Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability.

AIMS: Tumours of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumour (MMGC/T) components are usually diagnosed in postmenopausal women, and pursue an aggressive clinical course characterised by poor response to therapy and early relapses. These clinical features suggest that MMGC/T are somatic in origin, but objective molecular data to support this interpretation are lacking. This study evaluates the molecular features of nine MMGC/T, including seven tumours containing yolk sac tumour (YST), one tumour containing choriocarcinoma and one tumour containing epithelioid trophoblastic tumour. The objectives were to: (i) investigate whether MMGC/T show a distinct genetic profile and (ii) explore the relationship between the different histological components. METHODS AND RESULTS: Next-generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non-Mullerian components of the tumour were almost identical in all cases. Moreover, the driver mutations identified were those expected in the specific subtype of Mullerian component present in each case. In contrast, variants expected in postpubertal germ cell tumours and gestational trophoblastic tumours were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair-proficient MMGC/T (eight of nine) were characterised by a complex copy-number variant profile, including numerous focal, regional, arm-level and chromosome-level events. CONCLUSIONS: Comparison of paired samples supports that the YST and trophoblastic tumour components of MMGC/T have a somatic origin and often show numerous copy-number variants, suggestive of underlying genomic instability.

Müllerian adenosarcoma of the uterus with low-grade sarcomatous overgrowth characterized by prominent hydropic change resulting in mimicry of a smooth muscle tumor.

A 28-y-old woman was found to have a large subserosal uterine mass that was excised and interpreted as a "clear cell leiomyoma." Five years later, the tumor recurred as serosal-based ileal and uterine masses; they were treated by partial ileal resection and hysterectomy. All 3 masses were predominantly characterized by conspicuous edema separating bland cells growing in cords and clusters, with scant to moderately conspicuous clear cytoplasm. The edema was indistinguishable from the hydropic change commonly seen in benign smooth muscle tumors and the cords similar to those often present in them. However, the mass from the hysterectomy specimen had a small, grossly recognizable cystic region, which on microscopic examination was a typical low-grade müllerian adenosarcoma. The stroma of the latter ranged from cellular endometrial-type to edematous and hypocellular similar to that dominating the other specimens. The cellular and edematous regions focally had cords and tubules of sex cord-like type confirmed by inhibin and calretinin positivity. Smooth muscle differentiation was also seen as a "starburst" pattern. This case of adenosarcoma is unusual due to its (1) serosal location, (2) overgrowth of stroma, which differed from typical adenosarcoma with sarcomatous overgrowth by its low-grade nature, (3) hydropic change associated with cords and nests of cells with clear cytoplasm, which prompted the initial specimen to be considered an epithelioid leiomyoma, and (4) prominent smooth muscle metaplasia mostly with a "starburst" morphology. All these features have only rarely been documented in prior müllerian adenosarcomas.