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Hodgkin Lymphoma
Hodgkin lymphoma (HL) is an uncommon lymphoproliferative malignancy arising from B cells. It can affect all age groups but is most common in young adults. HL is the first adult malignancy to demonstrate the curative potential of combination chemotherapy. Today, more than 80% of patients with newly diagnosed HL can now expect to be cured of their disease.
The challenge now, particularly since many affected patients are young, is not only to improve cure rates further, but also to minimize the risk of long-term complications of treatment, which can impact quality of life and survival. Accordingly, HL provides a very important clinical model for ongoing cancer research involving both the development of novel targeted agents and the study of late effects of cancer therapy.
Traditionally, the choice of frontline therapy for HL has been determined by clinical stage and prognostic factors. A combined modality approach with chemotherapy and radiotherapy (RT) remains the standard of care for those with early-stage disease, although the routine use of RT has been challenged recently. For those presenting with more advanced stage diseases, chemotherapy alone has been widely adopted. The availability of highly effective chemotherapy combinations and sensitive imaging tests has allowed the development of less toxic therapeutic strategies for those with limited disease. This includes using more limited radiation fields such as involved-field radiotherapy (IFRT), more recently involved-site radiotherapy (ISRT) and, in some centers, involved node radiotherapy (INRT) and a reduction in the number of chemotherapy cycles. This more focused treatment delivery has allowed efficacy to be preserved while exposure to unnecessary toxicity is reduced.
The management of HL continues to evolve 18 fluorodeoxyglucose (FDG). Positron emission tomography (PET) imaging has emerged as a useful tool for assessing response and to guide further therapy that may allow RT—free regimens in appropriate patients. This, coupled with ongoing research to identify better biologic prognostic factors, is likely to allow for a more accurate risk-adapted approach to management, with the future treatment of patients with HL being tailored to the needs of the individual. In addition, improved understanding of the molecular mechanisms underlying HL has hastened the development of more effective, and often less toxic, targeted therapies for use either as monotherapy or in combination with traditional chemotherapy to augment efficacy and decrease overall toxicity.
Epidemiology and Etiology Incidence and Age of Onset
HL is a rare B-cell malignancy accounting for less than 1% of all cancers with approximately 9200 new cases diagnosed in the United States and approximately 5500 new cases diagnosed in Europe each year. The incidence of HL varies with economic status and geographic location. In developed countries it is associated with a bimodal age of onset distribution, with an early, larger, peak occurring in young adults aged between 20 and 40 years and a second, smaller, peak occurring in those over 55 years. In contrast, in developing countries, the disease predominantly occurs in childhood, with the incidence decreasing with age. Overall, men are affected slightly more frequently than women.
Etiology
The exact cause of HL remains unknown and clearly defined risk factors for the development of the disease are lacking. However, certain associations with its development have been identified. Although a clear genetic cause has not been established, familial susceptibility has been suggested by both an apparent increased risk among siblings of patients with HL, as well as concordance for HL observed in monozygotic twins. Increased maternal education, early birth order, low number of siblings and single-family dwellings in childhood have all also been positively associated with the occurrence of HL in younger patients.
Epstein-Barr virus (EBV)—positive Reed-Sternberg (RS) cells are found in approximately 40% of patients with HL using modern molecular techniques. The incidence of EBV positive HL among those with a past history of serologically proven infectious mononucleosis appears to be higher than those without previous exposure. EBV may play a role in promoting RS survival and has been associated with the increased production of molecules that are involved in mechanisms of immune escape, in turn influencing the microenvironment that supports HL development.
Pathobiology of Hodgkin Lymphoma
The World Health Organization (WHO) classifies HL into two distinct disease types: classic HL (cHL), representing 95% of all cases, and nodular lymphocyte-predominant HL (NLPHL), accounting for only 5%. Both cHL and NLPHL are neoplasms composed of a minor component of atypical large neoplastic cells, usually accounting for less than 10% of all cells that are present in a reactive nonneoplastic background. However, based on their distinct clinical and molecular genetic features, it is now evident that cHL and NLPHL are two biologically distinct entities. Within cHL, four histologic subtypes are recognized based on the morphology of the neoplastic cells, composition of the nonneoplastic infiltrate, and overall nodal architecture: nodular sclerosing (NSCHL), mixed cellularity (MCCHL), lymphocyte-depleted (LDCHL), and lymphocyte-rich (LRCHL). Of these, NSCHL predominates, accounting for 70% of cases of cHL in Europe and the United States ( Table 80.1 ). The rate of NSCHL, however, varies with geographic location and socioeconomic status and is much lower in developing countries, where MCCHL predominates. Furthermore, NSCHL occurs less frequently in patients infected with HIV, among whom the more common presenting subtype, again, is MCCHL.
Table 80.1
Frequency of Histologic Subtypes of Hodgkin Lymphoma
| Classic Hodgkin lymphoma (cHL) | 95% |
|
70% |
|
20−25% |
|
5% |
|
<1% |
| Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) | 5% |
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Typical cases of NLPHL show partial or complete nodal architectural effacement by a macronodular proliferation ( Fig. 80.1A ), where the nodules are composed of scattered neoplastic cells termed lymphocyte-predominant (LP) cells , formerly known as L&H cells. LP cells are large with single folded or multilobulated nucleus with distinct but smaller nucleoli than RS cells. Because of their highly complex nuclear lobation, they have also been widely referred to as “popcorn cells” (see Fig. 80.1B ). The background nonneoplastic infiltrate is composed of predominantly small B cells and a variable number of histiocytes. Mixed inflammatory cells such as eosinophils and neutrophils are rare to absent.
LP cells typically express B-cell markers including CD20 (see Fig. 80.1C ), PAX-5, and CD79a. In addition, LP cells consistently express CD45, and the B-cell transcriptional factors OCT-2 and BOB.1, that are usually not expressed by RS cells. In contrast to RS cells, LP cells typically lack CD15 and CD30 expressions. In keeping with their germinal center B-cell origin, LP cells are consistently positive for BCL6, although CD10 is usually not expressed. They may express EMA (epithelial membrane antigen) in a subset of LP cells in approximately 50% of the cases, and variably express IRF4/MUM1. A subset of cases with expression of IgD, and unique pathological and clinical features has also been described. EBV-encoded RNA (EBER) and latent membrane protein-1 (LMP1) are consistently negative.
The nodules in NLPHL are typically supported by an expanded meshwork of follicular dendritic cells that can be highlighted by CD21 and CD35, and populated by small B cells that are positive for immunoglobulin (Ig) M and IgD. There are a variable number of T cells, a significant proportion of which is positive for CD4, CD57, and programmed cell death protein 1 (PD-1) which frequently form rosettes around the LP cells (see Fig. 80.1D ). Immunoarchitectural patterns as determined relative abundance and distribution of reactive B cells and T cells have been described. Limited data suggests that as the disease progresses the nodules acquire T-cell-rich features, at the end resembling T-cell histiocyte-rich large B-cell lymphoma. These histological variants are associated with increased chance of advanced disease and relapse.
Genetic studies performed on microdissected LP cells show clonally rearranged Ig genes with high load of somatic mutations in the variable region, indicating the presence of ongoing mutations and consistent with germinal center B-cell derivation of NLPHL. In contrast to cHL, the Ig rearrangement is functional with detectable Ig mRNA transcripts. Acquired somatic mutations described in NLPHL include BCL6 gene rearrangements, mutations affecting PAX5, PIM1, RHOH, MYC, SGK1, DUSP2, and JUNB.
Classic Hodgkin Lymphoma
cHL is characterized by the presence of RS cells and their morphologic variants in a reactive background composed of mixed inflammatory cells (except in lymphocyte-rich variant). Classic (diagnostic) RS cells are large binucleated or multinucleated cells with pale chromatin, distinct nuclear membrane, single prominent eosinophilic, inclusion-like nucleolus in each nuclear lobe, and abundant amphophilic cytoplasm ( Fig. 80.2A ). Mononuclear variants with otherwise similar cytonuclear features are termed Hodgkin cells (see Fig. 80.2B ). Mummified cells are degenerated RS and Hodgkin cells with pyknotic nuclei and condensed cytoplasm (see Fig. 80.2C ). These variants are usually seen in various proportions in all four subtypes of cHL. In addition, lacunar cells are characteristic of nodular sclerosis cHL but usually not other subtypes, which have abundant pale cytoplasm that frequently retracts in formalin fixed tissue, creating an empty space (lacunae) around the cells (see Fig. 80.2D ).
NSCHL is characterized by sclerotic nodal capsule and presence of collagenous bands traversing through the nodal parenchyma, imparting a prominent nodular pattern ( Fig. 80.3A ). Within the nodules there are a variable number of RS cells and variants, especially lacunar cells, with a background of mixed inflammatory cells composed of a variable proportion of small lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. The RS cells and variants may be singly dispersed or form confluent aggregates/sheets.
In MCCHL the lymph node architecture is usually diffusely obliterated, although an interfollicular pattern may be seen in early involvement. In contrast to NSCHL, the nodal capsule is not thickened and there are no collagenous bands of fibrosis (see Fig. 80.3B ). RS cells and variants are usually easily identified and dispersed throughout the nodal tissue in a mixed inflammatory background. In comparison to NSCHL, MCCHL is more often associated with higher stage disease and EBV positivity and is more likely seen in the HIV-infected patient population.
LRCHL is a relatively recently defined subtype of cHL characterized by the presence of RS cells in a background of almost exclusively small lymphocytes, with a paucity or absence of eosinophils and neutrophils. The vast majority of the cases exhibit nodular growth pattern, although a rare diffuse variant has also been described. In the vast majority of the cases the affected lymph node is obliterated by multiple expansile nodules with expanded mantle zones and regressed, eccentrically located residual germinal centers (see Fig. 80.3C ).
LDCHL is exceedingly rare (<1% of cHL) with a highly variable histologic appearance, but in all cases characterized by a relative predominance of RS cells in comparison to the background lymphocytes. Some cases are characterized by scattered RS cells in a diffusely fibrotic background containing histiocytes, fibroblasts, and few lymphocytes. In others, sheets of bizarre, pleomorphic, or anaplastic-appearing RS cells are present, imparting a sarcomatous appearance (see Fig. 80.3D ).
The immunophenotypic profile of RS cells in all cHL subtypes is similar. RS cells are strongly positive for CD30 with membranous and Golgi pattern in nearly all cases ( Fig. 80.4A ), and CD15 with variable staining intensity in approximately 80% of the cases (see Fig. 80.4B ). Consistent with their B-cell derivation, RS cells express PAX-5 in almost all cases (95%) but with weaker intensity when compared with the surrounding nonneoplastic small B cells (see Fig. 80.4C ). However, in keeping with their defective B-cell program, RS cells lack Ig production as evidenced by absence of J chain, and are negative for most other B cell−associated antigens: CD20 (expressed in only 20% to 30% of cases; often only in a subset of RS cells with weak/variable intensity), CD19, and CD79a; as well as B-cell transcriptional factors octamer transcription factor-2 (OCT-2) and B-cell oct-binding protein 1 (BOB.1) (each expressed in 10% of cases; coexpression is rare). RS cells are almost always positive for IRF4/MUM1 and negative for CD45 and EMA, features that may help distinguish cHL from NLPHL. Expression of other hematopoietic lineage—associated markers, such as T cells (CD4, granzyme B), dendritic cells (fascin, CCL17), and myeloid cells (colony stimulating factor 1 receptor and α 1 -antitrypsin) is also often present. EBV LMP1 and/or EBER expression (see Fig. 80.4D ) by RS cells is seen in approximately 40% of cHL cases overall in Western countries, but mostly in MCCHL and LDCHL and less frequently in NSCHL and LRCHL. However, an association with EBV is seen in up to 90% of cHL cases in developing countries and nearly all cases in the HIV patient population.
The nonneoplastic background lymphocytes, with the exception of LRCHL, are composed of predominantly T cells with marked predominance of CD4-positive cells that coexpress CD25 and FOXP3, consistent with immunosuppressive regulatory T cells (TReg). In addition, there is a significant population of TH2 cells. TReg and TH2 cells are attracted by cytokines (CCL5, CCL17, and CCL22) secreted by RS cells. In HIV-infected patients there is often a predominance of CD8-positive T cells. In contrast to NLPHL, CD57-positive T cells are not increased in number in cHL.
Polymerase chain reaction studies performed on RS cells procured by microdissection demonstrated that in the vast majority of cHL cases (>98%), the RS cells harbor clonal IgH gene rearrangement. The rearranged IgH shows a high load of somatic hypermutation in the variable region without evidence of ongoing mutation, consistent with germinal center or postgerminal center B-cell derivation. Rare cases harboring T-cell receptor gene rearrangements have also been documented. Genetic structural alterations that modulate tumor cell biology and the tumor microenvironment have been recently reported. These include mutations leading to loss of MHC class I and class II expressions, upregulation of PDL-1 expression by gene amplification or rearrangements, deregulation of nuclear factor-kappa B (NF-κB) pathway, and activation of janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway ( Fig. 80.5 ).
Diagnosis and Staging
Diagnosis
The definitive diagnosis of HL must be made pathologically via excision biopsy of an affected lymph node or other suspected organ. Core needle biopsy is deemed inferior to excision biopsy because of the unique architecture of the lymph node in HL that comprises a relatively dilute population of malignant cells. The presence of RS cells in cHL, and LP cells in NLPHL in tissue biopsy, provides the basis for discriminating between these two major diagnostic subtypes, with immunophenotypic profiling representing a crucial adjunct for all new cases of HL.
Staging
Stage of disease is the major determinant of prognosis for patients with newly diagnosed HL, and accurate assessment is paramount when deciding upon optimal therapy. The current staging system used for patients with HL is the Lugano classification, which was based on the Cotswold-modified Ann Arbor classification system ( Table 80.2 ). Recently, a simplified staging and response assessment criteria were proposed. An integrated PET/computed tomography (CT) is used for staging of 18 F-2-deoxyglucose (FDG)—avid lymphomas, and reinforced its recommendation as an effective response assessment tool both early on during treatment and at the end of treatment to establish remission status.
Table 80.2
Cotswold-Modified Ann Arbor Staging System for Hodgkin Lymphoma
| Stage | Criteria |
|---|---|
| I | Disease affecting a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer ring) |
| II | Disease affecting two or more discrete lymph node regions confined to the same side of the diaphragm |
| II | Disease affecting two or more discrete lymph node regions or lymphoid structures on both sides of the diaphragm |
| IV | Disease that has spread to one or more extranodal site (that does not meet the criteria for E) or extralymphatic structure including involvement of the bone marrow, liver, or lungs |
| Designation | Criteria |
| A | Absence of B symptoms a |
| B | Presence of B symptoms a |
| S | Involvement of the spleen |
| E | Single extranodal site or involvement of an extranodal site that is contiguous to an involved nodal region. |
| X | Bulky disease as defined as >1/3 mediastinum at its widest part or a nodal mass >10 cm at its greatest diameter. |
a B symptoms: constitutional symptoms including night sweats, fevers, or weight loss (>10% over 6 months).
Bone marrow involvement occurs in less than 5% of patients with HL at diagnosis. Until recently, following pathologic diagnosis with excisional node biopsy, a bone marrow biopsy was also required as part of routine staging for all patients with newly diagnosed HL. However, because of the high sensitivity of PET/CT for bone marrow involvement, bone marrow biopsy is no longer mandated for the routine staging of patients with newly diagnosed HL, unless PET/CT imaging is unavailable.
In addition to excisional node biopsy and staging with PET/CT, assessment of the peripheral blood represents an important part of the diagnostic workup for patients with newly diagnosed HL with particular respect to risk stratification and treatment choice. Complete blood count, erythrocyte sedimentation rate (ESR), and serum biochemistry including C-reactive protein, alkaline phosphatase, lactate dehydrogenase, liver function tests, renal function tests, and albumin are required as part of standard care, and screening for HIV and hepatitis is strongly advised. In addition, given the potentially damaging effects of chemotherapy and RT, certain pretreatment investigations including cardiac and pulmonary function tests, thyroid function tests, reproductive counseling, and serum pregnancy testing, may also be warranted in selected patients.
Clinical Features
The importance of an accurate clinical history in facilitating the management of patients with HL should not be underestimated. Certain symptoms may provide clues as to the likely stage of disease or lead to further investigations that might identify additional sites of disease. This may result in important treatment modifications. An accurate past medical history, particularly with regards to lung, heart, and kidney function, is also crucial in highlighting those organs that might benefit from further investigation before commencing therapy, to ensure that treatment choices are both effective and safe for the individual.
Systemic symptoms that are known to influence prognosis in patients with HL include night sweats, fever, and weight loss. These constitutional symptoms have come to be known as “B symptoms” and their importance in HL is reflected by their inclusion as key components of the Cotswold-modified Ann Arbor staging system. B symptoms are a presenting feature in approximately 30% of patients with advanced stage HL. A particular type of fever that is considered characteristic of HL historically, is the Pel-Ebstein fever, which typically follows a swinging pattern, occurring on a daily basis for many weeks, with intermittent afebrile periods occurring between episodes. Other well-described clinical features associated with HL include fatigue, chronic pruritus, which may be an early sign of disease in up to 15% of patients, and the presence of a pain localized to the site of involved lymphadenopathy that is precipitated by the consumption of alcohol.
Prognostic Factors, Risk Stratification, and Treatment Groups
Prognostic factors have helped to predict the likely outcome for individual patients with HL at diagnosis. Clinical stage, presence of systemic symptoms, and tumor burden continue to be important prognostic factors in HL, and, in addition to disease histology and anatomic stage, are widely used for risk stratification and subsequent selection of appropriate initial therapy.
HL patients have traditionally been divided into two distinct prognostic groups according to clinical stage at diagnosis: early-stage disease, accounting for 45% of newly diagnosed patients, and advanced-stage disease, accounting for 55% of newly diagnosed patients.
The category of early-stage HL includes patients with stages I or II. Early-stage disease may also include patients with B symptoms, bulky disease, or extension to adjacent sites. Additional prognostic factors were developed to stratify early-stage disease into early “favorable” and early “unfavorable” disease subgroups. Early stage I or II HL is considered “favorable” if it is limited to an area above the diaphragm and is not associated with other risk factors. Early stage I or II HL is considered “unfavorable” in the presence of other risk factors related to age, tumor burden, ESR, and number of involved nodal areas ( Table 80.3 ). Early-unfavorable disease is often referred to as Intermediate stage disease and these terms may be used interchangeably. Thus, early-stage HL is a heterogeneous group and treatment algorithms have been developed for different subgroups based on these prognostic factors and response criteria.
Table 80.3
Prognostic Factors in Early and Advanced-Stage Hodgkin Lymphoma
| Prognostic Group | EORTC | GHSG | NCCN |
|---|---|---|---|
| Early-favorable | CS I-II without risk factors (supra-diaphragmatic) | CS I-II without risk factors | CS IA-IIA without risk factors |
| Early-unfavorable (Intermediate) | CS I-II with ≥1 risk factor (supra-diaphragmatic) | CS I-IIA with ≥1 risk factor C/D but not A/B | CS I-II with ≥1 risk factor |
| Advanced | CS III-IV |
|
CS III-IV |
| Prognostic factors |
|
CS , Clinical stage; EORTC , European Organization for Research and Treatment of Cancer; ESR , estimated sedimentation rate; GHSG , German Hodgkin Study Group ; NCCN , National Comprehensive Cancer Network.
a Bulky mediastinal mass: ratio ≥0.035 of the maximum horizontal chest diameter (EORTC); ratio ≥1/3 of the maximum horizontal chest diameter (GHSG); ratio greater than 1/3 of the maximum horizontal chest diameter (NCCN).
b B symptoms: night-sweats, fever, weight loss (unexplained, >10% over 6 months).
The prognostic criteria for advanced-stage HL again vary among different cooperative groups. The European Organisation for Research and Treatment of Cancer (EORTC) defines advanced stage as those patients with clinical stage III−IV disease only, whereas the German Hodgkin Study Group (GHSG) also includes those patients with clinical stage IIB disease and a large mediastinal mass and/or extranodal disease involvement in their definition (see Table 80.3 ).
Following the identification of more specific and more widely applicable prognostic factors, the International Prognostic Score (IPS) was developed as an internationally accepted means of distinguishing those patients with newly diagnosed advanced HL who might be cured by standard treatment, and, therefore, avoid overtreatment for those whom standard treatment might fail. In 1998, based on a multivariate analysis of survival data from 5141 patients with newly diagnosed advanced HL treated between 1983 and 1992, seven adverse prognostic factors were identified as being statistically meaningful when predicting 5-year freedom from progression (FFP) and overall survival (OS): age ≥45 years, male sex, albumin less than 40 g/L, hemoglobin less than 10.5 g/dL, Ann Arbor stage IV, leukocytosis ≥15 × 10 9 /L, and lymphocyte count less than 0.6 × 10 9 /L. Five-year FFP was 84% for those patients with no adverse prognostic factors, and each additional factor reduced FFP by 7%, with four to seven factors representing an FFP of 40%. Three risk groups were established as a result, allowing therapy to be chosen according to these specific clinical characteristics, with the consensus being that higher risk patients should receive more intensive therapy ( Table 80.4 ).
Table 80.4
International Prognostic Score for Advanced Hodgkin Lymphoma
| No. of Prognostic Factors | % of Patients | 5-year FFP (%) | 5-year OS (%) |
|---|---|---|---|
| 0−1 (low-risk) | 29 | 79 | 90 |
| 2−3 (intermediate-risk) | 52 | 64 | 80 |
| 4−7 (high-risk) | 19 | 47 | 59 |
FFP , Freedom from progression; OS , overall survival.
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