Histologic features predict local recurrence after breast conserving therapy of phyllodes tumors

Background: 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.Study Design: 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.Results: 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.Conclusions: 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.     

乳腺复发性叶状肿瘤临床病理分析

目的:探讨乳腺复发性叶状肿瘤临床及病理特征。方法:收集2011年01月至2019年12月在我院进行手术治疗的叶状肿瘤病例,并找出其中复发的病例,分析复发病例的临床及病理组织学特征。结果:叶状肿瘤137例,共有10例为复发病例,其中9例为单次复发,1例复发两次,复发病例中良性叶状肿瘤7例,交界性叶状肿瘤2例,恶性叶状肿瘤1例。所有的肿物均为局部复发,良性、交界及恶性叶状肿瘤复发率分别为5.9%、15.4%、20%。其中3例（30%）出现组织学升级,1例良性叶状肿瘤复发为交界性叶状肿瘤,1例交界性叶状肿瘤复发为恶性叶状肿瘤,1例良性叶状肿瘤第一次复发为交界性叶状肿瘤,第二次复发为恶性叶状肿瘤。免疫组化标记CD117、CD34、CD10、p53、p16在原发及复发肿瘤中表达无差异。Ki67增殖指数在复发病例中均升高,并且核分裂数也增多。结论:良性、交界性、恶性叶状肿瘤均可复发,其中恶性叶状肿瘤复发率最高,肿瘤多为局部复发,部分肿瘤复发后出现组织学升级,复发后肿瘤细胞增殖活性增强。     

Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression

Phyllodes tumors of the breast are rare fibroepithelial neoplasms with a potential for recurrence. Current histological classification is not always predictive of clinical behavior. The aim of this study was to identify genetic changes associated with the development of borderline and malignant phyllodes tumors in an Asian population, and to assess if genetic data supported the categorization of these tumors into the existing three grades of benign, borderline, and malignant. Expression profiling of 21 phyllodes tumors (6 benign, 10 borderline, 5 malignant) was performed using Affymetrix U133Plus 2.0 GeneChips^®. Gene expression among benign, borderline, and malignant tumors was compared and a 29 gene list was able to classify them according to their histologic grade. Among these 29 genes are those responsible for matrix formation, cell adhesion, epidermis formation, and cell proliferation. Comparative genomic microarray analysis showed that the most common chromosomal alteration associated with borderline and malignant tumors was 1q gain, and an increasing number of chromosomal changes was noted with increasing histological grade. Upregulation of HOXB13 was seen in malignant relative to borderline phyllodes tumors and further investigated by immunohistochemistry in a corresponding set of formalin-fixed, paraffin-embedded tumors. HOXB13 protein overexpression was found to be correlated with stromal hypercellularity and atypia (P = 0.03, P = 0.039, respectively) and may be implicated in the development of malignant phyllodes tumors.     

Chromosomal aberrations and genetic relations in benign, borderline and malignant phyllodes tumors of the breast: a comparative genomic hybridization study

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.     

Management of non metastatic phyllodes tumors of the breast: review of the literature

Phyllodes tumors of the breast are rare tumors, accounting for less than 0.5% of all breast tumors. These tumors are comprised of both stromal and epithelial elements; and traditionally they are graded by the use of a set of histologic features into benign, borderline, and malignant subtypes. Unfortunately, the histologic classification of phyllodes tumors does not reliably predict clinical behavior.The mainstay of treatment of non metastatic phyllodes tumors of the breast is complete surgical resection with wide resection margins. Lumpectomy or partial mastectomy is the preferred surgical therapy. However, despite the complete surgical resection, local failure rate may be high; and 22% of malignant tumors may give rise to haematogenous metastases. The most frequent site of distant metastases is the lungs. Several predictive factors of recurrence and metastases have been described in the literature, such as positive surgical margins, increased stromal cellularity, stromal overgrowth, stromal atypia and increased mitotic activity.Nevertheless, the role of adjuvant therapies (radiotherapy and chemotherapy) is presently undefined and should be tested in multicenter, prospective, randomized trials.     

Malignant phyllodes tumor of the breast: review of the literature and case report of stromal overgrowth

Cystosarcoma phyllodes constitutes only 0.3-0.9% of all breast tumors. The term "sarcoma" was initially used because of its fleshy appearance, a more modern term is Phyllodes tumor (PT). The behavior of PT constitutes a spectrum from benign and locally recurrent to malignant and metastatic. In a general surgical series, 6.2% of the tumors were malignant. The microscopic appearance of PT is that of epithelial elements and connective tissue stroma. Malignancy is determined by characteristics of the stroma. The metastatic spread of malignant PT is mainly hematogenous to lung, with infrequent lymphatic involvement. Wide local excision with 2 cm margins is the treatment of choice. In 20% of both benign and malignant cases, PT will locally recur. There is no proven benefit of radiation or chemotherapy, although radiotherapy may be useful in selected cases. We present a case of a sarcomatous overgrowth in a malignant phyllodes tumor involving multiple histologic types.     

Genome-Wide Analysis for Loss of Heterozygosity in Primary and Recurrent Phyllodes Tumor and Fibroadenoma of Breast using Single Nucleotide Polymorphism Arrays

Summary 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.     

乳腺叶状肿瘤的X线表现

目的探讨乳腺叶状肿瘤X线影像学特点,并与其病理对照,以提高对该病的诊断准确率。方法回顾性分析经手术病理证实有完整乳腺X线资料的乳腺叶状肿瘤50例共54个病灶,其中良性26个、交界性22个、恶性6个。结果 54个病灶中表现为伴或不伴钙化的肿块50个(92.6%),假阴性4个(7.4%)。50个肿块病变中良性23个、交界性21个、恶性6个。形状以分叶状、圆形或卵圆形最多见,分别占62.0%(31/50)、10.0%(5/50)、26.0%(13/50)。肿块边缘主要表现为清楚或部分清楚部分模糊,占80%(40/50),其余肿块呈浸润状及细小分叶状边缘,分别占18.0%(9/50)和2.0%(1/50)。肿块表现为高密度占74.0%(37/50),等密度占26.0%(13/50)。3个病灶肿块内含有钙化。边缘特征在良性与恶性肿瘤、交界性肿瘤与恶性肿瘤之间有明显差异,P_(良-恶)=0.003,P_(良-恶)=0.044。结论乳腺叶状肿瘤主要X线表现为分叶状或圆形、卵圆形的高密度肿块,钙化少见;边缘特征可在一定程度上提示良恶性叶状肿瘤的区别。     

Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors

Mammary phyllodes tumors are uncommon stromal-epithelial neoplasms, and are divided into benign, borderline malignant and frankly malignant groups on the basis of their histological features. Accumulating evidence shows that epidermal growth factor receptor (EGFR) is involved in the pathogenesis and progression of many malignancies. This study investigated 453 phyllodes tumors (296 benign, 98 borderline, 59 malignant) for EGFR expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for gene amplification. The staining was correlated to tumor margin status, degree of malignancy, stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. Cases with strong positive IHC staining were selected for FISH. The overall positive rate for EGFR was 16.2% (48/296), 30.6% (30/98) and 56% (33/59) for benign, borderline malignant and frankly malignant phyllodes tumors, respectively. FISH demonstrated egfr gene amplification in 8% of immunohistochemically positive cases. The results of this study provide strong evidence that EGFR overexpression is involved in the pathogenesis of phyllodes tumors, although gene amplification may not be the major underlying mechanism for overexpression.     

Metastatic Phyllodes Tumor Causing Small-Bowel Obstruction

Cystosarcoma phyllodes is an important but relatively uncommon fibroepithelial breast neoplasm that accounts for 0.5%–1.0% of female breast carcinomas. Malignant forms comprise nearly 25% of cases. These usually metastasize to the lung, pleura, bone, and liver. Metastases to the small intestine are extremely rare, with only 1 case of metastatic spread to the duodenum reported in the literature. No previous reports of metastatic spread to the ileum have been published. This report highlights a unique case of a metastatic phyllodes breast tumor leading to small bowel obstruction. Phyllodes tumors are generally classified into histologic subtypes of benign, intermediate, and malignant, using agreed classification systems. The tumor characteristics that can lead to the dedifferentiation of a relatively benign phenotype to an overt malignant process are discussed. Chemotherapeutic regimens that might be effective treatments are discussed, and the importance of regular clinical and radiologic follow-up in patients with poor prognostic factors is outlined.     

Cystosarcoma phyllodes of the breast: a case report in a 12-year-old girl

Breast tumors in adolescents are very rare and mostly benign. Fibroadenomas are the most frequent, but within the extensive differential diagnosis, the phyllodes tumor must be mentioned, which accounts for about 1% of breast tumors and the diagnosis of which is very rare in patients younger than 20 years. There are no specific symptoms or radiological images to distinguish phyllodes tumor from fibroadenoma; therefore, histological examination is mandatory for diagnosis. Histology also allows the classification of phyllodes tumor into benign, borderline, or malignant types for appropriate surgical treatment: freemargin excision in benign tumors and mastectomy in the other two types. Fortunately, the majority of these tumors are benign, and treatment maximizes breast conservation with free infiltration margins surgery, given that this fact is the most important factor to prevent local recurrence. In this article, we describe a rare case of borderline cystosarcoma phyllodes in a 12-year-old girl.     

Jejunal intussusception due to malignant phyllodes tumor of the breast

Phyllodes tumors are rare fibroepithelial neoplasms of the breast; classified as benign, borderline, or malignant based on the mitotic activity, cellular atypia, and stromal overgrowth. Wide surgical excision is the treatment of choice. The most common locations for metastasis are lung, bone, and liver; small intestinal metastasis is extremely rare. Here we present the first patient with jejunal metastases and intussusception due to malignant phyllodes tumor of the breast. Adjuvant treatment of malignant phyllodes tumor needs to be investigated.     

乳腺叶状肿瘤的诊断及治疗

目的探讨乳腺叶状肿瘤的诊断和治疗.方法对经手术和病理诊断的48例乳腺叶状肿瘤的临床病理资料进行回顾性分析.结果48例中平均年龄为43.2岁.根据肿瘤生长方式,瘤细胞异型,核分裂和肿瘤坏死进行乳腺叶状肿瘤分级,良性26例,交界性12例,恶性10例.全部病例采用手术治疗,肿瘤单纯切除术23例,良性、交界性、恶性复发分别为3/18、2/3、2/2;肿瘤扩大切除术15例,良性、交界性、恶性复发分别为0/8、1/5、1/2;乳房切除术10例,交界性、恶性复发转移分别为0/4、2/6.结论乳腺叶状肿瘤可分良性、交界性和恶性三种类别,确诊和分级主要依靠病理组织检查.提示首次肿瘤彻底切除是治疗的关键,应根据组织分级及肿瘤大小决定手术方式.     

Small sized phyllodes tumor of the breast

From 1970 to 1988, 106 women (aged 13-63 years) suffering from phyllodes tumor of the breast underwent surgery at the Day Hospital in the Istituto Nazionale Tumori, Milan. Treatment consisted of enucleation in 57, enucleoresection in 42 and wide resection in seven. Ninety-two cases (86.8%) were benign, 12 (11.3%) borderline and two malignant. All the borderline and malignant tumors were submitted to wider resection as inpatients. The 12 borderline cases underwent wide resection while a subcutaneous mastectomy was performed in the two malignant cases. A mean follow-up of 49 months was carried out on 85 patients (range 1-186). The relapses, all in the benign group (6 cases; 6.52%), were much lower than reported by other authors (20-33%). This may be related to neoplasia size (less than 40 mm in 85.3%) and not to type of limited surgery. Although limited surgery was performed in 93.4% of cases (pre-operative diagnosis being unknown) the number of relapses was so low that re-operation with wider resection in healthy glandular tissue was not justified. However it is still performed in borderline and malignant phyllodes. The natural history of this tumor requires a prolonged follow-up since relapses may occur many months after operation (in our series 52).     

Comparison of Clinical Characteristics Between Benign Borderline and Malignant Phyllodes Tumors of the Breast

Background: Phyllodes tumors of the breast are rare fibroepithelial lesions, so relatively little is known aboutthis disease entity. The present study was designed to identify differences in clinical features between benignborderline and malignant phyllodes tumors. Materials and Methods: Data from 246 women with phyllodestumors of the breast treated in Cancer Hospital Chinese Academy of Medical Sciences between 2002 and 2012were collected and analyzed, including age at presentation, age at treatment, course, size of primary tumor,location, histological type, type of surgery and treatment, local recurrence, distant metastasis, fibroadenomahistory, disease-free survival and number of mitosis per 10hpf. There are 125 (55%) benign, 55 (24%) borderlineand 47 (21%) malignant tumors. Results: In univariate analysis, average age at presentation, average age attreatment, size of primary tumor, ulceration or not, type of primary surgery, distant metastasis and number ofmitosis per 10 hpf turned out to be statistically different among the three PT types (p=0.014, 0.018, <0.000, 0.003,<0.000, 0.001 and <0.000, respectively), while recurrence and disease-free survival (DFS) demonstrated trendsfor statistical significance (P =0.055 and 0.060, respectively). Multivariate analysis revealed distant metastasisand excision were significantly different in benign, borderline and malignant phyllodes tumors of the breast(p=0.041 and 0.018, OR=0.061 and 0.051). At the same time, size of primary tumor with p=0.052 tended to bedifferent between groups (OR=1.127). However, age at treatment, ulceration and DFS showed no statisticallysignificant variation (p=0.400, 0.286 and 0.413, respectively). Conclusions: Benign borderline and malignantphyllode tumors have different distant metastasis risk, different primary tumor size and different surgicalprocedures, and malignant PTs are more likely to be bigger and to metastasize.     

Phyllodes tumors of the breast: natural history, diagnosis, and treatment

Phyllodes tumors of the breast are unusual fibroepithelial tumors that exhibit a wide range of clinical behavior. These tumors are categorized as benign, borderline, or malignant based on a combination of histologic features. The prognosis of phyllodes tumors is favorable, with local recurrence occurring in approximately 15% of patients overall and distant recurrence in approximately 5% to 10% overall. Wide excision with a greater than 1 cm margin is definitive primary therapy. Adjuvant systemic therapy is of no proven value. Patients with locally recurrent disease should undergo wide excision of the recurrence with or without subsequent radiotherapy.     

Cystosarcoma phyllodes: a clinicopathologic analysis of 42 cases.

A retrospective clinicopathologic evaluation of 42 patients with cystosarcoma phyllodes was undertaken to determine if tumor size, contour, degree of stromal atypia and mitotic activity were reliable indicators of clinical behavior. Excluding size, the latter three determinants showed a positive correlation with prognosis and served as the basis of a classification in which 18 benign, 5 borderline and 19 malignant cystosarcomas were diagnosed. The tumors occurred in women averaging 44.3 years of age who most often presented with a palpable occasionally painful mass with a median diameter of 5 cm. Excision or simple mastectomy were the more frequent forms of therapy. Local recurrences were experienced by 6 patients and occurred in all 3 categories of tumor. Only malignant neoplasms developed systemic metastases which was observed in 4 patients 3 of which have died. On borderline tumor recurred 14 times and eventually proved fatal as a result of contiguous pulmonary involvement. A plea is made to label the stroma of malignant cystosarcomas as to the cell(s) of origin so future investigators may evaluate the effect of various soft tissue patterns on prognosis.     

乳腺叶状肿瘤局部复发的临床风险因素分析

目的分析乳腺叶状肿瘤局部复发的临床风险因素。方法使用SPSSCox比例风险模型分析2002年12月至2008年12月中国医科大学附属第一医院66例乳腺叶状肿瘤患者各种临床风险因素与局部复发的关系。单因素分析采用X2检验。结果本组患者的发病年龄为17—83岁（中位年龄41岁）,良性40例,交界性24例,恶性2例。局部复发15例,其中12例复发发生于区段切除术。在不同手术方式、不同组织学等级的叶状肿瘤患者之间,复发率的差异均有统计学意义（P〈0．05）。手术方式为保护因素（RR=0．151）,扩大切除术和乳房切除术者的复发风险较区段切除术者下降至66／1000和53／1000;组织学等级为危险因素（RR=5．803）,恶性和交界性叶状肿瘤患者的局部复发风险分别为良性肿瘤者的12．26倍和4．37倍。结论恶性程度高和手术方式选择不当影响预后。叶状肿瘤以手术治疗为首选,应选择切除范围扩大的手术方式,尤其是对恶性程度高的患者。     

Histologic examination of two cases of cystosarcoma phylloaes with pulmonary metastases

BACKGROUND: Cystosarcoma phyllodes (CP) is a rare neoplasm of the breast. Many studies of the histology of CP have been reported. However, few reports have included an evaluation of the histologic appearance of pulmonary metastases, or the change in histologic grade as a function of time in patients with recurrent tumors. METHODS: We treated two patients with pulmonary metastases, CP from 1973 to 1995. One patient died of respiratory failure. The other underwent six operations for CP. We evaluated the histologic characteristics of these metastases and changes in the histologic grade of recurrent tumors. RESULTS: The primary lesions in these two cases were typical high-grade malignant tumors. Case 1 had multiple pulmonary metastases and histologic findings indicated typical malignant CP. Case 2 had a solitary pulmonary metastasis and histologic findings showed low-grade malignant CP, which could be resected. The first patient died of respiratory failure ten months after surgery. The second had no further pulmonary metastases although she had frequent local recurrences, and the histologic features of these tumors became progressively worse. CONCLUSION: We suggest that patients with malignant CP be followed closely and that when pulmonary metastases are detected, they should be resected if possible, because pulmonary metastatic tumors may represent lower-grade malignant CP.     

乳腺叶状肿瘤17例诊疗分析

目的:探讨乳腺叶状肿瘤的治疗原则和影响预后因素。方法:对经手术和病理诊断确诊的17例乳腺叶状肿瘤的临床资料进行回顾性分析。结果:17例患者中良性叶状肿瘤9例,交界性叶状肿瘤5例,恶性3例。行局部肿块切除7例,单纯乳房切除术6例,改良根治术3例,姑息性肿块切除术1例。其中随访13例,平均随访时间21(5~84)个月,1例行乳腺癌改良根治术后2.5年死于远处转移,2例行局部肿块切除术后复发。结论:乳腺叶状肿瘤的预后与手术方式有关,良性和交界性应首选扩大区段切除术,切除肿瘤边缘不少于2cm;复发的交界性和恶性应尽早行单纯乳房切除术。