Cyclin D1 as a Diagnostic Immunomarker for Endometrial Stromal Sarcoma With YWHAE-FAM22 Rearrangement

Lee, Cheng‐Han; Ali, Rola H.; Rouzbahman, Marjan; Mariño-Enríquez, Adrián; Zhu, Mei‐Jun; Guo, Xiangqian; Brunner, Alayne; Chiang, Sarah; Leung, Samuel; Nelnyk, Nataliya; Huntsman, David G.; Gilks, C. Blake; Nielsen, Torsten O.; Cin, Paola Dal; Rijn, Matt van de; Oliva, Esther; Fletcher, Jonathan A.; Nucci, Marisa R.

doi:10.1097/pas.0b013e31825fa931

Cited by 181 publications

(168 citation statements)

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“…Cyclin D1 immunohistochemistry should be useful in these cases because YWHAE-NUTM2A/B endometrial stromal sarcoma consistently shows diffuse (470%) and strong nuclear immunopositivity of the high-grade component. 6 To further explore the potential of KIT as therapeutic target in YWHAE-NUTM2A/B endometrial stromal sarcomas, we interrogated KIT mutations in KIT-positive YWHAE-NUTM2A/B endometrial stromal sarcomas, and found no mutations involving KIT or other receptor tyrosine kinases including PDGFRA. In the absence of an activating mutation, the rationale for targeting YWHAE-NUTM2A/B endometrial stromal sarcomas with imatinib and/or other small-molecule inhibitors of receptor tyrosine kinases remains questionable.…”

Section: Discussionmentioning

confidence: 99%

“…1,3 Hematoxylin-and eosin-stained and -unstained slides that showed high-grade round/epithelioid cell component only, 6 low-grade spindle cell component only 2 or both areas 6 were available for the study. This study was approved by the institutional research boards.…”

Section: Study Samplesmentioning

confidence: 99%

“…In half of the neoplasms, a second component of bland ovoid to spindle-shaped cells embedded in a fibroblastic to fibromyxoid background that morphologically and immunophenotypically resembles the fibroblastic/ myxoid variant of low-grade endometrial stromal sarcoma is seen. 4,5 Immunohistochemically, the high-grade epithelioid component of YWHAE-NUTM2A/B endometrial stromal sarcoma is negative for CD10, estrogen receptor and progesterone receptor, and consistently expresses strong and diffuse nuclear cyclin D1, 6 whereas the low-grade fibroblastic component shows the opposite profile (akin to typical low-grade endometrial stromal sarcoma) being CD10, estrogen receptor and progesterone receptor positive with variable cyclin D1 nuclear staining (negative to weakly positive).…”

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Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement

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Endometrial stromal sarcomas with the YWHAE-NUTM2A/B genetic fusion characteristically contain high-grade round to epithelioid cell component that is strongly and diffusely cyclin D1-positive and it may or may not show an associated low-grade fibroblastic/myxoid cell component. They are clinically more aggressive than endometrial stromal sarcomas with the JAZF1-SUZ12 genetic fusion and frequently demonstrate extrauterine extension at initial clinical presentation. In this setting, the tumor may be misdiagnosed as gastrointestinal stromal tumor. This study examines the expression of KIT and ANO1 in 14 YWHAE-NUTM2A/B tumors by immunohistochemistry. Staining localization was determined as membranous and/or cytoplasmic, and the staining intensity was assessed (negative, weak, moderate and strong). Of the 14 tumors, 6 contained only a high-grade round cell component, 2 only a low-grade fibroblastic component and 6 had both components in the slides evaluated. The high-grade round cell component displayed moderate to strong membranous/cytoplasmic KIT staining in all tumors (12 of 12). The low-grade fibroblastic cell component showed only weak cytoplasmic KIT staining in 3 of 8 tumors. In contrast, ANO1 was negative in all 14 neoplasms, irrespective of the component evaluated. Sanger sequencing analysis (exons 9, 11, 13 and 17) and Ampliseq Cancer Panel mutation screen (Ion Torrent) demonstrated no KIT mutations in three KIT-positive YWHAE-NUTM2A/B tumors. This study shows that the high-grade round cell component of YWHAE-NUTM2A/B endometrial stromal sarcoma consistently expresses KIT but lacks KIT hotspot mutations. KIT expression may represent a potential diagnostic pitfall in the evaluation of YWHAE-NUTM2A/B endometrial stromal sarcoma presenting with pelvic/ abdominal mass, particularly in situations where its uterine origin is not definitive, and thus a panel of antibodies that includes ANO1 and cyclin D1 is necessary.

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Section: Study Samplesmentioning

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Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement

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“…71 In the highgrade areas, the tumor cells are small with very brisk mitotic activity and are associated with a prominent sinusoidal vasculature. Although CD10, ER, and PR are typically positive in low-grade endometrial stromal sarcomas, it is important to keep in mind that the high-grade component is typically negative for these markers (but diffusely positive for cyclin D1) 72 and that very commonly leiomyosarcomas express CD10 as well as ER and PR. [73][74][75][76][77][78] Thus, when using immunohistochemistry, a panel rather than a single marker that includes desmin and h-caldesmon is necessary.…”

Section: Tumor Cell Necrosismentioning

confidence: 99%

Practical issues in uterine pathology from banal to bewildering: the remarkable spectrum of smooth muscle neoplasia

Oliva

2016

Modern Pathology

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Among mesenchymal tumors of the uterus, smooth muscle neoplasms are most common. The wide morphologic spectrum, especially within the category of leiomyomas, is responsible for diagnostic problems more frequently with leiomyosarcoma (including mitotically active, apoplectic, and leiomyoma with bizarre nuclei) but also with endometrial stromal tumors. In the former scenario, clinical information, gross appearance as well as strict utilization of morphologic criteria including cytologic atypia, mitotic activity, and tumor cell necrosis are clues in establishing the correct diagnosis. It is important to keep in mind that mitotic rate thresholds vary for the different subtypes of leiomyosarcoma. Of note, p16 should be used with caution in supporting a diagnosis of leiomyosarcoma as it is often positive in leiomyomas with bizarre nuclei and leiomyomas with apoplectic change (in the latter most frequently and more intense near areas of necrosis). MED12 mutations have also a very limited role in this differential diagnosis. Endometrial stromal tumors are by far, less common than smooth muscle tumors, but can be confused with leiomyosarcomas if they are associated with an undifferentiated uterine sarcoma and the low-grade component is overlooked or they have a myxoid/fibroblastic morphology. The differential diagnosis may be confounded if the latter is associated with a high-grade endometrial stromal sarcoma. It is important to highlight that CD10 is not a reliable marker in these differentials and should be used as a part of a panel of antibodies that also includes desmin and h-caldesmon. Two other recently categorized tumors in the uterus that merit special mention are PEComa and inflammatory myofibroblastic tumor as they enter in the differential diagnosis of smooth muscle tumors. PEComa may be part of the tuberous sclerosis syndrome and may show either a predominantly epithelioid or spindle morphology or combination thereof. Rarely, it may contain melanin pigment. There is variable positivity for HMB-45, MelanA, MiTF, and CathepsinK, and some tumors have been shown to express TFE-3 especially when associated with "clear cell" morphology. Patients with adverse outcome have tumors with ≥ 2 of the following features: ≥ 5 cm, infiltration, high-grade cytologic features, mitotic rate ≥ 1/50 high-power fields, necrosis, or lymphovascular invasion. Inflammatory myofibroblastic tumor is important to recognize as it often mimics myxoid smooth muscle tumors, either benign or malignant. The presence of an associated lymphoplasmacytic infiltrate should alert to that possibility and ALK studies (immunostain or FISH) are helpful in establishing this diagnosis. These tumors can behave in a malignant manner if large, associated with abundant myxoid change, brisk mitotic rate or show tumor cell necrosis.

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“…It is important to be aware that the low-and high-grade components have a different immunohistochemical profile (Figures 7e and f). 50 The low-grade component is typically positive for CD10, ER, and Figure 6 Uterine tumor resembling ovarian sex-cord tumor (UTROSCT). These unusual tumors are composed of epithelial-like cells that recapitulate the architecture patterns described in ovarian sex-cord stromal tumors (a).…”

Section: Distinction Of Lgess With Sex Cord-like Differentiation Frommentioning

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Practical issues related to uterine pathology: endometrial stromal tumors

Nucci

2016

Modern Pathology

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Uterine mesenchymal tumors continue to be a challenge to diagnose due to their non-specific clinical presentation, often non-distinctive gross appearance, varied (and many times overlapping) morphologic appearance, and unsuspected pitfalls in immunohistochemical expression. This review will focus on endometrial stromal tumors and those features that help in their distinction. In particular, a practical approach to the diagnosis of endometrial stromal neoplasia will be covered including recognition as a stromal process in a biopsy/curettage and distinction from a highly cellular leiomyoma. In addition, distinction of a stromal nodule from a low-grade endometrial stromal sarcoma (LGESS) and stromal sarcoma with limited infiltration in a hysterectomy specimen will be covered. The salient features that help distinguish a LGESS from a uterine tumor resembling ovarian sex-cord tumor as well as high-grade endometrial stromal sarcoma, the latter a tumor recently reintroduced in the WHO classification will also be discussed. Finally, a practical approach to the diagnosis of undifferentiated uterine sarcoma (UUS) will be presented.

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Cyclin D1 as a Diagnostic Immunomarker for Endometrial Stromal Sarcoma With YWHAE-FAM22 Rearrangement

Cited by 181 publications

References 37 publications

Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement

Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement

Practical issues in uterine pathology from banal to bewildering: the remarkable spectrum of smooth muscle neoplasia

Practical issues related to uterine pathology: endometrial stromal tumors

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