Endometrial hyperplasia
Progestin therapy related changes

Topic Completed: 1 August 2016

Minor changes: 15 October 2019

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PubMed Search: Progestin therapy related changes

Carlos Parra-Herran, M.D.
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Cite this page: Parra-Herran C. Progestin therapy related changes. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusprogestinrelated.html. Accessed August 11th, 2020.
Definition / general
  • Hysterectomy is the standard treatment for endometrioid intraepithelial neoplasia / atypical hyperplasia and endometrial endometrioid adenocarcinoma
  • However, the proportion of premenopausal women with these diagnoses is increasing: 15 - 25% are premenopausal (Int J Womens Health 2014;6:691), 10% are < 45 years, 4% are < 40 years
  • Hormonal therapy is now a valid alternative for pre-menopausal women who desire to preserve fertility
  • Two types of fertility sparing treatment are oral progestins and Levonorgestrel releasing intrauterine device
  • Indications for fertility sparing treatment:
    • Young woman
    • High desire to retain reproductive capabilities
    • Diagnosis of EIN / atypical hyperplasia or FIGO grade 1 endometrial endometrioid adenocarcinoma
    • No myometrial invasion on imaging (MRI)

  • The following patients are generally not eligible for fertility sparing treatment, but can be considered on a case to case basis: patients with obesity, anovulation, grade 1 endometrioid carcinoma and superficial myoinvasion on imaging, non myoinvasive grade 2 endometrioid carcinoma

  • Limitations:
    • 10 - 30% of patients present at advanced stage (FIGO stage III-IV), usually with ovarian / adnexal metastases, which may be only detected on hysterectomy / BSO but not with progestin treatment
    • Moreover, 5 - 29% of premenopausal women have a synchronous ovarian carcinoma, which may be only detected on hysterectomy / BSO but not with progestin treatment (Int J Womens Health 2014;6:691, Obstet Gynecol 2005;106:693)

  • Outcomes:
    • Regression / complete response: 74.6 - 76.2%
    • Recurrence after complete response: 35.4%
    • Persistence / progression: 25.4% within first 3 years, 51% after 3 years, 72% after 7 years
    • Pregnancy – live birth rate: 28 - 34.8% (73% for those who actively attempted pregnancy)
Microscopic (histologic) description
  • Progestin therapy related changes in the neoplastic endometrium include:
    • Architectural changes
      • Decreased volume of disease (% and number of involved fragments)
      • Decreased glandular crowding
      • Low to absent nuclear stratification
      • Decreased cellularity (associated with complete response)
    • Cytologic changes
      • Decreased nuclear to cytoplasmic ratio
      • Decreased nuclear size
      • Cytoplasmic eosinophilia
      • Nuclear rounding
    • Metaplasia (secretory, squamous, mucinous)

  • Progestin related glandular and stromal changes in the background benign endometrium:
    • Their presence is an indicator of patient compliance with the treatment
    • Conversely, their absence suggests lack of patient adherence (in case of oral progestins) or malfunction (in case of intrauterine device)

  • Diagnosis of the degree of response to progestin therapy:
    • Four categories: resolution, regression, persistence or progression
    • Regression or resolution are achieved in a span of 6 months in most cases (Am J Surg Pathol 2007;31:988)
      • It has been postulated that 6 months is a prudent period for conservative treatment and followup sampling
      • After 6 months, the likelihood of regression or resolution is less, and definitive management (hysterectomy) is indicated

  • Diagnostic workup of followup endometrial samples in patients with fertility sparing treatment:
    • Document the time interval between initial diagnosis and followup
    • Compare initial and followup samples (if possible)
    • Determine the degree of response (see chart above)
    • Determine the status of the background benign endometrium (with or without progestin therapy related changes)

Initial (pre-treatment) diagnosis
Atypical hyerplasia / EIN FIGO 1 endometrioid adenocarcinoma
Followup (post-treatment) interpretation Resolution Negative for residual hyperplasia or carcinoma Negative for residual hyperplasia or carcinoma
Regression Endometrial hyperplasia with progestin treatment effect Endometrial hyperplasia with progestin treatment effect
Atypical endometrial hyperplasia with no Progestin treatment effect
Persistence Atypical endometrial hyperplasia with no progestin treatment effect FIGO 1 endometrioid adenocarcinoma with no progestin treatment effect
FIGO 1 endometrioid adenocarcinoma with progestin treatment effect
Progression Endometrial endometrioid adenocarcinoma FIGO 2 or 3 endometrioid adenocarcinoma

Microscopic (histologic) images

Contributed by Dr. Carlos Parra-Herran

Various images

Additional references
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