Cytological Assessment of Paediatric Breast Lesions: A Systematic Review

Pathologic, Immunohistochemical, and Molecular Features of Benign and Malignant Phyllodes Tumors of the Breast

(1) Phyllodes tumors are uncommon breast tumors, but are not rare Over a 10-year period 3 % of the breast neoplasms were phyllodes tumors. Benign phyllodes tumors were about ten times more common than malignant, and about five times more common than borderline. In a busy surgical practice of 400 cases per year one could expect to see 12 patients with phyllodes tumors: nine benign, two borderline, and one malignant. (2) Margin negative resection of benign phyllodes tumors is associated with a very low incidence of local recurrence Many previous studies have described the result of local excision or wide local excision of benign phyllodes tumors, without clearly delineating the margin status. In a review of several of these studies in 1999, we found that benign phyllodes tumors recurred after local excision in 21 % of cases and after wide local excision in 8 % [2]. Since one may have a positive margin even after an attempted wide local excision, the key variable is the margin status. Kim et al. have now described 114 patients who underwent margin negative, breast conserving resections of benign phyllodes tumors with only four local recurrences (3.5 %). Achieving a margin negative resection, while optimizing cosmesis by excising a minimal amount of surrounding breast tissue is optimal treatment for patients with benign phyllodes tumors. (3) The histologic grade of phyllodes tumor (benign vs borderline vs malignant) predicts the likelihood of local recurrence after margin negative resection Kim et al. report that the chance of a local recurrence after breast conserving, margin negative resection of benign, borderline, and malignant phyllodes tumors is 4/114 (3.5 %), 4/23 (17.4 %), and 5/10 (50 %), respectively. (4) The risk of local recurrence after margin negative resection of borderline or malignant phyllodes tumors is substantial We have previously reviewed the literature on the incidence of local recurrence after margin negative breast conserving resection of borderline and malignant phyllodes tumors [3]. In that review, 12/50 (24 %) patients with borderline phyllodes tumors and 25/124 (20 %) patients with malignant phyllodes tumors locally recurred. Adding the data from Kim et al., the risk of local recurrence after margin negative breast conserving resection of borderline and malignant phyllodes tumors is 16/73 (22 %), and 30/134 (22 %), respectively. The similarity in rates of local recurrence of borderline and malignant phyllodes tumors may be explained by recent molecular evidence that these tumor grades share similar genetic profiles. Comparative genomic hybridization analyses, which quantify chromosomal copy number gains and losses, indicate that phyllodes tumors segregate into two groups, with the borderline and malignant group having much This is an invited commentary to article doi: 10.1007/s10549-0132684-x.

CD34, CD117, and actin expression in phyllodes tumor of the breast.

Phyllodes tumors are not quite rare fibroepithelial neoplasms of the breast that show a broad spectrum of clinical behaviour. The molecular genetic features of the heterogenous groups of neoplasms have not been studied in detail yet. We have used comparative genomic hybridization to analyze chromosomal copy number changes in 36 cases of phyllodes tumors (including benign, borderline and malignant phyllodes tumors, 12 cases each). The average number of chromosome copy changes (range) in benign, borderline and malignant phyllodes tumors were 5.58 (0-20), 14.08 (3-23), and 12.42 (0-29) respectively. In benign phyllodes tumors the number of gains and losses was in balance (2.50 vs 3.08), while in borderline and malignant phyllodes tumors gains occurred more often than losses (9.25 vs 4.83, 9.5 vs 2.92). The result suggests the molecular cytogenetics of borderline and malignant phyllodes tumors is similar, and the most striking difference with benign phyllodes tumors is an increased number of chromosomal gains in a nonrandom distribution. Gains of 4q12 seem especially to be involved in the progression of benign to borderline and malignant phyllodes tumors, possibly because of overexpression of oncogenes at these loci.

Pathologists can distinguish benign phyllodes tumors, which very rarely metastasize, from malignant phyllodes tumors, which metastasize in approximately one fourth of patients. However, whether these same histologic criteria can be used to predict the likelihood that a phyllodes tumor will locally recur after breast conserving therapy remains controversial. Since few patients with malignant phyllodes tumors have been treated with breast conserving surgery in any individual series, the literature was reviewed using a Medline search. After local excision, 21% (111/540), 46% (18/39), and 65% (26/40) of patients with benign, borderline, and malignant phyllodes tumors, respectively, recurred in the breast. Following wide local excision, 8% (17/212), 29% (20/68), and 36% (16/45) of patients with benign, borderline, and malignant phyllodes tumors recurred in the breast. Malignant phyllodes tumors are much more likely than benign phyllodes tumors to recur in the breast after breast conserving surgery. This high rate of local recurrence of borderline and malignant phyllodes tumors suggests that wide local excision is less than optimal therapy, and challenges us to look for methods to improve local tumor control.

Deposition of basement membrane extracellular matrix is influenced by adjacent tumor cells, and in some cases, the pattern of type IV collagen deposit is characteristic in malignant tumors. In this report, we analyzed the difference in type IV collagen deposition patterns between benign and malignant phyllodes tumors (PTs) of the breast. Of the 15 cases of PTs, 8 cases were benign PTs and 7 cases were malignant PTs. Three cases of other primary sarcomas of the breast (stromal sarcoma, angiosarcoma and osteosarcoma) and 2 cases of fibroadenomas were studied for comparison. The malignant PTs were distinguished from benign ones by increased mitotic figures, cellular atypism, and a higher proliferation index of stromal cells. Immunohistochemical staining against type IV collagen in malignant PTs revealed extensive to moderate deposition of type IV collagen around the small blood vessels in duplicate or multilayering pattern, while benign PTs showed minimal deposition in a single linear pattern. All of the three cases of other sarcomas revealed multilayering or meshwork pattern of type IV collagen around the blood vessels. The deposition of type IV collagen around the blood vessels may reflect the malignant behavior of the stromal tumors of the breast.

Phyllodes tumor (PT) is a variant of fibroepithelial proliferations of the breast, histologically demonstrating a leaf-like pattern. The WHO has categorized PTs as benign, borderline, or malignant based on their histological characteristics. The objective of this paper is to assess the clinicopathological factors with malignancy in PT of the breast. Medical records of 101 diagnosed PT patients in the Second Affiliated Hospital of Dalian Medical University between 2008 and 2023 were reviewed. Information on clinical presentation and histopathological findings of the lesions were retrieved from patient files and/or histological reports, respectively. Of the 101 patients, all were female and had a mean age of 44.35 ± 14.14 years and mean tumor size of 8.3 ± 5.8 cm The distribution for the histological type was benign (n = 54, 53.4%), borderline (n = 36, 35.6%) and malignant (n = 11, 10.8%). Most benign PTs were observed in younger patients, while borderline and malignant PTs involved elderly patients, with a mean age of 47.56 ± 11.86 years for borderline PT and a mean age of 46.55 ± 11.62 years for malignant PT. Benign PTs had a mean size of 5.58 ± 2.29 cm, while those of borderline and malignant were larger, with a mean size of 10.58 ± 6.79 cm and 14.90 ± 6.44 cm, respectively. Malignant PTs had higher lactate dehydrogenase (LDH) levels of 232 ± 91.5 U/L compared to borderline PTs, 177.9 ± 19.9 U/L, and benign PTs, 177.6 ± 39.9U/L. The course of the disease of the malignant PT group was slightly longer (436.9 ± 391.3 weeks) than that of the benign (44.17 ± 71.54 weeks) and borderline (54.33 ± 94.33 weeks). In histopathology, necrosis was observed only in malignant PTs (81.8%), and severe stromal atypia was seen in 72.7% of malignant cases. The mitotic count was highest in malignant PTs at 13.18 ± 4.43 HPF as compared to benign 3.52 ± 2.97 HPF and borderline PTs at 7.28 ± 2.21 HPF. Benign PTs were more common in this study than malignant or borderline PTs. There was a highly significant correlation between patient age, tumor size, LDH, and disease progression in all subtypes of PT. This analysis showed that malignant PTs were larger and observed in older patients with higher LDH and with a longer duration of the disease. Other factors, in addition to histological properties, are useful in determining PT behavior and management. More studies at an advanced level of evidence in the form of randomized trials are required when developing a risk classification for PT based on patient age, tumor size, and LDH.

BackgroundThe accurate graduation of a phyllodes tumor (PT) is critical for effective treatment as it allows correct surgical management, and avoids inadequate excision for malignant or borderline PT, or surgical overtreatment in benign PT. PTs of the breast are notoriously difficult to classify, and reliable differentiation of a benign PT from a borderline or malignant PT can be problematic, especially among relatively inexperienced pathologists. Although several authors acknowledge a strong relationship between the immunohistochemical expression of p53 and Ki-67 and the histopathological grade of PT—with potential impact on diagnostic accuracy—the literature lacks consensus about which cutoff defines a positive index test. The objective of this study is to establish a practical application score that increases the graduation accuracy of PT through the appropriate use of these auxiliary methods.MethodsA retrospective study cohort of 146 pathology reviewed PTs surgically removed between January 2000 and December 2015. The Ki-67 test was considered positive if > 10% of neoplastic cells showed nuclear staining. The p53 test was considered positive if > 10% of neoplastic nuclear cells showed nuclear staining in a moderate or strong intensity.ResultsOf the 146 PT cases reviewed, 110 were classified as benign, 16 as borderline, and 20 as malignant. The correlation between age and size with benign, borderline, and malignant subgroups was statistically significant (p < 0.001). Significance was observed in the expression of both Ki-67 and p53 in the comparison of benign, borderline, and malignant PT with p < 0.001 and a 95% confidence interval (CI). When correlating the presence of positivity in either of the two index tests with the diagnosis of borderline or malignant PT, we reached a sensitivity of 100% and a specificity of 91.8 (p < 0.001; 95% CI).ConclusionWe propose a practical methodology to achieve an accurate grade of PT, based on clearly defined and easy to apply cutoffs of a simple immunohistochemical panel of Ki-67 and p53. A PT positive for either of the index tests should be graded as borderline or malignant, so pathologists can use this test to improve accuracy. We hope this new approach might provide the basis for the development of standardization in using p53 and Ki-67 for grading PT.

This study aimed to assess their characteristics and clinical course of each histologic type of the behavior of phyllodes tumor (PT). We retrospectively reviewed 124 patients with PTs who underwent surgical treatment from 2003 to 2011. PTs were classified as benign, borderline, and malignant using surgical specimens. The clinicopathological characteristics according to solitary and multiple lesions on ipsilateral breast and histological change after local recurrence were examined. The median patient age was 42years (range 12-72years). The final pathologic diagnosis was benign PTs in 95 patients (76.6%), borderline PTs in 21 (16.9%), and malignant PTs in 8 (6.5%). The size of benign PTs [median 4.2cm (range 1-21cm)] was significantly smaller than that of malignant PTs [median 11.3cm (range 6-27cm)] (p < 0.001). Eight of the 95 benign PTs (8.4%) had multiple lesions, while all malignant PTs had solitary lesion. With a median follow-up period of 45months, five patients with malignant PTs (62.5%) developed distant metastases while 13 patients with benign PTs (13.5%) and 6 patients with borderline PTs (28.6%) had local recurrence only without malignant transition. The median overall survival period of those with malignant PTs was 22.5months (range 5-109months). Histologically benign and borderline PTs had a good prognosis without malignant transition even after developing repeat recurrence in contrast with malignant PTs that might be a solitary lesion.

Phyllodes tumor or cystosarcoma phyllodes is a rare fibroepithelial neoplasm which arises from the periductal stroma of the breast. They are classified as benign, borderline, and malignant based on the histologic features. However, all phyllodes tumor (PT) subtypes are regarded as having malignant potential and correct diagnosis is important for surgical management and optimal care. This study is a retrospective review of 76 women diagnosed as PT with highlights on the imaging characteristics, pathology, and surgical treatment over a 7-year period in a tertiary medical center of urban population in Malaysia. There were 45 benign, 16 borderline, and 15 malignant PT. The median age for benign PT was 43, borderline 48.5, and malignant 42 years. The Malay ethnic group constitute 52.6% of cases, with 27.6% and 18.4% in Chinese and Indian ethnic groups, respectively. On mammograms, most benign (64.3%) and 33.3% of malignant PT showed high-density lesions. Calcifications were only seen in 2 benign PT. On ultrasound, 86% of benign PT was well-circumscribed whilst 50.0% of malignant PT had irregular outline. Cystic spaces were seen in 40.0% of malignant and 9.5% of benign PT. 80% of malignant PT lesions were heterogenous. Malignant PT demonstrates tumor heterogeneity, cystic spaces, and posterior acoustic enhancement on ultrasound. Half of malignant PT showed regular borders on ultrasound and appear well circumscribed on mammogram. A total of 46 patients had wide local excision or excision biopsy whilst 30 underwent mastectomy as primary treatment. The majority of the borderline and malignant PTs in our study (75.0% and 85.7% respectively) and only 5 out of the 43 (11.6%) benign PT underwent mastectomy. There were 2 tumor recurrence in the benign PT group and 1 case in the borderline and malignant group respectively.

Increased p53 Protein Expression in Malignant Mammary Phyllodes Tumors

PurposeTo clarify the risk factors of phyllodes tumor (PT) for local recurrence (LR).MethodsData from 829 patients with pathologically confirmed benign, borderline and malignant PT of the breast, diagnosed from between 2011 to 2023, were retrieved from the electronic databases of the First Hospital of Jilin University and the First Affiliated Hospital of Xi’an Jiaotong University. Kaplan-Meier curves and Cox proportional-hazards model were conducted to determine the independent risk factors for LR in each group.ResultsOf 829 PT patients, 634 (76.5%), 142 (17.1%), and 53 (6.4%) were diagnosed with benign, borderline, and malignant PT, respectively. The LR rates were 5.4%, 9.9%, 13.2%, respectively. The median patient age was 38 years and the median follow-up time was 2.8 (range, 0.2-12.1 years). Of these patients, 13 (2.1%) were diagnosed with benign bilateral PT. Multivariate analysis identified bilateral involvement as a risk factor for LR of benign PT (p=0.010). Also, univariate analysis identified young age (≤35 years, p=0.046) as an independent risk factors for LR of borderline PT. Of the patients with malignant PT, univariate analysis found that breast-conserving surgery (BCS) (p=0.008) were associated with an increased risk for LR of malignant PT.ConclusionsBilateral PT was a risk factor for LR of benign PT, young age (≤35 years) was associated with poor prognosis of borderline PT, BCS were high risk factors for LR of malignant PT. This study identifies LR risk factors based on tumor grading, which contributes to individualized clinical risk assessment. Future research could further explore how to incorporate these factors into clinical decision-making models for PT and other soft tissue tumors.

Phyllodes tumors are group of biphasic fibroepithelial tumors of the breast of varying malignant potential, ranging from benign tumors to fully malignant sarcomas. According to the Egyptian National Cancer Institute, female malignant cases showed appreciable increase in the recent time period for breast cancer with the malignant phyllodes tumors representing 0.41% of cases in the year 2003-2004. This is an immunohistochemical study to compare CD10 expression in benign, borderline, and malignant phyllodes tumors, in order to highlight its diagnostic and prognostic values. This study conducted 34 Egyptian female cases of phyllodes tumors of different grades to be studied histologically and immunohistochemically using antibodies against CD10. The Chi-square test was used to determine differences in CD10 expression between benign, borderline, and malignant tumors. One-way ANOVA test was used to determine whether the difference was significant. Significance was established at P<0.05. In the 24 cases of benign phyllodes tumors, only four cases (16.7%) showed positive CD10 reactivity. Three cases (60%) out of five borderline phyllodes tumors showed positive CD10 reactivity, while four (80%) out of five cases of malignant phyllodes tumors showed positive CD10 staining. From these highly significant results, we believe that there is a strong correlation between CD10 expression and tumor grade, which could be an important observation that may have both diagnostic and prognostic implications as well as promising potential target for development of novel therapies.

Phyllodes tumors in the breast are exceptionally uncommon fibroepithelial tumors. In the literature, they are typically categorized as benign phyllodes tumor, borderline phyllodes tumor, and malignant phyllodes tumor. This study aims to assess and present the clinical and surgical outcomes of patients diagnosed with phyllodes tumor. The outcomes of patients aged 18 years and above diagnosed with phyllodes tumor between 2006 and 2023 were retrospectively reviewed. Patients were grouped as benign phyllodes tumor and borderline/malignant phyllodes tumor and compared by clinical and surgical results. Of all 57 patients with phyllodes tumor, 64.9% (n=37) were benign phyllodes tumor and 35.1% (n=20) were borderline/malignant phyllodes tumor [22.8% (n=13) borderline phyllodes tumor and 12.3% (n=7) malignant phyllodes tumor]. When the patients were divided into two groups as benign phyllodes tumor and borderline/malignant phyllodes tumor and compared, our cumulative (total) recurrence rate was 14.0%, with final surgical margin width between groups [(0<final surgical margin<2 mm vs final surgical margin≥2 mm) (p=0.154)] and recurrence [(8.1% benign phyllodes tumor vs 25.0% borderline/malignant phyllodes tumor) (p=0.080)]; there was no significant difference between our rates. Phyllodes tumors of the breast can be followed up with a narrow negative surgical margin (0 mm<final surgical margin<2 mm). However, after the initial surgery, re-excision is recommended for positive margins, while a wider surgical margin (≥10 mm) is not necessary for excision.

To determine whether any markers in biopsy specimens were useful for distinguishing (1) fibroadenoma (FA) from benign phyllodes tumors (PTs); and (2) from benign borderline PTs of the breast. Specimens of 80 breast tumors (20 FA, 38 benign, 12 borderline, and 10 malignant PTs) diagnosed at Tri-Service General Hospital from 1986 to 2006 and 10 normal breast tissue were investigated immunohistochemically for the expression of 11 biomarkers including p53, Ki-67, topoisomerase IIα, p16, retinoblastoma protein (pRb), fascin-1, estrogen receptor-β, CD117, osteopontin, hypoxia-inducible factor-1α, and cyclooxygenase-2. The binary logistic regression method was used to generate functions that discriminate between benign and borderline PT and also between FA and benign PT. On the basis of the most active area of stained stromal cells, the staining intensity, and the immunoscore, the expression of Ki-67, topoisomerase IIα, p16, and pRb was significantly higher in borderline or malignant PTs than in benign PTs. Ki-67 could discriminate benign from borderline PTs singly with a high sensitivity (91.7%), specificity (100%), and accuracy (98%). In addition, expression of Ki-67, p16, and pRb was significantly higher in benign PT than in FA. Binary logistic regression identified p16 and pRb as the only marker combination capable of distinguishing FA from benign PTs with sensitivity (94.7%), specificity (75%), and accuracy (87.9%). Ki-67 may be a useful marker for discriminating benign from borderline PTs, and p16 and pRb may be a useful combination of markers for distinguishing FA from benign PTs in core biopsy specimen.