Cystosarcoma Phyllodes and other Breast Sarcomas
PHYLLODES TUMORS ARE RARE fibroepithelial neoplasms that account for 0.3 to 1 per cent of all breast cancers in females. The term cystosarcoma phyllodes was coined by Johannes Muller in 1838 to describe the gross appearance of this "cystic, fleshy, leafy, tumor of the breast," which he clearly stated to be a benign tumor. Lee and Pack reported the first case of metastatic phyllodes tumor in 1931. Since then, metastatic disease has been noted to occur to the lung, pleura, axial skeleton, central nervous system, pancreas, duodenum, thigh, sacrum, and mandible.. The term cystosarcoma implies a relationship to cystic disease and tends to overstate the malignant potential of this lesion. Thus, cystosarcoma phyllodes is now felt to be a misnomer, and the World Health Organization now classifies this breast neoplasm as a phyllodes tumor (PT). (Breast sarcomas often appear quite large, see pic of angiosarcoma of breast and CT of the breast.)

The malignant counterpart of fibroadenoma is cystosarcoma phyllodes or the newer term of phyllodes tumor, in which the epithelial elements are benign, but the stromal tissue is malignant. It results from malignant degeneration of fibroadenoma, estimated to occur in 1% of patients, who have fibroadenoma for many years.

At presentation, most women are between 40 and 50 years with a typical presentation of a rapidly growing mass.

The phyllodes tumor has a lobulated, leaf-like appearance and varies in size from 1 cm to greater than 15 cm. Microscopically, the branching, hyperplastic ducts are surrounded by a stroma, which is mostly fibrous and much more cellular than fibroadenoma. In addition, nuclear atypia and increased mitotic activity occur.

The stromal components may contain liposarcoma, leiomyosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, angiosarcoma, chondrosarcoma and osteosarcoma. For this reason, it is important to adequately sample the neoplasm to determine whether ductal elements are present. In the absence of epithelial cells, the neoplasm is classified as primary stromal sarcoma of the breast, which is generally more aggressive than phyllodes tumor.

The clinical behavior of phyllodes tumor is unpredictable. The majority of phyllodes tumors are local problems and do not metastasize. Less than 20% of phyllodes tumors metastasize by vascular spread, most commonly to the lung, pleura, and bone. (Hart, 1978; Pietrusz, 1978). Thus, lymph node dissection is not indicated. Local recurrence is likely, if incompletely excised. Therefore, a wide local excision is required.

Some recent studies have attempted to separate cystosarcoma phyllodes into benign and malignant groups. The benign group is characterized by smooth, non-infiltrative borders and the fibrous elements have minimal nuclear atypia and low mitotic activity. This is in contrast to infiltrative borders, presence of nuclear atypia and increased mitotic activity usually greater than five mitotic figures per 10 high power fields in the malignant group (Hart et al; Pietrusz and Barnes). It should be mentioned that not all metastatic phyllodes tumors meet the above criteria. Thus, it is more appropriate to classify the phyllodes tumors into low and high grades and to treat these tumors with wide clear margins.

Diseases of the Breast
Editor(s): Harris, Jay R., Lippman, Marc E., Morrow, Monica, Osborne, C. Kent
3rd Edition 2004

Surgical Excision and Margins
The core principle of local therapy for phyllodes tumors, whether benign and malignant, is wide excision with negative margins, preferably more than 1 cm, to achieve definitive local control . Negative surgical margins independently predict improved disease-free survival and decreased local tumor recurrence. Mangi  found that recurrence correlated with excision margin, but not with tumor grade or size. In 40 patients, local recurrence occurred in 5, each who had margins less than 1 cm on initial excision or reexcision. These five patients remained disease free after reexcision with a 1-cm margin.The desired 1-cm margin width is based on retrospective analysis. Because these lesions are rare, any trial to study optimal margin width is impractical. A pseudocapsule of dense, compressed, normal tissue containing microscopic projections of the lesion commonly surrounds phyllodes tumors. As a result, more tissue typically needs to be removed to achieve the desired histologic 1-cm margin than might be predicted on the basis of preoperative physical examination or imaging findings. Some authors argue that 2 cm should be considered the standard desired surgical margin for excision of phyllodes tumors, and 2 to 3 cm once a phyllodes tumor locally recurs . In practice, margins of 2 to 3 cm can be difficult to achieve, except when the breast is quite large.

Breast-conservation Versus Mastectomy
In the M.D. Anderson experience of 101 patients with phyllodes tumors, surgery included local excision with breast conservation (47%) or mastectomy (53%). Microscopic surgical margins were negative in 99% of patients. Six patients received adjuvant radiotherapy. Local recurrence occurred in four patients, with an actuarial 10-year rate of 8%. The investigators concluded that local failure in this group of largely margin-negative patients with phyllodes of the breast was low, showing that breastconserving surgery with appropriate margins is the preferred primary therapy.
Some investigators recommend mastectomy for histologically aggressive lesions. Kok, Telesinghe  advocates breast-conserving surgery with adequate resection margin for benign and borderline lesions but recommend simple mastectomy without axillary dissection for malignant lesions. This distinction is based on clinical rationale rather than objective data. Kleer  found that histologically high-grade malignant phyllodes tumors have a favorable prognosis if widely excised without mastectomy. Most investigators have concluded that breast conservation is reasonable as long as margins more than 1 cm can be achieved, whether the lesion is benign, borderline, or malignant.

Reexcision following Narrow Margin Excision
Approximately 20% of phyllodes tumors recur locally if excised with no margin or with a margin of only a few millimeters . The proportion may be somewhat higher with borderline or malignant varieties and lower with benign phyllodes tumors. Nonetheless, authors' opinions differ over whether immediate reexcision is necessarily required when an unsuspected phyllodes tumor is diagnosed on permanent section after narrow-margin or no-margin excision. In a review of 106 patients with benign phyllodes tumors from Singapore, Chua, concluded that because only 16% of patients presumptively operated on for fibroadenoma develop a local recurrence, a policy of close follow-up may be acceptable. Zurrida  from Milan made a similar argument based on their series of 216 patients. With a mean follow-up of 118 months, they found that only 8% of benign lesions recurred (vs. 20% to 23% for borderline or malignant phyllodes tumors, respectively) and that these recurrences occurred significantly later following initial diagnosis (32 months vs. 18 to 22 months on average). On this basis, these authors suggest that a “wait-and-watch” policy for benign phyllodes tumors may be considered in place of mandatory surgical reexcision.

Technical Considerations in Lumpectomy
To achieve wide (?1 cm) surgical margins with lumpectomy, the surgeon may need to follow special “oncoplastic” approaches, particularly when a phyllodes tumor develops in a smaller breast. Tunneling through the fibroglandular tissue from a periareolar incision, though appropriate for a fibroadenoma biopsy, is contraindicated with phyllodes tumor excisions, because of the potential for tumor seeding in the tunneled bed. Even a standard curvilinear circumareolar incision directly over the mass without removal of skin may either be too small to obtain adequate surgical margins or leave excessive redundant skin behind when a large section of fibroglandular tissue is removed.
Like the quadrantectomy advocated by Italian surgeons for breast conservation in the 1980s, ample full-thickness excisions including skin and resection of glandular tissue down to chest wall muscle can be very helpful in increasing the surgical margins to the desired 1-cm width. To remove a generous amount of tissue around the phyllodes tumor, an incision can be designed to excise an island of skin immediately superficial to the phyllodes mass. This approach allows en bloc removal of skin, tumor, and surrounding fibroglandular tissue (Fig. 61.5B). The excision is then carried out full thickness from the skin island, widely around the mass, and down to and including the pectoral muscle fascia.
The remaining tissue defect typically requires a mastopexy flap advancement for closure, where fibroglandular breast tissue on each side of the residual tumor bed is widely mobilized and advanced across the tumor bed to close the tissue deficit, both at the level of the pectoral muscle and at the level just deep to the skin. This will improve the cosmetic result and prevent adhesion between the skin and muscle surface.

Axillary Dissection
Phyllodes tumors, like soft tissue sarcomas, are unlikely to have nodal metastases, making axillary dissection unnecessary in patients with phyllodes tumors. Although axillary nodes are palpable in 20%, fewer than 5% will have nodal metastases. In a series of 45 patients with phyllodes tumors who underwent axillary staging, none was found to have axillary metastases. Isolated cases of patients with gross nodal disease have been reported, albeit in association with locally advanced histologically aggressive disease . Thus, axillary dissection can be considered in the exceptional case with clinically suspicious axillary nodes, although minimally invasive nodal sampling is preferable, given the low-level likelihood of finding axillary disease.

Radiation and Systemic Therapy
Overall, the role of radiation therapy for phyllodes tumors has remained unclear. Clinical data supporting the use of adjuvant or neoadjuvant radiation and/or systemic therapy are based on anecdotal case reports as opposed to large patient series. No series has shown radiation therapy to be of benefit in the primary treatment of phyllodes tumors. The M.D. Anderson series did not support the use of adjuvant radiotherapy for patients with adequately resected disease.
Based on anecdotal experience, adjuvant radiation therapy may be appropriate treatment of locally recurrent phyllodes tumors in selected cases . Phyllodes tumors are so uncommon and biologically heterogeneous that no large series of locally recurrent phyllodes tumors is ever likely to be collected. Thus, individualized therapy choices must be made. For example, radiation therapy may be considered when phyllodes tumors recur following mastectomy. In these cases, adjuvant radiation therapy may be justified after reexcision, because any further local recurrence could be debilitating and difficult to treat, despite the absence of definitive proof of efficacy. Chest wall recurrence following mastectomy may demand extensive surgery such as multiple partial-rib resections with rigid chest wall methylmethacrylate reconstruction and myocutaneous flap coverage, which would be better avoided if possible.Anecdotal cases support the use of combined chemoradiation following phyllodes tumor recurrence. In a case study of a locally recurrent malignant phyllodes tumor, neoadjuvant hyperfractionated radiotherapy, superficial hyperthermia, and ifosfamide were administered after the second local recurrence of this tumor. Toxicity was reportedly mild. Resection of the tumor bed revealed a pathologically complete response, with an actual disease-free follow-up of 48 months. Although phyllodes tumors have been shown to variably express steroid receptors, there is no known value to adjuvant endocrine therapy with tamoxifen or aromatase inhibitors. There would be little rationale for using these drugs, because (a) steroid receptor protein expression decreases with increasing malignancy, (b) steroid receptors are primarily expressed by the epithelial component of phyllodes tumors, and (c) only the stromal component of phyllodes tumors metastasizes). Overall, the systemic treatment principles of phyllodes tumors are driven by similar principles to those governing the management of sarcoma. Chaney  observed that patients with stromal overgrowth, particularly when the tumor was larger than 5 cm, were found to have a high rate of distant failure. The authors suggest that such patients merit consideration of a trial that examines the efficacy of systemic therapy (2). Experimental data in a mouse xenograft model suggest that malignant phyllodes tumors may be sensitive to doxorubicin, vincristine, and cyclophosphamide. Burton  found that two of three patients with metastases achieved effective palliation when treated with cisplatin and etoposide combination chemotherapy. Ifosfamide may be an active agent for treatment of metastatic disease

Phyllodes tumors clinically resemble fibroadenomas with the following exceptions: (a) They tend to present in women about 10 years later than typical palpable fibroadenomas, (b) they are capable of rapid growth, and (c) in advanced cases, skin ulceration and open nonhealing wounds can occur. Clinical suspicion of phyllodes tumor based on clinical criteria (e.g., older age, rapid growth, or large tumor size) is important, because both imaging and tissue sampling have serious limitations with this tumor. When a phyllodes tumor is clinically suspected, mammograms and ultrasound evaluation are advised, although the imaging studies may fail to distinguish the phyllodes tumor from a benign fibroadenoma. Core needle sampling is preferable to FNA for preoperative tissue sampling, because fibroadenomas and phyllodes tumors have similar cytologic features. Even core needle sampling can misdiagnose phyllodes tumors, because their histology can resemble fibroadenomas, especially with low-grade benign phyllodes tumors. If core needle biopsy yields a diagnosis of phyllodes tumor and breast tissue is dense, breast MRI may be considered for assessment of associated pathology and extent of disease, as well as to serve as a baseline for surveillance.
Clinical management of phyllodes tumors consists of wide surgical excision to achieve surgical margins more than 1 cm to decrease the likelihood local recurrence in the breast. Wide resection of phyllodes tumors appears to be the most important aspect of therapy. When phyllodes tumors are excised with a narrow or no margin, reexcision should be performed, with the possible exception of benign phyllodes tumors in which reexcision is excessively difficult or deforming. Distant metastasis is uncommon, even with malignant phyllodes tumors, but is more common among tumors exhibiting stromal overgrowth. Histologic differentiation between benign, borderline, and malignant phyllodes tumors only loosely correlates with distant metastatic risk. Tumor markers (e.g., Ki-67, p53, ER, and PR) fail to predict long-term outcome and are not useful in clinical management questions.

The role of radiation therapy and systemic therapy is unproven and must be considered on a case-by-case basis. Radiation therapy has no role in the initial management of primary phyllodes tumors. However, phyllodes tumors that are initially excised with wide margins or mastectomy and that then recur locally may warrant adjuvant chest wall radiation after reexcision, because the high morbidity of second or third local recurrences from these locally aggressive lesions could be devastating. The role of systemic therapy remains unclear, because of lack of supportive clinical data other than from anecdotal reports. When used for treatment of metastatic disease, guidelines for treating sarcoma, rather than breast carcinoma, should be followed.

there is controversy about therapy, consider the following;

Cystosarcoma Phyllodes or Phyllodes Tumor.

This tumor is unique to the female breast. It should be clearly differentiated from a JUNEVILE FIBROADENOMA.

  • Clinical Presentation:   These tumors can be of any size but are usually diagnosed as a large, rapidly growing, bulky breast tumor (over 5 cm in size). They can occur at any age but is seen mostly in women in their fifties.

  • Mammographic Presentation: These tumors have the mammographic appearance of a fibroadenoma.

  • Diagnosis: The histological diagnosis is made by excisional biopsy. Most of these tumors are usually benign. However, a few can be malignant. We usually request that our pathologist classifies these tumors as, benign, malignant or borderline Cystosarcoma Phyllodes.

  • Treatment: The treatment of these tumors is surgical. As they have a significant rate of local recurrence, surgical local control is essential. For small benign cystosarcoma phyllodes, a wide local excision can be performed with meticulous, life long, post-operative monitoring. For large tumors or malignant / borderline tumors, a total mastectomy is the procedure of choice. No axillary lymphadenectomy is performed as the rate of axillary metastasis is less than 0.9%. Some authors have proposed a simultaneous sentinel lymphadenectomy; although this approach is reasonable, no guidelines have been set.

consider the following study which discusses the role of radiation:

An analysis of 78 breast sarcoma patients without distant metastases at presentation
S. McGowan, B.J. Cummings, B. O'Sullivan, C.N. Catton, N. Miller, T. Panzarella International Journal of Radiation Oncology*Biology*Physics, 46:2 : 383-390

Breast sarcoma is a rare tumor comprising less than 1% of breast malignancies. Recommendations for surgical treatment have been varied, with some advocating mastectomy , and others allowing that local excision may be acceptable therapy under certain conditions   Most authors have felt that nodal dissection is unnecessary.

A retrospective review of the experience at The Princess Margaret Hospital for the treatment of breast sarcoma was undertaken to correlate outcome with various patient and treatment factors.Purpose: A retrospective review of a single cancer center experience was undertaken to identify clinical or treatment prognostic factors for these unusual tumors, to allow for a recommendation regarding management.

Methods and Materials: The charts of 76 women and 2 men with breast sarcoma and without distant metastases at presentation registered from 1958 to 1990 were reviewed. Pathology was centrally reviewed in 54 cases. Histology, tumor size, grade, nodal status, age, menopausal status, history of benign breast disease, extent of surgery, resection margins, and radiation dose were each examined as potential prognostic factors by univariate analysis. To allow an analysis of radiation dose, total dose was normalized to a daily fraction size of 2 Gy.

Results: The median age at diagnosis was 50.5 years (13–82 years). The pathologic diagnosis was found to be malignant cystosarcoma phyllodes in 32 patients, with the remainder being stromal sarcoma (14), angiosarcoma (8), fibrosarcoma (7), carcinosarcoma (5), liposarcoma (4), other (8). Eighteen patients had grade I or II tumors, 43 had grade III or IV, and 18 were not evaluable. The 5- and 10-year actuarial rates for all 78 patients were 57% and 48% for cause-specific survival (CSS), and 47% and 42% for the relapse-free rates (RFR), respectively. The local relapse-free rate (LRFR) was 75% at both 5 and 10 years. The 5-year CSS for grade I or II tumors was 84% versus 55% for grade III or IV tumors (p = 0.01). Conservative surgery versus mastectomy did not lead to statistically significant different outcomes for CSS, RFR, or LRFR. The comparison of positive versus negative margins showed a 5-year LRFR of 33% versus 80% (p = 0.009). Pairwise comparisons of the 5-year CSS of 91% for > 48 Gy versus either 50% for le 48 Gy or 50% for no radiation showed p-values of 0.03 and 0.06, respectively.

Conclusion: The authors propose that if negative surgical margins can be achieved, breast sarcoma should be managed by conservative surgery with postoperative irradiation to a microscopic tumoricidal dose (50 Gy) to the whole beast, and at least 60 Gy to the tumor bed. The decision to treat should be preceded by a preoperative multidisciplinary assessment. It is also recommended that an axillary lymph node dissection is not indicated, with the possible exception of patients with carcinosarcoma.

The CSS, RFR, and LRFR experience, and median age at diagnosis found in this group of patients are consistent with the results reported elsewhere. With a 10-year CSS of 48%, a significant number of patients with this disease will survive; therefore, it would be helpful to be able to define a group of patients in whom a policy of breast conservation may be attempted. We have attempted to look carefully at the effect of completeness of resection, and adjuvant irradiation, as these have proven to be significant factors for sarcomas in other anatomic sites. Grade and size are such well-accepted prognostic factors for sarcomas that they are an integral part of the staging system for sarcoma as defined by the AJCC and UICC. In a historic series, we found grade to be significant for distant, but not local failure however, in more recent series, we, and others, have found that grade is an important prognostic factor for local and distant recurrence, as well as cause-specific survival. In the present series, we found that grade was statistically significant for CSS but not local control, which reflected a higher rate of distant failure for high-grade tumors. Despite the wide range of tumor sizes, size was not found to be an independent prognostic factor, for any endpoint on univariate analysis in this series, although it has been found to be an important prognostic factor in other anatomic sites.

Many authors have noted that virtually all recurrences and deaths from this disease occurred within 5 years. There was one patient who failed locally and distantly 21 years after presentation with what was felt to be recurrent disease. Excluding this one patient with a late failure, most patients recurred, and died within 5 years, and all did so by 7.5 years. All local failures were seen within 5 years.

We have elected to exclude benign cystosarcoma phyllodes, but to include all malignant histologic subtypes in our analysis. Some authors have excluded angiosarcoma, or cystosarcoma phyllodes  from an evaluation of breast sarcoma, while others have stated that malignant cystosarcoma phyllodes should be included in any review. The decision to include or exclude these specific histologies seems to be due to a belief about their behavior, rather than an observation that histology is a prognostic indicator independent of other factors such as grade. However, a prospective review of localized soft tissue sarcomas of the extremities by Pisters et al. has reported that the histologic subtypes leiomyosarcoma, liposarcoma, and malignant peripheral nerve tumors were independent prognostic factors for some end points. In our study, we found no prognostic significance to the histologic subtype, which is consistent with the generally held belief that histologic subtype is of minimal prognostic significance for sarcomas elsewhere; we would not advocate treating breast sarcoma patients differently based on histologic subtype, when grade and surgical margins are considered.

It is widely accepted that axillary lymph node involvement is uncommon in this group of patients, with most series reporting only occasional cases. Of 36 patients who had a nodal dissection, only 3 were found to have involved nodes, 2 of those 3 had carcinosarcoma, and the third had fibrosarcoma. In the patients with carcinosarcoma, only the epithelial component was found in the lymph node. In a separate series of 30 cases of breast sarcoma, 7 patients had clinically enlarged nodes, of which only 1 had pathologic involvement on node dissection. In a patient with a pure breast sarcoma, an axillary node dissection does not appear necessary. There may be some merit in performing an axillary dissection in patients with carcinosarcoma in light of our observation that 2 of 5 patients with this subtype had nodal metastases. One of 6 patients with carcinosarcoma had involved nodes in another series.

It is difficult to separate the issues of tumor size, extent of surgery, adequacy of margins, and postoperative irradiation in an evaluation of the most appropriate local therapy. In those patients with larger tumors, one might expect that clear margins would be more difficult to obtain, and it is those patients in whom it is likely that more aggressive surgery would be performed, and postoperative irradiation given. It was not possible to ascertain with accuracy if this sort of selection took place in our series. However, if that was the case, then it is reasonable to assume that those patients with larger tumors, those patients who received a higher dose of postoperative irradiation, and those patients who had a mastectomy would all do worse on univariate analysis. As would be expected, those patients who had positive margins had much worse local control. This relationship underscores the importance of obtaining negative surgical margins; however, it may be that the inability of a surgeon, using good surgical techniques, to obtain a negative margin, reflects the biology of the disease. The answer to the question of whether or not negative surgical margins are desirable is intuitively obvious, and consistent with our previous findings. However, the issue of the extent of surgery necessary, or the requirement for adjuvant irradiation, is not. There is no consensus on the recommendation for the extent of surgical therapy in the literature. Many authors have not found radiation to be of benefit, or have not commented on its use. while others have advocated mastectomy and radiation, or breast-conserving therapy in selected cases.We have not found any statistically significant difference in local control or survival between those patients treated with complete mastectomy or conservative surgery. We feel that in patients in whom negative surgical margins can be achieved, that breast conserving surgery is indicated. In our experience, a positive surgical margin predicted a higher rate of local failure; however, we did note that 2 of 3 patients who had microscopically positive margins after conservative surgery were controlled locally with radiotherapy. Two of 4 patients who had positive margins and radiotherapy failed locally, and 2 of 2 patients with positive margins who did not receive radiotherapy failed. This is compared to an overall local control rate of 80% in those patients with negative surgical margins. These results suggest that radiotherapy may be effective in reducing the risk of local relapse in patients with positive surgical margins, but that negative surgical margins give the best opportunity for local control. However, given the small number of patients in the positive margin group, conclusions must be interpreted with caution.

Our experience is consistent with the current understanding that sarcomas are no less radiocurable than epithelial tumors. Adjuvant radiation to a dose of at least 60 Gy in 6 weeks is a standard part of the therapy of many soft tissue sarcomas.. At our center, radiation is used for close margins, but is not routinely prescribed for margins of greater than or equal to 2 cm, or if a fascial plane separates the margin from the tumor. Given the fact that the standard dose of radiation delivered to patients with soft-tissue sarcomas is at least 60 Gy, it was not unexpected that there was little difference in the outcome between patients who did not receive radiation and those who received less than the normalized median dose of 48 Gy. When one examines the curves for local control versus dose, it can be seen that they separate, with the higher radiation dose patients having the best local control. However, the p-value was only 0.10 for the comparison of greater than 48 Gy versus less than 48 Gy. Statistical significance might have been achieved if there were more patients in the treatment groups, or if patient selection could be truly accounted for.Based upon the analysis presented in this paper, and the general acceptance of the principle of conservative management of soft tissue sarcoma where appropriate, we propose that if negative surgical margins can be achieved, breast sarcoma should be managed by conservative surgery with postoperative irradiation. The decision to treat should be preceded by a preoperative multidisciplinary assessment. Postoperative radiation should deliver a microscopic tumoricidal dose to the whole breast, and at least 60 Gy to the tumor bed. An axillary lymph node dissection is not indicated, except for patients with carcinosarcoma, due to the low incidence of metastatic lymph nodes observed in breast sarcoma patients.



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