Hodgkins lymphoma

Hodgkins Lymphoma

Lymphomas are the name given to the diseases associated with the malignancy of lymphocytes. There are two major sub-divisions:

1. Hodgkins lymphoma
2. Non-hodgkins lymphoma

Hodgkins lymphoma (HL) in the present day is now considered as a disease which we are able to treat and can be described as a "curable" disease. 

The name "Hodgkins" was derived from the man who first described the abnormalities of the lymphatic system in 1832. The abnormal cells which characterise HL were identified in 1898 by Reed and Sternberg, hence their name Reed-Sternberg cells, these are malignant cells.

HL may develop at any age, and is usually 1900 cases are diagnosed every year (1 in every 200 cancers). In men, it's most common between the ages 20-34 and 75-79 and 1 in 440 will develop HL. In women, it's most common between the ages of 20-24 and 70-74 and 1 in 500 will develop HL.

At the moment there is no one definitive cause for HL, however there are many factors associated with its occurrence:

• A possible cause of HL is the Epstein Barr virus, almost half of all HL cases have been related to a EBV infection.
• Previous NHL occurrence
• Hepatitis C
• Little research has been done of this, however the exposure to pesticides may play a role 
• Immuno-deficient patients, such as those with HIV, post transplant etc
• Lack of exposure to common infections, such as those from a higher socioeconomic background.
• Family history, via inheritance or a particular lifestyle trait.
• There is a supposed lowered risk of contracting HL in those who drink alcohol, however this does not affect those who also smoke.
• An increased risk can come from obesity, however this was only seen in males. 

Most people however do not show any signs of specific identifiable risk factors.

These malignant cells can accumulate in a single lymph node, and eventually may spread to other nodes, and also can pass into the blood stream and invade other organs of the body.

Reed-Sternberg cells and Hodgkin cells possess mechanisms which inhibit apoptosis.

In the pathogenesis of the disease, it is not fully understood as of yet. RS cells and H cells are all apart of the clones.

Clinical features

The clinical features of the disease include:

• Enlarged painless lymphadenopathy
• Lymph nodes can fluctuate in size
• The ingestions of alcohol can cause pain
• Itching
• Breathlessness and coughing
• Enlargement of the spleen and liver 
• Fever, weightloss, night sweats
• When the lymphoma leaves the lymph nodes and travels to other parts of the body, this is referred to as extra nodal disease, including the skin, lung, CNS, marrow etc
• Increase in the number of infections due to defective humoral and cell mediated immunity.

HL may arise in any part of the lymphatic system, however it is more common in some areas over others, such as the cervical nodes (located in the head/neck) where 60-70% of HL cases arise. The axillary nodes (located in the arm pit area) cause around 10-15% of cases, and the inguinal nodes (located in the stomach/hip/groin area) cause around 6-12% of cases. These areas will swell up, but will also be painless. Some people can be diagnosed as having extra nodal disease at the time of diagnosis. The most likely areas to have extra nodal disease are the liver and the bone marrow. The bone marrow can be associated with specific symptoms.

Diagnosis

A biopsy of the lymph nodes is carried out under the use of a local or general anaesthetic.

The WHO has varying histological classifications for HL.

Subtypes include classical:

• Nodular sclerosis: Most common type of HL in the UK, 60% of patients are diagnosed with this, most common in young adults. Found in the early stages where the lymph nodes in the neck have become swelled.
• Mixed cellularity: Around 15% of cases are of this type, it usually affects a number of lymph nodes, and these will each contain different types of lymphocytes and other cells.
• Lymphocyte depleted: 10% of HL cases are of this type. Lymphocytes appear to be very small, in a biopsy of the lymph nodes there are a lot of lymphocytes but very few Reed-Sternberg cells.
• Lymphocyte rich: This is quite a rare type of HL, the lymph nodes may either contain a lot of fibrous tissue, with very few Reed-Sternberg cells, or they may contain a high amount of a specific lymphocyte type referred to as the reticular lymphocyte, and many Reed-Sternberg cells.

Another subtype is the nodular lymphocyte predominant type (non classical type): Only 5% of HL cases are of this type, it is more common in the elderly however it can occur at most ages. The main difference between this specific type and the classical types, is that this type contains a very small amount of Reed-Sternberg cells (they're almost considered as absent), and they also contain a group of cells which are referred to as popcorn cells, these are RSC subtypes, they're small cells with a highly lobulated nucleus, and small nucleoli. This HL type is only ever diagnosed in localised HL. The treatment for this type differs from the classical types, and this type also has a slower growth rate.  

RSCs tend to have an owl like appearance which are multi-nucleated.

Specific factors can be looked for in the diagnosis of HL:

• Non specific peripheral blood manifestations
• Normocytic and normochromic anaemia
• Eosinophilia (increase in RBCs)
• Neutrophilia (increase in WBCs, only in 1/3 of patients)
• In the advanced disease, low lymphocyte count
• Platelet count is either normal or increased in the early stages of HL, however in the later stages the count becomes low.
• The involvement of the bone marrow can be detected.
• Raised erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) are useful prognostic markers and good for monitoring response.
• Serum lactate dehydrogenase (LDH) can sometimes be raised.
• HL can cause irregular liver function test results (LFTs), and urea and electrolyte test (U&E) results 
• Increase in the levels of urate

There are a number of tests which can be carried out in order to establish the stage at which the lymphoma is at in a patient.

Within the laboratory:

• Full blood count (FBC) and bone marrow check, ESR, CRP, LFTs, LDH

Radiology techniques:

• Chest X-ray; detects if lymph nodes within the chest are enlarged. 
• PET; Positron emission tomography, using a low dose of radioactive glucose to measure the activity of the cells in differing parts of the body. This is helpful in the detection of minimal residue disease.
• MRI; Magnetic resonance imaging, uses the use of magnetism in order to compose an image of the body within, this is especially helpful in showing soft tissue and the CNS.
• CT scans; Computerised tomography, uses a small amount of radiation to build up a computerised image of the inside of the body.

It is important to be able to diagnose the stage of HL, as this will affect the treatment and prognosis of each individual patient. 

Stages

HL can be broken down into 4 stages:

1. Indication of node involvement within one area (I)
2. Indication of disease involving 2 or more lymph node areas, however these are contained to one side of the diaphragm. (II)
3. Splenic disease is involved at this stage (III)
4. Involvement of HL outside of the lymph nodes, and also refers to diffuse disease within the bone marrow, liver and other extra-nodal sites. (VI)

Each stage can then be sub-typed with the use of different letters, each acting as an indication towards other factors involved at each stage, such as stage 3, as this involves spleen enlargement, it can be called IIIs.

Treatment

The treatment of HL depends mainly on the stage of diagnosis. It is possible to just use radiotherapy on patients whose HL is localised (NLPHL). However, a combination of varying therapies may be used, such as chemotherapy and radio therapy, this is called combined modality therapy. Due to secondary complications resulting from radiotherapy, this combined method is now usually preferred, except in the presence of NLPHL. Radiotherapy can be useful in the elimination of bulky disease which can remain after chemotherapy, and also in the elimination of painful skeletal, nodal, or soft tissue deposits which can form as a result of previous chemotherapy.  

Chemotherapy is used for those patients suffering from stage 3 and 4 of HL, but also those who are suffering with stage 1 and 2 alongside bulky disease (widening of the mediastinum (undelinated group of structures in the thorax, containing the heart, lymph nodes etc) of more than a third, or the presence of measuring more than 10cm in any dimension), and also those who have relapsed after previous radiotherapy. ABVD is most commonly used, other variants used can be ChlVPP and BEACOPP, the latter mainly for those with a poor prognosis. 

Autologus stem cell transplantation involves:

1. Either bone marrow aspirated from iliac crest OR leucopheresis of stem cells from peripheral blood after chemotherapy and G-CSF injections
2. Attempts to remove residual tumour cells e.g via use of monoclonal antibodies
3. Stem cells infused intravenously (after storage)
4. Intensive support therapy e.g with RBC, platelets and antibiotics

However, a patient who responds well to chemotherapy will straight to 4 after treatment.

The response to a treatment is assessed by clinical examination using imaging, to identify any residual masses present. If a patient does carry out relapse, they can be treated alternatively with combination chemotherapy, or radiotherapy for bulky disease. If they undergo relapse again, if the patient is under 65 years of age, autologous transplant is considered. 

Prognosis

The prognosis for those in stage 1 or 2 of the disease at the time of diagnosis that 91-94% of suffers will live for at least another 5 years. For those in stage 3 or 4 of the disease, 50-90% of suffers will live for at least another 5 years. The type of HL and the age of the patient will also contribute to the prognosis. Cure rates do decrease if the patient relapses, however the disease will be able to be kept under control for a period of time. 

European Organisation for Research and Treatment of Cancer (EORTC) stage 1 and 2 prognosis features:

Favourable:

• Clinical stage 1 and 2 with a max. of 3 nodal areas involved
• Age less than 50 
• ESR less than 50mm/hr without B symptoms, or ESR less than 30mm/hr with B symptoms
• Mediastinal/thoracic ratio below 0.35

Unfavourable

• Clinical stage 2 with the involvement of 4 or more nodal areas
• Age over 50 
• ESR over 50mm/hr is asymptomatic or ESR over 30mm/hr with B symptoms
• Mediastinal thoracic ratio over 0.35

HL can also have later effects, which can include secondary malignancies, for example lung and breast cancer are related to the use of radiotherapy, MDS (myelodysplastic syndrome) and AML (acute myeloid leukaemia) are related to the use of chemotherapy. Other effects include cardiac disease, dysfunction of the endocrine system, intestinal problems, damage to the lungs, psychological trauma, lower general health levels, and can cause problems in getting loans. Attention must always be paid to these later effects.