Non-Hodgkin Lymphoma

Non-Hodgkin lymphomas are malignant lymphomas that are not classified as Hodgkin's disease. They are characterized especially by painless adenopathy, fever, night sweats, fatigue and weight loss.

The disease is related to the following processes:  neoplastic and has an incidence of about  20 / 100.000.

Overview

Non-Hodgkin lymphomas are a group of lymphoid malignancies that includes all the cancerous conditions of the lymphoid cells except Hodgkin’s disease. The main differentiating feature between Non-Hodgkin and Hodgkin lymphoma is the absence of Reed Sternberg cells in non-Hodgkin’s lymphoma [1]. This separation between Hodgkin’s disease and non-Hodgkin’s lymphomas was done early in the twentieth century.

Lymphoid cell malignancies can range from benign to the most aggressive ones. Tumor cells arise from the immune system cells at different stages of differentiation and thus may give rise to wide variety immunologic, morphologic and clinical findings.
Non-Hodgkin cell lymphomas may present as leukemia (involvement of bone marrow and blood), lymphomas (solid tumors of the immune system) and both leukemia and lymphomas.

Etiology

The etiology of Non-Hodgkin lymphoma is very complex as numerous factors are responsible for its cause. Immunodeficiency states, both primary and secondary are thought to be the most important cause of Non-Hodgkin lymphoma. Patients with HIV infection, organ transplant, and with inherited immunodeficiency states like sicca syndrome and rheumatoid arthritis are more likely to have Non-Hodgkin lymphoma [2] [3] [4].

Common diseases or exposures increasing the risk of Non-Hodgkin lymphoma are listed below:

Environment plays a vital role in the causation of this disease with certain infectious agents, chemicals (specifically agricultural chemicals) and medical treatments being common examples [5].

Few specific infectious agents associated with certain subtypes of Non-Hodgkin lymphoma are:

  • Epstein-Barr virus: Burkitt’s lymphoma, Post organ transplant lymphoma, Primary CNS diffuse large B cell lymphoma, Hodgkin’s disease, Extranodal NK/T cell lymphoma, nasal type
  • HTLV-1 (human T cell lymphotropic virus): Adult T cell leukemia or lymphoma
  • HIV (human immunodeficiency virus): Diffuse large B cell lymphoma, Burkitt’s lymphoma
  • Hepatitis C virus: Lymphoplasmacytic lymphoma
  • Helicobacter pylori: Gastric MALT (mucosa associated lymphoid tissue) lymphoma
  • Human herpesvirus 8: Primary effusion lymphoma, Multicentric castleman’s disease

Patients who suffered from Hodgkin’s disease and were treated for that may develop Non-Hodgkin lymphoma. It is not sure whether the cause of Non-Hodgkin lymphoma in such cases is either the radiation exposure or the Hodgkin’s disease itself.

Epidemiology

The following list shows the relative frequency of the various types of Non-Hodgkin lymphoma:

Diffuse large B cell lymphoma: 31%
Follicular lymphoma: 22%
MALT lymphoma: 7.6%
Mature T cell lymphoma: 7.6%
Small lymphocytic lymphoma: 6.7%
Mantle cell lymphoma: 6%
Mediastinal large B cell lymphoma: 2.4%
Anaplastic large cell lymphoma: 2.4%
Burkitt’s lymphoma: 2.4%
Nodular marginal zone lymphoma: 1.8%
Precursor T lymphoblastic lymphoma: 1.7%
Lymphoplasmacytic lymphoma: 1.2%
Others: 7.4%

The most prevalent form of lymphoid neoplasm in Western world in chronic lymphoid leukemia (CLL). It occurs in older adults. According to a data in 2010, almost 15.000 new cases of chronic lymphoid leukemia were diagnosed in the United States. It is more common in men than in women. Moreover, whites are affected more than the blacks.

Acute lymphoid leukemias (ALLs) most commonly affect children and young adults. Burkitt’s lymphoma, one of the types of ALL occur due to infection with Epstein - Barr virus (EBV) in infancy. Trisomy 21 (Down syndrome) increases the chance of acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) in children. Radiation exposure increases the risk of T-cell acute lymphoid leukemia manifold.

A 4 % increase was observed in the United States in cases of Non Hodgkin lymphoma between 1950 and late 1990s. Globally this increases was 2 to 8%. In 2010, the number of new cases all over the world was 360,000 whereas in United States it was 65,000. These lymphomas are more common in men and in elderly. Elderly men are more frequently affected by the Non-Hodgkin lymphoma.

Sex distribution
Age distribution

Pathophysiology

Lymphoid cells are derived from a common progenitor known as hematopoietic stem cell. It gives rise to all the lineages including the lymphoid, myeloid, erythroid, monocyte and megakaryocyte. B cells are notorious for having almost 75% of all lymphoid leukemias and 90% of all lymphomas.

Phenotype of the cell surface of the lymphoid cells in malignancy are not much yielding in defining the nature of the tumor because there are certain examples in which the clinical outcome is contradictory to what is the phenotype. For example, clinically Burkitt’s lymphoma is the most aggressive lymphoid leukemia, yet it has a phenotype of mature B-cell. Leukemias having very primitive cells phenotypically are much less aggressive and respond to curative measures.

Lymphoid cell malignancies are very closely related to repeating genetic abnormalities. Certain types of genetic abnormalities leading to Non-Hodgkin lymphoma are gross chromosomal changes like additions, deletions, or translocations, rearrangement of specific genes, under expression, overexpression or mutation of some specific oncogenes.

Common chromosomes affected in lymphoid malignancies especially NHL are 2, 14 and 22 in B cells, and 7 and 14 in T cells. Cytogenetic abnormality leading to certain lymphoid disease are given in the table. Cytogenetic translocations for some common subtypes of Non-Hodgkin’s lymphoma are t(14;18) (follicular lymphoma), t(2;5) (anaplastic large T cell lymphoma), t(8;14) (Burkitt’s lymphoma) and t(11;14) (mantle cell lymphoma).

Prognosis

Although prognosis of Non-Hodgkin lymphoma varies from type to type of the tumor, however a central and well defined system has been devised to determine the prognosis of Non-Hodgkin lymphoma. It is known as International Prognostic Index for NHL. This one index is referred to as a very strong indicator to the outcome of all subtypes of Non-Hodgkin lymphoma.
According to this system patients are assigned a score based on the absence or presence of mainly five adverse prognostic factors. Some patients have none while others may have all the five adverse factors.

International prognostic index for NHL [7]
Five clinical risk factors

  • Age > 60 years
  • Serum lactate dehydrogenase levels elevated
  • Performance status > 2 (ECOG) or < 70 (Karnofsky)
  • Ann Arbor stage III or IV
  • >1 site of extranodal involvement

Patients are assigned a number for each risk factor they have
Patients are grouped differently based upon the type of lymphoma. (ECOG – Eastern Cooperative Oncology Group)

Presentation

Clinical presentation mostly depends on the subtype of Non-Hodgkin lymphoma and the area which it involves. It can either follow an indolent path or may progress in a very aggressive pace.

Most of the aggressive lymphomas present with a rapidly growing tumor mass, fever, night sweats, weight loss, and increased levels of serum lactate dehydrogenase and uric acid. Burkitt’s lymphoma and diffuse large B cell lymphoma are the common examples of aggressive tumors.

Slow growing or indolent lymphomas usually present with lymphadenopathy, hepatomegaly, splenomegaly or different types of cytopenias [6]. Common examples are follicular lymphoma and marginal zone lymphoma.
Few subtypes of Non-Hodgkin lymphoma may also present with rash, pruritus, generalized aches and pains.

Workup

Evaluation or workup of the patients with Non-Hodgkin lymphoma is quite similar to those suffering from Hodgkin's disease. The following investigations are mandatory to be carried out in the individuals suspected for Non-Hodgkin lymphoma [7] [8]:

  • Complete blood count
  • Erythrocyte sedimentation rate
  • Chemistry studies reflecting major organ function
  • Serum levels of lactate dehydrogenase (LDH) and β2 microglobulin and serum protein electrophoresis.
  • Computed tomography (CT) scan of the chest, abdomen and pelvis
  • Bone marrow biopsy
  • PET and gallium scan – although not required for primary staging of the tumor but if performed at the end of therapy, helps evaluating the persisting mediastinal radiographic abnormalities.

Staging of any type of tumor is a very critical issue and is addressed according. Staging for Non-Hodgkin lymphoma is done using the Ann Arbor Staging System which was first devised for Hodgkin’s disease.

I: Single lymph node region or lymphoid structure like (thymus, spleen or Waldeyer’s ring) is involved

II: Two or more lymph node regions on the same side of the diaphragm are involved

III: Lymph node regions or lymphoid structures on the both sides of diaphragm are involved

III 1: Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes

III 2: Subdiaphragmatic involvement of paraaortic, iliac and mesenteric nodes in addition to the structures involved in III1

IV: Extranodal sites beyond liver and bone marrow are involved.
More than one extranodal deposit at any location
Involvement of liver or bone marrow of any type

IV A: Symptomless

IV B: Unexplained weight loss more than 10% body weight during 6 months before initiating investigation, Unexplained, persistent and recurrent fever with tem more than 38 degree celcius in the last month, Drenching and recurrent night sweats in the last month

E: If extralymphatic tissue other than liver and bone marrow is involved, but the lesion is localized and solitary

Treatment

The treatment options depend on the type of lymphoma, its stage and other prognostic factors and include chemotherapy (most common), radiation therapy, Rituximab administration, bone marrow transplantation, radioimmunotherapy, antibiotics and surgery.

Prevention

There are no guidelines for prevention of Non-Hodgkin lymphoma.

Patient Information

Non-Hodgkin lymphoma includes a wide array of lymphoid malignancies and the most common subtype is diffuse large B cell lymphoma.

Infections with Epstein Barr virus (EBV) and human T cell leukemia virus (HTLV-1) are the two most common and well recognized causes. Other possible causes are exposure to radiations, nitrates in drinking water, pesticides, hair dye use, alcohol and tobacco. Certain drugs like amphotericin B and vancomycin also increase its susceptibility.
It presents with lymphadenopathy and systemic symptoms like fever, rigors, night sweats and weight loss.

If the above mentioned symptoms appear, patient must visit the physician as soon as possible. Important investigations that must be carried out in this setting are complete blood count, erythrocyte sedimentation rate, chemistry studies reflecting major organ function, serum levels of lactate dehydrogenase (LDH) and β2 microglobulin and serum protein electrophoresis, computed tomography (CT) scan of the chest, abdomen and pelvis and bone marrow biopsy. Once developed appropriate chemotherapy and radiotherapy must be carried out to get rid of it.

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References

  1. Greiner TC, Medeiros LJ, Elaine S. Jaffe ES., Non-Hodgkin's lymphoma; International Journal of the American Cancer Society Volume 75 2006, Issue Supplement S1, p 370–380.
  2. Smedby KE, Hjalgrim H, Askling J, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst 2006; 98:51.
  3. Ramos-Casals M, la Civita L, de Vita S, et al. Characterization of B cell lymphoma in patients with Sjögren's syndrome and hepatitis C virus infection. Arthritis Rheum 2007; 57:161.
  4. Martí-Carvajal AJ, Cardona AF, Lawrence A. Interventions for previously untreated patients with AIDS-associated non-Hodgkin's lymphoma. Cochrane Database Syst Rev. Jul 8 2009;CD005419.
  5. Chiu BC, Dave BJ, Blair A, et al. Agricultural pesticide use and risk of t(14;18)-defined subtypes of non-Hodgkin lymphoma. Blood 2006; 108:1363.
  6. Zhang QY, Foucar K. Bone marrow involvement by Hodgkin and non-Hodgkin lymphomas. Hematol Oncol Clin North Am. Aug 2009;23(4):873-902.
  7. Conlan MG, Armitage JO, Bast M, Weisenburger DD. Clinical significance of hematologic parameters in non-Hodgkin's lymphoma at diagnosis. Cancer 1991; 67:1389.
  8. McKenna RW, Bloomfield CD, Brunning RD. Nodular lymphoma: bone marrow and blood manifestations. Cancer 1975; 36:428.

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