Phyllodes breast tumor Joint Hospital Surgical Grand Round 26 April 2014 Ng Yuen Shan, Sandy (Tuen Mun Hospital)

Phyllodes tumor Rare fibroepithelial breast tumor (1% of all breast tumors, 2.5% of all fibroepithelial tumors) A spectrum of disease Epithelial and cellular stromal component Histological classification: Benign (60%) Borderline (20%) Malignant (20%)  distant metastasis

Median age of presentation at 40-50 years Palpable mass with rapid growth, large size (>2cm) Poor pre-operative diagnostic accuracy Triple assessment, in patients with phyllodes tumors, all three methods individually have low sensitivity and, even in combination, the diagnostic accuracy is often poor because mammary phyllodes tumors rarely develop and their clinical, imaging and cytology and histology findings are similar to those of fibroadenomatous breast tumor, which has a high incidence.

Case scenario Margin POSITIVE F/40 2.5cm L12H breast mass, interval growth. MMG/US: well-circumscribed lobulated mass FNAC: benign. Excisional pathology: Benign phyllodes tumor Margin POSITIVE

Pok Oi Hospital A review of 28 consecutive patients with phyllodes tumour excision in 2009-2012 in Pok Oi Hospital 11 operations performed for recurrent phyllodes tumour (6 patients) have been excluded. Recurrence 1-5 (mean = 2.5) Recurrence = 5: benign PT with close margin; 1st recurrence at 5mths; total 5 recurrences in 2.5 yrs

Operation type Indication Total no. Margin +ve Simple enucleation Benign breast mass 5 3 (60%) Wide local excision Clinical/ pathological diagnosis of phyllodes tumour 20 2 (10%) Mastectomy Large tumor-breast ratio, or suspicious malignant 4 1 (25%) Preoperative histology favour phyllodes tumor = 65.5% (19/29) 60% of the patients treated with simple enucleation had margin involvement, including the patient who suffered from recurrence. On the other hand, 10% (2/20) of wide local excisions and 25% (1/4) of mastectomies resulted in positive margin.

Margin status and histological grade   Involved Touch/ close <1 cm >/= 1 cm Malignant 2 4 Borderline 1 3 Benign Margin was involved in 6 specimens. 6 were described as touch or close, and 10 were measured to be less than 1 cm. 3 were measured to be more than or equal to 1 cm. 4 were described as clear. Close follow-up

Margin-involved outcomes   Age Grade Tumour size (cm) Primary Operation FU duration (months) Lost to FU Reoperation Patient A 63 Malignant 3.2 WLE 48 No Patient B 11 Mastectomy 18 Patient C 42 Borderline 6 14 Mastectomy for co-existing DCIS Patient D 50 Benign 7.5 Enucleation 57 Wide local excision for recurrent phyllodes Patient E 21 3.5 35 Yes Patient F 40 2.2 47 1 recurrence case: normal P/E; detected by MMG/US for FU other breast imaging abnormalities (3 years post-op) 6 cases, heterogeneous, difficult conclusion Malignant margin +ve: reoperation not done as the margin is not marked Mean FU period: 36 months

POH case series Results: Local recurrence rate in margin-involved = 16.7% No recurrence was detected in close or clear margin. Conclusion: Margin status of the primary resection is probably the most important factor in determining risk of recurrence. Limitation: Experience of surgeon not stratified Patients Tx in private sector not included; 7 lost to FU

Margin-involved phyllodes tumor Why does it matter? What to do next? How to “prevent”?

Local recurrence Meta-analysis (83 articles, 5530 patients) Spitaleri G, Toesca A, Botteri E, et al. Breast phyllodes tumor: a review of literature and a single center retrospective series analysis. Crit Rev Oncol Hematol. 2013 Nov;88(2):427-36.

Local recurrence Associated factors: - + Asoglu, 2004 Chen, 2005 Study Stromal atypia Positive margin Necrosis Fibroproliferation Asoglu, 2004 - + Chen, 2005 Barrio, 2007 Lenhard, 2007 Telli, 2007 Belkacemi, 2008 Stromal atypia: marked in borderline/ malignant Sample size: 50/ 172/ 293/ 33/ 443 Calhoun KE, Lawton TJ, Kim JN, Lehman CD, Anderson BO. Phyllodes tumors. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2010:781-792.

Disease-free survival curves of 42 patients treated with breast-conservative surgery for phyllodes tumor. Taira’s series of 45 patients (15 positive surgical margin, with 6 recurrences). In univariate analysis, a positive surgical margin, stromal overgrowth and histological classification were predictive factors for local recurrence after breast-conservation surgery. A positive surgical stump was the only independent predictor of local recurrence in multivariate analysis (P=0.012). Stromal overgrowth was a predictive factor for local recurrence in cases with a positive surgical margin (P=0.0139). Taira N, Takabatake D, Aogi K, et al. Phyllodes Tumor of the Breast: Stromal Overgrowth and Histological Classification are Useful Prognosis-predictive Factors for Local Recurrence in Patients with a Positive Surgical Margin. Jpn J Clin Oncol 2007;37(10)730–736

Factors involved in local recurrence were investigated in the 15 stump-positive cases, and stromal overgrowth was found to be a significant prognosis-predictive factor. Histological malignancy was excluded as an investigative factor in this analysis because it was found in stromal overgrowth-positive cases. Taira N, Takabatake D, Aogi K, et al. Phyllodes Tumor of the Breast: Stromal Overgrowth and Histological Classification are Useful Prognosis-predictive Factors for Local Recurrence in Patients with a Positive Surgical Margin. Jpn J Clin Oncol 2007;37(10)730–736

Margin-involved phyllodes tumor Why does it matter? Predictor of local recurrence What to do next? How to “prevent”?

If margin positive… Stromal growth as a predictive factor of local recurrence in positive margin cases One of the malignant features POH: benign, subcut Mx, margin clear, stromal overgrowth  total 5 recurrences in 3 yrs (1st recurrence at 5mths) Histological malignancy was excluded as an investigative factor in this analysis because it was found in stromal overgrowth-positive cases. Taira N, Takabatake D, Aogi K, et al. Phyllodes Tumor of the Breast: Stromal Overgrowth and Histological Classification are Useful Prognosis-predictive Factors for Local Recurrence in Patients with a Positive Surgical Margin. Jpn J Clin Oncol 2007;37(10)730–736

If margin positive… Some authors had suggested “wait-and-see” policy for benign phyllodes tumor Chua, 1989 (106 patients) Zurrida, 1992 (216 patients): recurrence 8% In a review of 106 benign phyllodes tumor patients (15-year period), in whom 71.7% were mistakenly operated on for fibroadenoma. Since only 15.8% of this group developed local recurrence, Chua et al. concluded that because only 16% of patients presumptively operated on fibroadenoma developed a local recurrence, a policy of close follow-up may be acceptable. Zurrida et al. from Milan based on their series of 216 patients, with a mean period of follow-up of 118 months, they found that only 8% of benign lesions recurred (vs 20% to 23% for borderline or malignant phyllodes tumors), 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 as an alterative to mandatory surgical reexcision. Chua CL, Thomas A, Ng BK. Cystosarcoma phyllodes: a review of surgical options. Surgery 1989;105(2 Pt 1):141-147 Zurrida S, Bartoli C, Galimberti V, et al. Which therapy for unexpected phyllodes tumour of the breast? Eur J Cancer 1992;28(2-3):654-657

Management strategy of Margin-involved phyllodes tumor Benign “wait-and-see” Malignant  Re-excision Follow-up every 6 months for initial 2-3 years (highest chance of recurrence) Then yearly Self breast examination Clinical suspicion on follow-up: triple assessment In margin-involved cases, POH recurrence rate: 16.7% (meta-analysis LR: benign 15%, borderline 17%, malignant 28%; overall 19%) POH: one case malignant margin +ve, no recurrence in 43 mths

Margin-involved phyllodes tumor Why does it matter? What to do next? How to “prevent”?

Phyllodes tumor Difficult preoperative diagnosis…..

Phyllodes tumor – Initial workup Patient presentation Triple assessment Clinical suspicious of phyllodes tumor - Palpable mass - Rapid growth - USG suggestive of fibroadenoma except for size (>2cm) / rapid growth - History and P/E - USG - MMG for >30yo Core needle biopsy Fibroadenoma Fibroadenoma or indeterminate Phyllodes tumor (benign, borderline, malignant) PT>FA: Round/lobulated shape, well-defined margins, heterogenous internal structure, non-enhancing internal septations Imaging (MMG/USG): unreliable in differentiating benign/malignant vs fibroadenomas FNAC will not, and core biopsy may not, distinguish FA from PT (some PT arise in a background of FA) Malignant PT: LN met <1%, therefore AD only when histologically positive malignant cells Core biopsy -> benign or borderline: observe -> malignant: as soft tissue sarcoma (e.g. RT to chest wall if margin close, chest wall involvement, >5cm with stromal overgrowth; or only partial Mx performed) XRT: if mastectomy was performed and margins were concerning/close, tumor involved the fascia or chest wall, or tumor was very large (greater than 5 centimeters), then recommend XRT to chest wall. Observe Excisional biopsy Wide excision (>=1cm) without axillary staging M D Anderson Cancer Center 2012

Margin-involved phyllodes tumor Why does it matter What to do next How to “prevent” ?

Thank you

WHO classification

Phyllodes tumors are usually differentiated histologically from FA by its increased stromal cellularity and mitotic activity. However, benign phyllodes tumor by definition lacks marked atypia and excess mitotic activity in its stromal component.

To improve preoperative diagnosis Paddington Clinicopathological Suspicion Score Clinical findings Sudden increase in size in a longstanding breast lesion Apparent fibroadenoma >3cm diameter or in patient >35 years Imaging findings MMG: Rounded borders/ lobulated appearance USG: Attenuation or cystic areas within a solid mass FNAC findings Presence of hypercellular stromal fragments Indeterminate features ANY 2 features mandate core biopsy criteria to assist in the selection of patients for core biopsy, for use in conjunction with existing local protocols. R K Jacklin, P F Ridgway, P Ziprin, et al. Optimising preoperative diagnosis in phyllodes tumour of the breast. J Clin Pathol 2006;59:454–459.

Phyllodes tumor - Recurrence Patient presentation Workup Local recurrent breast mass after excision of phyllodes tumor - History and P/E - MMG, USG - Core needle biopsy - Consider chest imaging No metastatic disease Metastatic disease Distant met (Hemat): 10%; usually w/o evidence of local recurrence; lungs (66%), bones (28%), brain (9%) Determined by tumor biology, not extend of initial surgery LN met <1% (LN enlargement in 10%); AD if histo malig +ve There is no prospective randomized data supporting the use of radiation treatment with phyllodes tumor. However, in the setting where additional recurrence would create significant morbidity e.g. chest wall recurrence following salvage mastectomy, radiation therapy may be considered, following the same principles that are applied to the treatment of soft tissue sarcoma. Re-excision with wide margins without axillary staging As soft tissue sarcoma Consider post-op RT M D Anderson Cancer Center 2012