Lymphomas: pathogenesis, clinical features and diagnosis
Lymphomas are some of the most common cancers in the UK, with a wide variation in disease progression and prognosis between subtypes.
Source: Steve Gschmeissner / Science Photo Library
The lymphomas are a large group of blood cancers with many subtypes. Hodgkin lymphoma has an incidence of 2.8 per 100,000 people per year in the UK, while non-Hodgkin lymphoma has an incidence of 15.5 per 100,000 people per year.
Both forms typically present with painless enlarged lymph nodes. Around a quarter of patients with Hodgkin lymphoma will also have night sweats, unexplained fever and weight loss. Diagnosis is made following a lymph node biopsy, a CT scan, and – in non-Hodgkin lymphoma – a bone marrow biopsy.
The lymphomas are a heterogenous group of blood cancers caused by the clonal proliferation of B or T lymphocytes. There are a large number of recognised subtypes of lymphoma, and it is beyond the scope of these articles to discuss each of them individually. Instead, the main focus will be on Hodgkin lymphoma and the most common forms of non-Hodgkin lymphoma.
Incidence and risk factors
Hodgkin lymphoma has an incidence in the UK of 2.8 per 100,000 people per year, which translates into just over 1,800 new cases per year. The incidence of both Hodgkin lymphoma and non-Hodgkin lymphoma has increased by 11-15% in the past decade. This is most likely because of a combination of better diagnosis and reporting, the ageing population and an increase in the number of patients with a compromised immune system, such as those with HIV and AIDS.
Hodgkin lymphoma has a bimodal distribution, with an initial peak in young adults aged 20–24 years and a second peak between the ages of 70 years and 80 years, although it can occur at any age.
The disease is slightly more common in men, with an incidence ratio of 1.2:1. The cause of Hodgkin lymphoma is not known, but it does have a strong association with being infected with Epstein-Barr virus, which is implicated in 45% of cases. It also occurs more commonly in patients who are immunocompromised; HIV infection is associated with an 11-fold increase in risk of Hodgkin lymphoma, and patients who are receiving immunosuppressant therapy following an organ transplant or with autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus are also at increased risk.
A small increase in risk of Hodgkin lymphoma has also been associated with tobacco exposure, having a first degree relative with the disease, and obesity. Rates of Hodgkin lymphoma in younger patients are lower for those with three or more siblings, suggesting that exposure to common childhood infections may somehow reduce the risk of developing the disease.
Non-Hodgkin lymphoma has an incidence in the UK of 15.5 per 100,000 people per year, with almost 14,000 new cases reported in 2011. It is the sixth most common type of cancer in the UK, and accounts for about 4% of all cancers. It has a relatively good prognosis and, despite its high incidence, is the tenth most common cause of cancer death in the UK.
The incidence of non-Hodgkin lymphoma correlates closely with increasing age, and the majority of cases occur in patients aged 65 years or older. One exception to this rule is the relatively uncommon Burkitt’s lymphoma, in which almost 50% of cases occur in patients younger than 45 years.
There is a strong association between immunodeficiency, such as HIV infection, and risk of developing non-Hodgkin lymphoma. Recipients of organ transplantation who are receiving immunosuppressants such as ciclosporin or tacrolimus are at risk of developing post-transplant lymphoproliferative disease (PTLD), a proliferation of B cells caused by the Epstein-Barr virus that, if untreated, can progress to non-Hodgkin lymphoma.
Burkitt’s lymphoma is a highly aggressive form of non-Hodgkin lymphoma that, in its endemic form, is associated with malarial regions of equatorial Africa. In the UK, it accounts for about 2% of cases of lymphoma. It is more common in children and young adults.
The Epstein-Barr virus is implicated in the development of Burkitt’s lymphoma, although its overall importance as a risk factor is much less than for Hodgkin lymphoma.
Helicobacter pylori infection is strongly associated with mucosa-associated lymphoid tissue (MALT) lymphoma, a form of non-Hodgkin lymphoma that occurs in the stomach. H.pylori eradication regimens are the mainstay of treatment for this relatively rare subtype.
Other risk factors for non-Hodgkin lymphoma include hepatitis B and hepatitis C, working in rubber production and exposure to chemicals such as benzene and ethylene oxide. There is no proven association between smoking and an increased risk of non-Hodgkin lymphoma.
A variety of classification systems has been developed for lymphomas. The World Health Organization (WHO) classification, last updated in 2008, is currently the most widely used and recognises more than 50 different subtypes.
Hodgkin lymphoma can itself be subdivided into two forms: classic Hodgkin lymphoma, which accounts for 95% of cases, and nodular lymphocyte predominant Hodgkin lymphoma.
The simplest way of classifying non-Hodgkin lymphomas is by the cell of origin. More than 90% originate in B-lymphocytes, with less than 10% being T-cell or NK cell lymphomas.
Clinically, it is often useful to separate non-Hodgkin lymphoma into aggressive (high grade) and indolent (low grade) forms (see ‘Aggressive and indolent lymphomas’).
|Classification||Aggressive (high grade)||Indolent (low grade)|
|Example||Diffuse large B cell lymphomaBurkitt’s lymphoma||Follicular lymphomaMarginal zone lymphoma|
|Presentation||Rapid onset of symptoms||Insidious onset|
|Natural history||Rapidly fatal if untreated||Slow growing and treatment not always required at time of diagnosis|
|Sensitivity to chemotherapy||Potentially curable||Responses seen with chemotherapy but rarely curable|
Hodgkin lymphoma commonly presents with painless swollen lymph nodes (lymphadenopathy), often affecting the cervical or supraclavicular nodes in the neck. About 25% of patients present with the three ‘B symptoms’: night sweats, unexplained fever and weight loss of more than 10% over six months. These symptoms are associated with a poorer prognosis. Other presenting features include fatigue, itching and alcohol-induced pain.
Non-Hodgkin lymphoma also classically presents with painless enlarged lymph nodes. These are usually widespread in indolent lymphomas (such as follicular lymphoma), whereas progression is more rapid and often accompanied by B symptoms in aggressive lymphomas, such as diffuse large B-cell lymphoma.
In both Hodgkin lymphoma and non-Hodgkin lymphoma, patients are more likely to be unwell due to chemotherapy side effects than their cancer. A minority of patients will have lymphoma present in the bone marrow, which can lead to symptoms related to myelosuppression. These include fatigue, breathlessness, increased susceptibility to infections and unexpected bruising or bleeding.
Rarely, the location of the lymphoma mass may cause life-threatening complications such as spinal cord compression or obstruction of the superior vena cava. These are medical emergencies that require urgent treatment with chemotherapy or radiotherapy.
A lymph node or extranodal tissue biopsy is used to diagnose lymphoma, and immunohistochemistry is used to guide classification.
For example, classic Hodgkin lymphoma is defined by the presence of Reed-Sternberg (RS) cells, which stain positive for the antigens CD30 and CD15 located on the cell’s membranes. In contrast, lymphocyte predominant cells, which characteristically stain positive for the antigens CD20 and CD45, are expressed by cells in lymphocyte-predominant Hodgkin lymphoma. These differences in surface antigen expression have important implications for treatment selection.
Determining the stage of the disease generally involves a contrast-enhanced computed tomography (CT) scan of the neck, chest, abdomen and pelvis and (in non-Hodgkin lymphoma) a bone marrow biopsy. Recently positron emission tomography (PET) scanning has become more widely used, both as part of diagnosis and as a means of accurately assessing response to treatment.
In addition, full blood count, lactic dehydrogenase, erythrocyte sedimentation rate, liver enzymes and urea and creatinine should be checked, and patients should be screened for hepatitis B, hepatitis C and HIV. Baseline cardiac function should be checked in patients who are going to receive anthracycline-based chemotherapy (see accompanying article).
Patients with either Hodgkin lymphoma or non-Hodgkin lymphoma are classified according to the Ann Arbor staging system (see ‘Ann Arbor staging system’).
For Hodgkin lymphoma, the following categories are then used to guide treatment:
- Limited stage – Ann Arbor stage 1 or 2 disease without risk factors
- Intermediate stage – Ann Arbor stage 1 or 2 disease with risk factors (e.g., age >50 years, large mediastinal mass, elevated erythrocyte sedimentation rate)
- Advanced stage – Ann Arbor stage 3 or 4 disease
Around one third of patients with Hodgkin lymphoma will have advanced stage disease at diagnosis, and their prognosis can be calculated further (see ‘Hasenclever International Prognostic Score’).
Similar scoring systems can be used to guide treatment for some non-Hodgkin lymphomas, such as the international prognostic index (IPI) for diffuse large B cell lymphoma, and the follicular lymphoma international prognostic index (FLIPI) for follicular lymphoma.
|1 (A or B)||One lymph node region or lymphoid structure or localised extra nodal site|
|2 (A or B)||Two or more lymph node regions on same side of the diaphragm|
|3 (A or B)||Lymph nodes on both sides of the diaphragm|
|4 (A or B)||Diffuse/disseminated extra nodal sites|
|A||Absence of B symptoms|
|B||Presence of B symptoms|
|Parameter||Value attracting a score of 1|
|Score||Overall survival at five years|
The prognosis for patients diagnosed with non-Hodgkin lymphoma in the UK has improved markedly in the past 30 years. The five-year survival rate is 63%, and half of all patients survive for at least ten years after diagnosis.
However, there are marked variations in survival rates between subtypes of the disease. The most recent UK statistics indicate that 87% of patients with follicular lymphoma survive for at least five years, compared with 27% of patients with mantle cell lymphoma. In general, patients with the rarer T-cell lymphomas have a poorer prognosis than patients with B-cell lymphomas.
Hodgkin lymphoma has a cure rate in the region of 80-90%. The prognosis after intensive chemotherapy (with or without radiotherapy) has improved so much in recent decades that the focus has begun to move towards potentially less intensive approaches, with the aim of reducing long-term complications of therapy such as cardiac and pulmonary toxicity.
Nick Duncan MRPharmS MSc is principal pharmacist in haematology and oncology at University Hospitals Birmingham NHS Foundation Trust.
Citation: Clinical Pharmacist DOI: 10.1211/CP.2014.20066739
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