Background
Hodgkin lymphoma is a potentially curable lymphoma with distinct histology, biologic behavior, and clinical characteristics. The disease is defined in terms of its microscopic appearance (histology) (see the image below) and the expression of cell surface markers (immunophenotype). [1]
Micrograph of Hodgkin lymphoma in a fine-needle aspiration lymph node specimen (field stain). Eosinophils, Reed-Sternberg cells, plasma cells, and histocytes can be seen.
The World Health Organization categorizes Hodgkin lymphoma as classic or nodular lymphocyte predominant and divides classic Hodgkin lymphoma into four types, as follows [1, 2] :
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Nodular sclerosis
-
Mixed cellularity
-
Lymphocyte depleted
-
Lymphocyte rich
Guidelines from the National Comprehensive Cancer Network (NCCN), [3] the European Society for Medical Oncology (ESMO), [4] and the International Harmonization Project [5] provide consensus opinions from leading experts on evidence-based approaches to the diagnosis and treatment of Hodgkin lymphoma.
Hodgkin lymphoma was originally known as Hodgkin's disease. The eponym honors the British physician Thomas Hodgkin, who published the first description of the disease in 1832. [6]
Etiology
The etiology of Hodgkin lymphoma is unknown. Infectious agents, particularly Epstein-Barr virus (EBV), may be involved in the pathogenesis. [7, 8] Depending on the study, data show that up to 30% of cases of classic Hodgkin lymphoma may be positive for EBV proteins. [9] In addition, a case control study supports an increased risk of classic Hodgkin lymphoma after EBV infection, with a risk of approximately 1 in 1000 cases. [10]
The incidence of EBV positivity varies with subtype. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) rarely expresses EBV proteins, [11] whereas in classic Hodgkin lymphoma, EBV positivity is most common in the mixed-cellularity variant. [12] However, the exact mechanism by which EBV can lead to Hodgkin lymphoma is not known.
HIV-positive patients also have a higher incidence of Hodgkin lymphoma compared with HIV-negative patients. However, Hodgkin lymphoma is not considered an AIDS-defining neoplasm.
Genetic predisposition plays a role in the pathogenesis of Hodgkin lymphoma. Approximately 1% of patients with Hodgkin lymphoma have a family history of the disease, and siblings of an affected individual have a 3- to 7-fold increased risk of developing the disease. [13] Most evidence for a genetic etiology has been established in the distinct subtype of nonsclerosing Hodgkin lymphoma (NSHL). NSHL has been shown to be one of the most heritable types of neoplasm, with a 100-fold increased risk in identical twins. [14, 15]
There is evidence that NSHL may result from an atypical immune response to a virus or other trigger, in an individual with a genetic predisposition to such a response. [16] For decades, specific human leukocyte antigen (HLA) class II genotypes, including HLA-DRB1 and HLA-DQB1, have been known to be associated with NSHL, and this has been confirmed by genome-wide association studies. [17] Several single-nucleotide polymorphisms in the 6p21.32 region, which is rich in genes associated with immune function, have also been associated with NSHL risk. [18]
Pathophysiology
The World Health Organization (WHO) classifies Hodgkin lymphoma into five types. [1] Nodular sclerosing, mixed cellularity, lymphocyte depleted, and lymphocyte rich are the four types referred to as classic Hodgkin lymphoma. The fifth type, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), is a distinct entity with unique clinical features and a different treatment paradigm.
In classic Hodgkin lymphoma, the neoplastic cell is the Reed-Sternberg cell (see the image below). [19, 20] Reed-Sternberg cells comprise only 1-2% of the total tumor cell mass. The remainder is composed of a variety of reactive, mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes.
A Reed-Sternberg cell in Hodgkin lymphoma. Reed-Sternberg cells are large, abnormal lymphocytes that may contain more than one nucleus. Image courtesy of National Cancer Institute.
Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers but no longer able to produce antibodies. Hodgkin lymphoma cases in which the Reed-Sternberg cell is of T-cell origin are rare, accounting for 1-2% of classic Hodgkin lymphoma.
The Reed-Sternberg cells consistently express the CD30 (Ki-1) and CD15 (Leu-M1) antigens. CD30 is a marker of lymphocyte activation that is expressed by reactive and malignant lymphoid cells and was originally identified as a cell surface antigen on Reed-Sternberg cells. CD15 is a marker of late granulocytes, monocytes, and activated T-cells that is not normally expressed by cells of B lineage.
Classic Hodgkin lymphoma
Classic Hodgkin lymphoma is classified into the following 4 types:
-
Nodular sclerosing Hodgkin lymphoma (NSHL)
-
Mixed-cellularity Hodgkin lymphoma (MCHL)
-
Lymphocyte-depleted Hodgkin lymphoma (LDHL)
-
Lymphocyte-rich classic Hodgkin lymphoma (LRHL)
Nodular sclerosing Hodgkin lymphoma
In NSHL, which constitutes 60-80% of all cases of Hodgkin lymphoma, the morphology shows a nodular pattern. Broad bands of fibrosis divide the node into nodules. The capsule is thickened. The characteristic cell is the lacunar-type Reed-Sternberg cell, which has a monolobated or multilobated nucleus, a small nucleolus, and abundant pale cytoplasm.
NSHL is frequently observed in adolescents and young adults. It usually involves the mediastinum (see the image below) and other supradiaphragmatic sites.
Nodular sclerosing Hodgkin lymphoma of the mediastinum. The diagnosis is strongly suggested by the presence of distinct nodules on the cut surface of this lymph node.
Mixed-cellularity Hodgkin lymphoma
In MCHL, which constitutes 15-30% of cases, the infiltrate is usually diffuse. Reed-Sternberg cells are of the classic type (large, with bilobate, double or multiple nuclei, and a large, eosinophilic nucleolus). MCHL commonly affects the abdominal lymph nodes and spleen. Patients with this histology typically have advanced-stage disease with systemic symptoms. MCHL is the histologic type most commonly observed in patients with human immunodeficiency virus (HIV) infection.
Lymphocyte-depleted Hodgkin lymphoma
LDHL constitutes less than 1% of cases. The infiltrate in LDHL is diffuse and often appears hypocellular. Large numbers of Reed-Sternberg cells and bizarre sarcomatous variants are present.
LDHL is associated with older age and HIV-positive status. Patients usually present with advanced-stage disease. Epstein-Barr virus (EBV) proteins are expressed in many of these tumors. Many cases of LDHL diagnosed in the past were actually non-Hodgkin lymphomas, often of the anaplastic large-cell type.
Lymphocyte-rich classic Hodgkin lymphoma
LRHL constitutes 5% of cases. In LRHL, Reed-Sternberg cells of the classic or lacunar type are observed, with a background infiltrate of lymphocytes. It requires immunohistochemical diagnosis. Some cases may have a nodular pattern. Clinically, the presentation and survival patterns are similar to those for MCHL.
Nodular lymphocyte-predominant Hodgkin lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) constitutes 5% of cases. It is a distinct clinical entity and is not considered part of the classic Hodgkin lymphoma type. Typical Reed-Sternberg cells are either infrequent or absent in NLPHL. Instead, lymphocytic and histiocytic (L&H) cells, or "popcorn cells" (their nuclei resemble an exploded kernel of corn), are seen within a background of inflammatory cells, which are predominantly benign lymphocytes (see the image below). Unlike Reed-Sternberg cells, L&H cells are positive for B-cell antigens, such as CD20, and are negative for CD15 and CD30.
Very high magnification micrograph of nodular lymphoctye predominant Hodgkin lymphoma (NLPHL), with a popcorn-shaped Reed-Sternberg cell (hematoxylin and eosin).
A diagnosis of NLPHL needs to be supported by immunohistochemical studies, because it can appear similar to LRHL or even some non-Hodgkin lymphomas.
Epidemiology
United States statistics
Information regarding the incidence and mortality of Hodgkin lymphoma in the United States can be found at the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) database Website. The NCI reports that age-adjusted rates for new Hodgkin lymphoma cases have been falling on average 2.3% each year over the last 10 years. As of 2017-2021, the age-adjusted annual incidence was 2.5 cases per 100,000 population. Death rates have decreased slowly but steadily in recent decades, but were stable at 0.3 per 100,000 population per year over 2017-2021. [21]
Data are also collected by the American Cancer Society (ACS). The ACS estimates that 8920 new cases of Hodgkin lymphoma will be diagnosed in 2026, with 1100 deaths. [22]
International statistics
In Europe and other developed countries, the incidence parallels US data. [23, 24] United Kingdom data from 2016-2018 show a crude incidence rate of 3.2 cases per 100,000 population (3.8 cases per 100,000 males and 2.7 cases per 100,000 females). Since the early 1990s, incidence rates of Hodgkin lymphoma in the UK have risen 37%. [25]
Race-, sex-, and age-related differences in incidence
Hodgkin lymphoma incidence rates in the United States vary by race and sex. The highest incidence is in non-Hispanic Whites; the lowest incidence is in American Indians/Alaska Natives and Asians/Pacific Islanders. In general, incidence is higher in males than in females. The sex predilection is most pronounced in children, with 85% of cases affecting boys. [21]
The incidence of Hodgkin lymphoma varies with age, with a clear bimodal distribution that is consistent across most countries and studies. The initial peak is in young adults (15-34 years); Hodgkin lymphoma is the most commonly diagnosed cancer in teens ages 15 to 19 years. The second peak is in older adults (> 55 years). [26] There is also a difference in subtype based on age, with young adults having nodular sclerosing Hodgkin lymphoma (NSHL) and older adults tending to have mixed cellularity Hodgkin lymphoma (MCHL).
Prognosis
Patient prognosis is largely based on the stage of the disease and various prognostic factors, which may be defined differently across various major cooperative groups (eg, German Hodgkin's Study Group [GHSG] vs European Organisation for Research and Treatment of Cancer [EORTC] and others). [27] (See also Staging.)
The SEER data report an 88.9% overall 5-year survival rate from 2014-2020. [21] Table 1 summarizes the stage distribution and 5-year relative survival at diagnosis for the same period for all races and both sexes. [21] In addition to the stage of the disease, many factors contribute to the likelihood of survival from Hodgkin lymphoma (see Staging). Factors that influence prognosis include patient age, presence or absence of B symptoms, stage of disease, and elevation of erythrocyte sedimentation rate. [28]
Table 1. Stage Distribution and 5-Year Relative Survival by Stage at Diagnosis for All Races and Both Sexes: 2011-2015 (Open Table in a new window)
Stage at Diagnosis |
Stage Distribution, % |
5-year Relative Survival, % |
Stage I (only in originating layer of cells) |
13 |
92.0 |
Stage II (confined to primary site) |
38 |
94.8 |
Stage III (spread to regional lymph nodes) |
20 |
87.1 |
Stage IV (cancer has metastasized) |
23 |
81.2 |
Unstaged |
5 |
82.6 |
Source: National Cancer Institute. SEER stat fact sheets: Hodgkin lymphoma. Available at: https://www.seer.cancer.gov/statfacts/html/hodg.html. Accessed: June 17, 2024 |
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The most commonly used prognostic system is the International Prognostic System (IPS), which uses the following variables to The most commonly used prognostic system is the International Prognostic System (IPS), which uses the following variables to determine prognosis [29] :
-
Serum albumin less than 4 g/dL
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Hemoglobin less than 10.5 g/dL
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Male sex
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Age of 45 years or older
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Stage IV disease (Ann Arbor classification)
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White blood cell (WBC) count greater than 15,000/mm3
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Absolute lymphocyte count less than 600/mm3, less than 8% of the total WBC count, or both
Each of the above variables is assigned 1 point. The total number of points for prognostic factors is used to determine risk. When applied to a group of 5141 patients with Hodgkin lymphoma the IPS produced the following groups of 5-year survival rates [29] :
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0 prognostic factors: 84%
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1 prognostic factor: 77%
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2 prognostic factors: 67%
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3 prognostic factors: 60%
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4 prognostic factors: 51%
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5 or more prognostic factors: 42%
These results have been validated in other populations as well, including in patients undergoing stem cell transplantation. [30, 31] However this scoring system is most applicable to patients with advanced-stage disease (stages III and IV).
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Micrograph of Hodgkin lymphoma in a fine-needle aspiration lymph node specimen (field stain). Eosinophils, Reed-Sternberg cells, plasma cells, and histocytes can be seen.
-
Nodular sclerosing Hodgkin lymphoma of the mediastinum. The diagnosis is strongly suggested by the presence of distinct nodules on the cut surface of this lymph node.
-
A Reed-Sternberg cell in Hodgkin lymphoma. Reed-Sternberg cells are large, abnormal lymphocytes that may contain more than one nucleus. Image courtesy of National Cancer Institute.
-
Mixed cellularity Hodgkin lymphoma showing both mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells (hematoxylin and eosin, original magnification x200).
-
Very high magnification micrograph of nodular lymphoctye predominant Hodgkin lymphoma (NLPHL), with a popcorn-shaped Reed-Sternberg cell (hematoxylin and eosin).
-
A positron emission tomography (PET) scan obtained with fluorodeoxyglucose (FDG) that shows increased FDG uptake in a mediastinal lymph node.
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A computed tomography (CT) scan showing bulk disease in a patient with Hodgkin lymphoma.
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This computed tomography scan is from a 46-year patient with Hodgkin lymphoma at the level of the neck. Enlarged lymph nodes are visible on the left side of the neck (red-shaded region).
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This image depicts a computed tomography (CT) scan, positron-emission tomography (PET) scan, and maximum intensity projection (MIP) PET scan from a patient with histologically proven Hodgkin lymphoma.
Tables
Stage at Diagnosis |
Stage Distribution, % |
5-year Relative Survival, % |
Stage I (only in originating layer of cells) |
13 |
92.0 |
Stage II (confined to primary site) |
38 |
94.8 |
Stage III (spread to regional lymph nodes) |
20 |
87.1 |
Stage IV (cancer has metastasized) |
23 |
81.2 |
Unstaged |
5 |
82.6 |
Source: National Cancer Institute. SEER stat fact sheets: Hodgkin lymphoma. Available at: https://www.seer.cancer.gov/statfacts/html/hodg.html. Accessed: June 17, 2024 |
||
Stage |
Area of Involvement |
I |
Single lymph node group |
II |
Multiple lymph node groups on same side of diaphragm |
III |
Multiple lymph node groups on both sides of diaphragm |
Stage |
Area of Involvement |
Extranodal (E) Status |
|
I |
Single node or adjacent group of nodes |
Single extranodal lesions without nodal involvement |
|
II |
Multiple lymph node groups on same side of diaphragm |
Stage I or II by nodal extent with limited contiguous extranodal involvement |
|
II bulky* |
Multiple lymph node groups on same side of diaphragm with bulk >10 cm |
N/A |
|
III |
Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement |
N/A |
|
IV |
Multiple noncontiguous extranodal sites |
N/A |
|
A/B |
B symptoms: weight loss >10%, fever, drenching night sweats |
N/A |
|
*Stage II bulky disease is defined as limited or advanced on the basis of histology and a number of prognostic factors. |
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- Goals of Therapy and Response Assessment
- Radiation Therapy
- Induction Chemotherapy Regimens
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- Treatment of Early-Stage, Low-Risk Disease
- Treatment of Early-Stage Disease with Unfavorable Factors
- Treatment of Advanced Disease
- Hematopoietic Stem Cell Transplantation
- Treatment of Nodular Lymphocyte-Predominant Hodgkin Lymphoma
- Treatment in Older Patients
- Treatment in HIV-Infected Patients
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