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Hodgkin's disease: symptoms and treatment

Hodgkin's disease

Hodgkin’s disease is a unique cancer in many regards but it is classified amongst the lymphomas.


The histological/microscopical picture in Hodgkin’s disease is that of a mixture of cells. The malignant cell itself is probably the so-called Sternberg-Reed (RS) cell (which probably originated from the lymphocyte lineage - the malignant clonal origin of the RS cell  has only recently been confirmed by PCR analysis) but this cell type may only comprise 1% of the total cellular picture in the material called Hodgkin’s disease and indeed there may only be variants of the classic Sternberg-Reed cell (which has two nuclei and is a large cell with an unmistakable microscopic picture) or even no typical examples in a biopsy specimen, making diagnosis a challenge.


In the rest of the background material of a microscopic specimen of Hodgkin's disease tissue, is a mixture of lymphocytes, eosinophils, plasma cells, granulocytes and histiocytes, such that most ‘white cell'  lineage cells are represented. How much these other cell populations are only reactive and whether the Sternberg-Reed cell is the only malignant cell is still discussed, but what every histologist agrees is that Sternberg-Reed cells or their variants must be present in any biopsy for it to qualify for the diagnosis of Hodgkin’s disease.


Having said the above, there are four classic types of Hodgkin’s disease recognised down the microscope: the first is the lymphocyte predominant type, where, as the name suggests, the lymphocyte is the dominant cell – this has the best prognostic outlook for the future but is relatively uncommon (less than 5%).


The second is called nodular sclerosing Hodgkin’s disease because microscopically there are well-defined microscopic nodules demarcated by sclerosing/fibrous strands. This sub-type of Hodgkin’s also has a good outlook and is common; approximately 70% of patients in the UK have nodular sclerosing disease and it is disproportionately common in females.


The third variety of Hodgkin’s disease is called mixed cellularity and is more commonly found in the Middle East and Asia and carries a worse prognosis unless treated aggressively; it only accounts for 20% in the UK. The typical histological features are the commoner occurrence of Sternberg-Reed cells and their variants in a background of mixed cell types and no sclerosis.


The worst type of Hodgkin’s disease to suffer is lymphocyte depleted where the Sternberg-Reed cells predominate and the lymphocytes are hard to come by and there is not a lot of reactive background. Fortunately, only 5% of the disease is of this variety, as it is the most aggressive type of the disease.


Symptoms of Hodgkin's disease

Presenting clinical features (what brings the patient to the doctor): At least 70-75% of patients present because they have noticed the painless development of lymphadenopathy (i.e. enlargement of lymph nodes), usually in their neck glands or armpits.


The child in the photograph represents a typical presenting picture, viz. a well looking individual with a large painless lump appearing over a few months in the neck, indeed two thirds of patient present in this way.


Approximately 5% of patients have groin lymph gland enlargement but the vast majority of patients have the disease predominantly in the lymph node regions above the diaphragm. In these patients, a majority will also be found to have disease in the chest - usually lymph node enlargement that is detectable on simple chest x-ray as widening of the central chest structure shadows.


When the patient presents late in the natural history of the disease, then he/she may have other symptoms such as fevers, night sweats and weight loss (the so-called 'B' symptoms as they denote a more advanced stage of disease); pruritus/generalised itching may also occur in these cases.


Treatment of Hodgkin's disease

Therapy is aimed at cure with least morbidity (i.e. side effects to the patient). As most cases of Hodgkin’s disease are curable, so this last caveat is most important.


Early stage Hodgkin’s disease, such as stage 1A of the neck glands, can be cured in most cases by the local application of moderate dose radiotherapy to the nodal region - 'involved field radiotherapy.'


For slightly more advanced disease (stage 2) or disease of higher grade (e.g. .mixed cellularity versus lymphocyte predominant) a different strategy is now employed. As has been said, Hodgkin's disease tends to spread logically from one set of lymph nodes to the next; so, for the last couple of decades a technique of radiotherapy called 'extended field radiotherapy' was used. This technique 'covered' the adjacent lymph node regions as well as the obviously involved ones, to sterilise any microscopic disease that might have travelled further. The technique accepted that quite a large area of the body received radiotherapy, but was justified in that the cure rate was higher than for involved field radiotherapy alone. However, although successful for many years this technique has now given way  to one in which less than full course chemotherapy is employed first (to 'mop up' cells that were outside the obviously involved nodal groups) followed by lesser dose radiotherapy to only the obviously involved nodal groups at the outset.


Both techniques are aimed to reduce the chance of relapse of disease out-with the originally affected node groups but the trend to (lesser) chemotherapy followed by lesser radiotherapy seems to be have less side effects in the long run for the patient. 


There are times when radiotherapy remains an important treatment in the management of Hodgkin's disease. For example, in the photograph (left panel) which shows a cross-sectional image of a patient's chest in which there is a large mass of Hodgkin's, it is obvious that there is a huge bulk of tumour to sterilise. Chemotherapy will shrink this down (see right panel) but this is the least likely site of Hodgkin's to be sterilised by chemotherapy alone.  Therefore, this patient was treated by local radiotherapy to the chest after the chemotherapy course was finished. Cure has thereby more certainly been achieved.


 From the foregoing, it must be clear that the strategy is one of primary chemotherapy to shrink the mass of Hodgkin’s disease right down to minimal size and then to deliver the radiotherapy (often to a lesser dose than in the days when radiotherapy was used as the sole modality of therapy).


For higher stage cases, the use of chemotherapy becomes more routine. It is one of the great success stories of modern times that combinations of cytotoxic chemicals can cure Hodgkin’s disease and the current controversies relate to the optimal regime. For example, one of the most tried and tested curative regimes (MOPP and variants thereof) is highly effective at curing patients but tends to sterilise (make infertile) the patients.  Also, these constituent drugs to increase the risks of late second cancers, particularly when used in combination with radiotherapy - (second cancer = the late development of a new cancer in a patient cured of one cancer type and caused by the previous cancer treatment). Therefore, not surprisingly, the search has been on for equally good drug regimes at sterilising the Hodgkin's disease but with lesser risks to the patients.

 ABVD is one good four drug regime that fulfils many of these wishes and others are being researched.


The consideration of late treatment effects is important in a population of young patients for whom one is expecting cure and the issue of maximising the chances of first time cure whilst minimising the risks of therapy is as heatedly argued in this disease as in any other in Oncology at present. This controversy has given rise to many new therapeutic attempts to obviate these side effects/complications of therapy. For example, many now use ‘hybrid’ chemotherapy for several reasons. Hybrid chemotherapy rotates different active combination drug regimens around, such that the disease is exposed to more agents and, in theory is less likely to develop drug resistance to any one, and, with the above toxicity considerations in mind, reduces the patient to cumulative exposure to any one drug type. However, it has to be said that none of these newer regimens has been shown to be better than ABVD, although a lot of research goes on in this area.


Furthermore, in a chemo-radiotherapy regimen, where the chemotherapy is nowadays almost always used first, the radiotherapy is reduced in dose and extent (e.g. more cardiac protection) where the patient’s disease has responded well to the primary chemotherapy.


In general, where the disease is very extensive, then the programme is very heavily biased in favour of chemotherapy whereas for more localised disease the use of radiotherapy is more common. In general terms, where chemotherapy is used alone, the first time cure rate is of the order of 67% overall, with the earlier stage patients doing better than this overall figure (with a 87-95% cure rate for early stage disease being routinely achievable) and the stage 4 patients with liver and bone marrow disease doing worse (with only a minority being cured).


For high risk patients in whom cure by such chemotherapy alone is not expected (less than 50% chance) then a regime of post chemotherapy 'high dose' chemotherapy plus a peripheral stem cell transplant (using the patient's own bone marrow stem cells to rescue the marrow after high dose ablative chemotherapy) now has a routine place in the improvement in cure rates of high stage patients - and also in the 'salvage cure' of patients who later relapse after conventional chemotherapy.


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