Abstract
Hodgkin lymphoma is characterized by progressive enlargement of lymph nodes. It is considered unicentric in origin and has a predictable pattern of spread by extension to contiguous nodes.
Keywords
EBV, Reed–Sternberg, IĸB kinase, nodular sclerosis, MCHL, CXR, PET, ICE
Etiology and Epidemiology
- 1.
Specific etiology is unknown.
- 2.
Overall there is a slight female predominance when considering all children less than 20 years (M:F=0.9).
- 3.
The Caucasian:African American ratio is 1.3:1.
- 4.
Comprises 8.8% of all childhood cancers under the age of 20, but 17.7% of cancers in adolescents between the ages of 15 and 19 years.
- 5.
Overall annual incidence rate in the United States is 12.1 per million for children under 20 years.
- 6.
Incidence increases to 32 per million for adolescents 15–19 years.
- 7.
Bimodal age—incidence curve with one peak at 15–35 years of age and the other above 50 years of age (incidence is highest among 15–19 year olds).
- 8.
Association with Epstein–Barr virus (EBV) is known.
- 9.
Incidence increased among consanguineous family members and among siblings of patients with HL.
Risk Factors
There are several factors that are known to increase the risk of HL, which include family history of HL, EBV infections, socioeconomic status, and social contacts.
Familial Hodgkin Lymphoma
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 sevenfold increased risk among siblings.
EBV-Associated Hodgkin Lymphoma
EBV incorporated into the tumor genome has been most commonly reported with the mixed cellularity histologic subtype. This subtype is most common in children from underdeveloped countries, in males under age 10 years, and in those with other immunodeficiencies. Conversely, in young adult HL, incorporation of EBV in the tumor genome is unusual but a history of infectious mononucleosis and high-titer antibodies to EBV are associated.
Tumor necrosis factor receptor-associated factor 1 (TRAF 1) is overexpressed in EBV-transformed lymphoid cells and Reed–Sternberg (RS) cells and is associated with activation of NF-ĸB and protection of lymphoid cells from antigen-induced apoptosis. Activation of NF-ĸB, in turn, leads to expression of TRAF1, thereby establishing a positive feedback loop that maximizes NF-ĸB-dependent gene expression. EBV latent membrane protein 1 (LMP1) interacts with TRAF1, and tumors with TRAF1-LMP1 aggregates exhibit high NF-ĸB activity. LMP1 activates NF-ĸB by promoting IĸBa turnover. RS cells express CD30 and CD30 ligation promotes proliferation of HL-derived cells with constitutive activation of NF-ĸB.
EBV genome fragments can be found in approximately 30–50% of HL specimens, and may play a role in the rescue and repair of RS cells, further aiding in their evasion of apoptosis and enhanced survival. Three latent viral antigens are expressed in EBV-positive HL in RS cells: Epstein–Barr nuclear antigen-1, required for viral episome maintenance, LMP1 with transforming properties, and LMP2, which is nontransforming.
Socioeconomic Status and Hodgkin Lymphoma
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. These findings may be related to an association with infections; increased infections in early childhood may decrease the risk of HL in young adults.
Biology
The hallmark of classical HL is the RS cell. Sequence analyses of RS cell clones reveal rearrangements of immunoglobulin variable-region genes resulting in deficient immunoglobulin production. RS cells then evade the apoptotic pathway, leading to the genesis of HL. The B lymphoid cells from which RS arise have high levels of constitutive nuclear NF-ĸB, a transcription factor known to mediate gene expression related to inflammatory and immune responses, and deregulation of NF-ĸB has been postulated as a mechanism by which RS cells evade apoptosis. NF-ĸB dimers are held in an inactive cytoplasmic complex with inhibitory proteins, the IĸBs. B-cell stimulation by diverse signals results in rapid activation of the IĸB kinase (IKK). The IKK complex phosphorylates two critical serine residues of IĸBs, thereby targeting them for rapid ubiquitin-mediated proteasomal degradation. Active NF-ĸB dimers are then released and translocated to the nucleus, where they activate gene transcription. Activation of NF-ĸB appears to be a final common effect of costimulatory interactions, genetic aberrations, or viral proteins that operate in HL. RS cell survival is dependent on several downstream pathways. RS cells express CD40 and CD40 ligand (CD40L) is expressed on inflammatory T and dendritic cells that surround them. CD40/CD40L interactions normally provide a second signal from activated helper T-cells to normal B-cells, resulting in activation of NF-ĸB. NF-ĸB in turn causes proliferation and induces expression of BCL-x L , which protects B-cells from apoptosis.
Pathology
Macroscopic Features
The spread of HL occurs most commonly by contiguity from one chain of lymph nodes to another. Involvement of the left supraclavicular nodes often follows abdominal para-aortic node involvement with spread up the thoracic duct, whereas involvement of the right supraclavicular nodes tends to be associated with mediastinal adenopathy. Para-aortic node involvement commonly occurs in association with involvement of the spleen, which in turn is commonly followed by liver or bone marrow involvement, or both. Nodular sclerosing classical HL shows the greatest propensity to spread by contiguity, whereas noncontiguous dissemination, when it occurs, is more than twice as frequent in the mixed cellularity and lymphocyte-depleted classical HL histologic types.
The RS cell is the hallmark of classical HL and is characterized by a binucleated or a multinucleated giant cell that is often characterized by a bilobed nucleus, with two large nucleoli, giving the classically described “owl’s eye” appearance. The RS cells are embedded within a benign-appearing reactive infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils. Important exceptions to this histologic picture apply to the categories of nodular sclerosis (NS) type and nodular variant lymphocyte predominance type in which peculiar variant forms of the tumor giant cells can be used to establish the diagnosis (lacunar cell variants).
Histology
Table 21.1 describes the histologic variants in HL which consist of two disease groups:
- 1.
Classical HL includes the NS classical HL, mixed cellularity HL (MCHL), lymphocyte-depleted and lymphocyte-rich classical HL subtypes. Adolescent and young adults are most likely to have disease of the nodular sclerosing subtype, which accounts for 74% of cases in those 15–19 years of age. Under the age of 20 years, the mixed cellularity subtype accounts for 16% of cases, but under the age of 10 years, 32% of cases and across the pediatric age group, it is more common in males.
- 2.
Nodular lymphocyte-predominant HL (NLPHL) is nonclassical HL with expression of different immunophenotypic features.
| CLASSICAL HODGKIN LYMPHOMA (CHL) | |
| Nodular Sclerosis Classical HL (NSCHL) | Characterized by collagen bands and lacunar variants of RS cells; the presence of one or more sclerotic bands is the defining feature. These bands usually radiate from a thickened lymph node capsule, often following the course of a penetrating artery, and are composed of mature, laminated, relatively acellular collagen. The sclerotic bands are birefringent in polarized light. In most cases, several broad collagenous bands can be identified, or fibrosis can be so extensive that isolated nodules of lymphoid tissue remain. The collagenous bands of nodular sclerosis enclose nodules of lymphoid tissue containing variable numbers of HCs and reactive infiltrates. Lacunar cells are a common type of RS cell present and may be found in large numbers or in sheets. They tend to aggregate at the center of nodules, sometimes forming a rim around central areas of necrosis. Diagnostic RS cells are present in variable numbers and may be difficult to identify in small biopsy specimens. Eosinophils, histiocytes, and sometimes even neutrophils are often numerous; plasma cells are usually less conspicuous. |
| Mixed Cellularity Classical HL | This intermediate subtype falls between lymphocyte-rich classical HL and lymphocyte-depleted classical HL. The capsule is usually intact and of normal thickness. A vague nodularity may be present at low magnification, but the presence of any definite fibrous bands would warrant classification as nodular sclerosis rather than mixed cellularity. At high magnification, a heterogeneous mixture of HCs, small lymphocytes, eosinophils, neutrophils, epithelioid and nonepithelioid, histiocytes, plasma cells, and fibroblasts are present. Diagnostic RS cells and mononuclear variants are usually easy to find. Small foci of necrosis may be present, but the extent is much less than that seen in nodular sclerosis. |
| Lymphocyte-Depleted Classical HL | Lymphocyte-depleted HL encompasses two variants: Diffuse fibrosis, and reticular. The most characteristic features are a marked degree of reticulin fibrosis surrounding single cells along with lymphocyte depletion. In contrast to nodular sclerosis, this subtype is not characterized by the presence of thick fibrous bands and the fibrosis envelops individual cells, not nodules of cells. HCs are usually easily identified, but increased numbers of HCs are not essential to the diagnosis. In the reticular variant, sheets of HCs, often showing pleomorphic features, are found. |
| Lymphocyte-Rich Classical HL | Many cases of lymphocyte-rich classical HL have a resemblance to mixed cellularity HL, with vaguely nodular and less often diffuse pattern at low magnification. Hodgkin and RS cells are relatively rare and the background is dominated by small mature lymphocytes. Eosinophils and neutrophils are usually absent and if present are scanty and usually within the interfollicular areas. RS cells and variants are not easy to find but when encountered have identical features to the HCs of mixed cellularity. Some cases of lymphocyte-rich HCs may show a distinctly nodular appearance that may closely mimic nodular lymphocyte predominance HL and often contain relatively small germinal centers, with Hodgkin and RS cells present in and near the mantle zone, a pattern that has been called follicular HL. |
| UNCLASSIFIED CASES (UC) a | |
| Nodular Lymphocyte-Predominant HL | This is a B-cell neoplasm with a nodular or nodular and diffuse proliferation of scattered large neoplastic cells termed “popcorn” cells (formerly called L&H cells, for lymphocytic and/or histiocytic RS cell variants). These large cells resemble centroblasts but are larger and have folded or multilobulated nuclei and multiple small basophilic nucleoli are often present adjacent to the nuclear membrane. The cytoplasm is broad and only slightly basophilic. These large cells are present within spherical nodules with numerous dendritic cells, histiocytes, and small lymphocytes. Ultrastructural studies demonstrate that popcorn cells have the appearance of centroblasts of germinal center. Epithelioid histiocytes are preferentially found in the outer rim of nodules. They are arranged in small groups or clusters and well-formed granulomas may be present in rare cases. Eosinophils and neutrophils are rare. Plasma cells are not common and are seen only between follicles. In diffuse areas, the popcorn cells are still often arranged in a vaguely nodular pattern. Classic Hodgkin and RS cells are completely lacking or are few in number. In some cases, popcorn cells may resemble lacunar cells because both cell types show irregularly shaped or lobulated nuclei, small nucleoli and broad pale to slight basophilic cytoplasm. The popcorn cells are often surrounded by rosettes of CD31, CD571 T-lymphocytes. |
a Any histopathology that does not fit into a definite or provisional category (they may be T-cell, B-cell, or undefined; they may be borderline between HL and NHL).
Immunophenotypic Features
RS cells in classic HL do not express B-cell antigens such as CD45, CD19, and CD79A, but virtually all express CD30 and approximately 70% express CD15, with only 20–30% expressing CD20. In comparison, the tumor cells of NLPHL always express B-cell antigens such as CD20, CD79a, and are almost always negative for CD30 and CD15. The majority of RS cells and popcorn cells express B-cell-specific activator protein PSX-5. Table 21.2 shows the common immunophenotypic markers in HL.
| CD15 | CD30 | CD45 | CD20 | CD79a | Pax5 | |
|---|---|---|---|---|---|---|
| Classical HL | +/− | + | − | −/+ | −/+ | + |
| NLPHL | − | − | + | + | + | + |
Clinical Presentation
Constitutional B Symptoms
Approximately 20% of patients have associated B symptoms defined as:
- 1.
Unexplained weight loss of >10% of body weight in the 6 months preceding the diagnosis.
- 2.
Unexplained fever with temperatures >38°C for more than 3 days.
- 3.
Drenching night sweats.
Mild, moderate, or severe pruritus in the absence of rash can also be seen with HL but is not considered a B symptom.
Peripheral Lymphadenopathy
- 1.
Painless swelling of one or more groups of superficial lymph nodes.
- 2.
Cervical nodes involved in the majority of cases.
- 3.
Other commonly affected peripheral nodal regions include supraclavicular, axillary, and inguinal.
- 4.
The bulk of palpable lymph nodes is defined by product of the perpendicular diameters using the single largest dimension (in centimeters) of the lymph node or conglomerate and that perpendicular to the same in each region of involvement. A node or nodal mass of >6 cm is generally defined as bulky .
Mediastinal Adenopathy
- 1.
Approximately 20% of patients have bulky mediastinal disease defined as a large mediastinal mass (>6–10 cm in maximum dimension) or which, on a posterior–anterior chest radiograph (CXR), has a maximum width equal to or greater than one-third of the internal transverse diameter of the thorax at the level of the T5–6 interspace (mass to thoracic ratio 0.33).
- 2.
Adolescents and young adults present with a mediastinal mass in 75% of cases, as opposed to children less than 10 years of age where mediastinal disease is present in only 35% of cases. This is thought to be due to these younger patients having either mixed cellularity or lymphocyte-predominant histology, where peripheral adenopathy is more common.
- 3.
With mediastinal involvement there may be persistent nonproductive cough; however, this site is often asymptomatic. Despite large mediastinal masses with compression on the airway, superior vena cava syndrome (enlargement of the vessels of the neck, hoarseness, dyspnea, and dysphagia) is uncommon.
Pulmonary
- 1.
Lung parenchymal lesions may occur from direct extension from mediastinal or hilar adenopathy or may be discrete lesions.
- 2.
Uncommonly lesions may be cavitating and must be differentiated from infectious etiologies. Such infections (e.g., fungal infections or tuberculosis) can exist alone or in combination with HL.
- 3.
Pleural effusion can accompany hilar, mediastinal, or pulmonary disease.
Spleen
- 1.
The spleen is commonly enlarged on physical examination or by imaging study.
- 2.
Size is not indicative of splenic involvement with HL.
- 3.
In splenic involvement, discrete hypodense lesions may be seen on computed tomography (CT) scan. Fluorodeoxyglucose positron emission tomography (FDG-PET) scan has high sensitivity and specificity for splenic lesions and is now used to identify splenic involvement from HL, although clinical trials may require CT-based lesions for definition as well. In 13% of cases, the spleen is the only site of subdiaphragmatic disease.
Bone
- 1.
Osseous HL typically presents with bone pain and the majority of patients have concurrent nonosseous lesions detected at staging.
- 2.
FDG-PET is an excellent imaging modality for osseous involvement and has generally replaced the need for technetium bone scans.
Hematology and Bone Marrow
- 1.
Blood count abnormalities can include a normocytic normochromic anemia, thrombocytopenia, neutrophilia or neutropenia, eosinophilia, and lymphopenia.
- 2.
Neutropenia, anemia, or thrombocytopenia may be related to marrow or splenic involvement or may be autoimmune in nature and can in those circumstances, precede the diagnosis of HL. Eosinophilia may be cytokine-mediated due to IL-5 production by RS cells.
- 3.
A positive direct antiglobulin test may or may not be associated with overt hemolysis.
- 4.
To confirm bone marrow involvement, multiple biopsies are indicated because HL tends to involve the marrow in a focal fashion. However, bone marrow disease is well characterized by FDG-PET and this may obviate the need for bone marrow biopsies in the future.
Liver
- 1.
Mild hepatomegaly and abnormal liver function tests do not correlate with actual histologic involvement of the liver.
- 2.
Discrete lesions should be noted on CT scan and liver biopsy is the most accurate method for confirmation of liver involvement.
Kidney
- 1.
Renal involvement may be unilateral or bilateral and may be present as diffuse involvement, discrete nodules, or microscopic disease.
- 2.
Renal involvement with HL may result from ureteral obstruction and patients with HL may also have renal dysfunction related to renal vein thrombosis, hypercalcemia, and hyperuricemia.
Nervous System
- 1.
Neurologic dysfunction is usually a late manifestation and extremely rare.
- 2.
There can be spread from paravertebral lymph nodes or hematogenous spread.
- 3.
Symptoms are related to area of neurologic involvement.
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