Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)

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Background

Infectious mononucleosis was first described by Sprunt and Evans in the Bulletin of the Johns Hopkins Hospital in 1920.[1] They described the clinical characteristics of Epstein-Barr virus (EBV) infectious mononucleosis. At the time, their article was entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)," because the causative organism, EBV, had yet to be described.

Since the 1800s, infectious mononucleosis has been recognized as a clinical syndrome consisting of fever, pharyngitis, and adenopathy. The term glandular fever was first used in 1889 by German physicians and was termed Drüsenfieber. The association between infectious mononucleosis and EBV was described in the late 1960s.

Pathophysiology

EBV is transmitted via intimate contact with body secretions, primarily oropharyngeal secretions. EBV infects the B cells in the oropharyngeal epithelium. The organism may also be shed from the uterine cervix, implicating the role of genital transmission in some cases. On rare occasion, EBV is spread via blood transfusion.

Circulating B cells spread the infection throughout the entire reticular endothelial system (RES), ie, liver, spleen, and peripheral lymph nodes. EBV infection of B lymphocytes results in a humoral and cellular response to the virus. The humoral immune response directed against EBV structural proteins is the basis for the test used to diagnose EBV infectious mononucleosis. However, the T-lymphocyte response is essential in the control of EBV infection; natural killer (NK) cells and predominantly CD8+ cytotoxic T cells control proliferating B lymphocytes infected with EBV.

The T-lymphocyte cellular response is critical in determining the clinical expression of EBV viral infection. A rapid and efficient T-cell response results in control of the primary EBV infection and lifelong suppression of EBV.

Ineffective T-cell response may result in excessive and uncontrolled B-cell proliferation, resulting in B-lymphocyte malignancies (eg, B-cell lymphomas).

The immune response to EBV infection is fever, which occurs because of cytokine release consequent to B-lymphocyte invasion by EBV. Lymphocytosis observed in the RES is caused by a proliferation of EBV-infected B lymphocytes. Pharyngitis observed in EBV infectious mononucleosis is caused by the proliferation of EBV-infected B lymphocytes in the lymphatic tissue of the oropharynx.

Epidemiology

Frequency

United States

EBV infectious mononucleosis is a common cause of viral pharyngitis in patients of all ages, but it is particularly frequent in young adults. In the United States, approximately 50% of the population seroconverts before age 5 years, with much of the rest seroconverting in adolescence or young adulthood. Approximately 12% of susceptible college-aged young adults convert each year, half of whom develop acute infectious mononucleosis.

International

See United States.

Mortality/Morbidity

Patients with EBV infection who present clinically with infectious mononucleosis invariably experience accompanying fatigue. Fatigue may be profound initially but usually resolves gradually in 3 months. Some patients experience prolonged fatigue and, after initial recovery, enter a state of prolonged fatigue without the features of infectious mononucleosis.

Mortality and morbidity rates due to uncomplicated primary EBV infectious mononucleosis are low. The rare cases of attributed mortality are usually related to spontaneous splenic rupture. Splenic rupture may be the initial presentation of EBV mononucleosis.

Most cases of EBV infectious mononucleosis are subclinical, and the only manifestation of EBV infection is a serological response to EBV surface proteins discovered with EBV serological tests. Airway obstruction and central nervous system (CNS) mononucleosis are also responsible for increased morbidity in infectious mononucleosis. Selective immunodeficiency to EBV, which occurs in persons with X-linked lymphoproliferative syndrome, may result in severe, prolonged, or even fatal infectious mononucleosis.

Hepatic necrosis caused by extensive EBV proliferation in the RES of the liver is the usual cause of death in affected males. EBV is the main cause of malignant B-cell lymphomas in patients receiving organ transplants.

Most instances of posttransplant lymphoproliferative disorder (PTLD) are associated with EBV. EBV in PTLD is acquired from an EBV-positive donor organ. The likelihood of PTLD is directly proportional to the degree of immunosuppressive drugs administered to the transplant patient.

Depending on the intensity, rapidity, and completeness of the T-lymphocyte response, malignancy may result if EBV-induced B-lymphocyte proliferation is uncontrolled. Hodgkin disease and non-Hodgkin lymphoma (NHL) may result. Other EBV-related malignancies include oral hairy leukoplakia in patients with HIV infection.

Leiomyomas and leiomyosarcomas in immunocompromised children, nasopharyngeal carcinoma, and Burkitt lymphoma are among other neoplasms caused by EBV.

Age

Although primarily a disease of young adults, EBV infectious mononucleosis may occur from childhood to old age.

History

Most patients with Epstein-Barr virus (EBV) infectious mononucleosis are asymptomatic and, therefore, have few if any symptoms. Most adults (approximately 90%) show serological evidence of previous EBV infection.

The incubation period of EBV infectious mononucleosis is 1-2 months. Many patients cannot recall close contact with individuals with pharyngitis. Virtually all patients with EBV infectious mononucleosis report fatigue and prolonged malaise. A sore throat is second only to fatigue and malaise as a presenting symptom.

Fever is usually present and is low grade, but chills are relatively uncommon. Arthralgias and myalgias occur but are less common than in other viral infectious diseases.

Nausea and anorexia, without vomiting, are common symptoms.

Various other symptoms have been described in patients with EBV infectious mononucleosis, including cough, ocular muscle pain, chest pain, and photophobia.

Importantly, patients without CNS involvement experience no cognitive difficulties. CMV infectious mononucleosis rarely involves the CNS.

Myalgias, which are uncommon, are rarely (if ever) severe.

Physical

See the list below:

Table 1. Differential Diagnoses of Infectious Mononucleosis



View Table

See Table

Causes

The only predisposing risk factor for EBV infectious mononucleosis is close contact with an individual infected with EBV.

EBV commonly persists in oropharyngeal secretions for months after clinical resolution of EBV infectious mononucleosis.

Patients with congenital immunodeficiencies are predisposed to EBV-induced lymphoproliferative disorders and malignancies.

Acquired immunodeficiencies due to the effects of immunosuppression (eg, PLDT) or infectious disease-induced immunosuppression (ie, HIV) may predispose to oral hairy leukoplakia or non-Hodgkin lymphoma.

Burkitt lymphoma has a distribution (ie, in Africa) that is the same as the distribution of malaria. The geographic location predisposes to Burkitt lymphoma in children.

Laboratory Studies

Epstein-Barr virus (EBV) infection induces specific antibodies to EBV and various unrelated non-EBV heterophile antibodies. These heterophile antibodies react to antigens from animal RBCs.

Heterophile test antibodies are sensitive and specific for EBV heterophile antibodies, they are present in peak levels 2-6 weeks after primary EBV infection, and they may remain positive in low levels for up to a year.

The latex agglutination assay, which is the basis of the Monospot test using horse RBCs, is highly specific. Sensitivity is 85%, and specificity is 100%.

The heterophile antibody test (eg, the Monospot test) results may be negative early in the course of EBV infectious mononucleosis. Positivity increases during the first 6 weeks of the illness. Patients who remain heterophile negative after 6 weeks with a mononucleosis illness should be considered as having heterophile-negative infectious mononucleosis.

Testing for EBV-specific antibodies is as follows:

Other antigens indicating EBV infection are less useful diagnostically and include early antigen (EA), which is present early in EBV infectious mononucleosis. EBV nuclear antigen (EBNA) appears after 1-2 months and persists throughout life. The presence of elevated EBNA titers has the same significance as elevated IgG VCA titers. The presence of these antibodies suggests previous exposure to the antigen (past infection) and excludes EBV infection acquired in the previous year.

As with heterophile antibody responses, specific EBV antibodies may not be present in children younger than 2 years.

Nonspecific tests are as follows:

Specific tests are as follows:

Table 2. EBV Serologic Responses in EBV-Associated Diseases



View Table

See Table

 

Other tests are as follows:

Imaging Studies

Patients with presumed CNS involvement with EBV infectious mononucleosis should undergo a CT scan and/or MRI to rule out other causes of encephalitis.

Other Tests

Patients with presumed CNS involvement with EBV infectious mononucleosis should also undergo an EEG to rule out other causes of encephalitis.

Procedures

Rarely, if ever, is a bone marrow biopsy or lymph node biopsy needed in patients with EBV infectious mononucleosis. In the diagnosis of EBV infectious mononucleosis, the assessment of lymph node enlargement can be made confidently based on specific EBV antibody testing, and surgery is almost never necessary.

Patients with presumed CNS involvement with EBV infectious mononucleosis should also undergo a lumbar puncture to rule out other causes of encephalitis.

Histologic Findings

Oropharyngeal epithelium demonstrates an intense lymphoproliferative response in the cells of the oropharynx. The lymph node and spleen show lymphocytic infiltration primarily in the periphery of a lymph node.

Medical Care

Closely monitor patients with extreme tonsillar enlargement for airway obstruction. Steroids are indicated for impending or established airway obstruction in individuals with Epstein-Barr virus (EBV) infectious mononucleosis.

Surgical Care

Surgery is necessary for spontaneous splenic rupture, which occurs in rare patients with EBV infectious mononucleosis and may be the initial manifestation of the condition.

Consultations

Consult an infectious disease specialist in all but the most straightforward cases of EBV infectious mononucleosis.

Consulting a hematologist may be necessary if unusual hematologic manifestations of EBV infectious mononucleosis are present (eg, in anemia to determine the cause of the patient's anemia).

Consulting a neurologist is advised for patients with potential CNS involvement.

Consultation with a cardiologist is advised for the rare patients with EBV infectious mononucleosis who have presumed myocarditis.

Consult a gastroenterologist for patients with EBV-induced acalculous cholecystitis or if anicteric hepatitis is in the differential diagnoses.

Diet

Normal diet is appropriate.

Activity

Patients with acute EBV mononucleosis should be encouraged to rest as much as possible and to refrain from active physical activity for 3 weeks.

Medication Summary

No effective antiviral therapy is available for Epstein-Barr virus (EBV) infectious mononucleosis in immunocompetent persons. Acyclovir and ganciclovir may reduce EBV shedding but are ineffective clinically.

Treatment of immunocompromised patients with EBV lymphoproliferative disease is controversial. Acyclovir has not been proven to be beneficial.

Short courses of corticosteroids are indicated for EBV infectious mononucleosis with hemolytic anemia, thrombocytopenia, CNS involvement, or extreme tonsillar enlargement. However, corticosteroids are not indicated for uncomplicated EBV infectious mononucleosis. Corticosteroids should be considered in those with impending airway obstruction.

Patients with EBV infectious mononucleosis who have positive throat cultures for group A streptococci should not be treated because this represents colonization rather than infection (see Workup).

Treatment of group A streptococcal oropharyngeal colonization in patients with EBV infectious mononucleosis may result in a maculopapular rash.

Further Outpatient Care

Monitor patients to be sure that the infection is improving over time. Serial CBC counts should document the increase in lymphocytes as well as atypical lymphocytes, and this may be monitored on a weekly basis until these values normalize.

Patients with positive heterophile tests should not be monitored with serial testing because the heterophile test may remain positive for as much as 1 year after infection.

Serial specific Epstein-Barr virus (EBV) antibody testing is usually not necessary in patients with acute infection. Caution patients that increased IgG, VCA, and EBNA levels persist for life. Also, inform patients that titers vary and that IgG titers have no relationship to disease activity or to how the patient feels.

Patients should be advised that fatigue may take some time to resolve, and some patients may develop a state of chronic fatigue that is induced, but not caused by, EBV infectious mononucleosis.

Further Inpatient Care

Patients with extreme tonsillar enlargement may require extended care if intubation is required.

Deterrence/Prevention

Avoid close contact with body fluid secretions, particularly saliva.

Complications

Extreme enlargement of the tonsils may result in airway obstruction (see Medical Care).

Encephalitis and myocarditis are rare complications.

Splenic rupture is a rare, but potentially lethal, complication of EBV infectious mononucleosis.

Rare patients with EBV infectious mononucleosis develop lymphoma.

Prognosis

If splenic rupture is recognized and expeditiously treated surgically, the prognosis is good.

Patients with EBV infectious mononucleosis who become asplenic as the result of splenic rupture and/or surgical removal should be treated as other patients with asplenia.

Patient Education

Counsel patients to refrain from strenuous physical activity for the first 3 weeks of illness.

Patients should avoid exposing other people to their body secretions because EBV remains viable in patients with EBV infectious mononucleosis for months after the initial infection.

For excellent patient education resources, visit eMedicineHealth's Bacterial and Viral Infections Center and Back, Ribs, Neck, and Head Center. Also, see eMedicineHealth's patient education articles Mononucleosis and Chronic Fatigue Syndrome.

When was Epstein-Barr virus (EBV) infectious mononucleosis (mono) first described and how was it characterized?How is Epstein-Barr virus (EBV) transmitted (the virus that causes infectious mononucleosis [mono])?What is the pathophysiology of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What is the role of the T-lymphocyte cellular response in determining the clinical expression of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How does the physiologic response to the Epstein-Barr virus (EBV) cause the symptoms of infectious mononucleosis (mono)?How common is Epstein-Barr virus (EBV) infectious mononucleosis (mono) in the US?How is fatigue characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What are the mortality and morbidity rates of Epstein-Barr virus (EBV) infectious mononucleosis (mono), and which characteristics or complications of the virus are associated with severe illness or death?How is posttransplant lymphoproliferative disorder (PTLD) acquired from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?When can Epstein-Barr virus (EBV) infectious mononucleosis (mono) result in malignancy, and which malignant conditions are associated with EBV?What are some of the neoplasms caused by Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What are the age-related demographics of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Do all people with Epstein-Barr virus (EBV) infectious mononucleosis (mono) have symptoms?What is the incubation period of Epstein-Barr virus (EBV) infectious mononucleosis (mono) and what are the common presenting symptoms?Which symptoms are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which physical findings are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What is the predisposing risk factor associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Where in the body does Epstein-Barr virus (EBV) persist in infectious mononucleosis (mono)?Which comorbidities are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono) in patients with congenital immunodeficiencies?Which comorbidities are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono) in patients with acquired immunodeficiencies?Which geographic location is predisposed to Burkitt lymphoma in children with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is fever in Epstein-Barr virus (EBV) infectious mononucleosis (mono) distinguished from fever associated with other conditions?What is the presentation of pharyngitis in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which conditions in addition to Epstein-Barr virus (EBV) infectious mononucleosis (mono) are associated with palatal petechiae?What does uvular edema indicate in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is posterior oropharynx characterized in patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) and how does it compare with the findings in chronic fatigue syndrome (CFS)?How is heterophile-negative infectious mononucleosis (mono) differentiated from Epstein-Barr virus (EBV) mono?How is lymphadenopathy distinguished from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which signs and symptoms differentiate rubella from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is acquired toxoplasmosis distinguished from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is HHV-6 infection distinguished from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What is the presentation of Epstein-Barr virus (EBV) infectious mononucleosis (mono) in patients with HIV infection?How is anicteric hepatitis differentiated from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which signs and symptoms are findings in both cytomegalovirus (CMV) mononucleosis (mono) and Epstein-Barr virus (EBV) infectious mono and how are they distinguished?How is drug-induced pseudolymphoma differentiated from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is anicteric hepatitis differentiated from Epstein-Barr virus (EBV) infectious mononucleosis (mono) in elderly patients?How is splenomegaly characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono) and how is it differentiated from other conditions that also present with splenomegaly?How is a finding of leukocytosis used to confirm or exclude Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is lymphocytosis characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is thrombocytopenia characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How are serum transaminases characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono), and which mononucleosislike illnesses may be indicated by other findings?How is the erythrocyte sedimentation rate (ESR) measurement used in the diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What does a maculopapular rash contribute to the clinical picture in the diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is the rash associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono) characterized?How is the rash of rubella differentiated from the rash that occurs with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is the external eye involvement of Epstein-Barr virus (EBV) infectious mononucleosis (mono) characterized, and what other findings of the periorbital area suggest a different diagnosis?How common is splenic rupture in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What are the diagnostic considerations for meningoencephalitis in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What is the role of fatigue in the diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is fatigue characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono) and what does chronic fatigue suggest?How common is chronic infectious mononucleosis (mono) and how is it differentiated from chronic fatigue syndrome (CFS)?Which antibodies does an Epstein-Barr virus (EBV) mononucleosis (mono) infection induce?What is the sensitivity and specificity of the heterophile antibody test in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What is the sensitivity and specificity of the latex agglutination assay in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is the heterophile antibody test used to differentiate heterophile-negative infectious mononucleosis (mono) and Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is testing for Epstein-Barr virus (EBV)-specific antibodies used in the workup of infectious mononucleosis (mono)?Which nonspecific tests are included in the workup for Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which lab studies are specific for Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which other tests may be indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?When are imaging studies indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?When is an EEG indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?When is a bone marrow or lymph node biopsy indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?When is a lumbar puncture indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What do histologic findings demonstrate in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How are patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) monitored and when are steroids used for treatment?When is surgery indicated in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Which consultations may be necessary in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What type of diet is appropriate in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What level of activity is encouraged in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Is antiviral therapy available in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?Is antiviral therapy available for immunocompromised patients with Epstein-Barr virus (EBV) lymphoproliferative disease?When are corticosteroids indicated in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How is group A streptococcal (GAS) infection treated in patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How are patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) monitored?What do patients need to know about fatigue and how Epstein-Barr virus (EBV) infectious mononucleosis (mono) titers?What does extreme tonsillar enlargement indicate in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?How can patients avoid contracting Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What are complications associated with infectious mononucleosis (mono)?What is the prognosis of splenic rupture in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?What do patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) need to know about physical activity restrictions?How can patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) prevent spreading the disease to others?What patient education resources are available for Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Author

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Charles S Levy, MD, Associate Professor, Department of Medicine, Section of Infectious Disease, George Washington University School of Medicine

Disclosure: Nothing to disclose.

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Clinical Parameters Epstein-Barr Virus Cyto-megalovirus Toxoplasmosis Viral Hepatitis
SymptomsFatigue+++++/-+
Malaise+++-+
Mild sore throat+++/-+/-
Early maculopapular rash±--+/-
SignsEarly bilateral upper eyelid edema±---
Unilateral localized adenopathy--+-
Bilateral posterior cervical adenopathy++-+/-
Tender hepatomegaly+/-+/--+
Splenomegaly++/-+/--
Laboratory abnormalitiesWBC countN*/-N/-N¯
Elevated SGOT/SGPT++++/-+++
Atypical lymphocytes (≥ 10%)++--
Thrombocytopenia+/-+/--+/-
Elevated IgM§ CMV titer-+--
Elevated IgM EBV VCAII titer+---
Elevated IgM toxoplasmosis titer--+-
Positive hepatitis (eg, A, B, D) test---+
*Normal



Serum glutamic-oxaloacetic transaminase



Serum glutamic-pyruvic transaminase



§ Immunoglobulin M



II Viral capsid antigen



EBV Diseases EBV Antibody Responses
Anti-VCA Anti-EA
IgM



Monospot/



Heterophile



IgM IgG Diffuse EA Restricted EA Anti-EBNA
Acute EBV mononucleosis++++--
Past EBV infection--+--+
Chronic active EBV infection--++++++
Burkitt lymphoma--++++/-++
Nasopharyngeal carcinoma--+++++/-+