Hemangiomas and angiosarcomas of the breast. Diagnostic utility of cell cycle markers with emphasis on Ki-67

Department of Pathology and Laboratory Medicine-Starr 1009, New York Presbyterian Hospital-Weill Medical College of Cornell University, 525 E 68th St, New York, NY 10021, USA.
Archives of pathology & laboratory medicine (Impact Factor: 2.84). 04/2007; 131(4):538-44. DOI: 10.1043/1543-2165(2007)131[538:HAAOTB]2.0.CO;2
Source: PubMed


Vascular tumors comprise a minor subgroup of tumors arising in the breast and represent variants of hemangiomas and angiosarcomas. Diagnostic challenges may arise when differentiating hemangiomas from types I and II angiosarcomas. Ki-67 expression has been used as an adjunct to distinguish between benign and malignant lesions exhibiting histologic overlap at various anatomic sites.
To investigate the utility of Ki-67 and other cell cycle regulatory proteins (S-phase kinase-associated protein 2 [Skp2], p27, and cyclin D1) in the differential diagnosis of mammary vascular lesions.
Thirty-four vascular tumors (21 hemangiomas and 13 angiosarcomas) of the breast were studied. The Ki-67 index and immunoreactivity for Skp2, p27, and cyclin D1 were determined in each case. Appropriate statistical methods were used.
The mean value of Ki-67 index was statistically different when comparing hemangiomas and angiosarcomas (P < .001). Angiosarcomas were typically positive for Skp2, whereas hemangiomas were negative (P < .001). Sensitivity and specificity cutoffs for Ki-67 index to distinguish hemangiomas from angiosarcomas showed a candidate cutoff point of 175. The mean values of Ki-67 of low-grade angiosarcomas were significantly different from all hemangiomas (P < .001) and also different from the subset of atypical hemangiomas (P = .02). Sensitivity and specificity cutoffs for Ki-67 index to distinguish all hemangiomas from low-grade angiosarcomas showed a candidate cutoff point between 150 and 175. Among angiosarcomas, positivity for Ki-67 was inversely related to that of p27 but not to Skp2 or cyclin D1. This was also true among hemangiomas.
Ki-67 index can be used as a diagnostic tool to distinguish between benign and malignant vascular lesions of the breast. This can be particularly helpful in cases of histologic overlap such as low-grade angiosarcoma and hemangioma.

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    • "Many studies have proved that Ki-67 can be used as the biomarker of the tumor in response to cellular proliferation. It also serves as a diagnostic tool to distinguish between benign and malignant vascular lesions including Has.38 In addition, CAS-3 is also involved in the development of HAs, and promotes the switch of HAs from proliferation to involution by inducing the apoptosis of HAs endothelia.39 "
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    ABSTRACT: Angiogenesis is a process of development and growth of new capillary blood vessels from pre-existing vessels. Angiogenic growth factors play important roles in the development and maintenance of some malignancies, of which vascular endothelial growth factor (VEGF)/VEGFR2 interactions are involved in proliferation, migration, and survival of many cancer cells. The aim of this study was to investigate the function of VEGFR2 in human hemangiomas (HAs). Using immunohistochemistry assay, we examined the expression levels of VEGF, VEGFR2, Ki-67, glucose transporter-1 (Glut-1), phosphorylated protein kinase B (p-AKT) and p-ERK in different phases of human HAs. Positive expression of VEGF, VEGFR2, Ki-67, Glut-1, p-AKT and p-ERK was significantly increased in proliferating phase HAs, while decreased in involuting phase HAs (P=0.001; P=0.003). In contrast, cell apoptotic indexes were decreased in proliferating phase HAs, but increased in involuting phase HAs (P<0.01). Furthermore, we used small hairpin RNA (shRNA)-mediated VEGFR2 knockdown in primary HA-derived endothelial cells (HemECs) to understand the role of VEGF/VEGFR2 signaling. Knockdown of VEGFR2 by Lv-shVEGFR2 inhibited cell viability and induced apoptosis in primary HemECs companied with decreased expression of p-AKT, p-ERK, p-p38MAPK and Ki-67 and increased expression of caspase-3 (CAS-3). Overexpression of VEGFR2 promoted cell viability and blocked apoptosis in Lv-VEGFR2-transfected HemECs. Taken together, our findings demonstrate that, increased expression of VEGFR2 is involved in the development of primary HemECs possibly through regulation of the AKT and ERK pathways, suggesting that VEGFR2 may be a potential therapeutic target for HAs.
    Full-text · Article · Jan 2014 · European journal of histochemistry: EJH
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    • "Nous n'avons pas observé ce type d'incident pour nos deux patientes également biopsiées avec une aiguille de 14G. L'immunohistochimie pourra être utile pour différencier un hémangiome d'un angiosarcome bien différencié, de bas grade [23]. La possibilité de transformation d'un hémangiome en angiosarcome a été décrite mais reste controversée et non établie [24]. "

    Preview · Article · May 2011 · Journal de Radiologie
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    • "Shin et al. (2007) showed that Ki-67 staining can be used to differentiate between types of vascular tumors, with hemangiomas having low Ki-67 expression and angiosarcomas having high Ki-67 expression. Whereas the tissue section of a control (a malignant lymphoma) was positively strained (Fig. 5c), nuclei of endothelial cells in the vascular neoplasms of the transgenic mice did not stain with Ki-67 (Fig. 5a, b), indicating that they were hemangiomas rather than angiosarcomas (Shin et al. 2007). "
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    ABSTRACT: In order to develop a model system of infantile hemangioma, transgenic mice were developed carrying the Polyomavirus Middle T (PyMT) gene driven by the SV40 late promoter. From the 520 fertilized eggs surviving microinjection, there were 25 live births. Three of these showed the hemangioma phenotype and carried and expressed the PyMT gene; the remaining descendants were normal. The tumors showed abnormal vascular proliferation with cavernous hemangioma-like structures in the skin surface, tongue, ear mucosa and gastric mucosal tissue in the transgenic mice with hemangioma phenotype. Immunohistochemical staining for Ki-67 was negative, showing the tumors were hemangiomas rather than angiosarcomas. None of the PyMT transgenic mice survived beyond 4 weeks. Previously reported PyMT transgenic mice under the control of various promoters induce many tumor types including hemangiomas. PyMT driven by the SV40 late promoter is an improved model system because it only induces hemangiomas. However, it is limited by the post-natal lethality. Thus, conditional variants of this model system would be desirable.
    Full-text · Article · Jun 2009 · Transgenic Research
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