The term "malignant lymphoma" is used to summarise a group of malignant diseases in which there is a rapid and uncontrolled proliferation of cells of the lymphatic system. The lymphatic system normally serves as a defence against pathogens and is found in lymph nodes, but also in the spleen, tonsils, bone marrow and many other organs. In many cases, a swelling of a lymph node is therefore the typical manifestation of this disease, but sometimes these diseases can also occur in other organs (such as the brain, skin or intestines).

Malignant lymphomas are not a uniform group of diseases. There are at least 50 subtypes. There is a current classification by the World Health Organisation (WHO), but this is constantly being updated and expanded. The three most important groups of lymphomas, some of which differ considerably in terms of treatment and prognosis, are defined below.

1. Hodgkin's disease
2. indolent (or low-malignant) non-Hodgkin's lymphomas, which primarily include follicular lymphoma
3. Aggressive non-Hodgkin's lymphomas, especially diffuse large cell lymphoma.

Malignant lymphomas are rare compared to so-called solid tumours (such as lung cancer or breast cancer). However, there has been an increase in the incidence over the last 10 to 15 years. The age of onset varies for different types of lymphoma. In the case of indolent lymphomas, most patients are over 60 years old. In the case of aggressive lymphomas, there are many patients who are significantly younger. Hodgkin's disease typically also occurs in young people (20-40 years), but there is a second age peak in patients over 60.

In most cases, the cause of malignant lymphomas is not known. As a rule, there is no familial clustering, i.e. the disease is not hereditary. Environmental toxins and radioactive irradiation can play a role, but in many cases a causal link is difficult to establish.

In a small group of lymphomas, however, there are indications of the cause. For example, the Epstein-Barr virus plays a role in lymphomas that occur in patients who have a reduced immune system due to HIV infection or after a transplant. Other viruses such as the hepatitis C virus, the so-called Kaposi's sarcoma-associated herpes virus or the HTLV virus have also been identified as triggers of very rare types of lymphoma. Gastric inflammation caused by a bacterium (Helicobacter pylori) plays an important role in low-malignant gastric lymphoma. These findings are partly used for therapy: in some cases, antibiotic therapy alone (in the case of gastric lymphoma) or viral therapy can lead to an improvement or even cure of the disease.

The swelling of a lymph node in the neck, armpits or groin is the most common symptom for which patients with lymphoma consult a doctor for the first time. Lymph node enlargement or enlargement of the spleen in the abdomen is often found as an incidental finding during an ultrasound examination, or in the chest as an incidental finding during an X-ray examination of the lungs. However, as in principle any other organ can be affected, completely different symptoms may be in the foreground, e.g. seizures in the case of lymphomas of the brain or bone fractures in the case of bone lymphomas or skin rashes in the case of skin lymphomas.

Patients with low-malignant lymphomas usually feel well and the disease is often discovered more or less by chance. In the case of aggressive lymphomas or Hodgkin's disease, general symptoms often occur, which are medically referred to as "B symptoms". Patients are often tired and exhausted, lose a lot of weight even though they eat normally, sweat profusely at night, which makes it necessary to change their nightdress or the entire bed linen, or have a fever without any signs of infection.

The diagnosis of malignant lymphoma is challenging due to the many subtypes, the constantly changing classification and the sometimes difficult differentiation from benign diseases. The prerequisite is usually a tissue sample (biopsy) taken from a lymph node or another organ. This tissue is usually automatically forwarded to one of a total of six reference pathologists in Germany (at the universities of Kiel, Lübeck, Berlin, Frankfurt, Würzburg or Ulm), where the diagnosis is made using the latest findings and sometimes complex methods. Such reference histology is an indispensable prerequisite for further therapy.

Once the diagnosis of malignant lymphoma has been confirmed, staging examinations are carried out to determine how far the lymphoma has spread in the body. The scope of the examinations depends largely on the type of disease (indolent or aggressive) and the therapeutic consequences. As a rule, this includes a discussion with the doctor and a detailed physical examination, an X-ray of the lungs and an upper abdominal sonography. A CT scan of the chest and abdomen and a bone marrow puncture often follow, particularly in the case of diseases for which intensive chemotherapy is planned. In some cases, further additional examinations are necessary, such as a scintigraphy of the bones, a puncture of the spinal fluid, an endoscopy of the stomach and intestines or a so-called PET scan.

Today, malignant lymphomas are categorised according to the histological picture (histology), the composition of the surface proteins (immunohistochemistry), genetic and molecular genetic aspects and clinical aspects. An international classification is provided by the World Health Organisation (WHO) and is revised at regular intervals. The subdivision of malignant lymphomas is very complex: more than 50 forms with further subtypes are differentiated.

To simplify matters, however, the subdivision into Hodgkin's lymphoma, the low-malignant and the highly malignant form of non-Hodgkin's lymphoma is sufficient. The next chapter ("Treatment options") is also subdivided on this basis.

In most cases, staging is based on the Ann Arbor classification, which distinguishes between four different stages. In stage 1, one lymph node localisation is affected. In stage 2, several lymph nodes on one side of the diaphragm are affected. In stage 3, lymph nodes on both sides of the diaphragm are affected. Stage 4 refers to diffuse organ involvement (e.g. if the bone marrow is also affected). The suffix "B" indicates the presence of symptoms such as fever, night sweats and weight loss; the suffix "A" indicates the absence of these symptoms. The suffix "E" indicates the presence of lymphoma outside the lymph nodes (e.g. stomach, lungs, skin, testicles).

Similar to the various diseases, there are major differences in the treatment of malignant lymphomas. What all non-Hodgkin's lymphomas have in common is that they are systemic diseases, i.e. surgery on a lymph node does not make sense as the lymph cells have quickly spread throughout the body and continue to grow elsewhere. Similarly, radiotherapy alone is usually not useful. Chemotherapy is therefore the most important measure, but it is adapted to the disease, age and general condition of the patient. There are therefore options ranging from mild chemotherapy (e.g. tablets that are taken at home) to very intensive procedures (e.g. high-dose chemotherapy, in which so-called blood stem cells are collected from the patient beforehand, frozen and given again so that the bone marrow can recover quickly).

The treatment options for the three most common groups (see above) are discussed below.

1. hodgkin's disease

The treatment results for Hodgkin's disease are excellent. Thanks to the new therapy protocols, sustained remissions can be achieved in over 80% of cases, even in advanced stages. Therapy is based on the stage of the disease and a number of well-defined risk factors (e.g. haematopoietic sedimentation rate, number of affected areas, diameter of a manifestation in the chest). In this way, three risk groups (low, medium and high risk) are defined. Standard therapy for low-risk groups is short-term chemotherapy (2 cycles, duration 2 months) and post-radiation, for medium-risk groups somewhat longer chemotherapy (4 cycles, duration 4 months) and post-radiation and finally for high-risk groups intensive chemotherapy (6 cycles, duration 6 months). However, the good treatment results are clouded by the relatively frequent late complications of such treatment. For example, 10-15% of cured patients have to reckon with other tumours caused by chemotherapy and radiotherapy after 15-20 years. For this reason, modern study protocols endeavour to reduce the intensity of treatment as far as possible and to reduce such late complications.

In the event of a relapse of the disease, a permanent remission can be achieved in many patients with high-dose chemotherapy with stem cell transplantation. In 2014, the drug Brentuximab vedotin was approved as an antibody coupled with a chemotherapeutic agent that can achieve very high remission rates. This antibody is directed against the protein CD30, which is found on all Hodgkin's cells. It leads to the chemotherapeutic agent coupled to the antibody being introduced directly into the cell. Brentuximab vedotin is used for relapses after autologous transplantation or in patients who cannot undergo autologous transplantation. Current study protocols are also testing the use of brentuximab vedotin in earlier lines of therapy. The approval of an immunologically effective antibody nivolumab for patients with brentuximab vedotin failure is expected at the end of 2016. This antibody removes the immunological "protective shield" of the cancer cell so that the cancer cell can be attacked by the body's own defences.

2. Low-malignant non-Hodgkin's lymphomas

The treatment strategy for low-malignant lymphomas differs significantly from other lymphomas. In many cases, patients do not require therapy for years. Studies have shown that starting treatment early has no advantages. Therefore, chemotherapy is only started when a patient feels symptoms of the disease (e.g. when lymph nodes press on other organs, when B-symptoms occur). If symptoms are present, the standard therapy today is a combination of chemotherapy and the antibody Rituximab. Antibodies are the body's own proteins with which the immune system can defend itself against pathogens. Nowadays, however, it is also possible to produce antibodies that are directed against lymphoma cells (but also against other cancer cells, e.g. in breast cancer). The main representative of these CD20 antibodies is called rituximab. Since 2016, however, another CD20 antibody called obinutuzumab has been approved for early relapses, which is effective if rituximab therapy has not previously been effective enough. On average, 6 cycles of treatment with chemotherapy and antibodies are required. For follicular lymphoma, so-called maintenance therapy with rituximab alone every fortnight for 2 years is authorised. Unfortunately, in most cases a relapse occurs after some time (usually years), so that low-malignant lymphomas are considered incurable. Nevertheless, many patients with this type of lymphoma can live well and without symptoms.

Only in a small proportion of patients with a localised stage are attempts made to achieve a cure through early radiotherapy.

In the event of a relapse, chemotherapy again leads to remission. In young patients with early relapse, however, the option of high-dose chemotherapy with stem cell transplantation should also be discussed. This intensive treatment method usually achieves a longer response than "normal" chemotherapy, especially if the last treatment was effective for less than 2 years.

Since 2014, the option of purely oral (tablet) therapy with idelalisib has also been available for the first time. This substance inhibits an important signalling pathway in the tumour cell. However, this substance can only be used if the previous chemotherapy and antibody therapy has responded for less than 6 months. Despite the tablet form, idelalisib has quite a few side effects, such as diarrhoea or pneumonia.

Overall, there are a variety of therapeutic approaches for follicular lymphoma, a disease that often has long treatment-free phases. The probability of survival has increased significantly in the last decade. Many patients do not die "from the lymphoma", but "with the lymphoma" from other age-typical diseases.

3. highly malignant non-Hodgkin's lymphomas

In the case of highly malignant lymphomas, similar to Hodgkin's disease, attempts are made to achieve a lasting remission and, if possible, a cure through rapid, intensive therapy. The standard for over 30 years has been chemotherapy according to the so-called CHOP scheme (each letter is an abbreviation for different substances: cyclophosphamide, doxorubicin, vincristine, prednisone). For some years now, this chemotherapy has been combined with the antibody rituximab (see chapter on low-malignant lymphomas). As a rule, 6-8 cycles of this R-CHOP therapy are administered. In certain cases, local radiotherapy may also be useful, for example if a lymph node was particularly large at the start of treatment or if organs other than lymph nodes were affected.

For patients with an increased risk of relapse (this can be determined using a risk score with 5 simple clinical parameters), slightly more intensive therapy is usually considered. In Germany, etoposide is added to the CHOP regimen and a total of 8 cycles are given every 14 days.

In the event of a relapse, high-dose chemotherapy with stem cell transplantation of the patient's own stem cells is the first option for young patients. If the disease does not respond to the first therapy or if there is a relapse within the first year, a stem cell transplant from a related or unrelated donor is also an experimental but nevertheless sensible measure.

In older patients, other chemotherapy combinations and sometimes local radiotherapy are usually considered. However, the chances of a cure are increasingly lower after the first or second relapse.

Overall, aggressive non-Hodgkin lymphomas that cannot be successfully cured with the first chemotherapy are often very difficult to treat. We therefore offer innovative new study concepts for this indication.

4. other non-Hodgkin's lymphomas

Due to the more than 50 different subtypes and the different localisations (brain, stomach, etc.), there are treatment protocols in special situations that deviate from the options described above. It is not possible to describe them all in this short section.

Mantle cell lymphoma, for example, has a special status. For a long time it was thought to be a low-malignant lymphoma on the basis of its microscopic appearance. It then emerged that the prognosis for this disease was particularly poor with conventional therapy. For this reason, high-dose chemotherapy with stem cell transplantation is recommended directly to young patients. For older patients or patients for whom such therapy is not an option, a combination of the monoclonal antibody Rituximab and conventional chemotherapy (R-CHOP or R-bendamustine) is recommended.

More new drugs have been approved for mantle cell lymphoma in recent years than for any other non-Hodgkin's lymphoma. In the event of relapses, therapy with weekly infusions (temsirolimus) and tablet therapy (ibrutinib) are available. A further tablet therapy (lenalidomide) can be given with the initial chemotherapy. Overall, current studies are investigating the exact status of the new substances, e.g. whether they should be given individually or in combination, or whether they should be given at the beginning or only after relapse. For example, the combination of the monoclonal antibody rituximab and conventional chemotherapy (R-CHOP or R-bendamustine) makes sense.

As different as the various subtypes of malignant lymphomas are, so different is the course of the disease. To put it simply, Hodgkin's lymphoma and aggressive lymphomas have a curative approach, i.e. intact chemotherapy or a combination of chemotherapy and radiotherapy leads to the long-term disappearance and cure of the disease in many cases. In the event of relapses (recurrences), it is still possible in many cases to start a new curative therapy.

Low malignant lymphomas are still not considered curable. However, in many cases no treatment is necessary for years, and treatment can restore freedom from symptoms for many years. As a result, it is often possible to lead a normal and symptom-free life despite this disease.

After chemotherapy or radiotherapy has been completed, aftercare begins. Examinations are carried out every three months, and after two years often every six months, in order to recognise relapses (recurrences) at an early stage. The type and scope of these examinations depends on the type of malignant lymphoma, the pattern of infection and any residual findings.

For some types of lymphoma, a dramatic improvement in the chances of recovery has been achieved over the last 30 years. In Hodgkin's disease, many studies are currently focussing on reducing side effects and long-term complications and improving the quality of life during treatment. However, the prognosis for patients with aggressive lymphomas in so-called high-risk situations is unsatisfactory, especially if the first therapy has not responded. The prognosis for young patients with low-malignant lymphomas in relapses is similarly unsatisfactory.

Current developments are focussed on the best combination and timing of standard therapies. In addition, attempts are being made to further reduce the side effects of intensive therapies such as stem cell transplantation from related or unrelated donors, so that this previously risky route is available to as many patients as possible. Finally, a whole series of new drugs are being developed. On the one hand, the possibility of producing antibodies against tumour cells and coupling these with effective substances (radioactive particles or cytotoxins) has created an exciting new therapeutic option (RIT). With increasing knowledge of the molecular processes in tumour cells, it is possible to produce drugs that specifically interfere with the metabolism of the tumour cell but not that of the healthy cell (e.g. bortezomib or temsirolimus in mantle cell lymphoma).