Lymphoma

Lymphoma can be classified into Hodgkin’s lymphoma and non-Hodgkin’s lymphoma, with the latter being more common in Hong Kong.

Non-Hodgkin’s lymphoma ranked ninth among the most common types of cancer in Hong Kong.  In 2021, there were 1,124 new cases of non-Hodgkin’s lymphoma, accounting for 2.9% of all new cancer cases in Hong Kong.

Non-Hodgkin’s lymphoma is the eighth leading cause of cancer deaths in Hong Kong. In 2021, a total of 388 people died from this cancer, accounting for 2.6% of all cancer deaths.

Lymphoma ranked second among the most common cancers in children and adolescents (0-19 years old) in Hong Kong. There were 20 new cases in 2021, accounting for 11.2% of newly diagnosed cancer cases in this age group.

What is lymphoma? 

Lymphoma is a cancer that originates in the lymphatic system, consisting of cancerous (malignant) lymphatic cells. The lymphatic system is part of the body’s immune system. It is a network of fluid channels that contains numerous lymph nodes and lymphatic vessels, carrying lymphatic cells all around the body to fight infection. When normal lymphatic cells undergo malignant transformation, they start to replicate uncontrollably in the lymph nodes, eventually causing cancer, which is lymphoma. There are different types of lymphatic cells in the body, each with different characteristics and functions. Hence, lymphoma that originates from different types of lymphatic cells can present diversely, adding complexity to the disease. Lymphoma does not refer to a single disease entity, but rather a general term that describes all cancers that originate from the lymphatic system.

• The cause of lymphoma is not completely understood, but it can be related to:
  • Genetic disease
  • Radiation
  • Chemotherapy
  • Autoimmune disease/ Immunodeficiency
  • Viral infection
  • Bacterial infection
• Recently, research has suggested that viruses such as Epstein- Barr Virus (EBV), Human T-cell leukaemia virus type-1 (HTLV-1), Hepatitis C virus, Kaposi sarcoma-associated herpes virus, etc. may be associated with various subtypes of non-Hodgkin lymphoma.
• Bacterial infection can cause lymphoma indirectly. Infection of the stomach by Helicobacter pylori is associated with a subtype of non-Hodgkin lymphoma known as gastric MALT lymphoma. Patients with gastric MALT lymphoma can be treated by antibiotics that target Helicobacter pylori.
• Although infections can be associated with the development of lymphoma, just like other cancers, lymphoma is not infectious nor transmissible.  

• Swelling of the lymph nodes (most common)
  • can involve 1 or more lymph nodes
  • is usually painless
  • most commonly affects lymph nodes of the neck, followed by the armpit and groin regions
  • The patient is often the first to realize that he/she has lymphoma
• Unexplained fever
• Heavy, drenching sweats at night
• Unexplained weight loss
• Itching of the skin
• Tiredness
• Of note, NK/T cell lymphoma may present with chronic nasal symptoms. 

If lymphoma has spread to the bone marrow where blood cells are produced, it can cause anaemia, bruising, bleeding and vulnerability to infections. However, the above symptoms are not unique to lymphoma. Although swelling of the lymph nodes is the most common symptom of lymphoma, other inflammatory conditions such as tonsillitis, tuberculosis and metastatic cancers can also cause enlargement of the lymph nodes, which thus complicates the diagnosis of lymphoma. If any of the above symptoms are found, one should seek medical help as soon as possible. As with other cancers, diagnosis at an early stage is directly related with chances of recovery.

In order to determine whether an enlarged lymph node is caused by lymphoma, the following components are essential:

• Medical history
• Clinical examination
• Pathological examination
  • Tissue biopsy to confirm the diagnosis of lymphoma

Once the diagnosis of lymphoma is confirmed, the patient will undergo the following investigations to access the severity and complications of the disease, to assess the fitness to receive treatment, to assess the stage of the lymphoma and to assess the prognosis: 

• Blood tests – to determine the blood counts, kidney and liver function, electrolytes, lactate dehydrogenase (LDH), urate levels, virology studies to assess the presence of Hepatitis B virus and HIV  
• Bone marrow biopsy for staging
  • The patient lies on their side on a couch, while a long, hollow needle is inserted into the back of the hipbone (pelvis). Bone marrow is extracted for examination under a microscope to determine if the cells are cancerous.
  • The process lasts about 15–20 minutes and can be done in the doctor’s clinic. Soreness can be reduced by mild painkillers in the following few days. Medical help should be sought if symptoms fail to resolve. 
• Investigations to access your fitness to receive chemotherapy such as an echocardiogram (an ultrasound to access the structure and function of the heart) and lung function studies 
• PET-CT scan
  • Assess the spread of cancer and to stage the lymphoma

• Can be classified into 2 main types based on different clinical manifestations and pathological features:
  • Hodgkin lymphoma (HL) – Two subtypes: Most commonly classical Hodgkin lymphoma (cHL) and rarely nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) 
  • Non-Hodgkin lymphoma (NHL)
• There are 4 subtypes of  Classical Hodgkin lymphoma and 3 major subtypes of non-Hodgkin lymphoma have been identified based on the cell-of-origin of the lymphoma (namely B-cell, T-cell and NK/T-cell lymphoma). B-cell lymphomas (the commonest subtype of lymphoma worldwide) is further subdivided into high-grade B-cell lymphoma (e.g. diffuse large B-cell lymphoma and Burkitt lymphoma) and low-grade B-cell lymphoma or lymphoproliferative disorders (e.g. follicular lymphoma)
• In Hong Kong, non-Hodgkin lymphoma is more prevalent, and is also one of the top ten causes of cancer death.

Classical Hodgkin Lymphoma

• Persons of any age can be affected. However, there is a bimodal age distribution, of whom people aged 15-30 and elderly are most commonly affected.
• Men are more commonly affected.
• In terms of its natural history, there is a usual pattern of progression. It tends to spread orderly from the lymph nodes of the neck, to the armpit, thorax, groin; eventually infiltrating the bone marrow and other distant organs.
• Both early and late stages Hodgkin lymphoma respond well to treatment. Overall, more than 80% of cases can be cured.

Non-Hodgkin Lymphoma 

• The clinical manifestations and pathological features are more complex and diverse when compared to classical Hodgkin lymphoma.
• In terms of pathological features, there are numerous subtypes. Nevertheless, they can be broadly separated into 3 main categories:
  • B cell lymphoma
  • T cell lymphoma
  • NK/T cell lymphoma
• B-cell lymphomas can be further classified into 2 subtypes depending on its clinical characteristics and behaviour:
  • Low-grade or indolent B-cell lymphomas or lymphoproliferative disorders
    • Without treatment, majority of patients diagnosed can still survive for 5-10 years due to its slow-growing nature. With treatment advances, may subtypes of indolent lymphomas can be cured or achieve a long-term remission.
    • Follicular lymphoma is the commonest subtypes. Less common subtypes include chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and marginal zone B-cell lymphoma and Waldenström Macroglobulinaemia.
  • High-grade or aggressive B-cell lymphomas
    • Without treatment, patients diagnosed with aggressive/ highly aggressive lymphoma can lose their lives in matter of months. These subtypes of lymphomas have higher cure rates with current treatment approaches.
    • Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype.  
    • Burkitt lymphoma is another aggressive subtype of high-grade B-cell lymphoma. 
• The incidence rate, epidemiology and treatment response all vary, depending on the exact subtype of non-Hodgkin lymphoma. Additionally, the pattern of natural disease progression is also less orderly when compared to Hodgkin lymphoma.
• It may affect organs that lie outside the lymphatic system (especially patients with NK/T cell lymphomas), e.g. nasal cavity, nasopharynx, skin, the gut, the central nervous system, etc. In such case, the disease shall be further classified into extranodal, since it is no longer localizd to the lymph nodes. 
• Accurate classification of non-Hodgkin lymphoma into the various subtypes play an important role in assessing the severity of condition, as well as formulating an appropriate management plan.

The Ann Arbor staging system was first system used in to describe the size and extent of cancer spread. There are 4 stages in total, stages I and II are considered early stages while stages III and IV indicate advanced stages.

Stage 1: Lymphoma is found in one lymphatic area (lymph nodes, tonsils, thymus, or spleen). 

Stage 2: Lymphoma is found in two or more lymph node groups but all affected nodes on the same side of (either above or below) the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen). 

Stage 3: Lymphoma is found in lymph nodes both above and below (on both sides of) the diaphragm. 

Stage 4: Lymphoma is found in one or more organs but not in the lymphatic area, i.e. outside lymph nodes, tonsils, thymus or spleen; or in an organ that is not in the lymphatic area and has spread to lymph nodes afar from that organ; or in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs. 

To fine-tune the main staging numbers I-IV, an alphabet may be attached to its right. If none of the three most common symptoms are found, including weight loss, fever and night sweats of lymphoma, the letter to add is “A” (e.g. stage IA); or if one or more of these symptoms are found, “B” should be the classifier (e.g. stage IB).

Lymphoma is a curable disease. With appropriate treatment, majority of patients will see their condition in remission for many years or even cured. Monoclonal antibodies and chemotherapy are the mainstay of treatment against lymphoma achieving good response rates. Radiotherapy may occasionally be used. 

Chemotherapy

• Anti-cancer drugs taken orally as tablets or capsules, or injected into a vein. Side effects include: 
  • Loss of appetite
  • Nausea
  • Oral ulcer
  • Hair loss 
  • Diarrhoea
  • Weakened immune system 

Steroid therapy

• Corticosteroids (Prednisolone is most commonly used) are often given with chemotherapy as part of the lymphoma therapy. It may also alleviates symptoms such as nausea. 
• Side effects: 
  • Indigestion, episgastric pain and peptic ulcer disease
  • Increased appetite
  • Restlessness/ Increased energy
  • Difficulty in sleeping
  • High blood sugar levels
  • Risk of infections 
  • Reactivation of tuberculosis 
  • Reactivation of hepatitis B-virus (prophylaxis with antiviral is necessary in all hepatitis B carriers) 
  • Osteoporosis 

Radiotherapy

• Radiotherapy releases targeted high-energy rays at the tumour to destroy cancer cells while causing minimum effects to normal ones. 
• Side effects: 
  • Tiredness 
  • Skin changes over the targeted area (e.g. Redness) 
  • Other side effects may depend on the specific treated area

Radiotherapy alone is not the mainstay nowadays for treating lymphomas. Chemotherapy and Radiotherapy may be used sequentially in order to increase the remission rates in certain subtypes of lymphomas such as Stage I or II Classical Hodgkin lymphoma.

Immunotherapy 

These drugs specifically bind to a target protein called CD20, that is expressed on the cell surface of most B-cell lymphomas:

• Rituximab 
• Obinutuzumab 

Using these targeted anti-cancer drugs not only has better efficacy, but also reduces collateral damage to unaffected areas of the body.

Monoclonal antibodies

• Monoclonal antibodies attach to the specific cell markers on lymphoma cells. 
• Rituximab and Obinutuzumab
  • Once in the body, Rituximab or Obinutuzumab binds to CD20 on the surface of B type cancer cells, causing cell death and ultimately destroying the tumour through a series of immune response.
  • Good treatment response has been shown
  • Anti-CD20 in combination with multi-agent chemotherapy is an important measure for treating B-cell lymphomas.

Newer treatment options

• Bendamustine: This chemotherapeutic agent can be used in combination with anti-CD20 mainly in low-grade or indolent B-cell lymphomas or lymphoproliferative distorders such as follicular lymphoma or mantle cell lymphoma. Older patients also tolerate this chemotherapy well. 
• Brentuximab vedotin (an immunoconjugate = a monoclonal antibody against CD30 attached to a cytotoxin called vedotin): 
  • Used for relapsed CD30-positive Classical Hodgkin lymphoma, anaplastic large cell lymphoma or other CD30-expressing lymphomas. This agent can also be used upfront in Classical Hodgkin Lymphoma replacing Bleomycin in the regimen “ABVD”.

Polatuzumab vedotin (an immunoconjugate targeting CD79a): this agent can be used in patients with relapsed or refractory Diffuse Large B-cell lymphoma and is used in combination with Rituximab and Bendamustine. This agent has also been recently proved to be effective when used upfront replacing vincristine in R-CHOP.

Immune check-point inhibitors: a form of immunotherapy that enables the patients own immune cells called T-cell to recognize and kill the lymphoma cells. Examples include Nivolumab and Pembrolizumab. They are most effective in patients with relapsed or refractory classical Hodgkin lymphoma. 

Targeted therapy: Examples include ibrutinib (a BTK Inhibitor) and Venetoclax (a Bcl-2 inhibitor). These oral targeted agents are most effective in patients with chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). Venetoclax is usually used in combination with an anti-CD20. Ibrutinib is also useful in rare low-grade B-cell lymphomas that express the gene called “MYD88” (examples include Waldenstöm macroglobulinaemia and marginal zone B-cell lymphoma). 

Chimeric Antigen Receptor (CAR) T-cell therapy (a form of cellular immunotherapy): First, the patient’s T-cells are “extracted” or “harvested”. The patient’s T-cells are then “genetically engineered” or “educated” to recognize the specific cell marker on the lymphoma cell (most commonly CD19 in diffuse large B-cell lymphoma). The “educated” T-cells are infused back to the patient to treat the lymphoma. CAR T-cell therapy is indicated in patients with relapsed or refractory diffuse large B-cell lymphoma failing multiple lines of chemotherapy.  

Choosing the right therapy

• An appropriate treatment plan must be devised according to the subtype, stage and the status of lymphoma

Hodgkin Lymphoma 

• Early stage (I, II): Combination of chemotherapy (e.g. Adriamycin-Bleomycin-Vinblastine-Dacarbazine =ABVD) with or without radiotherapy.Please note that Brentuximab vedotin may be used in place of Bleomycin.
  • 2-4 cycles of chemotherapy
  • May be followed by involve-field radiotherapy usually in patients with bulky disease.  
  • 80-90% of patients can be cured
  • Significantly reduces the risk and complications of treatment
• Advanced stage (III, IV):  Multi-agent-chemotherapy (e.g. ABVD or Escalated BEACOPP) 
  • The current chemotherapy regimen is very effective
  • 60-70% of patients can be cured

Non-Hodgkin Lymphoma 

• Treatment methods are more complex, and they vary depending on the exact classification of lymphoma.
• Indolent or low-grade B-cell lymphomas:
  • Often in an advanced stage when it is diagnosed, disease progression is slow. With treatment advances, most subtypes can be cured or achieve long-term remission.
  • Anti-CD20 in combination with chemotherapy is the mainstay of treatment. 
• Aggressive or high-grade B-lymphomas: 
  • Rapid disease progression, start treatment as soon as possible
  • 6-8 cycles of chemotherapy
  • In the case of diffuse large B-cell lymphoma, the patient can receive a combination of Rituximab and chemotherapy [Cyclophosphamide-Doxorubicin (Hydroxydaunorubicin)-Vincristine (Oncovin)-Prednisolone=-CHOP] (R-CHOP). 
  • Early stage: Curative rate is 70-80%
  • Advanced stage: Curative rate is 30-50% 

T-cell or NK/T-cell lymphomas: Treatment is more complicated and usually involve multi-agent chemotherapy. These lymphomas should be treated in hospitals and centres with expertise in these conditions. 

Relapsed or refractory  lymphoma

• Hematopoietic stem cell transplantation (HSCT)
  • High-dose or “myeloablative” chemotherapy to use to “wipe off” any residual lymphomas
  • Stem cells from patient himself or herself (autologous transplant) or from another person, such as a sibling or unrelated donor (allogeneic transplant) are infused to the patients.
  • In Autologous HSCT, the patient’s own stem cells are collected or “harvested” beforehand.  
  • Autologous HSCT is most commonly indicated in relapsed lymphomas that are chemosensitive achieving a second remission. 
  • Allogeneic HSCT is only done in very selected cases and is not the standard in lymphomas.
  • The risk involved is relatively high.

Chimeric Antigen Receptor (CAR) T-cell therapy: indicated in patients with relapsed or refractory CD19-expressing diffuse large-B cell lymphoma. The procedure is relatively safe when done in specialized centres. This type of therapy can also be used in some forms of low-grade B-cell lymphomas such as follicular lymphoma that are refractory to multiple lines of chemotherapy. 

Immune-check point inhibitors: Nivolumab and pembrolizumab are very effective in patients with classical Hodgkin lymphoma that relapse after autologous HSCT. 

How to look after yourself during treatment

Before starting any treatment, the doctor will explain the procedures, risks and side effects to the patient. Also, if you are young and want to plan a family, discuss issues on fertility and conception before starting treatment. Your doctor will refer you to a fertility specialist for further counselling and methods to preserve fertility as applicable to your condition.

During treatment, you should: 

• Follow your doctor’s instructions, the medicine as prescribed and have regular follow ups
• Keep a balanced diet
• Balance rest periods with moderate exercise
• Maintain good personal hygiene
• Rooms, clothes and utensils should be cleaned frequently
• Eat only thoroughly cooked food
• Stay away from crowded places

Most patients with lymphoma do not carry risk factors. Therefore, definitive ways of prevention are yet to be discovered.

The Hong Kong Anti-Cancer Society: Lymphoma (Chinese only)

American Society of Clinical Oncology (ASCO)

Canadian Cancer Society

Special thanks to Mr. Adrian Tin-Chung Lam (Class M23), Mr. Terence Hon-Ting Tsang (Class M23), Li Ka Shing Faculty of Medicine, the University of Hong Kong, and Dr. Harinder Harry Singh Gill, Department of Medicine, the University of Hong Kong for authoring and editing this article.

Last updated on 18th Dec, 2023.