Vaginal Adenosis

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Description

  • The normal vagina is lined with squamous epithelium. Adenosis is characterized by the presence of columnar epithelium or glandular tissue in the wall of the vagina.
  • Around week 15 of embryologic development, the müllerian system, which forms the upper 2/3 of the vagina, fuses with the invaginating cloaca or urogenital sinus to form the lower 1/3 of the vagina. Squamous metaplasia from the cloacal region then produces squamous epithelium within the vagina (1).
  • Adenosis occurs when this squamous epithelium fails to epithelialize the vagina completely.
  • Three main types of adenosis epithelium:
    • Endocervical
    • Endometrial
    • Tubal
  • System(s) affected: reproductive

Geriatric Considerations

  • Adenosis is a disorder of the young female. By menopause, the vagina and cervix should be completely epithelialized.
  • In a postmenopausal patient, the presence of glandular epithelium is an indication for excision and evaluation, given the risk of well-differentiated adenocarcinoma.

Pregnancy Considerations
Pregnancy produces a wide eversion of the transformation zone of the cervix. This can become so widely everted that it will extend onto the vaginal fornices, leading to the impression of adenosis. This will resolve after pregnancy.

Epidemiology

  • Spontaneous (non-diethylstilbestrol [DES]) adenosis is common in young women and usually resolves with age; prevalence decreases after puberty and is rare after age 30.
  • DES-associated adenosis: Up to 90% of “DES daughters” develop adenosis, with a 40-fold increased risk of clear cell adenocarcinoma

Incidence

  • Although the cumulative incidence of vaginal adenosis is unknown, the incidence of cloacal malformations is 1/20,000 to 1/25,000 live births.
  • Although spontaneous vaginal adenosis appears to be fairly common (10% of adult women), it is mostly an insignificant coincidental finding. Widespread symptomatic involvement is rare (2).

Prevalence

  • In the United States, adenosis is common in young women, affecting 10–20%. As maturation progresses with puberty, epithelialization occurs.
  • Predominant age
    • Age <1 month: 15%
    • Prepubertal: typically absent
    • Age 13 to 25 years: 13%
    • Age >25 years: decreasing prevalence, uncommon beyond age 30 years (2)

Etiology and Pathophysiology

  • In most young females, the etiology is incomplete squamous metaplasia or epithelialization. This occurs as a natural phenomenon and resolves with age.
  • Described as congenital or acquired:
    • Congenital: proliferation of the remnant müllerian epithelium in the vagina due to exposure to DES in utero (“DES daughters”). DES is a synthetic, nonsteroidal estrogen used to prevent miscarriage or premature deliveries from 1938 to 1971. An estimated 5 million women were prescribed DES during this period (3).
    • Transformation-related protein 63 (TRP63/p63) marks the cell fate of müllerian duct epithelium to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression and induces adenosis lesions (3). It has also been suggested that DES induces vaginal adenosis by inhibiting the BMP4 and Activin A-regulated vaginal cell fate through a downregulation of RUNX1.
    • Acquired: trauma and inflammation causing spontaneous de novo changes or changes in an acquired lesion in the vaginal epithelium
    • Additional reports documented adenosis subsequent to sulfonamide-induced Stevens–Johnson syndrome and after treatment of vaginal condylomas with 5-fluorouracil (4).

Genetics

  • Vaginal adenosis is not linked to inherited genetic mutations or familial syndromes.
  • Primarily associated with disrupted embryologic signaling, particularly after in utero exposure to DES. DES interferes with pathways such as BMP4 and Activin A-SMAD/RUNX1, leading to persistence of glandular epithelium in the vagina.
  • Genetic mutations such as TP53 and PTEN are implicated in vaginal adenocarcinoma, but not in benign adenosis.

Risk Factors

Adenosis of the vagina/cervix may arise in up to 90% of DES daughters and has a 40-fold increased risk of developing into clear cell adenocarcinoma.

General Prevention

None: Last DES exposure was in the 1970s.

Commonly Associated Conditions

DES exposure

  • Adenosis from DES exposure should lead to an evaluation of other DES-related abnormalities.
  • Müllerian tract anomalies associated with DES exposure include cervical hood, cervical ridge, shortened cervix, incompetent cervix, and T-shaped uterine cavity.
  • Patients with known DES exposure should have their reproductive tract evaluated prior to conception.
  • Most patients with adenosis have not been DES-exposed and do not require evaluation of the reproductive system.
  • The FDA issued a drug bulletin in 1971 advising physicians to stop prescribing DES to pregnant women because of its link to vaginal clear cell adenocarcinoma in DES daughters.

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