Non-Hodgkin Lymphoma

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Dr. José Tomás Navarro, Head Clinician. Catalan Institute of Oncology hematology laboratory -Hospital Germans Trias i Pujol (Badalona). Researcher at the Josep Carreras Leukaemia Research institute. Secretary of the Spanish Hematology and Hemotherapy Society (SEHH). (Co.28586​)


What are non-Hodgkin lymphomas and whom do they affect?

Lymphomas called non-Hodgkin lymphomas (NHL), to differentiate them from Hodgkin lymphoma, are diseases with different characteristics and prognoses. They are hematological neoplasms with the common feature of having their origin in lymphoid cells of different types.

Within the category of NHL are 30 different types of cancer, each with its own individual characteristics (see the table 2017 WHO classification table).

In NHL, a lymphoid cell, detained at a certain stage of maturation, reproduces uncontrollably, causing, with time, an increase in the size of the organ in which they are being produced. Given that lymphatic tissue is found all over the body, the lymphoma may appear in any part of the organism and, from there, spread to other organs and tissues. In most cases they start with an infiltration of a lymph node (nodal type), but in others they can appear in other organs such as the digestive system, the skin, brain, spleen, kidneys or other organs (extranodal type).

The general incidence of non-Hodgkin lymphomas in our country oscillates between 30 and 70 new cases per million, per year. They are slightly more frequent in men and amongst patients with immune system diseases (AIDS, immunodeficiencies, organ transplant receivers, autoimmune diseases), infections (helicobacter induced gastritis, Epstein Barr virus), and patients treated with chemotherapy or radiotherapy.

It is a kind of cancer that can also affect children, although that is much less frequent.

Types of non-Hodgkin lymphoma

From a practical point of view, NHL can be divided into two large groups depending on the speed of their growth.

Aggressive lymphomas, also known as high grade lymphomas, tend to grow and spread quickly and cause severe symptoms. The most frequent are diffuse large B-cell lymphoma (accounting for a third of all lymphomas), mantle cell lymphoma, peripheral T-cell lymphoma, Burkitt lymphoma and lymphoblastic lymphoma (equivalent to a type of acute lymphoblastic leukaemia).

Indolent lymphomas, also known as low grade lymphomas, behave less aggressively, with lymphadenitis evolving over years and with a generally conserved state, in spite of generally being very extensive (stages III and IV). The most frequent are follicular lymphoma, small lymphocytic lymphoma (equivalent to chronic lymphocytic leukaemia), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia), marginal zona lymphoma (including MALT lymphomas) and the cutaneous T-cell lymphomas (mycosis fungoid and Sézary syndrome).

Paradoxically, aggressive NHL tend to respond well to chemotherapy treatments, while the indolent lymphomas are very difficult to completely eradicate, although with present-day treatments, patients can live for many years and, for most of the time, without symptoms.


The symptoms of NHL are very varied and depend on each specific type of lymphoma and the organs affected.

A large percentage of patients are diagnosed upon the detection of lymphadenitis. The term lymphadenitis, or adenopathy, is used in medicine to describe an increase in the size, or inflammation, of a lymph node.

Characteristically, patients' symptoms can include fever, night sweats, weight loss, fatigue and repeated infections. There may also be manifestations as a consequence of the enlarged size of the spleen (abdominal pains), the compression of an organ by a large tumour, (cough, lumbar or abdominal pain), or the defective functioning of an organ on account of its infiltration by cancer cells.

Lymphomas are usually classified in four stages depending on the number and location of the affected lymph nodes, whether the affected lymph nodes are above, below, or on both sides of the diaphragm and whether the disease has spread to the bone marrow, spleen or organs outside the lymphatic system, such as the liver.


To adequately diagnose the type of lymphoma in question, a biopsy must be performed on one of the enlarged lymph nodes, and there needs to be an extension study (explorations to discover how many lymph areas have been affected). This entails a blood test, one or various imaging tests, (X-ray, echography, gammagraphy, thorax, abdomen and pelvic scan, full body PET scan) and a bone marrow biopsy (a biopsy of the hip bone) to determine whether it has been affected by the lymphoma.

The lymphomas are classified depending on the areas affected (Ann Arbor classification):

Stage I. The lymphoma affects a single lymph node region or affects only one organ outside the lymphatic system.

Stage II. Two or more lymph node regions or lymphoid structures on the same side of the diaphragm are affected.

Stage III. Various lymph node regions or lymphoid structures are affected on both sides of the diaphragm.

Stage IV. One or more extralymphatic regions are affected (bone marrow, skin, liver, or other organs), with or without lymph nodes being affected.

The Ann Arbor classification is accompanied by the letters A, B, E or S:

A. The patient does not present fever, weight loss or night sweats.

B. The patient presents fever, weight loss or night sweats.

E. Lymphoma is found in an organ or tissue that is neither a lymph node nor the spleen.

S. The spleen is affected.

In the case of aggressive lymphomas it may be necessary to perform a lumbar puncture in order to analyse the cerebrospinal fluid and detect any infiltration of the central nervous system by the disease.

In the case of young patients who so wish, given that it is not normally urgent to start treatment, semen cryopreservation may be provided for men and fertility preserved for women.


Like the symptoms, treatment for NHL varies depending on the kind of lymphoma, the age and general state of health of the patient, the extent of the disease and its progression.

As a general rule, lymphomas classified as indolent (or of low grade malignancy), in spite of the fact that they can sometimes have spread widely around the organism, evolve very slowly and may, therefore, not require immediate treatment after the disease has been diagnosed. In such cases treatment is usually quite effective, but it almost never provides a cure and, with the passage of time, the lymphoma will reappear.

In contrast, aggressive lymphomas (or of high grade malignancy) have a much quicker evolution, meaning that they must be treated quickly. Nevertheless, they tend to respond very well to treatment and total remission from the disease is often achieved (absence of symptoms, and absence of demonstrable disease through the application of the extension study methods described above), and in many cases a cure is achieved.

Treatment for indolent lymphomas varies according to the various subtypes. Thus, in the case of follicular lymphoma (the most frequent type), and with asymptomatic patients, therapeutic abstention is considered to be the best option. For patients with localised disease, radiotherapy may be the best treatment. For other patients there is no treatment that could be considered standard, but the treatments currently applied use Rituximab (a monoclonal antibody that acts against the CD20 receptor that is presented specifically by neoplastic lymphoid cells) in association with one or more classic chemotherapy agents. If there is no response to treatment, or if the disease returns, a different chemotherapy protocol may be considered that may also include monoclonal antibodies or drugs against new therapeutic targets. In some cases, depending on the response, the age and general state of health of the patient, an autologous transplant (from the patient themselves) may be considered, or a reduced intensity allogenic transplant (from a compatible donor).

In the case of MALT lymphomas treatment is based on combatting the antigen stimulus which has given rise to the neoplastic transformation (infections, local inflammatory processes, autoimmune diseases, etc.) and treatment may consist only of treating the infection or the incidental pathology, although, in advanced stages, or in cases in which the lymphoma does not respond to the treatments described above, it is usually necessary to add to the conventional chemotherapy itself, in association or not, with Rituximab.

Treatment for aggressive tumours is also variable depending on the type of lymphoma, its extension and the age and general state of health of the patient. In the case of the most frequent lymphoma, diffuse large B-cell lymphoma, the most frequently used chemotherapy protocol is known by the name of R-CHOP, which combines Rituximab with cyclophosphamide, Adriamycin, vincristine and prednisone, with a variable frequency of administration and number of cycles depending on each individual case. Radiotherapy may be effective for treating localised affected areas or very large masses. A transplant of hematopoietic progenitors (usually autologous, more exceptionally allogenic) is limited, in this disease, to patients who do not respond to the first line of treatment, or who relapse, as long as the disease remains chemosensitive.


The prognosis is very variable for each lymphoma subtype. In the case of follicular lymphoma, in spite of the very slim chances of the treatment achieving a cure, the chances of survival are very prolonged, with most patients living for more than ten years after diagnosis. In contrast, aggressive lymphomas tend to respond very well to treatment and the probability of a correctly treated patient with diffuse large cell lymphoma finding a cure is between 60-80%.

Follicular lymphoma

Follicular lymphoma is a kind of indolent non-Hodgkin B-cell lymphoma. It is a very prevalent kind of lymphoma in the western world (around 30% of all NHL). Although it can appear at any age, it usually affects adults, the average age at diagnosis being 60. It is very infrequently found in young people and children. The World Health Organisation (WHO) distinguishes three subtypes of follicular lymphomas:

Predominantly small cell follicular lymphoma, or type l

Mixed small and large cell follicular lymphoma, or type ll

Predominantly large cell follicular lymphoma, or type III

Patients with these diseases are frequently asymptomatic and often consult their doctors after perceiving painless lymphadenitis (an enlarged lymph node). 60% of patients present infiltration of the bone marrow at the time of diagnosis. Around 25% of patients also present splenomegaly (enlarged spleen) and in some cases there may also be infiltration of the digestive tract or liver. The usual lymphoma symptoms (night sweats, fever, weight loss) tend to be infrequent.

The evolution of this type of lymphoma is indolent and slow, with an average life expectancy from the time of diagnosis longer than 12 years. A complete cure for these patients is difficult and for patients at an advanced stage (80% of cases) is impossible with present-day conventional treatments. Although some patients may achieve complete remission, as the course of the FL progresses, relapses are more frequent and the periods of remission shorter. The absence of a cure, patients' relatively prolonged life expectation and their usually advanced age, are all factors that help determine treatment. For some follicular lymphoma patients (2-3% per year) the disease transforms into an aggressive lymphoma and necessitates appropriate treatment for an aggressive lymphoma.

For patients who are asymptomatic at the time of diagnosis, therapeutic abstention is considered to be the most suitable option since studies show that immediate treatment does not lead to an improvement in life expectancy. For patients with localised follicular lymphoma (I and II) radiotherapy must be considered, either on its own, or in combination with chemotherapy. Radiotherapy using various irradiation techniques produces excellent and prolonged control over the disease when it is very localised in up to 90% of patients. For other patients treatment is based on the administration of Rituximab (a monoclonal antibody that acts against the CD20 receptor specifically presented by neoplastic lymphoid cells) in association with one or various classic chemotherapy agents (chlorambucil, bendamustine, adriamycin, cyclophosphamide, fludarabine and mitoxantrone, amongst others).

If there is no response to treatment, or the disease reappears, a different chemotherapy protocol may be proposed, or a treatment that includes new monoclonal antibodies, or drugs aimed at therapeutic targets.

Diffuse large B-cell lymphoma

This is an aggressive non-Hodgkin lymphoma that accounts for approximately 30% of all NHL. It has an incidence of 50-60 new cases per million, per year, increasing with age. Although it can be observed at any age the average age of patients with large lymphomas is 60-65. As a result of the progress that has been made in diagnosing neoplastic diseases using techniques for analysing the genes implicated in the origin of the lymphomas, it has been possible to identify subtypes within this category that have varying prognoses. It is possible, in this respect, to talk about two main subtypes: germinal centre diffuse lymphoma, and activated B-cell lymphoma. The latter has a worse prognosis and more targeted treatments are being trialled which will probably lead to improved prognoses in coming years.

The WHO classification displays a wide clinical variety:

Unspecified diffuse large B-cell lymphoma (DLBCL):


Morphological: centroblastic, immunoblastic and anaplastic

Molecular: germinal centre and activated B-cell

Immunohistochemical: germinal centre and non-germinal centre

Patients with these diseases tend to visit their doctors after perceiving a painless lymphadenitis (enlarged lymph node) although, in almost half of cases, doctors are consulted due to a different clinical manifestation depending on where the lymphoma manifests itself (abdominal or intestinal pains, hemorrhages, bone pains, etc.). A third of patients present the general lymphoma symptoms (night sweats, fever, weight loss).

This kind of lymphoma has an aggressive evolution and the prognosis very much depends on the patient's age, general state of health, the extent of the tumour and response to treatment. Treatment is based on the association of chemotherapy and radiotherapy on the local, or large, affected areas (mediastinal mass, for example). The most widely used chemotherapy protocol at the present time is known by the name of R-CHOP, in which Rituximab is administered in association with cyclophosphamide, Adriamycin, vincristine and prednisone, with a variable frequency of administration and number of cycles, depending on each individual case. Radiotherapy can be effective for treating localised affected areas. A transplant of hematopoietic progenitors (usually autologous, more exceptionally allogenic) is limited, in this disease, to patients who do not respond to the first line of treatment, or who relapse, as long as the disease remains chemosensitive.

Up to 80% of young patients can find a cure with these procedures, but the probability of such a cure decreases with age.

Mantle cell lymphoma

Mantle cell lymphoma is a very infrequent B-cell non-Hodgkin lymphoma that accounts for around 10% of all NHL. It affects people of advanced age and is more prevalent in men than women. Most patients are older than 65 when diagnosed.

Most of these patients tend to visit their doctor when the disease is already at an advanced stage. The patient may present the general lymphoma symptoms (night sweats, fever, weight loss) and usually splenomegaly (enlarged spleen) and lymphadenitis (significant but painless enlargement of a lymph node). It very often spreads beyond the lymphatic system to invade especially the bone marrow and digestive tract. This type of lymphoma has a poor prognosis.

At the present time, treatment for this lymphoma depends on the patient's age at the time of diagnosis and the possibility of performing an autologous transplant of hematopoietic progenitors. Patients younger than, or at the age when autologous transplants can be performed, must be treated using immunochemotherapy protocols that employ high doses of the drug cytarabine (or Ara-C), followed by an intensification course with the autotransplant. Patients who are older than this or who are not candidates for a transplant are administered immunochemotherapy. A transplant from a donor may be indicated in cases that do not respond to treatment, or in cases of relapse, when the patient has a compatible donor and their age and general sate of health permit.

Although most cases of mantle cell lymphoma are aggressive, it should be borne in mind that there are a small number of cases that behave as if they were indolent. In such cases, the option of not yet administering treatment may be perfectly acceptable since years may pass before the lymphoma grows and produces symptoms.

Extranodal marginal zone B-cell lymphoma (MALT)

Mucosa associated lymphoid tissue lymphoma (MALT-type) is an indolent B-cell lymphoma known for frequently affecting the stomach. MALT stands for mucosa associated lymphoid tissue, such as that found in the digestive tract, lungs, salivary glands and conjunctiva of the eyes. Infection by a bacterium that infects the human gastric epithelium, typically Helicobacter pylori (in 90% of cases), makes mucosa associated lymphoid tissue appear in the form of follicular gastritis, and from there molecular changes can occur that may lead to MALT lymphoma.

There are other types of MALT lymphoma associated with other infections, such as:

  • Cutaneous and Borrelia burgdorferi MALT lymphomas
  • Ocular and Chlamydia psitacci lymphomas
  • Intestinal and Campylobacter jejuni lymphomas

Patients with MALT lymphomas tend to visit their doctor upon the appearance of gastric symptoms such as, heartburn, hemorrhage, and epigastric or abdominal pain. This type of lymphoma usually remains localised, but it can eventually spread to other areas such as the lungs, intestines and bone marrow. 10% of patients with a MALT lymphoma go on to develop an aggressive lymphoma with a poor prognosis.

In the case of localised gastric MALT lymphoma, the eradication of the Helicobacter pylori bacterium through the administration of antibiotics achieves the disappearance of the lymphoma at the microscopic level in most cases, although the response may be slow. If the disease is not resolved, or is not confined to the stomach, immunochemotherapy is required, usually based on agents such as chlorambucil, fludarabine, bendamustine or CHOP-type combinations in association with Rituximab (a monoclonal antibody that acts against the CD20 receptor that is presented specifically by neoplastic lymphoid cells). Once achieved, remission is maintained stable in 90% of cases. Radiotherapy has also proved effective with this type of lymphoma and may be applied locally to the area affected by it.

In addition to the chemotherapies mentioned above local radiotherapy may also be used on occasion for the treatment of extranodal MALT lymphomas.

Burkitt Lymphoma

Burkitt lymphoma, also known as small non-cleaved cell lymphoma, is an aggressive type of non-Hodgkin B-cell lymphoma. This type of neoplasm is infrequent and mainly affects young patients.

Three subtypes of Burkitt lymphoma have been distinguished. They have different characteristics and clinical manifestations:

Endemic Burkitt lymphoma. Observed in children in equatorial Africa. It is the most frequent disease amongst children in this region of the world. The disease tends to affect the jaw and other facial bones. It is associated with the presence of Epstein-Barr virus in 95% of cases.

Sporadic Burkitt lymphoma. This type is present throughout the world and mainly affects children and young adults. It accounts for a third of all childhood lymphomas.

Immunodeficiency-associated Burkitt lymphoma. This type is particularly associated with infection by the human immunodeficiency virus (HIV) or with patients who have received a transplant and who are being administered immunosuppressive drugs.

In our part of the world, the most frequent type (adult sporadic BL) accounts for just 2% of all lymphomas in the western world. It is characterised by a very aggressive initial phase, leading to large lymph node masses and affecting extranodal areas. When the lymph node is gravely affected, the disease is called mature B-cell lymphoblastic leukaemia, or Burkitt leukaemia.

First line treatment must commence immediately and is based on intensive chemotherapy with protocols that are somewhat different to those for other aggressive lymphomas, both in terms of their higher doses and their content. The most usual treatment consists of using a variety of chemotherapy drugs in association with the monoclonal antibody Rituximab and central nervous system infiltration prophylaxis. In other words, protocols that resemble those employed in cases of acute lymphoblastic leukaemia. 75-80% of children and young adults respond favourably with these drug combinations. Treatment must commence immediately because it is a disease in which the tumour progresses very quickly.

The autologous transplant of hematopoietic progenitors is not indicated as a first line treatment, being reserved for patients with a poor prognosis.

Peripheral T-cell lymphoma

Peripheral T-cell lymphomas are a heterogeneous group of very aggressive lymphomas, accounting for 5-10% of all lymphomas. They tend to present themselves at an advanced stage in adult patients and are diagnosed after the appearance of symptoms such as night sweats, fever or weight loss. Extranodal infiltration is very frequent.

A CHOP-type chemotherapy combination (cyclophosphamide, Adriamycin, vincristine and prednisone) constitutes the basis for treatment and, although the results are not satisfactory, no other therapeutic strategy has been found that offers better results. Some patients respond well to initial chemotherapy, but lengthy life expectation with this type of lymphoma is uncommon with a five year survival rate of 30%. The lymphoma tends to progress quickly and the prognosis is very unfavourable. Young patients with relapsed peripheral T-cell lymphoma are therefore good candidates for experimental treatments that may include a transplant of hematopoietic progenitors.

Anaplastic large-cell lymphoma

CD30 (KI-1) positive anaplastic large-cell lymphoma must be distinguished from the other T-cell lymphomas on account of its more favourable prognosis and its response to treatment. This type of lymphoma must be distinguished from cutaneous anaplastic lymphoma, which has an excellent prognosis, and other B- and T-cell lymphomas with anaplastic characteristics. It accounts for approximately 3% of all adult non-Hodgkin lymphomas and 10-30% of childhood lymphomas. The ALK positive type is more frequent in those under the age of 30 and it affects men more than women. The ALK negative type is more frequently found in older people, irrespective of sex. Most patients present the disease at an advanced stage with systemic symptoms (high fever above all) and with areas outside the lymphatic system being affected. The bone marrow is infiltrated in a large number of cases.

A CHOP-type chemotherapy combination (cyclophosphamide, Adriamycin, vincristine and prednisone), to which radiotherapy may be added for localised states of the disease, constitutes the basis for treatment for anaplastic large-cell lymphoma and complete remission is achieved in 70-80% of ALK+ patients.

T-cell lymphoblastic lymphoma

T-cell lymphoblastic lymphoma is an aggressive non-Hodgkin lymphoma that mainly affects children. It is relatively rare in adults, but accounts for a third of all lymphomas diagnosed in children and young people.

Lymphoblastic lymphoma is classified according to whether it has B- or T-cell precursors, but the latter is more frequent. Lymphoblastic lymphoma cancer cells are the same as in acute lymphoblastic leukaemia (ALL). In fact, the disease is classified as lymphoblastic lymphoma and is treated as such if the proportion of blasts in the bone marrow is lower than 25% and there are no blasts in the peripheral blood. Otherwise it would be classified as acute lymphoblastic leukaemia (ALL).

More than 90% of patients present the disease at an advanced stage (stages III and IV) and 60% go on to develop acute lymphoblastic leukaemia (ALL).

The CHOP chemotherapy combination that is usual for other aggressive lymphomas (cyclophosphamide, Adriamycin, vincristine and prednisone) does not provide good results. Treatment must therefore be based on protocols specific to acute lymphoblastic leukaemia in order to achieve high levels of remission (70-90%) in children, but much lower in adults. Given the poor response to treatment in adults, high doses of chemotherapy are sometimes recommended, followed by an autologous, or more fundamentally, allogenic transplant (from a related or voluntary donor) of hematopoietic progenitors.

Links of interest concerning medical issues relating to non-Hodgkin lymphoma

For more quality information about non-Hodgkin lymphoma you can consult the following websites:


Links of interest about other general issues that may be of interest to patients with non-Hodgkin lymphoma

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On our website you will also find the testimonies of people who are suffering, or who have suffered, from this disease. We would also like to invite you to follow us on our main social networks (FacebookTwitter e Instagram) where we often share patients' accounts of overcoming the disease.

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Webpage updated 01/09/2023 12:56:53