complex fibroadenoma pathology outlines

HHS Vulnerability Disclosure, Help LM DDx. An official website of the United States government. //--> Long-term risk of breast cancer in women with fibroadenoma. Complex fibroadenomas are often smaller than simple fibroadenomas (1.3 cm compared with 2.5 cm in simple fibroadenomas). sclerosing adenosis and The purpose of this study is to examine the breast cancer risk overall among women with simple fibroadenoma or complex fibroadenoma and to examine the association of complex fibroadenoma with breast cancer through stratification of other breast cancer risks. Disclaimer. Histopathology. Methods: From excisional biopsy or resected specimens of fibroadenoma (FA) cases treated at our institution from 2004 to 2013, we chose 46 . (b) Ultrasound shows a well-defined oval nodule in the right axilla which was confirmed to be a fibroadenoma on core biopsy. Mastopathic fibroadenoma of the breast: a pitfall of aspiration cytology. 8600 Rockville Pike We welcome suggestions or questions about using the website. Epub 2020 Aug 26. da Silva EM, Beca F, Sebastiao APM, Murray MP, Silveira C, Da Cruz Paula A, Pareja F, Wen HY, D'Alfonso TM, Edelweiss M, Weigelt B, Brogi E, Reis-Filho JS, Zhang H. J Clin Pathol. government site. Complex fibroadenomas are a fibroadenoma subtype harboring one or more complex features. Fibroadenomas are benign while phyllodes tumor range from benign, indolent neoplasms to malignant tumors capable of distant metastasis. In particular, these mutations are restricted to the stromal component. A simple fibroadenoma does not raise your risk for breast cancer. Said SM, Visscher DW, Nassar A, Frank RD, Vierkant RA, Frost MH, Ghosh K, Radisky DC, Hartmann LC, Degnim AC. Methods: .style1 { Giant juvenile fibroadenoma is a variant of fibroadenoma that occurs in children and adolescent age group. Conclusion: The .gov means its official. No calcifications are evident. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). doi: 10.7759/cureus.12611. An official website of the United States government. Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). Cardeosa G. Clinical breast imaging, a patient focused teaching file. 2004 Feb;21(1):48-56. We histologically re-classified them into two groups: CFA and NCFA. The complex fibroadenoma comprises 14.1-40.4% of . Closely packed uniform tubules, lined by a single layer of epithelial cells and an attenuated myoepithelial cell layer. phyllodes tumour, sarcoma, pseudoangiomatous . FNA of CFA can lead to erroneous or indeterminate interpretation, due to proliferative and/or hyperplastic changes of ductal epithelium with or without atypia. Giant fibroadenoma. This patient had atypical lobular hyperplasia at core needle biopsy. PMID: 8202095 (Free), 1996 - 2023 Humpath.com - Human pathology The lesion was shelled-out. There are numerous reports that the general risk of developing cancer in the breast parenchyma is elevated among women with complex fibroadenomas; these women are 3.1-3.7 times more likely to develop breast cancer than women in the general population (compared with a relative risk of 1.9 times in women with non-complex fibroadenomas). Am J Surg. MeSH If it grows to 5 cm or . Sat-Muoz D, Martnez-Herrera BE, Quiroga-Morales LA, Trujillo-Hernndez B, Gonzlez-Rodrguez JA, Gutirrez-Rodrguez LX, Leal-Corts CA, Portilla-de-Buen E, Rubio-Jurado B, Salazar-Pramo M, Gmez-Snchez E, Delgadillo-Cristerna R, Carrillo-Nuez GG, Nava-Zavala AH, Balderas-Pea LM. Lerwill MF. radial scar or papilloma) that is identified on imaging, May show enhancement on magnetic resonance imaging (, Associated with 1.5 - 2 times increased risk for subsequent breast cancer (, Risk may be slightly higher for patients with a positive family history of breast cancer (, Indicator of general breast cancer risk rather than direct precursor lesion, 30 year old woman with immature-like usual ductal hyperplasia in a fibroadenoma (, 75 year old woman with malignant phyllodes tumor with liposarcomatous differentiation and intraductal hyperplasia (, Usual ductal hyperplasia within gynecomastia-like changes of the female breast (, Proliferation of cells of luminal and myoepithelial lineages, occasionally with intermixed apocrine cells, Mild variation in cellular and nuclear size and shape, Relatively small ovoid nuclei with frequent elongated or asymmetrically tapered (pear shaped) forms, Lightly granular euchromatic chromatin and small nucleoli, Frequent longitudinal nuclear grooves (coffee bean-like) and occasional nuclear pseudoinclusions, Many examples demonstrate cellular maturation, where the cells shrink as they progress from a basal location to the center of the proliferation, becoming small and nearly pyknotic, Eosinophilic, nonabundant cytoplasm with indistinct cell borders, Cohesive proliferation with haphazard, jumbled cell arrangement or streaming growth pattern, Fenestrated, solid and occasional micropapillary patterns, Irregular slit-like fenestrations are common, especially along periphery, Cells run parallel to the edges of secondary spaces and do not exhibit a polarized orientation (this contrasts with the cells of atypical ductal hyperplasia and ductal carcinoma in situ, which have apical-basal polarity and radially orient their apical poles toward the spaces), Typically focal in a background of conventional pattern usual ductal hyperplasia, Short stubby papillae of roughly uniform height, Cytologic features of usual ductal hyperplasia, Cellular maturation present, with tips of papillae formed by tight knots of mature cells, Larger immature basal hyperplastic cells predominate or are increased beyond their usual 1 - 2 cell layers and are instead several cell layers thick, Most often encountered in fibroepithelial lesions with cellular stroma, Florid usual ductal hyperplasia can rarely demonstrate central necrosis, Typically occurs within a radial scar / complex sclerosing lesion, nipple adenoma or juvenile papillomatosis, Florid usual ductal hyperplasia within radial scars / complex sclerosing lesions can occasionally have more active appearing nuclei with mild nuclear enlargement, Other cytologic and architectural features of usual ductal hyperplasia remain intact, Sample may be moderately to highly cellular, Sheets and cohesive clusters of bland ductal cells with regular spacing and associated myoepithelial cells (, Lack of significant nuclear overlap / crowding, Ductal cell nuclei with finely granular chromatin and inconspicuous small nucleoli, Naked myoepithelial cell nuclei in the background may be present, Activating mutations in the PI3K / AKT / mTOR pathway may play a role in pathogenesis (, Round to oval nuclei with homogeneous, fine and hyperchromatic chromatin; inconspicuous nucleoli; and smooth nuclear contours, Increased amounts of pale eosinophilic to amphophilic cytoplasm with conspicuous cell borders, Cellular polarization around luminal and secondary spaces, Atypical architectural patterns formed by polarized growth (cribriform spaces, Roman arches, trabecular bars, micropapillae), Moderate nuclear enlargement throughout the proliferation, Abnormal chromatin, which may be hyperchromatic, cleared and clumped or coarsely granular, Solid epithelial proliferation showing marked expansion of multiple circumscribed duct spaces (, Thin fibrovascular cores punctuate the proliferation, with cellular palisading around the cores, Myoepithelial cells often sparse or absent along fibrovascular cores, Nuclei may superficially resemble those in usual ductal hyperplasia but demonstrate greater populational uniformity, are slightly larger and have abnormal chromatin, Often positive for neuroendocrine markers (, No change in risk compared to control populations, HMWCK mosaic positive / ER diffusely positive, HMWCK mosaic positive / ER heterogeneously positive. Powell CM, Cranor ML, Rosen PP. 2021 Jan 10;13(1):e12611. -->, Richard L Kempson MD pathology researchers that rely upon this methodology to perform tissue analysis in research. cysts larger than 3 mm. Fibroadenoma is a benign tumor that arises from the epithelium and stroma of terminal duct-lobular unit. (Sep 2005). 2013 Jul 12;6:267. doi : 10.1186/1756-0500-6-267 PMID: 23849288 (Free), Histopathology of fibroadenoma of the breast. Women with complex fibroadenomas may therefore be managed with a conservative approach, similar to the approach now recommended . 2008;190 (1): 214-8. abundant (intralobular) stroma usu. Background: To determine the cytomorphological features of complex type fibroadenoma (CFA), we reviewed fine needle aspiration (FNA) cytology with correlation to its histopathology findings, and compared them with non-complex type fibroadenoma (NCFA). The key to breast pathology is the myoepithelial cell. 1999 Aug;16(3):235-47. However, we cannot answer medical or research questions or give advice. Contact us for pricing; complex fibroadenoma pathology outlines Epub 2014 Feb 8. Degnim AC, Frost MH, Radisky DC, Anderson SS, Vierkant RA, Boughey JC, Pankratz VS, Ghosh K, Hartmann LC, Visscher DW. National Library of Medicine Maiorano, E.; Albrizio, M. (Dec 1995). Approximately 16% of fibroadenomas are complex. Can occur at any age, but most patients are young and in their reproductive age group. Tumors >500 g or disproportionally large compared to rest of breast. Bethesda, MD 20894, Web Policies However, women with complex fibroadenoma were more likely to have other, concomitant high-risk histologic characteristics (e.g., incomplete involution and PDWA). Careers. government site. LM. The border is well-circumscribed where seen. Med J Aust. Methods A retrospective review was performed of patients . Bethesda, MD 20894, Web Policies Richard L Kempson MD. Unauthorized use of these marks is strictly prohibited. Sabate, JM. We further re-assessed detailed characteristics of each FNA smears to identify cytomorphological features of CFA. No calcifications are evident. 2022 Apr 9;13(1):71. doi: 10.1186/s13244-022-01214-7. Up to 66% of fibroadenomas harbor mutations in the exon (exon 2) of the mediator complex subunit 12 (MED12) gene. At the time the article was last revised Patrick J Rock had no recorded disclosures. Before Biphasic lesions of the breast. Call Us Free: 714-917-9578 . Only one malignancy, an invasive lobular carcinoma, was found in 63 complex fibroadenomas (1.6%). View Patrick J Rock's current disclosures, see full revision history and disclosures, invasive ductal carcinoma not otherwise specified, intracystic papillary carcinoma of the breast, breast implant-associated anaplastic large cell lymphoma, columnar alteration with prominent apical snouts and secretions (CAPSS), lobular intraepithelial neoplasia (LIN III), pseudoangiomatous stromal hyperplasia (PASH), pleomorphic microcalcifications within breast, punctate microcalcification within breast, egg shell/rim calcification within breast, lobular calcification within breast tissue, intraductal calcification within breast tissue, skin (dermal) calcification in / around breast tissue, suture calcification within breast tissue, stromal calcification within breast tissue, artifactual calcification from outside the breast, granulomatosis with polyangiitis: breast manifestations, differential diagnosis of dilated ducts on breast imaging, hereditary breast and ovarian cancer syndrome. 2021 May 11;7(1):50. doi: 10.1038/s41523-021-00257-1. Benign breast disease and the risk of breast cancer. This website is intended for pathologists and laboratory personnel but not for patients. The https:// ensures that you are connecting to the More frequent in young and black patients. They fall under the broad group of adenomatous breast lesions. FNA diagnosis was retrospectively re-evaluated from FNA reports. Fibroadenoma is the most common benign tumor of the female breast. We found that 15 cases fulfilled the diagnostic criteria of CFA, in which 7 (46.7 %) had an FNA diagnosis of "suspicious for malignancy" or "indeterminate" while only 2 NCFA cases had that of "indeterminate" (p = 0.004). The pathology is in the stroma; so, the lesion is really a misnomer by the naming rules. Tumors of the Mammary Gland, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 7, 1993. document.write('') (2006) ISBN:0781762677. malignant papillary lesions of the breast. Limite G, Esposito E, Sollazzo V, Ciancia G, Formisano C, Di Micco R, De Rosa D, Forestieri P. BMC Res Notes. Stanford CA 94305-5342, Relative risk for development of invasive breast carcinoma, , Circumscribed breast mass composed of benign stromal and epithelial cells, Atypical ductal or lobular hyperplasia may be present, Carcinoma, in situ or invasive, may be present, Lacks significant stromal hypercellularity, Elevated stromal mitotic rate, usually >4-5 per 10 hpf, abnormal forms may be found, May contain poorly circumscribed areas of fibrocystic change, Lobules typically present (may be atrophic), Frequent intracanalicular or tubular glandular proliferation. 2006 Oct;17(5):233-8. doi: 10.1111/j.1365-2303.2006.00333.x. Incidence and management of complex fibroadenomas. 2006 Oct;192(4):545-7. doi: 10.1016/j.amjsurg.2006.06.011. 1997 Sep-Oct;42(5):278-87. No stromal overgrowth is seen. Aims: Breast myxoid fibroadenomas (MFAs) are characterized by a distinctive hypocellular myxoid stroma, and occur sporadically or in the context of Carney complex, an inheritable condition caused by PRKAR1A-inactivating germline mutations. Complex fibroadenomas are often smaller than simple fibroadenomas (1.3 cm compared with 2.5 cm in simple fibroadenomas). Conclusions: Bookshelf ~50% of these tend to be lobular carcinoma in situ (LCIS), ~20% infiltrating lobular carcinoma, ~20%ductal carcinoma in situ (DCIS), and the remaining 10% are infiltrating ductal carcinoma. FNA smears from CFA cases showed discohesiveness, enlarged nuclei, prominent nucleoli, and fewer myoepithelial cells more often than NCFA. Giant fibroadenoma. RSS2.0, bland-looking mammary spinlde cell tumors, molecular classification of mammary carcinoma. Please enable it to take advantage of the complete set of features! It is the most common type of salivary gland tumor and the most common tumor of the parotid gland.It derives its name from the architectural Pleomorphism (variable appearance) seen by light . The injection of sexually immature female rats with 1-methyl-1-nitrosourea results in a rapid induction of premalignant and malignant mammary gland lesions within 35 days of carcinogen administration. He Q, Cheng G, Ju H PLoS One 2021;16(7):e0253764. Nigam JS, Tewari P, Prasad T, Kumar T, Kumar A. Cureus. Fibroadenoma is a very common benign neoplasm typically occurring in patients between the ages of 20 and 35 years. Home > E. Pathology by systems > Reproductive system > Female genital system > Breast > complex fibroadenoma, Complex fibroadenoma is a sub type of fibroadenoma harbouring one or more of the following features: A benign gland has two cell layers - myoepithelial and epithelial. 3 Giant (juvenile or cellular) fibroadenoma is a . The mediator complex subunit 12 (MED12) gene is the most common gene involved in the pathogenesis of fibroadenoma. The pictured lesion is sclerosing adenosis, a benign breast lesion characterized by expansion of glands (with preserved 2 cell layers: inner epithelial and outer myoepithelial cells) within the terminal duct lobular unit with distortion by fibrosis / sclerosis. Complex fibroadenoma. The authors declare that they have no conflicts of interest. Fibroadenoma. Semin Diagn Pathol. Comparative Proteomic Profiling of Secreted Extracellular Vesicles from Breast Fibroadenoma and Malignant Lesions: A Pilot Study. Minimal mitotic activity is present (2 mitosis/10 HPF, where 1 HPF ~ 0.2376 mm*mm). Percutaneous radiofrequency-assisted excision of fibroadenomas. Am Surg. Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017, WHO Classification of Tumours Editorial Board: Breast Tumours, 5th Edition, 2019, Adenosis or lobulocentric processes with increase in glandular elements of terminal duct lobular unit (TDLU) with stromal fibrosis / sclerosis that distorts and compresses glands, Preserved 2 cell layer (inner epithelial and outer myoepithelial cells), Enlarged terminal duct lobular unit with distortion by stromal fibrosis / sclerosis, Coalescent foci of typical sclerosing adenosis, Rare; sclerosing adenosis with predominance of myoepithelial cells, presents as multifocal microscopic lesions (, Most frequent in third to fourth decades but occurs over a wide age range, Found in 12 - 28% of all benign and 5 - 7% of malignant biopsies (, Terminal duct lobular unit; otherwise, no specific location within the breast, Often an incidental finding or detected by screening, Can present as a palpable mass if nodular adenosis / adenosis tumor, Histologic examination of tissue with or without immunohistochemistry, Variable depending on the size / extent of breast involvement, If focal, may not be visualized (i.e. The .gov means its official. Background Fibroepithelial lesions of the breast include fibroadenoma (FA) and phyllodes tumor (PT). Clinically , fibroadenomas presents as solitary, freely mobile lump in the breast. Small capillary-like structures in the stroma. Unable to load your collection due to an error, Unable to load your delegates due to an error. The term fibroadenoma combines the words "fibroma," meaning a tumor made up of fibrous tissue, and "adenoma," a tumor of gland tissue. Well circumscribed tumor with bulging cut surface, Fibroadenoma with atypical ductal hyperplasia, Sign up for our What's New in Pathology e-newsletter, Copyright PathologyOutlines.com, Inc. Click, 30150 Telegraph Road, Suite 119, Bingham Farms, Michigan 48025 (USA). 2022 Jul;194(2):307-314. doi: 10.1007/s10549-022-06631-2. ; Holden, JA. The basal cells is myoepithelial. Epub 2022 May 31. Value of scoring system in classification of proliferative breast disease on fine needle aspiration cytology. Although no significant difference was noted in patients' age and tumor size between CFA and NCFA, 5 CFA cases (33.3 %) were accompanied by the presence of carcinoma in the same breast or the contralateral breast while no NCFA cases had carcinoma in the breast. Simple: Most fibroadenomas are the simple type; they are more common in younger people.There's usually just one mass in your breast, with a definite border and very uniform cells. Disclaimer. AJR Am J Roentgenol. incidental finding on histologic examination), Amorphous or pleomorphic clustered microcalcifications; architectural distortion or circumscribed to spiculated mass on mammogram (, Associated with increased mammographic breast density (, Heterogeneous echogenicity, irregular and ill defined mass, focal acoustic shadowing may be seen on ultrasound (, Small (< 1 cm) mass with benign kinetics on MRI (, As a single feature, increased risk of cancer of 1.5 - 2x, as seen with proliferative, 2x higher risk of breast cancer with increased, Does not provide further risk stratification in the presence of other proliferative disease / atypical hyperplasias (, Can mimic malignancy clinically and radiologically, 46 year old woman with sclerosing adenosis with mammogram and cytology mimicking malignancy (, 73 year old woman with sclerosing adenosis and coexisting ductal carcinoma in situ (, 82 year old woman with sclerosing adenosis in sentinel axillary lymph nodes (, Presence of sclerosing adenosis alone in a core biopsy does not require surgical excision, Coexisting atypia will typically prompt surgical consultation, Variable depending on extent of involvement and calcifications, May be indistinguishable from surrounding breast tissue, Multinodular, ill defined, cuts with increased resistance due to fibrosis, Gritty due to frequent calcifications but no chalky yellow white foci or streaks as seen in, Circumscribed to ill defined white, fibrotic mass if nodular adenosis / adenosis tumor, Low power: increase in glandular elements plus stromal fibrosis / sclerosis that distorts and compresses glands, Maintains lobular architecture at low power with rounded and well defined nodules, Centrally is more cellular with distorted and compressed ductules; peripherally has more open or dilated ductules, Often has microcalcifications, due to calcification of entrapped secretions, Preservation of luminal epithelium and peripheral myoepithelium (2 cell layer) with surrounding basement membrane, Myoepithelial cells may vary from being prominent to indistinct on routine H&E staining, Myoepithelial cells are readily apparent via immunohistochemistry, even if difficult to identify on H&E, Rarely penetrates walls of blood vessels or perineural spaces, Epithelium may be involved by proliferative, atypical lesions or in situ carcinoma, If involved by atypia or in situ carcinoma, If florid and overtly non-lobulocentric / (pseudo) infiltrative into fat or stroma, Conspicuous myoepithelial cells with attenuated epithelial cells can appear like stands of single cells and mimic invasive lobular carcinoma, Atypical apocrine metaplasia: nuclear atypia / rare mitosis (, Moderate to markedly cellular, with small to large groups of benign epithelial cells in acinar sheets / cohesive groups / tubules and scattered individual epithelial cells, Also small foci of dense hyalinized stroma (, Tubules may have an angular configuration (, Fibrocystic changes including sclerosing adenosis with microcalcifications, Haphazardly distributed glands (lacks lobulocentric pattern), Lacks myoepithelium but has intact basement membrane, Nodular growth may mimic nodular adenosis / adenosis tumor, Uniform, closely packed tubules (lacks significant distortion by fibrosis), May be difficult to morphologically distinguish from florid sclerosing adenosis with marked distortion and/or involvement by atypia or, More widely spaced tubules with single epithelial layer. Because of their high mobility, they are also referred to as mouse in the breast/breast mouse. Compression of glandular elements - very commonly seen. Fibroadenoma - slit-like spaces (webpathology.com), Fibroadenoma - lobulated appearance (webpathology.com), Tubular adenoma of the breast (webpathology.com), http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970216-9, http://www.imagingpathways.health.wa.gov.au/includes/dipmenu/image/image.html, http://www.breastpathology.info/fibro_variants.html#juvenile, http://www.breastpathology.info/fibro_variants.html#complex, https://librepathology.org/w/index.php?title=Fibroadenoma&oldid=51069, Attribution-NonCommercial-ShareAlike 4.0 International, abundant (intralobular) stroma usu. Materials and methods: Home; About Us; What makes us different? Background: Our study was to determine the select cytologic features that can accurately distinguish FA from PT. stromal nuclear pleomorphism) is predictive of phyllodes tumor (versus fibroadenoma) in core No cytologic atypia is present. Other names for these tumors include phylloides tumor and cystosarcoma phyllodes. As the name suggests, is typically found in younger patients. Grossly, the fibroadenomas are small, well-demarcated, . The definitive diagnosis is made histologically by the presence . In this review, the pathology of the fibroadenoma and phyllodes tumour is revisited, with emphasis on diagnostic and management implications. Mori I, Han B, Wang X, Taniguchi E, Nakamura M, Nakamura Y, Bai Y, Kakudo K. Cytopathology. Breast disease: a primer on diagnosis and management. To determine the cytomorphological features of complex type fibroadenoma (CFA), we reviewed fine needle aspiration (FNA) cytology with correlation to its histopathology findings, and compared them with non-complex type fibroadenoma (NCFA). No large cysts are seen. Multiple, giant fibroadenoma. } Left breast, at 5 o'clock and 4 cm from the nipple, ultrasound core needle biopsy: Breast tissue with pseudoangiomatous stromal hyperplasia, Hemorrhagic, soft, interanastomosing vascular channels containing red blood cells with invasion into breast parenchyma, Papillary endothelial growth and hyperchromatic endothelial cells, Neoplastic clonal tumors with characteristic genetic change (del 13q14) (this can be demonstrated by loss of Rb protein immunohistochemistry in myofibroblastoma), Solid mass of spindle cells which surrounds and involves ducts and lobules, Tumor cells arranged in long fascicles without significant clefting, nuclear, CD34-, CD31-, nuclear beta catenin+, AE1 / AE3+. Complex fibroadenoma does not confer increased breast cancer risk beyond other established histologic characteristics. An official website of the United States government. interlobular stromal mucopolysaccharides (, Lacks glandular elements (versus myxoid fibroadenoma), Stromal condensation around glandular structures, Stromal mitotic activity (7 - 8/10 high power fields), Most common benign tumor arising in the breast. Please enable it to take advantage of the complete set of features! Sosin M, Pulcrano M, Feldman ED, Patel KM, Nahabedian MY, Weissler JM, Rodriguez ED. sharing sensitive information, make sure youre on a federal (a) In a 42 year old woman with a right axillary palpable lump, the mammogram shows a well-defined, gently lobulated, oval nodule in the right axilla (white arrow).Accessory breast tissue is also seen (red arrow). We consider the term merely descriptive. 2003 Oct;12(5):302-7. doi: 10.1016/s0960-9776(03)00123-1. In analyses stratified by involution status and PDWA, complex fibroadenoma was not an independent risk marker for breast cancer. We sought to evaluate the incidence of complex fibroadenoma on biopsy and to propose decision criteria for managing patients with these breast lesions. Clipboard, Search History, and several other advanced features are temporarily unavailable. Carcinoma Breast-Like Giant Complex Fibroadenoma: A Clinical Masquerade. Int J Fertil Womens Med. Jacobs. They fall under the broad group of adenomatous breast lesions. "Normal and pathological breast, the histological basis.". The site is secure. Breast. Excision of breast fibroepithelial lesions: when is it still necessary?-A 10-year review of a regional centre. hall county inmate list font-family: Arial, Helvetica, sans-serif; http://surgpathcriteria.stanford.edu/,