Exploring the Genetic and Clinical Landscape of Dedifferentiated Endometrioid Carcinoma

Abstract

Dedifferentiated endometrioid carcinoma (DDEC) is rare, has a poor prognosis, and the genes responsible for dedifferentiation remain unclear. This study aimed to clarify the characteristics of DDEC in Japanese patients and develop treatment strategies. Eighteen DDEC cases were included; their clinicopathological features and prognoses were analyzed and compared to those of other histological subtypes. The samples were divided into well-differentiated and undifferentiated components; immunostaining and whole-exome sequencing (n = 3 cases) were conducted. The incidence of DDEC was 2.0% among endometrial cancers. The 5-year progression-free survival and the 5-year overall survival for DDEC was approximately 40% and 30%, respectively. Immunohistochemistry showed that 66.7% of patients were mismatch repair deficient. The rate of p53 mutations was higher than that reported in previous studies, and patients with p53 mutations in the undifferentiated components had a poor prognosis. Whole-exome sequencing revealed different gene mutations and mutation signatures between well-differentiated and undifferentiated components. New genetic mutations in undifferentiated regions were uncommon in all three cases. One case (case 1) exhibited homologous recombination deficiency, whereas the other two showed microsatellite instability-high and hypermutator phenotypes. Genetic analysis suggests that immune checkpoint and poly (ADP-ribose) polymerase inhibitors and drugs targeting the p53 pathway may be effective against DDEC.

Keywords: dedifferentiated endometrioid carcinoma; endometrial carcinoma; p53; whole-exome sequencing.

Figure 1

Kaplan–Meier analysis of progression-free survival (A) and overall survival (B). G1/G2, grade 1 and 2 endometrioid carcinoma; G3, grade 3 endometrioid carcinoma; others, other carcinomas; DDEC, dedifferentiated endometrioid carcinoma.

Figure 1

Kaplan–Meier analysis of progression-free survival (A) and overall survival (B). G1/G2, grade 1 and 2 endometrioid carcinoma; G3, grade 3 endometrioid carcinoma; others, other carcinomas; DDEC, dedifferentiated endometrioid carcinoma.

Figure 2

Immunohistochemical findings. (A) Hematoxylin and eosin staining showing WCs and UCs from case 9. (B) PAX8: expression in the WC and the loss of expression in the UC in case 7. (C) Cytokeratin: expression in the WC and the loss of expression in the UC in case 9. (D) Epithelial membrane antigen: expression in the WC and the loss of expression in the UC in case 9. (E1) p53: wild-type expression in the WC and UC in case 9. (E2) p53: overexpression in the WC and UC in case 7. (F) E-cadherin: expression in the WC and the loss of expression in the UC in case 7. (G) Fascin: the loss of expression in the WC and expression in the UC in case 9. (H) ARID1A: expression in the WC and the loss of expression in the UC in case 9. WC, well-differentiated component; UC, undifferentiated component.

Figure 2

Immunohistochemical findings. (A) Hematoxylin and eosin staining showing WCs and UCs from case 9. (B) PAX8: expression in the WC and the loss of expression in the UC in case 7. (C) Cytokeratin: expression in the WC and the loss of expression in the UC in case 9. (D) Epithelial membrane antigen: expression in the WC and the loss of expression in the UC in case 9. (E1) p53: wild-type expression in the WC and UC in case 9. (E2) p53: overexpression in the WC and UC in case 7. (F) E-cadherin: expression in the WC and the loss of expression in the UC in case 7. (G) Fascin: the loss of expression in the WC and expression in the UC in case 9. (H) ARID1A: expression in the WC and the loss of expression in the UC in case 9. WC, well-differentiated component; UC, undifferentiated component.

Figure 3

Summary of immunohistochemical findings. WC, well-differentiated component; UC, undifferentiated component; CK, cytokeratin; EMA, epithelial membrane antigen; N/A, not performed. Positive results are indicated in red, and negative results are indicated in white (for p53, wild-type is blue, mutant is white).

Figure 4

Mutation signatures. (A) Signature 2 exhibits the highest similarity with the mutation profile of the WC in case 1. (B) Signature 30 exhibits the highest similarity with the mutation profile of the UC in case 1. WC, well-differentiated component; UC, undifferentiated component.

Figure 5

The copy number alteration plot. The horizontal axis represents the chromosome location, and the vertical axis represents the gene copy number. (A) The CNA plot of the WC in case 1. (B) The CNA plot of the UC in case 1. CN, copy number; CNA, copy number alteration; VAF, variant allele frequency; WC, well-differentiated component; UC, undifferentiated component.