Cervix

• 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

• 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

• 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

• 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

• 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

• 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

• 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)

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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

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