In 1832, Thomas Hodgkin described seven patients with similar disease findings involving lymph nodes and spleen. Hodgkin made his observations on autopsy patient specimens and never used a microscope. Three decades later, Sir Samuel Wilks reported 15 similar cases, recognized the earlier work of Hodgkin, and coined the eponym “Hodgkin’s disease” (now Hodgkin lymphoma). Hodgkin’s study is a reasonable place to mark the beginning of lymphoma classification. It subsequently became apparent that there are many types of lymphoma in addition to Hodgkin lymphoma, and these neoplasms became known as non-Hodgkin lymphomas. In this regard, Hodgkin may be unique among persons in the history of medicine for whom a disease is named eponymously – not only does he have a disease named after him, he also has a large group of diseases specifically designated with his name used in the negative.
Technological advances, in large part, facilitated insights into lymphomas. For almost 150 years after the study by Hodgkin, light microscopic evaluation was the principal technology employed. Pathologists compared lymphomas to normal lymph nodes and began to recognize entities. Patterns (nodular versus diffuse) and cellular features (size and shape) were correlated with clinical features. We recognized that lymphomas composed of large cells were associated with aggressive clinical behavior; most composed of small cells were clinically indolent. Cases with a nodular pattern resembled germinal centers of lymphoid follicles – follicular lymphoma. Various morphologic classification systems were proposed, most of which separated Hodgkin from non-Hodgkin lymphomas and then further subclassified these groups.
New technologies led to seminal discoveries that changed our understanding of lymphocytes and lymphoma classification:
- Lymphocyte lineages were discovered. This began with Glick and colleagues’ recognition of B cells, followed by Miller and others’ identification of T lymphocytes and Klein and others’ discovery of NK cells.
- Lymphocytes – previously thought to be terminally differentiated cells – were shown to respond to antigens or mitogens by transforming into larger proliferating cells.
- Lymphocytes were discovered to have surface antigens we can exploit to identify normal and neoplastic cells – indicating their utility in diagnosing and classifying lymphomas. Simultaneous technological advances in immunophenotyping methods, particularly flow cytometry and immunohistochemistry, facilitated the characterization of lymphoid cells. Kohler and Milstein’s discovery of hybridoma technology was another major breakthrough that led to widespread availability of monoclonal antibodies.
These immunologic insights led to the proposal of two lymphoma classifications in 1974. Karl Lennert and colleagues proposed the Kiel classification; Robert Lukes and Robert Collins proposed the Lukes-Collins classification. For the remainder of the decade, immunology-based and morphology-based lymphoma classifications competed. The latter group included systems proposed by Henry Rappaport (the most popular at the time), the British National Lymphoma Investigation, Ronald Dorfman, and the World Health Organization (WHO). The situation, confusing for clinicians and pathologists alike, led to a National Cancer Institute-sponsored study in 1982 that compared all six classifications using morphology and outcomes. All systems rendered diagnostic categories that could broadly divide non-Hodgkin lymphomas into prognostic groups: low-grade indolent neoplasms (indolent), intermediate-grade neoplasms (aggressive), and high-grade neoplasms (very aggressive). A Working Formulation was proposed to serve as a common language for translating between systems. Although it became popular in the United States and functioned as a de facto classification, Europe and many other nations continued to use the Kiel system. A stalemate of sorts set in for the next decade.
Alongside advances in immunology, our ability to study human chromosomes blossomed. Fluorescent dyes that facilitated chromosome banding allowed improved recognition of chromosomal abnormalities in lymphomas. Chromosome 8q24 translocations were linked to Burkitt lymphoma, t(14;18)(q32;q21) to follicular lymphoma, t(11;14)(q13;q32) to mantle cell lymphoma, and t(2;5)(q23;q35) to anaplastic large cell lymphoma.
The field of genomics also began to emerge with Nathans’ 1971 discovery of restriction endonucleases, which allowed researchers to cut and manipulate DNA fragments. Subsequent application of molecular methods to the study of lymphomas yielded many insights. These methods enabled the cloning and characterization of oncogenes and tumor suppressor genes involved in various chromosome abnormalities. For example, MYC was identified at chromosome 8q24, BCL2 at chromosome 18q21, CCND1 at chromosome 11q13, and NPM1-ALK was shown to be a fusion gene created by t(2;5) – all translocations that upregulate gene expression. This type of information greatly enhanced our understanding of lymphomas, and it didn’t take long for the findings to be incorporated into lymphoma diagnosis, patient risk stratification, and prognostication. However, they were not incorporated in a consensus manner… and the stage was set for a new attempt at lymphoma classification.
In 1994, Nancy Harris and colleagues proposed the Revised European-American Lymphoma (REAL) classification, which used a multiparametric approach to lymphoma diagnosis by employing clinical data, morphology, immunophenotype, genetic information, and presumed cell of origin. The REAL classification was the foundation of the third edition of the WHO classification (2001), and the subsequent fourth edition (2008) and revision (2017). As part of the WHO classification effort, pathologists and clinicians worked collaboratively to develop a consensus classification of lymphomas, each more detailed and granular than the last. The current WHO classification is accepted internationally as a consensus classification for lymphoma diagnosis and as a tool to facilitate lymphoma discovery.
The completed human genome heralded the advent of high-throughput genomic testing to interrogate these genes in various cancers. In lymphomas, gene expression profiling was used for both discovery and classification. The results provided possible targets for therapy and showed the heterogeneity of a number of disease categories defined in the WHO classification. Then came next-generation sequencing of lymphomas. Targeted sequencing using gene panels has shown their molecular landscapes at the DNA and RNA level as never seen before. Molecular pathways critical for lymphomagenesis have been recognized and drugs that specifically target molecular abnormalities are being developed or are in clinical trials. Some novel agents are already approved, and many more will follow. Our understanding of lymphomas has never been greater, and the prospects for future targeted therapy that is more effective and less toxic have never been brighter. This new information also has been informing the WHO lymphoma classification over time, leading to reevaluation of entities and subsequent “splitting” (or “lumping”) in each successive edition.
Nevertheless, new information brings new challenges to lymphoma classification. Will certain targeted therapies make morphologic classification unnecessary? In other words, regardless of morphology, can one simply treat the target with equivalent success? So-called basket clinical trials are pursuing this strategy. As the complexity of genetic information grows, can we incorporate all clinically relevant information into a lymphoma classification in a somewhat practical manner? The various genetic approaches applied to lymphomas have yielded some information that seems incongruous with current concepts. These “grey areas” currently raise questions related to diagnosis, classification, or patient management that challenge current practices.
The following case presentations and commentaries address the diagnostic and therapeutic approach to lymphoma cases in the grey zone. These cases illustrate issues faced by pathologists in establishing a diagnosis, as well as issues encountered by our patient-facing colleagues. These challenges also underscore the importance of the communication between lymphoma pathologists and clinicians as we try to integrate new information into lymphoma diagnosis, classification, and management to improve outcomes for lymphoma patients.
Read on to discover our four lymphoid cases...
Case 1: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma – Accelerated Phase
Case 2: Lymphoma-Driven Hemophagocytic Lymphohistiocytosis
Case 3: High-Grade B Cell Lymphoma with Leukemic Presentation
Case 4: Low-Grade Follicular Lymphoma with Increased Proliferation Index
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