Adenosarcoma of the uterus: A gynecologic oncology group study of 31 cases

Kaku, Tsunehisa; Silverberg, Steven G.; Major, Francis J.; Miller, Alexander W.; Fetter, Bernard F.; Blessing, J A

doi:10.1016/0090-8258(91)90152-u

Cited by 56 publications

(113 citation statements)

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“…Overall, MA is associated with a better prognosis than other uterine sarcomas and carcinosarcomas [25,26]; however, when MA has overgrowth of the sarcomatous component, deep myometrial invasion, and spread beyond the uterus, the survival rate falls to less than 50% [7,15,25]. When distant metastasis is present, more than 80% of patients die of their disease [15,27].…”

Section: Discussionmentioning

confidence: 99%

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Targeted genomic analysis of Müllerian adenosarcoma

Howitt

Sholl

Cin

et al. 2014

The Journal of Pathology

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Müllerian adenosarcoma (MA) is a rare mixed mesenchymal tumour of the female genital tract, composed of malignant stroma and benign-appearing epithelium. Sarcomatous overgrowth (SO) is the only established histological variable associated with higher stage and shorter survival. Specific molecular or immunohistochemistry (IHC) tools for the diagnosis of MA are lacking. Our goal was to study genomic mutations and copy number variations (CNVs) in MA to understand better its pathobiology, and develop specific diagnostic and prognostic tools. DNA was extracted from 20 samples of MA from 18 subjects (12 without SO and 6 with SO), including two in which areas of both typical MA histology and SO were independently tested. Samples were analysed using a targeted next-generation sequencing assay interrogating exonic sequences of 275 cancer genes for mutations and CNVs as well as 91 introns across 30 genes for cancer-associated rearrangements. The mean number of mutations in MA with SO (mean 9.7; range 3-14) did not differ significantly from that in MA without SO (mean 9.6; range 5-16). MA with SO had significantly higher mean numbers of gene-level CNVs (24.6) compared to MA without SO (5; p = 0.0002). The most frequent amplification involved MDM2 and CDK4 (5/18; 28%), accompanied by focal CDK4 and MDM2 and diffuse HMGA2 expression using immunohistochemistry. MYBL1 amplification was seen in 4/18 (22%), predominantly in SO. Alterations in PIK3CA/AKT/PTEN pathway members were seen in 13/18 (72%). Notably, TP53 mutations were uncommon, present in only two cases with SO. Three out of 18 (17%) had mutations in ATRX, all associated with SO. No chromosomal rearrangements were identified. We have identified a number of recurrent genomic alterations in MA, including some associated with SO. Although further investigation of these findings is needed, confirmation of one or more may lead to new mechanistic insights and novel markers for this often difficult-to-diagnose tumour.

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Section: Discussionmentioning

confidence: 99%

“…Such tumours are treated primarily with surgery [5], whereas those with SO are often treated with chemotherapy, radiation therapy, or both. An additional histological parameter that may indicate a worse prognosis is deep (greater than 50%) myometrial invasion [1,2,6,7].…”

Section: Introductionmentioning

confidence: 99%

Targeted genomic analysis of Müllerian adenosarcoma

Howitt

Sholl

Cin

et al. 2014

The Journal of Pathology

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“…Tumors showing sarcomatous overgrowth or deep myometrial invasion, however, behave more aggressively. 4,[6][7][8] Adenosarcomas less frequently occur in the ovary, where they pose a greater risk of peritoneal spread and a worse prognosis. 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.…”

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confidence: 99%

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in 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. 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. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. 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. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. 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

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“…Adenofibroma and adenosarcoma feature benign glands and a stromal proliferation that varies from mitotically inactive and bland (adenofibroma) to bland stroma that demonstrates more than 2 to 4 mf/10 hpf (low-grade adenosarcoma) to frankly sarcomatous stroma (adenosarcoma) (33)(34)(35). Although the distinction between adenofibroma and low-grade adenosarcoma has been set somewhere between 2 and 4 mf/10 hpf, the two lesions typically have other differences (33,35).…”

Section: Adenofibroma and Adenosarcomamentioning

confidence: 99%