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Genome-wide analysis for loss of heterozygosity in primary and recurrent phyllodes tumor and fibroadenoma of breast using single nucleotide polymorphism arrays.

Phyllodes tumors of the breast are biphasic stromal and epithelial tumors histologically similar to benign fibroadenomas, but with a neoplastic stromal component. In contrast to fibroadenoma, phyllodes tumors can recur and be locally aggressive or be malignant. This study uses SNP array analysis to present a genome-wide map of loss of heterozygosity (LOH) in a cohort of phyllodes tumors and fibroadenomas. LOH is frequent and sometimes extensive in phyllodes tumors, but is rarely seen in fibroadenomas. There is heterogeneity between phyllodes tumors of different patients and no one LOH marker identifies a majority of these lesions. However, a subset of LOH loci occur in multiple cases of phyllodes tumors and are not found in fibroadenomas. Primary phyllodes tumors and paired recurrences from the same patient share common regions of LOH. In contrast, metachronous fibroadenomas from the same patient have different LOH patterns with no indication of a shared origin. Specific LOH loci may be associated with pathologic progression in recurrent phyllodes tumors. In a single case of phyllodes tumor containing a malignant epithelial component the malignant epithelium and stroma partially share an LOH genotype, suggesting a common precursor cell for the biphasic malignant components.

Breast Neoplasms↗

Immunohistochemical study of MIB1 expression in phyllodes tumor and fibroadenoma.

The histogenesis of phyllodes tumor (PT) and fibroadenoma (FA) is closely related, and discrimination between them by histopathological analysis is sometimes problematic. Moreover, objective criteria by which to categorize the grade of malignancy in PT are still controversial. The aim in this study is to clarify whether immunohistochemical evaluation using the MIB1 antibody, which reacts with the ki-67 antigen, correlates with the histological grade of malignancy in PT, and can discriminate between PT and FA. The 47 cases of phyllodes tumor (PT) were categorized into three groups (malignant, 4 cases; borderline, 6 cases; benign, 37 cases) according to the criteria proposed by Azzopardi (1979) and were investigated by immunohistochemistry. There were significant differences in stromal MIB1-index among the three groups (P < 0. 0001), and, unexpectedly, benign PT was easily divided into two groups according only to the MIB1-index. There were significant differences in the stromal MIB1-index (P < 0.001) and stromal cellularity (P < 0.01) between the two benign PT groups. A total of 478 cases of FA was reviewed and these were divided into 403 conventional fibroadenomas (CFA), 36 cellular fibroadenomas (CEFA) and 39 fibroadenomas with focal phyllodes structure (FAPS). All cases of CEFA and FAPS, and 140 cases of CFA were studied by immunohistochemistry. The 21/215 (9.8%) cases of FA, which were designated as FAMIB, showed a high stromal MlB1-index (more than 10/0.0625 mm2). Conversely, 77% cases of FA showed no MIB1-positive stromal cells. The incidence of MIB1-positive epithelium of FAMIB was much higher than that of FA. These results suggest that high proliferative activity may be present in both stromal and epithelial cells of FAMIB. Our study suggests that immunohistochemical evaluation using MIB1 antibody correlates with the histological grade of malignancy in PT, and can select FA with high proliferative activity. However, new objective diagnostic factors useful for discriminating FA from benign PT with a low MIB1-index should be developed.

Adenoma↗

Core needle biopsy as a diagnostic tool to differentiate phyllodes tumor from fibroadenoma.

HYPOTHESIS: Core needle biopsy is a useful diagnostic tool in differentiating phyllodes tumor from fibroadenoma. DESIGN: The radiology database was queried for patients who underwent core needle biopsies of fibroepithelial lesions that raised the possibility of phyllodes tumor. These diagnoses were then compared with the final pathological diagnoses after surgical excision. SETTING: The data were gathered from the Comprehensive Breast Center, Columbia Presbyterian Medical Center, a tertiary care, university-based medical center. RESULTS: From August 21, 1998, to December 14, 2001, 57 core needle biopsies were identified in which the specimen raised the possibility of phyllodes tumor. The median age of the patients was 42 years (range, 16-77 years). The median diameter of all lesions was 1.1 cm (range, 0.6-3.6 cm). Of the 57 specimens, 25 had core biopsies in which the pathological findings favored a diagnosis of fibroadenoma over phyllodes tumor. Twenty-three had initial core biopsies favoring phyllodes tumor. Nine of the core biopsies were equivocal. Of the 25 patients with specimens favoring fibroadenoma, excisional biopsy confirmed the diagnosis of fibroadenoma in 23, and phyllodes tumor was found in 2. The negative predictive value was 93%. Of the 23 core biopsies favoring phyllodes tumor, 19 were confirmed on excisional biopsy, while 4 were fibroadenoma. The positive predictive value was 83%. In the equivocal core biopsies, 5 were fibroadenoma and 4 were phyllodes tumor on final pathological analysis. None of the lesions studied were determined to be malignant on final analysis. CONCLUSIONS: Core needle biopsy can significantly reduce the need for operative management of fibroepithelial lesions. A core needle biopsy with results favoring fibroadenoma should allow the breast physician to treat the lesion as a fibroadenoma, with observation and close follow-up or with enucleation. Core needle histologic examination of phyllodes tumor allows the physician to preoperatively plan the definitive management at one surgical procedure, reducing the need for reoperations.

Adolescent↗

Cytogenetic findings in phyllodes tumor and fibroadenomas of the breast.

The cytogenetic data on fibroadenomas and cystosarcoma phyllodes tumor of the breast, which are both biphasic breast tumors composed of epithelial and stromal components, are quite limited. In this study, we report on clonal chromosomal alterations in three fibroadenomas and one cystosarcoma phyllodes analyzed by GTG banding. The fibroadenomas presented mostly numerical abnormalities involving chromosomes 16, 18, and 21. One case presented a deletion on 17p. The cystosarcoma phyllodes presented numerous numerical abnormalities, mostly chromosome gains, and several marker chromosomes.

Adolescent↗

Differentiation of phyllodes tumors versus fibroadenomas.

PURPOSE: To determine if mammographic and sonographic findings allow discrimination between phyllodes tumor and large sized fibroadenoma, which mimic each other in the clinical, radiologic and histopathologic appearances. MATERIAL AND METHODS: Thirty-one histopathologically proven masses including 12 phyllodes tumors and 19 fibroadenomas 3 cm or greater in diameter were compared. In total 28 women were retrospectively evaluated by mammography and pre-operative sonography. RESULTS: Mammography revealed a high-density mass compared with surrounding fibroglandular breast tissue to be present in 9 of the 12 (75%) phyllodes tumors and 7 of the 19 (37%) fibroadenomas. At sonography a mass, which had a round or lobulated shape, marked posterior acoustic enhancement and intramural cystic areas, were statistically significantly more likely to be phyllodes tumors than fibroadenomas. None of the other mammographic or sonographic characteristics proved to be useful in differentiating phyllodes tumors and fibroadenomas. CONCLUSION: Although masses of high density at mammography, circumscribed border associated with posterior acoustic enhancement and internal cystic areas at sonography should suggest the diagnosis of phyllodes tumors rather than large sized fibroadenomas, there was a substantial overlap in the mammographic and sonographic characteristics of these two tumors. Therefore, an excisional biopsy would be necessary for equivocal masses.

Adult↗

Differentiation of phyllodes breast tumors from fibroadenomas on MRI.

OBJECTIVE: The purpose of our study was to evaluate the MRI appearance of phyllodes breast tumors and to differentiate them from fibroadenomas. MATERIALS AND METHODS: MR images were obtained on a 1.5-T imager. T1- and T2-weighted sequences and dynamic 2D fast-field echo T1-weighted sequences were performed. MR images of 23 patients with 24 phyllodes breast tumors (one malignant, 23 benign) were analyzed with respect to morphology and contrast enhancement. The tumors were compared with the MRI appearance of 81 fibroadenomas of 75 patients. RESULTS: Well-defined margins were seen in 87.5% of the phyllodes tumors and 70.4% of the fibroadenomas, and a round or lobulated shape in 100% and 90.1%, respectively. A heterogeneous internal structure was observed in 70.8% of phyllodes tumors and in 49.4% of fibroadenomas. Nonenhancing internal septations were found in 45.8% of phyllodes tumors and 27.2% of fibroadenomas. A significantly greater increase in signal was seen on T2-weighted images in the tissue surrounding phyllodes tumors (21%) compared with fibroadenomas (1.2%). Most of both lesions appeared with low signal intensity on T1- and T2-weighted images. After the administration of contrast material, 33.3% of phyllodes tumors and 22.2% of fibroadenomas showed a suspicious signal intensity-time course. CONCLUSION: Phyllodes breast tumors and other fibroadenomas cannot be precisely differentiated on breast MRI. Phyllodes tumors have benign morphologic features and contrast enhancement characteristics suggestive of malignancy in 33% of cases.

Adolescent↗

Distinction of phyllodes tumor from fibroadenoma: a reappraisal of an old problem.

BACKGROUND: Using fine-needle aspiration (FNA) smears, it is difficult to distinguish low grade phyllodes tumor (PT) from fibroadenoma (FA) due to overlapping cytologic features between the two lesions. The authors retrospectively studied 45 histologically proven fibroepithelial breast tumors of which 33 were FA and 12 were PT (1 malignant, 8 borderline, and 3 benign) to define cytologic features that can help in the accurate categorization of these lesions by using FNA samples. METHODS: The cytologic features analyzed included: 1) epithelial component for number (<5 or >5), architecture, apocrine metaplasia, squamous metaplasia, nuclear pleomorphism, and mitosis; 2) stromal fragments for number (<5 or >5), cellularity (on a scale of 1+ to 3+), borders, cell characteristics, nuclear pleomorphism, and mitosis; 3) individual dispersed stromal cells in the background for cellularity (on a scale of 1+ to 3+), and cellular shape (short/round/oval or long spindle) based on whether they were smaller or larger than 2 times the size of a small round lymphocyte. RESULTS: The mean age of patients with FA was 34 years and of those with PT 44 years. The average size of FA was 2.0 cm, and the average size of PT was 4.0 cm. The characteristics of the epithelial fragments of PT and FA were not significantly different. Stromal fragments were noted in 60% of FA and 83% of PT samples examined. Fifty-six percent of PT and 30% of FA exhibited hypercellular stromal fragments (3+ cellularity), and the difference was not statistically significant. Large club-shaped hypercellular stromal fragments were present only in FA (in 21% of the samples). There was no difference in the overall cellularity of the background stromal nuclei in the two types of lesions. Long spindle nuclei averaging greater than 30% of the dispersed stromal cell population in the background were found only in cases of PT (in 57% of the samples; P < 0.001). Short/round/oval nuclei characterized most FAs. Long spindle nuclei constituting 10-30% of the dispersed stromal cells, however, occurred in both PT and FA to the extent of 43% and 21%, respectively. CONCLUSIONS: Hypercellular stromal fragments occur not only in PT, but also in FA, and hence they cannot be used as the sole criterion for making a diagnosis of PT on FNA. The proportion of individual long spindle nuclei (>30%) amid the dispersed stromal cells in the background is the most reliable discriminator between the two lesions. Lesions in which long spindle nuclei constitute between 10% and 30% may represent either PT or FA, and therefore such lesions should be categorized as indeterminate on FNA.

Adult↗

Platelet-derived growth factor expression in phyllodes tumors and fibroadenomas of the breast.

The development of normal breast tissue and the pathogenesis of various tumors are influenced by growth factor-mediated epithelial-stromal interactions. Similar interactions may occur in fibroepithelial breast tumors. We have studied the expression of platelet-derived growth factor (PDGF) and PDGF beta receptor (PDGFRbeta) in 46 phyllodes tumors (18 benign, 15 borderline, 13 malignant), 11 fibroadenomas, and 6 samples of normal breast. There was neoplastic stromal cell positivity for PDGFRbeta in almost 50% of phyllodes tumors and for PDGF in 24%. Both were associated with prominent nuclear pleomorphism (P<.01), PDGF with high grade (P<.01), and a higher mean Ki-67 labeling index (P = .013), and PDGFRbeta with conspicuous stromal overgrowth (P<.01). Co-positivity for stromal PDGF and PDGFRbeta was found in 15% of phyllodes tumors, and for epithelial PDGF and stromal PDGFRbeta in 43%. Both types of co-positivity were associated with prominent nuclear pleomorphism and the latter type with conspicuous stromal overgrowth (all P<.01). Follow-up of 41 phyllodes tumors showed that disease-related death was associated with established histologic features of malignancy including mitotic count, stromal overgrowth, an infiltrative tumor margin, and nuclear pleomorphism. In addition, stromal PDGFRbeta positivity (P =.013) and epithelial PDGF/stromal PDGFRbeta co-positivity (P =.0075) were associated with disease-related death. Stromal PDGF and PDGFRbeta expression in fibroadenomas was less common and less extensive (P<.05) than in phyllodes tumors. The results suggest that PDGF influences the pathogenesis of fibroepithelial breast tumors and that PDGF-dependent paracrine and autocrine mechanisms may operate. Also, it is possible that assessment of PDGF and PDGFRbeta expression could contribute to the management of these tumors in the future.

Breast↗

Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues.

To study the etiologic factors of non-familial breast cancer, the polymerase chain reaction (PCR) and Southern hybridization were used to detect six viruses including human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV)-1, HSV-2, and human herpesvirus (HHV)-8 DNA in 69 patients with breast cancer and 60 specimens from non-cancerous or other individuals with thyroid tumors or fibroadenoma (non-breast cancer controls). Two specimens from patients with a familial history of breast cancer and five breast cancer specimens with negative results for beta-globin, which was used as internal control, were excluded from this study. Eight (12.9%) HSV-1, 28 (45.2%) EBV, 47 (75.8%) CMV, 8 (12.9%) HPV, and 28 (45.2%) HHV-8 positive samples out of the 62 breast cancer specimens were detected; no HSV-2 DNA was detected in any group. Among the viral gene-positive breast cancer samples, 12 (23.1%) were positive for 1 virus, 16 (30.8%) were positive for 2 viruses, 21 (40.4%) were positive for 3 viruses, and 3 (5.8%) were positive for 4 viruses. Among the viral gene-positive specimens of the control groups, only one virus, CMV, was found in the non-cancerous and thyroid tumor specimens, while multiple viruses were found in the fibroadenoma specimens. The viruses associated with breast cancer were HHV-8 > EBV (P <0.01). The viruses associated with fibroadenoma were HSV-1 and HHV-8 > EBV (P <0.01). The presence of more than one virus was found predominantly in breast cancer and exclusively found in fibroadenoma. CMV was the only virus associated with thyroid tumors.

Adult↗

[Tumor and tumor-like benign mesenchymal lesions of the breast].

All the spectrum is encompassed of those miscellaneous pathologic entities occurring in the mammary stroma which are on record up to date other than "mixed fibroepithelial" tumors (fibroadenomas and phyllodes tumors) and tumors both "pure" and "mixed" originating from myoepithelium (adenomyoepitheliomas and pleomorphic adenomas). Also they were excluded those dysreactive-autoimmune diseases (sarcoidosis, sclerosing lymphocytic lobulitis, lobular granulomatous mastitis) and those inflammatory-infectious conditions (tuberculosis, actinomycosis, foreign body reactions, Mondor's disease) which can mimick breast tumors clinically or on image analysis, but on the contrary not evoking the idea of a tumor on histology. Specifically, inflammatory pseudotumor, myofibroblastoma, leiomyoma, neurinoma/neurofibroma, benign fibrous histiocytoma, hemangiopericytoma, fibromatosis, nodular fascitis, variants of lipoma, mesenchymoma, amartoma and its variants, hemangiomas, pseudoangiomatous hyperplasia of stroma, amyloid tumor, granular cell tumor, are consecutively described and discussed, with a large list of references enclosed to each rubric. Most of the pictures are taken from personally observed lesions of the breast. Only few pictures referred to are from their analogue lesions which occurred in soft parts of other locations, with specific mention of that when it was the case. Of note after reviewing the literature the fact that no glomus tumor, nor Kaposi's sarcoma either sporadic or in the context of any immunodeficiency, nor myelolipoma has been recorded yet.

Breast Neoplasms↗

Proliferating activity in differential diagnosis of benign phyllodes tumor and cellular fibroadenomas: is it helpful?

Benign phyllodes tumors and fibroadenomas are two types of fibroepithelial tumors of breast that are usually difficult to differentiate. The purpose of this study is to evaluate the proliferative activity of these tumors and to find out if it helps in differential diagnosis. Thirty-one benign phyllodes tumors and twelve cellular fibroadenomas were retrieved from the archives of Pathology Department of Akdeniz University, School of Medicine. Proliferating activity of epithelial and stromal cells were evaluated by using labeling index (LI) of proliferating cell nuclear antigen (PCNA) and Ki-67 antigen by immunohistochemistry. The results were compared with other clinicopathologic findings. There was not any significant difference between the proliferating activity of phyllodes tumor and cellular fibroadenomas. Mean LI of PCNA was 28.01 (+/-22.85) in stromal cells and 56.57 (+/-30.98) in epithelial cells of phyllodes tumor where it was 28.92 (+/-24.02) and 62.53 (+/-32.56) in fibroadenomas. Ki-67 indices were 0.05 (+/-0.19) in stromal cells, 2.65 (+/-12.53) in epithelial cells of phyllodes tumors and 0.0 (+/-0) in stromal cells, 0.43 (+/-0.63) in epithelial cells of fibroadenomas. There was no correlation between the diameter of tumors and proliferating activity in both groups. Proliferating activity, determined by immunohistochemistry with PCNA and Ki-67 antibodies did not reveal significant difference between phyllodes tumor and fibroadenoma.

Adolescent↗

Trace element content in breasts with fibrocystic disease.

The trace elements antimony, bromine, cesium, cobalt, iron, rubidium, scandium, strontium and zinc were determined by instrumental neutron activation analysis in breast tissue samples with fibrocystic disease and in samples with fibroadenoma tumors. The histological lesions of each breast sample with fibrocystic disease were recorded, and a statistical analysis of the lesions in combination with the determined trace elements was carried out. The results showed that the element mean values in fibroadenoma tumors are higher than those of fibrocystic disease. Some other remarkable results of statistical examination are also presented.

Breast↗

Magnetic resonance imaging of the human female breast. Current status and pathologic correlations.

Over the past decade, research in MR of the female breast has focused on in vitro studies of excised breast tissue samples or mastectomy specimens and on in vivo clinical imaging of patients, usually with biopsy correlation. The results of in vitro measurement of T1 and T2 times of excised benign and malignant breast tissue do not conclusively demonstrate a clear separation based on these values alone. In particular, benign tumors (fibroadenomas) cannot be distinguished from carcinomas and there is considerable overlap in values for cancer and fibrocystic disease. MR images produced from mastectomy specimens allow detailed correlation with mammographic and histologic findings but are incompletely applicable to in vivo images because of numerous factors including tissue changes associated with disruption of blood supply. In vivo studies have shown that benign tumors (fibroadenomas), fibrocystic changes, and cancers can be imaged successfully by MR. To date the best images show a resolution of about 2 mm. Small cancers and cysts have been imaged successfully but proliferative patterns of fibrocystic disease cannot be differentiated at this time. Carcinomas occurring in dense fibroglandular breasts which are a problem to image mammographically have not been successfully imaged by MR in vivo and in only one instance in vitro in a mastectomy specimen. Since MR cannot image microcalcifications, it does not appear likely to replace mammography as the imaging modality of choice at the present time. Newer magnets of increased strength, specialized surface coils specifically for breast imaging, and the use of contrast enhancing agents all may increase the usefulness of MR as an imaging modality for the detection of breast disease. In particular, increased resolution and contrast enhancing agents which may aid in tissue differentiation should be studied for their ability to detect carcinomas in dense fibroglandular breast tissue and to identify lesions of carcinoma in situ and proliferative patterns of fibrocystic disease. The need for careful collaborative studies between radiologists and pathologists will be essential for the success of these research efforts.

Adenofibroma↗

Clonal analysis of fibroadenoma and phyllodes tumor of the breast.

Clonality of fibroadenoma and phyllodes tumor of the breast was analyzed by means of the polymerase chain reaction using small DNA samples prepared from cryostat sections. The method of clonal analysis was based on restriction fragment length polymorphism of X-chromosome-linked phosphoglycerokinase gene and on differential methylation of the gene. Specimens from 10 fibroadenomas and 5 phyllodes tumors heterozygous for the BstXI polymorphism of PGK gene were subjected to clonal analysis. It was found that fibroadenoma was polyclonal, but phyllodes tumor was made up of both monoclonal and polyclonal cell components. Since these tumors contained both epithelial and stromal components, clonality of each component was analyzed separately. Analysis of clonality of each cell component showed that both the epithelial and stromal cells were polyclonal in fibroadenoma and that the epithelial cells were polyclonal, but the stromal cells were monoclonal in phyllodes tumor. When DNA samples were prepared from widely separated sites of phyllodes tumors, every sample was found to contain a monoclonal stromal cell component. These results demonstrate that fibroadenoma is a hyperplastic lesion rather than a neoplasm, and that phyllodes tumor is a neoplasm of the stromal cells.

Adenofibroma↗

Progression of fibroadenoma to phyllodes tumor demonstrated by clonal analysis.

BACKGROUND: The histogeneses of fibroadenoma and phyllodes tumor of the breast appear to be closely related, but it is still unclear whether fibroadenoma can progress directly to phyllodes tumor. METHODS: This issue was studied by conducting clonal analysis of fibroadenoma and phyllodes tumors that were obtained sequentially from the same patient. One patient developed local recurrence of phyllodes tumor twice, and the other two patients each developed a phyllodes tumor after excision of a primary fibroadenoma. The method for clonal analysis was based on trinucleotide repeat polymorphism of the X chromosome-linked androgen receptor (AR) gene and on random inactivation of the gene by methylation. RESULTS: Clonal analysis revealed that all the three primary fibroadenomas were monoclonal and all four recurrent phyllodes tumors were also monoclonal in origin. In addition, the same allele of the AR gene was inactivated in fibroadenoma and phyllodes tumor(s) in each patient. The probability that phyllodes tumors of different origin happen to inactivate the same allele of the AR gene as fibroadenomas in every case is quite low. Rather, it is more reasonable to assume that the phyllodes tumor has the same origin as fibroadenoma. CONCLUSIONS: These results identified monoclonal fibroadenomas that can progress to phyllodes tumors.

Adult↗