Principles of Classification of Lymphoid Neoplasms

Historical Background

The classification of lymphoid neoplasms used in this text is the one published by the World Health Organization (WHO) in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . Initially published in 2008, the WHO's fourth edition was recently revised and updated. The fourth edition built on the success of the third edition (2001), defining new entities and proposing solutions for problematic categories. However, the basic principles underlying this classification are essentially unchanged from those of the Revised European American Lymphoma (REAL) classification of lymphoid neoplasms published by the International Lymphoma Study Group (ILSG) in 1994. The REAL classification represented a new paradigm in the classification of lymphoid neoplasms ( Fig. 13-1 ), focusing on the identification of “real” diseases rather than a global theoretical framework such as survival, as had been used in the working formulation, or cellular differentiation, as had been applied in the Kiel and Lukes-Collins classification systems. Key events in the evolution of the classification of lymphoid malignancies are summarized in Table 13-1 .

The REAL classification defined distinct entities with a constellation of features: morphology, immunophenotype, genetic features, and clinical presentation and course. Each of these elements plays a part, and no one feature takes precedence over the others consistently. For some diseases, morphology alone is highly characteristic, allowing one to confidently make the diagnosis without additional ancillary studies. Most cases of chronic lymphocytic leukemia (CLL) or follicular lymphoma (FL) presenting in lymph nodes fall into this category. For other diseases, knowledge of the underlying genetics may be essential, such as in the diagnosis of anaplastic lymphoma kinase (ALK)–positive anaplastic large-cell lymphoma (ALCL) ( Fig. 13-2 ). The relative importance of each of these features varies among diseases, depending on the state of current knowledge, and there is no one “gold standard” by which all diseases are defined. Still, lineage is a defining feature and forms the basis for the classification system's structure, recognizing B-cell, T-cell, and natural killer (NK)-cell neoplasms. Additionally, a basic premise is the distinction between precursor lymphoid neoplasms and those derived from mature lymphoid cells.

In the twentieth century, the field of immunology shed light on the functional and immunophenotypic complexity of the immune system. Traditional morphologic approaches were recognized as insufficient to decipher the many benign and malignant cellular components of lymphoid malignancies. Monoclonal antibody technology provided a seemingly endless array of immunophenotypic markers that could delineate the various cells types, and technologic advances soon permitted the immunohistochemical detection of most relevant antigens in routinely processed formalin-fixed, paraffin-embedded sections. Many lymphoid malignancies have characteristic immunophenotypic profiles, but even among some very homogeneous entities, immunophenotypic variation may be seen. For instance, not all cases of CLL are CD5 positive and CD23 positive; not all FLs are BCL2 positive or CD10 positive. CD5 may be expressed in otherwise classical FL. Expression of ALK is essential for the diagnosis of ALK-positive ALCL, but it is also expressed in ALK-positive large B-cell lymphoma and some myofibroblastic tumors in children. Thus, knowledge of the immunophenotype is a highly effective tool, but one that must be used in context.

There has been equally dramatic progress in understanding the genetics of lymphoid malignancies. Recurrent cytogenetic abnormalities have been identified for many lymphoma subtypes. The first to be recognized were the t(14;18)(q32;q21) translocation of FL and the t(8;14)(q24;q32) translocation of Burkitt's lymphoma (BL). Subsequent studies led to the cloning of the genes involved in these translocations. The laboratories of Leder and Croce in 1982 both identified MYC as the gene that was translocated into the immunoglobulin genes in human BL ; other similar discoveries soon followed, such as IGH/BCL2 in FL and IGH/CCND1 in mantle cell lymphoma. The most common paradigm for translocations involving the immunoglobulin heavy-chain gene, IGH at 14q24, is that a cellular proto-oncogene comes under the influence of the IGH promoter. There are also less frequent but parallel alterations involving the T-cell receptor genes in T-cell malignancies.

The REAL classification recognized the importance of genetic abnormalities in defining disease entities. However, it has become clear that a purely genetic approach to defining diseases is not feasible. Although the MYC translocation is universally present in BLs, MYC translocations involving the immunoglobulin genes are found as either secondary or, less commonly, primary genetic abnormalities in other lymphoid malignancies, including some diffuse large B-cell lymphomas (DLBCLs), plasmablastic malignancies, and some cases of B-lymphoblastic lymphoma/leukemia. Similarly, IGH/BCL2 is found in only 85% to 90% of FLs and is present in up to 25% to 30% of de novo DLBCLs with no prior evidence of FL.

Finally, the inclusion of clinical criteria was one of the novel aspects of the ILSG approach. The REAL classification recognized that the site of presentation is often a signpost for underlying biologic distinctions, such as in extranodal lymphomas of mucosa-associated lymphoid tissue (MALT), primary mediastinal large B-cell lymphoma, and many types of T/NK-cell lymphomas. The ILSG appreciated that accurate diagnosis cannot take place in a vacuum and requires knowledge of the clinical history, because biologically distinct entities may appear cytologically similar. Integration of clinical features is an essential aspect in the definition of disease entities and in accurate diagnosis in daily practice. The pathologist must be provided with relevant clinical details to arrive at a correct diagnosis, and it is the pathologist's responsibility to insist on sufficient clinical data if it is not provided. The subsequent chapters in this part emphasize the pertinent clinical features of each disease entity discussed.

It is also evident that clinical features are important prognostic indicators, and in many instances, the treatment approach chosen is based on the clinical setting in conjunction with the pathologic diagnosis. For instance, some patients with FL can be followed with a “wait-and-see” approach, whereas in others a heavy tumor burden at diagnosis mandates immediate therapy. Response to therapy is influenced not only by underlying clinical features but also by biologic and prognostic factors. Cytologic grade varies in many disease entities and is discussed in the chapters that follow. Other prognostic factors are based on tumor cell biology, such as ZAP-70 expression in CLL, or host factors, such as the tumor microenvironment. For this reason, it is not possible to stratify lymphoma subtypes in a linear fashion according to their clinical aggressiveness. The pathologist and clinician are part of a management team that determines the therapeutic approach in each case.

The REAL classification was based on the building of consensus, and it recognized that a comprehensive classification system was beyond the experience of any one individual. The 19 members of the ILSG contributed their diverse perspectives to achieve a unified point of view. In addition, the ILSG made the decision to base its classification exclusively on published data; thus, for an entity to be included in the REAL classification, it had to be validated in more than one publication.

Recognition that the development of classification systems should be a cooperative effort was expanded with the third edition of the WHO classification. It represented the first true worldwide consensus classification of hematologic malignancies and was the culmination of the efforts of a 7-member steering committee, 11 pathology committee chairs, 75 author contributors, and 44 clinician participants in a clinical advisory committee meeting. In 2008, the fourth edition of the WHO classification involved the efforts of 138 authors and two clinical advisory committees comprising 62 clinical specialists with expertise in lymphoid and myeloid disorders. The clinical advisory committee meetings were organized around a series of issues, including disease definitions, nomenclature, grading, and clinical relevance. As with the third edition, the effort was coordinated by the European Association for Haematopathology (EAHP) and the Society for Hematopathology (SH), led by the eight editors, who served as a steering committee. This model was maintained for the revision of the fourth edition, with a clinical advisory committee meeting held in 2014 to address newly emerging issues related to the definition of specific entities ( Boxes 13-1 and 13-2 ).

Disease definitions are not static, and new data have helped to clarify areas of uncertainty in the 2008 fourth edition. The 2008 WHO classification introduced the category of “B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL” (BCLU) to recognize a subset of aggressive lymphomas that were difficult to categorize as DLBCL or BL ( Boxes 13-1 and 13-2 ). Further data have shown that many tumors in the BCLU group were “double-hit” or “triple-hit” lymphomas with MYC and BCL2 or BCL6 translocations. A consensus emerged that it was useful to segregate these tumors in a single category rather than classify them primarily on the basis of cytologic features. Newer genetic studies that use next-generation sequencing (NGS) and other methods have had an impact on the classification of T-cell lymphomas. The chapters that follow in this text will reflect these and other changes, many of which are highlighted below.

Early Events in Lymphoid Neoplasia: Borderlands of Malignancy

The multistep pathway of tumorigenesis has parallels in most organ systems and is best documented in the evolution of colonic adenocarcinoma. Histologic progression is a well-recognized feature of many lymphoid neoplasms, but the earliest events in lymphoid neoplasia are difficult to recognize. In fact, the lymphoid system historically has had no recognized “benign neoplasms,” a fact that may be related to the propensity of lymphoid cells to circulate and not remain confined to a single anatomic site. The current WHO classification addresses the problem of clonal expansions of B cells or, less often, T cells that appear to have limited potential for histologic or clinical progression.

The expanded knowledge of disease-specific genetic and phenotypic alterations has resulted in the detection of clonal lymphoid lesions sharing genetic and/or phenotypic aberrations with well-defined neoplasms like chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), multiple myeloma (MM), follicular lymphoma (FL) and mantle cell lymphoma (MCL) without fulfilling diagnostic criteria for overt malignancy. These include monoclonal B-lymphocytosis (MBL), in situ follicular neoplasia (ISFN), in situ mantle cell neoplasia (ISMCN), and monoclonal gammopathy of undermined significance (MGUS). Duodenal-type FL shares most phenotypic and genetic features with ISFN, but interestingly also has some characteristics of extranodal marginal-zone (MALT) lymphoma. New guidelines have been created for the diagnosis and management of these early lesions.

A second group of “indolent” and indeterminate clonal lymphoid proliferations do not have a counterpart among the currently recognized subtypes of lymphoma, but appear to have a limited potential for progression. Some of these are of T-cell derivation and include indolent T-cell lymphoproliferative disorder (LPD) of the gastrointestinal tract and primary cutaneous acral CD8-positive T-cell lymphoma as provisional entities. Pediatric-type follicular lymphoma falls into a similar category. This clonal B-cell proliferation appears to have very limited capacity for aggressive clinical behavior, with little risk for progression following simple surgical excision of the affected node. Recognition of these indeterminate clonal proliferations is important to avoid overtreatment of these patients.