used in Europe, and some in the U.S. used the Lukes and Collins classification. In addition, new entities were recognized and new immunophenotypic or genetic features were discovered for some recognized entities, but there was still no consensus among pathologists or clinicians on the definitions of entities or criteria for diagnosis.

In 1994, the International Lymphoma Study Group published the REAL classification, which was a consensus list of lymphoid neoplasms that could be recognized by pathologists and that were clinically distinctive, Harris continued. This also included input from a meeting with clinicians. In 1997, an international clinical study of the REAL classification found that it identified reproducible categories that covered more than 95 percent of lymphomas, and that were clinically relevant, not only in terms of prognosis, but with distinctive epidemiology and clinical presentations.

In 2001, in the Third Edition of its series of books on classification of tumors, the World Health Organization published the WHO Classification of Tumours of the Hematopoietic and Lymphoid Tissues. “The development of this classification provided us the opportunity to develop a broader consensus on lymphoid neoplasms and to apply the principles of the REAL classification to myeloid and histiocytic neoplasms,” Harris explained. “These classifications, like the REAL classification, continued to have clinical advisory committees and consensus meetings of pathologists, with more than 200 international pathologists and clinicians participating.”

The 2001 WHO classification represented the first international consensus on classification of hematologic malignancies, and in 2008, the 4th Edition was published.

REAL/WHO Classification Principles

The REAL/WHO Classification Principles are to define distinct disease entities that can be recognized by pathologists and that have clinical relevance, she said. A constellation of features (morphologic, immunophenotypic, genetic, and clinical) define each disease entity. The relative importance of each feature varies among diseases.

“Since we do not know the underlying cause of most lymphomas, the relative importance of each feature varies among diseases. There is no ‘gold standard,’” she said. Diseases are stratified according to postulated normal counterpart and stage of differentiation to the extent possible, and sorted according to clinical and morphologic similarities.

The 2008 Fourth Edition classification, compared with the 2001 Third edition, recognized more diseases, 108 in all, including 50 myeloid and acute leukemias, 53 mature B-cell lymphomas, T-cell lymphomas, and Hodgkin lymphomas, and five histiocytic lymphomas. “Many are defined by genetic and immunophenotypic features, as well as morphology. Correct classification is required to determine appropriate treatment,” Harris said.

Importantly, a number of subtypes of diffuse large B-cell lymphomas (DLBCL) are included in the Fourth Edition:

  • DLBCL not otherwise specified;
  • DLBCL associated with chronic inflammation;
  • Lymphomatoid granulomatosis;
  • Primary mediastinal (thymic) large B-cell lymphoma;
  • Intravascular large B-cell lymphoma; ALK-positive DLBCL;
  • Plasmablastic lymphoma;
  • Primary effusion lymphoma; and
  • Large B-cell lymphoma arising in HHV8-associated multicentric Castleman Disease.

The WHO 4th Edition includes an equally long list of mature T-cell and natural killer-cell neoplasms.

Regarding the details of what is new in the WHO update, Harris said that many of the changes are still under discussion, a final consensus has not been reached on some issues, and the actual writing is just beginning.

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