Cervix

Inflammatory / infectious

HPV overview


Editorial Board Member: David B. Chapel, M.D.
Deputy Editor-in-Chief: Jennifer A. Bennett, M.D.
Maryam Aghighi, M.D.
Teresa M. Darragh, M.D.

Last author update: 23 November 2022
Last staff update: 23 November 2022

Copyright: 2022, PathologyOutlines.com, Inc.

PubMed search: Cervical HPV

Maryam Aghighi, M.D.
Teresa M. Darragh, M.D.
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Cite this page: Aghighi M, Darragh TM. HPV overview. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cervixHPVoverview.html. Accessed April 15th, 2024.
Definition / general
Essential features
  • HPV 16 and 18 are the main cause of HPV associated precancers and cancers
  • Currently, there are 5 FDA approved HPV nucleic acid tests
ICD coding
Epidemiology
Sites
  • Cervix
  • Other anogenital sites (anus, vagina, vulva, perianus, penis) and oropharynx are also possible
Pathophysiology
  • Classified as a member of the Papovaviridae family, nonenveloped virus, 55 nm in diameter
  • Low risk HPV types are 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108: associated with genital condylomas and LSIL
  • High risk HPV types are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 (NIH: HPV and Cancer [Accessed 6 May 2022])
  • HPV 16 and 18 are the main cause of HPV related cancers
  • HPV results in cell destruction and tumor growth by interfering in cell cycle regulation and preventing cell apoptosis
  • E1 and E2 proteins have impact on HPV viral genome amplification
  • E6 and E7 proteins cause cancer by inactivating the tumor suppressor proteins p53 and pRb (which prevent cell apoptosis) and by disrupting cell cycle regulation (J Cancer Metastasis Treat 2016;2:201)
  • L1 and L2 code for the capsid proteins and are the target of HPV prophylactic vaccines
Etiology
  • Higher prevalence of HPV in:
    • Immunosuppressed people, including those living with HIV and posttransplant patients
    • Smokers
    • Patients with high parity or multiple sexual partners
Clinical features
  • May present as:
    • Asymptomatic (precancers and early stage cancers)
    • Abnormal cervical cancer screening test such as Pap test or HPV test
    • Vaginal bleeding, discharge and pain in later stage cancer
  • Colposcopy of high grade lesions typically shows acetowhite epithelium with regular borders and vascular changes with punctation or a mosaic pattern; cervical cancer may show a mass (exophytic or ulcerated) or irregular surface with atypical vessels
Development of cervical disease after HPV infection
  • Most HPV infections are transient
    • On average, 50% of infections are cleared within 8 months and 90% are cleared within 2 years
    • Duration of infection is related to HPV type with high risk HPV infections lasting longer than that of low risk HPV (13 months versus 8 months)
  • LSIL
    • Frequently multicellular in origin
    • Develops within field of latently infected cervical epithelium and frequently associated with multiple HPV types
  • HSIL
    • Unicellular in origin
  • HPV 18
Diagnosis
  • Cytology screening: Papanicolaou (Pap) test (American Society of Cytopathology: ASC Position Statement - Cervical Cancer Screening and Prevention [Accessed 6 May 2022]):
  • High risk human papillomavirus (HR HPV) testing
  • FDA approved HPV molecular testing: 5 HR HPV tests, 4 DNA based and 1 mRNA based (J Am Soc Cytopathol 2019;8:284)
    • Hybrid Capture II by Qiagen, DNA based using full genome probe by signal amplification for genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68
      • Sensitivity: 63.6 - 100%
      • Specificity: 60.2 - 98.4%
    • Cervista by Hologic, DNA based using L1, E6 and E7 genes by signal amplification for genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
      • Sensitivity: 92.8 - 100%
      • Specificity: 43 - 89%
    • Cobas by Roche, DNA based using L1 gene target by polymerase chain reaction for genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, providing genotyping of 16 and 18
      • Sensitivity: 71.1 - 99%
      • Specificity: 24 - 86.2%
    • Aptima by Gen Probe (Hologic), mRNA based using E6 / E7 gene target by polymerase chain reaction for genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
      • Sensitivity: 55.3 - 100%
      • Specificity: 28.8 - 99.2%
    • BD Onclarity by Becton Dickinson, DNA based using E6 / E7 gene target by polymerase chain reaction for genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, providing discrete detection of 16, 18 and 45
      • Sensitivity: 85.7 - 100%
      • Specificity: 17 - 98.8%
  • Cotesting: screening with cervical cytology and HPV test
    • Results lead to algorithmic referral to colposcopy, with short term follow up or routine long interval screening being based on the risk of precancer or cancer
  • Clinical applications of HR HPV testing (Gynecol Oncol 2015;136:178):
    • Primary HPV screening
    • Cotesting with cervical cytology
    • Reflex testing for ASCUS and in postmenopausal women, for low grade SIL
    • Genotyping for HPV 16, 18 or 45
    • Follow up for abnormal cervical cytology and HPV screening with negative colposcopy
    • Follow up after treatment for cervical precancer
  • Cervical cancer screening guideline (J Low Genit Tract Dis 2020;24:102):
    • U.S. Preventive Services Task Force (USPSTF) currently recommends:
      • 21 - 29 year old women: cervical cytology alone every 3 years
      • 30 - 65 year old women:
        • Cervical cytology alone every 3 years or
        • HPV testing alone every 5 years or
        • Cotesting every 5 years
    • American Cancer Society (ACS) recommends:
      • 25 - 65 year old women:
      • < 21 year old women: no screening is recommended
    • > 65 year old women: no screening is recommended for women with adequate prior screening for both ACS and USPSTF
      • If prior tests were normal or
      • After hysterectomy with cervix removal for benign reasons
    • FDA approved primary HPV testing for > 25 year old women:
      • Cobas HPV Test on specimens prepared with ThinPrep or SurePath
      • BD Onclarity HPV Assay for SurePath
Prognostic factors
  • Overall, 5 year disease free survival in patients with cervical cancer:
    • Stage IA: 95%
    • Stage IB1 and IIA: 70 - 85%
    • Stage IB2 and IIB: 50 - 70%
    • Stage III: 30 - 50%
    • Stage IV: 5 - 15% (Oncotarget 2017;8:66352)
  • Worse prognosis observed in HIV positive patients with lower CD4 counts
Case reports
Treatment
  • Prevention: vaccination against high risk HPV types
  • Low grade squamous intraepithelial lesions (LSIL)
  • High grade squamous intraepithelial lesions (HSIL):
    • Treatment of HSIL helps to reduce risk of cervical cancer
      • Ablative therapy:
        • Cryotherapy
        • Laser vaporization
        • Thermal coagulation
      • Excisional therapy:
        • Loop electrosurgical excision procedure (LEEP)
        • Cold knife conization
  • Cervical cancer:
    • Superficially invasive cancer:
      • Loop electrosurgical excision procedure
      • Conization
      • Simple hysterectomy
    • Early stage cancer:
      • Radical trachelectomy for early stage disease, to preserve fertility
      • Radical hysterectomy with pelvic lymph node dissection
    • High stage cancer:
      • Radiotherapy with or without cisplatin based chemotherapy
Microscopic (histologic) description
  • Diagnosis of squamous intraepithelial lesions is based on:
    • Nuclear atypia: variation in nuclear size and shape (raisinoid), hyperchromasia and coarse chromatin granules
    • N:C ratio
  • Low grade dysplasia / koilocytosis / koilocytic changes:
    • Histologically, the changes involve only the lower third of the epithelium or there are koilocytic changes in the upper epithelium (maturation seen)
    • Koilocytes are superficial or intermediate squamous cells with large and irregular, well defined perinuclear halos with a cookie cutter border and cytoplasmic thickening
    • Bi or multinucleation is often identified
    • Nuclei are enlarged (2 - 3 times normal size)
    • Nuclear changes are required for diagnosis of koilocytosis (Arch Pathol Lab Med 1990;114:1038)
  • High grade dysplasia (CIN 2 and CIN 3):
    • Striking nuclear atypia involving all layers of the epithelium
    • Lack of or minimal maturation
    • Nuclear changes include enlargement, membrane irregularities, variable shapes and abnormal chromatin
    • N:C ratio is high
Positive stains
  • Ki67 and p16 staining are highly correlated with HPV infection
  • HPV immunostains:
    • Normal cervix has some HPV background staining
    • HPV+: cervical condyloma, LSIL / CIN 1, HSIL / CIN 2, HSIL / CIN 3
    • Ki67: higher in HPV+ epithelium than inflamed or metaplastic squamous epithelium; very high with high risk HPV types, carcinoma
  • Diffuse and strong p16 is associated with high risk HPV (Am J Surg Pathol 2007;31:33, Eur J Gynaecol Oncol 2013;34:227)
Board review style question #1
What is the best management for a 32 year old woman with a Pap test of high grade squamous intraepithelial lesion?

  1. Colposcopy
  2. High risk human papillomavirus (HPV) test
  3. Radiotherapy
  4. Repeat Pap test in 4 - 6 months
Board review style answer #1
A. Colposcopy

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Reference: HPV overview
Board review style question #2
A 32 year old woman presents to her primary care physician with complaints of new onset labial ulcers. Her PCP swabs one of the ulcers and sends it for DNA testing by PCR. At that time, her physician also performs a Pap test and pelvic examination. The cytopathologist identifies several large squamous cells with orangeophilic cytoplasm and large, crinkled nuclei. Scattered, single cells of smaller size with hyperchromatic nuclei, nuclear enlargement, abnormal chromatin clumping and irregular nuclear contours are also seen. HPV testing is performed. What is the most likely HPV type, if any, associated with this patient's Pap test findings?

  1. HPV 6
  2. HPV 11
  3. HPV 16
  4. HPV 18
  5. HSV, as HPV is not a causative agent in this case
Board review style answer #2
C. HPV 16. Although the cytologic features describe predominantly koilocytic change, there are cells representative of HSIL present. HSIL is often identified in a background of LSIL. HPV 16 is the most commonly associated high oncogenic risk HPV type in HSIL. HPV 6 (answer A) and HPV 11 (answer B) are considered low oncogenic risk types and are associated with genital condyloma and LSIL. HPV 18 (answer D) is also a high oncogenic risk type but is less commonly associated with HSIL in comparison to HPV 16. HSV may be the cause of the patient's labial ulcers; however, infection with HSV would not explain the cytologic changes described.

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Reference: HPV overview
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