Enlarged lymph nodes in right axilla (armpit) shown positive on PET scan due to 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.


Most workers in the field have observed a higher incidence in the young adult population afflicted in countries of higher socio-economic development whereas the incidence in older patients does not seem to follow this pattern and may obey the converse pattern (i.e. be more common in areas of lesser socio-economic development).

Males are affected by the disease more commonly than females and in the ratio of 1.4:1.

No one causative agent has been identified but interest in a possible viral trigger is still very much discussed with the EB virus as the agent under closest scrutiny. Patients with a history of past EB virus related mononucleosis have a higher incidence of later Hodgkin’s disease and EB virus is detectable within the RS cells in at least 50% of cases of the disease, particularly those with mixed cellularity Hodgkin’s disease. However, the fact that the virus is not detectable in all cases infers that the situation is more complex than a simple infection trigger alone.

There is a slight familial tendency of developing the disease but whether this necessarily implies a genetic factor is also a topic of debate (as shared environment is also a factor that cannot be dismissed amongst families)


Hodgkin’s disease accounts for 1% of adult cancer and the incidence in the UK is 2.5 per 100,000 of the population. An interesting bimodal distribution in the presenting ages of patients has been found. Thus there is a first peak in incidence in young adults and then a lesser second peak in later life. There is a 1.4:1 male sex preponderance over females with the disease and almost three quarters of all cases have presented by 60 years of age.

Symptoms & diagnosis of Hodgkin’s disease

Lymph node enlargement on the left side of neck due to 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.


Microscopic appearance of Reed Sternberg cells

The biopsy (taking of a piece of tissue for microscopic analysis) of the enlarged lymph node gives the diagnosis. This is the only method of certain diagnosis and is always recommended.

Before performing the biopsy and before histological review, there must always be a differential diagnosis for any enlarged lymph node and this will include infection and other benign and malignant causes. Therefore, there is absolutely no alternative to biopsy for the certain diagnosis of Hodgkin’s disease.


Scanning of patient to detect the extent of cancer.

The staging of the tumour

One of the most interesting features of Hodgkin’s disease is that it tends to spread in a logical and orderly fashion. It tends to begin in one part of the lymphoreticular system and usually in a peripheral lymph node and then spreads to involve adjacent lymph nodal regions before going on again to the next and finally to disseminate to other organs, of which the liver and the bone marrow are the most important to detect and most prognostically serious. Unlike advanced lymphomas (non-Hodgkin’s lymphomas), Hodgkin’s disease does not tend to spread to the brain

The staging aims to look in all the places where Hodgkin’s disease may spread for the possibility of involvement. Thus, these patients have a CT scan of the neck, chest, abdomen and pelvis as well as a whole body PET scan and a bone marrow examination. Blood tests are performed.

From these staging tests are evolved the staging for each patient:

one set of nodes involved only is stage 1.

Where two sets of nodes are involved on one side of the diaphragm then the patient is stage 2.

When there are lymph nodes groups (or spleen) involved on both sides of the diaphragm then the patient is stage 3.

Where there is disease outside the lymphoreticular system e.g. live or bone marrow, the patient is stage 4.

Additionally, it has been observed that patients with symptoms of heavy night sweats or significant weight loss of more than 10% of body weight or fever have a worse outlook stage for stage and therefore there has been devised an A versus B system where each patient is divided stage-wise into suffix A or B cases; thus a patient might ultimately be staged as stage 3B etc.

The staging system is important with regard to the therapy chosen and the eventual prognosis. However, some other factors contribute to the prognosis and it is noteworthy that older patients do less well than younger patients and males do worse than females.

Treatment & outcomes of Hodgkin’s disease

Chest C.T. scans of patient with Hodgkin’s disease before (left) and after (right) chemotherapy showing good response of anterior chest mass.

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.

Indeed, the PET scan (that scan that is used to stage the patient in the first instance) is repeated after two courses of chemotherapy and, often, the use (or not) of radiotherapy to the nodes that were affected in the beginning (i.e. before any chemotherapy) is used to determine whether the patient needs any radiotherapy at all (or determines the dose that will be employed at the end of the chemotherapy.

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 or no  radiotherapy seems to be have less side effects in the long run for the patient.

Radiotherapy field used to treat neck and central chest

There are times when radiotherapy remains an important treatment in the management of Hodgkin’s disease. For example, in the photograph above (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 such a s Stanford V :  mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone )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 (Adriamycin, Bleomycin, Vinblastine, Darcarbazine)  is one good four drug regime that fulfills many of these wishes ( as it particularly dose not contain an alkylating agent, whose presence in a regime adds to the chance of mutations/second cancers and sterility) 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 postchemotherapy ‘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.

In chemo-refractory Hodgkin’s disease, the ‘Smart Drug’ : Ibrutinib (a Bruton’s Tyrosine Kinase inhibitor) can have a dramatically good effect on Hodgkin’s disease and is currently finding its place in the treatment of earlier stages of this lymphoma. It is indeed drug of the moment in this disease.


C.T. scans of a Hodgkin’s Disease patient with much enlarged lymph nodes lying beside the trachea (red arrowed in left figure) and after curative chemotherapy and radiotherapy.

C.T. scans of a Hodgkin’s Disease patient with much enlarged lymph nodes lying beside the trachea (red arrowed in left figure) and after curative chemotherapy and radiotherapy.

By the above means, most patients with Hodgkin’s disease will go into first time remission and hopefully never relapse i.e. are cured.

The cure rates for early Hodgkin’s disease are in the region of 87-95%. The photo (left panel) shows a CT scan of the chest (in cross-section) with a lump of Hodgkin’s disease arrowed in red. In the right panel it can be clearly seen that the lump has disappeared after a course of curative therapy- the structures that are left are the normal ones.

What happens if the treatment is not successful? If a patient relapses after a radiotherapy-only programme, given for stage 1 disease, then there is no compromise to the good expectations of cure from chemotherapy and, if the patient has been followed up assiduously, then the relapse will have been picked up early and the chance of cure from such chemotherapy will be good.

Where the patient has presented with more advanced Hodgkin’s disease and has relapsed after a full chemotherapy programme, then the situation is more complex. The chance of second time cure with alternative orthodox dosage chemotherapy is nothing like as high as first time around, perhaps only 25%-50% (depending on the intensity and durability of the firs time response).

In this group of patients, the practice of delivering the alternative orthodox dosage chemotherapy and then (having achieved a response) delivering high dose chemotherapy (so high as to take the patient beyond bone marrow death) and then performing bone marrow rescue with peripheral stem cells (harvested from the blood of the patient as a contingency plan when he was in remission) is the most promising plan of management. As has been outlined above, the new ‘Smart Drug’ Ibrutinib is an important addition to the therapy repertoire- probably before the high dose chemo and autologous transplant .

Booster radiotherapy to sites of bulky relapse may be also employed. By such means, cure may often be achievable.

Some patients develop drug and radiation resistant disease and then their management is, as for any other cancer that has progressed beyond hope of cure, palliative; with therapy directed towards symptoms of the moment and not at any bigger objective.


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