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REVIEW ARTICLE
Year : 2011  |  Volume : 5  |  Issue : 2  |  Page : 38-41

Epstein-Barr virus and associated head and neck manifestations


1 Department of Oral Pathology, Eklavya Dental College and Hospital, Kotputli, Rajasthan, India
2 Department of Prosthodontics and Implantology, Eklavya Dental College and Hospital, Kotputli, Rajasthan, India
3 Department of Oral Pathology, Government Dental College and Hospital, Srinagar, Jammu and Kashmir, India

Date of Web Publication17-Feb-2012

Correspondence Address:
Nitul Jain
Department of Oral Pathology, Eklavya Dental College and Hospital, Kotputli - 303 108, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0331-3131.92947

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   Abstract 

The Epstein-Barr virus (EBV), also called human herpes virus 4, is a virus of the herpes family, having linear double-stranded DNA as its genome. It is best known as the cause of infectious mononucleosis. Besides this, EBV is also associated with particular forms of malignancy, particularly Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma, all of which may show their prime manifestations in head and neck area, for which patient may seek a dentist referral initially. In addition, EBV is linked with oral hairy leukoplakia, which may be an earliest oral manifestation of HIV infection. This review article primarily deals with clinical manifestations of diseases associated with EBV infection particularly in head and neck area.

Keywords: Burkitt′s lymphoma, Epstein-Barr virus, Hodgkin′s disease, infectious mononucleosis, nasopharyngeal carcinoma, oral hairy leukoplakia


How to cite this article:
Jain N, Bhatia V, Lattoo S. Epstein-Barr virus and associated head and neck manifestations. Ann Nigerian Med 2011;5:38-41

How to cite this URL:
Jain N, Bhatia V, Lattoo S. Epstein-Barr virus and associated head and neck manifestations. Ann Nigerian Med [serial online] 2011 [cited 2019 Jan 20];5:38-41. Available from: http://www.anmjournal.com/text.asp?2011/5/2/38/92947


   Introduction Top


Epstein-Barr virus (EBV) is named after M. Anthony Epstein and Yvonne Barr, who discovered and documented the virus. The EBV, is also called human herpes virus 4 (HHV-4), is a virus of the herpes family. The virus consists of a linear double-stranded DNA core surrounded by a nucleocapsid and an envelope that contains glycoproteins. In addition, EBV has been defined as a category I human tumor virus by UICC (International Agency for Research on Cancer) in 1997. [1]

Most people become infected with EBV and gain adaptive immunity. Approximately 95% of the world's population sustains an asymptomatic life-long EBV infection. EBV persists in the memory B-cell pool of normal healthy individuals and any disruption of this interaction results in virus-associated B-cell tumors. [2] Infants become susceptible to EBV as soon as maternal antibody protection disappears. Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. When infection with EBV occurs during adolescence or teenage years, it causes infectious mononucleosis (IM) 35% to 69% of the time. [3],[4] For this reason, EBV is best known for as the cause of IM. It is also associated with oral hairy leukoplakia (OHL) and some particular forms of malignancy, especially Hodgkin's lymphoma, Burkitt's lymphoma (BL), nasopharyngeal carcinoma (NPC), and central nervous system lymphomas associated with HIV. [5],[6] Coincidentally many of the above mentioned diseases show their initial signs and symptoms particularly in head and neck area. Besides these, some investigators also have the evidence that infection with the virus is associated with a higher risk of certain autoimmune diseases, especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis. [5],[7]


   Infectious Mononucleosis Top


Infectious mononucleosis (IM) (also known as EBV IM or glandular fever or Pfeiffer's disease or Filatov's disease and sometimes colloquially as the kissing disease from its oral transmission or simply as mono in North America and as glandular fever in other countries) is an infectious, widespread viral disease caused by the EBV.

IM is an acute, self-limiting, non-neoplastic lymphoreticular proliferative disorder. [3] Although not classically defined as a sexually transmitted disease (STD), IM transmission occurs through intimate personal contact. IM is an infection that is caused, in at least 90% of cases, by the EBV. A similar condition can be caused by cytomegalovirus, but that one gives a negative on heterophile antibody test. [4],[5],[8]

EBV infections occur worldwide. These infections are most common in early childhood, with a second peak during late adolescence. By adulthood, more than 90% of individuals have been infected and have antibodies to the virus. Most EBV infections in infants and young children are either asymptomatic or present as mild pharyngitis with or without tonsillitis. In contrast, up to 75% of infections in adolescents present as IM. [9] The incubation period for IM in young adults is 4-6 weeks. The diseases produce the classic clinical triad of fever, pharyngitis, and lymphadenopathy. A prodrome of fatigue, malaise, and myalgia may last for 1-2 weeks before the onset of fever, sore throat, and lymphadenopathy. [10] Fever in IM is generally considered to be rather high (38-39°C) and lasts 1-2 weeks; however, it may persist for more than 1 month. [9]

Lymphadenopathy and pharyngitis are most prominent during the first 2 weeks of the illness, while splenomegaly is more prominent during the second and third weeks. A morbilliform or papular rash, usually on the arms or trunk, develops in 5% of cases. [8] After the acute infection, the virus remains latent in B lymphocytes for the life of the host.

The diagnosis is made on the basis of symptoms and a laboratory profile characterized by peripheral lymphocytosis (e.g., 50% lymphocytes [primarily T lymphocytes]) and at least 10% atypical lymphocytes, along with a positive heterophile (Monospot) antibody test. [3],[4],[8]

In normal blood smears, large reactive lymphocytes represent about 1-2% of cells. In IM, they constitute 10-40% of circulating white blood cells. [3] Reactive lymphocytes are not EBV-infected B lymphocytes but are T lymphocytes that react to the infection. Heterophile antibodies are immunoglobulin (Ig) M antibodies that bind (agglutinate) to erythrocytes from non-human species such as sheep and horses. This process forms the basis for the Monospot rapid latex agglutination test. Symptomatic patients who have a negative heterophile antibody test should be retested in 7-10 days because this test can be insensitive during the first week. If the second test is negative, tests for viral capsid antigen (VCA)-IgG and VCA-IgM antibody and EBV nuclear antigen (EBNA) should be performed. [3],[8]

Most cases of IM are self-limited. As such, treatment of patients with IM remains symptomatic. The lack of efficacy of antiviral drugs results from the fact that mononucleosis is largely due to the immune response. Deaths are very rare and most often are due to central nervous system complications, splenic rupture, upper airway obstruction, or bacterial super-infection. Acute EBV infection has also been associated with cranial nerve palsies (especially those involving cranial nerve VII), Guillain-Barré syndrome, acute transverse myelitis, and peripheral neuritis. [8],[9]


   Oral Hairy Leukoplakia Top


Oral hairy leukoplakia (OHL) presents as vertical folded, hyperkeratotic white patches seen most commonly on lateral surfaces of the tongue, which can not be wiped off. It is associated with the presence of EBV particles in patients with chronic immunosuppression such as those having HIV infection. OHL may be seen in all phases of HIV infection, but most commonly seen in individuals with CD4 counts below 200 cells/ mm 3 . [11] In addition, it has been reported in patients who receive organ and bone marrow transplantation. Evidences of any premalignant potential or epithelial dysplasia has not been reported in OHL. Although OHL does not have malignant potential and does not require therapy, it is important to diagnose suspicious lesions accurately because it is an indicator of immunodeficiency EBV can infect oral epithelial cells, but it is not found in oral cancers. It is also important to note that presence of OHL has not been associated with person to person transmission of EBV as it is for IM. Because of its clinical appearance, differential diagnosis must include chronic hyperplastic candidiasis. However, to establish a definitive diagnosis of OHL, it is mandatory to verify presence of EBV in superficial layers of epithelium in the vacuolated cells often referred to as koilocytes (cells suggestive of viral infection). [12],[13],[14]


   Nasopharyngeal Carcinoma Top


The World Health Organization defines Nasopharyngeal carcinoma (NPC) as "A carcinoma arising in the nasopharyngeal mucosa that shows light microscopic or ultra-structural evidence of squamous differentiation."

NPC is uncommon in the United States and in most other nations but is extremely common in southern regions of China, particularly in Guangdong accounting for 18% of all cancers in China. [15] It is sometimes referred to as Cantonese cancer because it occurs in about 25 cases per 100,000 people in this region, 25 times higher than the rest of the world. Although rare in Caucasian populations, NPC has endemic clusters in Alaskan Eskimos, Indians, and Aleuts.

There are three microscopic subtypes of NPC: a well-differentiated keratinizing type, a moderately differentiated nonkeratinizing type, and an undifferentiated type, which typically contains large numbers of non-neoplastic lymphocytes (chronic inflammatory cells), thus giving rise to the name lymphoepithelioma. The undifferentiated form is most common and is most strongly associated with EBV infection of the cancerous cells. [16],[17],[18],[19],[20]

NPC is primarily a tumor of adults with a peak occurrence between 40 and 60 years, although the tumor can occur in children. There is a strong male predominance of about three times, irrespective of geographic location. Most tumors arise on the lateral wall of the nasopharynx, especially common in the fossa of Rosenmuller. Most tumors are exophytic (about 75%), with a few described as ulcerated (about 10%). Cervical lymph node metastasis is also common. Most patients present with an asymptomatic cervical lymphoadenopathy (typically in the apex of the posterior cervical triangle or in the superior jugular chain of nodes), serous otitis media, epistaxis, or nasal obstruction. A blood-tinged postnasal drip is also seen. [16],[17],[18]

In situ hybridization or polymerase chain reaction (PCR) is generally needed to document the EBV. The EBV encoded early RNA (EBER) is the most sensitive and specific analysis available at present. Inactivation of the p16 tumor suppressor gene on 9p21 by homozygous deletion and methylation has been shown to be the most common molecular alteration in NPC tumorigenesis. Treatment requires radiation therapy and is increasingly combined with chemotherapy. [1]


   Burkitt's Lymphoma Top


Burkitt's lymphoma (BL) is an unusual type of non-Hodgkin's lymphoma occurring endemically in the narrow zone across central Africa, where malaria is endemic. [21],[22] This tumor was named after Denis Burkitt who first described cases of rapidly growing jaw and abdominal tumors late back in 1956. BL is the human cancer most closely linked with a virus known as EBV. The disease was first thought to be limited to African children, but subsequently it was reported in other parts of the world as well. [5],[6]

As of a study published in 2009, comprising 5-year retrospective review of pediatric solid tumors as seen at the Jos University Teaching Hospital, Nigeria, non-hodgkin's lymphoma and BL accounted for 17 (19.5%) and 12 (13.8%), respectively, of a total of 181 solid tumors of children. [23]

In an another study that analyzed the profile of cancers recorded in the first decade (1995-2004) of establishment of the Kano cancer registry (KCR), a histology/cytology-based registry in Kano, Nigeria, BL (31.4%), other lymphoreticular cancers (23.8%) and retinoblastoma (20%) predominated in children of a total of 1990 cancer cases. [24]

EBV is associated with 90% of African patients with BL, but this incidence is significantly lower for BL seen in other parts of the world. In addition, high levels of antibodies to EBV are found in all African children with BL, but in only half of normal African children. [14] The reason for this association remains largely unknown. The virus may be a prime etiologic agent, a cocarcinogen, or just an innocent passenger. But it has been suggested that malaria infection in Africa may impair cellular immunity to EBV and induce polyclonal B-cell activation with an expansion of EBV-infected B cells. [9] These changes may enhance the proliferation of B cells, increasing the likelihood of a c-myc translocation-the hallmark of BL. This gene is found at 8q24. [21],[22],[25],[26],[27],[28]

The African form of BL manifests as rapidly growing extranodal jaw tumor in young children, but it also may be first detected as abdominal mass involving kidneys or ovaries. The tumor expands rapidly and may double in size every 1-3 days, making it the fastest growing human tumor. The primary tumor cell has been shown to be a poorly differentiated B lymphocyte.

The diagnosis is based on characteristic microscopic pattern of small noncleaved B-cell lymphoid proliferation in a "Starry Sky" pattern. The treatment consists of combination of chemotherapy and radiotherapy. [21],[22],[25],[26]


   Hodgkin's Disease Top


Hodgkin's disease (HD) is a lymphoma, with a characteristic bimodal age incidence. In about 60-80% of cases, HD appears to start in regional lymph nodes of head and neck region, giving the first signs of cervical lymphadenopathy with associated symptoms including fever, unexplained weight loss, excessive sweating pruritus, and fatigue. [2],[5],[6],[29],[30],[31] The diagnosis of HD is based on the histologic presence of multinucleated Reed-Sternberg giant cells. EBV has been associated with HD, especially the mixed cellularity type. [30] EBV antigens can be detected in tumors in up to 40% of all HL cases Patients with HD often have elevated titers of antibody to EBV. In about half of cases, viral DNA and antigens are found in  Reed-Sternberg cells More Details. The risk of EBV-positive HD is significantly increased in young adults after EBV-seropositive IM. [30],[31],[32] About 50% of non-Hodgkin's lymphomas in patients with AIDS are EBV-positive. The treatment of disease consists of either chemotherapy or radiotherapy or a combination of both with the selection primarily dependent on staging of the disease.


   Summary Top


EBV is famous as the etiologic agent of acute IM but is also closely associated with the genesis of OHL, undifferentiated NPC, BL and HD. The relation of the virus to the malignancies varies from primary etiologic agent to necessary or contributory cofactor. The EBV-associated malignancies offer insights into the causation and early detection of cancer. Many of these diseases involve head and neck area, so the dentist and ENT surgeons should well know their clinical manifestations to make accurate diagnosis at the first stage.

 
   References Top

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9.Cohen JI. Epstein-Barr Virus-Infections, Including Infectious Mononucleosis. In: Fauci, Braunwald, Kasper, Hauser, Longo, Jameson, Loscalzo, editors. Harrison's Principles of Internal Medicine. 17 th ed. US: Mc Graw Hill Med. Pub; 2008. p. 1106-08.  Back to cited text no. 9
    
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14.Silverman SJ, Schubert MM. Leukemia and Lymphoma. In: Silverman SJ, editor. Oral Cancer. 4 th ed. Hamilton, Ontario: B. C. Decker Inc; 1998. p. 141  Back to cited text no. 14
    
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22.Chene A, Donati D, Orem J, Mbidde ER, Kironde F, Wahlgren M, et al. Endemic Burkitt's lymphoma as a polymicrobial disease: New insights on the interaction between Plasmodium falciparum and Epstein-Barr virus. Semin Cancer Biol 2009;19:411-20.  Back to cited text no. 22
    
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31.Depil S, Moralès O, Auriault C. Hodgkin's disease and Epstein-Barr virus. Ann Biol Clin (Paris) 2004;62:639-48.  Back to cited text no. 31
    
32.Adelusola KA, Titiloye NA, Rotimi O, Durosinmi M. Epstein Barr virus latent membrane protein-1 in Hodgkin's lymphoma in Nigerians. Afr Health Sci 2009;9:174-8.  Back to cited text no. 32
    




 

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  In this article
    Abstract
   Introduction
    Infectious Monon...
    Oral Hairy Leuko...
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   Burkitt's Lymphoma
   Hodgkin's Disease
   Summary
    References

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