Non-Hodgkin Lymphoma
by D. Grenzelias, M.D., Hematologist


The term lymphoma describes a heterogeneous group of malignancies of the immune system. In general, lymphomas are divided into 2 large groups of neoplasms: 

  • Non-Hodgkin Lymphoma
  • Hodgkin Lymphoma.

About 85% of all malignant lymphomas are Non-Hodgkin Lymphomas.

Non-Hodgkin Lymphoma includes many subtypes, each with distinct epidemiologies, etiologies and morphologic, immunophenotypic, genetic, and clinical features. Prognosis also varies considerably among the different sub-types of Non-Hodgkin Lymphoma.



Non-Hodgkin Lymphoma represents a progressive expansion of lymphocytes arising from an accumulation of genetic damage (mutations) resulting in cell immortalization. These mutations alter certain genes, giving them the potential to lead to tumors (oncogenesis), or inactivate protective (tumor suppressor) genes. In addition, the genetic material of certain lymphoma subtypes can be altered with the introduction of exogenous genes by various oncogenic viruses. Several mutations are associated with specific Non-Hodgkin Lymphomas, reflecting the presence of specific markers of diagnostic significance for Non-Hodgkin Lymphoma classification.

Several Non-Hodgkin Lymphoma classification schemas exist, reflecting the complex diversity of Non-Hodgkin Lymphoma. Currently, the World Health Organization (WHO) classification is widely used. This classification correlates certain types of Non-Hodgkin Lymphoma to normal counterpart lymphocyte subsets and divides Non-Hodgkin Lymphoma into two subtypes:

  • those of B-cell origin (from the antibody producing B lymphocytes), comprising 85% of all Non-Hodgkin Lymphomas and
  • those of T-cell and natural killer (NK)–cell origin (from the cells mediating the cellular immunity).

Each subtype of Non-Hodgkin Lymphoma is characterized by the maturity, size and proliferation rate of the cell of origin, as well as the histological pattern of growth. For many of the B-cell Non-Hodgkin Lymphoma subtypes, the pattern of growth and cell size may be important determinants of tumor aggressiveness. Tumors that grow in a nodular pattern are generally less aggressive than lymphomas that proliferate in a diffuse pattern. Lymphomas of small lymphocytes generally have a more indolent course than those of large lymphocytes, which may have intermediate-grade or high-grade aggressiveness. However, some subtypes of high-grade lymphomas are characterized by small cell morphology.

From a clinical point of view, the most practical way of sorting the currently recognized types of Non-Hodgkin Lymphoma is according to their predicted clinical behavior. Each classification schema contributes to a greater understanding of the natural evolution of each Non-Hodgkin Lymphoma subtype, which finally determines prognosis and treatment. In this respect, Non-Hodgkin Lymphomas can be grouped by how quickly they are likely to grow:

  • Indolent or low-grade lymphomas grow slowly and tend to cause few symptoms.
  • Aggressive lymphomas, including intermediate-grade and high-grade, grow and spread more quickly. They also tend to cause serious symptoms.

It is important to note that over time, some indolent lymphomas become aggressive.

The most common types of Non-Hodgkin Lymphoma are:

  • Diffuse Large B Cell Lymphoma (DLBCL)
  • Follicular Lymphoma (FL)
  • Marginal Zone Lymphoma (MZL)
  • Mantle Cell Lymphoma (MCL)
  • Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (SLL/CLL)
  • Burkitt Lymphoma (BL)
  • Anaplastic Large Cell Lymphoma (ANLCL)
  • Lymphoblastic Lymphoma (LBL)
  • Lymphoplasmacytic Lymhoma/Waldeström’s Macroglobulinemia
  • Primary Central Nervous System Lymphoma (PCNSL)
  • Peripheral T Cell Lymphoma (PTCL)



Non-Hodgkin Lymphoma is the most prevalent hematopoietic neoplasm, representing approximately 4% of all cancer diagnoses and ranking 7th in frequency among all cancers. Non-Hodgkin Lymphoma is more than 5 times as common as Hodgkin disease. Since the early 1970s, the incidence rates of Non-Hodgkin Lymphoma have increased considerably. Although some of this increase may be attributable to earlier diagnosis, as well as higher incidence of immunosuppressive treatments for various reasons and HIV infection, this rise remains largely unexplained.

The presentation of Non-Hodgkin Lymphoma peaks at ages older than 50 years for most subtypes of Non-Hodgkin Lymphoma. The only exception is high-grade lymphoblastic lymphoma, which is the most common type of Non-Hodgkin Lymphoma observed in children and young adults. In general, at diagnosis, low-grade lymphomas are more common in older patients and very rare in patients younger than 35 years. Low-grade lymphomas are extremely rare in children.



Non-Hodgkin Lymphomas are of unknown etiology but research has shown that there are some risk factors that increase the chance that a person will develop the disease.

These risk factors are:

Immunodeficiency states

Congenital immunodeficiency disorders, acquired immunodeficiency states (e.g. AIDS), and induced immunodeficiency states (e.g. certain drugs after an organ transplant) are associated with increased incidence of Non-Hodgkin Lymphoma. In these patients the disease is more often localized outside the lymph nodes (called extranodal involvement), particularly of the gastrointestinal tract and central nervous system, and presents with aggressive histology.

Celiac disease also has been associated with an increased risk of malignant lymphomas. The risk of lymphoma in individuals with celiac disease depends on small intestinal histopathology, with no increased risk in those with latent celiac disease.


Certain types of infection increase the risk of developing lymphoma. However, lymphoma is not contagious. Some infectious agents are implicated in the pathogenesis of Non-Hodgkin Lymphoma, probably because of their ability to induce chronic antigenic stimulation, which leads to uncontrolled B- or T-cell stimulation, proliferation, and lymphomagenesis.

The following are the main types of infection that can increase the risk of lymphoma:

  • Human Immunodeficiency Virus (HIV): people with HIV infection, the virus that causes AIDS, are at much greater risk of some types of Non-Hodgkin Lymphoma.
  • Epstein-Barr virus (EBV) is a virus that is associated with Burkitt lymphoma (especially the form endemic in Africa), Hodgkin Lymphoma and lymphomas in patients with immunodeficiency (eg, HIV infection, organ transplantation).
  • Helicobacter pylori infection is associated with the development of primary gastrointestinal lymphomas, particularly Gastric Mucosa-Associated Lymphoid Tissue (MALT) lymphomas.
  • Human T-cell leukemia virus type 1 (HTLV-1) causes a latent infection in activated T-helper cells. This virus is endemic in certain areas of Japan and the Caribbean islands, and approximately 5% of carriers develop adult T-cell leukemia or lymphoma.
  • Hepatitis C virus (HCV) is associated with the development of certain subtypes of Non-Hodgkin Lymphoma (i.e. marginal zone lymphoma).
  • Kaposi sarcoma-associated herpes virus (KSHV) is associated with the development of lymphomas in patients with HIV infection.

Environmental factors

Environmental factors linked to the development of Non-Hodgkin Lymphoma include chemicals (e.g. pesticides, herbicides, solvents, organic chemicals, wood preservatives, dusts and hair dye), chemotherapy, and radiation exposure.

Chronic inflammation

The chronic inflammation observed in patients with autoimmune disorders, such as Sjögren syndrome and Hashimoto thyroiditis, predisposes to the development of MALT Lymphoma. Hashimoto thyroiditis is a preexisting condition in 23-56% of patients with primary thyroid lymphomas.

Having one or more risk factors does not mean that a person will develop Non-Hodgkin Lymphoma. Most people who have risk factors never develop lymphoma.



  • Swollen, painless lymph nodes in the neck, armpits or groins
  • Weakness and tiredness
  • Unexplained weight loss
  • Fever
  • Soaking night sweats
  • Coughing, breathlessness or chest pain
  • Pain, swelling or feeling of fullness in the abdomen


Physical findings

Indolent Non-Hodgkin Lymphomas may present with painless swollen peripheral lymph nodes, splenomegaly (enlarged spleen), and hepatomegaly (enlarged liver). The spleen is rarely the only involved site at presentation.

Intermediate- and high-grade Non-Hodgkin Lymphomas may produce the following findings:

  • Rapidly growing and bulky lymphadenopathy
  • Splenomegaly
  • Hepatomegaly
  • Large abdominal mass (this usually occurs in Burkitt lymphoma)
  • Testicular mass
  • Skin lesions



Patients with Non-Hodgkin Lymphoma may present with one or more of the following complications:

  • Low neutrophil count (neutropenia), low platelets (thrombocytopenia) and anemia secondary to bone marrow infiltration. In some cases, hemolytic anemia or thrombocytopenia related to the development of an autoimmune mechanism (more often in Small Lymphocytic Lymphomas, Chronic Lymphocytic Leukemias, and indolent lymphomas).
  • Bleeding secondary to thrombocytopenia and recurrent infection secondary to neutropenia.
  • Cardiac problems secondary to large pericardial effusion or arrhythmias secondary to cardiac infiltration
  • Respiratory problems secondary to pleural effusion, high volume lymphadenopathy in the chest and/or lymphoma lung infiltrates.
  • Superior Vena Cava Syndrome: in patients with massive lymph node enlargement in the chest pressure in the veins of the face and arms causes swelling in these areas.
  • Neurologic signs from spinal cord compression secondary to vertebral disease deposits.
  • Neurologic problems secondary to primary Central Nervous System lymphoma or lymphomatous meningitis.
  • Gastrointestinal obstruction, perforation, and bleeding.
  • Leukocytosis due to high lymphocyte count (lymphocytosis) when some, especially indolent Non-Hodgkin Lymphomas, present with the leukemic phase of the disease (chronic lymphocytic leukemias, marginal zone lymphomas, Mantle Cell Lymphoma)


Diagnosis of Non-Hodgkin Lymphoma

Once from the medical history and physical examination the diagnosis of Non-Hodgkin Lymphoma is suspected, the doctor may order:

  1. Laboratory tests:
  • Full Blood Count (ESR).
  • Biochemistry tests, including Lactate Dehydrogenase (LDH), serum creatinine and alkaline phosphatase (ALP).
  • Screening for HIV infection, hepatitis B and C.
  1. Imaging studies, including:
  • Chest x-rays to check for swollen lymph nodes or other signs of disease in the chest.
  • Computed Tomography (CT), which has largely replaced chest x-ray. CT scans of neck, chest, abdomen, and pelvis may reveal enlarged lymph nodes, lesions in the liver and/or spleen, nodules or infiltrates in the lung, and pleural effusions.
  • Magnetic Resonance Imaging (MRI) and Ultrasound may also be used.
  • Positron emission tomography (PET) may be considered for the initial staging of Non-Hodgkin Lymphoma.

3. An excisional lymph node biopsy is recommended, since biopsy is the only sure way to diagnose Non-Hodgkin Lymphoma. An entire lymph node (excisional biopsy) or only part of a lymph node (incisional biopsy) may be removed. A thin needle (fine needle aspiration-FNA) cannot remove a good enough specimen for the pathologist to confirm Non-Hodgkin Lymphoma diagnosis.

4. Bone Marrow Biopsy is mandatory in Non-Hodgkin Lymphoma staging. In some cases, especially low-grade lymphomas, the diagnosis can be made from a bone marrow biopsy alone.

5. Spinal Tap must be done in some cases and spinal fluid be examined for the presence of lymphoma cells. In some Non-Hodgkin Lymphomas (ie. LBL and BL) prophylactic chemotherapy must be infused into the spine even with no lymphoma infiltration. 


Stages of Non-Hodgkin Lymphoma

The extent of lymphoma in the body as defined with the above investigations allows staging of the disease, which is very important for prognosis and treatment. For Non-Hodgkin Lymphoma staging the Ann-Arbor classification system is used:

  • Stage 1: Non-Hodgkin Lymphoma affects one only group of lymph nodes. Rarely, the disease may be found in an organ other than a lymph node and in only that one organ (such as in the lung, but not the liver, bone marrow or other organ). In this case it is designated as Stage IE (with E for extranodal).
  • Stage 2: Lymphoma is found in at least two lymph node groups, which are on the same side of the diaphragm (chest or abdomen)
  • Stage 3: Lymphoma cells are in lymph nodes on both sides of the diaphragm. The spleen may also be affected.
  • Stage 4: Disseminated disease or multiple involvement of organs others than lymph nodes such as liver and lung. Other less common sites of Non-Hodgkin Lymphoma involvement include bone, bone marrow, skin, kidneys, digestive tract, ovaries, breasts or testicles

Each stage may be further described as A or B:

A: without symptoms, such as weight loss, drenching night sweats, or fevers.

B: with one or more of the above symptoms.


Treatment of Non-Hodgkin Lymphoma

The treatment of Non-Hodgkin Lymphoma varies greatly, depending on the following factors:

  • Subtype of lymphoma (histology, phenotype, genetic characteristics).
  • Stage of Non-Hodgkin Lymphoma.
  • Presence of lymphoma related-symptoms.
  • Patient’s age and performance status.
  • Comorbidities (Diabetes, hypertension, renal, liver and heart disease).


Treatment of Indolent Non-Hodgkin Lymphoma

Follicular lymphoma comprises 70% of this group. Other entities in this group include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL).

The treatment of indolent B-cell lymphomas is a rapidly evolving field as new therapies with potent antitumor activity and limited toxicity are becoming available. Monoclonal antibodies have changed the treatment paradigm of patients with B-cell lymphomas. Rituximab (a monoclonal antibody targeting the CD20 molecule on the surface of lymphoma cells) has already been incorporated in all treatment combinations for patients with B-cell Non-Hodgkin Lymphomas. Furthermore, various biologic agents with anti-lymphoma potency (lenalidomide, ibrutinib, obinutuzumab, mTOR inhibitors and bcl2 inhibitors, to mention some) are already adding new options, even challenging traditional chemotherapy, for subsets of these patients.


Treatment of Indolent stage 2 and contiguous stage 2 Non-Hodgkin Lymphoma

Standard management consists of radiotherapy alone. 40% of patients with limited-stage disease remained disease-free at 10 years after radiation. There is no evidence that combined chemotherapy and radiation is better than radiation alone. Offering adjuvant chemotherapy to selected patients with stage 1-2 Non-Hodgkin Lymphoma who have unfavorable prognostic factors (e.g. B symptoms, >2 nodal sites) is not unreasonable.


Treatment of Indolent disseminated Non-Hodgkin Lymphoma

Patients with disseminated indolent Non-Hodgkin Lymphoma but without symptoms may not need treatment right away. They are watched closely until they develop lymphoma-related symptoms, since early intervention in asymptomatic patients does not appear to prolong survival. This is called “watch and wait” policy. The “watchful” period for some patients may last several years.

Advanced indolent lymphomas have been accepted to be incurable with currently available therapies, with the only exception being allogeneic bone marrow transplantation, when indicated. However, sustained complete remissions can be achieved with various treatment modalities. The disease course of indolent lymphomas is characterized by the acquisition of resistance to chemotherapy, which leads to a continuous decrease in the quality and the duration of response with each subsequent treatment.

Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone and/or Rituximab) is useful in elderly patients with significant comorbidities. Rituximab alone is also an excellent option for these patients.

Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Frequently used combination regimens are CHOP (cyclophosphamide, Doxorubicin, Vincristine and Prednisone), CVP (Cyclophosphamide, Vincristine, and Prednisone), and Fludarabine alone or in combination with Cyclophosphamide or Mitoxantrone. To all these regimens Rituximab is added and these combinations are called chemo-immunotherapy. Chemo-immunotherapy was established since it was shown that the addition of rituximab results in higher response rates, longer time to progression, and longer survival than chemotherapy. In follicular lymphoma, rituximab is also given as maintenance treatment, usually as one infusion every 2 months, in order to delay disease relapse.

Among the most important recent developments is the efficacy of the combination of Rituximab with Bendamustine as the first-line treatment of advanced follicular and mantle cell lymphomas. Other important results include the efficacy of Ibrutinib in patients with mantle cell lymphoma, which was recently licensed as 2nd line therapy for these patients. Furthermore, lenalidomide plus rituximab has shown comparable efficacy with chemotherapy plus rituximab in previously untreated follicular lymphoma patients, a fact challenging the need of chemotherapy for these patients.

For relapsed indolent lymphomas that still retain their low-grade histology, treatment options include:

  • Single alkylating agents (chlorambucil or bendamustine)
  • Novel biological agents and small molecule inhibitors showing promising results in patients with indolent lymphomas include ofatumumab, lenalidomide, ibrutinib and temsirolimus.
  • Combination chemo-immunotherapy as in induction phase.
  • Purine analogues (Fludarabine, 2-CDA).
  • Rituximab as single agent.
  • Radioimmunotherapy (ant-CD20 monoclonal antibody labeled with a radioactive isotope; 131Iodine or 90Yttrium). Radioimmunotherapy of relapsed or refractory indolent Non-Hodgkin Lymphoma achieves high overall response rates and complete response rates with minimal toxicity. Tositumomab (a monoclonal antibody directed against CD20 antigen) plus 131I (Bexxar) has been approved by the US Food and Drug Administration for relapsed or refractory, low-grade, follicular, or transformed Non-Hodgkin Lymphoma. Similarly, Ibritumomab tiuxetan plus 90Yttrium (Zevalin) also has been approved for use in relapsed indolent lymphoma. These radioimmunotherapy agents typically should be used only in patients with less than 25% bone marrow involvement with lymphoma to avoid serious hematologic toxicity.
  • Local relapse can be treated with radiotherapy.
  • Bone marrow transplantation may have a role in patients with relapsed high-risk disease, especially follicular lymphoma. Allogeneic transplants have lower relapse rates but higher transplant-related mortality than autologous transplants.  To proceed with transplantation disease chemo sensitivity to the salvage treatment must be confirmed. The precise role and timing of transplantation in indolent lymphomas is still under investigation.


Treatment of Aggressive Non-Hodgkin Lymphoma

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of all Non-Hodgkin Lymphomas. Other distinct entities with high-grade histology are immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like lymphomas.


Diffuse Large B-Cell Lymphoma (DLBCL), stage 1 or 2

  • Nonbulky (mass <10cm): R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) x3 with radiation, or R-CHOP x6 with or without radiation.
  • Bulky (mass >10cm): R-CHOP x6 with or without radiation.


Diffuse Large B-Cell Lymphoma (DLBCL), stage 3 or 4

  • R-CHOP x6, if a satisfactory response is confirmed after 2-4 cycles.


Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Salvage chemotherapy followed by High-Dose Chemotherapy plus Stem-Cell Transplantation (HDC-ASCT) is the treatment of choice for eligible patients (age under 65-70 years, no serious comorbidities) who have recurrent DLBCL and other types of aggressive lymphomas. Salvage chemotherapy regimens such as ICE (Ifosfamide, Carboplatin, Etoposide) and DHAP (Dexamethasone, high-dose Cytarabine, Cisplatin) are usually used with rituximab. There is no evidence in support of the superiority of any of the above regimens over the other. During recovery from the hematological toxicity, usually after the second salvage chemotherapy course, hematopoietic stem cells from peripheral blood are collected and stored in order to support the HDC-ASCT.

After the maximum response with salvage chemotherapy has been achieved, the patient proceeds to HDC-ASCT. The high dose regimen usually is BEAM (BiCNU, Etoposide, Cytarabine and Melphalan) and subsequently the stored peripheral hematopoietic stem cells are re-infused in order to support bone marrow recovery.

For patients ineligible for HDC-ASCT, various options are available, but these patients should be encouraged to participate in clinical trials.



The 5-year relative survival rate of patients with Non-Hodgkin Lymphoma is approximately 63% and it has steadily improved over the last 2 decades.

Generally, the prognosis for patients with Non-Hodgkin Lymphoma depends on the following factors:

  • Histology
  • Stage
  • Age
  • Tumor Bulk
  • Performance status
  • Serum lactate dehydrogenase (LDH) level
  • Presence or absence of extranodal disease

The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive Non-Hodgkin Lymphoma, also appears to be useful for predicting the outcome of patients with low-grade lymphoma and mantle cell lymphoma.

An age-adjusted model for patients younger than 60 years has been proposed. In younger patients, stage 3 or 4 disease, high LDH levels, and non ambulatory performance status are independently associated with decreased survival rates.

Clinical features included in the IPI that are independently predictive of survival include the following:

  • Age:  Younger than 60 years versus older than 60 years
  • LDH level: Within the reference range versus elevated
  • Performance status: Eastern Cooperative Oncology Group (ECOG) grade 0-1 versus 2-4
  • Ann Arbor stage: Stage 1-2 versus 3-4
  • Number of extranodal sites - Zero to 1, versus more than 1

Based on this model, the overall 5-year survival rates are as follows:

  • 0-1 risk factors: 73%
  • 2- risk factors: 51%
  • 3-risk factors: 43%
  • 4-5 risk factors: 26%

For patients with follicular lymphoma (the second most common subtype of Non-Hodgkin Lymphoma) the Follicular Lymphoma International Prognostic Index (FLIPI) score appears to be more applicable than the IPI. The FLIPI score is calculated on the basis of 5 adverse prognostic factors, as follows:

  • Age (>60 y)
  • Ann Arbor stage (3-4)
  • Hemoglobin level (< 12 g/dL)
  • Number of nodal areas (>4)
  • Serum LDH level (above normal)

Three risk groups are defined, with a corresponding 10-year survival rate as follows:

  • low risk (0-1 adverse factor): 70%
  • intermediate risk (2 factors): 50%
  • poor risk (3 or more adverse factors): 35%.

Low-grade lymphomas have indolent clinical behavior and are associated with a comparatively prolonged survival (median survival is 6-10 years), but they have little potential for cure. They also have the tendency to transform to high-grade lymphomas.



After treatment for Non-Hodgkin Lymphoma, regular checkups (every 3-6 months for 5 years and less often after that) are needed. Checkups help ensure that any health changes are noted and treated if needed. Checkups also help detect health problems related to treatment, such as heart disease and secondary cancer. They may include a physical examination, blood tests, chest x-rays, CT scans, or other tests.


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