Molecular Analysis of Mixed Endometrial Carcinomas Shows Clonality in Most Cases.
Mixed endometrial carcinoma refers to a tumor that comprises 2 or more distinct histotypes. We studied 18 mixed-type endometrial carcinomas-11 mixed serous and low-grade endometrioid carcinomas (SC/EC), 5 mixed clear cell and low-grade ECs (CCC/EC), and 2 mixed CCC and SCs (CCC/SC), using targeted next-generation sequencing and immunohistochemistry to compare the molecular profiles of the different histotypes present in each case. In 16 of 18 cases there was molecular evidence that both components shared a clonal origin. Eight cases (6 EC/SC, 1 EC/CCC, and 1 SC/CCC) showed an SC molecular profile that was the same in both components. Five cases (3 CCC/EC and 2 SC/EC) showed a shared endometrioid molecular profile and identical mismatch-repair protein deficiency in both components. A single SC/EC case harbored the same POLE exonuclease domain mutation in both components. One SC/CCC and 1 EC/CCC case showed both shared and unique molecular features in the 2 histotype components, suggesting early molecular divergence from a common clonal origin. In 2 cases, there were no shared molecular features, and these appear to be biologically unrelated synchronous tumors. Overall, these results show that the different histologic components in mixed endometrial carcinomas typically share the same molecular aberrations. Mixed endometrial carcinomas most commonly occur through morphologic mimicry, whereby tumors with serous-type molecular profile show morphologic features of EC or CCC, or through underlying deficiency in DNA nucleotide repair, with resulting rapid accrual of mutations and intratumoral phenotypic heterogeneity. Less commonly, mixed endometrial carcinomas are the result of early molecular divergence from a common progenitor clone or are synchronous biologically unrelated tumors (collision tumors).
Department of Pathology and Laboratory Medicine, Calgary Laboratory Services and University of Calgary, Calgary, Alberta, Canada.
Martin
M
Köbel
Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Alberta, Canada.
Bo
B
Meng
Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
Lien N
LN
Hoang
Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
Noorah
N
Almadani
Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Alberta, Canada.
Xiaodong
X
Li
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Robert A
RA
Soslow
Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
C Blake
CB
Gilks
Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Alberta, Canada.
Cheng-Han
CH
Lee
D000368:Aged; D000369:Aged, 80 and over; D000416:Alberta; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D060965:Clonal Evolution; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D019143:Evolution, Molecular; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D060787:Neoplasm Grading; D018193:Neoplasms, Complex and Mixed / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D011237:Predictive Value of Tests; D013997:Time Factors; D016896:Treatment Outcome
D014408:Biomarkers, Tumor