Cervix
Premalignant / preinvasive lesions
Human papillomavirus (HPV) (H&E)

Author: Erika M. Baardsen, D.O., Marilin Rosa, M.D.

Revised: 5 February 2018, last major update December 2017

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

PubMed Search: Cervix premalignant hpv [title] AND "loattrfree full text"[sb]

See also HPV (cyto)
Cite this page: Baardsen, E.M., Rosa, M. Human papillomavirus (HPV) (H&E). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixHPV.html. Accessed July 16th, 2018.
Definition / general
  • In 2008, Dr. Harold Hausen was awarded the Nobel Prize for his discovery of HPV as a cause of cervical cancer
  • Within the past 50 years, cervical cancer incidence and mortality has dramatically decreased in the U.S.; this is attributed to the effectiveness of the Papanicolaou screening test
  • High risk HPV is a known human carcinogen responsible for the development of cervical cancer
  • Cervical precursor and preinvasive lesions are associated with HPV
  • Low risk HPV is the cause of sexually transmitted vulvar, perineal and perianal warts (condyloma acuminatum)
  • Squamous cell carcinoma is the most common histologic subtype of cervical cancer, followed by adenocarcinoma and rarely neuroendocrine carcinoma, which are all associated with high risk HPV
  • As only a small portion of HPV infections progress; other factors are necessary for the development of cervical cancer
    • These other factors include exposure to co-carcinogens, type and duration of the infection and host immune status
Essential features
  • Within the past 50 years, cervical cancer incidence and mortality has dramatically decreased in the U.S.; this is attributed to the effectiveness of the Papanicolaou screening test
  • High risk HPV is a known human carcinogen responsible for the development of cervical cancer
  • Human papillomavirus is one of the most common sexually transmitted infections in sexually active women
  • HPV 16 is the single most commonly identified HPV type in CIN 2, 3
  • Diagnosis of squamous intraepithelial lesions (SIL) is based on:
    • Nuclear atypia: variation in nuclear size and shape (“raisinoid”), hyperchromasia and coarse chromatin granules
    • Nuclear / cytoplasmic (N/C) ratio
  • Features of high grade dysplasia (CIN 2 and CIN 3) include:
    • 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
    • High (N/C) ratio
  • Ki67 and p16 staining are highly correlated with HPV infection
  • In 2014, the U.S. FDA approved a HPV DNA test (Cobas® HPV test, Roche Molecular Systems, Inc.) as a first line primary screening test for use alone for women age 25 and older
  • Other FDA approved methods are also available
Epidemiology
  • Human papilloma virus is one of the most common sexually transmitted infections in sexually active women with prevalence rates as high as 82% in some populations
  • HPV is transmitted through direct contact by the skin or mucosal membranes
  • Worldwide, cervical carcinoma is the third most common cancer in women
  • In the U.S. within the last 50 years, the death rate has declined by two thirds and is now only the 13th most common cause of cancer mortality
  • Prevalence of HPV infection peaks between 20 - 24 years of age due to onset of sexual activity; subsequent decrease may reflect acquisition of immunity and development of monogamous relationships
  • HPV 16 is found in approximately half of all women with cervical cancers
  • HPV 16 is the single most commonly identified HPV type in CIN 2, 3
  • Approximately 60% of LSIL regress, 30% persist and 10% progress to HSIL
  • Approximately 30% of HSIL regress, 60% persist and 10% progress to carcinoma within 2 - 10 years
  • Infection with multiple HPV types is 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
  • Progression from HPV infection to invasive cancer is estimated to take 10 - 15 years or longer
Sites
  • High risk HPV is the most important factor in the development of cervical cancer
  • High risk HPV is also implicated in the development of squamous cell carcinoma at many other sites, including vagina, vulva, penis, anus, tonsil and other oropharyngeal locations
Diagrams / tables

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HPV life cycle

Screening recommendations
  • Under 21 years: no screening recommended
  • 21 - 29 years: cytology (Pap smear) alone every 3 years with HPV reflex if ASCUS
  • 30 - 65 years: Human papillomavirus (HPV) and cytology cotesting every 5 years (preferred) or cytology alone every 3 years (acceptable)
  • Over 65 years: no screening recommended if adequate prior screening has been negative and high risk factors are not present
Pathophysiology
  • Classified as a member of the Papovaviridae family, nonenveloped virus, 55 nm in diameter
  • HPV genome consists of about 8,000 base pairs of circular double stranded DNA that codes for 8 genes, which are classified as "early" (E) or "late" (L)
  • HPV infection is established in the basal layer of epithelium with a strong predilection for the transformation zone; as epithelium matures, gene amplification and viral assembly occur with expression of L1 (major viral capsid protein - major component of HPV vaccines) and L2 proteins
  • In high risk HPV, binding of E6 protein to p53 protein blocks apoptosis and upregulates the expression of telomerase; whereas binding of E7 protein to hypophosphorylated (active) form of the retinoblastoma (Rb) tumor suppressor protein leads to uninhibited cellular proliferation and impairs the ability of cells to repair DNA damage
  • Over 200 HPV types have been characterized; 40+ affect the genital tract
  • Low oncogenic risk (associated with genital condyloma and low grade squamous intraepithelial lesion [LSIL]):
    • HPV 6, 11, 40, 42, 43, 44, 54, 55, 61, 70, 72, 81 and CP6108
  • High oncogenic risk (associated with high grade squamous intraepithelial lesion [HSIL] and invasive carcinoma):
    • HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
    • HPV 16 causes approximately 60% of cervical cancer cases
    • HPV 18 contributes to another 10% of cases
    • Each of the other high risk types associated with less than 5% of cases
  • Unclear oncogenic risk:
    • HPV 26, 53, 73 and 82
Clinical features
  • Most precursor and premalignant HPV infections are asymptomatic
  • Infections with low risk HPV may cause condylomas and genital warts commonly seen as multiple (or single) white, flat or pedunculated, keratotic lesions that may cause pruritus or pain
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 vs. 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
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
    • Nuclear / cytoplasmic (N/C) ratio
  • Low grade dysplasia / koilocytosis / koilocytic changes:
    • Histologically, the changes involve only the lower 1/3 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
    • The N/C ratio is high
Microscopic (histologic) images

Images hosted on PathOut server:

Images contributed by Marilin Rosa, M.D.

CIN III / HSIL

HSIL Ki67

HSIL p16

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)
Molecular / cytogenetics description
  • HPV testing can be used as triage of abnormal cytology results, as co testing or as a primary screening test (Gynecol Oncol 2015;136:178)
  • In 2014, the U.S. FDA approved a HPV DNA test (Cobas® HPV test, Roche Molecular Systems, Inc.) as a first line primary screening test for use alone for women age 25 and older
  • This test detects each of HPV types 16 and 18 and gives pooled results for 12 additional high risk HPV types
  • Other FDA approved methods include:
    • Digene® HPV test using Hybrid Capture® 2 (hc2) technology
    • Cervista® HPV HR assay (Hologic, Inc., Marlborough, MA, USA)
    • APTIMA® HPV Assay (Gen Probe)
Molecular / cytogenetics images

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Missing Image

Cervix, large cell neuroendo carcinoma

HPV ISH

Board review question #1
    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 answer #1
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.