Hodgkin lymphoma (HL) is a cancer where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. As it affects a subgroup of white blood cells called lymphocytes, it is a lymphoma. The condition was named after the English physician Thomas Hodgkin, who first described it in 1832. Symptoms may include fever, night sweats, and weight loss. Often, non-painful enlarged lymph nodes occur in the neck, under the arm, or in the groin. People affected may feel tired or be itchy.
The two major types of Hodgkin lymphoma are classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. About half of Hodgkin lymphoma cases arise from Epstein–Barr virus (EBV), and these are generally the classic form. Other risk factors include a family history of the condition and having HIV/AIDS. Diagnosis is conducted by confirming the presence of cancer and identifying Reed–Sternberg cells in lymph node biopsies. The virus-positive cases are classified as a form of the Epstein–Barr virus-associated lymphoproliferative diseases.
Hodgkin lymphoma may be treated with chemotherapy, radiation therapy, and stem-cell transplantation. The choice of treatment often depends on how advanced the cancer has become and whether or not it has favorable features. If the disease is detected early, a cure is often possible. In the United States, 89% of people diagnosed with Hodgkin lymphoma survive for five years or longer. For those under the age of 20, rates of survival are 97%. Radiation and some chemotherapy drugs, however, increase the risk of other cancers, heart disease, or lung disease over the subsequent decades.
In 2015, about 574,000 people globally had Hodgkin lymphoma, and 23,900 (4.2%) died. In the United States, 0.2% of people are affected at some point in their life. Most people are diagnosed with the disease between the ages of 20 and 34.
Signs and symptoms People with Hodgkin lymphoma may present with these symptoms: Lymphadenopathy: The most common symptom of Hodgkin lymphoma is the painless enlargement of one or more lymph nodes. The nodes may also feel rubbery and swollen when examined. The nodes of the neck, armpits and groin (cervical and supraclavicular) are most frequently involved (80–90% of the time, on average). The lymph nodes of the chest are often affected, and these may be noticed on a chest radiograph. Systemic symptoms: About one-third of people with Hodgkin lymphoma may also present with systemic symptoms, including: Itchy skin Night sweats Unexplained weight loss of at least 10% of the person's total body mass in six months or less Low-grade fever Fatigue (lassitude) Systemic symptoms such as fever, night sweats, and weight loss are known as B symptoms; thus, presence of these indicate that the person's stage is, for example, 2B instead of 2A. Splenomegaly: Enlargement of the spleen is often present in people with Hodgkin lymphoma. The enlargement is seldom massive, and the size of the spleen may fluctuate during the course of treatment. Hepatomegaly: Enlargement of the liver, due to liver involvement, is infrequent in people with Hodgkin lymphoma. Hepatosplenomegaly: The enlargement of both the liver and spleen can be caused by the same disease. Pain following alcohol consumption: Classically, involved nodes are painful after alcohol consumption, though this phenomenon is very uncommon, occurring in only two to three percent of people with Hodgkin lymphoma,Page 242 in: thus having a low sensitivity. On the other hand, its positive predictive value is high enough for it to be regarded as a pathognomonic sign of Hodgkin lymphoma. The pain typically has an onset within minutes after ingesting alcohol, and is usually felt as coming from the vicinity where there is an involved lymph node. The pain has been described as either sharp and stabbing or dull and aching. Back pain: Nonspecific back pain (pain that cannot be localised or its cause determined by examination or scanning techniques) has been reported in some cases of Hodgkin lymphoma. The lower back is most often affected. Cyclical fever: People may also present with a cyclical high-grade fever known as the Pel–Ebstein fever, or more simply "P-E fever". However, there is debate as to whether the P-E fever truly exists. Nephrotic syndrome can occur in individuals with Hodgkin lymphoma and is most commonly caused by minimal change disease. May present with airway obstruction, pleural/pericardial effusion, hepatocellular dysfunction, or bone-marrow infiltration.
Diagnosis Hodgkin lymphoma must be distinguished from noncancerous causes of lymph node swelling (such as various infections) and from other types of cancer. Definitive diagnosis is by lymph node biopsy (usually excisional biopsy with microscopic examination). Blood tests are also performed to assess function of major organs and safety for chemotherapy. Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. PET scans are also useful in functional imaging (by using a radiolabeled glucose to image tissues of high metabolism). In some cases, a gallium scan may be used instead of a PET scan.
Types The two main types of Hodgkin lymphoma are classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. The prevalence of classic Hodgkin lymphoma and nodular-lymphocyte Hodgkin lymphoma are about 90% and 10%, respectively. The morphology, phenotype, molecular features, and, therefore, the clinical behaviour and presentation of the two types differ.
Classic Classic Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) can be subclassified into four pathologic subtypes based upon Reed–Sternberg cell morphology and the composition of the reactive cell infiltrate seen in the lymph node biopsy specimen (the cell composition around the Reed–Sternberg cell(s)). Presence of EBV in Reed-Sternberg cells is most commonly found in the subtypes lymphocyte depleted HL (>70%) and mixed cellularity HL (70%), whilst being less prevalent in lymphocyte-rich HL (40%) and relatively uncommon by comparison in nodular sclerosing HL. Name Description ICD-10 ICD-O Nodular sclerosing HL Is the most common subtype and is composed of large tumor nodules showing scattered lacunar classic RS cells set in a background of reactive lymphocytes, eosinophils and plasma cells with varying degrees of collagen fibrosis/sclerosis. Mixed-cellularity subtype Is a common subtype and is composed of numerous classic RS cells admixed with numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells without sclerosis. This type is most often associated with Epstein-Barr virus infection and may be confused with the early, so-called 'cellular' phase of the nodular sclerosing subtype. This type of Hodgkin lymphoma is most commonly seen in immunocompromised people. . Lymphocyte-rich Is a rare subtype, shows many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell non-Hodgkin lymphoma (B-NHL). This form also has the most favorable prognosis. Lymphocyte depleted Is a rare subtype, composed of large numbers of often pleomorphic RS cells with only few reactive lymphocytes which may easily be confused with diffuse large cell lymphoma. Many cases previously classified within this category would now be reclassified under anaplastic large cell lymphoma. Unspecified
For the other forms, although the traditional B-cell markers (such as CD20) are not expressed on all cells, Reed–Sternberg cells are usually of B cell origin. Although Hodgkin lymphoma is now frequently grouped with other B-cell malignancies, some T-cell markers (such as CD2 and CD4) are occasionally expressed.
Hodgkin cells produce interleukin-21 (IL-21), which was once thought to be exclusive to T-cells. This feature may explain the behavior of classic Hodgkin lymphoma, including clusters of other immune cells gathered around HL cells (infiltrate) in cultures.
Nodular lymphocyte predominant Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is another subtype of Hodgkin lymphoma distinct from classic Hodgkin lymphoma and is characterized by the presence of popcorn cells which express CD20. Due to these differences, among others, NLPHL is often treated differently from classic Hodgkin lymphoma, including using rituximab in combination with AVBD chemotherapy, though individual cases vary and clinical trials are ongoing.
Staging The staging is the same for both Hodgkin and non-Hodgkin lymphomas.
After Hodgkin lymphoma is diagnosed, a person will be staged by undergoing a series of tests and procedures that will determine what areas of the body are affected. These procedures may include documentation of their histology, a physical examination, blood tests, chest X-ray radiographs, computed tomography (CT)/positron emission tomography (PET)/magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis, and usually a bone marrow biopsy. PET scan is now used instead of the gallium scan for staging. On the PET scan, sites involved with lymphoma light up very brightly enabling accurate and reproducible imaging. In the past, a lymphangiogram or surgical laparotomy (which involves opening the abdominal cavity and visually inspecting for tumors) were performed. Lymphangiograms or laparotomies are very rarely performed, having been supplanted by improvements in imaging with the CT scan and PET scan.
On the basis of this staging, the person will be classified according to a staging classification (the Ann Arbor staging classification scheme is a common one): Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie); Stage II is involvement of two or more lymph node regions on the same side of the diaphragm (II) or of one lymph node region and a contiguous extralymphatic site (IIe); Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) or limited contiguous extralymphatic organ or site (IIIe, IIIes); Stage IV is disseminated involvement of one or more extralymphatic organs.
The absence of systemic symptoms is signified by adding "A" to the stage; the presence of systemic symptoms is signified by adding "B" to the stage. For localized extranodal extension from mass of nodes that does not advance the stage, subscript "E" is added. Splenic involvement is signified by adding "S" to the stage. The inclusion of "bulky disease" is signified by "X".
Pathology Macroscopy Affected lymph nodes (most often, laterocervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform; in some histological subtypes (e.g. nodular sclerosis) a nodular aspect may appear. A fibrin ring granuloma may also be seen.
Microscopy
Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (RSC) (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed–Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45−, CD30+, CD15+/− immunophenotype. In approximately 50% of cases, the Reed–Sternberg cells are infected by the Epstein–Barr virus.
Characteristics of classic Reed–Sternberg cells include large size (20–50 micrometres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed close to the nuclear membrane). Almost all of these cells have an increased copy number of chromosome 9p/9p24.1.
Variants: