Lymphoma

Patients who have lymphoma may experience painless swelling of the lymph nodes in the armpits, neck, and/or groin, although these may not be visible or palpable. Fatigue, fever, unexplained drenching night sweats, unintended weight loss and itchiness are known as ‘B-symptoms’ and they are associated with lymphomas. If the lymph node is in the chest, it may affect the person’s breathing; if it is in their abdomen, it can cause abdominal discomfort. Lymphoma can sometimes be difficult to diagnose because the signs and symptoms are often mild or non-specific and some patients may have no noticeable signs.

Lymphoma is classified into two primary groups, Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).

Hodgkin Lymphoma
HL is a relatively rare cancer caused by abnormal B-lymphocytes, accounting for less than 1% of all diagnosed cancers yearly. Prevalence is highest in young adults (20-30 years) with an average age at diagnosis of 39 years. Incidence peaks again in individuals 55 years of age and older. The disease is classified into two categories: Classical Hodgkin Lymphoma (CHL) and Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL). However, per the 2022 5th edition of the World Health Organisation (WHO) Classification of Haematolymphoid Tumours, it is recommended that NLPHL be referred to as Nodular Lymphocyte Predominant B-Cell Lymphoma. CHL can be further sub-classified into the following groups: Nodular Sclerosis CHL, Lymphocyte-Rich CHL, Mixed Cellularity CHL and Lymphocyte-Depleted CHL. HL is associated with distinctive cells called Reed-Sternberg (RS) cells. HL is strongly linked to Epstein-Barr Viral (EBV) infection and Human Immunodeficiency Virus (HIV) with a 4 times and 8 times increased risk of HL, respectively.

Non-Hodgkin Lymphoma
NHL is a large heterogeneous group of lymphoid cancers, accounting for approximately 4% of all diagnosed cancers yearly, and it is the 6th most common cancer in the UK. Prevalence is highest in elderly individuals (>80 years of age). This group of malignancies is further subdivided on the basis of the implicated lymphocyte lineage: B-lymphocytes, T-lymphocytes and NK cells. Akin to HL, NHL grows in the lymph nodes, however it is also common for NHL to grow in extranodal sites. NHL is strongly associated with HIV and it is also more common in individuals that are immunosuppressed.

The revised World Health Organisation (WHO) Classification of Haematolymphoid Tumours 2022 recognises two broad categories of B-NHL: Precursor B-Cell Neoplasms and Mature B-Cell Neoplasms. Within each of these categories the disease is further sub-classified and within each of these subgroups there are one or more types of lymphoma (see Table 1), the details of which are beyond the scope of this article. B-NHL is more common than T-NHL with approximately 90% of NHLs involving mature B lymphocytes and 10% involving T-lymphocytes. By far the most commonly diagnosed NHL is Diffuse Large B-Cell Lymphoma (DLBCL), followed by Follicular Lymphoma (FL) which each account for around 40% and 19% of all NHL diagnoses per year, respectively. In regards to T-Cell Lymphoma, the most common are Mature T-Cell Lymphomas and Cutaneous Lymphomas.

Disease staging takes into account the site of the cancer growth and the extent of its growth. It is useful to clinicians in establishing a baseline of disease for the patient and it can aid in prognostication. The current criteria for staging lymphoma patients is the Lugano classification system which served as an update and amendment to the Ann Arbor criteria. These anatomical staging criteria are outlined in Table 2. The gold standard technique for lymphoma disease staging is functional imaging in which patients are injected with a radioactive tracer, 18F-fluorodeoxyglucose (FDG), which is an analog of glucose. Cancerous tissues typically have a high demand for glucose and thus lymphoma can be detected based on the uptake of FDG. The sites of lymphoma growth can be visualised using PET/CT scanning and based on these scans, disease stage can be determined. The disease stage helps the clinician to decide on an appropriate treatment and it is common practice to treat patients based on whether they have limited or advanced disease. PET/CT is also used to monitor patients’ response to treatment and to guide therapy. Laboratory investigations are also necessary for disease staging.

Stages Found in Lymphomas 

A more useful staging system for prognosis is the “International Prognostic Index” of IPI. This scores one point each for

• Age over 60
• Ann Arbor stage 3 or 4 disease
• More than one non-nodal site involved (for example, bone marrow, liver or lung)
• High serum LDH
• an ECOG score greater than 1 (feeling unwell enough to spend a proportion of the day in bed resting).

Staging allows the physician to determine what choices of therapy are available. For example, localised disease may be cured by surgery or radiotherapy, with or without chemotherapy. More advanced disease may require chemotherapy. In some circumstances, chemotherapy may also have to be given into the fluid around the spinal cord (intrathecal chemotherapy, by lumbar puncture) to reduce the risk of spread of lymphoma to the brain.

The most commonly used staging tests performed in the clinical laboratory are the FBC, liver and kidney function studies, and bone marrow biopsy. Non-laboratory tests may include ultrasound, CT, MRI and PET scans.

Testing Patients that are being investigated for lymphoma will have a range of laboratory tests performed with the aim of ruling out any other causes of enlarged lymph nodes or other symptoms. All patients must have a lymph node biopsy taken to diagnose and stage the lymphoma and it is usually not necessary to have a bone marrow biopsy done, as PET/CT can detect marrow involvement. The following laboratory tests may be performed:

• Full blood count (FBC) – this will help to rule out any other causes of patients’ symptoms such as leukaemia or viral infection.
• Urea and Electrolytes (U&E) – assess kidney function, useful for clinicians to establish a baseline at disease diagnosis.
• Liver Function Tests (LFTs) – assess liver function; a decrease in albumin is associated with a poorer prognosis in certain lymphomas.
• Lactate Dehydrogenase (LDH) – a raised LDH is associated with a poorer prognosis in lymphoma.
• Alkaline Phosphatase (ALP) – a raised ALP is associated with a poorer prognosis in certain lymphomas.
• Erythrocyte Sedimentation Rate (ESR) – a raised ESR is associated with a poorer prognosis in certain lymphomas.
• Viral Infection Testing – patients must be tested for HIV, Hepatitis B and Hepatitis C to rule out these differential diagnoses.
• Blood Film – a blood smear is analysed by a specialist laboratory scientist to look for abnormalities in the number and appearance of red blood cells, white blood cells and platelets. A reduction in any of these cells types could indicate that the lymphoma is affecting the bone marrow where the cells are made.
• Lymph Node Biopsy – gold standard for lymphoma diagnosis and staging. Patients may have an excisional biopsy in which an entire node is removed or they may have a small portion of a node removed by either incisional biopsy with a scalpel or a core biopsy using a needle. The biopsy sample is examined under the microscope by a specialist laboratory scientist for signs of lymphoma such as Reed Sternberg cells, a giant multi-nucleate cell that is characteristic of HL. Immunophenotyping is also performed on lymph node samples to detect cell surface markers, or clusters of differentiation (CD) markers, that enable cell types to be distinguished. Flow cytometry analysis of CD markers can also be performed using liquid samples such as peripheral blood or bone marrow aspirates.
• Bone Marrow Biopsy – a biopsy may be taken from the bone marrow to determine whether the lymphoma has spread to the marrow and this can help with disease staging. A trephine sample may be taken which in a thin slice of the marrow is excised using a needle, or an aspirate which liquid marrow is drawn out through a syringe.
• Genetic Tests – cytogenetic testing may be performed to assess whether there are any structural changes to the chromosomes such as a translocation which involves the inappropriate exchange of genetic material between chromosomes, e.g. the t(14;18) translocation is diagnostic of Follicular Lymphoma. Molecular genetic testing may be also be performed to evaluate the patient’s DNA for genetic changes.

Non-Laboratory Tests
Primarily used to help stage and monitor lymphoma. They include:

• Physical examination – to check for lymph node enlargement, spleen enlargement and physical assessment of other symptoms.
• Ultrasound scan – used to identify sites for lymph node biopsy.
• PET/CT scan – identify sites of disease involvement, used for staging and disease monitoring.
• Chest X-ray – to look for intrathoracic lymph node enlargement and signs of mediastinal disease spread.
• Magnetic Resonance Imaging (MRI) – to investigate whether there is central nervous system (CNS) involvement.

The treatment offered will depend on the type of lymphoma and how aggressive it is as well as patient-specific factors such as age. In cases where the patient has a slow growing lymphoma and they are generally well without symptoms, an active monitoring approach may be taken. This means that the patient is monitored regularly but they are not initially offered treatment. If the disease progresses, the patient can be treated. Standard of care treatment for both HL and NHL is combined modality chemotherapy and radiotherapy. The chemotherapy regimen and the number of cycles given will largely depend on the disease stage and subtype. The need for radiotherapy should be assessed based on PET/CT imaging after the patient has received chemotherapy due to the risks associated with radiation such as secondary cancers. New treatments include immunotherapies which use antibodies to target the lymphoma cells for killing (e.g. Nivolumab for treatment of Classical HL) and treatment of NHL with CAR-T cells which involves the infusion of genetically modified patient immune cells that are programmed for cancer cell killing. Bone marrow and stem cell transplants are also treatment options for certain patients.