FIGHT AGAINST CANCER: Focus Cancer Cervix in Women.
A cancer which is potentially preventable as well as curable if proper health planning is done.
Cancer Cervix was once the most common cause of cancer deaths in women in the West. Widespread use of screening program (Pap smear testing) has substantially decreased mortality from this cancer in these countries. In India even today cancer cervix remains the number one cancer in women. On April 2, 2009 the Nargis Dutt Memorial Cancer Hospital Mumbai (along with IARC Lyon, France) published an important article in “New England Journal of Medicine” showing that in low resource countries like India, a single round for screening (which is economically viable) can substantially reduce deaths from cancer cervix in rural India. Developing countries including India need to fight against this cancer on similar grounds.
Cervix is the tubular canal forming the lower part of uterus (womb) and that which projects in to vagina. Of all the cancers in human body, cancer cervix has distinction of being caused by a virus named as Human Papilloma Virus (HPV). HPV is a double stranded DNA virus (50 to 55 nanometres in size) which infects skin and other lining cells of the body. More than 100 types of this agent are recognized and different types infect different sites causing different manifestations. Skin is infected with HPV-1 and is the cause of commonly encountered skin warts. HPV-6 causes anogenital warts. HPV-16, 18, 31, 33 & 45 infect human cervix and are high risk for cervical cancer precancer lesions (HR-HPV). Women get infected as soon after marriage. Once the lining of cervix is infected with HPV, the lining cells show a series of changes over the years in the women’s life. These changes are progressive culminating in to formation of cancer. Each stage can last for 10 to 20 years before transforming in to next stage. The first precancerous change is called ASCUS (Abnormal squamous cells of uncertain significance), second is called LSIL (Low grade squamous intra-epithelial lesions) and third is called HSIL (high grade squamous intra-epithelial lesions). Over the years, HSIL change in to cancer cells limited to mucosa called carcinoma-in-situ and finally these cells invade deep in to lining (invasive cancer). Invasive cancer cells can spread out of cervix in to surrounding organs leading to advanced cancer.
The biology of HPV infections of the cervix has been extensively studied. HPV has 2 proteins named as E6 & E7 proteins. Both these proteins have a peculiar property of inactivating tumor-suppressor genes namely Rb & p53. As genes which suppress tumor formation in body are inactivated, the cells show abnormal structural changes and growth pattern leading to epithelial changes defined earlier.
Cancer cervix often occurs at and above the age of 40 years. High risk groups include women with lower socioeconomic class, women with early marriage, women with multiple remarriages, and those who smoke or are immuno-suppressed (HIV infected). However, cancer cervix is encountered less in Muslim women understandably due practice of circumcision in men which reduces chances of transmission of HPV infection.
Cancer cervix is one cancer in the body whose fight and success of fight is ensured if proper healthcare policies are employed. Of course application of these policies needs financial support and organization to conduct program correctly. Also a population based cancer registry for this cancer and others is necessary to show impact of these programs.
Cancer cervix program in the West has heavily depended upon screening women for HPV induced epithelial changes in cervix. This is traditionally done by what is called Pap smear. Pap smear is done by taking a swab from cervix during routine physical examination of women. The procedure is painless, is done without anaesthesia and involves no additional facilities. Swab is smeared on a slide and looked for cytological changes which may be induced by HPV. These cytological changes need to be classified as ASCUS, LSIL or HSIL (see above). Also if cells have turned cancerous, changes of established cancer can be diagnosed. If women show ASCUS or LSIL she needs only observation. If HSIL or carcinoma-in-situ is diagnosed we need to take a proper biopsy (punch biopsy, cone biopsy or loop biopsy) to confirm changes on histology. This can be done during routine consultation by the physician with minimal pain and discomfort. Cancer cervix at this stage (advanced precancerous or early cancerous) can be managed with local treatment only.
Fig: Screening program algorithm for cancer cervix.
Pap smear has revolutionized control of cancer cervix in the West. The test is simple and if done correctly is highly accurate in picking up CMV-associated epithelial changes and also useful in identifying those with carcinoma-in-situ. What is the protocol followed up in the West? Every woman is recommended to have a Pap smear 3 years after marriage and repeated once after every 3 years if normal. Those with indeterminate cytological changes (ASCUS or LSIL) need repeat examination at 3 to 6 months and those with HSIL or carcinoma-in-situ need proper biopsy. In India with resource problems and also logistic issues of repeatedly approaching whole women society, it is recommended that all women around 40 years of age have Pap test at least once. This is useful in reducing mortality from cancer cervix to a large extent.
Fight against cancer cervix in our population is to recognize that this cancer is potentially preventable by Pap smear program. Pap smear needs to be introduced by the health department at every health centre and all women within the age group defined must have a Pap smear during routine physical examination. Also we need to reach to substantial proportion of those women in the community and cover as much population as possible. Pap smear has additional advantage for picking up cancer cervix at an early stage of the disease and cure at this stage by local treatment or combination of treatments is a real advantage.
The discovery that persistent cervical infection of high-risk human papilloma virus (HR-HPV) genotypes causes virtually all cervical cancer and its immediate precursors has led to the development of clinical DNA and RNA tests for HR-HPV. There are currently four US FDA-approved HR-HPV tests and several other tests being commercialized and validated. Many countries are switching to, or evaluating the switch to HR-HPV testing. There is overwhelming evidence that HR-HPV testing is more sensitive, but less specific, than cervical cytology (e.g., Pap smears or liquid-based cytology) for the detection of cervical precancer and cancer. Essentially, by using HR-HPV testing to first screen the population; it permits a shift from performing frequent cervical cytology testing on all women, to performing cervical cytology testing on just those who have the necessary cause of cervical cancer, HR-HPV.
Some screening programs use other tests than the Pap smear because Pap smear has shown inconsistent results in some countries. These tests include visual inspection of cervix by acetic acid (VIAA) or Lugol’s iodine or direct testing for HPV by what is called Hybrid Capture II assay (which looks for all possible cancerous HPV strains).
Apart from impact of Pap smear program, cancer cervix can be fought with primary prevention strategies. HPV infection in women can be prevented and if so cancer cervix can never occur. This is possible as vaccine against HPV (against those 4 strains which cause cervix cancer) is available. The vaccine is FDA approved and has to be given before marriage. Gardasil is the commercially available HPV vaccine in USA and is made by Merck & Co., Inc. The vaccine is given in 3 doses completed over 6 months and recommended at ages of 9 to 26 years. Married women may benefit if not infected with HPV. It does not help in women who are already infected with HPV. There are a number of studies published in Western literature showing effectiveness of HPV vaccine. Those vaccinated are protected from HPV infection and follow up studies have shown no epithelial changes in these women. Primary prevention program of cancer cervix by vaccination in developing countries like India may not be possible for some time to come in view of the financial implications involved.
Precancerous lesions of cervix and early cancers of cervix usually do not cause symptoms. Once symptoms occur usually cancer is locally invasive. Major symptoms are abnormal vaginal bleeding (bleeding between periods, bleeding after menopause, or excessive bleeding). Once cancer cervix occurs, cancer needs to be staged depending upon extent of spread of disease. The classification of cancer cervix is done by TNM basis (Tumor, Node & Metastases). This is done by physical examination, histology and imaging tools. Carcinoma in situ (cancer cells without invasion) can be treated by cone biopsy of the lesion or hysterectomy (surgical removal of uterus along-with cervix). Stage 1 disease is disease confined to cervix and can be cured by hysterectomy or radiation therapy. For stage II, III & IV combination of surgery, chemotherapy and radiation therapy need to be employed. Intra-cavitory radiotherapy is a specialized form of delivering radiation locally to the cancer by placing thin tubes (implants) containing radioactive substances.
Take home message is that women should get pap smears as a part of routine health check up in a drive to finish the fight against this dreaded cancer which is preventable as well as curable.
Mehnaaz Sultan Khuroo, MD (Pathology), Associate Prof, Dep’t. Pathology, Govt. Medical College, Srinagar, Kashmir, J&K, India. E-mail: firstname.lastname@example.org