Fact File

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Hodgkin lymphoma
(formerly known as Hodgkin's disease)

by Dr Bernadette Birtwhistle and Professor Barry Hancock

Bernadette Birtwhistle was, until recently, Clinical Research Assistant to Professor Hancock and is now a Staff Grade in Clinical Oncology at Weston Park Hospital, Sheffield.

Barry Hancock is Yorkshire Cancer Research Professor in Clinical Oncology and Director of Cancer Research in Sheffield. He has always had a major interest in Hodgkin lymphoma and in further improving the outlook for patients with lymphoma, by clinical trials. 

Introduction

Hodgkin lymphoma (HL) is a medically fascinating disorder that has been recognised as a separate disease entity since the late 19th century.  Thomas Hodgkin wrote his famous description ' On some morbid appearances of the absorbent glands and spleen' in 1832, and Sir Samuel Wilkes applied the description "Hodgkin's disease" in 1865.  The descriptions of the characteristic large cells (Reed-Sternberg cells) which are believed to be the malignant cells in HL were published by both Sternberg (1898) and Reed (1902) at the turn of the century, and they have since been named after both of them.

Histology (microscopic appearances)

The Rye classification which has been used since the mid 1960s divides HL into 4 types based on the appearances down the microscope.  This has now been included along with that of non-Hodgkin lymphomas in the REAL (Revised European-American Lymphoma) classification.  Further modifications were made in 2000 and this is now known as the WHO (World Health Organisation) classification. The main categories of classical HL are:

·         lymphocyte rich

·         nodular sclerosing

·         mixed cellularity

·         lymphocyte depleted

Lymphocyte depleted HL is now very rarely diagnosed and cases previously described as this are now often reclassified as a type of non-Hodgkin lymphoma.  Lymphocyte rich HL is also quite rare.  One other uncommon variant of HL (lymphocyte predominant, nodular) does not behave as classical HL and may give rise (often many years later) to non-Hodgkin lymphoma.  The vast majority of cases of HL fall into the categories of nodular sclerosing or mixed cellularity.  The diagnosis of HL can be difficult, as there are other diseases with similar appearances down the microscope, and pathologists who work in General Hospitals may only see a few cases a year.  It is now recommended that suspected cases of HL are reviewed in specialised laboratories by expert pathologists to check that they agree with the diagnosis.  Additional tests can also be carried out in the laboratory to confirm the exact diagnosis.

What causes HL and who is affected by it?

In most cases of HL the cause is not really known. However there are a few associations which have been observed and which may give us some clues to possible underlying causes.  The Reed-Sternberg cell seems to develop from an out of control B lymphocyte - one of the cells that form part of the normal immune system.  A viral infection, possibly by the same virus that causes glandular fever, may play a part in the early stages of the process ¹.  An abnormal immune reaction possibly in a person with an inherited genetic susceptibility may then lead to the development of a malignant progression.

The patient with HL can be reassured that (unlike many other diseases) there is no direct link between anything they themselves have done and the development of their illness.

The most striking observation about HL is that it peaks in two age groups ie young adults (late teens to early twenties), and the elderly, with relatively few in between. This tends to suggest the possibility of an infectious cause in the younger age group, which is normally at low risk of developing cancers, and other causes in older people who are more prone to malignant diseases.  This is by no means certain however.  It is also slightly more likely to occur in better-off groups; in those who have previously had glandular fever; in patients with known immune deficiencies; in those with close relatives with HL and in those with occupational exposure to certain chemicals including plastics and paper-mill workers ¹.

Clinical features/staging investigations

The patient with HL will usually have the diagnosis made after a biopsy of a lump, typically in the neck, but sometimes in the armpit or groin. The diagnosis is relatively easy to make in these circumstances. Other possible symptoms with HL are: chest symptoms, such as a persistent cough or breathlessness; digestive symptoms, such as indigestion, abdominal pain, or change in bowel habit, or general symptoms such as tiredness, sweating at night, having temperatures with no obvious infection, or losing weight without trying. These are known as ‘B’ symptoms. The diagnosis may be difficult to establish when there is no obvious lump, and may take several months.

Once a diagnosis of HL has been made, on a biopsy, the patient will usually be referred to a specialist, who may be a haematologist or an oncologist. A number of further tests ('staging investigations') will then need to be arranged. These will include a number of special blood tests, computerised tomography (CT) scans and possibly a bone marrow sample.  These tests will enable the doctor to decide the stage of the HL according to the Ann Arbor criteria (table 1). The stage is important in deciding the correct choice of treatment for HL, but other factors including age, sex and general condition of the patient; histological type; the size of any lumps; presence or absence of 'B’ symptoms; and results of blood tests will also contribute to the final decision. This is why patients with apparently the same stage of HL may receive different treatments.

   Table 1: Ann Arbor – criteria for staging

Other considerations prior to treatment

Additional investigations.  Sometimes doctors may recommend extra investigations prior to starting treatment with radiotherapy and/or chemotherapy. If the HL is at an unusual site, different types of scans, for example, magnetic resonance imaging (MRI ) or positron emission tomography ( PET) (please get in touch with the Helpline if you would like more information on any of the different scans), may occasionally be recommended to get a clear picture of the part of the body affected. Because the drugs used in chemotherapy can impair the function of the heart and lungs a baseline measurement of their function prior to treatment may also be recommended, especially if taking part in a clinical trial is a possibility.

Clinical trials.  Many treatment centres are taking part in clinical trials, often involving randomly allocating patients between two treatments, both of which are known to be effective, but one of which may be slightly better than the other.  If trials are available, patients have been shown to benefit by being involved. However, they will always be given the opportunity to opt for the standard treatment if they prefer. Sometimes extra investigations will be necessary for the trial, and usually the follow-up visits are slightly more frequent, once the treatment is finished.

Fertility:  As many patients with HL are young and may want to have children in the future, and as treatments for HL can impair future fertility, this has to be thought about carefully. In the case of young men, sperm samples can be stored for future use if necessary. At present there is no certain way of storing eggs for women, although it is less likely that permanent infertility will be caused by treatment, unless the woman is already close to being menopausal (ie late 30s or older). (Please get in touch with the Helpline if you would like to receive information on fertility issues).

Patients are usually advised to wait two years after treatment for HL before trying to achieve a pregnancy - partly to avoid any increased risk of the baby failing to develop normally during pregnancy, and partly to avoid the time when it is most likely that the HL could come back.

Pregnancy.  A diagnosis of HL in a young woman who is already pregnant poses particular problems. The solution will depend on the stage of pregnancy at which the diagnosis is made. In late pregnancy the best solution would be to delay starting treatment until the baby can be safely delivered, and then treat the mother as usual for her HL. Chemotherapy drugs are harmful to the developing baby in early pregnancy, but less so after the first 3-4 months. Sometimes local radiotherapy can be given to the neck and/or chest while shielding the baby and chemotherapy can then be given later if necessary.  It is only occasionally necessary to offer termination of the pregnancy in order to treat the mother. 

Treatment

Once all the staging investigations have been completed, and results are available, a decision can be made as to the most suitable form of treatment. This will be with radiotherapy, chemotherapy or a combination of the two.

There are two main groups of HL patients, which we will discuss in turn; a minority will have 'localised' or 'early' HL, and the majority will have 'advanced' HL.

Overall, with modern treatment a cure rate of about 80% can be expected and this is even better for localised HL. This is much better than for most other forms of cancer, so that patients should be able to approach their treatment very positively from the outset.

Treatment of localised HL

Patients with Stage IA ('A' denotes no B symptoms) HL, and sometimes Stage 2A, will fall into this category, provided there are no other test results which make their doctor prefer to treat them as for 'advanced' HL.

For many years the treatment for localised HL was radiotherapy.  This was either 'Mantle' radiotherapy, for HL of the upper half of the body, or an 'Inverted Y' for the lower half, and sometimes both were given.

In a large percentage of patients, radiotherapy for localised HL was successful, and many people are still alive and well today having been cured by radiotherapy.

However, in more recent years, some disadvantages of this approach have become apparent: i.e. relapse outside the radiotherapy field, and long-term after-effects of radiotherapy.

 1. Relapse outside the radiotherapy field. Because radiotherapy only treats the areas of the body within the field, it has no effect on any HL cells which have spread beyond this but are not detectable with current methods of investigation ('occult disease'). In a percentage of patients who initially appear to have localised HL, their disease will reappear later in a different part of their body. This can often still be treated successfully by chemotherapy but is disappointing and frustrating for both the patient and his/her doctor.

 2.       Long-term after-effects of radiotherapy. Radiotherapy damages normal cells as well as abnormal cells, and any organs within the field can become damaged to some extent, sometimes leading to problems years later. The main organs which can be affected are the heart, lungs and thyroid gland. There is also an increased risk of breast cancer in women who have had Mantle radiotherapy.

Now that many more patients are being cured of HL, and especially localised HL, the focus of treatment has changed somewhat. Rather than asking 'How much treatment do we need to give to be sure of curing HL?', doctors are having to consider 'Can we reduce the long-term after-effects of treatment without compromising the chance of a cure?'.

A lot of research has been carried out to see whether adding a small amount of chemotherapy to radiotherapy and then giving smaller doses of radiotherapy than previously would help to reduce the risk of relapse and also make potential long-term after-effects of treatment less likely. This is the approach that is currently being used and seems to be preferable, though research to find the optimum treatment continues.

The exact combination of chemotherapy and radiotherapy used will vary between different treatment centres, and will depend on whether a clinical trial is underway at the time, but a typical treatment would be 'short course' chemotherapy, followed by 'involved field' radiotherapy i.e. radiotherapy to the lymph node regions affected by the HL, but avoiding treating too much of the surrounding normal tissue. Hopefully this should mean that just as many patients are cured of their HL, but that some potential health problems in 20-30 years time can be avoided.

Radiotherapy - what does it involve?

Radiotherapy is usually given over about a month.  The patient will need to attend the radiotherapy department every weekday during this time. The first visit is usually the longest as this is when the treatment planning takes place and the doctor will work out the positioning of the radiotherapy fields and the patient, so as to give treatment to the right part of the body as accurately as possible. After this the patient should only need to attend for a few minutes each day for treatment.

The radiotherapy itself is completely painless, although side-effects can develop as the treatment continues. The main problems which may occur are: skin reaction (similar to sunburn); sore throat; painful swallowing and dry mouth (if the head and neck or upper chest are being treated); or bowel symptoms (if the lower half of the body is being treated).  Tiredness can also develop, but is not usually severe, and is partly due to the frequent travelling to the hospital. (Please contact the Helpline if you would like to receive a copy of the 'Radiotherapy' fact file).

Treatment of advanced HL

When radiotherapy was the only treatment available for HL, it was difficult to cure more advanced (or widespread) cases. The first chemotherapy to be used successfully for HL was MOPP (mustine, vincristine, procarbazine and prednisolone). This was discovered in the 1960s, and made a dramatic difference to the outlook in advanced HL. Unfortunately MOPP also caused quite severe side-effects, and still did not cure every patient.

Over the last 40 years many clinical trials have been carried out by groups of doctors in Britain, Europe and America, in attempts to improve both the long-term cure rate and to reduce the short and long-term side effects as much as possible.  These have included combinations of drugs, very similar to MOPP, substituting less toxic alternatives to the mustine (e.g. ChlVPP - chlorambucil, vinblastine, procarbazine and prednisolone), or adding in additional drugs. In the 1970s chemotherapy regimens including Adriamycin® (e.g. ABVD - Adriamycin®, bleomycin, vinblastine and dacarbazine) were developed and also found to be very effective.  ABVD resulted in less infertility, but still caused quite severe nausea and vomiting.

Comparisons between MOPP-like and ABVD-based combinations and alternating or hybrid regimens using drugs from both groups have shown similar results as ABVD alone.  The exact regimen used may vary between different centres for example ChlVPP/PABLOE (prednisolone, Adriamycin®, bleomycin, Oncovin®, etoposide), or ChlVPP/EVA (etoposide, vinblastine, Adriamycin®,) are also used, but ABVD is now generally regarded as the standard against which future comparisons will be made. Again there are ongoing trials attempting to refine the treatment further so that the cure rate is continually improving and short and long-term side-effects are minimised.

ABVD chemotherapy  - what does it involve?

Between 6 and 8 courses of treatment are needed so the treatment is spread over 6 - 8 months. The main side-effects are: hair-loss (which is usually complete after a few weeks); nausea and/or vomiting (which is usually much less of a problem than it used to be with modern anti-emetic drugs); sore mouth (treated with mouthwashes and sometimes antibiotics); tiredness; and sometimes pain along the vein at the injection site (which can be reduced with extra dilution of the dacarbazine).  The most important side-effect however, which is not always realised by the patient is the increased risk of infection due to a low white blood count (neutropenia) which is particularly a problem about 7 -10 days after each course of chemotherapy. Patients need to be made aware of this and to be told to report symptoms of infection, particularly a high temperature, to their doctor promptly so that antibiotics can be started at an early stage before the infection becomes severe.  Patients may need to be admitted for antibiotics to be given through a drip, although they usually improve rapidly once antibiotics are started and the white blood count recovers.  Until recently the only way doctors could deal with the problem of low white blood cell (neutrophil) counts during treatment was to delay treatment a few days or reduce the dose of the treatment.  However nowadays, doctors are able to prescribe growth factors to boost the patient's neutrophils, and these are now often used for patients on ABVD or similar chemotherapy to avoid too many unwanted dose delays or dose reductions.

Reassessments during chemotherapy

During treatment the patient will be reviewed regularly by their doctor, so that he/she can check that the treatment is working, and can treat any side-effects that may be occurring.

Usually CT scans are repeated about half-way through the treatment and again at the end to see how well the HL is responding.  Sometimes at the end of treatment, especially when there has been disease in the chest, the CT scan may not return completely to normal.  This may not necessarily mean that there is still HL left, as there can be a lot of fibrous (or scar) tissue, which is left behind after all the Hodgkin cells have been killed.  This causes a dilemma for the doctors who may decide either to give radiotherapy in addition to the chemotherapy, or to repeat the scan in about 3 months to see if there has been any change.  New types of scanners are being developed (positron emission tomography or 'PET' scanners), which may help to resolve this in the future.

Newer treatments

Although ABVD and alternating treatments are very effective in treating advanced HL, they still do not cure everyone.  Therefore research is continuing to find better treatments. Trials are ongoing in which higher doses of drugs are given over the first few weeks of treatment, eg the so-called BEACOPP ( bleomycin, etoposide, Adriamycin®, cyclophosphamide, Oncovin®, procarbazine, prednisolone) regimen, or in which chemotherapy is given every week over a shorter period and  combined with radiotherapy to sites of larger masses, ie the Stanford V regimen.  You may be asked if you would like to take part in these trials at your treatment centre.

Future developments

There is exciting experimental research going on into new treatments for HL, using an immunological approach.  It may become possible to target cytotoxic therapy against the malignant Hodgkin cells using monoclonal antibodies. This may lead to further improvements in cure rates, hopefully with fewer after-effects.

Treatment after relapse

Relapse after initial radiotherapy (or treatment with short-course chemotherapy plus radiotherapy)

If HL comes back in these circumstances, treatment with standard chemotherapy, as for advanced HL still has a very good chance of success.

Relapse after initial chemotherapy

 A number of treatments can be successfully used in these circumstances:

i) if the relapse is very localised, then radiotherapy to this area can be successful.

ii) if the disease has been in remission for a year or more after chemotherapy, then further chemotherapy, either similar to, or different from, the initial chemotherapy (e.g. ChlVPP after ABVD), will often still produce a good response. High dose chemotherapy may also be recommended for some patients.

Early relapse after chemotherapy or incomplete initial response

In these circumstances high dose chemotherapy with a peripheral blood stem cell autograft, or bone marrow autograft, can still cure or produce a long-term remission in a considerable proportion of patients. This involves first giving more chemotherapy, which may be either in-patient or out-patient, depending on the regimen chosen. This is called the induction/ priming chemotherapy.  After this the patient is given several days of growth factor treatment to increase the production and release of stem cells from the bone marrow into the blood stream.  An admission is arranged for a stem cell harvest, during which these immature blood cells are collected from the blood using a cell separator machine.  These are then stored until needed. Soon after this the patient is again admitted and given chemotherapy at a considerably higher dose than normal. This damages the bone marrow, and the stem cells have to be given back so that the bone marrow can recover. The recovery process takes about 2 weeks, and some of this time needs to be spent in isolation to allow the patient’s immune system to recover somewhat.

High dose chemotherapy is a bigger undertaking for the patient than conventional chemotherapy, which is why it is usually kept in reserve until it is really necessary (indeed, stem cells may be taken and stored without necessarily proceeding to a transplant). If HL relapses again after high dose chemotherapy, then the procedure can sometimes be repeated, or consideration may have to be given to the use of donor bone marrow, either from a sibling or from a bone marrow bank.  This is called an 'allogeneic' transplant.  Recent developments in these procedures, for example 'mini-allografts' (please contact the Helpline for further information about this procedure), in which the donor cells, rather than chemotherapy, attack the persistent HL, have resulted in them becoming safer and less toxic, but they are still only used in special circumstances.

Follow-up after treatment.

After their treatment is finished patients with HL will continue to be seen at the out-patient clinic for several years at least.  The first visit is usually about 6 weeks after completion of treatment, then visits will be 3 monthly, extending to 6 monthly and then annually.

There are several reasons for these visits. Initially the doctors will check that the patient is recovering from the side-effects of treatment, and that the treatment has worked (this is called being 'in remission').  After this the clinic visits are intended to detect any symptoms of relapse of the HL, as early as possible, so that any further treatment needed has the best chance of success.  Most patients who relapse do so within the first two years.  Relapse is still possible for many years, but becomes increasingly less likely.  The purpose of later clinic visits is mainly to monitor the development of any longer-term after effects of the chemotherapy and radiotherapy, so that any treatment that is needed can be started without any delay.  The main late effects which can occur are: problems with the heart or lungs, an under-active thyroid, early menopause and infertility, and occasionally second cancers, such as breast cancer or leukaemia.  Because of these long-term risks to their health, it is particularly important that patients who have been treated for HL avoid cigarette smoking and excessive sun exposure. There is currently some debate, as to the optimum timing of follow-up visits, but patients generally find it reassuring to have check-ups with their cancer specialist at regular intervals. These visits also enable doctors to learn more about the long term progress of their patients, which is vital for the continuous improvement of the treatment.

Conclusion

During the past half century the treatment of HL has come on in leaps and bounds. From being an inexorably fatal disease, often of young people, it is now usually curable; with expert treatment most patients can expect to live long and normal lives.

References

¹‘Malignant Lymphoma’ Arnold, London. 2000. BW Hancock, PJ Selby, K MacLennan, JO Armitage, (editors).

Other references

Editorial. Journal  of Clinical Oncology, Vol 21, No 4, February 15 2003, 583-585. Volker Diehl. ‘ABVD is better, yet is not good enough!’

Seminar. The Lancet, Vol 361, 943-951, March 15 2003. L Yung, D Linch.