Evidence of Correlations of Epstein-Barr virus (EBV) and Hodgkin’s lymphoma
By
Rawan A. Aldebeyan
Bachelor of Clinical Laboratory Sciences
Supervised By
Dr. Ahlam Albuhairan
Assistant Professor
College of Applied Medical Sciences
King Saud University
2016
Chapter 1
1.1 Introduction of The Lymphatic System
T
he lymphatic system has three main functions. First, of the fluid that leaves the capillaries to deliver nutrients to the cells, only 90 percent returns back to the blood and the 10 percent stay to become a part of the interstitial fluid and then is called lymph. This will eventually lead to accumulation of the fluid in the tissue, which will mess up the osmotic pressure of the cell and the volume of the blood. Therefore, the lymphatic system intervenes to return excess interstitial fluid back to the bloodstream. The second function is the ability of the lymphatic system to absorb fat and fat-soluble vitamins from the digestive system. The third and the most popular function is its ability to defend the body against invading foreign particles and microbes such as viruses or bacteria. (National Cancer Institute, 2004)
1.1.2 the lymphatic system consists of:
1.1.2.a Lymph (fluid):
That is a fluid derived from blood plasma that enters the cells.
1.1.2.b Vessels to transport the lymph:
That only carries fluid away from the tissue, unlike blood vessels, which carry fluid to the tissue. The tiniest lymphatic vessels are called lymph capillaries. These capillaries are distributed all over the body except regions that lack blood vessels, such as the bone marrow, central nervous system (CNS), and tissues like the epidermis.
1.1.2.c Organs, which contain lymphoid tissues:
Are differentiated by having clusters of lymphocytes and other immune cells, such as macrophages, and branching connective lymphoid tissues. The lymphocytes originate from the bone marrow then differentiate into B-lymphocytes and T-lymphocytes. The B-lymphocytes get matured and educated in the bone marrow as well. Unlike the T-lymphocytes, that are developed and educated in the thymus, which is one of the lymphatic system organs. The lymphocytes proliferate inside the lymphatic organs and are transported in the blood to the site of the infection.
I. Lymph Nodes:
They are small bean-shaped structures that are widely distributed throughout the body where the filtration of the lymph occurs before it returns back to the blood. Lymph nodes are present in the groin and they are called inguinal nodes, in the armpit and they called the axillary nodes, and in the neck and are called the cervical nodes.
II. Tonsils:
They are clusters on lymphatic tissue beneath the mucous membrane that line the nose, mouth, and throat. They are divided into three groups according to their location. The pharyngeal tonsils, the palatine tonsils and the lingual tonsils. Lymphocytes and macrophages that are present in the tonsils grant protection against pathogens that may enter the body the opening of the mouth or nose.
III. Spleen:
It is similar to the lymph node’s morphology, however it is much larger and is located exclusively at one region, which is the body’s trunk. In fact, it is the largest lymphatic organ. The spleen consists of two tissue types, the white pulp and the red pulp. The white pulp is relatively related to the immune system as is contains mainly lymphocytes, while the red pulp is solely related to destroying any aged red blood cells.
IV. Thymus:
It is a gland situated behind the sternum and between the lungs. It is large and active only in childhood, and then after puberty, it starts to shrink and become replaced by fat tissues. The thymus gland secretes a hormone named Thymosin that stimulates the development of t-lymphocytes.
Figure 1.1: The anatomy of the lymphatic system.
1.1.3 History of Hodgkin Disease
Lymphoma is a malignant disease in which lymphocytes that are cells of the immune system increase in number abnormally and uncontrollably into tumors accumulating in the lymph nodes, which will lead to destruction in the lymphatic system and eventually impair the immune system (Hoffbrand and Moss, 2011) (Cancer Research UK, 2014). Lymphoma can be classified into two main categories according to their morphology under the microscope, and the presence or absence of specific cells called Reed-Sternberg cells (RS cells), which are named after the two doctors who first identified them. RS cells are noticeably larger than normal lymphocytes. If RS cells were seen then it is most likely Hodgkin’s disease, however if RS cells were not seen then it is Non-Hodgkin’s disease. Additional tests may be performed to determine the specific type of lymphoma (Lymphoma Research Foundation, 2012). Hodgkin’s lymphoma is named after Thomas Hodgkin who was the first physician to encounter the first case of Hodgkin’s lymphoma in 1832 (Hoffbrand and Moss, 2011).
Figure 1.2: Normal lymphocyte vs. Reed-Sternberg cell under the microscope
1.1.4 Types of Hodgkin Disease
There are different types of Hodgkin’s lymphoma classified by the way they appear under the microscope:
1.1.3.a Classic Hodgkin disease:
I. Nodular sclerosis Hodgkin disease.
II. Mixed cellularity Hodgkin disease.
III. Lymphocyte-rich Hodgkin disease.
IV. Lymphocyte-depleted Hodgkin disease.
1.1.3.b Nodular lymphocyte predominant Hodgkin disease.
This is crucial because each type of Hodgkin’s lymphoma may has a unique way of growth and spreading, therefore must be treated differently.
1.1.5 Stages of Hodgkin Disease
The staging system for Hodgkin disease is acknowledged as the Cotswold system. There are for stages, I, II, III and IV. If Hodgkin disease affects an organ outside the lymphatic system, the letter E is added to the stage (e.g. stage IIIE or IVE). If it includes the spleen, the letter S is added.
1.1.5.a Stage I:
• When Hodgkin disease is present only in one lymph node area or lymphoid organ (I).
• When the cancer is present in a single area only of a one organ outside the lymphatic system (IE).
1.1.5.b Stage II:
• When the disease is present in two or more lymph node areas on the same side of the diaphragm (above or below) (II).
• When the cancer spreads locally from one lymph node area into a close organ (IIE).
1.1.5.c Stage III:
• When the disease is found on both sides of lymph node areas of the diaphragm (Above and below) (III).
• When the disease is found on both sides of lymph node areas, in addition to extending to a nearby organ (IIIE), the spleen (IIIS), or both (IIIES).
1.1.5.e Stage IV:
• When it spreads widely through one or more organs outside of the lymphatic system, bearing in mind that cancer cells may or may not be present in nearby lymph nodes.
• When Hodgkin disease is found in organs in two different parts of the body and not in close lymph nodes.
• Or when it is present in the liver, bone marrow, lungs, or cerebrospinal fluid.
1.1.6 Clinical Features
Some patients might be asymptomatic, but Hodgkin Disease usually causes symptoms, which are: (American Cancer Society, 2016)
1.1.6.a Lumps under the skin: is the most common symptoms of Hodgkin disease, especially in the neck, armpit or in the groin, which is where the lymph nodes are present. Although it might not cause pain, but some studies have observed that drinking alcohol may cause pain in the area. Swelling of lymph nodes is not solely related to Hodgkin disease, as other cancers might cause enlargement in lymph nodes as well.
1.1.6.b B symptoms: which some patients who suffer from Hodgkin disease may acquire like, a recurrent fever, excessive nocturnal sweating, anorexia, itchy skin, exhaustion, loss of appetite.
Identifying these symptoms might not only be helpful in diagnosing Hodgkin disease, but also important in determining the disease’s stage and prognosis. Sometimes, exhaustion and fatigue might be the only symptoms.
1.1.6.c Cough, difficulty in breathing and chest pain: which will occur if the lymph nodes inside the chest are swollen, therefore pressing on the trachea.
1.1.7 Epidemiology (Thomas et al., 2002)
1.1.8 Risk Factors
There are several factors that have shown some evidence in increasing the susceptibly of having Hodgkin lymphoma (HL) in some people more than others (Cancer Research UK, 2014):
a. Age and sex:
Statistics have proved that HL has clear bimodal (having two peaks) age distribution, with the first in incidence rates in young adults and the second one in older men and women. It is more common in males than females, as well.
b. Epstein-Barr virus (EBV):
c. Human Immunodeficiency virus (HIV):
d. Immune system-related conditions:
I. Organ transplant:
II. Autoimmune conditions:
e. Previous cancer:
f. Family history:
g. Overweight and obesity:
h. Height:
i. Tobacco:
1.1.9 Age distribution
1.1.10 Diagnostic Methods
1.1.11 Treatment
1.1.12 Introduction to EBV
1.1.13 History of EBV
1.1.14 Molecular Biology
EBV belongs to herpesviridae family. It is a ubiquitous human gammaherpesvirus with a 184-kbp long, a single molecule of linear, double-stranded DNA genome encoding more than 85 genes, depending on the species. (Tompson and Kurzrock, 2004). EBV, like all other herpesviruses, has an icosahedral capsid surrounded by an envelope that is derived from the host’s nuclear membrane (Harvey et al, 2013).
Figure 1.3: Morphology of Herpes viruses
1.1.15 Pathogenesis of EBV
1.1.16 Clinical features of Mononucleosis Infection (Kissing Disease)
1.1.17 Epidemiology of Mononucleosis Infection
1.1.18 Burden & prevalence of EBV
1.1.19 Mode of Transmission
EBV can be transmitted easily by saliva through (National Center for Immunization and Respiratory Diseases, 2014):
a. Kissing (hence the name kissing disease).
b. Sharing drinks and food.
c. Using the same cup, eating utensils, or tooth brushes.
d. Having contact with toys that children have drooled on.
1.1.20 Diagnosis
1.1.21 Treatment
1.2 Literature Review
References:
1. Hoffbrand, A., Moss, P. and Pettit, J. (2006). Essential haematology. Malden, Mass.: Blackwell Pub.
(Hoffbrand, Moss and Pettit, 2006)
2. Anon, (2016). [online] Available at: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/hodgkin-lymphoma/risk-factors#heading-Five [Accessed 14 Mar. 2016].
(Anon, 2016)
3. Lymphoma.org. (2016). Other Non-Hodgkin Lymphomas-Lymphoma Research Foundation – Welcome. [online] Available at: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300139 [Accessed 19 Mar. 2016].
(Lymphoma.org, 2016)
4. Cornelissen, C., Fisher, B. and Harvey, R. (2013). Lippincott's illustrated reviews. Philadelphia [etc.]: Lippincott Williams & Wilkins, Wolters Kluwer.
(Cornelissen, Fisher and Harvey, 2013)
5. Training.seer.cancer.gov. (2016). SEER Training:Components of the Lymphatic System. [online] Available at: http://training.seer.cancer.gov/anatomy/lymphatic/components/ [Accessed 19 Mar. 2016].
(Training.seer.cancer.gov, 2016)
6. Cancer.org. (2016). What is Hodgkin disease?. [online] Available at: http://www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-what-is-hodgkin-disease [Accessed 19 Mar. 2016].
(Cancer.org, 2016)
7. Tompson, M. P., and Kurzrock, R. (2004) 'Epstein-Barr Virus and Cancer', American Association for Cancer Research, 10(803–821), pp. 803-804.
(Thompson, 2004)
8. Cdc.gov. (2016). Epstein-barr | Mononucleosis | About Virus | Mono | CDC. [online] Available at: http://www.cdc.gov/epstein-barr/about-ebv.html [Accessed 19 Mar. 2016].
(Cdc.gov, 2016)
9. Cancer.org. (2016). Signs and symptoms of Hodgkin disease. [online] Available at: http://www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-signs-and-symptoms [Accessed 19 Mar. 2016].
(Cancer.org, 2016)
10. Thomas, R., Re, D., Zander, T., Wolf, J. and Diehl, V. (2002). Epidemiology and etiology of Hodgkin's lymphoma. Annals of Oncology, 13(suppl 4), pp.147-152.
(Thomas et al., 2002)
11. Kharazmi, E., Fallah, M., Pukkala, E., Olsen, J., Tryggvadottir, L., Sundquist, K., Tretli, S. and Hemminki, K. (2015). Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: a joint study from five Nordic countries. Blood, 126(17), pp.1990-1995.
(Kharazmi et al., 2015)
12. Coghill, A. and Hildesheim, A. (2014). Epstein-Barr Virus Antibodies and the Risk of Associated Malignancies: Review of the Literature. American Journal of Epidemiology, 180(7), pp.687-695.
(Coghill and Hildesheim, 2014)
13. Glaser, S., Keegan, T., Clarke, C., Trinh, M., Dorfman, R., Mann, R., DiGiuseppe, J. and Ambinder, R. (2005). Exposure to childhood infections and risk of Epstein-Barr virus-defined Hodgkin's lymphoma in women. International Journal of Cancer, 115(4), pp.599-605.
(Glaser et al., 2005)
14. Levin, L., Chang, E., Ambinder, R., Lennette, E., Rubertone, M., Mann, R., Borowitz, M., Weir, E., Abbondanzo, S. and Mueller, N. (2012). Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma. Blood, 120(18), pp.3750-3755.
(Levin et al., 2012)
15. Higgins, C., Swerdlow, A., Macsween, K., Harrison, N., Williams, H., McAulay, K., Thomas, R., Reid, S., Conacher, M., Britton, K. and Crawford, D. (2007). A Study of Risk Factors for Acquisition of Epstein‐Barr Virus and Its Subtypes. The Journal of Infectious Diseases, 195(4), pp.474-482.
(Higgins et al., 2007)
16. Sughayer, M., Haddad, H., Al-Yousef, R., El-Khateeb, M. and Abu-Rass, H. (2014). Epstein–Barr virus and Hodgkin lymphoma in Jordan. Hematology/Oncology and Stem Cell Therapy, 7(2), pp.85-89.
(Sughayer et al., 2014)