Jennifer A Bennett

GREB1 ‐rearranged uterine tumour shares a common DNA methylation signature with ESR1 ‐rearranged UTROSCT

Background and objectives GREB1 ‐rearranged uterine tumours encompass a group of uterine mesenchymal tumours with varied histologic appearances. The fusion partners to GREB1 include NCOA1‐3, SS18 and NR4A3 . Given that some GREB1 ‐rearranged uterine tumours exhibit histologic features of uterine tumours resembling ovarian sex cord tumour (UTROSCT), there is a general belief that GREB1 ‐rearranged uterine mesenchymal tumours are part of the UTROSCT family. Methods In this study, we applied global DNA methylation and copy number analyses to a series of 10 GREB1‐ rearranged uterine tumours and 21 classic UTROSCTs (7 of which were molecularly confirmed to harbour ESR1::NCOA2/3 fusions). Results We found that GREB1 ‐rearranged uterine tumors show an overlap in their global methylation profiles with UTROSCT, including ESR1::NCOA2/3 positive cases. Together, these tumours form a DNA methylation cluster separate from uterine smooth muscle tumours (leiomyomas and leiomyosarcomas), endometrial stromal sarcomas (low‐grade and high‐grade), embryonal rhabdomyosarcoma and SMARCA4‐deficient uterine sarcomas. However, despite their epigenetic similarity, there were two notable differences. First, GREB1 ‐rearranged uterine tumours as a group displayed a greater degree of genomic complexity with more extensive copy number alterations than conventional UTROSCTs, including those harbouring ESR1::NCOA2/3 . Second, GREB1 ‐rearranged uterine tumours frequently lacked overt sex cord morphology: while all 7 ESR1::NCOA2/3 UTROSCTs demonstrated corded, nested, trabecular and/or tubular/sertoliform patterns, only 1 GREB1 ‐rearranged uterine tumour displayed a prominent trabecular pattern, with the remaining cases showing exclusively or predominantly diffuse/solid growth. Conclusions Overall, our findings confirm that GREB1 ‐rearranged uterine tumours are part of the UTROSCT spectrum, though they frequently exhibit a more diffuse growth pattern and a higher degree of genomic instability.

The complex and often confusing history, histology and histogenesis of mesonephric, STK11 adnexal tumour and mesonephric‐like neoplasms of the upper female genital tract (including broad ligament)

Mesonephric lesions in the female genital tract are uncommon, with those arising from the upper tract being much less frequent than those developing in the lower tract (mesonephric hyperplasia and carcinoma). The most common upper tract lesions include rete cyst/cystadenoma and female adnexal tumour of Wolffian origin (FATWO). The integration of morphological, immunohistochemical and molecular studies on FATWOs has enabled recognition of a novel entity, the STK11 adnexal tumour, which is often associated with Peutz–Jeghers syndrome (~50%) and frequently has a salivary gland morphology but an unknown origin. Similarly, ‘mesonephric‐like’ adenocarcinoma, an entity with striking similarities to mesonephric carcinoma but currently favoured to be of Müllerian derivation based on its association with other Müllerian tumours and molecular findings, has also been recently described, and may histologically mimic both FATWOs and STK11 adnexal tumours. In this review, we provide a historical overview of upper female genital tract mesonephric proliferations and discuss mesonephric lesions, STK11 adnexal tumour, mesonephric‐like adenocarcinoma, and mimickers, the most common being endometrioid carcinoma.