Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations.
The Cancer Genome Atlas described four major genomic groups of endometrial carcinomas, including a POLE ultramutated subtype comprising ∼10% of endometrioid adenocarcinoma, characterized by POLE exonuclease domain mutations, ultrahigh somatic mutation rates, and favorable outcome. Our aim was to examine the morphological and clinicopathological features of ultramutated endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Hematoxylin and eosin slides and pathology reports for 8/17 POLE-mutated endometrial carcinomas described in the Cancer Genome Atlas study were studied; for the remaining cases, virtual whole slide images publicly available at cBioPortal (www.cbioportal.org) were examined. A second cohort of eight POLE mutated endometrial carcinomas from University of Calgary was also studied. Median age was 55 years (range 33-87 years). Nineteen patients presented as stage I, 1 stage II, and 5 stage III. The majority of cases (24 of the 25) demonstrated defining morphological features of endometrioid differentiation. The studied cases were frequently high grade (60%) and rich in tumor-infiltrating lymphocytes and/or peri-tumoral lymphocytes (84%); many tumors showed morphological heterogeneity (52%) and ambiguity (16%). Foci demonstrating severe nuclear atypia led to concern for serous carcinoma in 28% of cases. At the molecular level, the majority of the Cancer Genome Atlas POLE-mutated tumors were microsatellite stable (65%), and TP53 mutations were present in 35% of cases. They also harbored mutations in PTEN (94%), FBXW7 (82%), ARID1A (76%), and PIK3CA (71%). All patients from both cohorts were alive without disease, and none of the patients developed recurrence at the time of follow-up (median 33 months; range 2-102 months). In conclusion, the recognition of ultramutated endometrial carcinomas with POLE exonuclease domain mutation is important given their favorable outcome. Our histopathological review revealed that these tumors are commonly high grade, have obvious lymphocytic infiltrates, and can show ambiguous morphology. As they frequently harbor TP53 mutations, it is important not to misclassify them as serous carcinoma.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Yaser R
YR
Hussein
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Britta
B
Weigelt
Department of Surgery, Division of Gynecology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Douglas A
DA
Levine
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J Kenneth
JK
Schoolmeester
Department of Pathology, Mayo Clinic, Rochester, MN, USA.
Linda N
LN
Dao
Department of Pathology and Laboratory Medicine, Cedars-Sinai Hospital, Los Angeles, CA, USA.
Bonnie L
BL
Balzer
Department of Pathology and Laboratory Medicine, Cedars-Sinai Hospital, Los Angeles, CA, USA.
Georgia
G
Liles
Department of Obstetrics and Gynecology, Cedars-Sinai Hospital, Los Angeles, CA, USA.
Beth
B
Karlan
Department of Laboratory Medicine and Pathology, University of Calgary, Calgary, Alberta, Canada.
Martin
M
Köbel
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Cheng-Han
CH
Lee
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Robert A
RA
Soslow
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D004257:DNA Polymerase II / Q000235:genetics*; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D004257:DNA Polymerase II; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C112476:ARID1A protein, human; C513273:FBXW7 protein, human; C495901:TP53 protein, human; C484760:PIK3CA protein, human; C119525:POLE protein, human; C494929:PTEN protein, human