A Germline SETD2 Variant and Malignant Phyllodes Tumor: Extending the Spectrum of SETD2-Related Tumor Predisposition

Objective: 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.Method: 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.Results: 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.Conclusion: 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.

Real-world data on malignant and borderline phyllodes tumors of the breast: A population-based study of all 921 cases in the Netherlands (1989 −2020)

Increased p53 Protein Expression in Malignant Mammary Phyllodes Tumors

We read the case study by Frias et al. about a 54-years-old woman with a left breast phyllodes tumor (PT) with 2024 g and 30.0 x 28.0 x 19.5 cm, infiltrating the skin and the papillary areolar complex, that evolved during six years before the mastectomy 1 .Grossly, the tumoral mass presented with a grayish color, irregular edges, imprecise limits, and a nodular ulcerated surface, being classified as T4BN0M0 and 7 IIIB 1 .Histopathologic study showed an epithelial component with intraductal hyperplasia, and a mesenchymal component of numerous atypical spindle cells with irregular nuclei 1 .Immunohistochemistry revealed CD34, Ki-67, P53 protein, actin alpha-smooth muscle, CD10/CALLA Ab-2, and cytokeratin estrogen and progesterone receptors positivity 1 .The authors stressed the successful management with the zetaplasty repair for the scar closure, and the unusual follow-up without recurrence of a severe and advanced tumor 1 .In this setting, the aim of the following short comments on more recent literature is enhancing the awareness of non-specialists about this uncommon challenging tumor [2][3][4][5][6][7][8][9][10] .Chen et al. reviewed data of 1902 women with diagnoses of malignant PT of breast between 2000 and 2019 with a median follow-up of 87.5 months; and mastectomy occurred in 898 (47.2%) cases including 210 undergoing radiotherapies after surgery 2 .Age did not independently predict cause-specific survival (CSS) in tumors larger than 10 cm; mastectomy had worse CSS compared with conserving surgery in tumors smaller than 10 cm; and conserving surgery got better survival for the small tumors (T1 or T2) 2 .The authors concluded that treatment should be selected based on different tumor sizes 2 .Chen et al. reviewed recurrences and metastases of PT from 2008 to 2022; among 82 cases, 69 were malignant and 13 were borderline tumors, 96.3% had surgical treatment 3 .The median follow-up was 55.5 months, 20 patients had metastasis within 3 years in over than 80% of cases, and 32 had recurrence without deaths due to disease progression 3 .The survival was related to surgical method, tumor size and biological behavior; besides, the combination of antiangiogenic drugs improved the mean progression-free survival; while lactate dehydrogenase was an independent prognosis predictor for malignant PTs 3 .Hashmi et al. reviewed 146 biopsy-proven cases of PTs submitted to lumpectomy or mastectomy, and results were classified into benign, borderline, and malignant tumors 4 .PTs mean age was 40.65 12.17 years, the mean size was 9.40 6.49 cm, malignant PTs were more prevalent (43.2%), followed by borderline (34.9%) and benign (21.9%) 4 .Patients with malignant and borderline PTs were of older age groups (mean 42.82 12.94 and 42.05 11.31 years, respectively) than the benign PTs (mean age 34.12 9.75 years); and the malignant had larger (mean 11.46 6.08) sizes compared with the others types 4 .Ruan et al. studied a new stage-and age-stratification system and prognostic model for malignant PT, comparing 1085 patients with 382,718 invasive ductal carcinomas 6 .New T stage 1: tumor < 49 mm in greatest dimension; new T stage 2: tumor size: 49 mm, but < 100 mm in greatest dimension; new T stage 3: tumor size 100 mm in greatest dimension; and new T stage 4: tumor of any size with direct extension to the chest wall or to skin; new stablished Age Groups were: 1) age < 71 years, and 2) age 71 years 6 .They stressed the role of multi-data verification to survivalprediction of the new model.Sain et al. analyzed data of patients previously diagnosed or presented with PTs from 1996 to 2021, 87 patients presented with PTs, and 46 (52.87%) had actual recurrences 7 .All were females, with a mean age of 39 (15-70) years; those aged <40 years had the highest incidence of recurrence (54.35%), followed by the aged >40 years (45.65%);55.4% of PTs were primary and 44.6% recurrent at presentation; the mean time to local recurrence from the treatment end was 13.8 months, and to systemic was 15.29 months; the authors highlighted the adjuvant radiotherapy favoring a minimal recurrence of PT 7 .Sars et al. performed a survey from July 2021 to February 2022 involving sixteen countries in four

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.

Phyllodes tumor (PT) is a rare breast biphasic tumor with a potential risk of recurrence and metastasis. In this study, the frequency of MED12 mutations in 176 PTs (49 benign, 49 borderline, and 78 malignant) was determined and the prognostic effect of these mutations in malignant type PT was evaluated. Analysis of MED12 mutations was performed by Sanger sequencing targeting the hotspot mutation region (exon 2) of MED12. Immunohistochemistry was also applied for evaluation of MED12 protein expression on tissue microarray blocks for 133 PTs including 50 benign, 50 borderline, and 33 malignant cases. A notable difference in the frequency of MED12 mutations was found according to histologic grade (71.4% of benign PTs, 51% of borderline PTs, 26.9% of malignant PTs; P < 0.001). MED12 protein expression was not correlated with MED12 mutation status. Patients with malignant PTs that harbored MED12 mutations demonstrated improved disease-free survival (DFS) compared with those without MED12 mutation (P = 0.07). MED12 mutation was a common molecular alteration in PT and the frequency of MED12 mutation decreased with increasing histologic grade. In malignant PT, MED12 exon 2 mutations showed improved DFS but without significance. © 2016 Wiley Periodicals, Inc.

Malignant phyllodes tumor of the breast with metastases to the lungs: A case report and literature review

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

Phyllodes tumor (PT) is a rare fibroepithelial lesion of the breast with variable malignant potential. Black women have a higher incidence of a related benign tumor, fibroadenoma, but there are limited epidemiological data on PT. The aim of our study was to evaluate race-related differences in the clinicopathologic features and outcomes of PT. Our institutional pathology database was queried for breast specimen reports from 01/2009 to 10/2019 to identify patients with a pathologic diagnosis of PT. Chart review and detailed slide review were performed to obtain clinical and histopathologic variables, respectively. Among twelve patients, two had malignant PT, three had borderline PT, and seven had benign PT. All patients with malignant and borderline PT were black, compared with 29% of those with benign PT. There were no apparent race-related differences in specific histopathologic features among black vs. non-black women with benign PT. Malignant and borderline PT were relatively larger than benign PT, with mean tumor sizes of 9.0cm (standard deviation [SD] 4.7cm), 12.2cm (SD 9.4cm), and 5.4cm (SD 5.8cm), respectively. Two women had a local recurrence, both of whom were black. In this single-institution retrospective study, we observed disproportionate rates of aggressive histopathologic features and disparate outcomes among black women with PT. A multi-institutional PT registry would facilitate improved knowledge about race-related differences in the presentation and outcomes of this rare tumor.

Introduction Phyllodes tumor (PT) is an uncommon fibroepithelial neoplasm of the breast. It is a biphasic tumor with stromal and epithelial components, with a tendency to recur. Because of its wide range of disease manifestations, it has been subclassified into three categories, i.e., benign, borderline, and malignant, based on several histological parameters. This study was conducted to evaluate the clinicopathological features associated with malignancy in breast PTs. Methods We conducted a retrospective study at the Department of Histopathology at Liaquat National Hospital, Karachi, Pakistan. A total of 146 biopsy-proven cases of PTs were enrolled in the study. Clinical data were obtained from the clinical referral forms. Specimens were obtained from either lumpectomy or simple mastectomy. The specimens obtained were received at the laboratory where after gross examination, paraffin-embedded tissue blocks were prepared, which were sectioned, stained, and studied by a senior histopathologist. Pathological features, such as mitotic count, necrosis, stromal atypia, stromal overgrowth, and heterologous elements, were observed. Based on these features, the PTs were classified into benign, borderline, and malignant tumors. Results The mean age of the PTs in our setup was 40.65 ± 12.17 years with a mean size of 9.40 ± 6.49 cm. Malignant PT was found to be the most prevalent in our population, accounting for 63 (43.2%) cases, followed by borderline (51, 34.9%) and benign (32, 21.9%). A significant association was found between the tumor subtype and patient age, i.e., patients diagnosed with malignant and borderline PTs were found to be of older age (mean 42.82 ± 12.94 and 42.05 ± 11.31 years, respectively) than those diagnosed with benign PTs (mean age 34.12 ± 9.75 years). Moreover, malignant PTs were associated with larger tumor size (mean 11.46 ± 6.08) compared with the other two subtypes. Conclusion We found a significant association among patient age, tumor size, and PT subtype. Therefore, apart from the usual histological parameters, patient age and tumor sizeare important parameters for predicting the behavior of breast PT and should be considered for management.

Malignant phyllodes tumors are rare fibroepithelial breast neoplasms. Appropriate surgical management remains a subject of debate. The purpose of our study was to define optimal surgical treatment and to identify factors associated with outcome. After confirmatory pathology review, we identified 67 patients with borderline (n = 15) and malignant (n = 52) phyllodes tumors treated at our institution between 1971 and 2008. We used Cox proportional hazards models to evaluate associations between treatment, patient and tumor characteristics, and disease-free (DFS) and cancer-specific survival (CSS). Median patient age was 47 years. For 32 patients, definitive surgical treatment was wide local excision (WLE): 27 with margins ≥1 cm and 5 with margins <1 cm. Thirty-five underwent mastectomy. Two patients received radiotherapy after WLE and two after mastectomy with microscopically positive margins. After 10 years median follow-up, 16 patients (24 %) recurred locally (8 postmastectomy and 8 after WLE). Treatment type and margin extent did not impact local recurrence. Fifteen patients (22 %) developed distant disease. Overall 5-year DFS was 67.9 % and CSS 80.1 %. Tumor size >5 cm, mitotic rate ≥10/10 HPF, stromal overgrowth and cellularity (all p < 0.05) predicted DFS, whereas CSS was associated with the latter three variables. CSS was diminished for mastectomy patients who were significantly more likely to harbor tumors with adverse features. With long-term follow-up, extent of surgical resection did not affect DFS for patients with borderline and malignant phyllodes tumors. Tumor features, most notably stromal overgrowth, were predictive of recurrence and survival, suggesting these high-risk patients may benefit from additional therapeutic strategies.

A 47-year-old woman presented with a 1-year history of a palpable, asymptomatic breast mass. Her medical history was unremarkable. There was no family history of breast carcinoma. Her only medication consisted of oral contraceptives, and she was a nonsmoker. A solitary mass occupied most of the upper outer quadrant of the left breast. No axillary lymphadenopathy was identified. There were no palpable abnormalities of the right breast.The patient underwent ultrasound-guided core biopsies of the left breast, with the results suggestive of a malignant fibroepithelial neoplasm. A segmental mastectomy revealed a 5 × 5 × 5-cm, well-circumscribed, firm, and predominantly tan mass (Figure 1). This mass contained large clefts with leaflike projections, foci of tumor necrosis, and multiple areas that grossly resembled adipose tissue (arrow). Histologic examination of the tumor revealed a high-grade, malignant phyllodes tumor (PT) that was characterized by a pushing border and epithelial-lined clefts with hypercellular stromal overgrowth (Figure 2). The pleomorphic neoplastic stroma demonstrated a brisk mitotic rate and contained univacuolated and multivacuolated lipoblasts with hyperchromatic, pleomorphic, and scalloped nuclei (Figure 3). These areas resembled pleomorphic liposarcoma. No other sarcomatous elements were identified. The tumor was completely excised, and the patient remains well and disease free 16 months after surgery.Sarcomatous elements, including angiosarcoma, chondrosarcoma, leiomyosarcoma, osteosarcoma, and rhabdomyosarcoma, are rarely encountered in malignant PTs.1 Liposarcomas may also develop as stromal components of PTs. Liposarcomatous differentiation in PTs may consist of well-differentiated, myxoid, round cell, and pleomorphic liposarcomatous elements.23 Powell and Rosen3 described a series of 14 PTs with adipose differentiation that consisted of a single benign PT with lipomatous metaplasia (lipophyllodes tumor), 7 low-grade malignant PTs, and 6 high-grade malignant PTs. These tumors were all unilateral breast masses that developed in women with a mean age of 40 years. Mean tumor size was 4.0 cm. High-grade malignant PTs demonstrated large areas of stromal overgrowth that contained round cell and pleomorphic liposarcoma. No tumor recurrences were seen in the malignant PTs with adipose differentiation.3 The only tumor recurrence occurred when an incompletely excised lipophyllodes tumor recurred a year later as a high-grade malignant PT with pleomorphic liposarcomatous elements. In a series of 7 PTs with liposarcomatous elements, described by Austin and Dupree,2 only 1 patient experienced local tumor recurrence that developed 1 year after local excision.The clinical behavior of malignant PTs is difficult to predict. Liposarcomatous differentiation in malignant PTs, however, does not appear to equate with aggressive clinical behavior.23 Phyllodes tumors with liposarcomatous differentiation, like other PTs, require complete surgical excision to prevent local tumor recurrence.

Background: We aimed to explore prognostic risk factors in patients with malignant phyllodes tumors (PTs) of the breast and construct a survival prediction model.Methods: The Surveillance, Epidemiology, and End Results database was used to collect information on patients with malignant breast PTs from 2004 to 2015. The patients were randomly divided into training and validation groups using R software. Univariate and multivariate Cox regression analyses were used to screen out independent risk factors. Then, a nomogram model was developed in the training group and validated in the validation group, and the prediction performance and concordance were evaluated.Results: The study included 508 patients with malignant PTs of the breast, including 356 in the training group and 152 in the validation group. Univariate and multivariate Cox proportional hazard regression analyses showed that age, tumor size, tumor stage, regional lymph node metastasis (N), distant metastasis (M) and tumor grade were independent risk factors for the 5-year survival rate of patients with breast PTs in the training group (p < 0.05). These factors were used to construct the nomogram prediction model. The results showed that the C-indices of the training and validation groups were 0.845 (95% confidence interval [CI] 0.802–0.888) and 0.784 (95% CI 0.688–0.880), respectively. The calibration curves of the two groups were close to the ideal 45° reference line and showed good performance and concordance. Receiver operating characteristic and decision curve analysis curves showed that the nomogram has better predictive accuracy than other clinical factors.Conclusion: The nomogram prediction model constructed in this study has good predictive value. It can effectively assess the survival rates of patients with malignant breast PTs, which will aid in the personalized management and treatment of clinical patients.

BackgroundA giant phyllodes tumor of the breast is a rare fibroepithelial lesion, and its treatment is controversial. Many case reports have reported performing skin graft reconstruction after tumor excision. Chest wall resection may be required if the tumor has invaded the chest muscle layer. We speculated that transcatheter arterial chemoembolization (TACE) can improve the resectability of malignant phyllodes tumor of the breast without requiring skin grafting. The English literature contains only one case report similar to our experience.Case presentationWe report a rare case of a 51-year-old woman who had a giant malignant phyllodes tumor with heterologous sarcomatous differentiation in her right breast. The tumor was 19.43 × 12.98 × 21.47 cm. Whole-body computed tomography (CT) and bone scan did not reveal distant metastasis. Chest magnetic resonance imaging showed chest wall tumor invasion. Considering that skin defects after mastectomy can be extensive, we administered four courses of chemoembolization in the 5 weeks before surgery (30 mg of epirubicin and embozene microspheres [400, 500, and 700 μm]/week). Each process was well tolerated, with no serious complications. Only fever and local pain at the tumor site were noted, and these symptoms resolved with time. The follow-up CT scan showed a 45% reduction in tumor volume. Therefore, simple mastectomy was performed without skin grafting reconstruction. Wound healing was satisfactory, and the patient was discharged 1 week after surgery. Pathological and immunohistochemistry (IHC) findings showed a malignant phyllodes tumor with an angiosarcoma component. Because of tumor invasion of the chest wall, we recommended the patient receive radiotherapy, but she refused. Two months after surgery, recurrence of the malignant phyllodes tumor with right axillary lymph node involvement and lung metastasis was confirmed.ConclusionInitial surgical resection of giant phyllodes tumors is often challenging. For initial presentation with unresectable giant phyllodes tumor, we recommend to perform TACE prior to surgery. In our patient, preoperative TACE was effective and safe. If the tumor has invaded the chest wall, early radiotherapy after surgery may be recommended for preventing recurrence.

Breast phyllodes tumors (PTs) are biphasic, with epithelial and stromal components. Although the PT incidence is low (approximately 1% of all breast tumors), its clinical outcomes are unpredictable, and malignant PTs often progress rapidly. No effective treatment is currently available, thus resulting a high mortality rate from malignant PTs. PT cell lines must be established to facilitate the study of PTs. Herein, we established six PT cell lines through continuous passage or cell immortalization. We characterized these PT cell lines through in vitro functional assays, malignant PT marker detection and short tandem repeat identification. Benign PT cell lines (SYSH-BPT-01 and SYSH-BPT-02) were transfected with human papillomavirus 16 E6/E7, and two malignant PT cell lines (SYSH-MPT-01 and SYSH-MPT-02) were transfected with Simian virus 40 large T antigen. Two malignant PT cell lines (SYSH-MPT-03 and SYSH-MPT-04) were established through continuous passage. All malignant PT cell lines showed greater proliferation, colony formation, migration, invasion and collagen contraction ability than the benign PT cell lines. Moreover, the expression levels of malignant PT markers (α-smooth muscle actin and fibroblast activation protein) and short tandem repeat identification indicated that each PT cell line was identical to the parental primary cells. We successfully established PT cell lines that preserved the features of primary cells. These cell lines may serve as ideal experimental models for studying the function of breast PTs, thus opening new possibilities for PT drug screening and therapeutic target validation.