What To Call What We Treat, Part I: WHO Releases Updated Classification of Lymphoid Neoplasms

After nearly a decade since its last iteration, the World Health Organization (WHO) has revised its 2008 classification of lymphoid neoplasms, updating the current classification categories and adding new classification categories for neoplasms in certain disease states.

“In addition to adding a limited number of new provisional entities, the modifications impact the diagnostic criteria for some entities related to important prognostic or predictive factors,” Steven H. Swerdlow, MD, from the University of Pittsburgh School of Medicine in Pennsylvania, and lead author of the monograph told ASH Clinical News in a joint statement with co-authors Elias Campo, MD, PhD, from the University of Barcelona in Spain, and Elaine S. Jaffe, MD, from the National Cancer Institute in Bethesda, Maryland.

To develop this new monograph, the WHO convened a clinical advisory committee that met in 2014 to gain input, advice, and consent from clinical hematologists/oncologists, pathologists, and other physicians. The 2016 monograph features a review of the major changes in the understanding of lymphoid, histiocytic, and dendritic neoplasms that have been published in the years since the earlier edition.

“We have seen new insights into the biology and management of both clonal proliferations with limited malignant potential,” the authors wrote, “as well as the aggressive lymphoid neoplasms where more targeted and effective therapies are being investigated.”

The 2016 WHO classification and associated monograph will provide updated diagnostic categories and criteria, together with biological and clinical correlates, and facilitate state-of-the-art patient care, future therapeutic advances, and basic research in this field.

“The updated classification will allow physicians to better tailor therapies to the very specific type of neoplasm that a patient has,” said Drs. Swerdlow, Campo, and Jaffe. “We are far beyond the point where one regimen or drug fits all patients.”

“Furthermore, [the revised classification] facilitates communication between pathologists and clinicians,” Dr. Swerdlow and colleagues continued. “Evaluation of lymphomas requires a pathologist who understands what is needed to diagnose these neoplasms. In addition, the need for a multifaceted approach to diagnosis requires sufficient tissue biopsies.”

Read below for some of the major and proposed changes to the classification. For the full updated classification, visit www.bloodjournal.org.

Mature B-Cell Lymphoid Neoplasms

The many updates in the classification of small B-cell lymphomas result from the “explosion of new clinical, pathologic, and genetic data” on these diseases, including the following:

Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL): Cytopenias or disease-related symptoms are now insufficient to make a diagnosis of CLL with <5×109/L peripheral blood CLL cells. The monograph also recognizes mutations of potential clinical relevance (TP53, NOTCH1, SF3B1, ATM, and BIRC3).

Hairy cell leukemia: BRAF V600E mutation occurs in a vast majority of cases with MAP2K1 mutations in most cases that use IGHV4-34 and lack BRAF mutation.

Follicular lymphoma (FL): Pediatric FL will become a definite entity in the 2016 classification but is now known as pediatric-type FL because similar lymphomas may occur in adults. The mutational landscape is better understood, but the clinical impact remains to be determined.

In situ FL will be referred to as in situ follicular neoplasia to reflect the low risk of progression to lymphoma.

Mature T-Cell and NK-Cell Neoplasms

Advances in the classification of nodal and extra-nodal T- and NK-cell neoplasms have occurred since the previous WHO classification, prompting revisions and additions to this section. Many of these changes, the authors noted, are the result of genomic studies that have examined gene-expression profiling and the genetic landscape of T-cell and NK-cell neoplasms.

Nodal T-cell lymphomas with T follicular helper (TFH) phenotype: This umbrella category was created to highlight the spectrum of nodal lymphomas with a TFH phenotype, including angio-immunoblastic T-cell lymphoma, follicular T-cell lymphoma, and other nodal peripheral T-cell lymphoma (PTCL) with a TFH phenotype. Overlapping recurrent molecular and cytogenetic abnormalities have been recognized that could impact therapy.

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is now a definite entity that includes cytogenetic subsets that appear to have prognostic implications.

Breast implant–associated anaplastic large cell lymphoma (ALCL): A new provisional entity distinguished from other ALK-ALCL, identified as a non-invasive disease associated with excellent outcome.

Nodular lymphocyte predominant Hodgkin lymphoma (HL): Variant growth patterns should be noted in diagnostic report, if present, due to their clinicopathologic associations.

Cytotoxic T-Cell Lymphomas and Leukemias

In this heterogeneous group of diseases, the revised monograph reflects new data about certain neoplasms published since 2008.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and primary cutaneous acral CD8-positive (CD8+) T-cell lymphoma: These provisional entities are both clonal disorders, usually composed of CD8+ T cells, with an indolent clinical course.

Newly identified recurrent mutations affecting the JAK/STAT pathway: STAT3 mutations are common in large granular lymphocyte leukemia of both T- and NK-cell types, while STAT5B mutations are more uncommon and associated with more clinically aggressive disease. These findings have led to changes in the categorization of intestinal T-cell lymphomas.

Epstein Barr Virus–Positive T-Cell and NK-Cell Lymphomas

The updated monograph delineates the different clinical presentations and biology in Epstein Barr virus–positive (EBV+) T-cell lymphomas and leukemias. Specifically, EBV-associated T- and NK-cell lymphoproliferative disorders among the pediatric age group are now classified as chronic active EBV-infection and systemic EBV+ T-cell lymphoma of childhood, which is no longer referred to as a lymphoproliferative disorder.

Hodgkin Lymphoma

Although the classification of HL has not changed, the monograph updates the nodular lymphocyte predominant HL classification based on clinical data that indicate potential progression to T-cell histiocyte-rich large B-cell lymphoma and a more aggressive clinical course, therefore requiring different management.

Histiocytic and Dendritic Cell Neoplasms

Much of the 2008 classification is still accepted for histiocytic and dendritic cell neoplasms (HDCN), though Erheim-Chester disease (ECD) has been added as an entity. Other research has indicated that irrespective of myeloid or mesenchymal origin, some of these neoplasms are associated with or preceded by FL, CLL, B- or T-lymphocytic neoplasms, or PTCL.


Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood. 2016 March 15. [Epub ahead of print]

Editor’s note: The World Health Organization also revised its classification of myeloid neoplasms and acute leukemia, published in the April 11, 2016, edition of Blood. Look for our coverage of the revisions in “What To Call What We Treat, Part II: WHO Releases Updated Classification of Myeloid Neoplasms and Acute Leukemia” in our June issue.