Second Opinion on Malignant lymphoma

Malignant lymphomas (tumors of lymphoid tissue) are a general term for a group of malignant diseases that develop from lymphocytes, a subtype of white blood cells found in lymphoid tissue and responsible for the body's immune defense.

Therefore, in everyday language, they are sometimes referred to, although not entirely accurately, as “lymph node cancer.”

Treatment options and prognosis depend on the type of lymphoma and may vary considerably.

Why Does Lymphoma Develop?

The lymphatic system plays an important role in protecting the body against infections and foreign substances. Its main immune cells are lymphocytes, a type of white blood cell. Lymphocytes include B cells, T cells and natural killer (NK) cells, each of which performs different functions in the immune response.

As a result, lymphoma may develop in or spread to organs such as the skin, gastrointestinal tract, lungs, brain and bone marrow.

In most cases, the exact cause of lymphoma cannot be identified. However, certain lymphomas are associated with acquired changes in chromosomes and individual genes. These are not inherited changes passed down from parents. Instead, they develop during a person's lifetime within the malignant tissue. Such genetic abnormalities can disrupt the normal mechanisms that control cell growth and division, allowing an altered cell to become malignant and multiply uncontrollably.

Radiation exposure, smoking and contact with carcinogenic chemicals may increase the risk of developing particular types of lymphoma.

Classification of lymphomas

Malignant lymphomas are not a single disease but a large group of cancers with very different biological characteristics, clinical courses and responses to treatment. Establishing the exact lymphoma subtype is therefore essential for selecting the appropriate treatment strategy.

Traditionally, malignant lymphomas have been divided into Hodgkin lymphomas and other malignant lymphomas, which were commonly grouped under the term non-Hodgkin lymphomas. However, modern classification allows individual lymphoma entities to be defined much more precisely. As a result, the term “non-Hodgkin lymphoma” is increasingly used less often as a general category. Specific diagnoses such as follicular lymphoma or diffuse large B-cell lymphoma are preferred because the different entities may differ substantially in their biology, prognosis and treatment.

The current WHO Classification of Haematolymphoid Tumours takes into account the origin and characteristics of malignant cells, their stage of maturation, genetic abnormalities and other biological features. B-cell lymphoid proliferations and lymphomas include follicular and mantle cell lymphomas, diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, marginal zone lymphomas and other entities.

Another major group comprises T-cell and NK-cell lymphomas. These include T-lymphoblastic leukemia/lymphoma, primary cutaneous T-cell lymphomas, hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma and certain Epstein-Barr virus-associated T- and NK-cell lymphomas. Hodgkin lymphoma itself is divided into classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma.

The clinical behavior of these diseases varies considerably. Some are indolent, meaning that they grow slowly and may cause few or no symptoms for a long period of time. Others are highly aggressive and require treatment to begin promptly. Therefore, the diagnosis of “lymphoma” alone is not sufficient to determine a patient's prognosis or treatment plan.

Stages of the Disease

In addition to the numerical stage, doctors assess the presence of so-called B symptoms. If the patient experiences night sweats, fever and weight loss, the letter B is added to the stage designation, for example “Stage IIIB”. If these systemic symptoms are absent, the letter A is used, for example “Stage IIIA”.

The specific lymphoma subtype, its biological characteristics, growth rate, involvement of particular organs and the presence of symptoms are also important when selecting therapy.

Symptoms

The most characteristic symptom of malignant lymphomas is painless enlargement of the lymph nodes or other organs of the lymphatic system, such as the spleen and tonsils. In addition, general symptoms are often observed, including increased fatigue, night sweats, fever, unexplained weight loss, reduced performance, increased susceptibility to infections, a tendency to bleed, as well as other manifestations depending on the specific type of lymphoma.

It is important to remember that an enlarged lymph node does not necessarily mean lymphoma. It commonly happens as a result of infections or inflammation. Nevertheless, persistent, particularly painless, lymph node enlargement or any of the above-mentioned symptoms should be evaluated by a physician.

Lymphoma diagnosis

The diagnostic process begins with a detailed medical history and physical examination. The physician asks about the nature and duration of symptoms and previous illnesses, then examines the patient for enlarged lymph nodes, enlargement of the liver or spleen and possible signs of involvement of other organs.

The next step is blood testing. Doctors assess blood cell counts and their distribution, as well as markers of organ function, mineral metabolism and other parameters.

Molecular diagnostic methods, including FISH analysis and gene sequencing, may also be performed in selected cases to identify genetic abnormalities that provide information about the lymphoma subtype and may help guide treatment decisions.

The definitive diagnosis usually requires a lymph node biopsy. A lymph node or an appropriate tissue sample is removed and examined histologically using several techniques. The characteristics of the lymphoma cells, including their surface markers, are analyzed in order to establish the precise lymphoma subtype. Tissue examination is essential for distinguishing malignant lymphoma from benign lymph node enlargement.

Imaging studies are then used to determine the extent of disease. Ultrasound can provide information about lymph nodes and abdominal organs. More detailed cross-sectional imaging is provided by computed tomography or PET/CT. PET/CT can demonstrate the metabolic activity of lymphoma tissue, assess the extent and size of the disease, evaluate response to treatment and identify possible residual active tumor after therapy.

Since some lymphoma types can involve the bone marrow, a bone marrow biopsy may be part of the initial diagnostic evaluation.

Treatment of Lymphoma

Treatment varies considerably between different types of malignant lymphoma. It depends on the specific subtype, extent and aggressiveness of the disease and the presence of symptoms requiring treatment. There is therefore no single standard treatment that applies to all cases. Different treatment methods are frequently combined and adapted to the individual lymphoma type and patient.

For some slow-growing lymphomas, a Watch & Wait strategy may be appropriate. It is considered when immediate treatment offers no advantage over delayed therapy. This strategy may be appropriate in certain cases of follicular lymphoma and chronic lymphocytic leukemia.

In contrast, with aggressive lymphomas, such as diffuse large B-cell lymphoma and Burkitt lymphoma, treatment should be initiated immediately.

Chemotherapy uses drugs that interfere with cell division and cellular metabolism. Because malignant cells often divide rapidly, they are particularly sensitive to cytotoxic agents. Chemotherapy is generally administered in cycles, with treatment periods alternating with breaks. The overall duration depends on the lymphoma type and stage.

Radiotherapy uses high-energy ionizing radiation directed at the affected area. It can be particularly effective in certain early-stage lymphomas and may be used to eliminate localized tumor tissue. Depending on the lymphoma type and clinical situation, radiotherapy may also be given after chemoimmunotherapy, combined with targeted agents, or before or after CAR-T-cell therapy.

Antibody therapy uses specially produced proteins that recognize specific structures on the surface of malignant cells. By binding to these structures, antibodies can selectively target and destroy cancer cells. Antibodies may be used alone or in combination with chemotherapy, a strategy known as immunochemotherapy. Because of their targeted mechanism of action, antibody therapies are generally relatively well tolerated, although the specific side effects depend on the individual drug.

Modern lymphoma treatment also includes targeted drugs designed to interfere with specific molecular mechanisms that support the survival and proliferation of malignant cells. Some agents affect programmed cell death, or apoptosis, which is often disrupted in lymphoma cells. Others interfere with the B-cell receptor signaling pathway. Examples include Bruton tyrosine kinase inhibitors (BTK inhibitors) and BCL-2 inhibitors.

Antibody-drug conjugates (ADCs) combine two treatment principles. An antibody that specifically recognizes a cancer cell is linked to a cytotoxic drug. The antibody delivers the active drug to the target cell, allowing treatment to act more selectively and potentially reducing damage to healthy tissue.

Bispecific T-cell engager antibodies (BiTEs) use the patient's immune system in a different way. One part of the molecule binds to a T cell, while the other binds to a malignant cell. The BiTE molecule therefore brings the immune cell and cancer cell into close contact and activates the T cell, triggering a response that can lead to apoptosis of the cancer cell.

CAR-T-cell therapy is another form of modern immunotherapy. T cells are collected from the patient's blood and genetically modified so that they recognize specific structures on malignant cells. The modified cells are then returned to the patient's body, where they can bind to cancer cells and trigger an immune response leading to their destruction. Because both the manufacturing process and treatment are highly complex, CAR-T therapy is performed in specialized centers.

Depending on the clinical situation, the optimal approach may involve observation, chemotherapy, immunochemotherapy, radiotherapy, targeted drugs, modern immune-based treatments or CAR-T-cell therapy. Clinical trials may provide an additional treatment option for selected patients. They are used to evaluate new drugs and combinations as well as to optimize established treatment approaches and improve their effectiveness and safety.