bims-ovdlit 2025-05-11 papers

Am J Surg Pathol. 2025 May 08.

Uncloaking the Fimbria Ovarica: Histologic Recognition of an Elusive Anatomic Structure.

Jeffrey D Seidman, Rebecca Stone, Vasiliki A Moragianni, Jayashree Krishnan, Russell Vang.

A portion of the fimbriated end of the fallopian tube known as the fimbria ovarica extends along the lateral edge of the mesosalpinx to the ovary to which it is attached at its lateral pole. Seventy-four examples of fimbrial plicae that were attached to the ovary or broad ligament and lacked features of adhesions were studied. The fimbrio-ovarian attachments were characterized by one or more of the following: continuity between the tubal epithelium and either the ovarian surface epithelium, peritoneum, or both, in 51 cases; direct continuity of the ovarian stroma into the stroma of the fimbria ovarica in 42 cases; and direct insertion of plicae into the ovarian surface or ovarian stroma in 18 cases. In 21 cases, there was a direct attachment of plicae to the broad ligament close to the ovary. The mean size of the fimbria ovarica was 6.6 mm. The plicae were lined by normal tubal-type epithelium. The plical morphology was typically abnormal displaying one or more of the following features: short and blunted in 24 (32%), thickened in 18 (24%), elongated in 14 (19%), fusion in 13 (18%), edema in 13 (18%), and fibrosis in 11 (15%). Also noted were a mesothelial component in 69 cases (93%), the tubal-peritoneal junction in 53 cases (72%), transitional cell metaplasia/Walthard cell nests in 11 cases (15%), and foci resembling incipient fimbrial adenofibroma in 7 cases (9%). An understanding of the microanatomy and histology of the fimbria ovarica has important implications, particularly as: (a) portions may be left behind after prophylactic salpingectomy, providing a nidus for future development of high grade serous carcinoma (HGSC); (b) it constitutes an anatomic connection that may facilitate the spread of HGSC to the ovary, and (c) epithelial junctions are hotspots for carcinogenesis, and stem cells arising in such regions may be a source of HGSCs. In addition, understanding the fimbria ovarica has implications for the pathogenesis of ovarian surface epithelial inclusions, endosalpingiosis, and certain types of infertility. Its potential role as a site of origin of extrauterine HGSC, which typically arises in the fimbriae as serous tubal intraepithelial carcinoma, remains to be investigated.

Keywords: carcinoma; fallopian tube; fimbria ovarica; high grade serous carcinoma; infertility; ovary; peritoneum; serous tubal intraepithelial carcinoma; tubal-peritoneal junction

DOI: https://doi.org/10.1097/PAS.0000000000002414

Clin Cancer Res. 2025 May 06.

Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-Grade Serous Tumors with Histologic Transformation.

M Herman Chui, Eun-Young Kang, Ryan M Kahn, Sarah Chiang, Qin Zhou, Alexia Iasonos, Beryl Manning-Geist, Pier Selenica, Arnaud Da Cruz Paula, Kara Long Roche, Britta Weigelt, Rachel N Grisham.

PURPOSE: To characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma.
EXPERIMENTAL DESIGN: LGS-HTs were retrospectively identified from an institutional cohort of ovarian cancer patients and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS) were collected. Immunohistochemical profiling and next-generation sequencing were performed. OS comparisons were performed with our institutional cohorts of ovarian low-grade serous carcinoma (LGSC, n=109) and high-grade serous carcinoma (HGSC, n=1672).
RESULTS: From 4371 ovarian serous cancers, 40 (0.9%) LGS-HTs were identified: 30 with synchronous low-grade and higher-grade tumor components at initial diagnosis (LGS-HT-Sync) and 10 with an ovarian low-grade serous neoplasm that recurred as a higher-grade carcinoma (LGS-HT-Metac). The most common somatic driver mutations included TP53 (38.5%), KRAS (21.8%), NF1 (15.6%), BRAF (15.6%) and NRAS (12.5%), with co-existing TP53 and RAS/RAF mutations in 18.8% of cases. Alterations of DNA damage response genes (BRCA2, PALB2, CHEK2, ATM, NBN, RECQL4) were identified in LGS-HTs lacking TP53 genetic alterations. LGS-HT-Sync was associated with poorer OS (median 59.7 months) compared to LGSC (median 105.4 months; p=0.026), and was similar to HGSC (median 48.8 months, p=0.61). Severe nuclear atypia and absence of RAS/RAF-driver mutations were significant adverse prognostic factors.
CONCLUSIONS: LGS-HT exhibit both low-grade and high-grade morphologic and molecular features, representing an exception to the dualistic classification of ovarian serous neoplasms.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3168

Eur J Cancer. 2025 May 04. pii: S0959-8049(25)00271-0. [Epub ahead of print] 115490

Letter RE: Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high-grade serous carcinoma.

Berkan Karabuga, Kadriye Baskurt, Nurlan Mammadzada, Osman Sutcuoglu.

DOI: https://doi.org/10.1016/j.ejca.2025.115490

Mol Hum Reprod. 2025 May 08. pii: gaaf011. [Epub ahead of print]

Profiling (placental) DNA methylation in cell-free DNA across gestation: the Rotterdam Periconception Cohort.

Marjolein M van Vliet, Ruben G Boers, Joachim B Boers, Olivier J M Schäffers, Lotte E van der Meeren, Joost Gribnau, Sam Schoenmakers, Régine P M Steegers-Theunissen.

Placental DNA methylation varies across gestation and is associated with obstetrical complications. Cell-free DNA (cfDNA) from maternal plasma could provide a noninvasive approach to study placental DNA methylation in ongoing pregnancies. However, research on maternal cfDNA methylation is limited and technologically challenging. Therefore, we aimed to investigate DNA methylation in maternal cfDNA and placental tissues across gestation using the innovative methylation DNA sequencing (MeD-seq) technology. Secondly, we explored the origins of methylation differences in maternal cfDNA across gestation, and aimed to identify gestational age-associated placental DNA methylation markers directly in cfDNA. We longitudinally collected maternal cfDNA in all three trimesters and at birth (n = 10), alongside placental tissues from first trimester, second trimester and term pregnancies (all n = 10), and used previously collected maternal blood buffy coat samples (n = 20). Different placental cell types, including syncytiotrophoblasts/cytotrophoblasts (SCTs/CTBs) (n = 10), extravillous trophoblasts (EVTs) (n = 7) and syncytial knotting (SK) (n = 3), and maternal cell types including spiral arteries (n = 3) and endometrial epithelium (n = 3), were isolated using laser capture microdissection. Differentially methylated regions (DMRs) identified in cfDNA from pregnant compared to non-pregnant women (n = 6) ranged from 798 to 2163 in first and third trimesters, respectively. Gradual DNA methylation changes were observed across gestation in cfDNA, placental tissues and trophoblasts. We showed an increase in DMRs in cfDNA, that overlap with DNA methylation in placental tissues and especially trophoblasts, and in DNA methylation of placenta-specific markers across gestation, reflecting an increased placental-originated cfDNA fraction. Among 110 DMRs between first trimester and term placental tissues, those related to NXPH4, EPS8L2, AMOTL1 and IRX2 had the strongest association with gestational age in cfDNA, for which comparable associations were found in SCTs/CTBs. These DMRs were all hypomethylated in maternal buffy coat samples. This study indicates the feasibility of identifying gestational age-dependent placental DNA methylation marks in maternal cfDNA and can serve as reference for future studies.

Keywords: DNA methylation; cell-free DNA; epigenetics; gestational age; placenta; pregnancy

DOI: https://doi.org/10.1093/molehr/gaaf011

Lancet Oncol. 2025 May;pii: S1470-2045(25)00229-3. [Epub ahead of print]26(5): 529

The complex cartography of cancer care.

The Lancet Oncology.

DOI: https://doi.org/10.1016/S1470-2045(25)00229-3

Eur J Cancer. 2025 May 05. pii: S0959-8049(25)00272-2. [Epub ahead of print] 115491

Response to letter RE: Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma.

Robert L Hollis, C Simon Herrington, Charlie Gourley.

DOI: https://doi.org/10.1016/j.ejca.2025.115491

Clin Obstet Gynecol. 2024 Dec 01. 67(4): vi-viii

Contributors: Genetics and Gynecologic Cancer: Opportunity and Nuance.

DOI: https://doi.org/10.1097/01.grf.0001081336.90794.7f

Cancer Res. 2025 May 06.

HRProfiler Detects Homologous Recombination Deficiency in Breast and Ovarian Cancers Using Whole-Genome and Whole-Exome Sequencing Data.

Ammal Abbasi, Christopher D Steele, Erik N Bergstrom, Azhar Khandekar, Akanksha Farswan, Rana R McKay, Nischalan Pillay, Ludmil B Alexandrov.

Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1, BRCA2, and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational signatures due to the activities of HRD-associated mutational processes. At least three machine learning tools exist for detecting HRD based on mutational patterns. Here, using sequencing data from 1,043 breast and 182 ovarian cancers, we trained Homologous Recombination Proficiency Profiler (HRProfiler), a machine learning method for detecting HRD using six mutational features. The performance of HRProfiler was assessed against prior approaches using additional independent datasets of 417 breast and 115 ovarian cancers, including retrospective data from a clinical trial involving patients treated with PARP inhibitors. Individual HRD-associated mutational signatures alone did not consistently detect HRD or predict clinical response across datasets. Notably, while all tools performed comparably for whole-genome sequenced cancers, HRProfiler was the only approach that consistently identified HRD in whole-exome sequenced breast and ovarian cancers, offering clinically relevant insights. Retrospective analyses provided strong evidence that HRProfiler could serve as a valuable tool for predicting HRD and clinical response in breast and ovarian cancers. This study provides the rational for large-scale prospective clinical trials to validate the potential of HRProfiler as a routine predictive and/or prognostic HRD biomarker to guide clinical decision-making.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2639