Cervical Cancer

Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. There are 2 major histologic types of ICC: squamous cell carcinoma (SCC) and adenocarcinoma. High-risk human papillomaviruses (hrHPVs) cause > 99% of SCCs and > 85% of adenocarcinomas. Early cervical neoplasia is asymptomatic, and diagnosis is made using routine screening methods, including the cervical Papanicolaou test with cytology, hrHPV testing, and biopsy. Treatment of precursor or dysplastic lesions depends on the severity of the dysplasia and the age of the patient. Management of ICCs depends on the stage and varies from excisional biopsy by cervical cone biopsy for microinvasive ICC to radical hysterectomy for more advanced cases. If there is extracervical spread, radiation and chemotherapy would be recommended.

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Epidemiology and Risk Factors

Epidemiology

  • Worldwide: 
    • > 80% of new cases worldwide occur in less-developed countries.
    • 3rd most common cancer diagnosis and cause of death in women
    • 500,000 new cases diagnosed annually
    • > 50% will prove fatal.
  • In the United States:
    • 8th most frequent cause of cancer among women
    • Accounts for < 3% of all cancer deaths in women
    • 14,000 new cases of invasive cervical cancer (ICC) are diagnosed annually.
    • Mean age at diagnosis: 50 years
    • > 50% of ICCs are detected in women who did not participate in a regular cervical cancer screening program.

Risk factors

High-risk human papillomaviruses (hrHPVs, “oncogenic viruses”) are strongly associated with high-grade lesions and progression to invasive cancer.

  • These viruses cause 99% of SCCs and > 85% of adenocarcinomas.
  • HPV may also cause cancers in 5 other sites: 
    • Vulva
    • Vagina
    • Anus
    • Oropharynx
    • Penis
  • High-risk HPV types are responsible for most ICCs: 
    • HPV-16 (60%)
    • HPV-18 (10%)
    • < 5% for each of the 13 other hrHPVs

HPV-related:

  • Early onset of sexual activity
  • Multiple sexual partners
  • Multiparity and young age at first birth
  • History of vulvar or vaginal squamous intraepithelial neoplasia or cancer
  • Immunosuppression
  • Human immunodeficiency virus (HIV) infection
  • Co-infection with Chlamydia trachomatis or herpes simplex virus

Non–HPV-related:

  • Low socioeconomic status
  • African American race
  • Use of oral contraceptives
  • Cigarette smoking (associated with SCC)
  • Family history
  • Negative risk factor: circumcised male partners

Pathophysiology

Human papillomavirus

  • Persistent infection with 1 of the 15 genotypes of hrHPVs causes almost all cases of ICC.
  • Most HPV infections are:
    • Asymptomatic and do not cause tissue changes
    • Detected between 20 and 24 years of age
    • Prevalence ↓ after the age of 24 years as immunity develops
    • Cleared spontaneously:
      • 50% in < 8 months
      • 90% in < 24 months
      • On average, high-risk HPVs clear in 13 months and low-risk HPVs in 8 months.
  • Since only a small proportion of women infected with HPV develop cancer, other risk factors are likely involved.

Pathogenesis

  • Entry of hrHPV into immature basal epithelial cells at points of access:
    • Squamocolumnar junction (transformation zone): between the squamous epithelium of the ectocervix and the glandular epithelium of the endocervical canal
    • Any area where there is squamous epithelial trauma and repair
    • Surfaces covered with mature, intact squamous epithelium are resistant to HPV infection. 
  • Persistence of HPV infection in the maturing squamous epithelium
  • Progression of a clone of epithelial cells from persistent viral infection to precancerous lesions via E6 and E7 proteins from hrHPV:
    • In 70% of ICCs, HPV is integrated into the host cell genome.
      • ↑ The expression of E6 and E7 genes 
      • May dysregulate oncogenes near sites of viral insertion
    • E6 protein:
      • Binds p53 → degradation of p53 → ↓ ability to keep cells with damaged DNA in G1 phase and ↓ ability to initiate apoptosis 
      • More mutations are likely → ↑ the likelihood of cancer
      • Also ↑ the expression of telomerase → cellular immortalization
    • E7 protein:
      • Binds retinoblastoma (RB) protein → RB degradation → releases control of the transcription factor, E2F → uncontrolled proliferation
      • Binds and inhibits the cyclin-dependent kinase inhibitors (p21 and p27) → uncontrolled proliferation 
  • Development of invasive carcinoma
    • After additional mutations occur
    • Typically occurs after many years in a minority of women with precursor lesions

Pathology of precursor lesions

  • Squamous intraepithelial lesions (SILs) are premalignant (preinvasive) lesions of invasive squamous cell cervical cancer. 
    • The SIL terminology is part of the Bethesda System of Nomenclature.
    • SIL is also called cervical intraepithelial neoplasia (CIN), or dysplasia.
  • Adenocarcinoma in situ (AIS) is the less commonly seen premalignant lesion of invasive adenocarcinoma of the cervix.

SIL classification:

  • Low grade (LSIL):
    • Corresponds with CIN 1 (low grade dysplasia)
    • Usually regresses on its own
    • Only a small minority proceed to HSIL.
  • High grade (HSIL): 
    • Corresponds with CIN 2 or CIN 3 (moderate or high grade dysplasia)
    • ↑ Risk for progression to carcinoma (compared to LSIL) 
    • Due to progressive deregulation of the cell cycle, usually by an hrHPV

Gross appearance of HSIL: 

  • Most common on anterior lip of cervix
  • Seen best when they become white after application of acetic acid

Microscopic appearance: 

  • LSIL: 
    • Immature squamous cells are confined to the lower 3rd of the epithelium
    • Koilocytic atypia (perinuclear halos)
  • HSIL/CIN 2:
    • More atypia and expansion of immature basal cells involving two-thirds of the epithelial thickness
  • HSIL/CIN 3:
    • Also called carcinoma in situ
    • o’cDiffuse atypia and loss of maturation
    • Expansion of the immature basal cells to the epithelial surface

Pathology of invasive carcinomas

Gross appearance: 

  • Exophytic 
  • Infiltrating

Microscopic appearance:

  • SCC: 
    • 75% of cases 
    • Composed of nests and tongues of malignant squamous epithelium 
    • Either keratinizing or nonkeratinizing
    • Invades the underlying cervical stroma
  • Adenocarcinoma 
    • 20% of cases
    • Composed of malignant endocervical cells with large, hyperchromatic nuclei 
    • Smaller amounts of mucin than normal glands
  • Adenosquamous carcinoma 
    • < 3% of cases 
    • Composed of intermixed malignant glandular and squamous epithelium 
  • Neuroendocrine cervical carcinoma (< 2% of cases) 
    • Appearance is similar to that of small-cell carcinoma of the lung.
    • Positive for hrHPVs
Micrograph images of cervical carcinoma

Micrograph images of cervical carcinoma:
(a): histopathologic examination of a punch biopsy specimen showing large-cell nonkeratinizing SCC
(b): higher-power histopathologic examination of a punch biopsy showing large-cell nonkeratinizing SCC

Image: “Role of surgery in breast metastasis from carcinoma of the cervix” by Yadav P, Manjunath N, Deo S, Shukla N, Durgapal P, Muduly DK. License: CC BY 2.0

Clinical Presentation

General

  • Usually asymptomatic in the early stages 
  • Often discovered as a result of:
    • Routine cervical cancer screening
    • Pelvic examination, with visible lesion identified on the cervix
  • Symptomatic patients may have:
    • Vaginal bleeding 
      • Irregular and/or abnormally heavy menstrual periods
      • Postcoital bleeding
    • Vaginal discharge
      • Foul-smelling
      • Watery, mucoid, or purulent
      • More commonly seen in large cancers
      • Frequently mistaken for cervicitis

Advanced disease

Signs and symptoms caused by tumor extension and invasion:

  • Pelvic or lower back pain that may radiate to the legs
  • Palpable lymph nodes in the groin
  • Lymphedema of the legs
  • Constipation
  • Hydronephrosis
  • Vaginal passage of urine or stool caused by fistulization of the bladder or bowel
  • Pressure on the bowel or bladder can cause local ischemia.
    • Hematochezia 
    • Hematuria 
  • Sites of distant metastases:
    • Supraclavicular lymph nodes
    • Liver
    • Lungs
    • Bone

Pelvic exam findings

  • Friable cervix
  • Erosions
  • Cervical mass
  • Bleeding
  • Fixed adnexa
Progressive cervical adenocarcinoma

A progressive cervical adenocarcinoma:
The image shows a rapidly progressing mass protruding from the cervix.

Image: “A case of endocervical adenocarcinoma detected 16 months after vaginal delivery” by Ulu İ, Haberal ET, Gülşen MS, Yoğurtçuoğlu EE, Kıran G, Çekmez Y, Kır G. License: CC BY 4.0

Diagnosis

The diagnosis of ICC is made by histologic examination of a cervical biopsy.

  • Pap testing and cytologic evaluation
    • Used for cervical cancer screening
    • Ectocervical and endocervical cells are collected to evaluate the transformation zone (area at risk for cervical cancer). 
    • May be done in conjunction with hrHPV testing
    • Results are reported using a standardized system (Bethesda system).
  • Colposcopy with biopsy
    • A procedure in which a colposcope (magnifying device) is used to enhance visualization of the cervix, identify macroscopic abnormal areas, and guide biopsy
    • This procedure may be done as a follow-up after an abnormal Pap test or as part of the initial evaluation (e.g., for a pelvic exam with grossly abnormal results).
  • Conization (cone biopsy)
    • Diagnostic excisional procedure that removes a cone-shaped portion of the cervix around the endocervical canal
    • Allows pathologic review of the entire transformation zone
    • May be required if malignancy is suspected but not found on colposcopy-directed biopsy
    • Technique options:
      • Scalpel (cold knife)
      • Laser
      • Loop electrosurgical excision procedure

Staging

  • Based on the American Joint Committee on Cancer and Union for International Cancer Control 8th edition
  • Provides guidance on prognosis and management
  • Clinical staging may be done through:
    • Physical examination
    • Cervical biopsy
    • Endoscopy 
      • Hysteroscopy
      • Cystoscopy
      • Proctoscopy
    • Imaging studies
      • Intravenous pyelogram (IVP): to evaluate for urinary tract obstruction
      • CT
      • MRI
      • PET
  • Statistics on the extent of disease at diagnosis (in the United States):
    • Localized disease in 45%
    • Advanced disease:
      • Regional disease in 36%
      • Distant metastases in 15%

TNM staging

Table: Tumor staging
Tumor (T) stageDescription
TXPrimary tumor cannot be assessed
T0No evidence of tumor
T1Confined to the uterus
  • T1a: diagnosed only by microscopy (divided into T1a1 and T1a2 based on depth of invasion)
  • T1b: visible lesion (divided into T1b1 and T1b2 based on the dimensions)
T2Invading beyond the uterus but not to the pelvic wall or lower 3rd of the vagina
  • T2a: without parametrial (surrounding tissue) invasion (divided into T2a1 and T2a2 based on the dimensions)
  • T2b: with parametrial invasion
T3Extension into the pelvic wall or lower 3rd of the vagina or causing hydronephrosis
  • T3a: involves the lower 3rd of the vagina but not the pelvic wall
  • T3b: involves the pelvic wall and/or causes hydronephrosis
T4Invasion of the bladder or rectum or extends beyond the pelvis
Table: Lymph node staging
Node (N) stageDescription
NXCannot be assessed
N0No lymph node metastasis
N0(i+)Isolated cancer cells in lymph nodes (≤ 0.2 mm)
N1Lymph node metastasis
Table: Metastasis staging
Metastasis (M)) stageDescription
M0No distant metastasis
M1Distant metastasis

Prognostic staging

The TNM stage can then be used to determine the prognostic stage group.

Table: Summary of prognostic stage group
Prognostic stage groupTumor (T) stageMetastasis (M) stage
IIAT1aM0
IBT1bM0
IIIIAT2aM0
IIBT2bM0
IIIIIIAT3aM0
IIIBT3bM0
VIIVAT4M0
IVBAnyM1

Management

Management options

  • Conization:
    • Loop electrosurgical excision procedure
    • Cold knife
    • Laser
  • Radical cervicectomy: surgical removal of the cervix, upper part of the vagina, and adjacent parametrium
  • Hysterectomy:
    • Simple:
      • Cervix and uterus are removed.
      • Surrounding structures are spared.
    • Radical:
      • Cervix and uterus are removed.
      • Parts of the vagina and parametrium are also removed.
  • Radiation therapy:
    • External beam radiation therapy (EBRT)
    • Brachytherapy:
      • Localized radioactive implants to the cervix
      • Usually contain cesium
      • Allows a higher dose of radiation and spares surrounding tissue
  • Chemotherapy:
    • Platinum therapy: 
      • Cisplatin
      • Carboplatin
    • Paclitaxel
    • Fluorouracil
    • Gemcitabine
    • Topetecan
  • Immunotherapy:
    • Bevacizumab (vascular endothelial growth factor (VEGF) monoclonal antibody)
    • Pembrolizumab (programmed cell death 1 (PD-1) monoclonal antibody)

Management by stage

Management depends on the stage, extension to nearby lymph nodes and tissue, and the patient’s age, pregnancy status, and desire to maintain fertility.

  • LSIL (CIN-1): 
    • Observation, especially if the patient is < 25 years old, since most regress
    • Excision of the cervical transformation zone
      • Loop electrosurgical excision procedure 
      • Laser ablation 
  • HSIL (CIN-2, CIN-3): 
    • Treatment with loop electrosurgical excision procedure 
    • If CIN-2 and < 25 years old, observation is preferred
  • Stage IA:
    • Options to maintain fertility:
      • Conization with or without lymphadenectomy
      • If negative margins, the patient may be monitored closely
      • If positive margins, repeat conization or radical cervicectomy with lymphadenectomy
    • Options if fertility is not an issue:
      • EBRT plus brachytherapy
      • Simple hysterectomy or radical hysterectomy with lymphadenectomy
      • Surgery may be combined with EBRT or brachytherapy.
      • Chemotherapy is added if there is spread to the parametrium.
  • Stages IB‒IIA:
    • Radical cervicectomy with lymphadenectomy:
      • Option to maintain fertility 
      • For stage IB only
    • Radical hysterectomy with lymphadenectomy:
      • If spread to the parametrium, EBRT with chemotherapy is added.
      • Brachytherapy may be added.
    • Brachytherapy plus EBRT: 
      • For patients who are not surgical candidates
      • Chemotherapy may be added
  • Stages IIB‒IVA:
    • Chemotherapy plus radiation (EBRT and brachytherapy)
  • Stage IVB:
    • Not considered curable
    • Radiation with or without chemotherapy
    • Immunotherapy may be added.

Prognosis

  • 5-year survival rates in the United States:
    • Stage I: > 80%
    • Stage II: 60%–80%
    • Stage III: approximately 50%
    • Stage IV: < 30%
  • 3-year disease-free survival
    • Adenocarcinoma: 78% 
    • SCC: 57%
  • Small-cell neuroendocrine tumors have the worst prognosis. 
    • Overall survival rate is 29% at 5 years.
    • No patients survive if the stage is > IB1 or if there are lymph node metastases.
  • Most patients with advanced cervical cancer die because of the effects of local tumor invasion (e.g., ureteral obstruction and kidney failure) rather than metastases.

Differential Diagnosis

  • Endometrial cancer: a malignancy of the endometrium, usually due to adenocarcinoma. This is more commonly seen in women > 50 years of age with a history of unopposed estrogen exposure. Postmenopausal vaginal bleeding is a worrisome symptom. Imaging and endometrial biopsy will provide the diagnosis. Management depends on the stage but may include hysterectomy, chemotherapy, and radiation.
  • Cervicitis: an inflammatory or infectious condition of the cervix. Common causes include Chlamydia trachomatis, Neisseria gonorrhoeae, gynecologic procedures, and chemical irritants or allergens. Patients may have vaginal discharge and bleeding. Cervical edema, erythema, and friability may be noted on pelvic exam. Diagnosis is based on this history and testing for sexually transmitted organisms. Management includes antibiotics for infectious causes.
  • Pelvic inflammatory disease (PID): an ascending infectious process involving the uterus, fallopian tubes, and ovaries. This disease is closely linked with sexually transmitted diseases (especially C. trachomatis and N. gonorrhoeae). Pelvic inflammatory disease is an acute process that causes extreme tenderness on pelvic exam and a fever. Diagnosis involves identification of the causative organism. Treatment is with antibiotics.
  • Endocervical polyp: a common benign exophytic proliferation in the endocervical canal that may have a stalk and protrude through the cervical os. This may cause abnormal vaginal spotting or bleeding (postcoital or contact) or abnormal vaginal discharge. Diagnosis is usually obvious on colposcopic exam (polyps are soft, with smooth and regular contours).

References

  1. Frumovitz, M. (2020). Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis. UpToDate. Retrieved December 10, 2020, from https://www.uptodate.com/contents/invasive-cervical-cancer-epidemiology-risk-factors-clinical-manifestations-and-diagnosis
  2. Ellenson, L.H., Pirog, E.C. (2020). The Female Genital Tract. In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). Robbins & Cotran Pathologic Basis of Disease. (10th ed. pp. 294, 334, 997–1001).
  3. Wright, J. D. (2020). Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention. UpToDate. Retrieved December 11, 2020, from https://www.uptodate.com/contents/cervical-intraepithelial-neoplasia-terminology-incidence-pathogenesis-and-prevention
  4. Jung, E. J., et al. (Ed.) (2017). Cervical adenocarcinoma has a poorer prognosis and a higher propensity for distant recurrence than squamous cell carcinoma. International Journal of Gynecologic Cancer, 27(6). https://doi.org/10.1097/IGC.0000000000001009
  5. Hu, K., Wang, W., Liu, X., Meng, Q., Zhang, F. (2018). Comparison of treatment outcomes between squamous cell carcinoma and adenocarcinoma of cervix after definitive radiotherapy or concurrent chemoradiotherapy. Radiation Oncology, 13(1), 249. https://doi.org/10.1186/s13014-018-1197-5
  6. Viswanathan, A. N., et al. (Ed.) (2004). Small cell neuroendocrine carcinoma of the cervix: Outcome and patterns of recurrence. Gynecologic Oncology, 93(1), 27–33. https://doi.org/10.1016/j.ygyno.2003.12.027
  7. Ramirez, P.T., and Salvo, G. (2020). Cervical cancer. [online] MSD Manual Professional Version. https://www.msdmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/cervical-cancer
  8. Boardman, C.H., and Matthews, K.J. (2019). Cervical cancer. In Huh, W.K. (Ed.), Medscape. https://emedicine.medscape.com/article/253513-overview
  9. Boardman, C.H., and Matthews, K.J. (2019). Cervical cancer staging. In Sonoda, Y. (Ed.), Medscape. https://emedicine.medscape.com/article/2006486-overview
  10. American Cancer Society (2020). Treatment options for cervical cancer, by stage. https://www.cancer.org/cancer/cervical-cancer/treating/by-stage.html
  11. DeFilippis, R.A., Goodwin, E.C., Wu, L., and DiMaio, D. (2003). Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. Journal of Virology, 77(2), 1551–63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC140828/

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