Continuing Education Activity

After reviewing this article, participants should understand how to diagnose, treat, and post-treatment monitoring. This article reviews the natural history, epidemiology, clinical presentation, differential diagnosis, evaluation, treatment, complications, and prognosis of squamous cell cervical cancer. It also outlines the importance of patient education and healthcare teamwork in enhancing cervical cancer management outcomes.

Objectives:

• Identify the pathologic processes that can lead to the development of cervical cancer.
• Assess the differential diagnosis of cervical cancer.
• Evaluate the treatment options available for the management of cervical cancer.
• Communicate interprofessional team strategies for improving care coordination for effective management of cervical cancer.

Introduction

Cervical cancer is a cancer of the female reproductive system that originates in the cervix. It is the fourth leading cause of cancer in women after breast, lung, and colorectal cancer.[1] It is easily preventable, owing to the universal application of Papanicolaou smear screening that has resulted in the early detection of pre-cancerous lesions, which can be removed before they progress to invasive cancer. However, it is still a common genital cancer encountered in clinical practice in women of low and middle-income countries (LMICs) due to a lack of extensive screening.[2] Cervical cancers are often squamous-cell carcinomas that arise from infection with high-risk Human Papilloma Virus (HPV) serotype-16 and 18.

Anatomy Of Cervix

• Embryology: The cervix, along with fallopian tubes, the body of the uterus, and the upper third of the vagina, are all derived from the paramesonephric duct.
• Gross Structure: The cervix is the lowermost cylindrical part of the uterus in females, measuring about 2.5 cm in length. The interior cavity of the cervix is called the cervical canal. The cervical canal communicates above with the cavity of the body of the uterus through the internal os and below with the vaginal cavity through the external os. The lower part of the cervix projects into the anterior vaginal wall, which divides it into a supravaginal part and a vaginal part. The supravaginal part is related anteriorly to the bladder, posteriorly to the rectovaginal pouch (containing intestines) and rectum, and on either side to the ureter and uterine artery embedded in the parametrium. The space between the vaginal part of the cervix and the vagina forms the vaginal fornices.
• Microscopic Anatomy: The cervix is composed mainly of fibroelastic connective tissue. It can be divided into endocervix, cervical transformation zone, and ectocervix. The endocervix comprises simple columnar epithelium, which produces mucus, and the ectocervix comprises non-keratinized stratified squamous epithelium. The cervical transformation zone, or the squamocolumnar junction, represents the zone where the endocervix's columnar epithelium changes to the ectocervix's squamous epithelium. Cervical cancer mostly originates from this region.
• Vasculature:  Uterine artery.
• Lymphatics: External iliac, internal iliac, obturator, and sacral lymph nodes.
• Innervation: Sympathetic from T12 - L2 (contraction and vasoconstriction); parasympathetic from S2 - S4 (vasodilation); and viscerosensory fibers (pain sensations) pass along parasympathetic nerves.

Natural History And Pattern Of Spread

Cervical cancer incidence has dramatically declined in regions where screening programs have been implemented. About 70 percent of the current burden of cervical cancer comes from the low-socioeconomic areas where screening programs are not well-established.[1] Cervical cancer is most common in females who have multiple sexual partners and do not use condoms. High-risk sexual practices result in infection by the HPV. HPV integrates its DNA into the basal cells of the columnar junction (in the cervix's transformation zone), which results in the production of proteins (E6 and E7) that eventually cause dysplasia. Dysplasia of the cervical epithelium is also called cervical intraepithelial neoplasia(CIN). While CIN can progress to cervical cancer, regression can take place. Rates of progression to cancer vary in different studies.[3]

CIN does not necessarily develop in all women who get infected with HPV. The immune system clears off most of the HPV infection. The risk of CIN increases with the type of HPV (HPV 6 and 11 are low-risk types, whereas 16 and 18 are high-risk types), duration of infection, environmental factors like smoking, and immunosuppression in the patient. Fortunately, vaccination against HPV is available, which immunizes against several HPV types linked with cervical cancer, including HPV 16. As compared to other gynecological cancers, cervical cancer occurs in younger women. The mean age of diagnosis of cervical cancer is about 49 years. Most of these women are diagnosed with early-stage cancer and cured, though they might have to carry the burden of potential treatment-related side effects (eg, infertility). The majority of the women who are cervical cancer survivors are diagnosed with early-stage or locally advanced cancer. The median survival of women diagnosed with metastatic or recurrent cervical cancer is generally less than 2 years. The most common areas of metastases from cervical cancer are the lymph nodes, liver, lungs, and bones.

Etiology

About 95% of women with cervical cancer are infected with 1 or more HPV subtypes; HPV 16 and 18 are the most common (HPV-16 in 50% of women and HPV-18 in 10 to 15% of women).

High-Risk HPV (Oncogenic/Cancer-associated): type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69 and 82

Low-Risk HPV (Non-Oncogenic): type 6, 11, 40, 42, 43, 44, 54, 61, 72 and 81

However, not all women who harbor HPV infection develops cervical cancer. Most HPV infections 16 and 18 are asymptomatic and clear within 2 years. The presence of persistent infection and those who have associated co-factors like cigarette smoking or immunodeficiency are at higher risk for the progression of lesions to the development of invasive cancer. Apart from HPV 16 and 18 being the most common etiology discussed, studies have been conducted showing how cervical tar exposure can act synergistically with the co-existing HPV infection to cause cervical squamous cell cancer (co-carcinogenesis). The various ways of cervical tar exposure are cigarette smoking, the use of tar-based vaginal sanitization products, and fumes from burning wood, dung, and coal in poorly ventilated kitchens. Various other clinical characteristics that predispose an individual to cervical cancer are:

• Women with Sexually transmitted diseases (STDs) such as HIV, HSV 2
• Early-onset sexual activity
• Multiple or high-risk sexual partners
• Immunosuppressed individuals (following transplant surgery), viral infections, and HIV
• Combination of oral contraceptive and progestogen use
• Poor socioeconomic status and poor personal hygiene
• Tobacco use

Epidemiology

Incidence And Mortality

Cervical cancer is the fourth leading cause of cancer in women worldwide. In 2018, the incidence was approximately 569,847 and 311,365 deaths due to cervical cancer, which made it the fourth leading cause of cancer death in women.[1] About 84% of cervical cancer are from low socio-economic regions. This is because of the advent of PAP smear testing and HPV vaccination in developed countries, which have reduced the incidence and mortality by 75% in the last 50 years. In developing countries, cervical cancer is the second most common cause of cancer and the third most common cause of cancer mortality in women. In the United States, among gynecological cancers, cervical cancer ranks third in incidence and mortality.

Race Distribution

Cervical cancer occurrence is higher in certain racial groups. A United States national survey found age-corrected standardized mortality rates of hysterectomy to be higher in black women (10.1 per 100,000) as compared to white women (4.7 per 1000,00).[4] The incidence and mortality rates, respectively, per 100,000 in different races are as follows:[5]

• Hispanic/Latino: 9.6 and 2.6
• Non-Hispanic black: 9.1 and 3.6
• American Indian/Alaska Native: 8.7 and 2.5
• Non-Hispanic white: 7.1 and 2.1
• Asian/Pacific Islander: 6.0 and 1.7

Histopathology

Similar to squamous cell carcinoma elsewhere characterized by squamous differentiation where it can be affected by grade and degree of differentiation (well-differentiated, moderately differentiated, and poorly differentiated), (ranging from abundant to scant eosinophilic cytoplasm with or without intercellular bridges to small undifferentiated (primitive) cells), hyperchromatic nuclei, high nucleus to cytoplasmic ratio, mitosis (few to high) and abundant to lack of keratinization. WHO histologically classifies epithelial tumors of the cervix into squamous tumors and their precursor (squamous intraepithelial lesion) and squamous cell carcinoma into keratinizing, non-keratinizing, basaloid, warty, papillary, verrucous, squamotransitional, and lymphoepithelioma-like, each of these types has a specific morphologic and immunohistochemical characteristic. Some of the features that can help determine the invasiveness of squamous cell carcinoma include the presence of stromal inflammation, stromal desmoplastic reaction, numerous single or small clusters of highly dysplastic epithelial cells that look different from the ones in the rete ridges, elongated rete ridges, and loss of nuclear polarity. The histological grades include well-differentiated, moderately differentiated, and poorly differentiated. Recent data suggest that recurrence-free survival was significantly reduced in patients with poorly differentiated tumors.[6]

History and Physical

Cervical cancer is commonly diagnosed in women aged 35 to 45 years. A thorough history reveals the presence of essential risk factors that are associated with cervical cancer, such as an immunocompromised state, high-risk sexual behavior, multiple sexual partners, a history of sexually transmitted diseases, and tobacco smoking. Many women are asymptomatic. However, she can present with any of the following symptoms:

• Postcoital bleeding/intermenstrual bleeding
• Increased vaginal discharge
• Pelvic or low back pain

On inspection, the cervix often appears normal, or there may be cervicitis or erosion that bleeds with touch. Inguinal lymphadenopathy may be present.

Late complications that result due to the spread of cervical cancer include:

• Hydronephrosis may develop due to compression of the ureters by tumor
• Lower extremity edema may occur due to compression of veins and lymphatics in the pelvic region by tumor
• Lymphadenopathy, abdominal, chest, or bone abnormalities (eg, pain) due to metastases to these regions
• Advanced-stage cancer may present with acute heavy vaginal bleeding

Evaluation

There are 3 main tests involved in initial cervical cancer screening: cytology, HPV testing, and VIA ( Visual Inspection with Acetic acid). Abnormal results are followed by colposcopic evaluation and collection of specimens for biopsy testing, confirming the abnormal results and based on which further treatment would be planned.

Cervical Cytology (PAP Smear)

The PAP test is done by opening the vaginal canal with a speculum and getting cells from the squamocolumnar junction or the transformation zone. The obtained cells are examined under a microscope to look for abnormalities. Any abnormality warrant further evaluation. The collected specimen can be prepared for cytology by 2 methods: the conventional pap smear and the liquid-based-thin layer preparation.

It is performed in:

1. In all women from 21 to 65 years of age as a part of routine screening.

Current recommendations regarding screening for cervical cancer: (2012 ASCCP guidelines)

The following recommendations are valid for the general population, regardless of the age of sexual initiation or other risk factors. It does not concern those with a history of cervical cancer, high-grade cervical precancerous lesions, immunocompromised states like HIV infection, or those with DES exposure in utero.

• For women 21-30 years of age, pap testing is done every 3 years.
• For women 30-65 years of age, cervical cancer co-testing (PAP testing and HPV test) is done every 5 years or only PAP testing every 3 years. The screening is stopped at age 65, provided there is adequate prior negative screening result (3 consecutive negative cytology results or 2 consecutive negative co-testing results) in the last ten years, with the most recent test result being in the previous 5 years and no history of CIN 2 or higher in the previous twenty years. Screening should not be resumed even if the woman has a new sexual partner.
• Women with a post-hysterectomy status (done for benign conditions with the removal of the cervix) do not have a history of CIN 2 or higher in the past twenty years. Evidence of adequate prior negative screening is not required.[7]

2. Symptomatic women suspected of having cervical cancer (eg, those with post-coital bleeding, abnormal vaginal discharge, etc) 

 Various cytologic findings are described as

• Normal Cytology
• Atypical Squamous Cells of Undetermined Significance (ASC-US): Cells that do not display SIL but have abnormalities more than simple reactive changes
• Atypical Squamous Cells High-Grade Squamous Intraepithelial Lesion (ASC-H): Cells are raising concern about a high-grade squamous intraepithelial lesion (HSIL). Still, their presence is not sufficient to call them high-grade squamous intraepithelial lesions.
• Low-grade Squamous Intraepithelial Lesion (LSIL)
• High-grade Squamous Intraepithelial Lesion (HSIL)
• Atypical Glandular Cell (AGC)
• Squamous Cell Carcinoma
• Adenocarcinoma

HPV Testing

This test detects cellular changes or infections with high-risk HPV. Specimens for HPV testing can be obtained similarly to PAP smears. The sample is usually collected from the endocervix using a cervical spatula or a brush, and then the specimen is placed in the HPV transport medium. There are some liquid-based cytology sampling systems where the same sample can be used for cytology and HPV testing. Urine testing for HPV can also be an alternative in situations where routine cervicovaginal testing is not possible due to economic or cultural barriers. Commercial assays only test for high-risk HPV infections that are known to cause cervical cancer. In a limited resource setting, the self-collection of an HPV sample can be used. Self-sampling can be done using a tampon, cotton, dacron swab, or a cytobrush. Self-sampling is cost-effective and is 1 of the proposed strategies for increasing the number of women screened.[8][9] Self-collected samples are as sensitive as provider-collected samples.[10][11] The collected samples are checked for the presence of high-risk HPV DNA or mRNA. Studies have shown that mRNA-based HPV testing has higher specificity than DNA-based HPV testing.[12] It is also more cost-effective than DNA-based testing.[13]

The HPV test is recommended in women 30 years and older as a part of routine screening, as mentioned above. It can be used as a primary testing method or along with cytology (co-testing). HPV test has higher sensitivity than cytology testing, but there are concerns about specificity, especially in younger women.[14] Studies/systematic reviews have been conducted to compare the outcomes of HPV testing and cytology-based screening. Conclusions derived from these studies/systematic reviews are as follows:

• HPV testing is more efficient than cytology in earlier detection of persistent high-grade lesions, thus providing a more extended low-risk period. However, it can lead to overdiagnosis of regressive CIN 2, especially in younger women.[15]
• Primary HPV DNA screening detected more cervical lesions than primary cytology in 1 screening round of 5 years.[16]
• The incorporation of HPV testing along with pap tests in the screening program in women in their mid-30s has led to decreased incidence of CIN 2, CIN 3, and invasive carcinoma in subsequent screening exams.[17][18]

Though studies have shown increased detection rates with HPV testing, it has also been implicated in a higher rate of false-positive results and colposcopy, which could lead to overdiagnosis and overtreatment.[19][20]

Visual Inspection With Acetic Acid (VIA)

In this test, 5% acetic acid is applied to the cervix. Acetic acid dehydrates the abnormal areas containing increased amounts of nuclear material and protein. These abnormal areas turn acetowhite, whereas healthy cells containing glycogen remain normal. Schiller's iodine can also be employed (VILI-visual inspection with Lugol's iodine). In VILI, healthy cells containing glycogen take up iodine and turn mahogany brown, whereas abnormal areas remain unstained. These abnormal areas can then be biopsied. Dull white plaques with ill-defined borders are considered LSIL, and those with sharp and thick edges are considered HSIL. Though it has low specificity, its false-negative rate is quite low. Hence, VIA can be a good alternative in a low-resource setting where pap screening does not exist.

Colposcopy

Colposcopy is the magnified visualization of the cervix where abnormal areas, if identified, are biopsied. Colposcope is a binocular instrument with a magnification power of 10-20 times. Colpomicroscope, on the other hand, magnifies 100-300 times. In a colposcopic examination, the patient is put in a lithotomy position, and the cervix is exposed with a bivalve speculum. The colposcope is then focused on the external os at a distance of about 20cm. The cervix is then swabbed and cleaned with saline gently to remove mucus but not provoke any bleeding. The squamocolumnar junction is then visualized before and after the application of acetic acid. Acetic acid precipitates proteins, and abnormal areas appear acetowhite. Using a green light filter facilitates a better assessment of the vascular architecture. The cervix is then painted with Schiller's iodine, which differentiates darker glycogen-laden cells from the paler glycogen-free cells, which are abnormal. In postmenopausal women, a 1-2 week daily estrogen therapy can be given, which allows the squamocolumnar junction to pout out and hence improve visualization. In the context of cervical cancer, abnormal cells on a pap smear or follow-up of a treated cervical cancer lesion are the most common indications for colposcopy.

Colposcopic reporting is as follows:

• Satisfactory Colposcopic Examination: columnar epithelium, squamous epithelium, and squamocolumnar junction visualized.
• Unsatisfactory: squamocolumnar junction not adequately visualized. In such a case, a specimen for biopsy can be collected by endocervical curettage.
• Abnormal Findings: Mosaics, punctuations, acetowhite areas, keratosis, atypical vessels, negative iodine area, raised area, etc

Risk Assessment: The next step in evaluation is risk assessment. Based on history, cytology, and HPV results, the immediate and 5-year risk of developing CIN 3+ is calculated for every individual. Based on this risk percentage, further evaluation is decided.

If the immediate CIN 3+ risk is more than 4%, then further evaluation is carried out based on this percentage

• 4-24%- Colposcopy
• 25-59%- Treatment or colposcopy
• 60-100%- Treatment preferred

If the immediate CIN 3+ risk is less than 4%, then we look at the 5-year CIN 3+ risk, and further evaluation is carried out based on this 5-year CIN 3+ risk:

• Less than 0.15%- Return in 5 years
• 0.15- 0.54%- Return in 3 years
• 0.55% or greater- Return in 1 year

Hence, the provider can use 6 clinical actions while managing a patient with abnormal cervical cancer screening results: 1-year surveillance, 2-year surveillance, 5-year regular screening, colposcopy, optional colposcopy or treatment, and treatment.

Immediate And Five-Year Risk Assessment For CIN 3+

At Kaiser Permanente Northern California (KPNC), a prospective longitudinal cohort study was performed (from 2003 to 2017), where 1.5 million patients were followed up for over a decade. Tables of risk estimates have been generated from this study. These risk-assessment tables are based on the patient's history and current and previous screening results.[21] The applicability of these risk-assessment tables has been confirmed in regions and populations outside of The United States in other data sets obtained from clinical trials and screening programs.[22] These tables are organized under 5 clinical scenarios:

Scenario 1: Abnormal Screening Result

1. In patients with no/unknown prior HPV test results and a current HPV negative result, the following are management recommendations as per current cytology results:

• NILM: 5-year follow-up
• ASC-US: 3-year follow-up
• LSIL: 1-year follow-up
• ASC-H and AGC: Colposcopy
• HSIL+: Colposcopy or treatment
• ALL (primary HPV screening without cytology): 5-year follow-up

2. In patients with no/unknown prior HPV test results and  a current HPV positive status, the following are management recommendations as per current cytology results:

NILM: 1-year follow up

• ASC-US and LSIL: Colposcopy
• ASC-H, AGC, HSIL+: Colposcopy or treatment
• ALL: Reflex cytology testing

3. In patients with a prior HPV negative screen and a current HPV negative status, the following are the management recommendations as per current cytology results:

• NILM: 5-year follow-up
• ASC-US: 3 -year follow-up
• LSIL: 1-year follow-up
• ASC-H, AGC, HSIL+: Colposcopy
• ALL: 5-year follow-up

4. In patients with prior HPV negative screen and a current HPV positive status, the following are the management recommendations as per current cytology results:

• NILM, AS-CUS, LSIL: 1-year follow-up
• ASC-H, AGC: Colposcopy
• HSIL+: Colposcopy/treatment

Scenario 2: Surveillance for results not requiring immediate colposcopic referral

1. Follow-Up of HPV negative ASCUS and current HPV negative status, the following are the management recommendations as per current cytology results:

• NILM: 5-year follow-up
• ASC-US, LSIL: 1-year follow-up
• ASC-H, AGC, HSIL+: Colposcopy
• ALL: Followed up with co-test rather than the primary HPV test

2. Follow-Up of HPV negative ASCUS and current HPV positive status, the following are the management recommendations as per current cytology results:

• NILM, ASC-US, LSIL: 1-year follow up
• ASC-H, AGC: Colposcopy
• HSIL+: Colposcopy/treatment

3. Follow-Up of HPV negative LSIL and current HPV negative status, the following are the management recommendations as per current cytology results:

• NILM: 3-year follow-up
• ASCUS, LSIL: 1-year follow-up
• ASC-H, AGC, HSIL+: Colposcopy
• ALL: Follow-up with co-test rather than the primary HPV test

4. Follow-Up of HPV negative LSIL and current HPV positive status, the following are the management recommendations as per current cytology results:

• NILM: 1 year-follow-up
• ASC-US, LSIL, ASC-H, AGC: Colposcopy
• HSIL+: Colposcopy/treatment

5. Follow-up of HPV negative LSIL and 2 negative co-tests: 3-year follow-up is recommended

6. Follow-Up of HPV positive NILM and current HPV negative status, the following are the management recommendations as per current cytology results:

• NILM, ASC-US. LSIL: 5-year follow-up
• ASC-H, AGC: Colposcopy
• HSIL+: Colposcopy/treatment
• ALL: 1-year follow-up

7. Follow-Up of HPV-positive NILM and current HPV-positive status, the following are the management recommendations as per current cytology results:

• NILM, ASC-US, LSIL, AGC, ASC-H: Colposcopy
• HSIL+: Colposcopy/treatment

8. Follow-up of HPV positive NILM and 2/3 negative co-test: 3-year follow-up is recommended

Scenario 3: Receipt of Colposcopy/Biopsy Result

1. If the colposcopic biopsy diagnosis is normal or CIN 1, the recommended management is a 1-year follow-up, regardless of the results of preceding colposcopic results. However, patients with high-grade cytologic findings but low-grade histologic findings represent a high-risk group (eg, CIN 1 preceded by HSIL or ASC-H). They are managed as follows:

Management of histologic LSIL (CIN 1) preceded by HSIL cytology:

Three options can be opted for in such a case

I. Review of cytologic, histologic, and colposcopic findings and management of the revised diagnosis as per ASCCP guidelines

II. Observation with colposcopy and cytology at 1 year in women <25 years and observation with Colposcopy and HPV testing at 1 year in women 25 years and above. An observation is only recommended if the entire squamocolumnar junction and upper limit of the lesions are visualized and endocervical sampling is <CIN 2

III. Immediate diagnostic excision (except in pregnant women)

Management Of Histologic LSIL (CIN 1) Preceded By ASC-H Cytology: 

I. Review of cytologic, histologic, and colposcopic findings and management of the revised diagnosis as per ASCCP guidelines

II. Observation with cytology (for women under 25 years) and an HPV test (in women 25 years or older) at 1 and 2 years. The observation is only recommended if the entire squamocolumnar junction and upper limit of the lesions are visualized and endocervical sampling is negative.

For both HSIL and ASC-H, if an observation has opted and at 1 year, all tests are negative. Age-appropriate re-testing (ie, colposcopy and cytology in women less than 25 years and colposcopy and HPV testing in women more than 25 years) is done in 1 year. If all tests are again negative at 1 and 2-year follow-up periods, HPV-based testing is recommended in 3 years. Then, the patient can proceed with long-term surveillance (HPV-based testing for 3 years for at least 25 years even if it continues beyond 65 years of age; discontinuation of screening is recommended if a patient has limited life expectancy). If there is an abnormal result at any point in time during surveillance, repeat colposcopy and management based on biopsy results is recommended. An excisional biopsy is recommended for HSIL cytology at the 1-year visit if it persists (except in women under 25 years, where observation is preferred for 1 more year, and if it continues at the next 1-year follow-up, diagnostic excision is performed). An excisional biopsy is recommended for ACS-H cytology, which persists at the 2-year visit.

2. If the colposcopic biopsy result is CIN 2, CIN 3, AIS (adenocarcinoma in situ), or cancer, the patient is referred for treatment.

Scenario 4: Surveillance For Results Less Than CIN 2 (No Treatment) 

1. In patients with a previous colposcopy result of <CIN2+ (after referral for low-grade cytology (ASC-US or LSIL, regardless of HPV status, or HPV positive NILM)) and a current HPV negative status, the following are the management recommendations as per the current cytology results:

• NILM: 3-year follow up
• ASC-US/LSIL: 1-year follow-up
• ASC-H, AGC, HSIL+: Colposcopy
• ALL: 3-year follow-up

2. In patients with a previous colposcopy result of <CIN2+ ( after referral for low-grade cytology) and current HPV-positive status, the following are the management recommendations as per current cytology results:

• NILM, ASC-US, LSIL: 1-year follow-up
• ASC-H, AGC, HSIL+: Colposcopy

3. In patients with a previous colposcopy result of <CIN2+ (after referral for high-grade results- ASC-H, AGC, HSIL+) and a current HPV negative status, the following are the management recommendations as per current cytology results:

• NILM, ASC-US, LSIL: 1-year follow-up
• ASC-H, AGC: Colposcopy
• HSIL+: Treatment preferred

4. In patients with a previous colposcopy result of <CIN2+ (after referral for high-grade results- ASC-H, AGC, HSIL+) and a current HPV positive status, the following are the management recommendations as per current cytology results:

• NILM,ASC-US/LSIL: Colposcopy
• ASC-H, AGC: Colposcopy
• HSIL+: Treatment preferred

Scenario 5: Follow-up After Treatment For CIN 2/3

1. In patients with HPV negative status at follow-up, cytology triage is used for guiding management as follows:

• NILM, ASC-US, LSIL: 1-year follow-up
• High grade ( ASC-H, AGC, HSIL+): Colposcopy
• ALL: 1-year follow-up

2. In patients with HPV-positive status at follow-up, cytology triage is used for guiding management as follows:

• NILM, ASC-US, LSIL: Colposcopy
• High grade: Colposcopy/Treatment

3. In CIN, 2/3 treated patients with 2-3 negative follow-ups and current negative test results (either a negative co-test or negative HPV test); recommended management is as per previous testing results.

• Previous 1 X negative HPV /co-testing result: 1-year follow-up
• Previous 2 X negative HPV/co-testing result: 3-year follow-up
• The guidelines mentioned above may not be feasible everywhere, especially in LMICs, where cytology-based programs are challenging to implement. Based on the available evidence, WHO recommends a screen-and-treat approach using Visual inspection with acetic acid (VIA) and treatment with cryotherapy or, when feasible, HPV testing followed by treatment.

Treatment / Management

HPV VACCINATION

There are 3 HPV vaccines available. These are

1. Quadrivalent against HPV types 6,11,16 and 18

2. 9-Valent against 6,11,16,18,31,33,45,52 and 58

3. Bivalent against 16 and 18

HPV vaccination is recommended in both males and females. As men cannot develop cervical cancer, the HPV vaccine may prevent or reduce the risk of genital diseases such as genital warts, penile cancer, anal cancer, and the spread of HPV to sexual partners. It is not recommended in pregnant patients due to inadequate evidence of safety. These vaccines provide excellent seroconversion rates (93 to 100 % in females and 99-100 % in males). Higher antibody titers are obtained for younger individuals. Mild injection site reactions can be expected. It is not effective in clearing out HPV infections, warts, or intraepithelial neoplasia that is already present.

ACIP (Advisory Committee on Immunization Practices) Vaccination Recommendation For HPV

The 9-valent vaccine is the recommended one. For individuals less than 15 years of age, 2 doses are recommended that should be 6 months apart. For more than 15 years and immunocompromised, 3 doses are recommended at 0, 1, 2, and 6 months. The optimal time to administer the HPV vaccine is before the sexual debut. The recommended age for HPV vaccination is 11 to 12 years. Catch-up vaccination is recommended for 13-26 years if HPV vaccination is not previously received or completed. For older adults, catch-up vaccination is usually not recommended. For more than 26 years, the decision to vaccinate is an individual one. However, it can be considered in 27-45-year-old individuals if there is a high risk. Most insurance providers do not cover HPV immunizations for people over 26.

Various trials have been performed to demonstrate the effect of HPV vaccination in patients treated with excision for CIN 2+. Meta-analysis and systematic review of these studies have shown a decreased recurrence of any grade CIN in vaccinated patients who were CIN 2+ treated than those who were unvaccinated ( 6 versus 10 percent)[23]. Hence, the vaccine's potential role in CIN-managed individuals must be explored further. 

 Treatment Options For CIN 2,3

1. Local ablative therapy: Cryosurgery, fulguration/electrocoagulation, laser ablation. 
2. Excision of abnormal tissue (diagnostic/therapeutic): Cold knife conization, laser conization, LLETZ (large loop excision of the transformational zone), Loop electrosurgical excision procedure.
3. Surgery: Hysterectomy, hysterectomy with removal of vaginal cuff if CIN extends to the vaginal wall.

Treatment Of Invasive Cervical Cancer

Early-Stage Cervical Cancer includes FIGO (International Federation of Gynecology and Obstetrics) stages IA1, IA2, IB1, and IB2. The preferred management options are as follows:

• 1A1 With No Intermediate Or High-Risk Features: Cone biopsy or extra-fascial hysterectomy[24]
• 1A2-1B2: Modified radical hysterectomy with or without adjuvant therapy. Alternatives to modified radical hysterectomy include fertility-sparing surgery (conization, simple trachelectomy, or radical trachelectomy) in women who are in the reproductive age group. For those who cannot undergo surgery (co-morbidities or poor functional status), the preferred option is primary radiotherapy (RT) with or without chemotherapy.

Now those who undergo modified radical hysterectomy, adjuvant treatment if the following risk factors are present. For those having intermediate-risk factors (ie, tumor size more than 4cm; lymphovascular space invasion or deep cervical stromal invasion, RT is recommended. For those with high-risk factors (pathologically positive lymph nodes, parametrial invasion, positive surgical margins), chemoradiation is recommended.

Locally-Advanced Cervical Cancer: This includes FIGO stage IB3, stage II, stage III, and stage IVA. There is an initial pretreatment evaluation required before the recommended chemoradiation (weekly cisplatin- (40 mg/m²) with RT) for locally advanced cancer for the following purposes:

• Lymph node assessment by PET/CT scan to determine nodal metastases and accordingly design radiation fields.
• If the PET/CT scan reveals positive para-aortic nodal involvement, nodal metastases are confirmed by CT-guided biopsy, F-18 fluorodeoxyglucose (FDG) uptake, or a lymphadenectomy.
• Non-contrast CT/MRI in case of elevated creatinine/renal insufficiency to determine the cause of urinary tract obstruction (obstruction due to tumor or due to intrinsic renal disease). Hydronephrosis or kidney dysfunction is diagnostic of stage III, before chemoradiation treatment, treatment of urinary obstruction known to improve progression-free survival (PFS) and overall survival (OS).

For women undergoing chemoradiation, treatment must be completed in 8 weeks. Radiotherapy is delivered via External beam Radiotherapy (EBRT). Cervical brachytherapy can also be considered to maximize local control.

Recurrent/ Metastatic Cervical Cancer: About 15 to 61 % of women treated for early-stage cervical cancer develop distant metastases and multiple recurrences. For any suspected case of metastases/recurrence, a PET scan/CT scan is done to identify the metastases. It can be a locoregional recurrence (disease isolated to the pelvis) or a disease involving other organs outside of the pelvis. A vaginal recurrence, if suspected, then the suspected area is biopsied to prove the recurrent disease. The treatment options include hysterectomy or pelvic exenteration for those previously treated with radiotherapy. RT is preferred in those who are non-surgical candidates, provided they haven't already received RT. If the patient is a non-surgical candidate and has previously received RT, chemotherapy is the preferred option.

• Local Recurrence: Surgical resection occurs in the appropriate surgical candidates. RT plus chemotherapy is an acceptable alternative for non-surgical candidates, provided they have not received any radiotherapy previously.
• For disease limited to the nodes (para-aortic/supraclavicular lymph nodes), systemic chemotherapy or RT with/without chemotherapy. The choice depends on patient preference and institutional practice.
• Isolated metastatic disease (eg, involving the lung or liver): Surgical resection is preferred through which sustained clinical remission is possible to achieve.
• For patients who have recurrent cervical cancer along with metastases and are not surgical candidates, first-line therapy is chemotherapy plus bevacizumab. The preferred chemotherapy is a platinum-based regimen (cisplatin plus paclitaxel, carboplatin plus paclitaxel is an acceptable alternative for those with kidney disease or previous treatment with cisplatin). Treatment with a single chemotherapeutic agent is recommended for those not candidates for combination therapy or those in whom first-line treatment fails.

Differential Diagnosis

Based on the symptoms/examination findings, a few differential diagnoses of cervical cancer to be kept in mind are:

• Cervicitis (particularly granulomatous)
• Vaginitis
• Endometritis
• Pelvic inflammatory disorder
• Endometrial carcinoma
• Vaginal cancer
• Primary melanoma/Paget disease

Approach To Post-Coital Bleeding

The most common symptom of cervical dysplasia/cancer is post-coital bleeding. Benign conditions mostly cause it, but malignant diseases should be ruled out. Post-coital bleeding apart from cervical cancer can be seen in several other states as follows:

• Infectious causes like cervicitis, vaginitis, endometritis, and pelvic inflammatory disease
• Non-infectious reasons like other gynecologic malignancies (vulvar, vaginal, uterine cancers) and hormonal contraception can lead to change in the bleeding pattern, atrophic vaginitis, and lichen planes, lichen sclerosis, vulvar dermatitis, lacerations, and granulation tissue, etc

For any patient with post-coital bleeding, we need to take the following approach to come to a diagnosis:

1. History: A detailed history, we determine the volume and frequency of bleeding. Details about menstrual cycles, pregnancy, contraception, sexual activity, and previous pap smear testing results should be obtained.

2. Physical Examination: This reveals the most likely etiology/source of the bleed. It involves inspection of the external genitalia and urethra. Examination of the vagina and cervix with a speculum, the testing of uterus and adnexa bilaterally, and a general physical assessment should be done.

3. Lab Testing: Appropriate lab testing can be carried out based on examination and history, which usually includes

• Exclusion of pregnancy
• Pap testing
• Biopsy of the visible lesion or endometrial biopsy if there is a risk of endometrial cancer (especially older women having a high BMI)
• NAAT testing for chlamydia and gonorrhea
• Vaginal pH and wet mount for candida, trichomoniasis, and bacterial vaginosis

4. Colposcopy: This is performed in patients with a history of abnormal pap smear test results, a friable cervix on examination, or when no other cause of post-coital bleeding is identified.

5. Imaging: If the cause is not identified with the above approach, a pelvic ultrasound can be done to visualize the uterus. Hysteroscopy can be done if submucosal fibroids or endometrial polyps are identified on imaging.

Staging

One of the most distinctive features of an excellent staging method is defining the anatomical extent of the tumor, differentiating survival outcomes, and guiding its optimal management. As per FIGO, cervical cancer can be staged as follows:

STAGE I: Carcinoma confined only, to the cervix (extension to the corpus is disregarded)

IA: Invasive carcinoma, which can only be detected microscopically, maximum depth less than 5 mm

• IA1: measured stromal invasion less than 3mm in depth
• IA2: measured stromal invasion equal or more to 3mm but less than 5mm in depth

IB: Invasive carcinoma with measured deepest invasion equal to or greater than 5mm, ie (as clinically visible), cancer confined to the cervix.

• IB1: Equal to or greater than 5mm of stromal invasion and less than 2cm in greatest dimension
• IB2: Equal to or greater than 2cm but less than 4cm in the greatest dimension
• IB3: Equal to or greater than 4cm in greatest dimension

STAGE II: Carcinoma extends beyond the uterus, but the lower third of the vagina and the pelvic walls are not involved.

IIA: Cancer confined to the upper two-thirds of the vagina without the involvement of the parametrium.

• IIA1: Less than 4cm
• IIA2: Equal to or greater than 4cm

IIB: There is parametrial involvement but not up to the pelvic wall.

STAGE 3: Cancer involves 1 or some or all of the following: the lower third of the vagina,  the pelvic sidewalls, hydronephrosis or nonfunctioning kidney, paraaortic, or pelvic lymph nodes.

IIIA: Involvement of lower-third of the vagina with no extension to the pelvic sidewall.

IIIB: Extension to the pelvic sidewalls, hydronephrosis, or nonfunctioning kidney

IIIC: Involvement of pelvic, para-aortic lymph nodes, irrespective of tumor size and extent

• IIIC1: Metastasis to pelvic lymph nodes only
• IIIC2: Metastasis to para-aortic lymph nodes

STAGE IV: Extend beyond the true pelvis or involvement of the bladder or rectal mucosa (biopsy-proven)

IVA: Spread to the adjacent pelvic organs

IVB: Spread to distant organs

Prognosis

The significant prognostic factors that affect the survival in cervical squamous cell carcinoma include:

• Stage
• Nodal status
• Tumor volume
• Depth of cervical stromal invasion
• Lymphovascular space invasion

Staging is the most important prognostic factor, followed by nodal status. It was observed that for the same stage of cancer (stage IB or IIA), the 5-year survival after hysterectomy and lymphadenectomy were lower (50 to 74%) in those with lymph node metastases as compared to those without lymph node metastases (88-96%). The involvement of para-aortic nodes is associated with worse outcomes.

As per FIGO 2018 staging of cervical cancer, the 5-year overall survival rates (OS), and 5-year progression-free survival (PFS) rates of patients were determined.

The 5-year overall survival (OS) rates for different stages of cancer were as follows:

• Stage IB1- 95.3%
• Stage IB2- 95.1%
• Stage IB3- 90.4%
• Stage IIA1- 92.4%
• Stage IIA2- 86.4%
• Stage IIIC1- 81.9%
• Stage IIIC2- 56.3%

The 5-year progression-free survival (PFS) rates were as follows:

• Stage IB1- 94.0%
• Stage IB2- 91.0%
• Stage IB3- 88.5%
• Stage IIA1- 91.4%
• Stage IIA2- 86.4 %
• Stage IIIC1- 79.5%
• Stage IIIC2- 43.8%
• The 5-year OS and 5-year PFS for patients with 1-2 positive pelvic lymph nodes (PLNs) were 86% and 84%, respectively. The 5-year OS and 5-year PFS for patients with more than 2 PLNs were 73.7% and 70.2%, respectively.

Complications

Direct Complications Of Cervical Cancer:

• Hydronephrosis: Due to infiltration of ureter resulting in urinary obstruction
• Fistula Formation: Rectovaginal, vesicovaginal, urethrovaginal can occur in locally advanced disease.
• Congestion of lower limbs due to compression of veins/lymphatics
• CACS - cancer-anorexia-cachexia syndrome

Complications Of Treatment:

From many studies, it has been observed that quality of life is better after surgery/ chemotherapy as compared to those treated with either radiotherapy or chemoradiation. Various treatment-associated complications include:

• Ovarian Failure: That can result in infertility, premature menopause, sexual dysfunction.
• Sexual Dysfunction: This includes decreased vaginal lubrication and elasticity, orgasmic difficulties, changes in length and caliber of the vagina, dyspareunia
• Bowel/bladder dysfunction
• Intraoperative/postoperative bleeding, infection, uterine perforation are some of the complications associated with conization. Late complications include cervical insufficiency and cervical stenosis.

Deterrence and Patient Education

Patient education should be considered an important aspect when it comes to better management of any disease. In the context of cervical cancer, counseling should begin during their regular screening appointments for cervical cancer. Any clinician needs to maintain a good doctor-patient relationship, which allows them to covey their concerns freely. The patient should be educated about

• Importance Of pap smear screening: Women should be explained about the benefits of pap smear testing, how early detection of lesions can be effectively treated, the worsening prognosis associated with higher stages of cervical cancer, and complications of a more toxic modality of treatment required for higher stages of cervical cancer.
• Importance of HPV vaccination.
• Pros and cons of treatment vs no treatment
• Risk factors for cervical cancer and how it can be prevented
• Answering the various concerns regarding fertility and sexual functioning after treatment.

Enhancing Healthcare Team Outcomes

Various healthcare providers involved in the management of cervical cancer include primary physicians, gynecologists, obstetricians, radiologists, oncologists, and nurses. Effective management of any disease requires excellent interpersonal communication and collaboration between team members for providing improved patient-centered care. There is also a potential role of Emergency room doctors in cervical cancer screening. A study found a high prevalence of cervical dysplasia amongst women screened with pap smears in the urban ED.[25] ED screening has found to be feasible and has yielded a high rate of cancer detection.[26] In cervical cancer, there is a better understanding of etiology, earlier screening, and management exists. Despite this, there are a lot of barriers that exist against its effective management. One of the most important advances in the management of cervical cancer was the routine pap smear screening in sexually active women. However, screening is not routinely done in many LMICs, and as a result, they contribute to 70% of the worldwide burden of cervical cancer. Some of these barriers include:

• Barriers of lack of knowledge and awareness
• Psychological barriers (embarrassment, shyness, pain while undergoing the screening procedures)
• Structural barriers ( time-consuming procedure, expensive procedure, lack of transportation, settings at the health center such as infrastructure, cleanliness, lack of trained staff, malfunctioned equipment, insufficient medical advice from the health care provider were a few barriers mentioned in a study)
• Sociocultural and religious boundaries

Managing and eradication these barriers do not only require an active team of health care providers, but the government had a significant role to play in providing resources and funds. Many of these barriers mentioned above are reported from LMICs, where lack of resources is not uncommon. Education regarding cervical cancer screening can be 1 of the most effective tools, especially in LMICs, where there are various false notions about screening and cervical cancer. Amongst the LMICs, where the patient load is exhaustive, clinicians are often unable to educate every patient thoroughly. In such settings, every member of the health care system must be it the primary provider, the radiologist, or the nurse take the responsibility of educating and explaining the patient regarding the disease and management. Effective communication between a patient and healthcare provider alone can alone be beneficial in removing the taboo and stigma that exists about cervical cancer screening.

• Most importantly, screening and management guidelines exist as a result of various conferences and exhaustive research (clinical trials, meta-analysis, systematic reviews) where health care providers come and work together towards common goals and share their ideas. Revision of guidelines is critical to incorporate better, practical, and more feasible methods. In situations where enough data isn't available, expert opinion from a specialist may be taken to help better guide management. All this is possible with effective communication and coordination of care amongst different health care providers.

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Disclosure: Manisha Jain declares no relevant financial relationships with ineligible companies.

Disclosure: Faten Limaiem declares no relevant financial relationships with ineligible companies.