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A Closer Look at HPV and Ovarian Cancer

While HPV-driven cervical cancer is a sure fact, its link with ovarian cancer is still unclear. This article explores the studies done on the subject, and established if there really is a link between HPV and ovarian squamous cell carcinomas.

If you are a woman and you're sexually active, then you've probably heard of the human papillomavirus or HPV. At the very least, you should know about HPV. One in 10 women worldwide has HPV. What's more alarming is that it causes almost all cervical cancers, 85% of anal cancers, and 70% of vaginal cancers in both men and women. 

Strictly speaking, HPV is a family of viruses with close to 200 strains. It infects the outermost layer of skin or the genitals called the squamous epithelium. HPV gets its name from the telltale warts or papillomas that it causes in these areas. Yes, warts - who would have known that wicked witches had HPV? Most strains of HPV don't appear as warts, but around 20 cause different kinds of warts to grow in different areas of the body. At least 5 strains of HPV lead to ugly warts in the genitals and anus. 4 HPV types cause common and flat warts on the face, hands, neck, knees and wrists, while painful plantar warts on the soles of your feet are caused by 4 kinds of HPV. Another 5 strains of HPV causes papillomas in the mouth and throat. More than 15 HPV types cause pimple-like growths on the hands and feet characteristic of a condition called epidermodysplasia verruciformis. 

Most forms of HPV are benign or non-cancerous, but there are about 15 types of HPV that can cause cancer. These HPVs are called high-risk HPVS and are often sexually transmitted between partners. Besides cervical, anal, and vaginal cancer, HPV has also been linked to 40% of vulvar cancers, 40% of penile cancers, 35% of throat cancers and 25% of mouth cancers.

In the past two decades there has been a growing interest in identifying the role of HPV in ovarian cancer. Ovarian cancer affects 12 in 100,000 women in the United States and has the highest mortality rate of all cancers of the female reproductive system. This is because ovarian cancer is very hard to detect in its early stages, and when it is detected it becomes harder to treat and more widespread. Most cancerous tumors in the ovaries are found in the epithelium. Since HPV is a cancer-causing virus that also thrives in the epithelium, scientists have wanted to find out if ovarian tumors may also be caused by HPV.

The first study on HPV and ovarian cancer was done in 1987, when Dr. Raymond H. Kaufman and his colleagues found HPV-6 DNA in 10 out of 12 patients with ovarian cancer. Succeeding studies, however, have shown no conclusive link between HPV and tumors in the ovaries. These include a 1989 study headed by Dr. Jonathan Leake, a 1990 study led by Dr. Robert McLellan, and studies by Drs. Ann-Marie Beckmann and Anne-Marie Trottier in 1991 and 1995, respectively.

In 1998, however, a study in China by doctors of the Jilin City Center Hospital found strong associations between ovarian growths and HPV types 16 and 18, the same HPV types that cause cervical cancer. Another study in the same year by a British team led by Dr. Tom Manolistas also point out a correlation between HPV 16 and ovarian tumors. In 1999, Dr. Maarit Antilla and colleagues did a high-sensitivity analysis on 98 epithelial ovarian tumors as well as reviewed all the previous HPV-ovarian tumor studies done with a total of 175 samples. They concluded that HPV is "highly unlikely" to cause epithelial ovarian cancer.

Research done in the past 10 years have been similarly conflicting. A 2003 study done by doctors from the Inner Mongolia Medical College in China found that 36% of epithelial ovarian tumors in 50 cases had HPV-16. Another study in 2005 found HPV-16 in 60% of ovarian tumors analyzed, but concluded that it was statistically insignificant. The researchers, led by Esra Kuscu of the Baskent University School of Medicine in Turkey, postulated that HPV may lead to some ovarian tumors by interacting with the tumor suppressing gene called p53. This was further reinforced by another study by Funda Atalay and colleagues at the Ankara Oncology Research and Educational Hospital. Out of 94 patients with ovarian cancer, they found 6 with HPV-16 and 2 with HPV-33. In contrast, 20 ovarian tumors analyzed in 2006 by Jeffrey Quirk and his team were negative for HPV types 16, 18, and 33. Another case of HPV-related ovarian squamous cell cancer was reported extensively by Dr. Jasper Verguts of the Belgian University Hospital Gasthuisberg in 2007. In Italy, 3 out of 71 patients with ovarian epithelial tumors were reported to have HPV in 2008.

Another question that begs to be asked is whether HPV in ovarian tumors actually cause the cancerous growth or are just a result of some other unknown process. An article published by Giovanna Giordana and colleagues in 2008 found that HPV, when present in ovarian growths, may not be the driving cause of tumors. In the same year Dr. Brigitte Ronnett and her team confirmed that cancerous cervical tumors may very well travel or metastasize to the ovaries. This means that HPV-positive ovarian tumors may have possibly come from similar growths in the cervix. A new study published in 2011 further confirms this - Japanese researchers from the University of Toyama in Japan reports a case of ovarian squamous cell carcinoma that metastasized 8 years after a woman had a part of her cervix removed because of cervical tumors. One study published in 2008 is at odds with these findings though. A group led by Nicolas Wentzensen of the University of Heidelberg in Germany tested for metastatic cervical tumor cells in 74 ovarian tumors but found none.

What do all these studies mean? Basically, that the link between HPV and ovarian cancer is still poorly understood. While there are cases where HPV was found in ovarian epithelial tumors, it is still not clear how it got there and how it can be related to cancer. The relationships between HPV, ovarian tumors, and concurrent growths in the cervix and other parts of the female reproductive system still have to be analyzed. What is sure is that HPV in epithelial ovarian tumors are still very rare. So it is still safe to count out ovarian cancer as another dreadful product of HPV.

References/ Further Reading: 

"Human Papillomavirus (HPV)." cdc.gov. Centers for Disease Control and Prevention. 11 March 2011.

"Human Papillomaviruses and Cancer."  cancer.gov.  US National Cancer Institute, 13 Dec 2010. 

"Human Papillomavirus Infection." acog.org. The American Congress of Obstetricians and Gynecologists. Nov 2010. 

"Ovarian Cancer."  cancer.gov. US National Cancer Institute, n.d..

"SEER Stat Fact Sheets: Ovary." seer.cancer.gov. National Cancer Institute Surveillance Epidemiology and End Results, Nov 2010.

Anttila, M. et al. "Failure to demonstrate human papillomavirus DNA in epithelial ovarian cancer by general primer PCR.". Gynecologic Oncology 72.3(1999):337-41. PubMed.

Atalay, F. et al. "Detection of human papillomavirus DNA and genotyping in patients with epithelial ovarian carcinoma." Journal of Obstetrics and Gynaecological Research 33.6(2007):832-888. PubMed.

Beckmann, AM et. al. "Genital-type human papillomavirus infection is not associated with surface epithelial ovarian carcinoma." Gynecologic Oncology 43.3(1991):247-51. PubMed

Fujuan, Pan et al. "Study of the p16 gene mutation and HPV infectioin in ovarian epithelial tumor." Chinese Journal of Birth Health and Heredity. (Apr 1998). en.cnki.com.

Giordano, G. et al. "Human papilloma virus (HPV) status, p16INK4a, and p53 overexpression in epithelial malignant and borderline ovarian neoplasm." Pathology Research and Practice 204.3(2008):163-174. ScienceDirect.

Giordano, G. et al. "Role of human papillomavirus in the development of epithelial ovarian neoplasms in Italian women." Journal of Obstetrics and Gynaecological Research 34.2(2008):210-217. PubMed.

Hidaka, T. et al. "Ovarian Squamous Cell Carcinoma Which Metastasized 8 Years After Cervical Conization for Early Microinvasive Cervical Cancer: A Case Report." Japanese Journal of Clinical Oncology (2011). OxfordJournals.

Kaufman, RH, et al. "Detection of human papillomavirus DNA in advanced epithelial ovarian carcinoma." Gynecologic Oncology. 27.3(1987):340-9. PubMed.

Kuscu, E. et al. "HPV and p53 expression in epithelial ovarian carcinoma." European Journal of Gynaecological Oncology 26.6(2005):642-645. PubMed.

Leake, JF et al. "Human papillomavirus and epithelial ovarian neoplasia." Gynecologic Oncology 34.3(1989):268-73. PubMed

McLellan, Robert et al. "Investigation of ovarian neoplasia of low malignant potential for human papillomavirus." Gynecologic Oncology 38.3(1990):383-85. ScienceDirect.

Quirk, JT et al. "Analysis of ovarian tumors for the presence of human papillomavirus DNA." Journal of Obstetrics and Gynaecological Research 32.2(2006):202-205. PubMed.

Ronnett, BM. et al. "Endocervical Adenocarcinomas With Ovarian Metastases: Analysis of 29 Cases With Emphasis on Minimally Invasive Cervical Tumors and the Ability of the Metastases to Simulate Primary Ovarian Neoplasms." American Journal of Surgical Pathology 32.12(2008):1835-1853. journals.lww.com.

Trottier, AM et al. "Absence of human papillomavirus sequences in ovarian pathologies." Journal of Clinical Microbiology 33.4(1995):1011-13. PubMed

Verguts, J. et al. "HPV induced ovarian squamous cell carcinoma: case report and review of the literature." Archives of Gynecology and Obstetrics 276.3(2007):285-289. PubMed.

Wentzensen, N. et al. "No metastatic cervical adenocarcinomas in a series of p16INK4a-positive mucinous or endometrioid advanced ovarian carcinomas: an analysis of the AGO Ovarian Cancer Study Group." International Journal of Gynecological Pathology 27.1(2008):18-23. PubMed.

Wu, GQ et al. "Detection of human papillomavirus-16 in ovarian malignancy." British Journal of Cancer 89.4(2003):672-675. PubMed.

Image Credit: "ovarian-cancer-prevention-00.jpg" ovca.org. National Ovarian Cancer Network.

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