Emily+Barker

Kaposi’s Sarcoma In recent years, the Guardasil vaccine has become widely available, protecting young women and men from the human papilloma virus (HPV) which can cause cervical cancer. While not as widely known, other cancers also exist that are linked the viruses. One of these is called Kaposi’s sarcoma, a cancer of the cells that line blood and lymph vessels. Kaposi’s sarcoma is caused by the human herpesvirus 8 (HHV-8). There are four subtypes of Kaposi’s sarcoma: classic, iatrogenic, AIDS-associated, and endemic (1). The classic variety affects older men of Eastern European and Mediterranean origin (2). Iatrogenic Kaposi’s sarcoma is associated with organ transplant patients (2). The human immunodeficiency virus along with HHV-8 is found in AIDS-associated Kaposi’s sarcoma (2). And endemic Kaposi’s sarcoma affects young children only in Sub-Saharan Africa (2).
 * Introduction **

In a Ugandan village, a pair of parents bring their three-year-old son into a small local hospital. Like all young boys, he spends his time tussling with other children in the village. However, recently the boy spends less time playing with friends – he tires easily and returns to their hut to rest. Also, his neck is swollen. Upon examination, the doctor finds that the young boy exhibits diffuse lymphadenopathy, or abnormal lymph nodes, in his neck, groin and armpits (1). The swollen area is non-tender, firm and mobile. The doctor asks the parents how long their son has exhibited these symptoms. They reply saying it has been a couple months. Neither parent has HIV so the doctor rules out HIV-related diagnoses. The doctor decides to treat the boy for extra pulmonary tuberculosis (1).
 * The Patient **

Fast-forward two months, and the parents see no improvement – the boy’s symptoms are worse. He no longer acts like an energetic toddler, and the swelling has increased. The boy and his parents return to the hospital where testing reveals a deficiency in red blood cells, white blood cells and platelets (1). The doctor uses a needle to remove cells from one of the swollen areas for testing (1). While waiting for results, the boy begins treatment for Burkitt’s lymphoma (1).

Another month passes, and the boy’s lesions worsen. He is visibly uncomfortable and in pain. The boy now exhibits massive 2-3 cm swollen lymph nodes in his lower jaw, neck and groin, and behind his ears, which causes shortness of breath and swelling in the legs (1, 2). A visiting dermatologist performs a biopsy, removing a superficial lymph node to determine histologically why the boy is experiencing such severe swelling and symptoms (1). The histology report shows narrow, elongated cells, leaking red blood cells, and stained, transparent, dense masses (1, Figure 1). This, along with a strong staining of the lymph nodes for human herpesvirus-8 (HHV-8), which means that HHV-8 is present, allows the doctor to diagnose the boy with Kaposi’s sarcoma (1, 3, Figure 2). The prognosis for lymphadenopathic Kaposi’s sarcoma is poor in children. And the boy has already entered the last stage, the tumor stage, of Kaposi’s sarcoma, evident by the large nodules. The boy begins treatment immediately (3).

The doctor struggled to diagnose the young boy with Kaposi’s sarcoma because most cases are associated with HIV – the cancer arises when a person has a compromised immune system as well as an infection with HHV-8 (2). This is especially true in Africa where HIV has become more common. Therefore, a case in which the patient has Kaposi’s sarcoma but does not have HIV, as did the young boy in the case study above, is rare (2). Infection of HHV-8 does not always lead to Kaposi’s sarcoma – 30-80% of children in Africa produce antibodies to HHV-8 but do not exhibit clinical symptoms of Kaposi’s sarcoma (1). Most likely, the young boy in Uganda contracted the virus while playing with his village playmates (1). Then, the boy developed cancer from some type of immunodeficiency caused by a genetic mutation or by a previous illness which would weaken the immune system (1, 2).

Kaposi’s sarcoma in children presents itself differently than in adults. In adults, skin lesions, the hallmark of Kaposi’s sarcoma, are almost always seen. However, the young boy did not have skin lesions – in children, skin lesions do not manifest – the only visible symptom of Kaposi’s sarcoma is lymphadenopathy (2). Unfortunately, lymphadenopathy is a symptom of many other childhood maladies such as tuberculosis and lymphoma so, without a histology report, it is difficult to accurately diagnose Kaposi’s sarcoma. But Kaposi’s sarcoma does look histologically distinct from the other diseases. Especially in Africa, a correct diagnosis for Kaposi sarcoma using histology can be challenging because of a lack of pathologists (1).

Because the human herpes virus 8 (HHV-8) is associated with Kaposi’s sarcoma, the development of this cancer is broken down into two steps – viral infection and integration of the viral genome into the cell and the transition from infected cell to cancerous cell. First, HHV-8 invades endothelial cells which are the cells that line the inside of blood vessels, and the virus enters a dormant, or latent, state in which it does not reproduce. Most cells with Kaposi’s sarcoma exhibit HHV-8 in the latent phase because the proteins involved with Kaposi’s sarcoma are expressed when the virus is latent (4). Two of these viral proteins are Latency-associated nuclear antigen (LANA) and vFLIP which are coded for by the viral genes, ORF-73 and K13, respectively (5). While there are many more viral proteins involved in the formation of Kaposi’s sarcoma, these are the two that will be discussed here.
 * The Tumor **

Infection with HHV-8 does not equal cancer – more than 40% of the population in parts of Africa test positive for HHV-8 infection – however, much less of the population exhibits Kaposi’s sarcoma (2). Therefore, an event must occur that allows the virus to become oncogenic. Researchers know that a cell overexpresses HHV-8’s genes in association with Kaposi’s sarcoma, but the switch from typical viral infection to oncogenesis is not well known – these same genes are also active in typical HHV-8 infection. However, the role that the viral proteins, such as LANA and vFLIP play in Kaposi’s sarcoma are known. LANA plays a role in proliferation of Kaposi’s sarcoma and angiogenesis – two basic hallmarks of cancer (5).LANA ensures the correct replication of viral DNA during cell division so that the new cells also contain virus (5). Without the virus present, cells would not be cancerous because proliferative cancer cell growth requires viral DNA. LANA also inhibits apoptosis (cell death) and checkpoint proteins, such as p53, during the growth phase of mitosis (5, figure 3). Without normal functioning p53, a cell will continue to grow and divide even if there is DNA damage and the cell should undergo apoptosis. Without proper regulation, a cell will not pause to repair damaged DNA which continues the proliferative cell growth seen in cancer cells.

LANA also plays a role in angiogenesis which the doctors detected by the leaking red blood cells seen in the histology report of the Ugandan boy (figure 1). In cancer cells, angiogenesis is the formation of new blood vessels that allows more nutrients to reach the tumor. However, the blood vessels located at the tumor site do not attain the same integrity as typical blood vessels – they are not as tight, so they allow leaking to occur. Besides serving as a marker for Kaposi’s sarcoma, leaking blood vessels lead to the fatigue exhibited by the Ugandan boy. LANA again, is a key protein in blood vessel growth – it induces the expression of a cellular protein called emmprin (5). Emmprin induces the secretion of vascular endothelial growth factor (VEGF). Cells release VEGF, causing tip cells in blood vessels to branch out and grow toward the source of VEGF, creating a new blood vessel. Emmprin also increases the production of matrix metalloproteases (MMPs) which cleave the junctions that hold the cells together (5). Without these junctions, the cancer cells move and become more invasive. While cells express LANA even in the absence of Kaposi’s sarcoma to maintain the integrity of viral DNA, in cancer, they overexpress the gene.

Cox2 is another cellular protein  overexpressed in Kaposi’s sarcoma tissue that actives MMP expression (5, figure 4). And like emmprin, it is induced by a viral protein, vFLIP (5). Cox2 also induces the expression and secretion of chemicals that cause inflammation (5). Inflammation is important in Kaposi’s sarcoma tumorigenesis because it facilitates the growth and spread of the tumor (5). While Cox2 plays a role in invasion and inflammation, the HHV-8 virus also uses it to up-regulate or increase LANA expression (5). vFLIP also works with LANA to prevent cell death by preventing cellular proteins from arresting the cell cycle when internal and external signals tell the cell not to continue dividing (5, figure 3). The viral gene vFLIP is also responsible for the narrow elongated cells that are another marker for Kaposi’s sarcoma. The presence of these cells on the Ugandan boy’s histology report aided the doctors in diagnosing his cancer (5).

While children with endemic Kaposi’s sarcoma, such as the Ugandan boy only exhibit lymphatic lesions, adults with Kaposi’s sarcoma also exhibit skin lesions. The reason for this difference is unknown. However, latent HHV-8 in blood endothelial cells cause these cells to become lymphatic endothelial cells, which accounts for the swollen lymph nodes, a symptom of Kaposi’s sarcoma.

Little research has been done on treatment for endemic Kaposi’s sarcoma in children, because the focus is on AIDs-associated Kaposi’s. Therefore, no clear standard of care exists. Another barrier to treating endemic Kaposi’s sarcoma is its prevalence in the developing world. Many parts of Africa where Kaposi’s sarcoma is found do not have access to the therapies and drugs (1). Also, systemic or widespread Kaposi’s sarcoma is incurable so treatment aims to reduce the disease and improve quality of life (6). However, with more research and knowledge of the molecular processes involved in Kaposi’s sarcoma, prospective targeted therapies may be used in the future for treatment.
 * <span style="font-family: 'Times New Roman',Times,serif;">The Treatment **

<span style="font-family: 'Times New Roman',Times,serif;">Looking at the case study from Uganda, the boy received vincristine/bleomycin chemotherapy regimen, a systemic treatment, every 21 days for 6 cycles (1, 7). Because the boy’s cancer already spread throughout his body, localized treatments for Kaposi’s sarcoma, such as removal of lesions or radiation therapy, alone would not work (8). Vincristine and bleomycin are both systemic drugs. Vincristine is injected quickly into the IV and bleomycin is administered slowly through the IV over ten minutes (7). Both drugs target cells undergoing cell division. Vincristine binds to the microtubules within a cell and prevents them from pulling apart sister chromatids during cell division (figure 5). Bleomycin binds to DNA and prevents it from replicating (10). Both of these mechanisms prevent cells, including cancer cells, from dividing. Therefore, the cancer cannot continue to grow. While this combination therapy works well, these drugs cause nausea, vomiting, hair loss, sores in the mouth and throat, and loss of appetite or weight along with over 20 other side effects (11). So, while it fulfills the goal of disease reduction, it does not greatly improve the quality of life of the patient.

<span style="font-family: 'Times New Roman',Times,serif;">Oral etoposide is another systemic drug that works just as effectively as vincristine/bleomycin, however, it significantly improves quality of life (6). Besides having less side effects, oral etoposide reduces the number of hospital visits and injections, which could make it a better option in Africa than other treatments (6). Etoposide inhibits topoisomerase, a protein within a cell responsible for preventing hypercoiling of DNA during replication (12). Without topoisomerase, DNA will break and not be replicated, and the cell will not divide. While both oral etoposide chemotherapy and vincristine/bleomycin regimen are effective in reducing Kaposi’s sarcoma and keeping the patient as comfortable as possible, they are still not ideal because they cannot eliminate the cancer which is oncology’s ultimate goal.

<span style="font-family: 'Times New Roman',Times,serif;">Therefore, researchers look to new fronts for a drug that would be more effective at curing Kaposi’s sarcoma. The newest drugs used to treat cancer are those that target the specific molecules in the cancer rather than just targeting dividing cells. For Kaposi’s sarcoma, one such molecule could be Cox2 which is known to play a role in inflammation and invasion. Cox2 is not found in typical cells so it would be optimal to target for treatment because other normal dividing cells would not be affected, like they are in systemic chemotherapy (13). Research on the use of Cox2 inhibitors in the treatment of Kaposi’s sarcoma is still in its earliest stages. While Cox2 inhibitors have been used to treat pancreatic, colon, breast, skin, and prostate cancers they have not been tested in people with Kaposi’s sarcoma (14). In 2012, the first study was conducted testing the efficacy of a Cox2 inhibitor, celecoxib, in treating Kaposi’s sarcoma //in vitro// (14). The researchers discovered that celecoxib reduces the levels of matrix metalloproteases (MMPs) (14). MMPs allow cancer cells to invade and move so eliminating them would aid in defeating the cancer (14). While the study shows promising results in the use of celecoxib, no studies have been done that explore how celecoxib actually interacts in a tumor. Therefore, it is not known if celecoxib would actually be effective in treating Kaposi's sarcoma. If it is effective, celecoxib could be used to treat systemic cases of Kaposi's sarcoma in which surgery is not an option. More studies need to be done to better understand how the mechanisms that allow celecoxib and other targeted therapies to treat Kaposi’s sarcoma work. Until then, systemic chemotherapies such as vincristine, bleomycin and oral etoposide will remain the standard of care for Kaposi’s sarcoma such as the young Ugandan boy.

<span style="font-family: 'Times New Roman',Times,serif;">Apercú: With much more to be discovered and learned about HHV-8 and Kaposi’s sarcoma, in the future the goal should include a longer life along with a higher quality of life.

<span style="font-family: 'Times New Roman',Times,serif;"> Works cited <span style="font-family: 'Times New Roman',Times,serif;">1) Arkin, L. M., Cox, C. M., Kovarik, C. L., (2009) “Kaposi’s Sarcoma in the Pediatric Population: The Critical Need for a Tissue Diagnosis” Pediatr Infect Dis J 28:426-428. ([])

<span style="font-family: 'Times New Roman',Times,serif;">2) Jackson, C. C., Dickson, M. A., Sadjadi, M., et al. (2016) “Kaposi Sarcoma of Childhood: Inborn orAcquired Immunodeficiency to Oncogenic HHV-8” Pediatr Blood Cancer 63: 392-397. ([])

<span style="font-family: 'Times New Roman',Times,serif;">3) Radu, O., Pantanowitz, L., (2013) “Kaposi Sarcoma” Archives of Pathology & Laboratory Medicine 137: 289-294 ([])

<span style="font-family: 'Times New Roman',Times,serif;">4) Purushothaman, P., Dabral, P., Gupta, N., Sarkar, R., Verma, V. C., (2016) “KSHV Replication and Maintenance” Front. Microbiol 7(54): 1-9. (http://journal.frontiersin.org/article/10.3389/fmicb.2016.00054/full)

<span style="font-family: 'Times New Roman',Times,serif;">5) Gramolelli, S., Schulz, T. F., (2014) “The role of Kaposi sarcoma-associated herpesvirus in the pathogenesis of Kaposi sarcoma” J Pathol 235: 368-380. (http://onlinelibrary.wiley.com/doi/10.1002/path.4441/abstract)

<span style="font-family: 'Times New Roman',Times,serif;">6) Chagaluka, George, et al. "Kaposi’s sarcoma in children: An open randomised trial of vincristine, oral etoposide and a combination of vincristine and bleomycin." European Journal of Cancer 50.8 (2014): 1472-1481. ([])

<span style="font-family: 'Times New Roman',Times,serif;">7) “Kaposi Sarcoma Protocal.” Baylor International Pediatric AIDS Initiative. Texas <span style="font-family: 'Times New Roman',Times,serif;">Children’s Hospital. ([])

<span style="font-family: 'Times New Roman',Times,serif;">8) Antman, Karen, and Yuan Chang. "Kaposi's sarcoma." New England Journal of Medicine 342.14 (2000): 1027-1038. (http://www.nejm.org/doi/full/10.1056/NEJM200004063421407)

<span style="font-family: 'Times New Roman',Times,serif;">9) “NCI Drug Dictionary – vincristine sulfate.” National Cancer Institute. National Institutes of Health. ([])

<span style="font-family: 'Times New Roman',Times,serif;">10) “NCI Drug Dictionary – bleomycin sulfate.” National Cancer Institute. National Institutes of Health. ([] )

<span style="font-family: 'Times New Roman',Times,serif;">11) “Vincristine Injection.” MedlinePlus. U.S. National Library of Medicine. (https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682822.html)

<span style="font-family: 'Times New Roman',Times,serif;">12)Panigrahy, Dipak, et al. "Inhibition of tumor angiogenesis by oral etoposide."Experimental and therapeutic medicine 1.5 (2010): 739-746. (https://www.spandidos-publications.com/etm/1/5/739?text=fulltext)

<span style="font-family: 'Times New Roman',Times,serif;">13)Masferrer, Jaime L., et al. “Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.” Cancer research 60.5 (2000): 1306-1311. (http://cancerres.aacrjournals.org/content/60/5/1306.full.pdf+html)

<span style="font-family: 'Times New Roman',Times,serif;">14)Sharma-Walia, N., et al. “COX-2/PGE2: molecular ambassadors of Kaposi’s sarcoma- associated herpes virus oncoprotein-v-FLIP.” Oncogenesis 1.4 (2012): e5. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412643/)