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Carcinogenic HPV infection

HPV is a non-enveloped, double-stranded, circular DNA virus of the Papillomaviridae family that causes epithelial proliferation at cutaneous and mucosal surfaces

HPV is a non-enveloped, double-stranded, circular DNA virus of the Papillomaviridae family that causes epithelial proliferation at cutaneous and mucosal surfaces

  • HPV infection: M/C STD in United States (~80% women acquire an infection by 50 years age)
  • Cervical cancer:
    • M/C cancer in women in India (25% of all female cancers; #2 breast cancer)
    • #3 M/C cancer in United States in women (#1 skin cancer, #2 breast cancer)

History:

The link between genital HPV infections and cervical cancer was first demonstrated in the early 1980s by Harold zur Hausen, a German virologist. Since then, the link between HPV and cervical squamous cell carcinoma has become well established. The magnitude of the association between HPV and cervical squamous cell carcinoma is higher than that for the association between smoking and lung cancer. In 1996, the World Health Association, along with the European Research Organization on Genital Infection and Neoplasia and the National Institutes of Health Consensus Conference on Cervical Cancer, recognized HPV as an important cause of cervical cancer.


Microbiology

Human papillomavirus (HPV):

HPV is a non-enveloped, double-stranded, circular DNA virus of the Papillomaviridae family that causes epithelial proliferation at cutaneous and mucosal surfaces

The virus enters the epithelium through disruption to the skin/mucosa and infects basal stem cells. Its genome contains seven early (E) and two late (L) phase genes required for viral propagation. The viral DNA may remain as an independent episome for a period before integrating into the host’s genome. HPV preferentially integrates at fragile sites in the human DNA where the strand is prone to breakages.

HPV structure and genome organization. a) Human papillomavirus (HPV) particles (55 nm in diameter) are shown in the negatively stained transmission electron micrograph. b) The genome organization typical of the high-risk Alpha HPV types, illustrated as HPV16. The early (P97) and late (P670) promoters are marked by arrowheads. The six early open reading frames (ORFs), namely E1, E2, E4 and E5 (in green) and E6 and E7 (in red), are expressed from the different promoters at different stages during epithelial cell differentiation. The late ORFs (L1 and L2 (in yellow)) are expressed from the P670 promoter in the upper epithelial layers as a result of changes in splicing. The long control region (LCR, sometimes referred to as the upstream regulatory region) is a non-coding region of the genome that contains the replication origin as well as post-transcriptional control sequences that contribute to viral gene expression. The binding sites for the E1 and E2 viral gene products and the SP1 transcription factor are shown. The gene products (denoted with an asterisk (*)) are core viral proteins that are required for genome replication, viral assembly and release; those denoted by a double dagger () are accessory proteins with functions that include cell cycle entry and immune evasion. | Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

Low risk (non-oncogenic) HPV:

Associated with low-grade precancerous lesions like anogenital condyloma or genital wart
  • Serotypes: 6, 11, 40, 42, 43, 44, and 54
    • HPV 6 & 11: M/C strains associated with genital warts (90% cases)

High-risk (oncogenic) HPV:

Associated with high-grade intraepithelial lesions that progress to malignancies such as cervical, vulvar, vaginal, and anal cancers
  • Subtypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, and 58
    • HPV 16: M/oncogenic (50% cervical cancer cases)
    • HPV 16 & 18: 70% cervical cancer cases
Attribution of carcinogenic HPV types to cervical disease categories. Expanded from the work of Wentzensen and colleagues (11). The type attribution is based on the hierarchical attribution model for carcinogenic genotypes present in multiple infections. HPV genotyping is based on concurrent cytologic specimens, not on tissue specimens. | Schiffman, M., & Wentzensen, N. (2013). Human Papillomavirus Infection and the Multistage Carcinogenesis of Cervical Cancer. Cancer Epidemiology Biomarkers &Amp; Prevention, 22(4), 553 LP – 560. https://doi.org/10.1158/1055-9965.EPI-12-1406

Molecular pathology:

  • E6 viral oncoprotein: Target p53 gene products
  • E7 viral oncoprotein: Target retinoblastoma gene (RB) products
Mechanisms of human papillomavirus (HPV) carcinogenesis: Whereas transient infections are largely subclinical, progression is closely related to the persistence of viral DNA. This process goes frequently with viral disruption in the E1/E2 regions and integration into the cellular DNA. E2 disruption releases the viral promoters of E6 and E7 and increases the expression of these transforming genes. The E6 and E7 viral proteins are capable of selectively degrading the p53 and retinoblastoma gene (RB) products, respectively, leading to inactivation of two important cellular negative regulatory proteins. | HSIL, high grade squamous intraepithelial lesion; LSIL, low grade squamous intraepithelial lesion; RB, retinoblastoma gene. | Bosch FX, Lorincz A, Muñoz N, et al. The causal relation between human papillomavirus and cervical cancer. Journal of Clinical Pathology 2002;55:244-265.

Aetiology

Risk factors:

  • Sexual activity, age of first sexual intercourse and number of sexual partners
  • Smoking
  • Use of oral contraceptives (more than 5 years)
  • Chewing betel nut
  • Exposure to radiation and UV light
Factors that influence the age-specific HPV prevalence in women: a) A populations average age of first sexual initiation determines the age at which the human papillomavirus (HPV) incidence and prevalence curves start to rise. b) The early, typically highest, peak of the prevalence curve is highly variable across populations, reflecting global variation in the interchange of new sexual partners. c) Cell-mediated immune control of acquired infections and partial, antibody-mediated immunity to re-infection, combined with reduced interchange of sexual partners, are likely explanations for a rapid decline in incidence years after the initial peak. During a plateau that begins around 30-35 years of age, a certain proportion of infections represent persistence linked to increased risk of developing precancer or cancer. Widespread use of high-quality cervical cancer screening during this plateau can target prevalent HPV-related lesions and infections. The arrows demark the shifts in the curve possible depending on these factors. | Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

Pathophysiology

Natural history:

Cervical cancer natural history model. | Schiffman, M., & Wentzensen, N. (2013). Human Papillomavirus Infection and the Multistage Carcinogenesis of Cervical Cancer. Cancer Epidemiology Biomarkers &Amp; Prevention, 22(4), 553 LP – 560. https://doi.org/10.1158/1055-9965.EPI-12-1406
  • CIN I → CIN III (5 years)
  • CIN III → Carcinoma-in-situ (10 years)

Cervical intraepithelial neoplasia (CIN):

Also known as cervical dysplasia, is the potentially premalignant transformation and abnormal growth (dysplasia) of squamous cells on the surface of the cervix.
  • Transformation zone (M/C site)
HPV infection and the transformation zone: The deregulation of high-risk human papillomavirus (HPV) gene expression is thought to depend on the specific characteristics of the basal epithelial cell that the virus infects, as well as on the susceptibility of this infected cell to external stimuli, such as hormones and growth factors. Most cancers at the cervix arise at the transformation zone and adjacent endocervix, a region of the cervix comprising initially of columnar epithelium but then undergoes metaplasia particularly at puberty to form a fully differentiated squamous epithelial layer. The stratified layers of the ectocervix are thought to be maintained by conventional epithelial stem cells that are located in the basal layer. The nature of these cells has not been established, and several models of epithelial homeostasis have been suggested. By contrast, the stratified layers of the transformation zone, and the single layer of columnar cells that line the endocervix, are thought to be maintained by the cervical reserve cells. Although reserve cells are typically abundant at sites of metaplasia, recent studies have additionally suggested the involvement of a second type of stem-like cell with cuboidal appearance that are located more precisely at the squamocolumnar junction (SCJ). Current thinking suggests that productive high-risk HPV infection is favoured at the ectocervix and that lesion formation begins from infection of an epithelial stem cell (reserve or cuboidal stem cell) at the transformation zone or endocervix. The immunohistochemistry images on the right show a normal cervix, a low-grade clinical lesion pathologically labelled as cervical intraepithelial neoplasia grade 1 (CIN1) and a high-grade CIN3 lesion stained to detect the HPV E4 protein (green) and the cell cycle marker minichromosome maintenance protein complex (red) | Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

Invasive cervical cancer (ICC):

Develops over a period of years and is preceded by precancerous changes of the cervix
  • Squamous cell cancer (SCC) (M/C type)
    • Site: Transformation zone
  • Adenocarcinoma (AdenoCa) (#2 M/C)
    • Site: Endocervix
Molecular events during progression and invasion in the cervix: Productive infection (producing virion particles) is thought to involve low-level regulated expression of human papillomavirus (HPV) genes E6 and E7 and does not necessarily require the stimulation of extensive cell cycle entry in the basal and parabasal cell layers (noted by the absence of the cell cycle marker minichromosome maintenance protein complex (red) in the first immunofluorescence image). In such lesions, E6 and E7 gene expression is required primarily for genome amplification in the mid-epithelial layers in preparation for virus assembly. E4 and late viral (L1 and L2) gene expression can be extensive (green on immunofluorescence imaging). However, low-grade lesions are heterogeneous and can show more-extensive suprabasal cell cycle entry (increasing red on immunofluorescence imaging). Pathologically, such lesions would be labelled cervical intraepithelial neoplasia grade 1 (CIN1; BOX2) | Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

Clinical features

Cervical cancer:

  • Metrorrhagia (irregular vaginal bleeding) (M/C symptom)
  • Postcoital bleeding (M/specific symptom)
  • Watery discharge
  • Pelvic pain/pressure
  • Rectal or urinary tract symptoms (late/bad sign: indicates metastasis)

Diagnosis

Universal cervical screening:

  • PAP smear
  • Human papillomavirus (HPV) DNA testing
Cervical screening strategies in high-resource and low-resource settings: In high-resource regions, screening strategies currently include cytology (microscopic evaluation), human papillomavirus (HPV) testing (DNA or RNA typing) or a combination of the two (co-testing). HPV testing is increasingly accepted owing to its favourable negative predictive value (NPV). Co-testing provides slightly greater reassurance against developing cancer than HPV testing alone but at greater cost; co-testing is mainly used in the United States. Triage options to determine who would require colposcopy (cervical examination) are varied and debated, and include HPV typing and cytology. Colposcopic biopsy remains the diagnostic standard for guiding treatment, which often relies on excision to provide histopathology driven decisions. By contrast, in low-resource regions, cytology, colposcopy and histopathology services are limited. Visual inspection with acetic acid (VIA) followed by treatment of screen-positive women (screen and treat) is an inexpensive but inaccurate strategy. Low-cost HPV tests, when fully developed, would provide more-accurate screening if resources are available; however, affordable and effective choices of triage and diagnostic tests, and treatment modalities, are in development and still unsettled. The greatest opportunity to extend and improve cervical screening might be in middle-income countries that lack existing, nationally effective programmes. Emerging technologies here include E6 and E7 oncoprotein detection and computer-assisted visualization and strategies | Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

Diagnostic tests:

If screening comes positive
Summary of management options for screen‐positive women. Screening and treatment can be completed in a single visit if there is a point‐of‐care screening test and the lesion is suitable for ablative treatment with a simpler method such as cryotherapy or thermal coagulation. | Basu, P., Meheus, F., Chami, Y., Hariprasad, R., Zhao, F. and Sankaranarayanan, R. (2017), Management algorithms for cervical cancer screening and precancer treatment for resource‐limited settings. Int J Gynecol Obstet, 138: 26-32. https://doi.org/10.1002/ijgo.12183

Cervical biopsy:

Via colposcopy, cervical biopsy or fractional curettage
Histology of squamous intraepithelial lesions. CIN, cervical intraepithelial neoplasia; CIS, carcinoma in situ; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade intraepithelial lesion. | Bonnez W. Papillomavirus. In: Richman DD, Whitley RJ, Hayden FJ, editors. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology Press; 2002. pp. 557–596.

Bethesda cytological classification:

Uniform format for cytopathology reports
  • ASC-US: Atypical Squamous Cells of Undetermined Significance
  • ASC-H: Atypical Squamous Cells – cannot exclude HSIL
  • LSIL: Low-grade Squamous Intraepithelial Lesion (includes HPV infection/mild dysplasia/CIN 1
  • HSIL: High-grade squamous intraepithelial lesion (includes moderate and severe dysplasia, CIN2/3, and carcinoma in situ
  • AGC: Atypical glandular cells (specify endocervical or not otherwise specified [NOS])
  • AIS: Endocervical Adenocarcinoma In Situ
  • AdenoCa: Adenocarcinoma
  • SCC: Squamous Cell Carcinoma
Terminology of cervical disease categories. The figure shows histological and cytological terminologies of cervical disease categories. CIN; LAST; NILM, negative for intraepithelial lesion or malignancy. | Schiffman, M., & Wentzensen, N. (2013). Human Papillomavirus Infection and the Multistage Carcinogenesis of Cervical Cancer. Cancer Epidemiology Biomarkers &Amp; Prevention, 22(4), 553 LP – 560. https://doi.org/10.1158/1055-9965.EPI-12-1406

FIGO classification:

Revised FIGO Staging Criteria for Carcinoma of the Uterine Cervix | Son, H., Kositwattanarerk, A., Hayes, M. P., Chuang, L., Rahaman, J., Heiba, S., … Kostakoglu, L. (2010). PET/CT Evaluation of Cervical Cancer: Spectrum of Disease. RadioGraphics, 30(5), 1251–1268. https://doi.org/10.1148/rg.305105703
Revised FIGO staging system (2009) | Comprehensive Cervical Cancer Control: A Guide to Essential Practice. 2nd edition. Geneva: World Health Organization; 2014. 6, Diagnosis and treatment of invasive cervical cancer. Available from: https://www.ncbi.nlm.nih.gov/books/NBK269603/

Management

Cervical intraepithelial neoplasia (CIN):

  • Large loop excision of transformation zone (LLETZ) or loop electrosurgical excision procedure (LEEP) (M/C performed)
  • Electrocoagulation
  • Cold-knife conization (CKC)
  • Needle excision of transformation zone (NETZ)
Management protocol for Cervical Intraepithelial Neoplasia (CIN) | Dr .Vijayachandar – CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=74228098

Microinvasion of cervix neoplasia:

  • Suspicion: Conization
  • Confirmation: Hysterectomy

Cervical cancer:

Algorithm for the management of Papanicolaou smear findings and invasive cervical cancer. | CIN = cervical intraepithelial neoplasia | Cannistra SA, Niloff JM. Cancer of the uterine cervix. N Engl J Med 1996;334:1030–8.

Vaccination:

  • Cervarix
  • Gardasil
  • Gardasil 9
Salient differences between the two commercially marketed HPV vaccines | Pandhi D, Sonthalia S. Human papilloma virus vaccines: Current scenario. Indian J Sex Transm Dis 2011;32:75-85
(2020) Immunization Awareness Month: Gardasil 9 | The Anal Cancer Foundation. Retrieved November 18, 2020, from https://www.analcancerfoundation.org/2015/08/07/immunization-awareness-month-gardasil-9/

Summary:

Carcinogenic HPV infection. Nat Rev Dis Primers 2, 16087 (2016). https://doi.org/10.1038/nrdp.2016.87

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