Self Study CME Series > Series No. 98
Series No. 98

Update on Management of non-Hodgkin's Lymphoma - Part I


Lymphoma is the most common haematological cancer and is classified into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma has increased incidence and it is the 9th most common cancer in Hong Kong . There are about 600-700 new cases per year. Non-Hodgkin's lymphoma is also more common than Hodgkin's lymphoma with ratio of about 9:1, which is different from the figure of 7:3 in western countries. It can occur in all age groups and the incidence rises with age.

The prognostic features are related to patient and disease such as histologic type, stage, tumour bulk. The treatment response and survival are improved nowadays with the new treatment options.


[Figure 1]
The World Health Organization (WHO) classification

Lymphoma is mainly classified into non-Hodgkin's lymphoma and Hodgkin's lymphoma which is characterized by the presence of Reed-Sternberg cells.

Non-Hodgkin's lymphomas are broadly classified as B-cell or T-cell lymphomas. B-cell lymphomas account for 88% of all NHL, while T-cell lymphomas account for remaining 12% of NHL. Expression of cell surface antigens and immunoglobulin proteins is dependent on the type of lymphocyte and its stage of differentiation.


In the majority of non-Hodgkin's lymphoma, the cause is not identified.

Infectious agents

Infections are close to being regarded as established causes. There are three mechanisms causing the lymphoma. First, certain lymphocytes-transforming viruses can directly infect lymphocytes, disrupt normal cell functions and promote cell division. Second, human immunodeficiency virus (HIV) infection can cause depletion of CD4 T lymphocytes, leading to elevated risk of B cell lymphoma. Third, some infections induce chronic immune stimulation and persistent activation of lymphocytes, increasing risk of lymphoma.

Epstein-Barr virus (EBV) is an example of transforming virus implicated in several NHL subtypes. EBV is usually acquired in early childhood in developing countries. Following primary infection, EBV persists lifelong in the host in a latent state in memory B lymphocytes. In healthy infected people, outgrowth of EBV-transformed B lymphocytes is prevented by presence of intact T lymphocyte-mediated immunity.

EBV is associated with several types of non-Hodgkin's lymphoma like Burkitt's lymphoma, AIDS-associated NHL, post-transplant lymphoproliferative disorder (PTLD), extranodal natural killer/T-cell NHL.

HIV causes NHL by inducing profound cell-mediated immunodeficiency, which permits dysregulated proliferation of B lymphocytes. EBV is often involved in AIDS-associated NHLs. Three NHLs are characteristic of AIDS: central nervous system NHL, diffuse large B-cell lymphoma and Burkitt's lymphoma.

HTLV-1 (Human T-cell lymphotropic virus-1) is causative of adult T-cell leukaemia/lymphoma. Hepatitis C is associated with splenic marginal zone lymphoma.


Lymphoma is more common in immunosuppressed patients as in AIDS patients and solid organ and stem cell transplant recipients. Lymphoma has been reported to occur in 4-10% of AIDS patients. The increased risk of infection with viruses such as EBV, chronic antigen exposure and cytokine stimulation arising repeated infections result in polyclonal B-cell activation

Lymphoma develop in <1% of allogenic stem cell transplant recipients and the risk is higher in patients receiving heavy post-graft immunosuppression. Most post-transplant lymphomas are EBV related.

Benzene exposure

Benzene is an important industrial chemical and is a component of gasoline. Evidence supports an association between occupational benzene exposure and NHL. Potential mechanisms include immunotoxicity and the induction of double-strand breaks with subsequent chromosome damage resulting in translocations and deletions.

Occupational factors

Occupational exposure to chemicals like benzidine, mineral, cutting or lubricating oil, pesticides and herbicides seem to play a role in the development of NHL. However, the exact impact of these factors are still controversial.


There was increased risk of NHL in first-degree relatives of lymphoma compared with the general population.

Clinical Features

The majority of patients present with painless lymphadenopathy, most often in cervical and supraclavicular areas. It can also occur in almost any part of body (extranodal lymphoma). The GI tract is the most commonly involved extranodal site other than bone marrow. Skin, brain, testis or thyroid are sometimes involved. Skin involvement is closely related to T-cell lymphomas: mycosis fungoides and Sezary syndrome. Liver and spleen may be enlarged and involvement of retroperitoneal or mesenteric nodes. Constitutional B symptoms include fever, night sweating, weight loss and their presence is usually associated with disseminated disease

[Figure 2]
Patient with lymphoma has enlarged lymph node, biopsy later confirmed primary mediastinal B-cell lymphoma

Laboratory Investigations

Histological diagnosis from biopsy of a lymph node is important. It is usually obtained from an excisional biopsy of an abnormal lymph node or incisional biopsy of an involved organ. Fine needle aspiration may help to exclude or suggest lymphoma, but histological examination is essential to complete the diagnosis.

Chest radiograph, computed tomography (CT) scans of chest, abdomen and pelvis, bone marrow examination are used for staging of disease. Positron emission tomography (PET) is useful for identifying sites of disease and for response assessment. Gallium scan is less sensitive and specific than PET.

Viral testing such as HIV, hepatitis B and C serology, HTLV-1 (for T-cell lymphoma) are recommended. Lumbar puncture with cytology is performed for patients at risk of central nervous disease such as Burkitt's lymphoma, lymphoblastic lymphoma and diffuse large B-cell lymphoma with bone marrow involvement.


Ann Arbor Staging system is used and staging is related to the prognosis of disease.

Stage I Single lymph node region or single extralymphatic organ or site (IE)
Stage II Two or more lymph node regions on the same side of diaphragm or single extranodal site adjacent nodes (IIE)
Stage III Nodal regions on both sides of diaphragm (III) or involving single extranodal site with adjacent nodes (IIIE), or spleen (IIIS) or both (IIISE)
Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs; bone marrow, liver, brain involvement

Absence of associated symptoms is designated A; Presence of symptoms is designated B. 'B' symptoms include unexplained fever, unexplained >10% weight loss, sweating


The following features are associated with a poor prognosis: Stage III/IV, Age >60, WHO classification performance status 2-4, raised LDH, more than one extranodal site, bulky disease (>10cm in diameter), transforming from low-grade to high-grade NHL, AIDS-related disease.

An International Prognostic Index (IPI) was developed based on 5 most significant factors: Age > 60, performance status of 2 or higher, stage III/IV, extranodal sites of 2 or more, LDH level > 1x normal.

The 5-year overall survival was 82% for patients with diffuse large B-cell lymphoma who have up to 2 adverse IPI factors, compared with 32% for patients with IPI of 3-4.

Response criteria

Complete remission (CR) - total clinical eradication of disease
Partial remission (PR) - more than 50% reduction of tumour
Stable disease - failure to achieve CR or PR but not fulfill the criteria of progressive disease
Progressive disease - new lesion or assessable disease progression


Treatment options include chemotherapy, radiotherapy, combination therapy, monoclonal antibody such as rituximab, radioimmunotherapy (use the targeting features of a monoclonal antibody to deliver radiation from an attached radionuclide, an example is zevalin/ ibritumomab) , stem cell transplant (autologous or allogenic transplant) etc.

Treatment of NHL is guided by clinical behaviour. It can broadly classified by cell type and clinical behaviour as indolent, aggressive, or highly aggressive. Therapeutic options are also taken with regard to patient's age, performance status and disease extent.

The details of treatment will be discussed in next paper and some common lymphomas such as diffuse large B-cell lymphoma which is the commonest lymphoma in Hong Kong and follicular lymphoma will also be discussed in detail.

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Q1. Which is the commonest lymphoma in Hong Kong?

Q2. Which of the following virus is associated with lymphoma?

Q3. The commonest presentation of lymphoma is

Q4. Which of the following is not included in International Prognostic Index?

Q5. Laboratory investigations of newly diagnosed lymphoma include