Cancer

Background

Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, cervical cancer is relatively uncommon. The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it continues to rise in many developing countries. The change in the epidemiological trend in the United States has been attributed to mass screening with Papanicolaou tests.

Frequency
United States
In the United States, 11,150 new cases of cervical cancer are diagnosed each year. In addition, more than 50,000 cases of carcinoma in situ are diagnosed.
International
Internationally, 500,000 new cases are diagnosed each year.
Mortality/Morbidity
Of the 11,150 patients with cervical cancer, 3,670 will die from their disease each year in the United States. This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.
Race
In the United States, cervical cancer is more common in Hispanic, African American, and Native American women than in white women.
Sex
Cervical cancer is found only in women.
Age
Cervical cancers usually affect women of middle age or older, but it may be diagnosed in any reproductive-aged woman.

History
Because women are screened routinely, the most common finding is an abnormal Papanicolaou test result.
Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital.
Vaginal discomfort, malodorous discharge, and dysuria are not uncommon.
The tumor grows by extending upward to the endometrial cavity, downward to the vagina, and laterally to the pelvic wall. It can invade the bladder and rectum directly.
Symptoms that can evolve, such as constipation, hematuria, fistula, and ureteral obstruction with or without hydroureter or hydronephrosis, reflect local organ involvement.
The triad of leg edema, pain, and hydronephrosis suggests pelvic wall involvement.
The common sites for distant metastasis include extrapelvic lymph nodes, liver, lung, and bone.

Physical
In patients with early-stage cervical cancer, physical examination findings can be relatively normal.
As the disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or mass. These abnormalities can extend to the vagina.
Rectal examination may reveal an external mass or gross blood from tumor erosion.
Bimanual examination findings often reveal pelvic metastasis.
Leg edema suggests lymphatic/vascular obstruction from tumor.
If the disease involves the liver, some patients develop hepatomegaly.
Pulmonary metastasis usually is difficult to detect upon physical examination unless pleural effusion or bronchial obstruction becomes apparent.

Causes
Early epidemiological data demonstrated a direct causal relationship between cervical cancer and sexual activity. Major risk factors observed include sex at a young age, multiple sexual partners, promiscuous male partners, and history of sexually transmitted diseases. However, the search for a potential sexually transmitted carcinogen had been unsuccessful until breakthroughs in molecular biology enabled scientists to detect viral genome in cervical cells.
Strong evidence now implicates human papillomaviruses (HPVs) as prime suspects. HPV viral DNA has been detected in more than 90% of squamous intraepithelial lesions (SILs) and invasive cervical cancers compared to a consistently lower percentage in controls. Both animal data and molecular biologic evidence confirm the malignant transformation potential of papilloma virus–induced lesions. SILs are found predominantly in younger women, while invasive cancers are detected more often in women aged 10-15 years older, suggesting slow progression of cancer.
HPV infection occurs in a high percentage of sexually active women. Most of these infections clear spontaneously within months to a few years, and only a small proportion progress to cancer. This means that other crucial factors must be involved in the process of carcinogenesis.
Three main factors have been postulated to influence the progression of low-grade SILs to high-grade SILs. These include the type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; host conditions that compromise immunity, such as multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use, or vitamin deficiencies. In addition, various gynecologic factors, including age of menarche, age of first intercourse, and number of sexual partners, significantly increase the risk for cervical cancer.
Human papilloma virus
HPV is a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1, L2), which make up the viral capsid.
To date, 77 different genotypes of HPV have been identified and cloned, among which, types 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, and 68 have the propensity to infect anogenital tissues.
The HPVs that infect the human cervix fall into 2 broad categories. The low-risk types consist of HPV 6b and 11, which are associated with low-grade SILs but are never found in invasive cancer. The high-risk types, mostly HPV 16 and 18, are found in 50-80% of SILs and in up to 90% of invasive cancers. Although less common, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should also be considered carcinogenic.
The major difference between the 2 types is that after infection, the low-risk HPVs are maintained as extrachromosomal DNA episomes, while the high-risk HPV genome is found integrated into the host cellular DNA. The recombination event often leaves E6 and E7 directly coupled to the viral promoter and enhancer sequences, allowing their continued expression after integration. Because E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, the functional loss of both TP53 and the RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in progression to malignancy.
Human immunodeficiency virus
The role of human immunodeficiency virus (HIV) infection in the pathogenesis of cervical cancer is not fully understood. Studies have shown a higher prevalence of HPV in HIV-seropositive women than in seronegative women, and the HPV prevalence was directly proportional to the severity of immunosuppression as measured by CD4 counts.
Impaired lymphocyte function has been postulated to enhance latent or subclinical HPV activity, resulting in a higher rate of persistent infection.
Whether HIV has a synergistic effect on HPV infection, either by direct molecular interaction or through an indirect immunologic effect, remains unclear.