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Hodgkin Lymphoma
Definition
Hodgkin lymphoma, one of the B-cell lymphomas, consists of two major types: classic Hodgkin lymphoma, with a characteristic neoplastic cell, the Hodgkin-Reed-Sternberg cell; and the much less common (~10% of cases) nodular lymphocyte-predominant Hodgkin lymphoma, with a characteristic predominance of small lymphocytes. Both types have a distinct natural history, and most important, an excellent response to treatment, with the large majority of patients being cured. Highly effective multiagent chemotherapy is the cornerstone of treatment. Carefully selected patients may require the addition of radiation or, if the lymphoma recurs after primary treatment, high-dose chemoradiation therapy and autologous hematopoietic cell transplantation. The major challenge to clinicians managing this neoplasm is to cure the disease while minimizing long-term toxicity.
Epidemiology
The incidence of Hodgkin lymphoma varies substantially around the world. The highest rates occur in the United States, Canada, Switzerland, and northern Europe. Intermediate rates are seen in southern and eastern Europe and low rates in eastern Asia. No clear explanation for this variation has been found. Postulated reasons include differences in the age at onset or genotype of an associated Epstein-Barr virus infection; crowding during childhood as a result of lower socioeconomic status, predisposing to passage of an as-yet-undiscovered infectious vector; and intrinsic genetic differences in susceptibility.
Approximately 30,000 new cases are diagnosed annually in North America and Europe. The age-adjusted incidence of Hodgkin lymphoma declined modestly over the 20 years before 1990 but has leveled off since then at approximately 2.7 per 100,000. Age-adjusted annual mortality is 0.5 per 100,000. Hodgkin lymphoma occurs slightly more often in men and is seen more frequently in Whites than Blacks and much less frequently in Asian populations. Much of the difference in incidence between Whites and Blacks in North America can be attributed to the higher incidence seen in higher socioeconomic classes. The cumulative lifetime risk for Hodgkin lymphoma is approximately 1 in 250 to 1 in 300 in North America.
The incidence of Hodgkin lymphoma is bimodal in age distribution, rising from very low in childhood to an early peak in young adulthood (25 to 30 years) and a later peak in late adulthood (>50 years). In the Western world, only about 5% of cases occur in persons younger than 15 years of age and 5% in individuals older than 70 years of age. In contrast, the age distribution in the Indian subcontinent is strongly shifted into childhood.
Pathobiology
The cause of Hodgkin lymphoma remains unclear. It is not associated with exposure to radiation, chemicals, biocidal agents, working in health care–related professions, or previous tonsillectomy. The leading suspect remains Epstein-Barr virus, based on much suggestive evidence but no definitive proof.
Epstein-Barr Virus
Epstein-Barr virus is a large B-lymphocyte tropic herpesvirus ( Chapter 348 ). Approximately 90% of the general population acquires infection by early adulthood. In the developing world, this infection usually occurs in childhood, but in developed countries, infection is often delayed into the teens, when it is associated with the syndrome of infectious mononucleosis in up to 30% of new cases. A history of infectious mononucleosis increases the likelihood for subsequent Hodgkin lymphoma three-fold. Antibodies to the viral capsid antigen reach higher levels in patients with Hodgkin lymphoma than in controls, and these higher levels appear several years before the neoplasm. In situ hybridization studies have demonstrated that the Hodgkin-Reed-Sternberg cells in approximately 50% of cases of Hodgkin lymphoma contain Epstein-Barr virus-encoded small RNA. In these cases, virtually all the Hodgkin-Reed-Sternberg cells are positive for the virus; the Epstein-Barr virus genome is amplified 50-fold or more in Hodgkin-Reed-Sternberg cells; and is monoclonal in an individual patient’s Hodgkin-Reed-Sternberg cells. In some populations, virtually all cases of Hodgkin lymphoma occur in Epstein-Barr virus–positive individuals (<15 or >65 years of age; non-European ancestry; low socioeconomic status), but up to 50% of patients in developed countries do not have Epstein-Barr virus in their Hodgkin-Reed-Sternberg cells. Thus, although Epstein-Barr virus may play an important role in the development of Hodgkin lymphoma, that role is neither straightforward nor universal.
Genetic Factors
Circumstantial evidence for a genetic contribution to the etiology of Hodgkin lymphoma comes from studies showing that Hodgkin lymphoma is almost 100-fold more likely to develop in the monozygotic twin of an affected individual than in a dizygotic twin. First-degree relatives of individuals with the disease have up to a five-fold increased risk for development of the lymphoma. Genome-wide association studies have identified multiple genetic risk variants, which have been detected primarily in immune-related genes. For example, variants in GATA3 , IL13 , and genes controlling the expression of HLA class II molecules have been associated with the Epstein-Barr virus–negative nodular sclerosing subtype of classic Hodgkin lymphoma, which is seen predominantly in adolescents and young adults.
Polymerase chain reaction–based genotypic analysis has demonstrated the clonal derivation of Hodgkin-Reed-Sternberg cells, including identical p53 mutations from multiple Hodgkin-Reed-Sternberg cells extracted from a single biopsy specimen, thereby unequivocally establishing clonality. The presence of clonal immunoglobulin gene rearrangements from multiple cells in the same biopsy specimen also confirms a B-cell origin. Only a few rare cases with a T-cell genotype have been reported. Finally, identification of cells with identical immunoglobulin gene rearrangements, both at diagnosis and at relapse, verify that the B-cell clonality of the disease is preserved over time.
Aneuploidy and hyperploidy consistent with the multinucleated nature of Hodgkin-Reed-Sternberg cells are frequent, but no consistent chromosomal translocations have been detected. Several susceptibility loci for Hodgkin lymphoma have been localized to active chromatin with an overrepresentation of determinants of B-cell development and immune response.
Despite their B-cell origin, the neoplastic cells of Hodgkin lymphoma are incapable of making intact antibodies, perhaps because they lack the ability to make the transcription factors necessary to activate the immunoglobulin promoter. B cells that are incapable of manufacturing antibody should undergo apoptosis and immune destruction, but the Hodgkin-Reed-Sternberg cells avoid cell death by activating NFκB and thereby impeding apoptosis and inducing immune blockade by overexpressing checkpoint inhibitors such as programmed cell death ligands 1 and 2.
Clinical Manifestations
Hodgkin lymphoma is usually manifested as lymphadenopathy ( Chapter 154 ), typically in the cervical, axillary, or mediastinal areas for the predominant classic Hodgkin lymphoma, and only about 10% of patients present with nodal disease below the diaphragm. Although peripherally located nodes seldom reach large size, very large mediastinal masses or, less often, retroperitoneal masses can develop with only modest symptoms. Lymph node involvement in Hodgkin lymphoma is usually painless, but an occasional patient notes discomfort in involved nodal sites immediately after drinking alcohol.
Approximately 25% of patients with Hodgkin lymphoma have constitutional symptoms. The classic B symptoms—significant weight loss (>10% of baseline), night sweats, and persistent fever—usually signal widespread or locally extensive disease and imply a need for systemic treatment. Generalized pruritus, occasionally severe, can antedate the diagnosis of Hodgkin lymphoma by up to several years. Some patients have symptoms suggestive of a growing mass lesion, such as cough or stridor as a result of tracheobronchial compression from mediastinal disease or bone pain secondary to metastatic involvement. Because Hodgkin lymphoma can rarely involve the bone marrow extensively, an occasional patient presents with symptomatic anemia or incidentally noted pancytopenia. Paraneoplastic neurologic or endocrine syndromes ( Chapter 164 ) have been reported with Hodgkin lymphoma but are rare.
Diagnosis
The diagnosis of classic Hodgkin lymphoma is based on recognition of Hodgkin-Reed-Sternberg cells ( Fig. 172-1 ) or Hodgkin cells (or both) in an appropriate cellular background in tissue sections from a lymph node or extralymphatic organ, such as bone marrow, lung, or bone. Fine-needle aspiration biopsy is not adequate for the diagnosis of Hodgkin lymphoma. Open biopsy and standard histochemical staining are required to establish the diagnosis unequivocally and to determine the histologic subtype.
Hodgkin lymphoma can typically be classified into well-described subtypes ( Table 172-1 ), including a relatively new category of lymphocyte-rich classic Hodgkin lymphoma, which must be distinguished from nodular lymphocyte-predominant Hodgkin lymphoma. The most common subtype is nodular sclerosing, which has characteristic coarse bands of sclerosis surrounding nodules composed of typical Hodgkin-Reed-Sternberg cells in the usual background mixture of reactive and inflammatory cells.
TABLE 172-1
WORLD HEALTH ORGANIZATION CLASSIFICATION OF HODGKIN LYMPHOMA SUBTYPES
| SUBTYPE NAME | FREQUENCY (%) ∗ |
|---|---|
| Classic Hodgkin lymphoma Nodular sclerosing Lymphocyte rich Mixed cellularity Lymphocyte depleted |
60 3 9 1 |
| Nodular lymphocyte-predominant Hodgkin lymphoma | 8 |
| Hodgkin lymphoma, not otherwise classifiable | 19 |
∗ Frequency based on all new cases (N = 2488) seen in British Columbia from January 1998, when the category of lymphocyte-rich classic Hodgkin lymphoma became well established, to December 2020.
In classic Hodgkin lymphoma, scattered large Hodgkin-Reed-Sternberg cells either are multinucleated or have large polyploid nuclei. Variations include mononuclear cells that are similar to the usual polylobated or multinuclear cells but have only one large nucleus with a prominent nucleolus, as well as lacunar cells, which are Hodgkin-Reed-Sternberg variants with abundant cytoplasm that has retracted as an artifact of formalin fixation. The infrequent Hodgkin-Reed-Sternberg cells are usually present in a background mixture of polyclonal lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and histiocytes. A high number of associated macrophages has been demonstrated to be a strong predictor of treatment resistance. Occasionally, granulomas form with a prominent histiocytic component. In contrast, in nodular lymphocyte-predominant Hodgkin lymphoma the cellular pattern predominantly consists of small lymphocytes and scattered histiocytes, epithelioid histiocytes, and characteristic large neoplastic lymphocytic cells ringed by non-neoplastic T lymphocytes.
The immunophenotype of the neoplastic cells in Hodgkin lymphoma can help identify the specific subtype. Typically, the Hodgkin-Reed-Sternberg cells stain positively for CD30 (90 to 100% of cases), CD15 (75 to 85% of cases), and B-cell-specific activating protein (BSAP), which is the product of the PAX5 gene (>90% of cases). CD20, a generally reliable marker of B-cell lineage, is positive in about 40% of cases of classic Hodgkin lymphoma, but usually only in a minority of cells, and the staining can be weak. In contrast, nodular lymphocyte-predominant Hodgkin lymphoma almost always stains strongly positive for CD20 and for the specialized B-cell markers CD79a and CD45 but is negative for CD30 and CD15. Anaplastic large cell lymphoma ( Chapter 171 ) is positive for CD30 but reliably negative for CD15, CD20, and CD79a.
Differential Diagnosis
Depending on the site of occurrence and associated symptoms, the differential diagnosis of Hodgkin lymphoma includes non-Hodgkin lymphoma ( Chapter 171 ), primary mediastinal B cell lymphoma, mediastinal gray zone lymphoma, germ cell tumors ( Chapters 184 and 185 ), thymoma ( Chapter 390 ), sarcoidosis ( Chapter 83 ), histiocytosis ( Chapter 155 ), and tuberculosis ( Chapter 299 ). However, the specific diagnosis is readily determined by obtaining an adequate biopsy specimen for review by an experienced hematopathologist. T-cell/histiocyte–rich B-cell lymphoma ( Chapter 171 ) is distinguished from nodular lymphocyte-predominant Hodgkin lymphoma, which it otherwise closely resembles, by being CD30 negative but positive for IgD mantle cells and follicular dendritic cell networks. Proceeding to a biopsy early in the assessment of patients with lymphadenopathy ( Chapter 154 ), especially of the mediastinum, often saves time and avoids delay in diagnosis. With appropriate biopsy procedures to investigate enlarged central thoracic or intra-abdominal lymph nodes, the diagnosis of Hodgkin lymphoma seldom presents difficulty. The immunophenotype helps distinguish Hodgkin lymphoma from other diseases. The combination of appropriate immunohistopathologic evaluation by an expert hematopathologist and clinical assessment has virtually eliminated difficulties with the differential diagnosis. Problems mostly arise when inadequate or improperly processed material is all that is available for diagnosis.
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