Phyllodes tumors of the breast

INTRODUCTION — Phyllodes tumors are uncommon fibroepithelial breast tumors that are capable of a diverse range of biologic behaviors. In their least aggressive form, phyllodes tumors behave like benign fibroadenomas, although with a propensity to recur locally. At the other end of the spectrum, malignant phyllodes tumors can metastasize distantly, sometimes degenerating histologically into sarcomatous lesions that lack an epithelial component [1,2].

The term "phyllodes," which means leaf-like, describes the typical papillary projections that are seen on pathologic examination. Although they were originally called "cystosarcoma phyllodes" by Johannes Müller in 1838 [2], phyllodes tumors only occasionally have cystic components and are not true sarcomas by either cellular origin or biologic behavior. The terminology has since evolved, with over 60 synonyms having been applied to this entity before the term "phyllodes tumors" was adopted by the World Health Organization [3,4].

The clinical presentation, diagnosis, treatment, and prognosis of breast phyllodes tumors are discussed in this topic. Other benign (eg, fibroadenoma) or malignant lesions of the breast are discussed elsewhere. (See "Overview of benign breast diseases" and "Clinical features, diagnosis, and staging of newly diagnosed breast cancer" and "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

EPIDEMIOLOGY AND RISK FACTORS — Phyllodes tumors account for less than 1 percent of all breast neoplasms [4,5]. Given their rarity, epidemiologic data are scant. In a study from Los Angeles county over a 17 year period, the average annual incidence rate of malignant phyllodes tumors was 2.1 per million women, and the incidence was higher in the Latina White population than in the non-Latina White population, Asian population, and African American population [6].

The vast majority of phyllodes tumors occur in women, with a median age of presentation of 42 to 45 years (range 10 to 82 years) [3,6-8]. Higher-grade tumors are more common in older patients [9]. In men, phyllodes tumors usually occur in association with gynecomastia [3].

Phyllodes tumors have been associated with Li-Fraumeni syndrome, a rare autosomal dominant condition that is characterized by the development of multiple tumors [10]. In a contemporary multicenter cohort of 550 patients with phyllodes tumors, only 34 underwent expanded multigene panel testing; a deleterious mutation was identified in about 10 percent (1 BRCA1, 2 TP53); another two patients had a BRCA2 variant of uncertain significance [11]. The TP53 mutation prevalence in this cohort exceeded the published baseline mutation rate of 2 percent in the general population of women with a diagnosis of breast adenocarcinoma. (See "Overview of hereditary breast and ovarian cancer syndromes" and "Li-Fraumeni syndrome".)

No other etiologic or predisposing factors have been linked to phyllodes tumors.

CLINICAL PRESENTATION — Phyllodes tumors are usually identified as a breast mass. On examination, most patients have a smooth, multinodular, well-defined, firm mass that is mobile and painless [2,7]. Tumor size is variable, ranging from 1 to 41 cm (average 4 to 7 cm) [4,8]. Shiny, stretched, and attenuated skin may be seen overlying a large tumor [2]. Nipple retraction, ulceration, chest wall fixation, and bilateral diseases are rare but have been described for phyllodes tumors [2,12].

Phyllodes tumors may grow slowly or rapidly or exhibit a biphasic growth pattern. As they grow larger, phyllodes tumors can form a visible mass that distorts the contour of the breast or even cause pressure necrosis of the overlying skin.

Although palpable axillary lymphadenopathy can be identified in up to 20 percent of patients, most are reactive; metastatic involvement of lymph nodes with phyllodes tumor is rare [4,7].

DIAGNOSTIC EVALUATION

Diagnosis — Phyllodes tumors should be suspected when a patient presents with a large (>3 cm), rapidly growing breast mass that is usually palpable. Although imaging features of a phyllodes tumor can be suggestive of fibroadenoma, the large size and history of rapid growth indicate otherwise. Phyllodes tumors can only be diagnosed histologically. Breast masses suspicious for a phyllodes tumor should undergo percutaneous core needle biopsy, with some being diagnosed after surgical excision of presumed fibroadenomas.

Imaging — Phyllodes tumors can present as an abnormal finding on screening mammography. Suspicious lesions should be examined with breast ultrasound. Breast magnetic resonance imaging (MRI) may also be useful in select patients.

Mammography — Approximately 20 percent of phyllodes tumors present as a nonpalpable mass identified on screening mammography [13]. The typical appearance of a phyllodes tumor on mammography is a smooth, polylobulated mass resembling a fibroadenoma [2]. (See "Breast imaging for cancer screening: Mammography and ultrasonography" and "Diagnostic evaluation of suspected breast cancer".)

Ultrasonography — Patients with a palpable breast mass or suspicious lesion on mammography should have an ultrasound examination. Phyllodes lesions are primarily solid, hypoechoic, and well circumscribed on ultrasonography. Suspicion for a phyllodes tumor, rather than a fibroadenoma, is based on clinical features such as large tumor size at presentation and rapid growth [2]. Although not always present, cystic areas within the mass on ultrasonography may increase the level of suspicion for phyllodes tumors [14].

Magnetic resonance imaging — Phyllodes tumors and fibroadenomas cannot be reliably differentiated by breast MRI [15]. However, when a phyllodes tumor has been diagnosed on core biopsy, breast MRI may help determine the extent of disease and resectability in selected cases [16]. However, the routine use of breast MRI in surgical planning for phyllodes tumors is controversial and not supported by data.

Malignant phyllodes tumors are seen as well-circumscribed tumors with irregular walls, high signal intensity on T1-weighted images, and low signal intensity on T2-weighted images [17]. Cystic change may be seen as well. A rapid enhancement pattern is seen more commonly with benign rather than malignant phyllodes tumors, which is the opposite of the pattern seen with adenocarcinomas of the breast [17,18].

Biopsy — Breast lesions suspicious for phyllodes tumors should undergo core biopsy, which is typically diagnostic. Compared with core biopsy, fine needle aspiration (FNA) is less accurate. If the core biopsy results are indeterminate or if there is clinical-pathologic discordance, an excisional biopsy should be performed.

Fine needle aspiration — In general, FNA has been associated with a high false negative rate and low overall accuracy for the diagnosis of phyllodes tumors [19]. Some experts, however, advocated paying special attention to three major cytological features (fibromyxoid stromal fragments with spindle nuclei, fibroblastic pavements, and spindle cells of fibroblastic nature) to improve the accuracy of FNA [20].

Core needle biopsy — On core needle biopsy, additional features can help distinguish phyllodes tumors from fibroadenomas. Such features include increased cellularity, mitosis, stromal overgrowth, and fragmentation (stroma with epithelium at one or both ends of the fragment). (See 'Histologic' below.)

Excisional biopsy — If the result of a core biopsy is indeterminate or discordant, an excisional biopsy is required. A core biopsy diagnosis of "cellular fibroadenoma," "cellular fibroepithelial lesion," or "fibroepithelial lesion with cellular stroma" should prompt surgical excision of the lesion, regardless of its appearance on imaging studies. Further pathologic characterization of the lesion may reveal a phyllodes tumor. Additionally, core biopsy has a 25 to 30 percent false negative rate when used to diagnose phyllodes tumors [21-23]. Thus, if a solid mass has a benign core biopsy but subsequently grows rapidly or becomes symptomatic, an excisional biopsy is also indicated.

Pathology

Gross — Grossly, phyllodes tumors may be indistinguishable from fibroadenomas. They are round to oval multinodular masses with a grayish-white appearance that resemble the head of a cauliflower (picture 1) [2]. Phyllodes tumors grow radially, creating a pseudocapsule through which tongues of stroma may protrude and grow into adjacent breast tissue [24]. Necrosis and hemorrhage can occur in larger tumors [2].

Microscopic — Microscopically, the range of appearances covers the spectrum from resembling a benign fibroadenoma to a high-grade sarcoma. The characteristic leaf-like architecture consists of elongated cleft-like spaces that contain papillary projections of epithelial-lined stroma with varying degrees of hyperplasia and atypia (figure 1) [3]. The stromal elements are a key component in differentiating phyllodes tumors from fibroadenomas and in differentiating a benign tumor from a malignant one [24]. (See 'Histologic' below.)

Histologic — Histologically, phyllodes tumors are classified as benign, borderline, or malignant based upon the assessment of four features [2,4,6,7,25-28]:

●The degree of stromal cellular atypia

●Mitotic activity

●Infiltrative or circumscribed tumor margins

●Presence or absence of stromal overgrowth (ie, presence of pure stroma devoid of epithelium)

Benign tumors are characterized by increased stromal cellularity with mild-to-moderate cellular atypia, circumscribed tumor margins and low mitotic rate (less than 4 mitoses per 10 high-power fields), and lack of stromal overgrowth.

Borderline tumors have a greater degree of stromal cellularity and atypia, a mitotic rate of 4 to 9 mitoses per 10 high-power fields, microscopic infiltrative borders, and lack of stromal overgrowth.

Malignant tumors are characterized by marked stromal cellularity and atypia, infiltrative margins, high mitotic rate (more than 10 mitoses per 10 high-power fields), and the presence of stromal overgrowth [4,7,27-29].

Of the four histologic features listed above, stromal overgrowth is most consistently associated with aggressive (metastatic) behavior [1,30]. Most clinically malignant/metastatic phyllodes tumors have had overgrowth of one or several sarcomatous elements. These elements include liposarcoma, rhabdosarcoma, chondrosarcoma, and undifferentiated/unclassified sarcoma [31,32].

Undifferentiated/unclassified sarcoma was previously included within the terms of "malignant fibrous histiocytoma (MFH)" and "undifferentiated pleomorphic sarcoma (UPS)" but is now a separate soft tissue sarcoma category with an undifferentiated pleomorphic variant [33]. Close examination of the stroma is imperative as the sarcomatous component may be present in only a small portion of the tumor [34]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Histopathology'.)

Although the exact figures vary, more than 50 percent of phyllodes tumors are classified as benign and 25 percent as malignant in most large studies [1,2,35-37].

Histologic grades of phyllodes tumors have clinical implications and thus it is critical to have an accurate assessment. The College of American Pathologists developed a protocol to evaluate resection specimens of phyllodes tumor to standardize these classifications [38]. Patients with benign tumors generally have better local control and disease-free survival compared with those with borderline or malignant tumors [39]. Benign and borderline phyllodes tumors rarely recur following wide excision [40]. (See 'Breast surgery' below.)

Clinical behaviors of phyllodes tumors can also be influenced by factors other than histologic grades [1,8]. In a study of 605 cases of phyllodes tumors, stromal atypia, mitoses, overgrowth, and surgical margin status (defined as complete, focally involved, and diffusely involved) were shown to be independent predictors of recurrence, with surgical margin status being the most important. A nomogram was developed by the use of a mathematical formula that could be applied to an individual patient to guide clinical decision making [41].

Molecular — In phyllodes tumors, the status of tumor markers, such as p53, Ki-67, epidermal growth factor receptors, c-kit, and platelet-derived growth factor, has failed to predict outcomes [34]. The expression of estrogen and progesterone receptors is common in the epithelial but not the stromal component of phyllodes tumors [12].

On a molecular level, genetic heterogeneity has been observed intratumorally, with increasing numbers of aberrations coinciding with increased malignant potential [42]. Some believe that phyllodes tumors arise from benign epithelial fibroadenomas due to their close histologic resemblance and molecular similarities [2,3,43]. As an example, molecular analysis showed high frequencies of MED12 (mediator complex subunit 12) mutations in both fibroadenomas and phyllodes tumors [44]. In one study of 112 breast phyllodes tumors, MED12 mutations were detected in 65, 66, and 43 percent of benign, borderline, and malignant phyllodes tumors, respectively [45]. In another study using targeted next-generation sequencing, malignant phyllodes tumors were shown to harbor additional mutations in key tumor suppressor genes and oncogenes, such as TP53, RB1, NF1, and CAN [46]. Although controversial, some thought that the acquisition of additional mutations explains the aggressive biological behaviors of malignant phyllodes tumors.

TREATMENT — Phyllodes tumors should be completely excised; axillary lymph node dissection is not necessary. Adjuvant radiation therapy may benefit borderline or malignant, but not benign, tumors. Adjuvant chemotherapy is reserved for highly selected patients with large, high-risk, or recurrent malignant phyllodes tumors. Hormonal therapy is not used to treat phyllodes tumors. Given the rarity of the disease, treatment principles are based mainly on retrospective series and case reports.

Surgical resection

Breast surgery — A complete surgical excision is the standard of care for phyllodes tumors. Current National Comprehensive Cancer Network (NCCN) guidelines recommend excisional biopsy for benign phyllodes tumors and wide excision with intention of obtaining surgical margins of 1 cm or more for borderline and malignant phyllodes tumors, with a statement that a narrow margin is not an absolute indication for mastectomy when partial mastectomy fails to achieve a margin width of 1 cm or more [47].

Margins — Phyllodes tumors should be completely excised because most [40,48-53], but not all [37,54,55], studies have associated positive margins with unacceptably high local recurrence rates. In a multivariate survival analysis that included 172 patients with phyllodes tumors, a positive surgical margin was associated with an almost fourfold higher risk of a tumor-related event such as local recurrence or distant disease (hazard ratio [HR] 3.9, 95% CI 1.1-14.3) [49]. Positive margins often occur when phyllodes tumors are misdiagnosed as fibroadenomas and either enucleated or locally excised without attention to margins [4,5,13,14,25,39,40,50,56-59].

However, the minimal acceptable margin beyond "clear" is controversial and depends on tumor grade [13,48,49,60]:

●For benign phyllodes tumors, we aim for a clear margin but do not require a wide (eg, 1 cm) margin.

Furthermore, emerging evidence suggests that a positive surgical margin may not be related to local recurrence for benign phyllodes tumors [61]. A 2019 meta-analysis of 54 observational studies also found that a positive margin only correlated with a higher local recurrence risk for malignant, but not for benign and borderline, phyllodes tumors [29]. Consequently, it has become controversial whether a negative margin should be strictly obtained for a benign phyllodes tumor [37,62-64]. Some authors advocate only a "grossly complete excision," arguing that it would make re-excision of benign phyllodes tumors unnecessary when they are mistaken for fibroadenomas on core biopsy and excised with narrow margins or enucleated, as long as no gross tumor is left behind and regardless of microscopic margin status [65]. This approach was also favored according to a Canadian National Consensus document after extensive review of available literature [66]. Despite the controversy, however, it appears safe to accept a clear margin for benign phyllodes tumors without mandating re-excision for margins narrower than 1 cm.

●For borderline or malignant phyllodes tumors, we also aim for a 1 cm margin. However, for patients with a clear but narrower than 1 cm margin, we determine the need for re-excision on a case-by-case basis.

Surgical margins of ≥1 cm have been associated with a lower local recurrence rate in borderline and malignant phyllodes [1,4,57]. In a retrospective review of 48 women with high-grade malignant phyllodes tumors, 10 patients were treated with local excision (margins <1 cm), 14 with wide local excision (margins ≥1 cm), and 24 with mastectomy [50]. At a median follow-up of nine years, the local recurrence rate was higher after local excision with narrow margins than after wide local excision (60 versus 28 percent). Local recurrence and cancer-specific survival were related to tumor size and excision margins. The average tumor size was 7.8 cm in this study. In another review of 125 malignant/borderline phyllodes tumors surgically treated at an academic cancer center, the 10-year locoregional recurrence rate was 12 percent. Patients with close (<1 mm) or positive margins after surgery had a 33 percent 10 year locoregional recurrence rate, compared with 9 percent in those with negative margins, highlighting the importance of achieving at least a 1 mm margin after lumpectomy or mastectomy to minimize the risk of local recurrence [53].

A multi-institutional cohort of 550 phyllodes tumors treated between 2007 and 2017 at 11 comprehensive cancer centers in the United States demonstrated wide variability in the management of margins for phyllodes tumors among surgeons with instances of omission of re-excision not only for close but also for positive margins. Interestingly, on univariate analysis, positive margins and margins <2 mm were not associated with local recurrences when evaluating all three subtypes together. Multivariate analysis was not feasible, due to the small number of local failures. The authors conclude that these data suggest a shift toward less stringent margin recommendations on phyllodes tumors and a more individualized approach to margin management, which is supported by Canadian consensus guidelines [37,66].

Breast-conserving surgery versus mastectomy — There are limited data comparing breast-conserving surgery with mastectomy in the treatment of phyllodes tumors. However, where adequate margins can be achieved and adjuvant radiation therapy given, breast-conserving surgery seems to be as effective as total mastectomy in treating malignant phyllodes tumors [1,4,13,67].

In a study of 821 women with malignant phyllodes tumors from the Surveillance, Epidemiology, and End Results (SEER) database, mastectomy and wide local excision were performed in 52 and 48 percent, respectively [13]. Compared with mastectomy, breast-conserving surgery was associated with equivalent or improved cause-specific survival regardless of tumor size.

Mastectomy is generally not indicated for benign phyllodes unless the tumor is so large that breast-conserving surgery would result in suboptimal cosmetic outcomes.

Axillary surgery — Axillary lymph node involvement by phyllodes tumors is rarely reported, even when tumors are malignant [5,7,13,37,58,68]. In the SEER database study cited above, only 8 of 498 women with known lymph node status had involved nodes [13]. Thus, axillary surgery is rarely indicated in patients diagnosed with phyllodes tumors.

Radiation therapy — When adequate surgical margins cannot be achieved because of tumor location, adjuvant radiation therapy (RT) should be administered, even after mastectomy. However, when adequate surgical margins can be achieved, there is less agreement about the need for adjuvant RT. We base our decision about adjuvant RT on tumor grade:

●We do not suggest adjuvant RT for patients with benign phyllodes tumors that have been completely excised.

●We suggest adjuvant RT for all patients undergoing breast-conserving surgery for a borderline or malignant phyllodes tumor as it substantially reduces local recurrence rates [27,28,36,39,57,68,69].

In a meta-analysis of eight observational studies, adjuvant RT reduced local recurrences of borderline or malignant phyllodes tumors after breast-conserving surgery (HR 0.31, 95% CI -0.10 to 0.72) [70]. The effect of adjuvant RT on local recurrences after mastectomy was less pronounced (HR 0.68, 95% CI -0.28 to 1.64). Another meta-analysis of 17 studies concluded that radiation is effective in decreasing local recurrence over surgery alone [71].

Adjuvant RT has not been shown to improve survival compared with surgery alone. In a meta-analysis of eight observational studies, adjuvant RT had no effect on overall or disease-free survival [70]. In a retrospective analysis of 3080 patients analyzed using the National Cancer Database, radiation did not improve overall survival [72]. In a retrospective analysis using the SEER database, although there was no benefit in terms of overall survival for the group as a whole, there was a trend toward a survival benefit with the addition of adjuvant radiation in the subgroup of patients with tumors larger than 5 cm [73,74].

In clinical practice, the utilization of adjuvant RT for phyllodes tumors appears to be modest. In a retrospective review of the National Cancer Database that included 3120 patients with malignant phyllodes tumors, only 14 percent received adjuvant RT [75]. Patients were more likely to receive radiation therapy if they were diagnosed later in the study, were 50 to 59 years old, had tumors >10 cm, or had lymph nodes removed. In adjusted models, adjuvant radiation reduced local recurrence but did not impact survival after a median follow-up of 53 months.

Chemotherapy — Based on limited data, the role of systemic chemotherapy in phyllodes tumors is limited. Patients with benign or borderline phyllodes tumors are usually cured with surgery and should not be offered chemotherapy unless they develop unresectable metastases, which is exceedingly uncommon.

The role of adjuvant chemotherapy in malignant phyllodes tumor is controversial and should not be routinely offered. Malignant phyllodes tumors are pathologically and clinically most similar to soft tissue sarcomas; however, localized malignant phyllodes tumors have a better prognosis than most high-grade sarcomas of similar stage [76]. Thus, systemic chemotherapy should be considered for malignant phyllodes tumors with even more caution.

There have been no randomized studies of adjuvant chemotherapy specifically for phyllodes tumors. In a small observational study, 28 patients with malignant phyllodes tumors were treated with either adjuvant doxorubicin plus dacarbazine or observation alone after surgical resection based upon patient preference [77]. Although the five-year relapse-free survival was not different between the two groups, the study was retrospective, nonrandomized, and underpowered. It did not utilize ifosfamide in combination with doxorubicin (which is superior to dacarbazine plus doxorubicin in other soft tissue sarcomas).

Based on experience and limited data, we recommend adjuvant chemotherapy only to a small minority of patients with high-risk (>10 cm) or recurrent malignant phyllodes tumors who have excellent functional status and minimal comorbidities, and only after a thorough discussion about the risks, benefits, and controversial nature of such treatment. When systemic chemotherapy is indicated, malignant phyllodes tumors should be treated according to protocols designed for soft tissue sarcoma, such as an anthracycline plus ifosfamide, rather than breast cancers. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

Hormone therapy — Hormone therapy is not effective against phyllodes tumors [12,78]. Despite the presence of hormone receptors in the epithelial component of some phyllodes tumors, the stromal component is the principle neoplastic cell population responsible for the metastatic behavior. The stromal component primarily expresses estrogen receptor beta instead of estrogen receptor alpha, which is expressed by breast cancer [79,80].

POSTTREATMENT SURVEILLANCE — Given the small number of patients with malignant phyllodes tumors of the breast, there are no evidence-based recommendations for surveillance after therapy [81,82]. The following follow-up guidelines are adapted from those for soft tissue sarcoma (see "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Posttreatment sarcoma surveillance'):

●Since most recurrences occur in the first two years after treatment [57], we perform a history and physical examination every six months for the first two years, then annually until five years. For patients with borderline and malignant phyllodes tumor, more frequent surveillance of the affected breast may be warranted. (See 'Local recurrence' below.)

●Patients with large (≥5 cm) or malignant phyllodes tumors are at higher risk of developing metastatic disease. For such patients, surveillance may be performed more frequently and with chest radiograph or chest computed tomography (CT) as recommended by the National Comprehensive Cancer Network (NCCN) on soft tissue sarcomas [83]. (See 'Metastatic disease' below.)

●Patients who have not had mastectomy should resume routine breast surveillance. If suspicious lesions are found on imaging or breast examination, further imaging and/or biopsy may be required. (See 'Imaging' above.)

RECURRENT AND METASTATIC DISEASES

Local recurrence — Despite best surgical efforts, phyllodes tumors are known to recur locally with rates that vary with tumor grade. In earlier reports, benign, borderline, and malignant phyllodes tumors had local recurrence rates of 8, 21, and 36 percent, respectively [40,57]. More contemporary series reported lower rates of local recurrence [84]. As an example, a 2019 meta-analysis of 54 retrospective studies reported an overall local recurrence rate of 12 percent (95% CI 10-14 percent) and pooled local recurrence rates of 8, 13, and 18 percent for benign, borderline, and malignant tumors, respectively [29]. In the previously mentioned multi-institutional cohort of 550 phyllodes tumors treated between 2007 and 2017 at 11 comprehensive cancer centers in the United States, local recurrences occurred in 1.3 percent of benign, 5.6 percent of borderline, and 6.9 percent of malignant phyllodes tumors with a median follow-up of 36.7 months [37]. Recurrent phyllodes tumors require surgical and/or radiation therapy. (See 'Treatment' above.)

When phyllodes tumors recur, they typically recur locally within two years of the initial excision [4,12]. Some series have found that the time to local recurrence was shorter for malignant than for benign or borderline tumors [4,34,40].

Although recurrences typically have the same grade as the original tumors, there have been several case reports of benign tumors transforming into malignant ones upon recurrence [1,8,36,85]. In one series of 293 phyllodes tumors, for example, six benign tumors recurred locally as malignant tumors [8]. A systematic review of 54 retrospective studies reported some 26 percent (range 13 to 38) of benign and 21 percent (8 to 33 percent) of borderline tumors that recurred underwent upgrade [29].

Recurrent phyllodes tumors are treated with surgery and/or radiation, with the goal of avoiding re-recurrence and the need for additional surgical intervention. Resectable recurrent disease is treated with either re-excision with wide margins or mastectomy, followed by radiation therapy (RT). Unresectable recurrences are treated with palliative radiation alone [14]. (See 'Surgical resection' above and 'Radiation therapy' above.)

Metastatic disease — Metastatic disease has been reported in 13 to 40 percent of patients with phyllodes tumors [1,2,4,19]. The median overall survival ranges from approximately 11 to 24 months in patients who develop metastatic disease [86,87].

Phyllodes tumors metastasize most often to the lungs, although given their hematogenous spread, bones and nearly all organs can be affected. Tumors that metastasize are typically large (≥5 cm) or have malignant histologic features (see 'Histologic' above):

●In a series of 101 patients, eight developed distant metastases, seven of whom had malignant tumors and one benign [1]. All tumors had stromal overgrowth, and six were ≥5 cm in size.

●In another retrospective review of 293 phyllodes tumors treated between 1954 and 2005, five patients developed distant disease. All tumors that metastasized had one or more malignant histologic features such as infiltrative borders, marked stromal overgrowth, marked stromal cellularity, high mitotic count, and necrosis and were ≥7 cm in size [8].

For patients with metastatic disease, chemotherapy may be administered with palliative intent based upon treatment guidelines for soft tissue sarcomas [4,88].

●Most regimens have limited or short-lived benefit, with the highest levels of efficacy seen in doxorubicin and alkylating-based therapies [86,89].

●Two malignant phyllodes-specific case series reported highest response rates to an anthracycline given in combination with ifosfamide (45 and 56 percent), but with a limited median progression-free survival (5.7 and 9.1 months) [90,91].

●Other regimens such as single agent anthracycline or ifosfamide, gemcitabine-based regimens, trabectedin, and tyrosine kinase inhibitors yielded lower rates of activity [90,91].

Given the paucity of efficacious agents in the metastatic setting, patients should be referred for investigational treatments in clinical trials [86]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

Similar to metastatic soft tissue sarcoma, there may be a role for metastasectomy in select cases with oligometastatic disease. As an example, pulmonary metastases of phyllodes tumors should be resected when technically feasible in the appropriate context. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

SURVIVAL — The majority of patients with benign and borderline phyllodes tumors are cured by surgery. The survival rate for malignant phyllodes tumors is approximately 60 to 80 percent at five years [1,13,56].

●The impact of histology on survival was explored in the SArcoma and PHYllode Retrospective (SAPHYR) Study, a retrospective study of 70 patients with primary breast sarcomas and phyllodes tumors treated from 1966 to 2004 [56]. The overall three-year survival rate for combined benign and borderline tumors was 100 percent. The overall three-year survival rate for malignant phyllodes tumors was 54 percent, similar to that of nonangiosarcoma primary breast sarcomas (60 percent).

●Similarly, in a retrospective study of 101 patients treated between 1944 and 1998, the five-year overall survival rate for patients with benign/borderline and malignant tumors was 91 and 82 percent, respectively [1].

●In a contemporary series of 125 malignant/borderline phyllodes tumors surgically treated at an academic cancer center, uniformly poor pathologic features, including stromal cellularity, stromal overgrowth, infiltrative borders, and ≥10 mitoses per 10 high-powered fields, were identified in 20 percent of malignant phyllodes tumors and predicted for a poor prognosis, with all distant recurrences occurring in this group and with a 63 percent 10 year disease-specific survival. The 10 year disease-specific survival for malignant/borderline phyllodes patients without uniformly poor pathologic features was 100 percent [53].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Evaluation of breast problems".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Phyllodes tumors are uncommon fibroepithelial breast tumors that are capable of a diverse range of biologic behaviors. Most phyllodes tumors present as smooth, multinodular, painless breast lumps. While they can be confused for fibroadenomas, phyllodes tumors typically have larger sizes and grow rapidly. Twenty percent of phyllodes tumors present as abnormal findings on screening mammography. (See 'Introduction' above and 'Clinical presentation' above.)

●Imaging – The typical appearance of a phyllodes tumor on mammography is a smooth, polylobulated mass. On ultrasound examination, these lesions are solid, hypoechoic, and well circumscribed. The presence of cystic areas within the mass may increase the level of suspicion for phyllodes tumors. (See 'Imaging' above.)

●Biopsy – Breast masses suspicious for phyllodes tumors should undergo core biopsy; fine needle aspiration is less accurate. If the core biopsy results are indeterminate or if there is clinical-pathologic discordance, an excisional biopsy should be performed. (See 'Biopsy' above.)

●Surgical excision – A complete surgical excision is the standard of care for all phyllodes tumors; however, the minimal acceptable margin beyond "clear" depends on tumor grade (see 'Breast surgery' above):

•For benign phyllodes tumors, we aim for a clear margin. A wide (eg, 1 cm) negative margin is not required. 

•For borderline or malignant phyllodes tumors, we suggest a 1 cm negative margin (Grade 2C). However, we will determine whether to re-excise to a 1 cm negative margin on a case-by-case basis.

●No routine axillary dissection – For most patients with phyllodes tumors, we suggest not performing routine axillary dissection (Grade 2C). Axillary lymph node involvement is rare, even with malignant tumors. (See 'Surgical resection' above.)

●Adjuvant radiotherapy – Following surgical excision of a phyllodes tumor, the need for adjuvant radiotherapy also depends on tumor grade (see 'Radiation therapy' above):

•For benign phyllodes tumors that are completely excised, we suggest not performing adjuvant radiotherapy (Grade 2C).

•For borderline or malignant phyllodes tumors, we suggest performing adjuvant radiotherapy, even after a complete excision (Grade 2C). Radiation therapy substantially reduces the local recurrence rates of these tumors.

●Adjuvant chemotherapy – The role of adjuvant chemotherapy in phyllodes tumors is reserved for highly selected patients. Chemotherapeutic agents should be chosen based upon treatment guidelines for soft tissue sarcomas, rather than breast cancer. (See 'Chemotherapy' above.)

●No hormonal therapy – Hormone therapy is not effective against phyllodes tumors. (See 'Hormone therapy' above.)

●Posttreatment surveillance – We perform a history and physical examination every six months for two years after the initial treatment of phyllodes tumors, then annually until five years. Patients at higher risk for developing metastatic diseases (≥5 cm or malignant tumors) may require more frequent surveillance with chest radiograph or chest computed tomography (CT) per guidelines for soft tissue sarcoma. (See 'Posttreatment surveillance' above.)

●Recurrence and metastasis – Locally recurrent phyllodes tumors that are resectable should undergo wide re-excision followed by adjuvant radiotherapy. Unresectable recurrences are palliated with radiation therapy. Resectable pulmonary metastasis should be resected; unresectable metastatic phyllodes tumors are palliated with chemotherapy according to soft tissue sarcoma protocols. (See 'Recurrent and metastatic diseases' above.)

●Survival – The majority of patients with benign and borderline phyllodes tumors are cured by surgery. The survival rate for malignant phyllodes tumors is approximately 60 to 80 percent at five years. (See 'Survival' above.)