Premalignant / preinvasive lesions

Author: Seema Khutti, M.D. (see Authors page)

Revised: 17 April 2017, last major update September 2013

Copyright: (c) 2003-2017, PathologyOutlines.com, Inc.

PubMed Search: HPV[title] cervix
Cite this page: HPV. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixHPV.html. Accessed December 14th, 2017.
Definition / general
  • Association between HPV and cervical cancer was suggested by Dr. Harald Hausen in late 1970s
  • Causes spectrum of changes ranging from condyloma acuminatum (flat, spiked and inverted condyloma and warty atypia) to invasive squamous cell carcinoma
  • Presence of HPV used to triage ASCUS cases (HPV+ are more likely to have HSIL at followup) and to confirm cervical origin of squamous cell or adenocarcinoma
Virology / pathophysiology
  • Classified as member of the family Papillomaviridae
  • 100 HPV have been characterized, > 40 identified in the genital tract
  • Nonenveloped viruses, double stranded DNA genome, 55 nm in diameter
  • HPV acts via E6 and E7, which differ in high vs. low risk HPV types
  • HPV is integrated in premalignant lesions with tumor DNA vs. present in episomes (not integrated) in condylomas
  • E6 and E7 are small zinc binding proteins; E6 binds with p53 (blocks apoptosis), E7 binds to retinoblastoma gene (Rb gene)
  • Both cause unrestricted cell proliferation and blockage of apoptosis (J Clin Virol 2005;32 Suppl 1:S25)
  • Other cofactors are important, because:
    • Most HPV+ patients do not get cervical cancer
    • 10 - 15% of cervical cancer is NOT associated with HPV
  • Low oncogenic risk (associated with genital condyloma and low grade SIL):
    • 6, 11, 42, 43, 44, 53
  • High oncogenic risk (associated with high grade SIL and invasive carcinoma):
    • 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66
  • Unclear oncogenic risk:
    • 26,68,73,82
  • Transmitted directly skin to skin or mucosa to mucosa
  • Infection with multiple HPV types seen in 20 - 30% of infected young men and women
  • Higher levels of viral DNA (higher viral load) correlates with risk of cervical neoplasia
  • Persistent infection by same HPV type is strongly associated with risk of cervical neoplasia
  • High risk human papillomavirus (HR HPV) prevalence correlates with cervical cancer incidence (Asian Pac J Cancer Prev 2013;14:4015, BMC Infect Dis 2013;13:53)
Genomic organization
  • Viral genome:
    • 3 regions: upstream regulatory region (long control region or LCR), early region, late region
Life cycle
  • Initial site is basal / primitive cells of immature squamous epithelium; HPV exists within cells in two forms:

    • Nonproductive / latent infection: HPV DNA resides in basal cells but infectious virions are not produced
      • HPV genome remains in nucleus in circular form called an episome
      • Replication is tightly coupled with replication of epithelial cells
      • Characteristic cellular changes are not present
      • Cannot be detected with routine molecular detection method due to low copy number

    • Productive viral infection:
      • Viral DNA replication occurs independent of host chromosomal DNA synthesis
      • Results in infectious virions
      • Replications takes place in intermediate and superficial cell layers
      • Characteristic viral associated effects of HPV (koilocytosis) can be detected both cytologically and histologically

Diagrams / tables

Images hosted on other servers:

HPV life cycle

Development of Cervical Disease after HPV Infection
  • LSIL
    • Frequently multicellular in origin
    • Develops within field of latently infected cervical epithelium and frequently associated with multiple HPV types
  • HSIL
    • Unicellular in origin
Koilocytosis / koilocytotic atypia
  • Related to expression of viral E4 protein and disruption that this causes in cytoplasmic keratin matrix
  • Koilocyte is superficial or immature squamous cell with sharply outlined perinuclear vacuoles, dense and irregular staining peripheral cytoplasm, enlarged nucleus with undulating (raisin-like) nuclear membrane and rope-like chromatin
  • Often bi or multinucleation and variation in nuclear size
  • Nuclear changes are required for diagnosis of koilocytosis since glycogen accumulation is otherwise common (Arch Pathol Lab Med 1990;114:1038)
  • Perinuclear halos can be prominent in postmenopausal cervix without HPV
  • HPV 18:
  • Note:
    • Report presence of HPV associated changes, even if SIL is also present
Microscopic (histologic) description
  • Normal basal cell layer, expanded parabasal cell layer, with orderly maturation
  • Mitotic figures (normal)
  • Koilocytosis (described above)
Microscopic (histologic) images
  • See HPV topic in Stains chapter
Cytology description
  • See HPV topic in Cervix-cytology chapter
Positive stains
  • HPV immunostains
    • Normal cervix has some HPV background staining
    • HPV+: cervical condyloma, LSIL / CIN1, HSIL / CIN2, HSIL / CIN3
    • 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)
Electron microscopy description
  • Intranuclear crystalline or filamentous inclusions
Molecular / cytogenetics description
  • Two FDA approved methodologies to detect high risk HPV on cervical cytology are available today:
    • Hybrid Capture 2 HPV DNA Assay; Cervista HPV HR and Cervista HPV 16/18
  • Hybrid Capture 2 HPV DNA Assay detects HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
  • Cervista HPV HR detects all HPV types detected by Hybrid Capture 2 HPV DNA Assay plus HPV 66
  • Cervista HPV 16/18 specifically detects HPV 16 and HPV 18
Molecular / cytogenetics images

Images hosted on other servers:

Sample of cervical
cancer with high
(episomal) viral load

Additional references