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Classifying Non-Hodgkin's Lymphomas

CLASSIFYING non-Hodgkin's lymphomas makes sense for several reasons:

  1. The categories appear to correspond to biological entities that behave distinctly. Thus the pathologist gives the clinician important guidance for treating the lymphoma and assessing its prognosis.
  2. A knowledge of the features of each category helps the pathologist to recognize a lymphoma. Since lymphomas can assume a bewildering variety of appearances, it's helpful to know what the coherent patterns are.
  3. By observing how the lymphomas group themselves, one can discover important biological principles that underlie their appearance and behavior.
H&E stained tissue
       Pathologists have traditionally depended heavily on the morphologic appearances of lymphomas to categorize them. Thirty years ago, morphology was the only tool available. Suspicious lymphoid tissue was (and still is) fixed in formalin or a mercury-containing fixative, embedded in paraffin, sliced very thinly (5 microns or less), placed on a glass slide, and stained with the all-purpose tissue stain, hematoxylin and eosin. The earliest attempts to categorize lymphomas relied solely on this method.
       Starting in the 1970's additional techniques have been developed to study the nature of both benign and malignant lymphoid cells.
  • ImmunophenotypingMembrane antigens: Different types of lymphoid cells express different molecules on their surface cell membrane. Clever scientists enhance their careers by making antibodies that will adhere specifically to these molecules, in this context called antigens. If the antibodies are altered in special ways so their presence can be detected (for example, they may be rendered fluorescent), this technique can be used to assess what kinds of antigens decorate the cell membrane. These antibodies are eventually given so-called "cluster designation" or "CD" numbers. Immunophenotyping has become important in evaluating 1) the malignancy of a lymphoid proliferation and 2) the lymphoma category to which it belongs. Three methods of immunophenotyping that yield the similar information are:
      1) immunohistochemistry
      2) immunofluorescence
      3) flow cytometry.
  • Cytogenetics: Like all cells, malignant lymphoid cells can be made to proliferate in vitro, and their metaphase chromosomes can be examined for characteristic translocations (call "karyotyping"). It is encouraging to the morphologically oriented hematopathologist that his or her careful microscopic observations very frequently correspond to genetic distinctions uncovered by "scientific" techniques. As Oscar Wilde said, only very superficial people are uninterested in surface appearances.
  • FISH: Besides the technique of karyotyping, which displays whole chromosomes from metaphase spreads of dividing cells, fluorescent in-situ hybridization (FISH) can be used to look for specific chromosomal abnormalities in the DNA of interphase cells. The advantages of this technique are its ability to utilize non-dividing cells, to examine 200 or so cells at a time rather than the 20 of conventional karyotyping, and to find subtle defects invisible to the coarser technique of karyotyping. Its major drawback is that it uses probes for specific anomalies and so can find only the defect for which the probes were designed.
  • Molecular analysis: The major contemporary techniques of molecular analysis include:
    • Polymerase chain reaction (PCR) is used to markedly expand the copy number of a specific DNA sequence or segment. The amplified DNA can be further analyzed to determine if a proliferation of lymphoid cells is clonal or to interrogate the status of genes that may be mutated in malignancy. It has the major advantage of working with minute quanitities of DNA. The same methodology can apply to RNA using reverse-transcript PCR, in which the RNA is first converted to DNA.
    • Next generation sequencing (NGS), also known as high-throughput sequencing, refers to a number of technologies that can sequence DNA and RNA much more quickly and cheaply than was previously possible. NGS is performed to discover mutations in genes that may play a role in causing various diseases. The entire genome may be sequenced or, more frequently, only exons or a subset of them.

Lymphoma Classification
Most classifications are based on the assumption that lymphoma cells are the malignant counterparts of benign lymph node cells. The various lymphomas are often named after the benign cell from which they are assumed to derive.
      The current accepted and authoritative classification of lymphomas is part of the 2016 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. The goal of the WHO classification of lymphomas is to identify as many different lymphoid diseases as feasible using morphology, immunophenotyping, genetics, and molecular means. These lymphomas are distinct biological entities. The classification attempts to be exhaustive and verges on the daunting with its long list of diseases. It is a departure from earlier classifications which used, for example, cell size and shape and overall architecture as criteria, an approach that often lumped different diseases in the same category.
       The WHO classification appeared first in 2008. In 2016/2017 a revision was completed. It is the classification used by virtually all pathologists who diagnose lymphomas. It is presented below.

Mature B-cell neoplasms

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma
  • Monoclonal B-cell lymphocytosis*
  • B-cell prolymphocytic leukemia
  • Splenic marginal zone lymphoma
  • Hairy cell leukemia
  • Splenic B-cell lymphoma/leukemia, unclassifiable
  •    Splenic diffuse red pulp small B-cell lymphoma
  •    Hairy cell leukemia-variant
  • Lymphoplasmacytic lymphoma
  • Waldenstrom macroglobulinemia
  • Monoclonal gammopathy of undetermined significance (MGUS), IgM*
  • Mu heavy-chain disease
  • Gamma heavy-chain disease
  • Alpha heavy-chain disease
  • Monoclonal gammopathy of undetermined significance (MGUS), IgG/A*
  • Plasma cell myeloma
  • Solitary plasmacytoma of bone
  • Extraosseous plasmacytoma
  • Monoclonal immunoglobulin deposition diseases*
  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
  • Nodal marginal zone lymphoma
  •    Pediatric nodal marginal zone lymphoma
  • Follicular lymphoma
  •    In situ follicular neoplasia*
  •    Duodenal-type follicular lymphoma*
  • Pediatric-type follicular lymphoma*
  • Large B-cell lymphoma with IRF4 rearrangement*
  • Primary cutaneous follicle center lymphoma
  • Mantle cell lymphoma
  • In situ mantle cell neoplasia*
  • Diffuse large B-cell lymphoma (DLBCL), NOS
  •    Germinal center B-cell type*
  •    Activated B-cell type*
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Primary cutaneous DLBCL, leg type
  • EBV+ DLBCL, NOS*
  • EBV+ mucocutaneous ulcer*
  • DLBCL associated with chronic inflammation
  • Lymphomatoid granulomatosis
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • ALK+ large B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • HHV8+ DLBCL, NOS*
  • urkitt lymphoma
  • Burkitt-like lymphoma with 11q aberration*
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements*
  • High-grade B-cell lymphoma, NOS*
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
Mature T and NK neoplasms
  • T-cell prolymphocytic leukemia
  • T-cell large granular lymphocytic leukemia
  • Chronic lymphoproliferative disorder of NK cells
  • Aggressive NK-cell leukemia
  • Systemic EBV+ T-cell lymphoma of childhood*
  • Hydroa vacciniforme-like lymphoproliferative disorder*
  • Adult T-cell leukemia/lymphoma
  • Extranodal NK-/T-cell lymphoma, nasal type
  • Enteropathy-associated T-cell lymphoma
  • Monomorphic epitheliotropic intestinal T-cell lymphoma*
  • Indolent T-cell lymphoproliferative disorder of the GI tract*
  • Hepatosplenic T-cell lymphoma
  • Mycosis fungoides
  • Sezary syndrome
  • Primary cutaneous CD30+ T-cell lymphoproliferative disorders
  • Lymphomatoid papulosis
  • Primary cutaneous anaplastic large cell lymphoma
  • Primary cutaneous gamma-delta T-cell lymphoma
  • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
  • Primary cutaneous acral CD8+ T-cell lymphoma*
  • Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder*
  • Peripheral T-cell lymphoma, NOS
  • Angioimmunoblastic T-cell lymphoma
  • Follicular T-cell lymphoma*
  • Nodal peripheral T-cell lymphoma with TFH phenotype*
  • Anaplastic large-cell lymphoma, ALK+
  • Anaplastic large-cell lymphoma, ALK-*
  • Breast implant-associated anaplastic large-cell lymphoma*
Hodgkin lymphoma
  • Nodular lymphocyte predominant Hodgkin lymphoma
  • Classical Hodgkin lymphoma
    •    Nodular sclerosis classical Hodgkin lymphoma
    •    Lymphocyte-rich classical Hodgkin lymphoma
    •    Mixed cellularity classical Hodgkin lymphoma
    •    Lymphocyte-depleted classical Hodgkin lymphoma
Posttransplant lymphoproliferative disorders (PTLD)
  • Plasmacytic hyperplasia PTLD
  • Infectious mononucleosis PTLD
  • Florid follicular hyperplasia PTLD*
  • Polymorphic PTLD
  • Monomorphic PTLD (B- and T-/NK-cell types)
  • Classical Hodgkin lymphoma PTLD
Histiocytic and dendritic cell neoplasms
  • Histiocytic sarcoma
  • Langerhans cell histiocytosis
  • Langerhans cell sarcoma
  • Indeterminate dendritic cell tumor
  • Interdigitating dendritic cell sarcoma
  • Follicular dendritic cell sarcoma
  • Fibroblastic reticular cell tumor
  • Disseminated juvenile xanthogranuloma
  • Erdheim-Chester disease*

Provisional entities are listed in italics.
*Changes from the 2008 classification.

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