The symptoms, diagnosis and treatment of Non-Hodgkin’s lymphoma


Lymphomas arise from malignant clones of lymphocytes. Lymphocytes are a normal part of the peripheral blood population of circulating white cells and normally serve the functions of immune protection and inflammatory responses to foreign (or self) antigens. They are derived from progenitor cells in the bone marrow and the lymph nodes.

Lymphocytes are classified into B and T cells. Originally this classification was because the T cells derived from a Thymic origin, whereas the B cells came from an origin in the gut mesentery, which in the chicken was termed the Bursa of Fabricious.

The two groups of lymphocytes normally sub-serve different lymphocyte functions.

Lymphomas are classified into those arising from B or T lymphocytes but this is only part of a very complex classification system.

Nowadays the origins of the cells and the identification of different subsets of lymphoma has become much more complicated and the consequence is  that the term non-Hodgkin lymphoma encompasses a  very large and heterogenous spectrum of diseases, many of which are not described here in detail.


Non-Hodgkin’s Lymphoma (NHL) is the cause of 5% of cancers in the UK, is considerably more common than Hodgkin’s disease and tends to occur at a later age than Hodgkin’s disease with a peak incidence in the age group 45-60 years. It is nevertheless an important disease in childhood accounting for 15% of all childhood cancer.

The topic of lymphomas is of particular importance because they are so responsive to therapies, potentially curable and their therapy has often paved the way for new methods of therapy for other malignancies.

With regards the aetiology (cause) of NHL, there is no one answer, but there are undoubtedly well established clues and predisposing factors. A viral link has been well demonstrated for two types of NHL, adult T-cell NHL is causally related to a viral infection by HTLV-1 retrovirus and the Burkitt NHL, so prevalent in African children, is causally related to infection by the Epstein Barr virus.

The HIV virus, associated with AIDS, predisposes to the development of a high grade NHL and with the longer survival of patients with AIDS, so a higher proportion of these individuals develop NHL.

Other viral associations have been made with other lymphoma types (e.g. Epstein Barr infection) but are not well substantiated in the sense that often they may be co-factors in aetiology.

It is envisaged that the viral load induces chronic antigenic stimulation and eventually a clone of these hyper-stimulated or proliferating B cell lymphocytes become malignant.

The role of Heliobacter pylori infection in the aetiology of gastric lymphoma has a similar basis.

Immunodeficiency in the form of congenital syndromes (of which the Ataxia telangiectasia syndrome and the Wiskott Aldrich syndrome are best recognised) leave the affected patient prone to the development of NHL, which is a common form of death in these patients. Patients who are immunosupressed by drugs (e.g. kidney transplant recipients) are also much more prone to develop NHL and all these data imply that the normal body (i.e. in the non-immunosuppressed state) monitors effectively for ‘rogue’ transformation of lymphocytes or that the immunosuppressed state predisposes to lymphocytes becoming malignantly transformed.

Patients with auto-immune disease are predisposed to develop NHL usually in the afflicted organs e.g. auto-immune thyroiditis tends to lead to the development of a high grade NHL of the thyroid and Sjogren’s syndrome also predisposes to a similar NHL development. Once again, it is envisaged that the prolonged B cell proliferation against the auto-antigen leads eventually to the development of a malignant clone of lymphocytes (the lymphoma).

Environmental factors also play a part in the incidence of NHL, although the size of the problem in terms of overall incidence is so far un-quantified. Occupational exposure to pesticides, such as the organophosphate insecticides and hair spray/dye solvents has been associated with a higher incidence of NHL.

The photo shows a non-Hodgkin lymphoma arising on an eyelid.


The incidence of non-Hodgkin lymphoma across the world is approximately one case per 10,000 of the adult population. However, there are higher incidences in certain societies and amongst those who are predisposed.

Symptoms & diagnosis: Non-Hodgkin’s lymphoma

Presenting clinical features/ what brings the patient to the doctor. The majority of patients present with an enlargement of lymph node groups, for example the enlargement of nodes in the neck. Such presentations are usually as the painless development of the lumps, which the patient soon realises are abnormal.

In low grade NHL the development of these nodal lumps is slow and insidious but in high grade tumours the growth may be fast and very worrying to the patient. Occasionally, the lymph nodes develop deep inside the patient; for example, a lymph node mass in the chest may remain silent (i.e. un-noticed by the patient) until it presses on the wind-pipe and then the patient comes urgently to the doctor because he has difficulty in breathing.

Sometimes, the nodal mass may be in the abdomen and disturbance of bowel function may cause the presenting symptom.

Sometimes the NHL occurs outside the lymph nodes and the thyroid has already been cited above and is a good example. Others include primary stomach NHL, conjunctival or even intra-ocular NHL and primary brain NHL is a rare form (although commoner in kidney transplant recipients). In the preceding section, there is a photo of a lymphoma arising on the skin of the eyelid.

In patients with a large bulk of lymphoma in their bodies, there may be significant weight loss or sweating (the so-called ‘B’ symptoms).


Diagnostic tests are run by the doctor. The critical test is the lymph node (or other mass) biopsy. Here, the surgeon takes a small piece of tissue from the lump and it is analysed histologically (i.e. down the microscope) and for various other diagnostic immunopathological parameters (see below).

Once the diagnosis has firmly been established, then the doctor will move to staging: here, a search is conducted to see where else the NHL may be present. A CT scan is performed throughout the whole body to see if any other lymph node groups are affected or if any extra-nodal disease is present. PET scanning powerfully images non-Hodgkins lymphoma.

As the bone marrow is often affected in the higher stages of the disease, it is always sampled in the work-up of this disease.

In some high grade NHL, it may be appropriate to sample the CSF (the cerebrospinal fluid, usually by lumbar puncture) to see if any abnormal cells are present in this fluid, which surrounds the brain and spinal cord, and which is ‘accessed’ relatively poorly by intravenous chemotherapy.

A large number of blood tests also form part of routine staging. By the above methods, a staging of the patient is achieved (according to a system that was originally evolved at a conference at Ann Arbor so called the Ann Arbor system):

Stage 1: NHL affecting one group of lymph nodes only (e.g. node swelling/involvement only affecting the lymph node chain down the left side of the neck).

Stage 2: Two or more lymph node groups affected on one side of the diaphragm (e.g. neck and armpit groups of nodes).

Stage 3: Lymph nodes (and in this nomenclature the spleen is counted as a lymph node organ) affected on both sides of the diaphragm (e.g. neck nodal and groin nodal involvement).

Stage 4: Lymph nodes involved and other organs (e.g. bone marrow, CSF or liver)


After the diagnosis of NHL has been made, the doctor is interested to know from his pathologist as to whether the NHL is of high grade or low grade and whether it is of T or B cell origin. The first is assessed by the pathologist by microscopic analysis of the biopsy specimen; in low grade tumours the cells often resemble normal small lymphocytes in many regards but will show some characteristics that are diagnostic of NHL and others which help the pathologist to further subtype the NHL.

For example the pathologist may say that the tumour is a follicular, low grade NHL, which means that he has seen the typical small round lymphocyte NHL population but also that this is enveloped within groupings/follicles; this is a common type of low grade NHL.

In high grade lymphomas, the pathologist often encounters large bizarre looking malignant lymphocytes, often with many in cell division (mitosis); this is a more aggressive/faster growing cancer. The distinction between T and B cells is made by a process called immunophenotyoping, and there nowadays further subdivisions within the lineages made other immunological tests. For example there are now available a battery of antibodies directed at surface immunoglobulin light chains and the presence of some of these on B cell lineage NHL can be used to subtype (e.g. CD numbering).

Recently, genetic analysis of NHL cells has become a recent science in itself; gene re-arrangement is found in many NHL and engenders excitement in the profession who believe that it is getting closer to the exact genetic defect in this cancer. Recently, the technique of PCR (polmerase chain reaction) technology has been used in gene re-arrangement analysis to detect clonal populations at incredibly low levels and is therefore of extreme interest in the establishment of cure (i.e. that there is no NHL left in the body at the end of a therapy programme).

The above histopathological analysis of the biopsy specimen is the first and a critical first step in the assessment of the type of disease from which the patient suffers. The next question is “how far has it spread and where else may the disease be?”

All patients will have complete body scanning (at least by CT scan and usually nowadays by PET scanning) as well as blood tests, bone marrow and perhaps CSF (for high grade disease).

Thus staging of the patient is achieved (according to a system that was originally evolved at a conference at Ann Arbor so called the Ann Arbor system):

Stage 1: NHL affecting one group of lymph nodes only (e.g. node swelling/involvement only affecting the lymph node chain down the left side of the neck).

Stage 2: Two or more lymph node groups affected on one side of the diaphragm (e.g. neck and armpit groups of nodes).

Stage 3: Lymph nodes (and in this nomenclature the spleen is counted as a lymph node organ) affected on both sides of the diaphragm (e.g. neck nodal and groin nodal involvement).

 Stage 4: Lymph nodes and other organs involved (e.g. bone marrow, CSF or liver).

The overall outlook for the patient presenting with NHL is worse the higher the stage at presentation. A poorer perceived prognosis can be nowadays reversed by the more aggressive therapies that are given to higher stage patients.

There is one small addendum: After these staging groupings, the doctor will often place a suffix A or B. If the patient has a suffix B after his staging then he has been observed to exhibit sweating (sufficient to wake him from sleep), more than 10% body weight loss and/or persistent fever at the time of presentation and this suffix B denotes a slightly worse outlook – stage for stage. Stage suffix A patients do not exhibit any of these clinical features at presentation. In general, patients with B symptoms have a higher bulk of disease and are treated as more extensive disease, than their Ann Arbor stage might suggest.

A special category is recognised where there is only one extranodal site of lymphoma and no lymph node involvement per se: this is referred to as stage 1E.

For some small, isolated skin or conjunctival (MALT) lymphomas presenting as stage 1E disease, the results of local therapy alone (radiotherapy) are excellent, indicating that these particular forms of lymphoma have a lesser and later tendency to spread.

Treatment & outcomes: Non-Hodgkin’s lymphoma

For localised (stage 1) disease and for low grade histology disease, then regional radiotherapy to the affected lymph node region may be recommended, followed by a careful watch policy. Perhaps 50% of stage 1 low grade cases can be cured by such therapy; for the rest, there is no prejudice to their long term survival by adopting a watch policy rather than an ‘up front’ chemotherapy policy, so long as they are carefully followed such that any relapse is picked up early and appropriate chemotherapy introduced then.

The situation is different in the higher grade histology, stage 1, NHL patients; here, there is a higher overall cure rate if several cycles of chemotherapy are delivered before radiotherapy to the site of origin of the NHL. The difference is that short course (multi-agent) chemotherapy used first is this situation for high grade NHL lowers the late relapse rate and thereby increases the overall cure rate. Even though radiotherapy alone may cure up to 60% of cases without any chemotherapy at all, a short course of primary chemotherapy is recommended to all patients fit enough to undergo this.

This difference between the policy for stage 1, low grade and high grade NHL is worth stressing: take low grade follicular lymphoma, for example; here, any up front chemotherapy seems to delay relapse but not stop it and therefore primary chemotherapy in this low grade NHL does not increase overall survival. This is in contrast to that for stage 1 high grade NHL.

For higher stage disease (either high or low grade disease) the emphasis moves heavily towards chemotherapy. In low grade disease, there is the difficulty already mentioned that it is very difficult to eradicate the disease completely. In such low grade NHL, it is customary to start therapy with simple chemotherapy which is highly likely to cause the disease to go into remission.

Overall, the combination of intravenously delivered drugs such as Vincristine, doxorubicin, cyclophosphamide and prednisolone, together with (in CD20 expressing ‘B’ cell lymphomas) a Smart Drug: Rituximab (a Monoclonal antibody directed at that ‘B’ cell  specific CD20 determinant, a characterisitic to the common ‘B’cell lymphomas. If the disease does not remit on this simple drug, then the doctor uses a combination of intravenously administered drugs (of drug regimens by the acronyms: COP and even CHOP) are used.

Many of these low grade NHL cases have demonstrated CD 20 positivity (see section on immunophenotyping above) on their original biopsy specimen and this has allowed the clinically useful development of a humanised monoclonal antibody directed at this antigenic (immunoglobulin light chain) determinant and this drug (trastuzumab/rituximab) is now combined with chemotherapy in poor responding low grade NHL and  High grade ‘B’ cell lymphoma .

There are variants of therapy depending on the type of lymphoma. For example: For MALT/marginal zone lymphoma of the stomach or conjunctiva, there is the unexpected observations that heliobacter gastritis or chlamydial conjunctivitis respectively are the drivers for the lymphoma and, very surprisingly, therapy for these infections by antibiotics, can lead to reversal of the phenomenon. For low grade Mantle cell lymphoma, which responds badly to orthodox therapy, the ‘Smart’ drug : ibrutinib can be highly effective and in follicular lymphoma drugs such as bendamustine and the non-chemotehrapy combination regime : Lenalidomide with rituximab has recently proven to be as effective as the first line combination chemotherapy

It is in the nature of uncured, low grade NHL to have a relapsing and remitting course; at first, it is relatively easy to put the disease into remission and then there follows a period of observation, which may be into years. Then the second time around it may be slightly more difficult to achieve as long a remission and so on and so forth until it eventually becomes impossible to achieve a further remission using conventional therapy.

Everything happens quicker in high grade lymphomas and it is essential to use multiple cytotoxic drugs, in combinations, in high stage disease to have any chance of cure. The drug regimens are often called by the acronym of the first letters of the constituent drugs, thus CHOP (Cyclophosphamide, Hydroxydaunorubicin- also called adriamycin or doxorubicin, Oncovin – also called vincristine and Prednisolone), with or without Rituximab – depending on CD20 positivity.

The drug courses are delivered by intravenous injection as close together as possible; this implies that as soon as the blood count has recovered from one course of chemotherapy the next is delivered; by this way, a progressively cumulative cell kill is affected on the lymphoma but the normal bone marrow is allowed to recover between courses. Using most of these chemotherapy regimens, the normal bone marrow has recovered the damage of one chemotherapy course by day 18 to 21 after drug delivery and therefore it is often found that chemotherapy is delivered at 21 day intervals.

For high stage and high grade NHL, it is customary to deliver two course of such chemotherapy and then re-asses the state of the disease by a repeat PET scan – indeed many protocols demand this and subsequent therapy – both in type and duration – are formulated on the early response at this time. For bone marrow positive cases, this may be re-assessed at this time also.

Where the response is good (the majority of cases) then the same chemotherapy regimen is continued for a further three course or so. The aforementioned CHOP regimen is still the favoured regime for most high grade lymphoma patients, although  young patients with T cell lymphoblastic lymphoma are treated with an acute lymphoblastic leukaemia regimen. Approximately 60% of all patients will go into remission with CHOP type chemotherapy and two thirds of these are cured, giving an overall 40% cure rate in rough and ready statistics. As mentioned above, there are variations on this base chemotherapy for different subtypes and stages of lymphoma and T cell lymphoma regimes vary considerable and are often more complex.

Where the response after three courses of first line chemotherapy is inadequate, then the chemotherapy is changed to an alternative drug regimen. If there was an initial very large bulk of NHL at one site or one such site was slow to go into remission, then the doctor may recommend radiotherapy to this region. However, the place of radiotherapy in higher stage patients is very limited and chemotherapy would be altered, with or without the introduction of ‘Smart’ drugs – as highlighted above.

Following completion of the chemotherapy course and in patients who remit ‘completely’, the patients are carefully observed with particular regard to the sites of initial disease (i.e. at presentation). Most high grade NHL patients who relapse will do so in the first two years off therapy and so follow up is concentrated on these first two years and thereafter the intervals between out-patient attendances will increase. for follicular lymphoma cases, there are data supporting the continuation of delivery of Rituximab (adjuvantly as maintenance therapy) at two monthly intervals for two years – but the case for continued maintenance therapy for other lymphomas is not convincing.

In high risk patients who remit with difficulty or are perceived to be at high risk of relapse despite achieving first time complete remission (i.e. a high IPI – International Prognostic Index) high dose therapy (or even a regimen that includes a high dose of total body irradiation) and some form of bone marrow rescue or transplant (i.e. a peripheral blood stem cell [PBSC] auto-transplant or an allogeneic – that is from another individual with similar tissue typing antigen profile – bone marrow transplant). In fact, the evidence of allogeneic transplant in first remission is very weak to non-existent for NHL patients (and carries considerable risks) and the evidence in favour of high dose chemotherapy and an autologous procedure in these patients should still be considered a research procedure, although some data do look persuasive for very high risk patients at presentation (e.g. T cell lymphoblastic lymphoma) who get into first time remission.

It is worth stressing that there is no place for an attempt at high dose chemotherapy and rescue/transplant in patients who have failed to get into remission or are in overt relapse and show no signs of remitting on conventional therapy; the use of this higher risk therapy in this situation is fraught with risk and is not attended by a cure rate that justifies these risks. High dose therapy with rescue/transplant is only useful for patients who are still chemosensitive and have been ‘debulked’ maximally by conventional chemotherapy (i.e. have minimal residual tumour burden).

What to do if the lymphoma has become resistant to the foregoing, including high dose therapy?

A genomic analysis of the lymphoma at the  time of resistance to standard therapies is worthwhile- either from a fresh tissue biopsy or from cell free DNA. Occasionally a driving genetic mutation is found, which is ‘druggable’ (e,g, the author is aware of such a resistant high grade lymphoma that had a JAK mutation which was ‘druggable’ and responded to a JAK inhibitor). the accumulating number of Smart drugs (ibrutinib. brentuximab, lenalidomde and others) can have a role in chemoresistant disease and a genomic analysis can give a steer to the Oncologist in this regard.

Immunotherapy (Rituximab apart), checkpoint immunotherapy has become established in the therapy of refractory Classic Hodgkin’s disease and, although at an earlier stage of acceptance (validation) in non-Hodgkin’s lymphoma, nevertheless, there are accumulating data on the usefulness of this therapy in refractory lymphoma – the apotheosis at present being CART therapy – a therapy in which the patient’s own T-lymphocytes are programmed in vitro to attack a lymphoma antigen/epitope after they are infused back into the patient’s blood.

Credit: Dr. P. N. Plowman MD , The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632


Overall, this is a rare disease and a population based screening programme is not indicated.


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