Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis

INTRODUCTION — Cancer of the uterine cervix is the third most common gynecologic cancer diagnosis and cause of death among gynecologic cancers in the United States [1]. Cervical cancer has lower incidence and mortality rates than uterine corpus and ovarian cancer, as well as many other cancer sites. However, in countries that do not have access to cervical cancer screening and prevention programs, cervical cancer remains a significant cause of cancer morbidity and mortality.

Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7 percent of cervical cancers [2]. The most common histologic types of cervical cancer are squamous cell (70 percent of cervical cancers) and adenocarcinoma (25 percent) [3].

The epidemiology, risk factors, clinical manifestations, and diagnosis of invasive cervical cancer will be reviewed here. Screening and prevention, staging, and the management of cervical cancer and preinvasive disease are discussed separately.

●(See "Screening for cervical cancer in resource-rich settings".)

●(See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

●(See "Management of early-stage cervical cancer".)

●(See "Management of locally advanced cervical cancer".)

●(See "Cervical intraepithelial neoplasia: Management".)

In this topic, we will use the terms "female" or "patient" to describe genetic females. We recognize that not all people with cervical cancer identify as female, and we encourage the reader to consider the specific counseling needs of transgender and gender nonbinary individuals.

EPIDEMIOLOGY

Incidence and mortality — In 2020, cervical cancer accounted for an estimated 604,000 new cancer cases and 342,000 deaths worldwide [4] and was the fourth most common cancer in females [5]. Eighty-four percent of cervical cancer cases were from resource-limited regions [6]. In females in resource-limited countries, cervical cancer was the second most common type of cancer (15.7 per 100,000 females) and the third most common cause of cancer mortality (8.3 per 100,000). On the continent of Africa and in Central America, cervical cancer is the leading cause of cancer-related mortality among females [4,7]; at least one study suggests that the incidence of cervical cancer has been increasing in some parts of Africa since the early 2000s [8].

In the United States, approximately 13,960 new cases of invasive cervical cancer and 4310 cancer-related deaths occur each year [1]. Cervical cancer is the third most common cancer diagnosis and cause of death among gynecologic cancers in the United States, with lower incidence and mortality rates than uterine corpus or ovarian cancer.

Global incidence and mortality rates depend upon the presence of screening programs for cervical precancer and cancer and of human papillomavirus (HPV) vaccination, which are most likely to be available in resource-rich countries. (See "Screening for cervical cancer in resource-rich settings" and "Screening for cervical cancer in resource-limited settings" and "Human papillomavirus vaccination".)

●Due to these interventions, there has been a large downward trend (approximately 75 percent decrease) in the incidence and mortality of cervical cancer over the past 50 years in resource-rich countries [9,10], though there are some exceptions [11].

●By some estimates, if vaccine rates of 70 percent worldwide are achieved, we would expect to see a decrease of 344,520 new cases of cervical cancer annually and avoid 178,182 cervical cancer-related deaths [12]. However, due to the latency period of 10 to 15 years between HPV exposure and cervical cancer development, there are not likely to be significant decreases in cervical dysplasia or cancer for many years after the implementation of vaccination programs. Surprisingly, in countries such as Australia that have achieved vaccination rates >70 percent, there has already been a 38 percent reduction in high-grade dysplasia [13]. Even in countries with lower vaccination rates, such as the United States, there has been a decrease in the incidence of high-grade cervical dysplasia. As an example, in Connecticut between 2008 and 2011, the vaccination rate increased from 45 to 61 percent [14]. During that same time period, there was a decrease in high-grade cervical dysplasia of 18 percent. As high-grade dysplasia is a necessary precursor for squamous, adenocarcinoma, and adenosquamous carcinomas of the cervix, this sharp decrease in high-grade cervical dysplasia should translate into decreased incidence of cervical cancer in the next decade.

●Data suggest that cervical cancer screening in conjunction with HPV vaccination can greatly reduce the incidence of cervical cancer in resource-limited settings. These data are discussed in detail elsewhere. (See "Screening for cervical cancer in resource-limited settings", section on 'Importance of HPV vaccination'.)

Race distribution — Estimates of incidence and mortality for cervical cancer vary depending on race/ethnicity. The United States National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program reported estimates of new cancer cases and deaths (per 100,000 population) as follows [15]:

●American Indian/Alaska Native (10.1 and 2.9)

●Hispanic American (10 and 2.5)

●Non-Hispanic Black American (9 and 3.3)

●Non-Hispanic White American (7.1 and 2)

●Asian American or Pacific Islander (6.3 and 1.6)

A higher magnitude of difference in cervical cancer mortality between Black and White females was found in a United States national survey [16]. The study excluded those who reported a prior hysterectomy (thereby changing the denominator and making the cervical cancer mortality rates higher overall) and found the following mortality rates: Black females (10.1 per 100,000) and White females (4.7 per 100,000). The study raises the question of whether there is a higher than previously calculated risk of cervical cancer mortality when only vulnerable females are included (those with a cervix). A limitation of the study is that no differentiation was made between total and supracervical hysterectomy.

Age distribution — Worldwide in 2012, the cumulative risks of developing cervical cancer and of cervical cancer mortality by age 74 years were as follows: resource-rich countries (0.9 percent incidence/0.3 percent mortality) and resource-limited countries (1.6 percent/0.9 percent) [6].

The lifetime risk of developing cervical cancer for United States females, based on national data from 2017 to 2019, was 0.7 percent [15]. The median age at diagnosis of cervical cancer in the United States from 2015 to 2019 was 50 years. Only 2.5 percent of cases were diagnosed in patients ages 85 years or older. In 2019, the United States hysterectomy- and age-adjusted incidence of cervical cancer in females <24 years was 0.08 per 100,000, rising to 4 per 100,000 in females ages 25 to 29 years, and peaking at 19.2 per 100,000 in females ages 60 to 64 years [17]. Thus, some clinicians continue screening females with a prolonged life expectancy through age 74 [16,18]. (See "Screening for cervical cancer in resource-rich settings", section on 'Age >65 years'.)

RISK FACTORS — The two major histologic types of cervical cancer, adenocarcinoma and squamous cell carcinoma, and the preinvasive disease that corresponds with these histologies share many of the same risk factors [19-29].

HPV-related — In almost all cases, cervical cancer is due to human papillomavirus (HPV) infection. Risk factors that are associated with HPV-related cancers include:

●Early onset of sexual activity – Compared with age at first intercourse of 21 years or older, the risk is approximately 1.5-fold for 18 to 20 years and twofold for younger than 18 years [19].

●Multiple sexual partners – Compared with one partner, the risk is approximately twofold with two partners and threefold with six or more partners [19].

●A high-risk sexual partner (eg, a partner with multiple sexual partners, history of prior sexually transmitted disease[s], or known HPV infection).

●History of sexually transmitted infections (eg, Chlamydia trachomatis, genital herpes).

●Early age at first birth (younger than 20 years old) and increasing parity (three or more full-term births); these are likely due to exposure to HPV through sexual intercourse [19].

●History of vulvar or vaginal squamous intraepithelial neoplasia or cancer (HPV infection is also the etiology of most cases of these conditions).

●Immunosuppression (eg, HIV infection).

Non-HPV-related

●Low socioeconomic status – In the United States, cervical cancer incidence and mortality are higher in patients who live in communities with higher poverty levels compared with lower poverty levels, likely due to limited access to health care and screening programs [30-32].

●Contraceptive use

•Oral contraceptives – A collaborative analysis of data from 24 epidemiologic studies found that, among current users of oral contraceptives, the risk of invasive cervical cancer increased with increasing duration of use (≥5 years of use versus never use: relative risk [RR] 1.9, 95% CI 1.69-2.13). The risk declined after use ceased, and by 10 or more years had returned to that of never users [28]. A systematic review that included 12 studies of patients with cervical cancer found that, in those who were known to be HPV positive, increased duration of oral contraceptive use was associated with an increase in the rate of cervical cancer [33]. The incidence of cervical cancer by duration of use included the following: 5 to 9 years (odds ratio [OR] 2.82) and ≥10 years (OR 4.03). While some studies suggest that adenocarcinoma appears to have a stronger association with oral contraceptives than does squamous cell cancer [34], others found a similar risk increase with increasing duration of oral contraceptives for both adeno- and squamous cell carcinomas [35].

•Intrauterine device – By contrast, both the copper and levonorgestrel intrauterine devices (IUDs) may be associated with lower rates of cervical cancer [36]. This is discussed in detail separately. (See "Intrauterine contraception: Background and device types", section on 'Benefits'.)

●Cigarette smoking – Smoking is associated with an increased risk of squamous cell carcinoma of the cervix but not of adenocarcinoma [19,25]. In one study, smoking increased the risk of squamous carcinoma by approximately 50 percent (RR 1.50, 95% CI 1.35-1.66) but did not increase the risk of adenocarcinoma (RR 0.86, 95% CI 0.70-1.05) [25].

●Genetics – While there is no well-established model of a genetic basis for cervical cancer, population studies have shown an increased incidence of cervical cancer within families. In the past, such familial clustering had been attributed to shared environmental exposures. However, subsequent data comparing full and half-siblings have demonstrated that heritable risk factors far outweigh the shared environmental components. As an example, a Swedish study of over 9000 siblings or half-siblings with cervical cancer or precancer attributed 64 percent of cases to genetics and only 36 percent to environmental exposures [37]. Investigations are ongoing to identify genetic alterations that may make patients less likely to clear persistent HPV infections and more susceptible to the development of cervical cancer. Findings to-date include an association of cervical cancer with a large variety of polymorphisms in a wide variety of genes, including germline variants [38], and those that regulate immunity and susceptibility [39], cytokine production [40,41], angiogenesis [40], tumor suppressor pathways [42,43], and signal transducers and activators of transcription pathways [44].

●Cervical cancer is less common in patients whose sexual partners are circumcised males [20]. (See "Neonatal circumcision: Risks and benefits", section on 'Cervical cancer in partners'.)

PATHOGENESIS — Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7 percent of cervical cancers [2]. The virology and molecular pathogenesis of HPV-associated malignancies are discussed in detail separately. (See "Virology of human papillomavirus infections and the link to cancer".)

Among the more than 40 genital mucosal HPV types identified, approximately 15 are known to be oncogenic (table 1). Subtypes HPV 16 and 18 are found in over 70 percent of all cervical cancers.

There are four major steps in cervical cancer development [45]:

●Oncogenic HPV infection of the metaplastic epithelium at the cervical transformation zone (the junction between the squamous epithelium of the ectocervix and the glandular epithelium of the endocervical canal).

●Persistence of the HPV infection.

●Progression of a clone of epithelial cells from persistent viral infection to precancer.

●Development of carcinoma and invasion through the basement membrane.

While genital tract HPV infection is extremely common, cervical cancer results in only a small proportion of infected patients. It has been estimated that 75 to 80 percent of sexually active adults will acquire genital tract HPV before the age of 50 [46,47]. Most HPV infections are transient, and the virus alone is not sufficient to cause cervical neoplasia. When HPV infection persists, the time from initial infection to development of high-grade cervical intraepithelial neoplasia and, finally, invasive cancer takes an average of 15 years, although more rapid courses have been reported [48].

Herpes simplex virus-2 infection as a cofactor in cervical cancer pathogenesis has been reported in some, but not all, studies [49-52]. Further investigation of this issue is needed.

The disease burden of genital HPV infection includes conditions other than cervical cancer, including anogenital warts, and cancer of the vulva, vagina, anus, and penis [53,54]. (See "Human papillomavirus infections: Epidemiology and disease associations".)

HISTOPATHOLOGY — The most common histologic types of cervical cancer are squamous cell carcinoma and adenocarcinoma; such cancers can be HPV associated or HPV independent [55]. The histopathologic types of cervical cancer are listed in the table (table 2).

The distribution of histologic types in the United States is [56,57]:

●Squamous cell carcinoma – 75 percent.

●Adenocarcinoma (including adenosquamous) – 25 percent; the incidence of invasive cervical adenocarcinoma and its variants has increased dramatically over the past few decades, particularly in younger patients [56,58,59]. (See "Invasive cervical adenocarcinoma", section on 'Epidemiology and risk factors'.)

Adenosquamous tumors exhibit both glandular and squamous differentiation. They may be associated with a poorer outcome than squamous cell cancers or adenocarcinomas [60-62].

●Other histologies – Neuroendocrine or small cell carcinomas can originate in the cervix in patients but are infrequent [63]. Rhabdomyosarcoma of the cervix is rare and typically occurs in young patients [64,65]. Primary cervical lymphoma and cervical sarcoma are also rare [66-68]. (See "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging" and "Small cell neuroendocrine carcinoma of the cervix", section on 'Introduction' and "Invasive cervical adenocarcinoma".)

Human papillomavirus (HPV) subtypes associated with squamous cell carcinoma are different from those associated with adenocarcinoma. In an international study of over 30,000 cervical cancers, the distribution of HPV subtypes was [69]:

●Squamous cell carcinoma – HPV 16 (59 percent of cases), 18 (13 percent), 58 (5 percent), 33 (5 percent), 45 (4 percent).

●Adenocarcinoma – HPV 16 (36 percent), 18 (37 percent), 45 (5 percent), 31 (2 percent), 33 (2 percent).

CLINICAL MANIFESTATIONS — Early cervical cancer is frequently asymptomatic, underscoring the importance of screening. In asymptomatic patients, cervical cancer may be discovered as a result of cervical cancer screening or incidentally if a visible lesion is discovered upon pelvic examination. (See "Screening for cervical cancer in resource-rich settings" and 'Physical examination' below.)

For those with symptoms, the most common ones at presentation are [70]:

●Irregular or heavy vaginal bleeding

●Postcoital bleeding

Some patients present with a vaginal discharge that may be watery, mucoid, or purulent and malodorous. This is a nonspecific finding and may be mistaken for vaginitis or cervicitis.

Approximately 44 percent of patients have localized disease at diagnosis, 34 percent have regional disease, and 15 percent have distant metastases [1]. Advanced disease may present with pelvic or lower back pain, which may radiate along the posterior side of the lower extremities. Bowel or urinary symptoms, such as pressure-related complaints, hematuria, hematochezia, or vaginal passage of urine or stool, are uncommon and suggest advanced disease. A discussion regarding how cervical cancer spreads and its staging is found elsewhere. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

DIAGNOSIS — The diagnosis of cervical cancer is made based upon histologic evaluation of a cervical biopsy.

Physical examination — A pelvic examination should be performed in any patient with symptoms suggestive of cervical cancer. Visualization of the cervix upon speculum examination may reveal a normal appearance or a visible cervical lesion; large tumors may appear to replace the cervix entirely. Any lesion that is visible should be biopsied regardless of previous benign cervical cytology results [71]. The only visible lesions that do not require biopsy are Nabothian cysts and only when this diagnosis is confirmed by an experienced examiner. (See "Benign cervical lesions and congenital anomalies of the cervix", section on 'Nabothian cysts'.)

Cervical cancer usually originates at the transformation zone (the junction between the squamous epithelium of the ectocervix and the glandular epithelium of the endocervical canal). The lesion may manifest as a superficial ulceration, exophytic tumor in the exocervix, or infiltration of the endocervix. Endophytic tumors can result in a cervix that appears enlarged, smooth, and indurated, often referred to as a "barrel shaped cervix." Among cervical adenocarcinomas, approximately one-half are exophytic, others diffusely enlarge or ulcerate the cervix, and approximately 15 percent have no visible lesion because the carcinoma is within the endocervical canal.

A thorough pelvic examination, including rectovaginal examination with assessment of tumor size and vaginal or parametrial involvement, is required for staging cervical cancer. This is discussed in detail separately. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Staging procedure'.)

Other suspicious physical examination findings are palpable groin or supraclavicular lymph nodes.

Cervical cytology — Cervical cytology is the principal method for cervical cancer screening in the United States and is the method of choice when cervical cancer is suspected. In other countries, such as Australia, the United Kingdom, and Netherlands, human papillomavirus (HPV) testing is the principal method for cervical cancer screening, with cervical cytology being performed only if the HPV high-risk nucleic acid test is positive.

Cervical cancer screening, techniques for cervical cytology testing, the use of HPV testing, and interpretation of results are discussed in detail separately. (See "Screening for cervical cancer in resource-rich settings" and "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing" and "Cervical cancer screening: The cytology and human papillomavirus report".)

Cervical biopsy and colposcopy — Cervical biopsy may be performed as part of an initial evaluation or along with a full staging procedure, depending on the level of suspicion of malignancy and the patient's access to health care. The approach to cervical biopsy differs depending upon the patient's presentation and findings on pelvic examination:

●In patients with a grossly visible lesion, a suspected diagnosis of cancer must be confirmed by a biopsy of the lesion. We prefer to take the biopsy from the area of the lesion that looks most suspicious with care to avoid grossly necrotic areas, as these are often nondiagnostic. Any cervix that is unusually firm or expanded should be sampled by punch biopsy and endocervical curettage, even if the cervical cytology test does not show evidence of neoplasia. Biopsy in patients with gross lesions may result in significant bleeding and even hemorrhage, and practitioners should be adequately prepared with hemostatic agents such as Monsel solution and the ability to pack the vagina should bleeding be significant.

●Patients without a visible lesion (eg, symptomatic, abnormal cervical cytology) should undergo colposcopy with directed biopsy. Patients in settings in which colposcopy is not available may undergo directed biopsy with the aid of visual inspection methods. (See "Colposcopy" and "Screening for cervical cancer in resource-limited settings", section on 'Alternate: Visual inspection methods'.)

●Cervical conization or loop electrosurgical excision procedure is necessary if malignancy is suspected but is not found with directed cervical biopsies (eg, some patients with high-grade cervical intraepithelial neoplasia, inadequate colposcopy, and in patients with an endocervical curettage that is positive for moderate to severe dysplasia). Conization is also required in the setting of microinvasive cancer to determine whether conservative or radical surgery is required for treatment.

●Techniques for colposcopy and cervical biopsy are discussed in detail separately. (See "Colposcopy".)

Other diagnostic modalities — Imaging studies are not typically part of cervical cancer diagnosis, although some are used for staging and evaluation of patients with known malignancy. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Staging procedure'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of cervical cancer includes other conditions that result in irregular or heavy vaginal bleeding, vaginal discharge, or a visible cervical lesion. Postcoital bleeding, which is the most specific presentation of cervical cancer, may also result from cervicitis and other benign conditions. Evaluation of patients with these conditions is discussed in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Approach to the patient with postmenopausal uterine bleeding" and "Vaginitis in adults: Initial evaluation".)

Benign tumor-like lesions that may mimic cervical cancer include Nabothian cysts, mesonephric cysts, cervical ectropion, ulcers associated with sexually transmitted infections, reactive glandular changes from inflammation, and endometriosis. (See "Benign cervical lesions and congenital anomalies of the cervix".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management" and "Society guideline links: Treatment of cervical cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cervical cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Cervical cancer treatment; early-stage cancer (Beyond the Basics)" and "Patient education: Fertility preservation in early-stage cervical cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology

•Cancer of the uterine cervix is the third most common cancer diagnosis and cause of death among gynecologic cancers in the United States. In countries that do not have access to cervical cancer screening and prevention programs, cervical cancer remains the second most common type of cancer and third most common cause of cancer deaths among all types of cancer in females. (See 'Incidence and mortality' above.)

•The lifetime risk of developing cervical cancer for United States females is 0.7 percent. The median age at diagnosis of cervical cancer in the United States is 50 years old. (See 'Age distribution' above.)

●Pathogenesis – Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7 percent of cervical cancers. Subtypes HPV 16 and 18 are found in over 70 percent of all cervical cancers (table 1). (See 'Pathogenesis' above.)

●Risk factors – Risk factors for cervical cancer are mostly associated with an increased risk of acquiring or having a compromised immune response to HPV infection; these include early onset of sexual activity, multiple sexual partners, a high-risk sexual partner, history of sexually transmitted infections, history of vulvar or vaginal squamous intraepithelial neoplasia or cancer, and immunosuppression. Oral contraceptive use appears to be associated with an increased risk of cervical cancer. Cigarette smoking appears to be associated with an increased risk of squamous cell cancer but not adenocarcinoma. (See 'Risk factors' above.)

●Histopathology – The most common histologic types of cervical cancer are squamous cell (75 percent of cervical cancers) and adenocarcinoma (25 percent). The histopathologic types of cervical cancer are listed in the table (table 2). (See 'Histopathology' above.)

●Clinical presentation – Early cervical cancer is frequently asymptomatic, emphasizing the importance of screening. The most common symptoms at presentation are abnormal vaginal bleeding (including postcoital bleeding) and vaginal discharge. A lesion may or may not be visible or palpable on physical examination. (See 'Clinical manifestations' above and 'Physical examination' above.)

●Diagnosis – The diagnosis of cervical cancer is established by biopsy. Symptomatic patients without a visible lesion and those who have only abnormal cervical cytology should undergo colposcopy with directed biopsy and, if necessary, diagnostic conization. (See 'Diagnosis' above.)