Paediatric Case Of Childhood Lymphoma Biology Essay


Immune system is made up of network of cells, proteins, tissues, and organs that work together to protect the body against infection. In most cases, the immune system does an excellent work of keeping people healthy and prevent from infections. However, sometimes problems may occur with the immune system that can lead to an infection.

Immunity refers to the ability of a body to fight against diseases. The immune system is the body's defence system that has evolved against various infectious agent and cancer.

Immune system attacks organisms and harmful substances that invade body systems through a series of steps known as immune response.

About the Immune System

The cells involved in immune system are leukocytes (WBCS). Leukocytes are found in many locations of the body, including spleen, thymus, and bone marrow.

Also lymphatic system.....

Leukocytes circulate throughout the body via blood vessels and lymphatic vessels. In this way, the immune system monitors the body for microorganism or substances that might cause disease. The two general types of leukocytes are:

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phagocytes, cells that engulf invading organisms

lymphocytes, cells that fights against infection.

A number of different cells are considered phagocytes. The most common type is the neutrophil, which primarily fights bacteria. If doctors are worried about a bacterial infection, they might order a blood test to see if a patient has an increased number of neutrophils triggered by the infection. Other types of phagocytes have their own jobs to make sure that the body responds appropriately to a specific type of invader.

Lymphocytes are the chief cells of immune system. The two types of lymphocytes are B lymphocytes and T lymphocytes. Both of these types of lymphocytes develop from stem cells (haemocytoblasts) found in liver during foetal stage and in bone marrow cells of adult stage. The process of production of lymphocytes in bone marrow is called haematopoeisis. While differentiating from stem cells, those which migrate to the thymus gland and develop are called T-cells. The others that continue to develop in the bone marrow develop into B-cells. The young lymphocytes so produced, migrate to lymphoid tissues like spleen, lymph nodes

Lymphocytes start out in the bone marrow and either resides there and matures into B cells, or they leave for the thymus gland, where they mature into T cells. B lymphocytes and T lymphocytes have separate functions: B lymphocytes are like the body's military intelligence system, seeking out their targets and sending defences to lock onto them. T cells are like the soldiers, destroying the invaders that the intelligence system has identified.

Here's how it works:

When invasion of foreign substances in body are detected, several cells work together to recognize them and respond. These cells trigger the B lymphocytes to produce antibodies, specialized proteins that lock onto specific antigens.

Once produced, these antibodies continue to exist in a person's body, so that if the same antigen is presented to the immune system again, the antibodies are already there to do their job.

This is also how immunizations prevent certain diseases. An immunization introduces the body to an antigen in a way that doesn't make someone sick, but does allow the body to produce antibodies that will then protect the person from future attack by the germ or substance that produces that particular disease.

Immunization stimulates the body to produce highly efficient antibodies that can attack tumors.

Although antibodies can recognize an antigen and lock onto it, they are not capable of destroying it without help. That's the job of the T cells, which are part of the system that destroys antigens that have been tagged by antibodies or cells that have been infected or somehow changed. (Some T cells are actually called "killer cells.") T cells also are involved in helping signal other cells (like phagocytes) to do their jobs.

Antibodies also can neutralize toxins (poisonous or damaging substances) produced by different organisms. Lastly, antibodies can activate a group of proteins called complement that are also part of the immune system. Complement assists in killing bacteria, viruses, or infected cells.

All of these specialized cells and parts of the immune system offer the body protection against disease. This protection is called immunity.

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Immune system has two main components in the body: Humoral and cell-mediated immune systems. Cells of acquired immune system consist of two major groups of cells which are lymphocytes and antigen presenting cells.


NHL is a rare disease found in children and appears in forms that are notably different from those of its adult counterpart.

NHL patients usually present clinical features that correlate with histologic subtype. Most often patients with lymphoblastic lymphoma present with an intrathoracic tumor, particularly a mediastinal mass in 50-70% cases and frequently have a pleural effusion. The presenting features may include chest pain, dyspnea, dysphagia. Usually the lymphadenopathy is above diaphragm and the immunophenotype T cell type.

NHL is a rapidly growing neoplasm, thus rapid diagnosis is necessary. Appropriate selection of mass for histological material is essential. Histology is the primary means for definitive diagnosis and if possible should be supplemented with immunophenotypic and cytogenetic studies. In some cases, patient's condition is not suitable for biopsy due to large mediastinal mass; the diagnosis should be performed with less invasive methods such as percutaneous needle aspiration of a lymph node, examination of body fluids or bone marrow.

The diagnosis of NHL is usually set up by examination of tissue obtained by biopsy of the tumor site. Enough tissue is required obtained for histology and also for immunophenotypic, cytogenetic, and molecular studies. In children with suspected NHL, a bone marrow and lymph node biopsy may be diagnostic, preventing the need for more invasive procedures and possible increased morbidity. Initial laboratory analysis should include a complete blood count, a LDH and an HIV screen.

Evaluation of patient with lymphoblastic NHL

History and physical examination

Chest radiograph, CT scan

CBC, Pleural fluid examination

Lactose dehydrogenase test

Bone marrow aspiration



Cytology from body fluids like pleural fluids

Immunohistochemistry, Flow Cytometry

Case History

An 8 year old girl, presented with mediastinal mass and cervical, axillary, left ingunal lymphadenopathy. Chest radiograph revealed opaque left hemithorax and mediastinal shift to right. CT scan showed presence of necrotic mass in the left hemithorax. Abundant eosinophils were observed in pleural fluid examination. Tumor biopsy showed 98 % of tumor cells expressing CD3, CD4 and CD8, which conclude that tumor mass was derived from double-positive CD4+CD8+ population of thymocytes. Figure 1 shows a electron micrograph of the tumor, which revealed high nuclear to cytoplasmic ratio and irregular convoluted nuclei.

Figure 1- Electron Micrograph of Tumor

Courtesy- Young et al, 1985

On admission, leukocyte count was found to be high (to 11,400 cells/ml). Also, blood test showed rise in level of eosinophils and depletion of neutrophils and lymphocytes. Bone marrow examination to pin point abnormal leukocyte count showed hypercellular marrow and many large, immature appearing cells with numerous eosinophils. A serum IgE level was found to be >10,000 IU/ml because of the blood and bone marrow eosinophilia. IgE was polyclonal in origin. Skin tests to a battery of 24 inhalant allergens and stool examination results for parasitic infestation were negative. Serum levels of IgG, IgM and IgA were normal. Remission after cytotoxic chemotherapy treatment showed reduction in serum IgE levels (upto <200 IU/ml). After 7 month of remmision, recurrence of the lymphoma was observed with risk in serum IgE (upto 3900 IU/ml). . Eosinophilia resolved rapidly with treatment of prednisone.

In this study, a patient is described with lymphoblastic non-Hodgkins lymphoma accompanied with elevated serum IgE. The serum IgE returned to normal level with the relapse of tumor, only to rise again when tumor recurred.

In humans, eosinophils are mainly found in extravascular space. Thus increase in peripheral blood eosinophils suggest eosinophilia and reflect recruitment of tissue eosinophils by chemoaatractant substances. Administration of corticosteroids mostly induces eosinopenia. However, the mechanism for this effect remains obscure. Corticosteroids may inhibit the accumulation of eosinophils by affecting the chemotaxis and/or adherence of these cells. After production of eosinophils in the bone marrow, it appears in the peripheral blood and lastly distributes themselves into the tissues. Thus mechanism involve in administration of prednisone: (1) reduction in eosinophil adherence, (2) inhibition in eosinophil chemotaxis. The effect of chemotaxis inhibition is nontoxic, dose-dependent, cell-directed and reversible. Role of inhibition of eosinophil adherence and chemotaxis explains how corticosteroids (e.g. Prednisone) results in rapid decrease in levels of circulating and tissue eosinophils.

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The primary stimuli for eosinophilia are IL-5, IL-3 and GM-CSF. Also, chemotactic cytokines (ie, chemokines) such as eotaxin-1, eotaxin-1 and RANTEs causes migration of eosinophils from their site of production i.e. bone marrow into the blood and peripheral tissues. Source of eosinophils include a large number of cytokines, viz. IL-2, IL-3, IL-4, IL-5, IL-7, IL-13, IL-16, TGF-β, TNF-α, and RANTES. Differentiation of eosinophilia occurs in bone marrow through the actions of IL-3, IL-5, and GM-CSF.

Most often, hypereosinophilic syndrome (HES) cases exhibit clonal expansion of abnormal lymphocytes. Immunophenotypically, they are characterized by abnormal and immature T cells, which exhibit abnormal cytokine production. Such T cells produce high levels of IL-5, which may be the causes of hypereosinophilia.


The normal leucocytes count is 5000-1000 cells/ml which is normally increased in lymphoblastic NHL. Eosinophils are types of WBC's and they engulf the particles released during antibody-antigen reactions and responsible for fighting against inflammations and infections. Normal Eosinophils percentage is 0-4% of total WBC. Increased number eosinophil count is known as eosinophilia. Eosinophilia is seen in conditions like inflammation, allergy, asthama and cancerous conditions like Hodgkin's and Non-Hodgkin's lymphoma, stomach and lung cancer. In lymphoblastic NHL peripheral blood eosinophilia is seen. Mechanism of pleural fluid eosinophilia in malignant effusions is not known till date. Recently, within the pleural space the local secretion of interleukin-5 by helper T cell lymphocytes has been identified as the mechanism underlying post-traumatic pleural fluid eosinophilia. Thus it may play an important role in malignant effusion too as helper-T-lymohocytes outnumber suppressor T-cells in pleural fluid. Reason behind the effusion immune mediated inflammatory reactions may also contribute as the stimulus for crowding of eosinophil. The clinical analyses of peripheral blood eosinophilia in this case, may indicate a common factor, yet not clear. Further studies are required in this field of study.


Neutrophils are type of WBC's which respond to bacterial and pyogenic infection. Neutrophils counts usually elevated in any acute inflammation, burns, malignancy and after treatment with some drugs. In lymphoblastic non-Hodgkin's lymphoma, neutrophils proliferate out of control and enter the blood stream due to which blood neutrophil count elevated. In Elizabeth case, the corticosteroid (predinosone) lead to high blood neutrophil count, causing marginated neutrophils to enter the blood stream.


There are many treatments options available for lymphoblastic non-Hodgkin's lymphoma. Treatment options vary because of the heterogeneous nature of non-Hodgkin's lymphomas (NHLs). But treatments for lymphoblastic non-Hodgkin's lymphoma depend upon patient medical history, age, physical development, sexual maturity, tolerance for specific medications, procedure, extent and expectation for the course of the disease.

Standard treatment for the lymphoblastic NHL include Chemotherapy, Radiation therapy, monoclonal antibody therapy, Radio immunotherapy, surgery, stem cell transplantation, Antibiotics to treat infection and supportive care for side effect of drugs. The lymphoblastic NHL is most commonly treated by chemotherapy. In this therapy, drugs like Cytosine arabinoside, VP16, Prednisone, CHOP, CVAD (cytoxan, vincristine, adriamycin, and dexamethasone), Chlorambucil, Vincristine, Fludarabine, Pentostatin and Rituxan (Rituximab). These cytotoxic drugs selectively destroy lymphoma cells which rapidly divide but cannot eliminate all of the cancerous cells. Chemotherapy for lymphoblastic lymphoma is given either as combination of drugs or single high dose drug. Recurrent lymphoblastic NHL is treated with combination therapy or high dose chemotherapy plus radiation therapy. Chemotherapy shows side effects like loss appetite, nausea, vomiting, and diarrhoea whereas radiotherapy destroys normal cells along with cancerous cell. In Monoclonal antibody therapy, drugs recognise specific type of cancer cell and destroy them by attaching themselves on cancerous cell. Monoclonal antibody therapy uses drugs like Rituximab which destroy normal lymphocytes as well as lymphoma cells. Patient shows no sign of symptoms and tumour after having treatments for some weeks. But lymphoblastic NHL recurred with the sign of recurrence of tumour mass.Treatment for recurrent lymphoblastic lymphoma includes high-dose chemotherapy with stem cell transplantation..


Elizabeth was showing symptoms like chest pain, shortness of breath and coughing. Chest pain was due to presence of lymphoma in chest region. Because of lymphoma in left hemithorax thymus was enlarged which in turn put pressure on nearby structure like trachea, due to pressure on trachea symptoms like shortness of breath and cough showed by Elizabeth. The enlargement of lymph node, liver and spleen were also seen. Enlargement of lymph node and spleen were seen because of rapid lymphatic cell division and production, accumulation of malignant cells or immature cells in the lymph node, liver and spleen.

Lymphoma overview

The human body is composed of many cells that develop to carry out their normal functions. They divide to replace the damaged cells. The uncontrolled growth and spread of these damaged cells can lead to the development of cancer cells. These cells develop when there is damage to their DNA due to some inherited genetic disorder or exposure to chemicals. Lymphomas are cancer of leukocytes. In lymphomas, the lymphocytes convert into cancer cells, grow uncontrollably and accumulate in the lymph nodes and lymphatic system. And thus a cancerous tumor is formed.

Lymphatic system

The circulatory system made up of many branching lymph vessels is known as lymphatic system. It was first described by Olaus Rudbeck and Thomas Bartholin. Plasma surrounding the body tissues leaks out of the capillaries and drains into lymph vessels. The lymph vessels carry this colourless fluid (lymph) containing large number of lymphocytes to all the tissues of the body. Along the lymph vessels are the bean shaped lymph nodes which filter the lymph fluid. Spleen, thymus, tonsils, adenoids are the other lymphatic system organs. A small gland under the breast bone helps to produce white blood cells. The tonsils and adenoids prevent the entry of micro organisms in digestive system and the lungs. The white pulp of spleen contains many lymphocytes. Lymphocytes are produced by bone marrow. B-lymphocytes and T- lymphocytes are the two main types of lymphocytes that help the body in fighting infections. The B cells invade the microorganisms by producing anti bodies. Among the two types of T cells, helper T cells stimulate the B cells to produce antibodies, IgE production and helps in the development of killer cells. Usually helper T cells differentiate into CD4 from TH0 cells but they may also be CD8. Killer T cells may be CD4 but they are usually CD8 .They prevent the reproduction of microorganisms in the cell by the body's own cells. The lymph flows through lymph nodes and spleen, bone marrow, etc. where it is filtered to remove microorganisms and foreign substances from the body. However, the lymphatic system filters the lymph and the blood, fights infection and drains the fluid from the tissues back into the bloodstream.

There are two general types of lymphomas: Hodgkin disease and Non Hodgkin lymphoma.

Hodgkin disease is named after Dr. Thomas Hodgkin who first discovered it. It contains specific sells called Reed-Sternberg cells which are not present in non Hodgkin lymphoma.

Reed-Sternberg cell; photograph shows normal lymphocytes compared with a Reed-Sternberg cell, which are large, abnormal lymphocytes that may contain more than one nucleus. These cells are found in Hodgkin lymphoma.


NHL is the 3rd most common childhood lymphoma. It is a heterogeneous disease that constitutes 60% of childhood lymphomas. It is divided into two main groups: B-cell lymphomas and T-cell lymphoma. It usually occurs in children of ages between 7 to 11 years.


According to the WHO, there are 61 types of NHL. Following are the common types of childhood NHL.

Burkitt lymphoma: Burkitt lymphoma is an aggressive B cell lymphoma. It accounts for 40% of childhood lymphoma each year. Sporadic, endemic and immunodeficiency-related Burkitt lymphomas are three main types. It is linked with Epstein-Barr virus infection. It usually affects eyes, kidneys, breasts, etc.

Diffuse large B cell lymphoma: Diffuse large B cell lymphoma is an aggressive B cell non Hodgkin lymphoma. It accounts for 20% of childhood lymphoma each year. Often involves lymph nodes, spleen, liver,etc.

Anaplastic large cell lymphoma: Anaplastic large cell lymphoma is a rare form of indolent non Hodgkin lymphoma that affects T cells. It accounts for about 10% of childhood lymphoma each year. It often affects lymph nodes, skin, liver, etc.

Lymphoblastic lymphoma: Lymphoblastic lymphoma is a most common type of aggressive cancer that can affect either type of lymphocyte. Most commonly found in T cells but some arise from immature B cells. It accounts for about 35% of lymphomas in children.

Peripheral T-cell lymphoma: Peripheral T-cell lymphoma is a rare type non hodgkin lymphoma. It is a heterogeneous disease in which lymph nodes and extra nodal sites derived from the clonal expansion of mature T-lymphocytes are involved.

The staging of the disease is very important as it helps in diagnosis and treatment of the disease. The following are the four stages of non hodgkin lymphoma:

Stage 1: in this stage only one lymph node or an organ is involved.

Stage 2: lymphoma involves 2 or more lymph node areas but on the same side of the diaphragm.

Stage 3: lymph nodes on both sides of diaphragm are involved.

Stage 4: there is an invasion of lymphoma into an organ like bone marrow, kidney, liver, lungs, etc.

The staging of childhood lymphoblastic lymphoma is similar to non hodgkin lymphoma but stage 3 may show involvement of the lungs or a mass in the thorax region.


Lymphoblastic lymphoma accounts for about 35% NHL in children. Usually they are positive for TdT having >75% T-cell immunophenotype and remaining precursor B-cell. Its chromosomal abnormalities are unclear but according to one study the risk of relapse increases due to the loss of heterozygosity on chromosome 6q. Mediastinal mass is present in almost 75% patients showing swelling of the head and neck, stridor, wheezing, dyspnea or dysphagia. Lymphoblastic lymphoma occurring in bone, lymph node and subcutaneous tissue is considered as low stage but not the one occurring in mediastinum. There may be the involvement of skin, CNS, bone marrow but the involvement of abdomen, testes and Waldeyer ring of lymphoid tissue is rare. To avoid the confusion whether the patient has lymphoma or leukemia (when the bone marrow is involved) with extramedullary disease, it is distinguished depending on the marrow blasts present. Patients having >25% are considered to have leukemia and fewer than that lymphoma.


Analysis of T-cell receptor and recurrent, non random chromosomal translocations has helped in understanding the molecular pathogenesis of lymphoblastic lymphoma. Few tumors have alpha and delta T-cell receptor loci translocations at band 14q11.2, the β locus at band 7q35, and the γ locus at band 7p14-15. Such translocations results in juxtaposition T-cell receptor promoter and enhancer elements involving various transcription factors like TAL1/SCL, TAL2, LYL1 and HOX11/TLX1, which enhance high levels of expression in precursor thymocytes.

Risk factor for non-hodgkin diseases

The main causes for the development of non Hodgkin lymphoma are still not clear. Non-Hodgkin ' s lymphoma can cause in people at all ages, including children, it is most common in adult. Non Hodgkin lymphoma is more commonly seen in men than women. The overall risk factor for non Hodgkin lymphoma is higher in Caucasians than in African-Americans and Asian Americans. People with family history of developed NHL are at higher risk for this disease. However, still no accurate hereditary link has been set up. Lifestyle do not play an important role in risk factor for non Hodgkin lymphoma, but some studies states that obesity may cause an increasing risk factor. Over exposure to a wide variety of industrial and agricultural chemicals have a high risk of causing lymphomas. Immune suppression plays an important role in non Hodgkin lymphoma. Patient infected with human immunodeficiency virus re at higher risk of developing lymphoma. Some of the other immunodeficiency syndromes that can cause the risk of non Hodgkin lymphoma are Chediak-Higashi syndrome, ataxia-telangiectasia, B-cell lymphoproliferative syndrome, Bruton agammaglobulinemia, common variable immunodeficiency, and Wiskott-Aldrich syndrome. Non Hodgkin lymphoma is caused by the exposure to certain viruses and bacteria. Infection causes intense lymphoid cell proliferation, increasing the rate of cancer causing process in a cell. Some of the examples of virus and bacterium are Epstein-barr virus, human T-lymphotropic virus and helicobacter pylori. Epstein-Barr virus plays an important role in increasing the risk factor of non Hodgkin lymphoma in patient with immune suppression, due to organ transplantation and its associated therapy. The Helicobacter pylori causes ulcers in the stomach and in the stomach wall there is development of mucosa-associated lymphoid tissue (MALT) lymphoma. The hepatitis C virus (HCV) may also increase the risk factor for some types of lymphomas. People with medical history of autoimmune diseases, which include rheumatoid arthritis (RA), systemic lupus erythematosus, Hashimoto's thyroiditis, Crohn's disease, and Sjogren syndrome are at an high risk for certain types of non Hodgkin lymphoma.

After activation, T cell divide into Th1 and Th2 cells then it is not considered as a part of T cell. Development of mature T-cells occurs in thymus from T cell precursor. The expression of specific cell surface markers is identified in the stages of T cell development. The proliferation and differentiation of T cells are induced by cell to cell interaction mechanism between these cells and thymic cells. Precursor T cells do not express specific cell surface markers. At this stage precursor T cells are known as CD4 and CD8 double negative. The α-chain of T cell receptor undergoes rearrangement and a successful rearrangement serves further proliferation. At this point, both CD4 and CD8 are known as double positive cells. At this time the β-chain of T cell receptor undergoes rearrangement and follows the processes of positive and negative selection.

During development process 98% of thymocytes die in the thymus by failing either positive selection or negative selection, while rest 2% survive and develops into mature immunocompetent T cells.

Double-positive cells (CD4+/CD8+) positively selected on MHC class II develop CD4+ cells, while cells positively selected on MHC class I mature into CD8+ cells. A T cell develops a CD4+ cell by down regulating CD8 cell surface receptors expression. If the cell failed to lose its signal, it will continue down regulating CD8 and develop a CD4+, single positive cell. However, the cell stops down regulating CD8 during signal drop and switches over to down regulating CD4 molecules, normally developing a CD8+, single positive cell.

In negative selection, T cells activated strongly by self MHC plus self peptides eliminates in the thymus. If they escape this elimination, they may subsequently react again, and cause autoimmune disease. 

Positive selection selects T cells that react with MHC that is self-antigen whereas negative selection excludes T cells that react strongly with MHC that is self-antigen. Hence, successful T cell differentiation selects MHC restricted T cell receptor which possess low affinity for self-antigens. Cells outside this range eventually die through a process known as apoptosis. The important role of T cell that weakly binds to self MHC/self antigen doesn't activate T cell whereas activated T cell binds strongly to self MHC/foreign antigen.