1. The African form of Burkitt Lymphoma
2.  B-cell lymphomas in immunosuppressed individuals
3.  A subset of Hodgkin lymphoma 
4. Some rare T and NK cell lymphomas
5. nasopharyngeal, and some gastric carcinomas.

1. Which of the EBV tumors are/are not B-Cell tumors?
2. To which family does EBV belong?
3. To which cells does EBV adhere and how?

1. All are B-cell except for the nasopharyngeal.
2. Herpesvirus
3. Infects B cells and epithelial cells (less commonly) of the oropharynx. It binds to the CD21 (Complement R') of B cells. The infection is latent, and it immortalizes the B cells.

1. Latent Membrane Protein 1 (LMP-1) is encoded by EBV and expressed on the surface of B cells. It acts like a constitutively-activated CD40 and activates NF-κB and JAK/STAT, both of which promote survival and proliferation. LMP-1 also activates BCL2, which is antiapoptotic.
2. EBNA-2 is a nuclear protein that acts as a constitutively-activated Notch R'→ activates cyclin D (cell cycle) and Src family. 
3. vIL-10 (a viral cytokine that was taken at one point from a host genome) will prevent Macrophages and monocytes from activating T cells and is important for B cell transformation.

1. What is the effect of EBV on a non-immunosuppressed individual?
2. What is the epidemiology of Burkitt Lymphoma?
3. Is EBV endemic only to Africa?

1. The polyclonal B cell proliferation is controlled, and the patient is either asymptomatic or has infectious mononucleosis
2. Common to children of Africa and New Guinea.
3. EBV infects almost all humans, but is only present in 15-20% of lymphomas outside of Africa.

1. What is the difference between EBV-transformed B cell (non-tumorigenic) and Burkitt lymphoma cells?
2. Why does this occur?

1. The EBV transformed cells express LMP-1 and EBNA-2, while Burkitt Lymphoma cells do not. 80% of Burkitt Lymphoma cells do not have any of the EBV Genome in them, but they all have t(8;14)
2. Those infected B cell which express LMP-1 and EBNA-2 will be selected against by CTLs. This will select for infected cells which do not express many of these antigens, but the infection will still promote t(8;14).  

1. Why is Burkitt Lymphoma most common in Africa?
2. Is EBV oncogenic?

1. Diseases such as malaria (and AIDS) will suppress the immune system enough to allow EBV-infected B cells to proliferate. 
2. Not directly. It is mitogenic, allowing for more mutations to occur.

1. What is unique about the tumors caused by EBV in patients who are immunosuppressed?
2. What is the epidemiology of Nasopharyngeal Carcinoma?
3. What is unique about these tumors?
4. What is the pathogenesis of Nasopharyngeal Carcinoma?

1. They will express the LMP-1 and EBNA-2. This is because there is no selection from T cells.
2. Common to southern China, Africa and the Inuit population.
3. 100% contain the EBV genome.
4. When EBV infects the epithelial cells of the nasopharynx, these cells will express LMP-1→activates NF-kB and pro-angiogenic factors like VEGF, FGF-2, MMP9 and COX2

Look to fig 13-15 for morphology of Burkitt Lymphoma

1. What is the Immunophenotype of Burkitt Lymphoma cells?
2. What don't these cells express?

1. IgM, CD19, CD20, CD10 and BCL6 (this is the same as a B cell in the germinal center)
2. BCL2 (you will see many apoptotic bodies)

1. What is the difference in the breakpoints in the IgH regions of Sporadic and Endemic Burkitt?
2. What enzyme induces the translocation?
3. What other mutations are commonly found in Burkitt?

1. The sporadic breakpoints are in the class-switch regions, while in endemic, they are in the 5' V(D)J region.
2. AID
3. There is often a point mutation in c-Myc that increases its activity, and a mutation in p53 that decreases its activity.

Both occur at extranodal regions.

Endemic will often present as a mass involving the mandible and occasionally the viscera (kidneys, ovaries and adrenal glands)

Sporadic is often a mass in the ileocecum and the peritoneum.

1. What is HTLV-1?
2. What does it cause?
3. What cells are affected?
4. What is the epidemiology of this disease?

1. Human T-cell Leukemia Retrovirus type 1
2. Adult T-Cell Leukemia/lymphoma
3. CD4+ T Cells
4. Endemic to Japan, West Africa and the Caribbean basin. 

1. What are the clinical features of adult T-Cell leukemia/lymphoma?
2. What is a common histological feature of the tumor cells?
3. What is the oncogenic gene for HTLV-1?

1. Skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis and hypercalcemia.
2. Multiloculated nuclei give a "Cloverleaf" or "Flower" apearance.
3. Tax is an activator of NF-kB, and it is encoded in the provirus (found in tumor cells).

1. What is the prognosis for Adult T-Cell Leukemia/lymphoma?
2. What is another disease of HTLV-1?

1. Most cases are fatal within months to a year despite aggressive chemo. Patients with HTLV-1 can also present with an indolent, skin-specific tumor
2. Sometimes it will cause a progressive demyelinating disease of the CNS and spinal cord.

1. What virus causes Extranodal NK/T-cell Lymphomas?
2. Where are these tumors found?
3. How do we know the tumors are of NK-Cell origin?
4. What histological finding indicates this virus infected the cells?

1. EBV
2. Commonly in the nasopharynx, and less commonly in the testis or on the skin.
3. The tumor cells are CD3-, have no CD21 and the tumor cells show azuorphilic granules similar to those of NK Cells. Also, the cells show NK-like Ig R's.
4. EBV episomes can be seen in all of the tumor cells (means the tumor came from one infected cell)

1. What is the treatment for Extranodal NK/T-Cell Lymphoma?

1. Responds well to radiation, but not well to chemotherapy. This means the prognosis is poor for patients with advanced disease.

What are the 5 subtypes of Hodgkin Lymphoma?

Which are infected with EBV?

Nodular Sclerosis

Mixed Cellularity

Lymphocyte Rich

Lymphocyte Depletion

Lymphocyte predominance 

Mixed Cellularity, Lymphocyte depletion and Lymphocyte Rich

Reed-Sternberg Cells

70% are infected in Mixed Cellularity

40% in Lymphocyte Rich

90% in Lymphocyte Depletion

1. Which form of HL typically presents in HIV patients?
2. What are some common molecular markers for Reed-Sternberg cells infected with EBV?

1. Lymphocyte Depletion. This is also common in the elderly.
2. CD15+, CD30+