POLE-mutated uterine carcinosarcomas: A clinicopathologic and molecular study of 11 cases Journal Article
| Authors: | Hammer, P. M.; Momeni-Boroujeni, A.; Kolin, D. L.; Kingsley, L.; Folkins, A.; Geisick, R. L. P.; Ho, C.; Suarez, C. J.; Howitt, B. E. |
| Article Title: | POLE-mutated uterine carcinosarcomas: A clinicopathologic and molecular study of 11 cases |
| Abstract: | Uterine carcinosarcomas (UCS) are high-grade biphasic neoplasms with generally poor outcomes. Based on The Cancer Genome Atlas molecular classification of endometrial carcinomas, the majority of UCS are classified as copy-number high/serous-like (p53-abnormal); however, a small subset represent other molecular subtypes, including those that harbor POLE mutations. We identified 11 POLE-mutated (POLEmut) UCS across 3 institutions and assessed the clinical, histopathologic, immunohistochemical, and molecular features of these tumors. POLEmut UCS occurred in adult women (median age, 64 years; range, 48-79 years) and usually presented as The International Federation of Gynecology and Obstetrics 2009 clinical stage IA (n = 4) or IB (n = 3). Almost all tumors were predominantly carcinomatous (n = 10), with most showing endometrioid morphology (n = 7), followed by ambiguous (n = 4) and serous (n = 3) histotypes. By immunohistochemistry, 7 tumors showed aberrant or subclonally aberrant expression of p53, 6 of which harbored pathogenic mutations in TP53 by sequencing. Other frequent mutations included PIK3CA (10/11), PTEN (8/11), RB1 (7/11), ARID1A (7/11), ATM (6/11), PIK3RA (5/11), and FBXW7 (4/11). Two tumors demonstrated loss of mismatch repair protein expression, and 1 had subclonal loss. Heterologous differentiation was uncommon, and only chondrosarcomatous type (n = 2) was observed. Mean and median follow-ups were 24.3 and 14.1 months, respectively (range, 1.4-61.1 months). Ten patients (91%) had no recurrences or death from disease, although 3 of these had follow-up periods <1 year. One patient, with the subclonal POLE variant, presented with stage IV disease and died 1.4 months after surgery. In conclusion, POLEmut UCS demonstrate unique morphologic and immunohistochemical features compared with their p53-abnormal counterparts and may have significant prognostic differences. Our study supports full molecular classification of UCS. We also raise awareness for potentially assessing POLE mutation allele frequency and clonality in consideration of classifying a tumor as POLEmut. © 2024 United States & Canadian Academy of Pathology |
| Keywords: | immunohistochemistry; adult; cancer chemotherapy; clinical article; human tissue; protein expression; aged; middle aged; unclassified drug; gene mutation; gene sequence; promoter region; clinical feature; histopathology; cancer radiotherapy; cancer staging; molecular genetics; follow up; antineoplastic agent; hysterectomy; endometrium cancer; tumor volume; protein depletion; tumor differentiation; genetic association; gene frequency; genetic variation; protein p53; uvomorulin; clonal variation; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; atm protein; neoadjuvant chemotherapy; cancer classification; estrogen receptor; progesterone receptor; exonuclease; postmenopause; retinoblastoma protein; beta catenin; chondrosarcoma; endometrial carcinoma; mismatch repair protein; protein msh6; apc protein; myogenin; uterus carcinoma; appendix tumor; dna directed dna polymerase epsilon; oncogene n ras; retinoblastoma protein 1; transcription factor pax7; germline mutation; international federation of gynecology and obstetrics; uterine carcinosarcoma; brg1 protein; retinoblastoma binding protein 2; depth of invasion; cancer prognosis; high throughput sequencing; phosphatidylinositol 4,5 bisphosphate 3 kinase; phosphatidylinositol 4,5 bisphosphate 3 kinase catalytic subunit alpha; human; female; article; pole; transcriptional regulator atrx; f box/wd repeat containing protein 7; desmin (protein); uterus biopsy; bilateral salpingooophorectomy; molecular classification of endometrial carcinomas; dna polymerase epsilon catalytic subunit; appendiceal metastasis |
| Journal Title: | Modern Pathology |
| Volume: | 38 |
| Issue: | 3 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2025-03-01 |
| Start Page: | 100676 |
| Language: | English |
| DOI: | 10.1016/j.modpat.2024.100676 |
| PUBMED: | 39615841 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Erratum issued, see DOI: 10.1016/j.modpat.2025.100784 -- Source: Scopus |
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