Diffuse large B-cell lymphoma


Diffuse large B-cell lymphoma is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms.
The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma or, in rare cases termed Richter's transformation, chronic lymphocytic leukemia. An underlying immunodeficiency is a significant risk factor for development of the disease. Infections with the Epstein–Barr virus, Kaposi's sarcoma-associated herpesvirus, human immunodeficiency virus, and the Helicobacter pylori bacterium are also associated with the development of some subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained stepwise accumulation of gene mutations and changes in gene expression that occur in and progressively promote the malignant behavior of certain B-cell types.
Diagnosis of DLBCL is made by removing a portion of the tumor through a biopsy, and then examining this tissue using a microscope. Usually, a hematopathologist makes this diagnosis. Numerous subtypes of DLBCL have been identified that differ in clinical presentation, biopsy findings, aggressiveness, prognosis, and recommended treatments. However, the usual treatment for most subtypes of DLBCL is chemotherapy combined with monoclonal antibody therapy, usually rituximab. Through these treatments, more than half of all patients with DLBCL can be cured; the overall cure rate for older adults is less than this, but their five-year survival rate has been around 58%.

Subtypes of diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes, many of which are difficult to separate from one another based on well-defined and widely accepted criteria. The World Health Organization, 2008, classification system defined more than a dozen subtypes, each of which was identified based on the location of the tumor, the presence of other cell types such as T cells in the tumor, and whether the patient had certain other illnesses related to DLBCL. Based on further research, the World Health Organization, 2016, reclassified DLBCL into its most common subtype, diffuse large B-cell lymphoma, not otherwise specified. DLBCL, NOS represents 80–85% of all DLBCL. The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology,, immunophenotype,, clinical findings, and/or association with certain pathogenic viruses. Some cases of DLBCL, NOS, while not included in the 2016 World Health Organization's classification, are clearly associated with, and caused by, chronic infection by the bacterium, Helicobacter pylori.

Diffuse large B-cell lymphoma, not otherwise specified

DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype, and/or pathogen-associated criteria of other DLBCL subtypes are termed Diffuse large B-cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases, is a diagnosis of exclusion. In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment.

Presenting signs and symptoms

About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases, the most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach, or, less commonly, in other sites such as the testicles, breasts, uterus, ovaries, kidneys, adrenal glands, thyroid gland, or bone. The presenting signs and symptoms in these cases reflect the presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction. Individuals with nodal or extranodal disease also present with: systemic B symptoms such as weight loss, night sweats, fevers, and/or fatigue in ~33% of cases; unexplained elevations in their blood levels of lactic acid dehydrogenase and beta-2 microglobulin in many cases; malignant cells infiltrating their bone marrow in 10–20% of cases; and/or localized Stage I or II disease in up to 50% of cases and disseminated Stage III or IV disease in the remaining cases. Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis. Uncommonly, DLBCL may arise as a transformation of marginal zone lymphoma in individuals who have been diagnosed with this indolent cancer 4–5 years previously.
Prognostic indicators based on clinical presentation
The International Prognostic Index and more recently, the Index's age-adjusted variant use age >60 years, elevated serum lactate dehydrogenase levels, low performance status, and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS. In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the central nervous system while disease initially involving the kidneys, adrenal glands, ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses.

Pathophysiology

Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of gene changes such as mutations, altered expressions, amplifications, and translocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate the maturation, proliferation, survival, spread, evasion of the immune system, and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this disease's development and/or progression.
As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, PI3K/AKT/mTOR, JAK-STAT0, MAPK/ERK, B-cell receptor, toll-like receptor, and NF-κB signaling pathways and thereby uncontrolled pro-malignant behaviors.

Diagnosis

Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins ], CD30, and in ~20–25% of cases PD-L1 or PD-L2. These cells arrange in a diffuse pattern, efface the tissues' architecture, and resemble Centroblast cells, Immunoblast cells, or anaplastic cells. Rarely, these neoplastic cells are characterized as having signet ring or spindle shaped nuclei, prominent cytoplasmic granules, multiple microvillus projections, or, when viewed by electron microscopy, tight junctions with other cells. These neoplastic tissue infiltrates are often accompanied by small non-malignant T-cell lymphocytes and histiocytes that have a reactive morphology.