This article looks at how Non Hodgkin's Lymphoma (NHL) is classified and treated, with focus on the more common subtypes of NHL. The article on Hodgkin's lymphoma details clinical findings and investigations, which are essentially the same as those for NHL. An attempt to explain all the molecular differences between lymphomas is not made, but instead an overview of the key NHL types is given, to avoid unecessary complexity.

Classification of diseases in heamato-oncology is a potentially complex issue. Lymphoma classification is the subject of extensive revision as new advances in genotyping technology mean lymphomas are sub-classified increasingly. In addition to this, there are many different classification systems, for example Working Formulation, REAL and WHO 2008. The latest one is WHO 2008, however its use is not without controversy as some feel it unnecessarily sub-classifies. This classification system seeks to categorise NHL on the basis of what the normal biological counterpart cell is, which is a far from simple undertaking in some cases.

What is and is not NHL?

Lymphomas are always malignancies of lymphocytes that are predominantly 'solid' cancers (as opposed to leukaemias [white blood] which are mainly 'fluid'). A non Hodgkin's lymphoma is marked by the absence of a Reed-Sternberg or Hodgkin's Cell in biopsy material, usually visible under a light microscope. See the Hodgkin's lymphoma article for more information about these cells.

Because NHL is defined as being a lymphoma that doesn't have these cells, it means that many different tumours can fall under this definition. Usually NHL is due to the proliferation of a malignant B cell, however T and NK cells can also be responsible for disease and tend to have a worse outcome. B cells pass through many stages of maturation, and the stage of B cell development at which a malignant clone develops will determine what form of lymphoma the patient has.

Although it was mentioned that leukaemias are mainly liquid and lymphomas are solid, both diseases can have fluid and solid components, some more than others. Thus it is better to imagine the diseases on a sliding scale, as shown in figure 1 below with an assortment of different lymphomas (please note this diagram is conceptual and not to scale). NHL commonly appears in lymph nodes, however 25% of NHLs are extranodal. This is in contrast to HL which is mainly nodal. Sites that can be affected in extranodal disease are the stomach (known as gastric MALToma as mucosa associated lymphoid tissue is affected), terminal ileum, CNS, thyroid, lungs and skin. The GI system is by far the most commonly affected system.

Chronic lymphoid leukaemia is commonly included in NHL classification, which may at first be confusing as it is not usually thought of as a solid disease. Although it is still a leukaemia as it is mainly fluid, solid deposits can be found in nodes and the bone marrow.

Figure 1

Classification and Staging of NHL

There are many ways of classifying NHL. For ease of clinical understanding it is best to think of NHL in terms of whether the subtype is slowly proliferating or rapidly proliferating, i.e. low grade or high grade. This will govern treatment and affect prognosis. Examples of indolent and aggressive types of NHL are listed below.

From a diagnostic standpoint, you cannot clinically differentiate between low grade and high grade entities. Instead, lymph node and bone marrow biopsies need to be examined. Examination of these tissues is by conventional microscopy, immunohistochemistry (explained in HL article), cytogenetic analysis (chromosome translocations) and molecular testing (individual mutations).

Once you know the type of lymphoma and have an idea of how it will behave, you then need to determine the extent of disease. The Ann Arbor staging system is used for this, which is detailed in the HL article. Usually the indolent lymphomas are widely spread at presentation, but grow slowly. They do not respond well to treatment. Aggressive lymphomas will cause dramatic symptoms in a short time frame, but are less disseminated at presentation and respond better to treatment. However, formal assessment of stage using CT or PET scans is needed.

Indolent lymphomas can also undergo aggressive transformation, usually follicular lymphoma transforming to diffuse large B cell lymphoma.

NHL Types


  • Diffuse Large B Cell Lymphoma (DLBCL)
  • Burkitt's Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Diffuse Mixed Cell Lymphoma


  • Follicular Lymphoma (FL)
  • Mantle Cell Lymphoma (MCL)
  • Marginal Zone Lymhoma (MZL)

History, Examination and Investigations

History and examination findings are essentially the same as for HL (see article). However as NHL can be extranodal, symptoms other than lymphadenopathy can be the presenting problem. For example, NHL in Peyer's patches in the ileum can cause intussusception, causing blood in stools. CNS lymphomas may mimic strokes and are space occupying lesions so will cause symptoms of intracranial hypertension (headaches, blurred vision, VI cranial nerve palsy, seizures). A key difference between HL and NHL is that Waldeyer's ring of lymphoid tissue in the pharynx is usually not involved in HL but can be in NHL, causing throat symptoms.

Like HL, NHL can have systemic 'B' symptoms. These are the same as for HL and their presence is associated with a worse prognosis.

Investigations will be the same as those for HL, however radiology and endoscopy of the GI system and investigations such as IV urograms will be more relevant for extranodal disease.

Follicular Lymphoma in a Nutshell

Features: Cleaved cells on biopsy, translocation of (14;18) which causes BCL-2 overexpression, stopping programmed cell death. Usually indolent but may transform to DLBCL with a median survival of 12 months. Patients are usually in their fifties.

Treatment: If localised (stage 1), radiotherapy alone may be used. Other stages can be treated with watchful waiting or R-CVP (Rituximab, cyclophosphamide, vincristine, prednisolone). Relapsed disease will need high dose chemotherapy and stem cell transplants.

Prognosis: 91% 5year survival rate if low risk, 52% 5yr survival rate if high risk. Most live 8-10yrs.

Marginal Zone Lymphoma in a Nutshell

Features: Typically found in extranodal sites. Subdivided into 3 entities- MALToma of GI tract, nodal MZL and Splenic MZL with villous lymphocytes. Gastric MALToma is associated with H. Pylori infection. Nodal MZL is usually found in the eye, thyroid, parotid or lung. Splenic MZL shows white pulp invasion in the spleen and circulating villous lymphocytes (see diagram) may be seen in the blood.

Treatment: Gastric MALToma responds to H. Pylori eradication regimens, nodal MZL can be treated with the same regimen as follicular lymphoma, splenic MZL can be treated with splenic irradiation.

Prognosis: Gastric MALToma has a 90% 5yr survival rate, others depend on risk factors such as age and serum LDH level, but 5yr survival rate is generally >50%.

Burkitt's Lymphoma in a Nutshell

Features: Prevelant in the malarial belt of Africa, associated with Epstein-Barr Virus infection (probably due to immune supression owing to malaria). Maxillary involvement is typical, can cause displacement of surrounding tissues. Biopsy of involved area shows sheets of lymphocytes with 'starry sky' involvement of macrophages (see diagram). 8;14 translocation causes overexpression of the oncogene c-myc and is a characteristic abnormality.

Treatment: CODOX-M/IVAC (Cyclophosphamide, doxorubicin, vincristine, methotrexate, etoposide, ifosfamide, cytarabine), methothrexate is given intrathecally (into the CSF via lumbar puncture) to give CNS cover. The regimen is heavily emetogenic so metoclopramide and a 5HT antagonist should also be prescribed.

Prognosis: 50% of patients can be cured, however long term prognosis depends on other risk factors e.g. age, HIV status.



DLBCL in a Nutshell

Features: Mainly a disease of the over 40s, can be widespread and involve extranodal sites frequently, including the CNS and GI system. It is subdivided into many different histological types, and recent DNA microarray technology has allowed two genetically different subtypes to be discerned, activated B cell (poor prognosis) and germinal B cell type (good prognosis). The diagram shows a microarray result, red areas are where a gene is upregulated and green areas are where expression is lower. The expressed genes can then be clustered to categorise lymphomas into different subtypes. This level of analysis is not widely available.

Treatment: R-CHOP (Rituximab, Cyclophosphamide, Vincristine, Prednisolone) Intrathecal methotrexate and scrotal irradiation are considered in at risk individuals with disseminated disease.

Prognosis: 5 year survival is usually around 58%

Mantle Cell Lymphoma in a Nutshell

Features: A typically incurable lymphoma which can have a leukaemic component where mantle cells are visible in peripheral blood as shown in the diagram. An 11;14 translocation is a characteristic that causes cyclin D1 overexpression leading to a lack of cell death.

Treatment: CHOP, however entry onto clinical trials should be strongly considered as this treatment is not regarded as curative.

Prognosis: Poor, median survival is 3-5years.


NHL consists of many different types of lymphoma that are characterised by the lack of RS cells. These can be grouped into lymphomas that are high grade (aggressive) or low grade (indolent). In addition to grade, stage is important in determining prognosis, which is judged by CT scans to determine how far spread the disease is. Treatment is usually with chemotherapy, regimen depending on type of lymphoma. Prognosis is dependant on stage, grade, presence of B symptoms and other indices such as LDH level and HIV status.


Cleaved cell picture adapted from :

Villous lymphocyte picture taken from: lymphocytes

Burkitt's Lymphoma picture taken from:

DLBCL Microarray taken from: Wright G.,Tan B., Rosenwald A., Hunt EH., Wiestner A., Staudt LM.'A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma' PNAS 2003 100 (17) 9991-9996 

Mantle Cell Lymphocyte Picture taken from:


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