ER & PR Expression in Endometrial Hyperplasia and Carcinoma – Detailed Study Notes

Background & Rationale

  • Endometrial carcinoma = 3rd most common gynaecological malignancy in SE-Asia (after cervical & ovarian).
  • Endometrium is hormone-sensitive; expresses both Estrogen Receptor (ER) & Progesterone Receptor (PR).
    • Imbalance in ER-α/ER-β and PR-A/PR-B ratios implicated in transition from normal endometrium ➜ hyperplasia ➜ carcinoma.
  • In breast cancer, ER/PR IHC status = established prognostic/predictive marker; analogous data in endometrial cancer remain limited.
  • Study motivation:
    • Clarify ER/PR expression pattern across the spectrum: normal cyclical endometrium, simple hyperplasia (SH), atypical hyperplasia (AH), and endometrial carcinoma (AC).
    • Evaluate potential for hormonal therapy guidance & prognostication.

Aims & Objectives

  • Statistically compare H-Scores of steroid hormone receptors (ER & PR) in:
    • Normal proliferative endometrium (PE)
    • Normal secretory endometrium (SE)
    • Simple hyperplasia (SH)
    • Atypical/complex hyperplasia (AH/CH)
    • Endometrial carcinoma (AC)
  • Determine significance of differences in epithelial vs. stromal compartments.

Study Design & Setting

  • Design: Prospective pathological study (reported retrospectively for analysis)
  • Centre: Government tertiary care hospital, Ranchi (Jharkhand, India)
  • Ethical approval: Institutional Ethics Committee (IEC) – RIMS, Ranchi

Materials & Methods

  • Specimens: Formalin-fixed paraffin-embedded (FFPE) uterine curettings / hysterectomy blocks.
  • Inclusion:
    • Histologically proven SH, AH, AC
    • Control: normal PE & SE from women aged 30-50 y (non-pregnant)
  • Exclusion:
    • Pregnant patients
    • Histologically inadequate tissue
  • Sample distribution (n = 62):
    • SH = 24
    • AH = 3 (all complex/atypical hyperplasia)
    • AC = 15
      • 12 endometrioid adenocarcinoma (Gr 1–3)
      • 1 carcinosarcoma (MMMT)
      • 1 type II endometrioid carcinoma
      • 1 undifferentiated carcinoma
    • Controls: 20 normal cycles (10 PE, 10 SE)
Immunohistochemistry (IHC)
  • Primary antibodies: ER & PR (nuclear staining expected)
  • Scoring compartments:
    • Epithelium (glandular/malignant)
    • Stroma
  • Semi-quantitative assessment: H-Score H-Score=3×%strong+2×%moderate+1×%weak\text{H-Score}=3\times\%\text{strong}+2\times\%\text{moderate}+1\times\%\text{weak}
    • Range: 0–3000–300
    • Positivity threshold: ≥75\ge 75
  • Statistics:
    • Student’s t-test for group comparisons
    • Significance: p<0.05p<0.05

Results

Normal Endometrium
  • PE & SE: Moderate-to-intense ER & PR in epithelium + stroma (baseline high receptor milieu).
Simple Hyperplasia (SH)
  • Epithelium: Moderate-to-intense ER/PR in all 24 cases.
  • Stroma: 100 % positive but heterogeneous % of stained cells.
  • No significant ER/PR difference vs. PE (epithelial); stromal PR differed vs. PE (p = 0.0034).
  • Significant stromal ER & both epithelial + stromal PR differences vs. SE.
Atypical Hyperplasia (AH)
  • 3 cases: Moderate-to-intense ER + PR in both compartments.
  • Numbers too small for meaningful statistics.
Endometrial Carcinoma (AC)
  • ER/PR markedly reduced versus SH (p = 0.0001 in both epithelium & stroma for both markers).
  • Detailed staining pattern:
    • PR: 3/12 adenocarcinoma weak epithelial; 1 mod-positive epi+stroma; 1 intense stromal only.
    • ER: 2 weak epi+, 1 moderate epi+stroma.
    • Carcinosarcoma, Type II carcinoma, undifferentiated carcinoma: ER & PR negative in malignant cells, but adjacent normal glands/myometrium retained positivity (internal control).
  • Grade correlation (limited by n): inverse trend; PR present in 3/4 Grade 1, 1/4 Grade 2, 1/4 Grade 3; ER positive only in some Grade 1 & one Grade 3 (weak-moderate).
Comparative Statistics (Key p-values)
  • SH vs. PE:
    • ER (epi p = 0.4361; stromal p = 0.9750): NS
    • PR (epi p = 0.5844; stromal p = 0.0034): stromal significant
  • SH vs. SE:
    • ER (epi p = 0.1882; stromal p = 0.0489): stromal significant
    • PR (epi p = 0.0068; stromal p = 0.0053): both compartments significant
  • SH vs. AC (ER & PR): all comparisons p = 0.0001 (highly significant)
Illustrative Figures (microscopy x400)
  • Fig 1: ER/PR staining in PE & SE.
  • Fig 2: ER/PR in adenocarcinoma vs. complex hyperplasia.

Discussion Highlights

  • Confirms literature trend: descending ER/PR expression from normal/SH ➜ AH ➜ AC.
  • Consistent with Nyholm, Bergeron: receptor loss parallels malignant progression & higher grade.
  • Biological implications:
    • Receptor-rich lesions may respond to progestin therapy.
    • Loss of receptors may signify poorer prognostic group & limit hormonal therapeutic options.
  • IHC advantages: retains tissue architecture; differentiates stromal vs. epithelial expression; feasible on archived FFPE.

Clinical & Research Implications

  • Recommend routine ER/PR IHC in:
    • Simple & atypical hyperplasia (to stratify for progestin therapy)
    • Endometrial carcinoma (prognostication; therapeutic decisions)
  • Potential to introduce ER/PR-tailored hormonal therapy analogous to breast cancer protocols.
  • Need for larger, multi-centre cohorts to validate thresholds & integrate molecular sub-classification (e.g., TCGA groups).

Limitations

  • Small sample size, especially AH (n = 3) & individual carcinoma subtypes.
  • Single-centre, potential selection bias.
  • HER-2/neu mentioned in abstract but data not presented – incomplete biomarker panel.

Key Take-Home Messages

  • ER & PR are retained in normal and simple hyperplasia; progressively lost in carcinoma.
  • Stromal compartment provides additional discriminatory power (significant differences where epithelial alone may not).
  • H-Score ≥ 75 is practical positivity cut-off.
  • p-value < 0.05 adopted for significance; several highly significant (p = 0.0001) reductions in carcinoma.
  • Routine ER/PR IHC could inform prognosis & hormonal therapy in endometrial pathology.

Select Foundational References (for deeper reading)

  • Nyholm HC et al., Am J Obstet Gynecol 1992 – biochemical & IHC ER/PR in hyperplasia & carcinoma.
  • Bergeron C et al., Cancer Res 1988 – PR in hyperplastic/neoplastic tissues.
  • Carcangiu ML et al., AJCP 1990 – ER/PR in 183 endometrial carcinomas.
  • Reid-Nicholson M et al., Mod Pathol 2006 – immunophenotypic diversity of endometrial adenocarcinomas.