Recently, the unraveling of the genetic background of adenosarcomas has begun. The previous lack of knowledge regarding the molecular and genetic basis of Müllerian adenosarcomas has hindered our ability to develop tumor-specific therapeutic strategies. 8 The mainstay of treatment for localized Müllerian adenosarcomas is surgery, 9 whereas more advanced diseases often entail other modalities of treatment, although the roles of adjuvant chemotherapy and/or radiation therapy in the management of adenosarcomas are not well-defined. 4, 6, 7, 8 Adenosarcomas less frequently occur in the ovary, where they pose a greater risk of peritoneal spread and a worse prognosis. Tumors showing sarcomatous overgrowth or deep myometrial invasion, however, behave more aggressively. 2, 5 Clinically, a majority of adenosarcomas present with low-stage disease and follow an indolent clinical course after surgical treatment. Sarcomatous overgrowth, defined as the presence of at least 25% tumor area overgrown by a pure sarcomatous component, is seen in a subset of cases. Histologically, adenosarcomas display a biphasic appearance with admixed sarcoma components and benign-appearing Müllerian glands. 3, 4 Most Müllerian adenosarcomas present as polypoid endometrial masses, and can be accompanied by extensive myometrial invasion and extrauterine spread. 1, 2 They account for approximately 5% of all primary uterine sarcomas and can affect women from a wide age range. Müllerian adenosarcomas are malignant mixed epithelial–mesenchymal neoplasms that arise most frequently in the uterine corpus.

To our knowledge, this is the first time that evidence of chromothripsis has been demonstrated in paraffin-embedded clinical tissues and in adenosarcomas. Global chromosomal instability and chromothripsis were more frequent in cases with sarcomatous overgrowth. In conclusion, we identified frequent chromosome 12q amplifications, including loci containing potential pharmacological targets.

With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin tissue. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Advanced staging and sarcomatous overgrowth predict poor prognosis.

Müllerian adenosarcomas are malignant gynecologic neoplasms.

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