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MEDICINE

The new faces of cancer

The frequency of cases of head and neck tumors caused by HPV, transmitted by sexual contact, has increased in young people and non-smokers

Câncer_01_2JG7873_1LÉO RAMOSTumors of the tongue, roof of the mouth, pharynx, larynx and tonsils, generically known as tumors of the head and neck, which used to be found primarily in men over the age of 50, smokers and habitual consumers of alcoholic beverages, are now appearing in younger people, between the ages of 30 and 45, who do not smoke and drink little or not at all. Doctors and researchers have concluded that the human papillomavirus, HPV, microorganism commonly found in everyone at some point in their lives, must be the cause of infections that facilitate the formation of these tumors. If 10 years ago HPV accounted for 25% of cases of tonsil cancer, one of the most frequent in this region, today it is associated with 80% of these tumors, according to recent studies conducted by experts at the AC Camargo Cancer Center in São Paulo, and confirmed by other research groups.

Prior to these studies, HPV was best known as the main causative agent of genital warts and cervical cancer—the third most common type of tumor in women, after breast, and colon and rectal cancer—and, rarely, of tumors of the penis and anus, the latter more common in gay and bisexual men. The fact that HPV is now being associated with tumors in the head and neck region is likely due to the same reason: sexual practices, in these cases primarily unprotected oral sex with many partners. Even the use of condoms may not be sufficient to avoid infection, experts caution. HPV is transmitted by direct contact with infected skin and often can hide in areas not covered by a condom, such as in the scrotum. “The lack of intimate and oral hygiene increases the risk of transmission of the virus and the development of tumors, especially on the tonsils, oropharynx (back of the throat just behind the mouth) and the tongue,” says Dr. Luiz Paulo Kowalski, a surgeon and director of the Head and Neck Center at AC Camargo.

Head and neck tumors are the sixth most common cancer group in the world, accounting for approximately 650,000 new cases each year. According to the National Cancer Institute in Rio de Janeiro, 32,130 people in Brazil were diagnosed with some of these types of cancers in 2014. Cancers in this part of the body are often devastating because changes occur in an extremely visible area, the face, which is directly associated with a person’s identity. Often, as part of the treatment, the tongue and other parts of the mouth and throat covered with tumors must be removed. As a result of the surgery, people often have difficulty eating, speaking and breathing.

040-045_cancer cabeca_233 1DESENHO: REPRODUÇÃO DE ESTUDOS DE CABEÇA DE LEONARDO DA VINCI / LÂMINA: LÉO RAMOSThe first symptoms indicating the formation of tumors are small sores that bleed easily and grow until they reach the muscles and nerves and become painful. “About 80% of people diagnosed with head and neck cancers in São Paulo have tumors in advanced stages, because they did not pay attention to the early symptoms, which are painless,” says Kowalski. He says problems with chewing and swallowing, and moving the tongue or jaw are late-stage symptoms. In such cases, the consequences are more extreme. “Sometimes it is necessary to remove half or even all of the tongue or vocal cords.”

Many patients in treatment become depressed. “Some see no reason to go on living and need counseling,” says psychologist Mariana Meloni, who for four years has been counseling people with head and neck tumors who are about to undergo surgery at the São Paulo State Cancer Institute (Icesp). “The fact that they have to give up old habits, often associated with drinking and smoking, and that they can not return to work or even feed themselves makes them feel like they have lost control of their lives.”

Besides the need to redesign one’s life, feelings of guilt emerge, as described by the American writer Susan Sontag in the essay Illness as Metaphor  (1978) before she herself died of cancer in 2004 at age 71. “The myth surrounding cancer suggests that the person is the one responsible for the disease, and cancer then is seen as synonymous with failure.” And moreover: “Treating cancer as a demonic enemy makes it not only a lethal disease, but also a shameful one.”

Câncer_07_2JG7879_1LÉO RAMOSThere are no solid estimates of the number of cases in Brazil of head and neck tumors caused by HPV. In the United States, it is estimated that 42,440 cases of tumors of this type were recorded in 2014, with 14,410 just of the oropharynx, of which it is calculated that 9,000 were caused by the virus in men and 2,000 in young women, according to the American Cancer Society. “These data reinforce the hypothesis that the number of cases of tumors caused by HPV in that part of the body is likely to surpass those caused by alcohol and smoking by 2020 in the United States,” says Kowalski. “Brazil will probably follow the same trend.”

The first signs that younger people, non-smokers and those in good health—even some athletes—were manifesting more head and neck tumors arose in the United States starting in 2000; this changed the epidemiological profile of the previous decade comprised of people over age 50 who drank and smoked excessively. Kowalski detected these changes in Brazil in 2011 when he and his team compared the molecular analysis of 114 samples of oral tumors of two groups of people treated at AC Camargo: one made up of individuals between the ages of 30 and 45 who neither smoked nor drank, and another group comprised of people over age 50 who smoked and drank before they contracted the disease. Kowalski found stretches of HPV DNA in 68.2% of the 47 samples from the youngest group and 19.2% of 67 samples from the group who smoked and drank, as described in an article published in 2012 in the International Journal of Cancer.

Alcohol, cigarettes and HPV
Doctors at AC Camargo observed that younger people, whose cancers were associated with HPV, responded better to treatment and had better survival rates than older people whose tumors were more aggressive and resistant overall. According to Kowalski, these differences could be related to the fact that younger patients are healthier for not having been drinkers or smokers. “People with tumors caused by alcohol and tobacco, in addition to being older, often suffer from pulmonary and cardiovascular problems, and the diagnosis is usually made ​​when tumors are at an advanced stage, which makes treatment more difficult,” says Kowalski. In July, he will preside over the 5th edition of the World Congress of the International Academy of Oral Oncology, being held for the first time in Brazil, which will bring together professionals from various fields to discuss strategies for encouraging the prevention and early diagnosis of these tumors.

040-045_cancer cabeca_233NOVOEven if there are signs that head and neck tumors caused by HPV behave differently, they are treated in the same way, with chemotherapy, radiation therapy and surgery, often successfully, as in the case of the former president of Brazil, Luiz Inacio Lula da Silva, who in 2011 had cancer of the larynx not linked to HPV. In other cases, the treatment may not be enough to contain the disease. One of the founders of psychoanalysis, Sigmund Freud, died in 1939 from mouth cancer, against which he struggled for 16 years, having had almost all of his jaw replaced by a prosthesis. Freud smoked up until his death at age 83.

Rossana López, an Icesp researcher, found another clue that HPV might be the cause of tumors in this area. In 2011, she assessed the prevalence of viral infections in 1,475 people with head and neck cancer using data from two studies. The first was conducted ​​from 1998 to 2003 by the International Agency for Research on Cancer (IARC) in five Brazilian cities, although she has used data only from Goiânia, Rio de Janeiro and São Paulo, to restrict the sample and be able to compare it with data from the second study, conducted between 2003 and 2010 by an international research network, the Head and Neck Genome Project (Gencapo), of São Paulo. By analyzing tissue samples with tumors, López found that the prevalence of HPV type 16, one of 200 known varieties, increased from 1% in cases from the older study, done in the late 1990s, to 6.7% in the more recent data, from the 2000s. She also identified antibodies against HPV-16 in 55% of the IARC study samples and 72% of the Gencapo study samples.

Internal battle
Infected people, however, do not always produce antibodies against the virus. That was the finding of Luisa Villa, coordinator of the Institute of Science and Technology for the Study of Diseases Associated with HPV and researcher at the Nuclear Medicine Center, Department of Radiology and Oncology, University of São Paulo School of Medicine (FMUSP), who collaborates with the AC Camargo team. One her group’s studies indicated that only 50% of infected women and 10% of infected men produced specific antibodies against the virus. “Seven in 10 women may contract HPV at some point in their lives,” says José Eduardo Levi, of USP’s Institute of Tropical Medicine (IMT). “Most women’s bodies will eliminate the virus, but this is not true for men,” he says. For this reason women can reacquire the virus, even after having already eliminated it several times, by being re-infected by their partners. A strategy adopted in Brazil to avoid HPV-16 infection and re-infection has been to vaccinate girls starting at age 9 (see Pesquisa FAPESP  Issue No. 157). However, to control the spread of HPV more efficiently, says Villa, the men must also be taken into account. “If we do not include them in this process, it is possible that the same woman, after having eliminated the virus, will become infected again.”

In studies conducted at the Institute of Biomedical Sciences (ICB/USP) in 2013, a candidate substance for an experimental DNA vaccine forced ​​the immune cells of mice to identify and eliminate tumor cells caused by HPV-16. The experimental vaccine acts after the infection has already been caused by the virus—unlike traditional vaccines that are exclusively preventive—activating cells (T lymphocytes CD8) that identify these signals and release toxic proteins that kill infected cells.

040-045_cancer cabeca_233 2DESENHO: REPRODUÇÃO DE ESTUDOS DE CABEÇA DE LEONARDO DA VINCI / LÂMINA: LÉO RAMOSThe idea that microorganisms can cause cancer is not new. In 1901, the French physician Eugène-Louis Doyen informed the French Academy of Medicine in Paris that he had isolated the microorganism responsible for the disease: Micrococcus neoformans. It was soon discovered that he was wrong. Almost 10 years later, at the Rockefeller Institute in New York, virologist Francis Peyton Rous, upon transplanting the tumor of one chicken to another healthy chicken, concluded that the tumors were caused by a tiny parasite. In this case, he was right. It is known that viruses such as Epstein-Barr and bacteria such as Helicobacter pylori are responsible for 15% of all cancer cases. In the case of HPV, it is estimated that at least half of all sexually active people harbor at least one of the 200 known varieties of the virus, but that does not mean that the infection will develop into a cancer. Some varieties of HPV are harmless and  cause only bumps that are easily confused with warts.

Studies by Levi’s team suggest that HPV prefers to lodge at the base of the tongue and in the tonsils. The virus can favor the formation of tumors as it interacts with the genes of human cells and may inactivate the p53 protein production process, which is primarily responsible for DNA repair. “If the HPV inactivates the p53, the cells begin to multiply uncontrollably,” he says. One strategy to stop the virus and the formation of abnormal cells, therefore, would be to restore and enhance the action of p53. A molecule known as P-MAPA, developed by the Farmabrasilis research network, which includes researchers from the University of Campinas (Unicamp), USP and universities in the United States—funded by FAPESP—managed to restore p53 protein activity in rats with induced bladder cancer, according to a study published in 2012 in the journal Infectious Agents and Cancer. In laboratory tests, the molecule has shown itself to be capable of reducing the tumors of these animals by 95% through the activation of cellular receptors of the innate immune system (toll-like receptors). It also favors the production of a type of protein that blocks the process leading to the formation of blood vessels that nourish the tumors and help them spread through other tissues.

A non-invasive molecular test developed by researchers and physicians at the Federal University of São Paulo (Unifesp), AC Camargo and the Barretos Cancer Hospitals may help in the early detection of the risk for recurring head and neck tumors in people who have already had them, before the first clinical signs, thus increasing the efficacy of treatment. The test consists of a molecular examination of the epithelial cells found in saliva. The DNA of these cells is extracted and the test determines whether tumor suppressor genes show a specific type of change, hypermethylation. People whose suppressor genes have undergone this change have a fivefold greater risk of the reappearance of head and neck tumors than those whose genes were unchanged. Researchers believe the test could also be used to identify harmful genetic changes in those who have not had the disease to see if there is a risk of developing it.

Projects
1. Institute of Science and Technology to Study Diseases Associated with Papillomavirus (nº 2008/57889-1); Grant Mechanism Thematic Grant; Principal Investigator Luisa Lina Villa (FM-USP); Investment R$4,949,181.38 (FAPESP).
2. Clinicopathological and molecular aspects of oral squamous cell carcinoma in patients aged less than or equal to 40 years (nº 2007/56117-2); Grant Mechanism Regular Research Grant; Principal Investigator Luiz Paulo Kowalski (AC Camargo Hospital ); Investment R$224,989.95 (FAPESP).
3. Environmental, clinical, histopathological and molecular factors associated with development and prognosis of head and neck squamous cell carcinomas (nº 2010/51168-0); Grant Mechanism Thematic Grant; Principal Investigator Eloiza Tajara Helena da Silva (São José do Rio Preto School of Medicine); Investment R$1,644,520.00 (FAPESP).

Scientific articles
LOPEZ, R.M. et al. Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection. Cancer Causes and Control. V. 25, No. 4, p. 461-71. 2014.
BETIOL, J., VILLA, L.L. and SICHERO, L. Impact of HPV infection on the development of head and neck cancer. Brazilian Journal of Medical and Biological Research. V. 46, No. 3, p. 217-26. March 2013.
FÁVARO, W.J. et al. Effects of P-MAPA immunomodulator on toll-like receptors and p53: Potential therapeutic strategies for infectious diseases and cancer. Infectious Agents and Cancer. V.7, No. 1, June 2012.
KAMINAGAKURA, E. et al. High-risk human papillomavirus in oral squamous cell carcinoma of young patients. International Journal of Cancer. V. 130, No. 8, p. 1726-32, April 2012.
RIBEIRO, K.B. et al. Low human papillomavirus prevalence in head and neck cancer: results from two large case-control studies in high-incidence regions. International Journal of Epidemiology. V. 40, No. 2, p. 489-502, April 2011.

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