Non-Hodgkin's lymphoma

Last updated date: 18-Oct-2022

Originally Written in English

Non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma

Non-Hodgkin lymphomas are a heterogeneous group of malignancies of the lymphoid system. Non-Hodgkin lymphoma is divided into subgroups, each having its own epidemiology, etiology, immunophenotypic, genetic, clinical characteristics, and response to therapy. Based on the disease's prognosis, it is classified as 'indolent' or 'aggressive.

These diseases have been categorized as B-cell and T-cell neoplasms by the World Health Organization's classification of hematological and lymphoid malignancies. B-cell lymphomas account for roughly 90% of all lymphomas, with follicular lymphoma and diffuse large B-cell lymphoma being the two most frequent histological disease types. 

Approximately 55,000 to 60,000 new cases of non-Hodgkin lymphoma are diagnosed annually in the United States, a number that has nearly doubled during the past 3 decades.


What is Non-Hodgkin's lymphoma?

Non-Hodgkin lymphoma (NHL) is a neoplasm of the lymphoid tissues originating from B cell precursors, mature B cells, T cell precursors, and mature T cells.

These affected lymphocytes start to multiply in an abnormal way and begin to collect in certain parts of the lymphatic system, such as the lymph nodes. These affected lymphocytes lose their infection-fighting properties, making the human bodies more susceptible to infection.

Follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, Mantle cell lymphoma, marginal zone lymphoma, and primary CNS lymphoma are the most frequent adult B cell neoplasms. Adult T cell lymphoma and Mycosis fungoides are the most prevalent mature T cell lymphomas.


Non-Hodgkin's lymphoma epidemiology

There are geographical variations in the incidence of individual subtypes, with follicular lymphoma being more common in Western countries, T cell lymphoma more common in Asia.

Overall, Non-Hodgkin lymphoma is most frequent in those aged 65 to 74, with a median age of 67. The highest incidence in children occurs between the ages of four and seven years, and the male: female ratio is around 2 to 1.

Non-Hodgkin lymphoma is the fifth most common diagnosis of pediatric cancer in children under the age of 15 years, and it accounts for approximately 7 percent of childhood cancers in the developed world. Annually, around 800 new pediatric cases are identified in the United States, with a frequency of 10 to 20 cases per million per year. High-grade lymphomas such as lymphoblastic and small non cleaved lymphomas are the most common types of NHL observed in children and young adults.

Lymphomas are rare in infants (≤1 percent) and account for approximately 4, 14, 22, and 25 percent of neoplasms in children age 1 to 4, 5 to 9, 10 to 14, and 15 to 19 years, respectively. There is a male predominance, and whites are more commonly affected than African Americans.

Burkitt lymphoma caused by the Epstein-Barr virus is more frequent in Africa. Burkitt lymphoma is an endemic disease occurring in equatorial Africa and New Guinea. In the U.S and Western Europe, sporadic Burkitt lymphoma is observed but is roughly 50 times more common in Africa than in the United State. 

In the United States, Burkitt lymphoma accounts for 30% of pediatric lymphomas and < 1% of adult non-Hodgkin lymphomas. Sporadic cases are more common among White race individuals than in African or Asian Americans, and the majority of patients are male with a 4 to 1 male: female ratio. 


Etiology of Non-Hodgkin's lymphoma

  • Chromosomal translocations: Non-Hodgkin lymphoma develops from either B cells, T cells, as a result of chromosomal translocation or mutation/deletion. Chromosomal translocation activates proto-oncogenes, while chromosomal deletion or mutation inactivates tumor suppressor genes. The most prevalent chromosomal anomaly in non-Hodgkin lymphoma is the t (14;18) translocation. This translocation occurs most frequently in follicular lymphoma. Mantle cell lymphoma is related with the t (11;14) translocation.
  • Helicobacter pylori: associated with gastric lymphoma, e.g., MALT lymphoma, diffuse large B-cell lymphoma.
  • Immunodeficiency: congenital immunodeficiencies, AIDS, history of chemotherapy and/or immunosuppressive therapy.
  • Viral infection: Epstein–Barr virus, Human T-lymphotropic virus type 1, Human Herpesvirus-8 and Hepatitis C
  • Autoimmune and chronic inflammatory disorders: Rheumatoid arthritis, Sjogren syndrome, and Systemic lupus erythematosus.
  • Autoimmune diseases: Hashimoto thyroiditis, rheumatoid arthritis
  • Ultraviolet radiations
  • Occupational exposure: pesticides like phenoxy acids, organophosphates, and organochlorines).


Non-Hodgkin's lymphoma vs Hodgkin's lymphoma

  • Non-Hodgkin lymphoma is more common than Hodgkin lymphoma:

Non-Hodgkin lymphoma is more prevalent than Hodgkin lymphoma, and males are somewhat more likely to get both forms. Although both can be diagnosed at any age, Hodgkin lymphoma is more frequent in young individuals aged 15 to 40 and elderly persons aged 55 and older. Non-Hodgkin lymphoma is most commonly diagnosed in persons over the age of 60.


  • Each type of lymphoma has different subtypes:

Classic Hodgkin lymphoma makes up 95% of Hodgkin lymphoma cases in the U.S., but there are a few other subtypes, including nodular lymphocyte predominant Hodgkin lymphoma.

Non-Hodgkin lymphoma is classified as either B-cell lymphoma or T-cell lymphoma. B-cell lymphomas are far more frequent, accounting for 85 % of all lymphoma diagnoses in the United States. B-cell lymphoma can be classified into the following types: mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.


  • Inflammation is a more common symptom for Hodgkin lymphoma:

Hodgkin and non-Hodgkin lymphoma both occur in the lymphatic system and can impact white blood cells. A high white blood cell count may indicate lymphoma.

The earliest signs of both Hodgkin and non-Hodgkin lymphoma are frequently fever, unexplained weight loss, and night sweats.

Hodgkin lymphoma patients can also experience more inflammatory symptoms. In some cases, the patient may experience lymph node pain when taking a hot bath or drinking alcohol. Patients may also have an unexplained rash which is not common in non-Hodgkin lymphoma.


  • Hodgkin lymphoma treatment typically includes a combination of therapies:

A combination of chemotherapy and radiation therapy are the standard treatment regimen for early-stage Hodgkin lymphoma while Chemotherapy alone is the standard treatment for non-Hodgkin lymphoma. Patients with both Hodgkin and non-Hodgkin lymphoma may also require a stem cell transplant if they don’t respond to chemotherapy, or if the cancer returns.


  • Hodgkin's lymphoma has favourable prognosis

More than 86%of patients diagnosed with Hodgkin lymphoma survive five years or more while About 70% of patients diagnosed with non-Hodgkin lymphoma survive five years or more.


Non-Hodgkin's lymphoma symptoms

Patients present with complaints of fever, weight loss, or night sweats, also known as B symptoms. Systemic B symptoms are more common in patients with a high-grade variant of non-Hodgkin lymphoma. More than two-thirds of the patient presents with painless peripheral lymphadenopathy. Patients have different presentations and vary according to the site involved. Clinical features of the patients according to the subtypes, are:

Burkitt Lymphoma: 

Burkitt Lymphoma

Patients frequently have tumor masses that are quickly growing. Tumor lysis syndrome may occur with this form of lymphoma.

In 50 to 60% of cases, the endemic type will develop jaw or face bone tumors. The main involvement of the abdomen is rare. Extranodal locations such as the mesentery, ovary, testis, kidney, breast, and meninges might be affected by the primary tumor.

The non-endemic variant affects the abdomen and is most commonly characterized by extensive ascites affecting the distal ileum, stomach cecum and/or mesentery, and bone marrow. Symptoms of bowel blockage or gastrointestinal bleeding are common, often having features of acute appendicitis or intussusception, can be seen.  If lymphadenopathy is present, it is generally limited to a specific area. At the time of initial presentation, bone marrow and CNS involvement are found in 30 and 15% of patients, respectively, but are more frequent in recurrent or treatment-resistant disease. The jaw or facial bones are involved in around 25% of cases.

Patients with Burkitt Lymphoma caused by an immunodeficiency appear with signs and symptoms associated to the immunodeficiency (e.g., AIDS, congenital immunodeficiency, acquired immunodeficiency due to hematopoietic or solid organ transplantation). Lymph nodes, bone marrow, and the central nervous system are commonly involved in immune deficiency disorders.


Gastrointestinal Lymphoma: 

Epigastric pain or discomfort, anorexia, weight loss, nausea and/or vomiting, occult GI bleeding, and/or early satiety are the most common symptoms.


Mantle cell Lymphoma: 

At the time of presentation, up to one-third of patients had systemic B symptoms such as fever, night sweats, and unintentional weight loss.

At the time of diagnosis, the majority of individuals with mantle cell lymphoma are in late stages of the illness. With about 75 % of patients, lymphadenopathy is the first symptom; the extranodal disease is the primary presentation in the remaining 25 %.  The lymph nodes, spleen (45 to 60 %), Waldeyer's ring, bone marrow (>60 %), blood (13 to 77 %), and extranodal locations such the gastrointestinal system, breast, pleura, and orbit are also common sites of involvement. 

Orbital structures like the eyelid, extraocular muscles, lacrimal apparatus, conjunctivae can be involved in the marginal zone, mantle cell lymphoma, and primary central nervous lymphoma. Therefore, these structures should be examined.


Primary central nervous system lymphoma: 

Headache, fatigue, focal neurologic impairments, convulsions, paralysis, spinal cord compression, or lymphomatous meningitis are all symptoms of primary central nervous system lymphoma.

Epidural spinal cord compression can cause irreversible loss of motor, sensory, and/or autonomic function. NHL is thought to first involve the paraspinal soft tissues and then invade the cord via the vertebral foramen without first causing bony destruction.


Involved lymphoid sites should be carefully examined. These include Waldeyer's ring (tonsils, the base of the tongue, nasopharynx), cervical, supraclavicular, femoral, axillary, mesenteric, inguinal, liver, spleen and retroperitoneal nodal sites should be examined. The involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. 

Extranodal illness (secondary extranodal disease) affects around half of patients, while primary extranodal lymphoma affects 10 to 35 percent of patients at the time of diagnosis. The gastrointestinal system is the most prevalent location of primary extranodal illness, followed by the skin. The testis, bone, and kidney are also involved in aggressive NHLs at the time of presentation. The ovary, bladder, heart, adrenal glands, salivary glands, prostate, and thyroid are all rare locations. Extra lymphatic illness signs are most commonly found in patients with aggressive NHL and are not evident in those with indolent lymphomas.

Testicular NHL is the most common malignancy involving the testis in men over age 60. It usually presents as a mass and comprises 1 percent of all NHL and 2 percent of all extranodal lymphomas.


Diagnosis Non-Hodgkin's lymphoma

Workup in Non-Hodgkin Lymphoma should include the following routine laboratory studies:

Complete blood count (CBC): Anemia, thrombocytopenia, leukopenia, pancytopenia, lymphocytosis, and thrombocytosis may all be present. Widespread bone marrow infiltration, hypersplenism from splenic involvement, or blood loss from gastrointestinal tract involvement can all cause alterations in peripheral blood counts.

Serum chemistry tests: Can help rule out tumor lysis syndrome, commonly in rapidly proliferative NHL such as Burkitt or lymphoblastic lymphoma. Hypercalcemia and high uric acid levels may present in some cases.

Liver chemistries: may be abnormal in patients with liver infiltration or primary hepatic lymphoma. Lactate dehydrogenase level can also be elevated due to high tumor burden or extensive infiltration of the liver.

Imaging: A CT scan of the neck, chest, abdomen, and pelvis, or a PET scan, is frequently used. It's possible that specialized imaging, such as MRI of the brain and spinal cord or testicular ultrasonography, is required.

Lumbar puncture: CSF sample for both cytology and flow cytometry is highly recommended in those with Highly aggressive NHL (Burkitt lymphoma, peripheral T cell lymphoma, grade 3b Follicular lymphoma, mantle cell lymphoma, precursor T or B lymphoblastic leukemia/lymphoma, human immunodeficiency virus (HIV)-positive NHL)with epidural, bone marrow, testicular, or paranasal sinus involvement, or at least two extranodal disease sites.

Immunophenotypic analysis of lymph node, peripheral blood, and bone marrow: Surface immunoglobulin (Ig) of the IgM type and immunoglobulin light chains (kappa more frequently than lambda), B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center-associated markers (CD10 and BCL6), as well as HLA-DR and CD43, are all expressed by tumor cells in Burkitt lymphoma. The expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor, is influenced by the tumor's EBV status.

All endemic BL cases are EBV positive and express CD21, whereas the great majority of non-endemic BL cases in non-immunocompromised individuals are EBV negative and lack CD21 expression. Mantle cell tumor cells have significant quantities of surface membrane immunoglobulin M (IgM) and IgD, which is often of the lambda light chain type. 


Lymph node and/or tissue biopsy (Histopathology):

Histopathological studies are required to diagnose lymphoma. Large samples are preferred as intact tissue architecture is required to classify the subtype. If initial biopsy results are negative in patients with symptoms that are highly suggestive of lymphoma, consider obtaining a larger biopsy sample and repeating the studies.

Fine Needle Aspiration of the lymph node is avoided. An intact node excisional biopsy provides enough tissue for histopathological, immunologic, and molecular biologic evaluation. Specific yields of peripheral lymph nodes in patients who are subsequently proven to have NHL are as follows: supraclavicular nodes are 75 to 90 percent, cervical and axillary nodes are 60 to 70 percent, inguinal nodes are 30 to 40 percent.


Staging non Hodgkin lymphoma:

Lugano classification is the preferred classification method for primary nodal NHL. Previously, a version of the Cotswolds-modified Ann Arbor system was used, excluding the presence of B symptoms. 

Imaging is used to assess the number and location of affected lymph nodes, tumor bulk, and liver and spleen involvement.Bone marrow biopsy to assess bone marrow involvement.

The disease is then classified as either:

Limited disease (stage I + II): one node or conglomerate (stage I), or ≥ 2 nodes or conglomerates on one side of the diaphragm (stage II) 

Advanced disease (stage III + IV): nodes on both sides of the diaphragm or supradiaphragmatic nodes with splenic involvement (stage III), or diffuse or disseminated disease (stage IV).


Non-Hodgkin's lymphoma cure

Non-Hodgkin's lymphoma cure

Most patients with newly diagnosed NHL require chemotherapy, radiotherapy, or both. In some patients with indolent NHLs, such as follicular lymphoma, occasionally a watch and wait strategy can be used.

Pre-treatment evaluation:

  • Baseline laboratory studies with CBC, BMP, and liver chemistries
  • Screen for hepatitis B /C. 
  • Cardiologic assessment: ECG and echocardiogram 

Selection of treatment: based on the subtype of NHL, staging, and prognosis 

  • Most patients will receive treatment with systemic chemotherapy and/or radiotherapy.
  • Low-grade NHL (initial stages): Consider radiotherapy with curative intent.
  • Low-grade NHL (advanced stages): usually palliative chemotherapy 
  • High-grade NHL: usually chemotherapy with curative intent

Treatment of Non-Hodgkin lymphoma is based on the type, stage, histopathological features, and symptoms. The most common treatment includes chemotherapy, radiotherapy, immunotherapy, stem cell transplant, and in rare cases, surgery. Treatment, according to the type of lymphoma as follow:

Follicular lymphoma: This form of lymphoma is slow-growing and responds well to therapy, although it is difficult to cure. Relapse is typical after a number of years. Patients with a low burden of illness can be watched and treated only if they are symptomatic. Radiotherapy is the primary treatment in the early stages of stage I and stage II. Chemotherapy, along with a monoclonal antibody, is another option. 

Treatment in stage III, IV, and bulky stage II lymphoma is a monoclonal antibody (rituximab or obinutuzumab) along with chemotherapy. Among the chemotherapy options, bendamustine or a combination regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) are commonly used. After the response to initial treatment, the role of maintenance therapy is conflicting.


Diffuse Large B cell lymphoma: In Stage I or II, the R-CHOP regimen is frequently used for 3 to 6 cycles, with or without radiation treatment to the afflicted lymph node. Six cycles of R-CHOP are the optimum therapy in stage III or IV. After 2-4 cycles, imaging tests such as a PET/CT scan are used to assess therapy response. In the presence of or at high risk of central nervous system involvement, patients are administered intrathecal chemotherapy or large doses of methotrexate intravenously.


Mantle cell lymphoma (MCL): In eligible patients, MCL with numerous regions of involvement is usually treated with strong chemotherapy plus rituximab. R-Hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, alternatively administered with high-dose methotrexate with cytarabine + rituximab.  After the response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation is undertaken in eligible patients. This is usually followed by three years of maintenance rituximab.


Primary CNS lymphoma: The most successful treatment has been demonstrated to be a high-dose methotrexate-based chemotherapy regimen. If the patient achieves complete response to initial chemotherapy, high-dose treatment followed by autologous stem cell transplantation should be explored for appropriate individuals.


Burkitt lymphoma: This is a very fast-growing lymphoma. Some chemotherapies used for this lymphoma are Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) alternating with high dose methotrexate and cytarabine plus rituximab, Intrathecal methotrexate is given when there is evidence of involvement of the brain and spinal cord. Tumor lysis syndrome is a frequent complication of Burkitt lymphoma. As a result, prevention and monitoring for tumor lysis syndrome are essential.


Adult T cell leukemia/lymphoma: It has been related to HTLV-1 viral infection. There are four subtypes, and therapy differs according to subtype. Subtypes such as smoldering and chronic grow slowly. These frequently do not necessitate therapy. Interferon and the antiviral medication zidovudine are used to treat HTLV-1 infection, and skin-directed therapy is used if the skin is implicated. Antiviral medication or chemotherapy are used to treat the acute subtype. If it responds to chemotherapy, consider an allogeneic stem cell transplant. Lymphoma subtype is often treated with chemotherapy; antiviral therapy is not helpful for this subtype. 


Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: 

If Helicobacter pylori infection is present and the lymphoma is restricted to the stomach and peri-gastric lymph nodes, therapy with antibiotics and Histaminic (H2) blockers can eradicate the organism-related antigenic stimulation, and the lymphoma may regress permanently.


Prognosis for Non-Hodgkin's lymphoma

Typically, the prognosis of NHL is worse than that of Hodgkin lymphoma.

Low-grade lymphomas: median survival of 6–10 years.

High-grade lymphomas: survival typically several months.

Indicators of poor prognosis: old age, number of involved nodal and extranodal sites, and high LDH.



Lymphomas are malignancies that arise from lymphocytes and are classified as either Hodgkin lymphomas (characterized by Reed-Sternberg cells) or non-Hodgkin lymphomas (NHLs), which comprise all other types of lymphoma. NHLs are further classified according to cell type such as B cells, T cells, and natural killer (NK) cells; location (nodal or extranodal) and tumor grade. 

Low-grade tumors originate from mature cells that have a slow growth rate and an indolent clinical course. The most common low-grade B-cell lymphoma is follicular lymphoma, while the most common low-grade T-cell lymphomas are cutaneous T-cell lymphomas, such as mycosis fungoides. 

High-grade tumors have a rapid growth rate and an aggressive clinical course. Certain subtypes of NHL, such as Burkitt lymphoma are more common in children and young adults than in older adults. 

NHL is diagnosed by obtaining a biopsy of the affected tissue and carrying out a detailed assessment, including immunophenotyping, genetics, and molecular testing. These studies allow for the identification of specific NHL subtypes, which guides treatment. Generally, treatment involves a combination of chemotherapy and radiation therapy. Patients with high-grade NHLs and those with low-grade tumors and limited disease are treated with curative intent. Patients with advanced, low-grade tumors who experience symptoms usually receive palliative treatment.