Hodgkin Lymphoma & Reed-Sternberg

Introduction

Lymphomas are a group of diseases caused by malignant lymphocytes that accumulate in lymph nodes leading to lymphadenopathy. The major subdivision of lymphomas is into Hodgkin lymphoma (presence of Reed-Sternberg cells) and non-Hodgkin lymphoma. 

Hodgkin lymphoma is distinguished from non-Hodgkin lymphoma by two main features.

1. Presence of Reed-Sternberg cells.
2. Strong tendency for Hodgkin lymphoma to arise within a single lymph node group and spread from one lymph node group to the next.

Thus, staging has a greater influence on the treatment of Hodgkin lymphoma than on non-Hodgkin lymphomas.

What are Reed-Sternberg cells?

Reed-Sternberg cells are large, abnormal white blood cells that are found in the lymph nodes of people with Hodgkin lymphoma. They are the hallmark of this type of cancer. Reed-Sternberg cells are thought to be derived from B cells, a type of white blood cell that produces antibodies.  This B cell has a ‘crippled’ immunoglobulin gene caused by the acquisition of mutations that prevent synthesis of full-length immunoglobulin. They have lost many of the characteristics of B cells and have become cancerous.

Reed-Sternberg cells are typically large and have multiple nuclei. Reed-Sternberg cells may also contain eosinophilic inclusion bodies, which are structures that stain pink with eosin, a type of dye used in histology.

Reed-Sternberg cells can produce a variety of cytokines, which are proteins that communicate with other cells. These cytokines can help to promote the growth and survival of Reed-Sternberg cells and can also suppress the immune system.

What are the different subtypes of Hodgkin lymphoma?

The World Health Organization (WHO) divides Hodgkin lymphoma into two main subtypes. They are the Classical Hodgkin lymphoma and Nodular lymphocyte-predominant Hodgkin lymphoma. Classical Hodgkin lymphoma is the more common subtype, accounting for about 90% of cases. Nodular lymphocyte-predominant Hodgkin lymphoma is a less common subtype, accounting for about 10% of cases.

Classical Hodgkin lymphoma

Classical Hodgkin lymphoma has four subtypes. 

1. Nodular sclerosis is the most common form of Hodgkin lymphoma in young adults. It is characterized by two pathologic findings.
   • The presence of lacunar cells which are variant Reed-Sternberg cells. Their ample cytoplasm tends to retract during formalin fixation so that they are surrounded by empty space. 
   • The presence of large bands of collagen that are deposited by reactive fibroblasts. This subtype is rarely associated with Epstein-Barr virus. 
2. Mixed cellularity Hodgkin lymphoma. This subtype is most common in older males where the lymph nodes are composed of a mixture of inflammatory cells and numerous Reed-Sternberg cells with intermediate numbers of lymphocytes. About 70% of cases are associated with EBV. 
3. Lymphocyte-rich Hodgkin lymphoma. This is not a common subtype with predominantly small lymphocytes. About 40% of cases are associated with EBV. 
4. Lymphocyte-depleted subtype. This is a rare subtype except in HIV positive patients. There is a dominance of Reed-Sternberg cells with a sparse number of lymphocytes. It is almost always associated with EBV.

Nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by the presence of lymphocyte-predominant cells, sometimes termed “popcorn cells,” which are a variant of Reed-Sternberg cells. It is uncommon and found primarily in young to middle-aged males within axillary or cervical lymph nodes. Classic Reed-Sternberg cells are rare or absent. 

It is important to know the subtype since it plays a large part in determining the type of treatment the patient will receive.

Summary of Hodgkin Lymphoma (HL) Classifications

Classification	Characteristics
Classical Hodgkin Lymphoma
Nodular Sclerosis	Most common in young adults Presence of lacunar cells (a variant of Reed-Sternberg cells) Presence of large collagen bands deposited by reactive fibroblasts
Mixed Cellularity	Most common in older males A combination of inflammatory and Reed-Sternberg cells with lymphocytes ~70% associated with Epstein-Barr virus (EBV)
Lymphocyte-rich	Predominantly small lymphocytes with scanty Reed-Sternberg cells 40% associated with EBV
Lymphocyte-depleted	Rare other than in HIV patients PredominantlyReed-Sternberg cells with scanty lymphocytes Almost always associated with EBV
Nodular lymphocyte-predominant Hodgkin lymphoma Uncommon Primarily in young to middle-aged males The tumor cells have nuclei that are lobulated or popcorn-kernel like (a variant of Reed-Sternberg cells) Classic Reed-Sternberg cells are rare or absent

Hodgkin Lymphoma Symptoms

Hodgkin lymphoma (HL) is a type of cancer that starts in the lymphatic system. The lymphatic system is a network of vessels and nodes throughout the body that helps to fight infection. Hodgkin lymphoma is a relatively rare type of cancer, accounting for about 1% of all cancers.

The most common clinical sign of Hodgkin lymphoma is a painless, asymmetrical enlargement of the lymph nodes in the neck, underarms, or groin. The most common lymph node involvement is the cervical nodes followed by the axillary nodes and then the inguinal nodes. The lymph nodes may be firm, discrete and rubbery to the touch. Clinical splenomegaly occurs during the course of the disease in 50% of patients and is seldom massive. 

• Fever
• Pruritus / itching
• Alcohol-induced pain in the areas where disease is present
• Hypermetabolism Hodgkin lymphoma symptoms
  • Weight loss
  • Night sweating
  • Anorexia
  • Cachexia

Less common Hodgkin lymphoma symptoms and signs may include:

• Bone pain
• Headache
• Skin rash
• Jaundice (yellowing of the skin and eyes)
• Peripheral neuropathy (numbness and tingling in the hands and feet)

How is Hodgkin lymphoma diagnosed?

Staging is performed by thorough clinical examination together with chest X-ray and CT scan to detect intrathoracic, intra-abdominal or pelvic disease. MRI scanning may be needed for particular sites while PET scan may be useful for staging and when combined with CT may detect small foci of residual disease following treatment.  

Laboratory tests

• Complete blood count (CBC) and peripheral blood smear: A CBC can show normochromic, normocytic anemia, lymphocytosis (an increased number of lymphocytes), or neutrophilia (an increased number of neutrophils) in some patients with Hodgkin lymphoma. Eosinophilia is also frequent. Advanced disease is associated with lymphopaenia and loss of cell-mediated immunity. 
• Serum protein electrophoresis (SPEP): A SPEP can show an elevated albumin level in Hodgkin lymphoma.
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP): Usually raised
• Serum lactodehydrogenase (LDH): Increased in 30 – 40% of cases. 
• Immunofixation electrophoresis (IFE): An IFE can show an elevated monoclonal gammopathy (M protein) level in Hodgkin lymphoma.

Imaging studies

• X-rays: X-rays can show enlarged lymph nodes and other signs of Hodgkin lymphoma.
• Computed tomography (CT) scans: CT scans can provide more detailed images of the lymph nodes and other organs in the body. CT scans can be used to look for enlarged lymph nodes and other signs of Hodgkin lymphoma.
• Positron emission tomography (PET) scans: PET scans can show areas of increased metabolic activity in the body. PET scans can be used to look for enlarged lymph nodes and other signs of Hodgkin lymphoma.

Diagnosis of Hodgkin lymphoma

The diagnosis of Hodgkin lymphoma is confirmed by the presence of Reed-Sternberg cells in a biopsy specimen of lymph node tissue. Reed-Sternberg cells are large, abnormal white blood cells that are characteristic of Hodgkin lymphoma. The Reed-Sternberg cells stain CD30 and CD15 positive but CD45- and for other B-cell markers. In contrast, nodular lymphocyte-predominant HL are uniformly positive for B-cell markers such as CD20 but CD15, CD30 and EBV negative. 

Once a diagnosis of Hodgkin lymphoma is confirmed, the doctor will need to determine the stage of the disease. The stage of Hodgkin lymphoma is determined by the location of the cancer and the presence of certain clinical signs. The stage of Hodgkin lymphoma is important for determining the prognosis for patients with Hodgkin lymphoma and for guiding treatment decisions.

What are the stages of Hodgkin lymphoma? 

The Ann Arbor staging system is the most commonly used staging system for Hodgkin lymphoma (HL). The Ann Arbor staging system is based on the location of the cancer and the presence of certain clinical signs. The stage of Hodgkin lymphoma is important for determining the prognosis for patients with Hodgkin lymphoma and for guiding treatment decisions.

The Ann Arbor staging system for Hodgkin lymphoma is as follows:

• Stage I: The cancer is limited to a single lymph node region or to a single organ outside of the lymphatic system.
• Stage II: The cancer is limited to two or more lymph node regions on the same side of the diaphragm, or to a single organ outside of the lymphatic system and to adjacent lymph node regions.
• Stage III: The cancer is located in lymph node regions on both sides of the diaphragm, or it is located in the spleen or bone marrow.
• Stage IV: The cancer is disseminated to multiple organs outside of the lymphatic system for example it refers to diffuse or disseminated disease in the bone marrow, liver and other extranodal sites.

In addition to the stage number, the letters A, B, E, or X may be used to further classify the stage of Hodgkin lymphoma.

• Category A: The patient does not have B symptoms (unexplained fever above 38 °C, night sweats, or weight loss).
• Category B: The patient has B symptoms.
• Category E: The patient has Hodgkin lymphoma cells in organs or tissues outside of the lymphatic system.
• Category X: Indication of bulky disease,  a lymphoma that is greater than 10 cm (4 inches) wide

For example, a patient with Hodgkin lymphoma that is localized to a single lymph node region in the neck and who does not have B symptoms would be classified as stage I, category A (I, A). A patient with Hodgkin lymphoma that is located in lymph node regions on both sides of the diaphragm and who has B symptoms would be classified as stage III, category B (III, B).

Hodgkin lymphoma treatment

Hodgkin lymphoma treatment depends on the stage of the disease and the patient’s age and health. The main goal of treatment is to achieve remission, which is a state in which there is no evidence of the disease.

Radiation therapy

Radiation therapy is a type of Hodgkin lymphoma treatment that uses high-energy rays to kill cancer cells. Radiation therapy is often used to treat early-stage Hodgkin lymphoma (stage I or II). Radiation therapy is typically given in short daily sessions over several weeks.

Chemotherapy

Chemotherapy is a type of Hodgkin lymphoma treatment that uses drugs to kill Hodgkin lymphoma cancer cells. Chemotherapy is typically given in cycles, with each cycle lasting several weeks. Cyclical chemotherapy is used for stage III or IV disease and also in stage I and II patients who have bulky disease, type B symptoms or have relapsed following initial radiotherapy. The combination of adriamycin, bleomycin, vinblastine and dacarbazine or ABVD is now most widely used.

Stem cell transplantation

Stem cell transplantation is a procedure in which healthy stem cells are transplanted into the patient’s body. Stem cells are the immature cells that develop into different types of blood cells. Stem cell transplantation can be used to treat patients with Hodgkin lymphoma who have relapsed after initial treatment or who have not responded to initial treatment.

Immunotherapy

Immunotherapy is a type of treatment that uses the patient’s own immune system to fight cancer. Immunotherapy drugs can help to activate the immune system to kill cancer cells. Immunotherapy is a newer type of treatment for Hodgkin lymphoma and is still under investigation.

Hodgkin lymphoma treatment according to stage

The following is a general overview of the Hodgkin lymphoma treatment according to stage:

• Stage I: Radiation therapy is the most common treatment for stage I Hodgkin lymphoma. Patients with stage I Hodgkin lymphoma have a very good prognosis and can be cured with radiation therapy alone.
• Stage II: Radiation therapy is also the most common treatment for stage II Hodgkin lymphoma. Patients with stage II Hodgkin lymphoma may also need chemotherapy, depending on the specific characteristics of their cancer.
• Stage III: Patients with stage III Hodgkin lymphoma typically receive chemotherapy. Patients with stage III Hodgkin lymphoma who respond well to chemotherapy may also receive radiation therapy.
• Stage IV: Patients with stage IV Hodgkin lymphoma typically receive chemotherapy. Patients with stage IV Hodgkin lymphoma may also receive other treatments, such as radiation therapy or stem cell transplantation.

Hodgkin lymphoma prognosis

The Hodgkin lymphoma prognosis is generally good. With treatment, most patients with Hodgkin lymphoma can achieve remission. However, the prognosis for patients with Hodgkin lymphoma depends on a number of factors, including the stage of the disease, the patient’s age and health, and the type of treatment received.

Patients with early-stage Hodgkin lymphoma (stage I or II) have a very good prognosis and can be cured with radiation therapy or chemotherapy. Patients with advanced-stage Hodgkin lymphoma (stage III or IV) have a worse prognosis, but many patients can still be cured with more aggressive treatment regimens.

Frequently Asked Questions (FAQs)

What is the survival rate for Hodgkin lymphoma?

The survival rate for Hodgkin lymphoma varies depending on several factors, but overall, it is a highly treatable cancer with encouraging statistics.

General survival rates

• 5-year relative survival rate: This compares people with Hodgkin lymphoma to the general population. In the United States, it’s around 89%, meaning 89% of people with the disease are expected to survive at least 5 years after diagnosis.
• 10-year relative survival rate: This figure rises to around 80%.

Survival rates by stage

• Early-stage (localized): 5-year survival rate is 93-95%.
• Advanced-stage: 5-year survival rate is around 83%.

Factors affecting survival

• Stage of cancer: Earlier stages have better prognoses.
• Age and overall health: Younger, healthier individuals tend to fare better.
• Subtype of Hodgkin’s lymphoma: Certain subtypes have slightly different survival rates.
• Treatment response: How well the cancer responds to therapy plays a crucial role.

Important points to remember

• These are estimates and cannot predict individual outcomes.
• Advancements in treatment are constantly improving survival rates.

Who is most likely to get Hodgkin lymphoma?

While anyone can develop Hodgkin lymphoma, certain factors put some individuals at higher risk:

Age

• Young adults (20-40 years old): This is the most common age group for diagnosis, with a second peak occurring in older adults (over 75).

Gender

• Men: Slightly more likely than women to develop Hodgkin lymphoma. However, the specific subtype called nodular sclerosis Hodgkin lymphoma is more common in women.

Weakened immune system

• Medical conditions: Individuals with HIV/AIDS, autoimmune diseases, or who have received organ transplants have a higher risk due to compromised immune function.
• Immunosuppressive medications: Taking medications that suppress the immune system, such as after an organ transplant, can increase risk.

Previous infections

• Epstein-Barr virus (EBV): This virus, responsible for mononucleosis, is linked to some Hodgkin lymphoma cases, although the exact connection isn’t fully understood.

Family history

• Siblings or identical twins of someone with Hodgkin lymphoma have a slightly higher risk, though still uncommon.

Other factors

• Obesity: Being significantly overweight, particularly in women, might be associated with a higher risk.
• Smoking: While the link isn’t as strong as with other cancers, smoking may slightly increase the risk of Hodgkin lymphoma.

Important points to remember

• Having one or more of these risk factors doesn’t guarantee you will develop Hodgkin lymphoma. Many people with these factors never get the disease.
• Conversely, some individuals with no known risk factors can still develop it.

Is lymphoma a type of leukemia?

These are two distinct types of blood cancer, despite some similarities. Here’s a breakdown to clarify the differences:

Origin

• Lymphoma: Starts in the lymphatic system, specifically in lymph nodes. The lymphatic system plays a crucial role in immunity, transporting white blood cells that fight infection.
• Leukemia: Begins in the bone marrow, where blood cells are produced. Bone marrow is the spongy tissue inside bones responsible for generating various blood cell types.

Target cells

• Lymphoma: Primarily affects a specific type of white blood cell called lymphocytes. Lymphocytes are crucial for immune function and come in different types (B-cells and T-cells), each with distinct roles.
• Leukemia: Can affect various blood cell types, including lymphocytes, but also other white blood cells like granulocytes and monocytes, as well as red blood cells and platelets.

Spread

• Lymphoma: Typically spreads through the lymphatic system, involving lymph nodes in different parts of the body. In some cases, it can also spread to other organs or the bloodstream.
• Leukemia: Spreads mainly through the bloodstream, affecting bone marrow and potentially other organs.

Symptoms

• Lymphoma: Common symptoms include swollen lymph nodes, fever, fatigue, weight loss, night sweats, and itchiness.
• Leukemia: Symptoms can vary depending on the type and affected cell type, but might include fatigue, fever, infections, easy bleeding or bruising, and pale skin.

Treatment

• Lymphoma: Treatment options depend on the type and stage of the disease, but often involve chemotherapy, radiation therapy, and sometimes immunotherapy.
• Leukemia: Similar to lymphoma, treatment depends on the specific type and severity, but frequently involves chemotherapy, radiation, and potentially stem cell transplantation.

Is lymphoma benign or malignant?

The term “lymphoma” itself doesn’t specify whether it’s benign or malignant. It refers to a group of cancerous and non-cancerous tumors that develop in the lymphatic system, which plays a crucial role in your immune system.

Feature	Benign Lymphoma	Malignant Lymphoma
Growth Pattern	Non-cancerous; lymphocytes don’t spread uncontrollably	Cancerous; lymphocytes grow abnormally and spread through lymph nodes and potentially other organs
Examples	Castleman’s disease, Lymphoid hyperplasia, Lipoma-like lymphoma	Hodgkin’s lymphoma, Non-Hodgkin lymphoma (various subtypes)
Symptoms	May include swollen lymph nodes, fever, night sweats, fatigue, weight loss (depending on type and severity)	Similar symptoms as benign lymphoma, but typically more persistent and severe
Spread	Localized, mostly affecting specific lymph node groups	Can spread to other lymph node groups, organs, and the bloodstream
Prognosis	Good; no risk of spreading or becoming cancerous	Varies depending on stage and type; some types highly treatable, others require ongoing management
Treatment	May involve monitoring, medication (steroids), or surgery; often no treatment needed	Typically involves chemotherapy, radiation therapy, or stem cell transplantation
Risk Factors	Unknown or linked to autoimmune disorders, infections, or abnormal blood vessel development	Risk factors not fully understood; may include age, weakened immune system, genetic predisposition
Overall Impact	Usually manageable with minimal impact on lifespan	Can significantly impact quality of life and lifespan, though advancements in treatment offer improved outcomes

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

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