Reed sternberg cells are present in hodgkins lymphoma

Publisher Summary

Hodgkin lymphoma (HL) is characterized by progressive enlargement of the lymph nodes. It is considered unicentric in origin and has a predictable pattern of spread by extension to contiguous nodes. Etiology of HL is unknown and it comprises 8.8% of all childhood cancers under the age of 20. Overall annual incidence rate in the United States is 12.1 per million for children under 20 years. Several factors have been associated with an increased risk of developing HL. These include family history of HL, EBV infections and socioeconomic status. Familial HL represents 4.5% of all HL cases. For adolescents and young adults there is a 99-fold increased risk among monozygotic twins and a 7-fold increased risk among siblings. EBV incorporated into the tumor genome has been most commonly reported with the mixed cellularity histologic subtype. In turn, this subtype is most common in children from underdeveloped countries, in males under age 10 years and in those with other immunodeficiencies. There is an association between HL and socioeconomic status. In children less than 10 years of age and in underdeveloped nations, HL is associated with lower socioeconomic status and in households with more children. However, in young adult patients and in developed nations, HL incidence increases with higher socioeconomic status and with smaller households with fewer children.

Overview of Hodgkin lymphoma

Hodgkin lymphoma represents approximately 30% of all lymphomas. Over the years, the absolute incidence remains unchanged. In general, Hodgkin lymphoma arises in lymph nodes, most often the cervical region, spreading to contiguous lymph nodes. Young adults are most often affected. There is a childhood form of Hodgkin lymphoma (0–14 years), which is seen more often in developing countries. There is a male preponderance of Hodgkin lymphoma (male to female ratio of 1.5:1), but this male preponderance is however not seen in nodular sclerosis subtype.

Neoplastic tissues usually contain a small number of tumor cells. Hodgkin lymphoma is characterized by a small number of scattered tumor cells residing in an abundant heterogeneous admixture of nonneoplastic inflammatory and accessory cells. The tumor cells produce cytokines which are responsible for the presence of the background cells, lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils.

Epidemiology and Etiology

Nodular Lymphocyte Predominance Hodgkin's Lymphoma

NLPHD makes up 5% of Hodgkin's lymphoma cases. The malignant cells of NLPHD are the lymphocytic-predominant (LP) cells, which are also known as popcorn cells due to their characteristic appearance. The pathogenesis of LP cells is probably distinct from that of HRS cells but probably shares constitutive NFκB activity.38 Unlike classic Hodgkin's lymphoma, the neoplastic cells of NLPHD typically lack the expression of CD15 and CD30 markers but are consistently positive for CD20 and CD45.38 A nodular pattern is seen, usually completely or partially replacing the lymph node. The nodules tend to be large and closely packed, and L&H cells are typically seen within or around the nodules. There are usually large numbers of CD57-positive small lymphocytes in the nodules, often with ringing around the L&H cells. In about 3% to 5% of cases, transformation to diffuse large B-cell lymphoma may occur.

Epidemiology and Risk Factors1

Hodgkin's disease accounts for less than 1% of cancers diagnosed in the United States each year.2,3 There is a slight male predominance. The median age at the time of diagnosis is 26 to 30 years. The disease is uncommon in children younger than 10 years and the age-adjusted incidence is bimodal.4 Both peaks, at ages 20 to 24 and 75 to 84, show an annual incidence of approximately 5.5 cases per 100,000. A recent decline in the height of the incidence peak for older adults may be attributed to improved diagnostic accuracy and the ability to differentiate mixed cellularity or lymphocyte depletion Hodgkin's disease from diffuse large-cell or anaplastic large-cell lymphomas.

There are no well-defined risk factors related to the development of Hodgkin's disease.5 Older reports associating an increased risk with tonsillectomy have been refuted. There are no definite associations between Hodgkin's disease and human leukocyte antigen (HLA) loci. The slight increased risk associated with small sibship size and higher degree of education has not been explained, but contributes to the hypothesis of an infectious cause. A relationship between Hodgkin's disease and prior infection with Epstein-Barr virus (EBV) has been proposed. Components of the EBV genome have been detected in the cellular deoxyribonucleic acid (DNA) of Reed-Sternberg cells,6 and elevated levels of immunoglobulin G and immunoglobulin A against the EBV capsid antigen and elevated levels of antibody against the EBV nuclear antigen and early antigen D have been detected in the serum of patients who later develop Hodgkin's disease.7 The risk for developing Hodgkin's disease appears to be higher in the presence of a prior history of infectious mononucleosis.8 Evidence of prior EBV infection is most common in mixed cellularity Hodgkin's disease and in pediatric Hodgkin's disease in underdeveloped countries.9

Publisher Summary

Hodgkin lymphoma (HL) is a clonal B-cell neoplasm as demonstrated by the detection of clonal immunoglobulin (Ig) V-gene rearrangements in isolated tumor cells using microdissection and single-cell polymerase chain reaction (PCR) techniques. Based on its clinical behaviors, as well as morphologic, immunophenotypic, and genotypic profiles, HL is divided into two entities of nodular-lymphocyte-predominant HL (NLPHL) and classical HL (CHL). Nodular-lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct but rare subtype of HL. NLPHL is a monoclonal B-cell lymphoma characterized by nodular pattern, presence of sparse large pleomorphic lymphocytic and histiocytic (L&H) cells admixed with abundant B-lymphocytes that reside in an expanded meshwork of follicular dendritic cells. Normal nodal architecture is partially to completely effaced by the neoplastic infiltrate, which, by definition, demonstrates at least partially nodular growth pattern. L & H cells in NLPHL represent transformed germinal center B-cells. There are only few reported cytogenetic and molecular mutations in NLPHL, including common rearrangements of the BCL-6 gene [34] and that of SHM of SOCS1 loci. The differential diagnosis of NLPHL includes T/HRBCL and lymphocyte-rich classical Hodgkin lymphoma.

Abstract

Hodgkin lymphoma (HL) is a highly treatable cancer, with current treatments curing 80-90% of newly diagnosed patients. The presence of Hodgkin Reed-Sternberg (HRS) cells characterizes classical Hodgkin lymphoma (cHL). Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct clinicopathological entity from cHL. Treatment options for patients with primary cHL is determined by stage, bulk and contemporaneous factors including age, pregnancy and HIV. Positron emission tomography/computed tomography (PET/CT) is recommended in diagnosis, staging and remission assessment. Standard treatments for cHL include chemotherapy and in some cases radiotherapy (RT). The use of early interim PET/CT scans to escalate or de-escalate treatment has been the subject of investigation with the goal of maximizing efficacy and minimizing toxicity. Unlike cHL, there is no consensus on the definitive treatment of NLPHL. Relapsed cHL patients are usually treated with autologous stem cell transplant (ASCT), although heterogeneity exists with respect to pre-transplant salvage therapy, ASCT preparative regimen and the use of RT. Current therapies cure approximately 50% of patients with relapsed and/or refractory cHL, novel agents including brentuximab vendotin and PD-1 inhibitors are being trialed in the unresponsive patient population. With 10% to 15% of newly diagnosed HL patients aged less than 20 years and nearly one third in the 20- to 34-year age range, minimizing serious late effects is critical when measuring the success of HL treatments. Similarly, selection of patients who would benefit from more intensive or novel first-line approaches, as well as those who would benefit from less therapy is an ongoing challenge.

Pathophysiology

Hodgkin's disease is now considered a lymphoma. The cells involved appear to belong to the T, B, macrophage, and dendritic cell lineage.There appears to be heterogeneity within the cells of this disease, with the cells in different subgroups belonging to different lineages.The histology of HD is unusual because an infiltrate of normal lymphocytes, plasma cells, and eosinophils accompanies the malignant Reed–Sternberg cells Hudson and Donaldson (1997). The Reed–Sternberg cells have a large size and unusual appearance that distinguishes them from adjacent cells in the background Mauch and Armitage (2000). Recent investigations have documented the expression of surface markers on Reed–Sternberg cells that are consistent with a T or B lymphocyte lineage. Immunophenotyping has also indicated expression of several activation antigens, including the IL-2 receptor, CD30, the transferrin receptor, and HLA DR epitopes. CD 30 levels have been shown to correlate with disease activity. Production of cytokines is thought to be responsible for many of the nonspecific clinical features of this condition. Although cytogenetic abnormalities are common in Reed–Sternberg cells, no consistent pattern has been described. The four-stage clinical and pathologic Ann Arbor system has been widely used for more than 25 years. The stages, which fall into two groups with respect to survival, encompass a favorable group that includes stages I, II, and IIIA, and a less favorable group that consists of IIIB and I V. Overall survival rates are approximately 80% for the first group and 60% for the second. The Cotswolds classification, proposed in 1989, is a modification using information from staging and treatment over the 1970's and 1980's Lister et al (1989).

General Overview and Incidence

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Definition of Hodgkin lymphoma (HL): lymphoid neoplasm affecting lymph nodes; paucity of neoplastic cells with rich inflammatory background

Classic Hodgkin lymphoma (cHL) 90% to 95% of cases

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) 5% to 10% of cases1,2

Hodgkin lymphomas

Clinical Relevance

Hodgkin lymphoma

B-cell lineage established in nearly all cases.

Reed–Sternberg cell, the hallmark of the disease, represents a “crippled” germinal-center B cell.

Nodular lymphocyte-predominant Hodgkin lymphoma considered a related but distinct entity.

Eighty percent of patients are curable with current therapy.

Stage of disease guides the choice of therapy; even patients with advanced-stage disease may be cured.

Late complications from treatment include acute leukemia (alkylating agents with extended-field radiation therapy), second solid tumors (radiation therapy), and premature atherosclerotic coronary artery disease (radiation therapy).

Cause of death in the first 5–10 years is mainly Hodgkin lymphoma; after 10 years, mainly secondary malignant tumors.

Hodgkin lymphoma (HL) and non-Hodgkin lymphoma have long been regarded as distinct disease entities based on their differences in pathology, phenotype, clinical features, and response to therapy. It is now accepted the malignant cell of HL is an altered B cell.65 Therefore, it is not surprising that both biological and clinical overlaps should occur between these two lymphoma groups, as also shown by GEP in PMBCL and classic Hodgkin cell lines.24,25 Although we have become aware of this closer relationship from the histogenetic point of view (hence the name Hodgkin lymphoma), these disorders are still treated with different modalities.

The diagnosis of classic HL (CHL) depends on the identification of Hodgkin/Reed–Sternberg (HRS) cells in an appropriate inflammatory background composed of small T lymphocytes, plasma cells, histiocytes, and granulocytes (often eosinophils). All cases of CHL share certain immunophenotypic and genotypic features. The phenotype is CD30+, CD15+/-, CD45-, and EMA-. Expression of B-cell-associated antigens is seen in up to 75% of cases. However, when present, CD20 staining is weaker than that seen in normal B cells with variable in intensity among individual tumor cells. CD79a is usually negative. Ig and T-cell receptor genes are usually germline, due to the paucity of tumor cells in the inflammatory background, but using microdissection and polymerase chain reaction (PCR) amplification for clonal rerrangement of the IG genes can generally be shown. In addition, the presence of somatic mutations indicates transit through the germinal center.65

Sufficient evidence has emerged in recent years to warrant the recognition of nodular lymphocyte-predominant HL as a distinct entity. Although it resembles other types of HL in having a minority of putative neoplastic cells on a background of benign inflammatory cells, it differs morphologically, immunophenotypically, and clinically from classic HL. The preferred term of Hodgkin lymphoma over Hodgkin disease reflects current knowledge concerning the nature of the neoplastic cell as a lymphocyte.