GYN 23

• Premalignant vulvar lesions

  • Vulvar intraepithelial neoplasia (VIN)
  • Paget's disease
  • Lichen sclerosus
  • Squamous cell hyperplasia
  • Condyloma accuminata
  • Melanoma in situ

  
• Vulvar intraepithelial neoplasia (VIN)

  Earlier classification: VIN I—Mild cellular atypia, limited to the deeper one-third of the epithelium. VIN II—Moderate cellular atypia involving up to middle-third of the epithelium. VIN III—Severe cellular atypia involving more than 2/3 of epithelium and carcinoma in situ (CIS)
• Vulvar intraepithelial neoplasia (VIN)

  International Society for Study of Vulvar Diseases (ISSVD, 2004) introduced a simplified classification. VIN I has been eliminated. VIN II and III are combined. VIN now encompasses only those lesions having high grade squamous cell abnormalities

  
• VIN

  • More frequent in patients in the age group 20–40 years
  • Often related with STIs such as condyloma accuminata, herpes simplex virus II, gonorrhea, syphilis or Gardnerella vaginalis
  • HPV associated VIN is seen more in young women
  • HPV 6 and 11 are associated with vulvar condylomas. HPV 16, 18, 31, 33, 35 are associated with VIN and invasive lesions
  • There is increased prevalence of associated CIN (10–80%)
  • Regression frequently occurs in young woman, during pregnancy or when it is caused by viral infection
  • Progression to invasive carcinoma high in high grade VIN (VIN 2 and 3) lesions. It takes 20–30 years (for CIN 10–15 years)
• HPV DNA has been found in 80% of VIN lesions. However, of all vulvar cancer specimens only 40% are positive for HPV DNA

  
• Symptoms of VIN


  • May be symptomless
  • Pruritus, burning
  • Pain
  • Dysuria
  • Discharge/bleeding
  • Vulvar ulcer
  • Difficult sexuality
  • Warty growth/lump
• Local examination reveals a lesion in the vulva with white, gray, pink or dull red color. Lesions look rough, raised from the surface and often multifocal. Application of 5% acetic acid turns VIN lesions white with punctuation and mosaic patterns. These changes are seen with a colposcope. Toluidine blue test is discarded as it is nonspecific

  
• A complete pelvic examination is to be done. To exclude vaginal or cervical neoplasia, cytologic evaluation has to be performed

  
• Biopsy


  Confirmation of diagnosis is done by biopsy. Usually 3–5 mm diameter dermal punch is taken under local anesthetic using a Keye's punch biopsy forceps. The small amount of bleeding is controlled using Monsel's paste (ferrous subsulfate). Larger biopsy when required may be taken using a scalpel. Multiple site biopsies are useful
• Histology of VIN


  The cells exhibit features of malignancy. There is complete loss of polarity and stratification. Cellular immaturity, nuclear abnormalities and mitotic activity vary depending upon the grade of VIN. There is hyperkeratosis, acanthosis (hyperplasia of epidermis) and chronic inflammatory cell infiltration. Koilocytes may be present. The rete ridges are large and elongated. Basement membrane remains intact. There is no evidence of involvement of the dermis

  
• Treatment of VIN

  VIN 1 should not be treated and is followed up. All high grade VIN (VIN 2 and 3) lesions should be treated
• Paget's disease

  A special type of VIN (intraepithelial disorder). The lesion grows horizontally within the epidermis. The rete ridges tend to push into the dermis without actually penetrating it. The characteristic histologic picture is presence of Paget cells in the epidermis. Associated adenocarcinoma of apocrine gland (adenocarcinoma in situ) is present in about 10% of the cases. There is high incidence (30%) of associated carcinomas of other organs (breast, cervix, ovary, stomach, GI tract and bladder)

  
• Patients with high grade VaIN need long-term follow up with vaginal cytology and vaginoscopy. Recurrence risk for VaIN is 2/3 (20–30%)
• Terminology changes for cervical intraepithelial neoplasia

  • Carcinoma in situ (CIS) (Rubin, 1910)
  • Dysplasia (Walters and Regan, 1956)
  • Cervical intraepithelial neoplasia (CIN) (Richart, 1967)
  • The Bethesda System (TBS) in 1988 and modified on 2014

  
• Squamocolumnar junction (SCJ) is the meeting point of columnar epithelium, that lines the endocervical canal, with squamous epithelium that lines the ectocervix. Transformation zone is the metaplastic squamous epithelium between the original squamocolumnar junction (OSCJ) and the active squamocolumnar junction (ASCJ). Cervical neoplasia originates almost always from the transformation zone

  
• Pathogenesis of cervical intraepithelial neoplasia

  1. Replacement of endocervical columnar epithelium by squamous epithelium through squamous metaplasia of the subcolumnar reserve cells

  2. Squamous epidermalization by ingrowth of the squamous epithelium of the ectocervix under the columnar epithelium

  3. Acidic pH of vagina is an important trigger for the metaplastic process

  4. Prolonged effect of carcinogens can produce continuous changes in the immature cells which may progress to malignancy

  5. Early age sexual activity and multiple sexual partners are the most consistent risk factors

  6. HPV infection is transmitted through sexual activity. Microtrauma (sexual intercourse) causes viral entry to the epithelium (basal or parabasal cells) of the transformation zone adjacent to the SCJ

  
• Women with multiple partners have high HPV-DNA positivity rate (60%) compared to women with single partner (21%)
• Pathogenesis of CIN and invasive carcinoma

  1. Metaplastic cells have potentiality to undergo atypical transformation by trauma or infection

  2. Prolonged effect of carcinogens can produce continuous changes in immature cells which may progress to malignancy

  3. Early age sexual activity and multiple sexual partners are risk factors

  4. HPV infection is transmitted through sexual activity

  5. Microtrauma (sexual intercourse) causes viral entry to epithelium

  6. HPV-DNA positivity is strongly related with number of sexual partners

  
• Transformation zone

  • Before puberty, ectocervix is covered with squamous epithelium
  • Heightened estrogenic activity exposes columnar epithelium onto ectocervix
  • New squamocolumnar junction situated at or slightly outside external os during reproductive period
  • Replacement of columnar epithelium by squamous epithelium forms TZ
  • Squamocolumnar junction is dynamic and changes with life phases
  • Indrawing of squamocolumnar junction and TZ into cervical canal occurs after menopause

  
• Factors in genesis of cervical cancer

  • Infection with high-risk HPV
  • Multiple types of HPV
  • Persistence of infection
  • Age >30 years
  • Smoking
  • Compromised host immunodefense

  
• CIN I or II

  Most often related to infection and may revert back to normal
• CIN III

  More susceptible to progress into invasive carcinoma, especially in cases of CIS
• Some epithelial atypia remain stationary, regress or progress to invasive carcinoma

  
• Even CIN I or II should not be ignored, but followed up carefully
• Prevalence of CIN, CIS and cervical cancer

  • CIN commonly seen around 20 years
  • CIS around 25-35 years
  • Incidence of cervical cancer rises significantly by 40 years

  
• Condoms may not be 100% protective against HPV infection
• More than 90% of immune competent women will have spontaneous resolution of HPV infection by 2 years

  
• About 10% have persistent high risk HPV infection which leads to CIN and invasive cancer

  
• Risk factors for CIN and cervical cancer

  • Infection: HPV, HSV2, HIV, Chlamydia
  • Early sexual intercourse (≤16 years)
  • Sexually transmitted infections
  • Early age of first pregnancy
  • Multiparity
  • Too many and too frequent births
  • Poor genital hygiene
  • Multiple sexual partners
  • Immunosuppressed (HIV positive) individuals
  • Husband with multiple sexual partners
  • Dietary deficiency of vitamins and folic acid
  • Increasing age
  • Inadequate screening
  • Oral pill users
  • Smoking habit

  
• Koilocyte


  Large, vacuolated squamous cells with clear perinuclear halo, hyperchromatic and irregular nuclei, multinucleate forms
• Over 99.7% of patients with CIN and invasive cancer are HPV-DNA positive

  
• Pathogenesis of HPV infection

  1. HPV is epitheliotropic

  2. Infects cervical epithelium (latent/active with virus replication)

  3. Oncogenic HPV-DNA integrates into human genome

  4. Upregulation of viral oncogenes

  5. Expression of E6 and E7 oncoproteins

  6. Interference of tumor suppressor genes (p53 and Rb)

  7. Host cell immortalization and HPV induced neoplastic transformation

  
• HPV triage strategy


  Pap smear test (LBC) → Atypical smear (HSIL, ACS-H) → HPV testing → High-risk HPV positive → Colposcopy
• Dyskaryotic cells

  • Increased cell size
  • Pleomorphism
  • Cells vary in size and shape
  • Multinucleation
  • Clumping of chromatin
  • Aneuploidy
  • Alteration in nuclear membrane
  • Perinuclear halo
• CIS cells

  • Hyperchromatic nuclei
  • Coarse chromatin
  • Lesser cytoplasm
  • Multiple nuclei
  • Abnormal mitotic figures
• Mild dyskaryosis is correlated with CIN II/III in 50% cases, severe dyskaryosis with 90% CIN II/III or CIS
• HR HPV-DNA testing


  • Hybrid capture method can reliably detect high-risk HPV types
  • Only 2-5% of HPV-DNA positive women will develop CIN
  • 80% test positive women will clear the infection
  • Positive test in elderly (>30 years) suggests colposcopy
  • HR HPV-DNA testing is an adjunct to cytology
  • Quantitative HPV testing is more important than qualitative

  
• Visual inspection with acetic acid (VIA)


  Acetic acid applied to cervix, those with acetowhite lesions considered for colposcopy and/or biopsy
• Colposcopy


  • In situ examination of cervix with low magnification microscope
  • Complementary and not substitute for cytology
  • Recommended for women with persistently positive HPV-DNA test
  • Identifies site for biopsy, while cytology identifies presence of neoplasm

  
• Indications of colposcopy


  • Cytology report: HSIL, ASC-H, ASCUS with HPV +ve
  • Clinically abnormal cervix despite normal cytology
  • Persistent HR HPV-DNA test result
  • Abnormal cervical cytology with positive HPV testing
  • Unexplained postcoital bleeding
  • Vulvar or vaginal neoplasia