Classic Hodgkin lymphoma

by Jason Wasserman MD PhD FRCPC
September 28, 2024

Classic Hodgkin lymphoma (CHL) is a type of cancer that starts in the lymph nodes, which are part of the body’s immune system. It involves a specific type of cell called the Reed-Sternberg cell, which is abnormal and larger than normal lymphocytes (a type of white blood cell). This type of cancer is known for its unique appearance under the microscope and for being highly treatable, especially when caught early.

What are the symptoms of classic Hodgkin lymphoma?

Symptoms of classic Hodgkin lymphoma can vary, but some common signs include:

• Swollen lymph nodes, often in the neck, underarms, or groin.
• Unexplained weight loss.
• Persistent fever.
• Night sweats.
• Feeling tired.

Other conditions can also cause these symptoms, so it is important to see a doctor if you experience them.

What causes classic Hodgkin lymphoma?

The exact cause of classic Hodgkin lymphoma is not known. It is thought to occur when certain genetic changes cause some cells in the lymph nodes to grow abnormally, leading to the formation of Reed-Sternberg cells. While the exact reasons for these changes are unclear, some risk factors, such as having a weakened immune system or a history of Epstein-Barr virus (EBV) infection, might increase the likelihood of developing this type of cancer. However, not everyone with these risk factors will develop classic Hodgkin lymphoma.

What are the subtypes of classic Hodgkin lymphoma?

Classic Hodgkin lymphoma is divided into four subtypes. Each subtype has unique features when looked at under a microscope and can behave slightly differently.

Nodular sclerosis classic Hodgkin lymphoma (NSCHL)

Nodular sclerosis classic Hodgkin lymphoma (NSCHL) is the most common subtype of classic Hodgkin lymphoma. It is characterized by bands of fibrotic tissue that divide the lymph nodes into nodules. These nodules contain large Reed-Sternberg (HRS) cells along with a mix of other immune cells. NSCHL often affects the lymph nodes in the chest and is usually associated with fibrosis (thickening of the lymph node capsule).

A unique feature of NSCHL is the presence of “lacunar cells.” This type of Reed-Sternberg cell appears to sit in a hole or space (lacuna) due to how the cell’s cytoplasm retracts during tissue processing. In some cases, NSCHL can look similar to other subtypes, especially lymphocyte-rich CHL (LRCHL). A “syncytial variant” variation involves sheets of numerous tumour cells, often with areas of necrosis (cell death).

Mixed cellularity classic Hodgkin lymphoma (MCCHL)

In mixed cellularity classic Hodgkin lymphoma (MCCHL), the structure of the lymph nodes is destroyed and replaced by a mix of different immune cells, including Reed-Sternberg cells, small lymphocytes, histiocytes (a type of immune cell), eosinophils, and plasma cells. The amount of each type of immune cell can vary from case to case. Reed-Sternberg cells in MCCHL often have more than one nucleus and are scattered throughout the lymph node.

MCCHL is more likely to be associated with Epstein-Barr virus (EBV) infection than other subtypes. Unlike NSCHL, fibrosis (thickening) in MCCHL is usually not as noticeable, and the fibrous bands or capsule thickening seen in NSCHL are not present in this subtype.

Lymphocyte-rich classic Hodgkin lymphoma (LRCHL)

Lymphocyte-rich classic Hodgkin lymphoma (LRCHL) is characterized by a nodular or sometimes diffuse pattern made up mainly of small lymphocytes (a type of white blood cell). Neutrophils and eosinophils (other types of white blood cells) are usually absent. In nodular cases, the nodules compress the surrounding tissue and may contain germinal centers (areas where B cells develop) that are small or shrunken. Reed-Sternberg cells are found mostly in the nodules but outside the germinal centers.

LRCHL can be confused with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). However, the presence of Reed-Sternberg cells with certain features typical of classic Hodgkin lymphoma helps distinguish LRCHL from NLPHL. Sometimes, other types of lymphoma, like small lymphocytic lymphoma, may have scattered Reed-Sternberg cells, mimicking LRCHL.

Lymphocyte-depleted classic Hodgkin lymphoma (LDCHL)

Lymphocyte-depleted classic Hodgkin lymphoma (LDCHL) is the rarest subtype, making up less than 2% of classic Hodgkin lymphoma cases. It is strongly associated with EBV infection. LDCHL usually shows a diffuse pattern, where Reed-Sternberg cells are the main feature, with few other lymphocytes present. Eosinophils and plasma cells are also scarce, and there are no fibrous bands like those seen in NSCHL. LDCHL can appear in two forms: one with sheets of Reed-Sternberg cells and another with areas of dense fibrosis (scarring) and many histiocytes. LDCHL and MCCHL are thought to represent different ends of a spectrum of classic Hodgkin lymphoma.

Microscopic features

When pathologists examine classic Hodgkin lymphoma under a microscope, they look for specific features:

• Reed-Sternberg (HRS) cells: These are the hallmark cells of classic Hodgkin lymphoma. They are much larger than normal lymphocytes and have large nuclei (the cell’s control center) with prominent nucleoli (small, round structures inside the nucleus). A classic Reed-Sternberg cell has at least two nuclei with a prominent, reddish nucleolus in each, giving it an “owl-eye” appearance. HRS cells are often rare, making up only a small percentage (0.1–10%) of the cells in tumour.
• Hodgkin cells: These are mononuclear (having a single nucleus) cells that are related to Reed-Sternberg cells. They are also larger than normal lymphocytes and have a prominent nucleolus.
• Lacunar cells: These cells are characteristic of NSCHL and appear to sit in holes or spaces (lacunae) because they shrink during tissue processing.
• Mummified cells: These are cells with dense cytoplasm and shrunken (pyknotic) nuclei, representing apoptotic (dying) cells.
• Microenvironment: The area around the Reed-Sternberg cells is made up of non-cancerous cells, including various types of immune cells like T cells, eosinophils, histiocytes, and plasma cells. The types of surrounding cells can vary depending on the subtype of classic Hodgkin lymphoma and the presence of EBV. This microenvironment is important in the progression of the disease and the patient’s response to therapy.

Immunohistochemistry

Immunohistochemistry (IHC) is a technique pathologists use to identify specific proteins on the surface of cells. This helps confirm the diagnosis of classic Hodgkin lymphoma. In this type of cancer, the following patterns are typically seen:

• CD30: Almost all cases of classic Hodgkin lymphoma show the presence of a protein called CD30 on the Reed-Sternberg cells. This protein is usually found on the cell membrane with a more intense staining near the Golgi area (a part of the cell that processes proteins).
• CD15: Most classic Hodgkin lymphoma cases also express CD15, though it may appear in different patterns and sometimes be focal (only in certain areas).
• PAX5: This is a marker that indicates the B cell origin of Reed-Sternberg cells. In classic Hodgkin lymphoma, PAX5 is usually present but weaker than normal B cells.
• Other markers: Proteins like CD20 and other B cell antigens (CD19, CD79a) may sometimes be present, though less frequently. Reed-Sternberg cells also express a protein called IRF4 (MUM1). A few cases may show the presence of proteins usually found on T cells, like CD4.
• EBV: In some cases, Epstein-Barr virus (EBV) is found in Reed-Sternberg cells, which can be detected using a special test called in situ hybridization for EBER.

The background cells, including T cells and B cells, also vary among the subtypes of classic Hodgkin lymphoma and are important in the diagnosis.

What is the prognosis for a person diagnosed with classic Hodgkin lymphoma?

Classic Hodgkin lymphoma has a high cure rate, especially when detected early and treated promptly. With modern treatment options like chemotherapy, radiation therapy, and targeted therapies, many patients achieve long-term remission or even a complete cure. The prognosis can depend on factors like the disease’s stage at diagnosis, specific symptoms (like fever, night sweats, and weight loss), and how well the patient responds to treatment.

Overall, classic Hodgkin lymphoma is considered one of the most treatable forms of cancer, and patients often do very well with appropriate care. Regular follow-up is important to monitor for any signs of recurrence or late effects of treatment.