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Non-Hodgkin’s Lymphoma

Image : “Mantle cell lymphoma – intermed mag” by Nephron. License: CC BY-SA 3.0


Non-Hodgkin’s lymphoma (NHL) consists of a heterogeneous group of cancers originating from lymphoid tissues—mainly lymph nodes—that are derived from B-lymphocytes, T-lymphocytes, natural killer (NK) cells and their precursors.

Epidemiology of Non-Hodgkin’s Lymphoma

The Non-Hodgkin’s lymphoma is the 6th most commonly diagnosed cancer, accounting for about 4 % of all cancers in the USA. It is predicted that about 72,240 new cases will be diagnosed in 2017 just in the USA. The overall rate is increasing at about 3 % per year. Moreover, the number of patients has doubled up since 1970, perhaps due to the advance in the means of early diagnostics. NHL occurs five times as often as HL (Hodgkin’s lymphoma).

The incidence of Non-Hodgkin’s lymphoma increases with age, with the median age being 50 years and older, for most subtypes of NHL. Further, the NHL has race and gender preferences. It is more common in white people and is 1.4 times more common in men than in women.

Etiology of Non-Hodgkin’s Lymphoma

Non-Hodgkin’s lymphoma may result from various pathological insults such as chromosomal translocations, molecular rearrangements, infections, chronic inflammation, and environmental factors.

Chromosomal translocations and molecular rearrangements

Chromosomal translocations and molecular rearrangements occur in 85 % of follicular lymphomas and 28 % in high-grade NHL mantle cell lymphoma and high-grade small noncleaved lymphomas (Burkitt and non-Burkitt types).

Infection and Chronic inflammation

Infection plays a pivotal role as a triggering factor of NHL development because of the uncontrolled B- or T-cell stimulation, enhanced proliferation and lymphomagenesis. The oncoviruses, including Epstein-Barr virus (EBV), the human T-cell lymphotropic virus I (HTLV-I) and human herpesvirus-8 (HHV-8), cause a latent condition resulting in leukemia or lymphoma. HIV causes NHL by causing immunosuppression, instead of directly introducing oncogenes. H. pylori provokes gastrointestinal (GI) lymphomas.

Environmental issues (pollution):

Exposure to pesticides, herbicides, solvents, organic chemicals, wood preservatives, dust, hair dye, chemotherapy, and radiations plays a role in triggering NHL. Smoking during the early stages of pregnancy may predispose the development of NHL in the child.

Classification of Non-Hodgkin’s Lymphoma

The World Health Organization (WHO) has classified NHL into B-cell and T-cell/NK neoplasms using a multidisciplinary approach. The common subtypes of NHL are given in the following table:

Precursor B-cell lymphoblastic lymphoma Precursor T-cell lymphoblastic lymphoma
Mature B-cell lymphomas Anaplastic T-cell lymphoma
Diffuse large B-cell lymphoma Angioimmunoblastic lymphoma
Mediastinal large B-cell lymphoma Peripheral T-cell lymphoma, NOS
Follicular lymphoma Cutaneous T-cell lymphoma (mycosis fungoides)
Small lymphocytic lymphoma Extranodal T/NK-cell lymphoma
Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia) Adult T-cell leukemia/lymphoma
Mantle cell lymphoma
Burkitt lymphoma
Marginal zone lymphoma
MALT type

Clinical Presentation of Non-Hodgkin’s Lymphoma

The clinical presentation of Non-Hodgin’s lymphoma differs greatly depending upon the NHL subtype and the involved areas. Some indolent NHL subtypes behave benignly with waxing and waning chronic lymphadenopathy, while some other types behave aggressively, resulting in death within weeks or months if left untreated. In general, the clinical features of NHL are similar to those of Hodgkin’s lymphoma (HL). These are:

  • Painless lymphadenopathy
  • Fever (> 38º C)
  • Unexplained weight loss ( >10 % of body weight over the past six months)
  • Drenching night sweats
  • Fatigue
  • Feeling of fullness after even a small meal
  • Chest pain, shortness of breath
  • Abdominal tenderness
  • Hepatosplenomegaly
  • Engagement of Waldeyer ring (back of the throat, including the tonsils), occipital or epitrochlear areas
  • Superior vena cava syndrome and acute respiratory distress (in cases of massive mediastinal lymphadenopathy)

The presence of one or more constitutional symptoms, such as fever, unintentional weight loss, and drenching night sweats, is labeled as the B-symptoms.

Diagnosis of Non-Hodgkin’s Lymphoma

The clinical features of NHL are nonspecific, and a high degree of suspicion is needed to further evaluate for the diagnosis. It is important to pay attention to risk factors, family history and immune system condition of the patient. Furthermore, following investigations help in the diagnosis of NHL.

Laboratory studies

primary central nervous system b-cell non-hodgkin lymphoma

Image: “Brain MRI showing primary central nervous system B-cell non-Hodgkin lymphoma of the sella turcica and hypothalamus, continuing to the tectum.” by Steven Fruitsmaak – Own work. License: CC BY-SA 3.0

The lymph node biopsy (excisional or incisional) with the histological examination is essential to diagnose Non-Hodgkin’s lymphoma and identify the subtype of NHL. The fine needle aspiration (FNA), or core needle biopsy, may be used together with the CT scan, in the case of deeply seated lymph nodes, to confirm the diagnosis.

Bone marrow aspiration and biopsy are normally carried out in advanced stages of the disease.

Lumbar puncture (spinal tap) is necessary in those cases when the CNS is involved in the pathogenic process, or in some particular types of lymphomas.

Pleural or peritoneal fluid sampling (thoracentesis and paracentesis) as some malignant tumors make fluids build-up; the biomaterial obtained after the procedure may contain evidence of the tumor presence.

The immunohistochemistry (specific antibodies to a tumor can cause color changes and are clearly seen under microscope), flow cytometry (immunophenotyping is used for identification of type of malignant cells, regarding the antigen on their surface) and molecular genetic tests, such as fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) are used to identify the exact subtype of NHL.

Complete blood counts (in order to detect anemia, lymphopenia, pancytopenia or increased WBC counts). Lactate dehydrogenase (LDH) is usually increased in lymphomas.

Imaging studies

Chest x-ray detects enlarged lymph nodes in the chest and mediastinum. CT scans of the chest, abdomen and pelvis (used in order to detect abnormal findings include enlarged lymph nodes, hepatomegaly and/or splenomegaly, lung nodules or infiltrates and pleural effusions).

Magnetic resonance imaging (MRI) scan, similar to a CT scan, helps in the diagnosis of NHL. Positron emission tomography, gallium scan, and bone scans are informative in the diagnosis of NHL.

Staging of Non-Hodgkin’s Lymphoma

The clinical staging of Non-Hodgkin’s lymphoma is done after confirming the diagnosis to measure the extent of the disease as well as make a prognosis and guide treatment. Staging in NHL is done according to the Ann Arbor staging system, which is as follows:

Stage I: Involvement of a single lymph node region (I) or of a single extra-lymphatic organ or site (IE).

Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm, alone (II) or with the involvement of limited, contiguous extra-lymphatic organ or tissue (IIE).

Stage III: Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm (III) which may include the spleen (IIIS) or be limited to a contiguous extra-lymphatic organ or site (IIIE), or it may involve both (IIIES).

Stage IV: Diffuse or disseminated foci of involvement of one or more extra-lymphatic organs or tissues, with or without associated lymphatic involvement.

All stages are subclassified to indicate the absence (A) or presence (B) of one or more of the constitutional symptoms, i.e., significant unexplained fever, night sweats or unexplained weight loss.

High-grade non-Hodgkin lymphoma

The most important subtype is Diffuse Large B Cell Lymphoma (DLBCL). As with all NHL, the disease may present in lymph nodes or in other tissues (extranodal disease). Treatment is with use of the anti-CD20 antibody together with combination chemotherapy e.g. R-CHOP. Overall survival is around 65% after 5 years.

The International Non-Hodgkin’s Lymphoma Prognostic Index

The International Non-Hodgkin’s lymphoma prognostic index is one of the strongest predictors of prognosis for patients with Non-Hodgkin’s lymphoma. It can be easily calculated in the clinical setting and is based upon the following characteristics:

  • Age > 60 years
  • Stage III or IV disease
  • Elevated serum LDH
  • Performance status
  • More than 1 extranodal site

A single point is awarded to each characteristic.  The sum of the points allotted correlates with the following risk groups:

Risk Points 5-year survival
Low 0—1 73 %
Low-intermediate 2 51 %
High-intermediate 3 43 %
High 4—5 26 %

Management of Non-Hodgkin’s Lymphoma

The management of Non-Hodgkin’s lymphoma depends on its staging, subtype, general health and age of the patient, comorbidities and complete blood counts. The general treatment options of the NHL are:

  • Chemotherapy
  • Targeted therapy
  • Radiation
  • Immunotherapy
  • Stem cell transplantation
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