Uterus

• TCGA Research Network identified 4 molecularly distinct endometrial carcinoma subgroups with different clinical outcomes (Nature 2013;497:67):
  1. POLE ultramutated (POLEmut), ultramutated
     • Pathogenic POLE exonuclease domain mutations
  2. Mismatch repair deficient (MMRd), hypermutated
     • Abnormal expression of mismatch repair proteins by IHC, highly concordant with MSI H status
  3. p53 abnormal (p53abn), copy number high; also referred to as serous-like
     • Aberrant p53 expression by IHC, frequent TP53 mutations
  4. No specific molecular profile (NSMP), copy number low
     • Pathogenic POLE mutation absent, MMR proficient and p53 nonaberrant
• POLE gene encodes the catalytic subunit of DNA polymerase epsilon
  • DNA polymerase epsilon synthesizes DNA of the leading strand and plays a major role in proofreading (e.g., nucleotide and base excision repair) (Nat Rev Cancer 2016;16:71)
  • Defects in exonuclease domain of POLE → ultramutational state / high tumor mutational burden → high neoantigen loads (immunogenic) → associated with increased tumor infiltrating lymphocytes / peritumoral lymphocytes and elevated PD-1 / PDL1 expression (JAMA Oncol 2015;1:1319)
    • Enhanced T cell antitumor response may play a role in the observed favorable prognosis

Contributed by Carlos Parra-Herran, M.D.


Images hosted on other servers:

Contributed by Lucy Ma, M.D.

• Majority of pathogenic POLE mutations are within exons 9, 11, 13 and 14, which encode the proofreading exonculease domain
  • 5 recurrent POLE exonuclease domain mutation variants account for the majority of POLEmut cases: P286R, V411L, S297F, A456P and S459F
• Characteristic genomic signatures:
  • High prevalence of C → A substitutions
  • Low proportion of small insertion and deletion mutations (indels)
  • High tumor mutational burden (TMB: > 100 mut/Mb)
• Diagnostic interpretation (i.e., evaluation of pathogenicity of novel POLE mutations may be guided by POLE score) (J Pathol 2020;250:323)

• Endometrium, curettage:
  • High grade endometrial carcinoma (see comment)
  • Comment: Sections show fragments of endometrial carcinoma with varied morphology, including areas with endometrioid and focal serous differentiation. The tumor shows complex glandular, solid and focal papillary architecture. The lining cells show predominantly high grade cytologic atypia, characterized by enlarged hyperchromatic nuclei with high nuclear to cytoplasmic ratio, loss of polarity and increased mitotic activity. Scattered markedly atypical bizarre cells are also noted. Immunohistochemical stains show that the tumor cells are positive for ER (80%, variable intensity) and PR (20%, weak). p53 shows predominantly nonaberrant (wild type) expression but a small subset of tumor cells show aberrant p53 overexpression. Mismatch repair protein (MLH1, PMS2, MSH2 and MSH6) expression is intact (retained / normal). POLE mutational analysis by Sanger sequencing has been requested and the result, along with the final molecular classification of this tumor, will be issued in an addendum report.
  • Addendum: final molecular classification: POLE ultramutated (pathogenic POLE mutation detected - see molecular report #. Mismatch repair protein expression is intact. p53 shows subclonal aberrant overexpression.)

• Uterus, fallopian tubes and ovaries, total hysterectomy and bilateral salpingo-oophorectomy:
  • Endometrial endometrioid carcinoma, FIGO grade 2; final molecular classification: POLE ultramutated (see synoptic report and comment)
    • Tumor invades the inner half of the myometrium (< 50%)
    • Lymphovascular invasion is absent
    • Cervix, uterine serosa, bilateral fallopian tubes and ovaries are uninvolved
  • Comment: Pathogenic POLE mutation detected (see molecular report #). DNA mismatch repair protein (MLH1, PMS2, MSH2 and MSH6) expression is intact. p53 expression is nonaberrant (wild type).

Shown above are representative images from an endometrial tumor in a 60 year woman. The tumor shows intact nuclear PMS2 and MSH6 expression, as well as p53 mutant overexpression by immunohistochemistry (seen in image 3). What additional test is required for accurate molecular classification of this endometrial cancer?

1. ARID1A immunohistochemistry
2. HER2 gene amplification by FISH
3. p16 immunohistochemistry
4. POLE exonuclease domain mutation analysis
5. Promoter hypermethylation testing of MLH1

D. POLE exonuclease domain mutation analysis. TCGA defined 4 molecular and prognostic subgroups of endometrial carcinoma: POLEmut, MMRd, p53abn and NSMP. Accurate molecular classification relies on correct interpretation of tests following the recommended algorithm (see Diagram 1).

Comment Here

Reference: POLE ultramutated endometrial carcinoma

Which of the following molecular subgroups of endometrial carcinoma confers the most favorable prognosis?

1. MMR deficient
2. No specific molecular profile
3. p53 abnormal
4. POLE ultramutated

D. POLE ultramutated

Comment Here

Reference: POLE ultramutated endometrial carcinoma