Cervical cancer

Cervical cancer is a malignancy that arises from the cervix, usually adjacent to the squamocolumnar junction region and most of them are associated with persistent infection of Human Papilloma Virus (HPV). The most common histotypes are squamous cell carcinoma (80-90%) and adenocarcinoma (10-20%), while other histotypes are rare [1].

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Cervical cancer is the fourth most common cancer in women accounting for an estimated 604,000 new cases and 342,000 deaths worldwide [2, 3]. Almost 90% of the cases occur in resource-limited countries [2] and due to absence of screening and Human Papilloma Virus (HPV) vaccination programs it remains a significant cause of cancer morbidity and mortality [1]. It is often diagnosed in women in their sixth decade of life with a median age of 51. Adenocarcinoma appears earlier than SCC, with a mean patient presentation at 40-42 years [1]. Several risk factors are associated with HPV infection including early onset of sexual activity, multiple sexual partners, history of sexually transmitted infections, history of vulvar, vaginal or anal squamous intraepithelial neoplasia and immunosuppression (particularly HIV) [4].

HPV plays a crucial role in the development of cervical carcinoma and can be detected in almost all the cases.

While genital tract HPV infection is extremely common, cervical cancer appears in only a small proportion of patients where the infection persists.

There is a well-established set of necessary transitions leading from normal cervix to invasive cancer that includes:

• 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 precancerous lesions.
• Development of carcinoma and invasion through the basal membrane.

Progression to pre-invasive neoplasia and ultimately to cancer highly depends on the HPV type and time of persistence. Factors associated with HPV persistence and progression include immunosuppression, particularly due to HIV, multiparity and smoking.[1]

The time from initial infection to development of high-grade cervical intraepithelial neoplasia and, finally, invasive cancer takes an average of 15 years [5-7].

The most common histopathologic types of cervical cancer are squamous cell carcinoma and adenocarcinoma and both can be related to the presence or absence of HPV infection.

HPV-associated cervical squamous cell carcinoma develops from a high-grade squamous intraepithelial lesion (HSIL) and is mostly associated with HPV 16, 18, 58 and 33.

HPV-independent squamous cell carcinomas are less common (5-7% of all squamous cell carcinomas) and are usually associated with p53 mutation, but its pathogenesis is less known.

Most adenocarcinomas are related to high-risk HPV infection, most commonly to 18, 16 and 45 types.

Adenocarcinomas which are HPV-independent include gastric, clear cell and mesonephric types. Gastric type is the most common of this group (10% of all adenocarcinomas) and occurs later, around 50-55 years of age. Clear cell carcinomas are usually associated with diethylstilbestrol (DES) exposure. The mesonephric type is extremely rare (<1% of adenocarcinomas) and is thought to arise from remnants of the embryological male reproductive system. [1]

Early cervical cancer is frequently asymptomatic and usually detected in the context of screening programs.

For symtomatic patients, vaginal bleeding, especially post-coital, is the most common symptom. Unfrequently women experience abnormal vaginal discharge (watery, mucoid purulent,  or malodorous). Other symptoms may be related to advanced stages of the disease due to the local or distant spreading of the cancer. [8]

Cancer of the uterine cervix has traditionally been staged clinically, but surgical and radiologic evaluation are now part of staging assessement. Patients with cervical cancer should be staged according to  2021 TNM  classification but FIGO 2018 staging system  should also be documented. [9-11]

In experienced hands, ultrasound seems to be an effective alternative to MRI in the diagnostic approach to cervical cancer patients in order to detect extent of loco-regional disease in the pelvis. [12]

Local tumor extent and pelvic lymph nodes can be assessed by a transvaginal or transretal approach. Transrectal placement decreases the risk of bleeding and allows a better view of the exocervix. Transabdominal ultrasound is used to assess tumor spread. [13]

The following ultrasound parameters influence cervical cancer management, therefore should be included in a systematic checklist:

• Tumour identification: cervical cancer usually appears as a richly vascularized hypoechogenic (squamous cell carcinoma) or iso/hyperechogenic mass (adenocarcinoma).
• Tumour site of origin: endocervical, exocervical or combined
• Tumour size (three dimensions): maximum craniocaudal, antero-posterior, laterolateral
• Depth of stromal invasion: proportion of infiltrated stroma to the whole cervix: < 50%, 50-75%, >75%
• Lateral tumor-free distance: minimum diameter between the tumour and pericervical fascia
• Cranial tumour-free margin: from the upper margin of the tumour until the internal orifice (Cranial tumour-free margin ≥ 10mm).
• Parametrial involvement: hyperechogenic line on ultrasound and hypointense line on MRI
  • Grade 0: Intact pericervical fascia (negative predictive value of 98-100%);
  • Grade 1: disrupted pericervical fascia but no tumor progression through the fascia into the parametrium;
  • Grade 2: incipient infiltration of pericervical fascia usually in depth ≤5 mm;
  • Grade 3: nodular infiltration of parametrium;
  • Grade 4: discontinued parametrial involvement (metastatic paracervical LNs)
• Bladder and rectal invasion:  assessed by sliding sign maneuver. A positive sliding (i.e. the tumour slides over the bladder or the rectum) has a high negative predictive value for bladder/rectal invasion.
• Lymph node status: assessment by standardized VITA terms [14, 15]

In locally advanced cervical cancer PET-CT or CT are recommended to evaluate extra-pelvic spreading. [16]

Approximately 44% of patients have localized disease at diagnosis, 34% have locally advanced disease, and 15% have distant metastases. The 5-year survival rate are 85% for stage I, 56% for stage II, 39% for stage III and 12-24% for stage IV [8, 17].

FIGO staging and node status are the most important prognostics factors. [18]

The two main strategies to control cervical cancer include: prevention of invasive cancer by HPV vaccination and screening for precancerous lesions. [10]

Vaccination is proved to be effective in reducing prevalence of high-risk HPV types and high-grade cervical lesions.[10]

Several cervical screening strategies have been found to be effective (HPV DNA testing, cytology and visual inspection with acetic acid). [10, 19]

HPV DNA testing leads to a greater reduction in cervical cancer incidence and  mortality than cytology does.[10]

A single screening modality is unlikely to be universally applicable, but it is possible to find a cost-effective of cervical cancer screening to each country.

The combination of HPV vaccination and screening has the potential to eliminate cervical cancer in the future.[10]

1.           Board, W.C.o.T.E., Female Genital Tumours. 2020: International Agency for Research on Cancer.

2.           Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424.

3.           Sung, H., et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021. 71(3): p. 209-249.

4.           International Collaboration of Epidemiological Studies of Cervical, C., Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer, 2007. 120(4): p. 885-91.

5.           Schiffman, M., et al., Carcinogenic human papillomavirus infection. Nat Rev Dis Primers, 2016. 2: p. 16086.

6.           Schiffman, M., et al., Human papillomavirus and cervical cancer. Lancet, 2007. 370(9590): p. 890-907.

7.           Demarco, M., et al., A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs. EClinicalMedicine, 2020. 22: p. 100293.

8.           Siegel, R.L., et al., Cancer statistics, 2022. CA Cancer J Clin, 2022. 72(1): p. 7-33.

9.           Bhatla, N., et al., Revised FIGO staging for carcinoma of the cervix uteri. Int J Gynaecol Obstet, 2019. 145(1): p. 129-135.

10.         Bhatla, N. and L. Denny, FIGO Cancer Report 2018. Int J Gynaecol Obstet, 2018. 143 Suppl 2: p. 2-3.

11.         Olawaiye, A.B., et al., The new (Version 9) American Joint Committee on Cancer tumor, node, metastasis staging for cervical cancer. CA Cancer J Clin, 2021. 71(4): p. 287-298.

12.         Epstein, E., et al., Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial. Gynecol Oncol, 2013. 128(3): p. 449-53.

13.         Fischerova, D., Ultrasound scanning of the pelvis and abdomen for staging of gynecological tumors: a review. Ultrasound Obstet Gynecol, 2011. 38(3): p. 246-66.

14.         Fischerova, D., et al., Terms, definitions and measurements to describe sonographic features of lymph nodes: consensus opinion from the Vulvar International Tumor Analysis (VITA) group. Ultrasound Obstet Gynecol, 2021. 57(6): p. 861-879.

15.         Palsdottir, K., et al., Interobserver agreement of transvaginal ultrasound and magnetic resonance imaging in local staging of cervical cancer. Ultrasound Obstet Gynecol, 2021. 58(5): p. 773-779.

16.         Cibula, D., et al., The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients With Cervical Cancer. Int J Gynecol Cancer, 2018. 28(4): p. 641-655.

17.         Wright, J.D., et al., Prognostic Performance of the 2018 International Federation of Gynecology and Obstetrics Cervical Cancer Staging Guidelines. Obstet Gynecol, 2019. 134(1): p. 49-57.

18.         Cole, L. and M.H. Stoler, Issues and inconsistencies in the revised gynecologic staging systems. Semin Diagn Pathol, 2012. 29(3): p. 167-73.

19.         Sankaranarayanan, R., Screening for cancer in low- and middle-income countries. Ann Glob Health, 2014. 80(5): p. 412-7.

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