Introduction
The developments in the understanding of cervical cancer in the twentieth century, which has led to means to combat a disease that afflicts women and is responsible for a high rate of mortality among women is a remarkable achievement for humanity in its continuous fight against diseases. Such success has come from the unraveling of the etiology of the disease and an understanding of the epidemiology of the diseases on one side and the advances made by science and technology on the other side.
The greater awareness of causes and risk factors for cervical cancer has led to more efficient preventive measures being put in place that has led to a decrease in the incidence of the disease more markedly in the developed world. There is an air of expectancy that greater strides would be achieved in the fight against cervical cancer in the prevention, as well as treatment and care for cervical cancer.
History of Cervical Cancer
Our understanding of cervical cancer along with its primary causative agent the human papillomavirus (HPV) has an intriguing background. Four groups of characters from the actors in this human drama. They are prostitutes, nuns, second wives, and generations of dedicated researchers. Epidemiologists nearly a century ago observed two curious phenomena in the incidence of cervical cancer. The first was that cervical cancer was common in prostitutes, but rarely afflicted nuns except for those nuns, who had been sexually active prior to entering the convent. The second observation was in married couples.
The incidence rate of cervical was strikingly high among women who were married to spouses, whose previous wives had died of cervical cancer causes. Putting these clues together scientists concluded that the common cause of cervical cancer was the sexual activity of the woman and that there had to be a sexually transmitted agent that lay at the root of cervical cancer in women. Confirmation of this conclusion would take another seven decades when the outcome of dedicated research was seen in German researchers identifying HPV, which was known to cause cutaneous as well as genital warts as the causative agent in the late 1970s. (1)
Like in all cancers, treatment options in cervical cancers were limited in the early twentieth century. This meant that women contracting the disease mostly died from the spread and consequences of the disease. Cervical cancer was dreaded by women, but with no means to prevent and treat the disease, women continued to contract the disease and die from it. Identifying the causative agent provided the means of developing preventive methods aimed at reducing the incidence of the disease on one hand, while advances in medical science and its tool medical technology-enabled means of identifying the disease in its early stages, which was much easier to fight, and more effective treatment methods.
One of the remarkable achievements in the fight against cervical cancer was the development of the cervical smear test by George Papanicolaou and Herbert Traut in the 1950s, and its routine use as early detection means against cervical cancer. Cervical cancer-preventive methods, early identification of cervical cancer, and more effective treatment methods led to reduced incidence of cervical cancer and reduced mortality in women from cervical cancer. The understanding of the disease coupled with these advances meant that women were more knowledgeable of the disease, understood the means to reduce its prevalence, and if afflicted were not doomed to death, bit could look forward to successful remission of the disease, particularly when detected in its early stages. (2).
Epidemiology of Cervical Cancer
Cervical cancer is the second most prevalent type of cancer among women around the world, which results in more than five hundred thousand new cases every year, leading to nearly three hundred thousand deaths on a yearly basis worldwide. Eighty percent of the cervical cancer occurrence happens in developing countries and in the developing world, it is the most common cause of death in middle-aged women, as nearly two-thirds of the cervical cancer cases are detected at an advanced stage of the disease with poor prognosis for survival. (3).
Up to the middle of the twentieth-century cervical cancer was the leading cause of cancer death in women in developed nations including the United States of America. The advent of the cervical smear test and its routine test has caused a sea change in the incidence of cervical cancer and death due to cervical cancer. From the topmost cause of cancer death in women, in the twenty-first century cervical cancer has dropped to the thirteenth position.
Prior to the advent and use of cervical smear death, it is estimated that cervical cancer was responsible for the death of thirty-five thousand women every year. By 2003 this figure had dropped drastically to about four thousand deaths of women due to cervical cancer every year. These drop-in figures have resulted from the early detection of precancerous cervical lesions, which are more easily and successfully treatable.
However, in the United States of America, there is a wide disparity in the incidence rates of cervical cancer with the lower socio-economic groups bearing the brunt of the disease. This is a reflection of the worldwide scenario, where lower socio-economic groups are more affected by cervical cancer, which is an indication of the lower penetration of preventive and early detection of cervical cancer into these populations all across the world. Cost, logistics, lack of trained healthcare personnel, lack of equipment, cultural barriers to cervical cancer screening, and lack of awareness among women are considered to be the reasons for the continued high incidence of cervical cancer in women belonging to the lower socioeconomic population. (3).
Etiology of Cervical Cancer
The etiology of cervical cancer was one of the first clues to the cause of the disease. Early sexual activity, multiple partners, and promiscuity are at the center of the risk factors involved in cervical cancer. Cervical cancer is more commonly seen in women, who are married or have been married, than in single women. Evidence has emerged that male partners have a role to play in the spread of cervical cancer. Sexual activity with women infected and then with an unaffected woman could lead to the transfer of the disease to the unaffected woman. This makes women married or living with men, who have multiple partners at risk for contracting cervical cancer.
The common factor in all these risk factors is likely to be a viral infection, which can be transmitted. There is evidence to suggest that viral infection with herpes type 2 infections and the human papillomavirus (HPV) are implicated in cervical carcinogenesis. (4).
Research has not been able to identify positively any single etiological factor for cervical cancer so far. Besides the established link to sexually transmitted infection in particular the HPV types 11, 16, and 18, and women in the deprived class, additional risk factors include smoking and medical history of cervical dysplasia.
However, it has been established that cervical cancer can be prevented through population-oriented screening programs for cervical cancer. (5).
Pathology of Cervical Cancer
Nearly three-fourths of cervical cancers have a squamous origin, while fifteen percent are adenocarcinomas, and the rest consisting of adenosquamous, clear, and undifferentiated tumors. Malignant transformation of metaplastic cells gives rise to squamous tumors from the squamocolumnar junction. Quite often cervical intraepithelial neoplasia is seen at the margins of the tumor. The spread of the tumor in the cervix is through the direct penetration into the surrounding stroma, into the vaginal epithelium, and directly into the paracervical tissues oriented towards the wall on the pelvic side.
The invasion of the tumor into the lymphovascular spaces permits the occurrence of tumor embolism along the paracervical lymph channels into the deep pelvic node groups of the internal and external iliac and obstructor nodes. Subsequent spread then occurs along the common iliac and para-aortic chain. Spread through blood circulation is not often seen, but can occur with more aggressive tumors. (5).
The pre-invasive disease leading to cervical cancer can be subdivided into three namely CIN I, CIN II, and CIN III, which are histological terms used to describe the increasing degrees of dysplasia ranging from mild to severe. CIN III or severe dysplasia is inclusive of what was previously called carcinoma in situ. The three terms represent mild, moderate, and severe dyskaryosis as observed in cervical cytology. In the United States of America, the Bethesda System is employed, wherein CIN II and CIN III reflect high-grade squamous intraepithelial lesions and CIN I and changes as a result of HPV considered as low-grade squamous intraepithelial lesions.
In earlier times CIN III lesions were not discovered and treated leading to the development of invasive cancer and increased mortality in women. Presently screening and early detection of CIN III, with particular emphasis on the developed world has led to these lesions being prevented from developing into invasive disease. The natural history of CIN demonstrates that the development of cancer is a very slow process, which may take even up to ten to twenty years to develop, however, once.cervical cancer has progressed to a very large extent the prognosis s not encouraging, very often leading to the death of the patient. (6).
Clinical Features of Cervical Cancer
Dysplasia or CIN of all grades in women remains asymptomatic. However, the coexistence with other conditions like cervical erosion may cause some incidental symptoms. The presence of invasive cervical cancer is marked with vaginal bleeding in nearly eighty percent of the cases, which may be accompanied by a discharge that has an offensive smell and is discolored. In many cases, women tend to look at these symptoms as part of the normal feature of their monthly discharge and fail to seek medical advice. Sexual intercourse quite often is followed by vaginal bleeding. Other commonly occurring symptoms include abdominal pain, dyspareunia, or low back pain.
These symptoms are suggestive of a bulky or advanced lesion. The development of symptoms in the rectum or urinary tract is suggestive of the local spread of the disease. The tumor in cervical cancer can be usually seen with the help of simple speculum techniques.
Exophytic lesions are bulky, tending to form large friable polypoid growths, easing the diagnosis. Infiltrative tumors present with little to show in the way of visible growth, as the normal tendency with these tumors is for the abnormal growth to be directed towards the body of the uterus, usually replacing the cervix and the upper vagina with a large confluent malignant ulcer. In the case of recurrence of the disease after treatment classical clinical syndromes occur consisting of pelvic, back, and buttock pain; bowel disturbances; and unilateral swelling in the leg, as a result of lymphatic and venous blockages. (5).
Role of HPV in Cervical Cancer
Persistent genital HPV infection is considered to be the principal risk factor for cervical cancer. HPV infection is the most common sexually transmitted infection in the world, with the highest incidence in young women, making them potential targets for cervical cancer as they advance in age. Fey and Beal 2004, p. 6, define HPV as a small, non-enveloped, double-stranded circular deoxyribonucleic (DNA) tumor virus, classified in the genus papillomavirus of the Papoviridae family of viruses”.
The number of HPV distinct types that have been identified up till now exceed a hundred, with approximately half these types capable of infecting the epithelial membranes of the anogenital tract. Based on their oncogenic potential and ability to induce viral associated tumors genital HPV have been differentiated into two groups. The strains HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 are called high-risk strains due to their association with intraepithelial neoplasia and increased possibility of advancing to severe lesions.
Among these high strains, HPV 16 and 18 stand out as the most carcinogenic and most prevalent. Around the world, barring Southeast Asia, the HPV 16 is the most predominant strain. In Southeast Asia, the HPV 18 is the prevalent strain. In the United States of America, it is estimated that nearly twenty percent of women are infected with the HPV 16 strain. (2).
The mode of action in this infection is for the HPV DNA to incorporate itself into the target cell genome, exerting effects through the activation of oncogenes and suppression of the host cell immune response. Products of HPV protein prevent the repair of DNA and upset the programmed cell death leading to instability and unchecked cell growth and malignant tumor in the cervix. Cervical carcinogenesis occurs as a result of the HPV DNA integration in the host cell genome and the over-expression of the viral E6 and E7 oncogenes.
Additional factors for the progress of the cancer are the changes that occur in the DNA content and chromatin structure, and changes in nuclear morphology, which are caused by the oncogenic HPV subtypes. There is a long period of latency between the time of HPV infection and the actual development of a cancerous tumor, which ranges between ten to twenty years. A notable feature in this development is that only a small proportion of those infected with HPV develop cancer. This makes HPV infection alone insufficient for the development of cancer. Several other cofactors and molecular events are believed to influence the transformation of the cervical epithelial cells into cancerous cells. (2).
Active and passive smoking, along with the use of oral contraceptives have been identified as two cofactors for the development of cervical cancer. The independent association of active and passive smoking with cervical cancer has been established. Metabolites of nicotine get concentrated in the cervical tissues of women who smoke or are exposed to cigarette smoke, making women with HPV who smoke or are exposed to cigarette smoke at a higher risk for the development of high-grade intraepithelial lesions.
The higher the number of cigarettes smoked daily the greater the chances of developing severe cervical cancer. Another factor with smoking is that it lowers the immune response, thereby increasing the probability of persistent HPV infection. There is emerging evidence that extended use of oral contraceptives for five years or more is a possible cofactor in the development of cervical cancer. Thus position comes from the suggestion that long-term use of oral contraceptives may promote some step in the natural history of HPV infection, thereby enhancing the possibility of progress to cervical cancer. Oral contraceptives however have no influence on the initial HPV infection, or on the persistence of the infection. (2).
Cytological examination shows that cervical cells infected with HPV are enlarged with a clear zone around the nucleus, which appears as a perinuclear halo. These changes that are visible through cytological examinations are termed koilocytosis. This distinctive koilocytosis was used in the early stages of cervical smear tests as an indicator for HPV infection. However subsequent evidence has emerged that reliance on this factor alone is not conclusive evidence for HPV infection. (2).
Screening for Cervical Cancer
Cervical screening is a cost-effective means to reduce mortality in women due to cervical cancer. The result of a World Bank study in 1993 showed that screening women every five years with the required follow-up for identified cases would cost about $100 per disability-adjusted life year (DALY), while it would cost approximately $2,600 per DALY in the treatment of invasive cancer and the required palliative care. The screening intervention as a preventive measure in the development of cervical cancer is essentially founded on the natural history of cervical cancer.
The HPV virus is the primary underlying cause of the development of cervical cancer. The prevention of sexually transmitted HPV infection is extremely difficult, with even the use of condoms partially successful, as the virus can exist in any part of the anogenital area and remain infectious over an extended period of time. A significant factor in HPV infections is that although HPV infection is almost untreatable, in a vast majority of the cases the infection becomes undetectable.
Only in a small fraction of women infected with HPV does the infection persist and develop into pre-cancerous cells called dysplasia. Women who are at high risk for persistent infections are immuno-compromised women. HPV infections that can be detected are most common in women of the younger age group between twenty and twenty-four. Above the age of thirty, there is a clear decline in detectable HPV infections in women. In the vast majority of women, in whom HPV is detected, the likelihood is that the HPV infection will only develop into mild dysplasia, which regresses on its own or does not develop into cervical cancer, particularly in women with HPV infection below the age of thirty-five. Thus only in a few young women is the infection found to progress to cervical cancer. (7).
The progression of HPV infection to detectable precancerous lesions can take as long as ten years. Women above the age of thirty-five, who have been identified with severe or moderate precancerous lesions, are the group with the highest risk for developing cervical cancer. It has been observed that cervical cancer develops most often in women above the age of forty, and cervical cancer is most frequent in women above the age of fifty. Other factors that contribute to the enhanced risk for cervical cancer in HPV-infected women are the use of tobacco, use of oral contraceptives, and young age at first birth.
While screening for cervical cancer every year has been found to cause a reduction of more than ninety percent in the progress to cervical cancer, infrequent screening of women above the age of thirty is also useful in reducing the overall are of incidence of cervical cancer. This is because women with a negative cervical smear have a very low probability of developing cervical cancer in ten years. Data compiled from South Africa and analyzed suggest that even just one cervical screening at the age of thirty-five in women reduces the mortality from cervical cancer by twenty-six percent. (7).
The cervical smear test developed by George Papanicolaou and Herbert Traut in the 1950s called the Pap test was designed to detect precancerous cellular changes and has remained the conventional means for cervical cancer screening. In the United States of America, Pap test screening is recommended for all women above the age of eighteen leading sexually active lives. Two new technologies have since become available to improve the conventional Pap test techniques.
The first is the thin-layer, liquid-based cytology, which received approval from the Food and Drug Administration in 1996. The second is the more recent computer-assisted automated slide interpretation. Both these techniques in the screening for cervical cancer are fairly new, and hence the costs and long-term benefits in their utility for the prevention of cervical cancer are yet to be ascertained. (2).
Treatment of Cervical Cancer
Treatment of cervical cancer in essence starts with patients with CIN III, which means patients with severe dysplasia. A therapeutic cone biopsy is the normal treatment used that generally results in complete excision and cure while retaining the reproductive function in the woman. (5)
This is particularly important in women capable of childbearing, as loss of this function leads to emotional stress. Prior to the understanding of disease processes and development, and the development of cone biopsy the treatment for cervical cancer involved hysterectomy or removal of the uterus. Such a complete loss of childbearing capability is no longer necessary in CIN III and the use of cone biopsy, which enables women to maintain their purpose in life. Hysterectomy may be still performed in women with CIN III, but only when they are past the childbearing age or have no desire to have any more children. (5).
On patients demonstrating evidence of frank invasion of the disease surgery and radiotherapy remain the main modalities for treatment. Management of the disease is invariably based on the International Federation of Gynecology and Obstetrics (FIDO) staging system as shown in Table 1 of the Appendix.
Stage I b and II a cancers make up nearly half of all carcinomas of the cervix. It has been found that in some patients at these stages there is less invasion of the disease than previously recognized. This has led to a more conservative approach with this group of patients, wherein micro-invasive or non-confluent early invasive disease therapeutic intervention is the preferred choice for the treatment of this group.
There is a realization of the importance to distinguish between true micro-invasive lesions from those with microscopic evidence of involvement of the lymphatic system and/or the vascular system. The use of surgery or radiotherapy has proven to be equally effective in stage I b patients with high five-year survival rates of over eighty-five percent in patients at this stage of the disease. This has led to the use of either surgery or radiotherapy as standard treatment procedures depending on the institution in which the patient is. (5)
The surgical treatment series is more selective, with an operability rate in patients with the I b stage of the disease being about half the number of patients referred for surgical treatment. In patients with I b stage of the disease found suitable for surgical treatment radical or Wertheim’s hysterectomy is the chosen intervention strategy. Radical hysterectomy involves total abdominal hysterectomy consisting of removal of two to three centimeters of the vagina and all supporting tissues within the true pelvis.
Complete lymphadenectomy is the surgical treatment used in nearly twenty percent of these patients, because of the involvement of the lymph node. Bilateral oophorectomy is another possible surgical treatment but is not often done as the tumor rarely metastasizes to the ovary. The advantage of surgery over radiotherapy in young women is that conservation of the ovary is possible in radical surgery, while it is not so with radiotherapy. (5)
Surgical treatment in this stage of cervical cancer involves great skill in the procedure, as the operation is extensive, requiring removal of all the invasive parts of the disease, and at the same time avoiding damage to the non-involved parts like the ureters. An important feature of surgical treatment at this stage of the disease is the understanding that can be obtained through the procedure is the true state of the spread of the disease, which allows for more definite and accurate planning of the required treatment. This is a definite advantage in surgical treatment over radiotherapy, as the radiotherapist is forced to plan and execute the treatment procedure without the assistance of such a clear picture of the spread of the disease. (5).
However surgical treatment results in greater early morbidity than radiotherapy in the younger age group but makes up for it through fewer late complications arising from the treatment procedure. Through surgical treatment, it is possible to conserve at least one ovary, and thus the child-bearing capacity in young women, which is not possible, when radiotherapy is used to treat the disease, at this stage of the disease. Taking into consideration the advantages of treatment through surgery over radiotherapy at this stage of the disease, with particular emphasis on the retention of childbearing capabilities, treatment through surgery remains the treatment of choice in young women at this stage of the disease. (5).
However, in older patients, there is hardly any doubt that radical irradiation is the appropriate treatment mode. Such a position finds support in the evidence that has emerged that though there are identical results in overall survival rates and disease-free survival after five years through the use of radical surgical treatment and radical radiation therapy, the late or severe morbidity rates in the older women at this stage of the disease was much higher with radical surgical treatment than with radical radiation therapy. (5).
For patients in the stages of the disease ranging from II bright through to IV b radiation remains the treatment of choice with hardly any surgical options that give any comparable means of treatment. However, the advent of chemotherapy has provided the means to more efficient means of addressing the treatment concerns in these groups of patients. Studies have shown that a combined approach using radical irradiation and chemotherapy gives better results in patients at the various stages of the disease in these groups. Several chemotherapy regimens have been employed in combination with radical irradiation.
More commonly cisplatin-based chemotherapy together with radical radiation therapy has been used in these groups of the patient in the advanced stages of the disease. Such combination therapy is gradually becoming the standard in the treatment of patients in these advanced stages of cervical cancer. (5).
Conclusion
More than a hundred years ago the understanding of cervical cancer was limited and so were the options in the treatment of cervical cancer, condemning many women to a painful death. Over the last century understanding of the disease has led to means whereby it has become possible to detect the early stages of the diseases greatly enhancing the success rates in the treatment of cervical cancer. Advances in medical science and technology are aiding in the development of enhanced screening techniques for greater efficiency in the detection of the early stages of cervical cancer in women on one side and on the other side benefits in more efficient treatment procedures are being witnessed.
Surgery and radiotherapy have been the mainstay in the treatment of the different stages of cervical cancer. In the early stages of the disease in young women, the benefits of surgery make it the choice treatment. In older women in the early stages and in all women in the more advanced stages, radiotherapy remains the treatment of choice. Chemotherapy has been a recent addition to the means of treatment for advanced stages of the disease. The combination of radiotherapy along with chemotherapy has become the standard in the treatment of the more advanced stages of the disease.
Appendix
Table 1 – Clinical Staging in Carcinoma of the Cervix.
Works Cited
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- Fey, C. Molly & Beal, W. Margaret. “The Role of Human Papilloma Virus Testing in Cervical Cancer Prevention”. Journal of Midwifery & Women’s Health, 49.1 (2004): 4-13.
- Carr, Camacho, Katherine & Sellors, W. John. “Cervical Cancer Screening in Low Resource Settings: Using Visual Inspection With Acetic Acid”. Journal of Midwifery & Women’s Health, 49.4 (2004): 329-337.
- Neal, J. Anthony & Hoskin, J. Peter. Clinical Oncology: Basic Principles and Practice. Oxford University Press: New York, 2003.
- Souhami, Robert & Tobias, Jeffrey. Cancer and its management. Fourth Edition. Blackwell Science Ltd. Oxford, 2003.
- Blake, Peter. Lambert, Hannah & Crawford, Robin. Gynaecological Oncology. Oxford Medical Publications: Oxford, 1998.
- “Cervical Cancer Prevention: FACT SHEET”. Alliance for Cervical Cancer Prevention. 2007. Web.