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Phyllodes tumors of the breast: Analysis of 35 cases from a single institution
Journal of the Egyptian National Cancer Institute (2016) xxx, xxx–xxx
Cairo University
Journal of the Egyptian National Cancer Institute www.elsevier.com/locate/jnci www.sciencedirect.com
Full Length Article
Phyllodes tumors of the breast: Analysis of 35 cases from a single institution Gerges Attia Demian *,1, Salah Fayaz, Heba El-Sayed Eissa, Nashwa Nazmy, Suzanne Samir, Thomas George, Mustafa El-Sherify, Sadeq Abuzalouf Radiation Oncology Department, Kuwait Cancer Control Center, Kuwait Received 17 May 2016; revised 11 June 2016; accepted 21 June 2016
KEYWORDS Breast; Phyllodes; Surgery; Radiotherapy
Abstract Background: Phyllodes tumors are rare fibroepithelial breast tumors with diverse biological behavior. Our study aim is to review the clinico-pathological features, prognostic factors and treatment outcome for patients presenting with phyllodes tumors of the breast to the Kuwait Cancer Control Center (KCCC). Patients and methods: We retrospectively reviewed the clinical and pathological data of 35 women of histologically proved phyllodes tumors of the breast retrieved between January 1994 and December 2012. Results: The median age was 40 years (21–63 years). The median pathological tumor size was 6.8 cm (3–25 cm). Histologically, one patient (3%) presented with benign, 13 (37%) with borderline and 21 (60%) with malignant phyllodes. Twenty-eight patients (80%) were premenopausal. Twenty (57%) were ultimately treated with mastectomy (3 borderline, and 17 malignant) and 15 (43%) with conservative surgery (1 benign, 10 borderline and 4 malignant). Axillary staging was carried out in 9 patients (1 borderline and 8 malignant), none of them had nodal metastasis. Four patients with malignant phyllodes received postoperative radiotherapy. After a median follow-up period of 52 months (range 5–211 months), 5 developed local recurrence (1 benign, 2 borderline and 2 malignant). One patient with malignant phyllodes developed distant lung metastasis. The overall 5-year relapse free survival (RFS) was 74% (68% for borderline and 84% for malignant phyllodes). According to the treatment modality, the 5-year RFS was 69% for conservative surgery compared to 87% for mastectomy. It was 100% for irradiated patients versus 71% for non irradiated patients. Conclusion: Phyllodes tumors are rare tumors that occur in relatively young women, when compared with the classical adenocarcinoma of the breast. They have a tendency to reach large sizes with absence of nodal metastasis. Although surgery is the mainstay of management, postoperative radiotherapy also appears to decrease the local recurrence rates in certain presentations. Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
* Corresponding author at: National Cancer Institute, Cairo, Egypt. E-mail address: [email protected] (G.A. Demian). 1 Postal address: Al-Hassan Al-Basry St. district 8, Hawally, Kuwait. Fax: +965 24840838. Peer review under responsibility of The National Cancer Institute, Cairo University. http://dx.doi.org/10.1016/j.jnci.2016.06.004 1110-0362 Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
2
G.A. Demian et al.
Introduction
Patients and methods
Phyllodes tumors are rare fibroepithelial breast tumors that account for fewer than 0.5% of all breast malignancies [1,2]. They are characterized by a diverse range of biologic behavior. The least aggressive form may behave similar to fibroadenomas, yet with a high local recurrence rate if excised without wide margins, while its malignant form can give distant metastasis [3,4]. Phyllodes tumors are classified as benign, borderline or malignant [1,3,5] according to the degree of stromal cellular atypia, mitotic activity, infiltrative versus circumscribed tumor margins and presence or absence of stromal overgrowth [6–9]. The stromal elements are key components in the differentiation of phyllodes tumors from fibroadenomas and in distinguishing a benign from a malignant phyllodes tumor [7]. The main treatment of phyllodes tumors remains surgical excision. Wide local excision, with a margin of at least 1 cm is the most effective surgery [1,4,10] for nonmalignant as well as malignant lesions. Re-excision is indicated when necessary to ensure adequate margins as the recurrence rates are unacceptably high following excision with inadequate margins [11–17]. The local recurrence rates following wide local excision are 8% for benign phyllodes tumors and 21–36% for borderline and malignant tumors [10,12]. Adjuvant radiotherapy (RT) for phyllodes tumors is controversial. Radiotherapy is unnecessary for benign phyllodes tumors that are widely excised. However, adjuvant RT appears to be effective in decreasing recurrences after breast conserving resection for borderline or malignant phyllodes tumors [10,14,17] particularly when it is not possible to obtain a wide margin of P1 cm of resection. For some tumors a 1 cm margin may not be possible even with a total mastectomy due to their size or location. Available data indicate that RT will substantially reduce recurrence for these patients [10]. There is less agreement about the role of adjuvant RT when wide margins P1 cm can be obtained. The benefit of adjuvant chemotherapy is controversial. It should be administered only for a minority of patients with large, high-risk or recurrent malignant tumors, and only after a thorough discussion about the risks and benefits of treatment. Hormone therapy is not effective for phyllodes tumors despite the presence of positive hormone receptors in the epithelial component of some of these tumors [18,19]. The majority of patients with benign and borderline phyllodes tumors are cured with surgery. The survival rate for malignant phyllodes tumors is reported as approximately 60– 80% at 5 years [4,11,20]. Metastatic disease has been reported in 13–40% of patients [1,3,4]. Metastases most frequently involve the lungs. After the development of metastases, mean overall survival is 30 months [21].
The medical index of the KCCC is a computerized record of all the diagnoses made or revised at the KCCC. The KCCC is the only multidisciplinary cancer center in the State of Kuwait to which all patients are referred from different provinces of Kuwait. A search of the index from January 1994 to December 2012, using the term phyllodes tumors, revealed 35 cases. The clinical and pathological data were retrospectively studied from the medical and pathologic records. Disease free survival was estimated using Kaplan Meier method. DFS was defined as the time from diagnosis to the date of first recurrence. Patients without documented recurrent disease were censored at the last date of their follow up. Statistical significance was calculated by using the log-rank test and defined as P < 0.05.
Aim of the study This is a retrospective study that aims at revision of the clinicopathological features, prognostic factors and treatment outcome for patients who presented with phyllodes tumors of the breast to the Kuwait Cancer Control Center (KCCC).
Results The characteristics of the 35 patients are summarized in Table 1. All patients were females with a median age at diagnosis of 40 years (range 21–63). The median follow-up was 52 months (range 5–211 months). Twenty-eight (80%) were premenopausal. No patients reported family history of breast cancer. All patients presented with a breast mass, four with tumor ulceration. Mammography was employed in 11 patients, 5 were reported as BIRADS 3, 4 as BIRADS 4 and 2 as BIRADS 5. One patient presented with benign phyllodes, thirteen had borderline phyllodes (37%) and 21 had malignant phyllodes (60%). Initially 18 were subjected to conservative surgery however 7 showed inadequate surgical margin. Secondary surgery was wider excision in 4 and mastectomy in 3. Overall mastectomy was the definitive surgery in 20 (57%). Surgical axillary staging was performed in 9 patients (axillary sampling in 5 patients and formal dissection in 4 patients), all of them showed no nodal metastasis. The most frequent tumor site was the upper outer quadrant reported in 17 patients (48.5%) while the second frequent was the involvement of the whole breast in 11 patients (31.5%). The median pathologic tumor size was 6.8 cm (range 3–25 cm), however for ulcerative tumors it was 18 cm (range 12–25). Adjuvant RT was employed in 4 patients (following mastectomy in 3 patients and conservative surgery in one). The four patients presented with large malignant phyllodes tumors (median size of 16 cm). The dose of postmastectomy RT was 50 Gy/25 fractions in two and 60 Gy/30 fractions in the third. Following conservative surgery, the RT dose was 50 Gy/25 fractions + 14 Gy/7 fractions as a tumor bed boost. None of the 4 patients experienced local recurrence. Local recurrence was experienced in 5 patients (one benign, 2 borderline and 2 malignant phyllodes). Histopathology of recurrence was similar to the original pathology in all cases. Two patients were treated with wide local excision and 3 with mastectomy. One patient treated for malignant phyllodes developed distant lung metastasis and lost follow-up. One patient who was treated for malignant phyllodes with wide excision and RT developed ipsilateral DCIS after 10 years and was managed with mastectomy (see Figs. 1–4). The relapse group had a median age of 37 years (25–63 years) and a median tumor size of 5 cm (3–16 cm).
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
Phyllodes tumors of the breast Table 1
3
Patients and tumor characteristics of 35 cases of phyllodes tumors of the breast presented to KCCC from 1994 to 2012. All cases
Borderline phyllodes
Malignant phyllodes
Age Median Range
40 years 21–63 years
40 years 30–63 years
39 years 21–53 years
Differentiation Benign Borderline Malignant
1 (3%) 13 (37%) 21 (60%)
NA NA NA
NA NA NA
Menopausal status Premenopausal Postmenopausal
28 (80%) 7 (20%)
10 3
17 4
Clinical tumor size Median Range
5.7 cm 3–20 cm
4 cm 3–14 cm
7.5 cm 3–20 cm
Site of the tumor UOQ LOQ UIQ LIQ Retroareolar More than 1 quadrant
17 (48.6%) 3 (8.6%) 2 (5.7%) 1 (2.9%) 1 (2.9%) 11 (31.3%)
7 2 1 1 1 1
(53.8%) (15.4%) (7.7%) (7.7%) (7.7%) (7.7%)
9 (42.9%) 1 (4.8%) 1 (4.8%) 0 0 10 (47.6%)
Initial surgery Mastectomy Conservative surgery
17 (48.5%) 18 (51.5%)
3 (23%) 10 (77%)
14 (66.7%) 7 (33.3%)
Pathologic size Median Range
6.8 cm 3–25 cm
4.5 cm 3–20 cm
11.5 cm 3.5–25 cm
Surgical margin Negative Positive
28 (80%) 7 (20%)
11 (85%) 2 (15%)
16 (76%) 5 (24%)
Overall surgery Mastectomy Conservative surgery
20 (57%) 15 (43%)
3 (23%) 10 (77%)
17 (81%) 4 (19%)
Axillary staging Yes No
9 (26%) 26 (74%)
1 (7.7%) 12 (92.3)
8 (38%) 13 (62%)
Radiation therapy Yes No
4 (11.5%) 31 (88.5%)
0 13 (100%)
4 (19%) 17 (81%)
Recurrence Yes No
5 (14%)* 29 (86%)
2 (15.5%) 11 (84.5%)
2 (9.5%) 19 (89.5%)
Surgery of recurrence Wide excision Mastectomy
2 (40%) 3 (60%)
2 (100%) 0
0 3 (100%)
Distant metastasis Yes No
1 (3%) 34 (97%)
0 13 (100%)
1 (5%) 20 (95%)
Follow-up Median Range
52 months 5–211 months
52.5 months 12–154 months
45 months 5–211 months
*
One patient treated for benign phyllodes had local recurrence.
The 5-year relapse free survival (RFS) was 74 ± 10%. It was 68 ± 20% for borderline and 84 ± 8% for malignant phyllodes (P = 0.9). The four patients who received adjuvant RT did not develop relapse (5-years RFS 71 ± 11% for non
irradiated versus 100% for irradiated patients, P = 0.3). According to the type of surgery the 5-year RFS was 69 ± 14% for WLE versus 87 ± 9% for mastectomy patients (P = 0.4).
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
G.A. Demian et al. 1.0
1.0
.9
.9
.8
.8
Relapse Free Survival
Relapse Free Survival
4
.7 .6 .5 .4 .3
.7 .6 .5 .4
Radiotherapy
.3
Adj RT
.2
.2
.1
Survival Function
.1 0.0
Censored 0
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4
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10
12
14
16
18
No RT
0.0 0
20
2
4
6
8
10
12
14
16
18
20
Follow-up in years
Follow-up in years
Figure 1 Relapse free survival curve for the 35 patients presented with phyllodes tumor of the breast.
Figure 3 Relapse free survival curve for patients treated with and without adjuvant radiotherapy for phyllodes tumors of the breast.
1.0 1.0
.9 .9
.8
.6 .5 .4
Differentiation
.3
Malignant
.2
Relapse Free Survival
Relapse Free Survival
.8
.7
.7 .6 .5 .4
Type of Surgery
.3
Mastectomy
.2
.1
Borderline
.0 0
2
4
6
8
10
12
14
16
18
20
Follow-up in years
Figure 2 Relapse free survival curve for patients presented with malignant and borderline phyllodes tumors of the breast.
.1
WLE
0.0 0
2
4
6
8
10
12
14
16
18
20
Follow-up in years
Figure 4 Relapse free survival curve for patients treated mastectomy versus conservative surgery for phyllodes tumors of the breast.
Discussion Phyllodes tumors are rare tumors with an average annual incidence rate of 2.1 per million women [6]. We retrieved 35 female patients diagnosed in KCCC in a 19 year period. Phyllodes tumors of the breast present in a younger age population compared to adenocarcinoma. The median age is 40 years compared to 52 years for breast adenocarcinoma in Kuwait [22] and comparable to the reported 42–45 years worldwide [6,23,25]. Phyllodes tumors are generally first identified as a breast mass or an abnormal mammographic finding. The median tumor size in our study is 5.7 cm, larger for malignant phyllodes (7.5 cm) compared to the borderline subtype (4 cm) likely due to more rapid growth pattern. Larger tumors ulcerated by pressure necrosis to the skin. The reported median size in the
literature is 4–7 cm [1,23]. However, for borderline and malignant phyllodes, Mallick et al. reported a median size of 13.6 cm [24]. The typical appearance of a phyllodes tumor on mammography is a smooth, polylobulated mass resembling a fibroadenoma explaining why five out of the eleven mammographies done reported a probably benign mass (BIRADS 3). Generally, mammography was underused in our patients as many patients were managed in general hospitals and in the early 1990s. Also, many patients presented with locally advanced disease making the mammographic assessment of no value. Suspicion for a phyllodes tumor rather than a fibroadenoma is based on large tumor size at presentation or rapid growth [3]. Image guided core biopsy is now our standard of care before surgical management of any breast mass.
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
Phyllodes tumors of the breast Only one patient presented with benign phyllodes in our series while in many series, benign phyllodes represented 50% of phyllodes tumors [3,8]. This may be explained by the reluctance of surgeons operating on benign phyllodes to refer patients to a cancer center. In our study, the probability of having a positive surgical margin after conservative surgery is higher with malignant phyllodes compared to borderline (24% vs. 15%) likely due to the infiltrative nature of the tumor. The overall mastectomy rate for the malignant phyllodes was 81% compared to 23% for the borderline secondary to larger tumor size and higher positive margin rate. Despite axillary node metastases being rare (only eight of 498 women in the SEER database) [11], nine patients had axillary surgical staging (sentinel lymph node biopsy in 3, axillary sampling in 2 and axillary dissection in 4) mostly for malignant phyllodes. None of them had nodal metastasis. Axillary dissection is not recommended, however many patients were referred to our center following surgery. Adjuvant radiotherapy lowered the rates of local recurrence in malignant and borderline tumors [17]. Radiotherapy was underused in our study. It was employed in only 4 patients with large malignant tumors, none of them experienced local relapse. The local recurrence rate was 14% comparable with the recurrence rates reported in the literature (8–19%). In some reports, it reached to 36% [17]. Only one patient developed distant metastasis in our study, the reported rates of distant metastasis ranged from 2.4% to 7.5% [1,14,26,27]. The number of patients who relapsed was relatively small. The tumor, patients and treatment characteristics were not significantly different between the relapsed and non relapsed groups. The follow-up of our patients who were treated for phyllodes tumors follows the same breast cancer follow-up protocol as defined by NCCN guidelines [28]. However, a report from UK advices against routine follow up of these cases [29]. Conclusion Phyllodes tumors are rare tumors that occur in relatively young women, when compared with the classical adenocarcinoma of the breast. They have a tendency to reach large sizes with absence of nodal metastasis. Although surgery is the mainstay of management, postoperative radiotherapy also appears to decrease the local recurrence rates in certain presentations. Conflict of interest None declared. References [1] Reinfuss M, Mitus´ J, Duda K, Stelmach A, Rys´ J, Smolak K. The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 1996;77:910–6. [2] Geisler DP, Boyle MJ, Malnar KF, McGee JM, Nolen MC, Fortner SM, et al. Phyllodes tumors of the breast: a review of 32 cases. Am Surg 2000;66:360–6. [3] Calhoun KE, Lawton TJ, Kim JN, Lehman CD, Anderson BO. Phyllodes tumors. In: Harris J, Lippman ME, Osborne CK, Morrow M, editors. Diseases of the breast. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 781–92.
5 [4] Chaney AW, Pollack A, McNeese MD, Zagars GK, Pisters PW, Pollock RE, et al. Primary treatment of cystosarcoma phyllodes of the breast. Cancer 2000;89:1502–11. [5] De Roos WK, Kaye P, Dent DM. Factors leading to local recurrence or death after surgical resection of phyllodes tumours of the breast. Br J Surg 1999;86:396–9. [6] Bernstein L, Deapen D, Ross RK. The descriptive epidemiology of malignant cystosarcoma phyllodes tumors of the breast. Cancer 1993;71:3020–4. [7] Norris HJ, Taylor HB. Relationship of histologic features to behavior of cystosarcoma phyllodes. Analysis of ninety-four cases. Cancer 1967;20:2090–9. [8] Hawkins RE, Schofield JB, Fisher C, Wiltshaw E, McKinna JA. The clinical and histologic criteria that predict metastases from cystosarcoma phyllodes. Cancer 1992;69:141–7. [9] Fajdic´ J, Gotovac N, Hrgovic´ Z, Kristek J, Horvat V, Kaufmann M. Phyllodes tumors of the breast diagnostic and therapeutic dilemmas. Onkologie 2007;30:113–8. [10] Barth Jr RJ, Wells WA, Mitchell SE, Cole BF. A prospective, multi-institutional study of adjuvant radiotherapy after resection of malignant phyllodes tumors. Ann Surg Oncol 2009;16:2288–94. [11] Macdonald OK, Lee CM, Tward JD, Chappel CD, Gaffney DK. Malignant phyllodes tumor of the female breast: association of primary therapy with cause-specific survival from the Surveillance, Epidemiology, and End Results (SEER) program. Cancer 2006;107:2127–33. [12] Barth Jr RJ. Histologic features predict local recurrence after breast conserving therapy of phyllodes tumors. Breast Cancer Res Treat 1999;57:291–5. [13] Mangi AA, Smith BL, Gadd MA, Tanabe KK, Ott MJ, Souba WW. Surgical management of phyllodes tumors. Arch Surg 1999;134:487–92. [14] Belkace´mi Y, Bousquet G, Marsiglia H, Ray-Coquard I, Magne´ N, Malard Y, et al. Phyllodes tumor of the breast. Int J Radiat Oncol Biol Phys 2008;70:492–500. [15] Chen WH, Cheng SP, Tzen CY, Yang TL, Jeng KS, Liu CL, et al. Surgical treatment of phyllodes tumors of the breast: retrospective review of 172 cases. J Surg Oncol 2005;91:185–94. [16] Soumarova´ R, Seneklova´ Z, Horova´ H, Vojkovska´ H, Horova´ I, Budı´ kova´ M, et al. Retrospective analysis of 25 women with malignant cystosarcoma phyllodes-treatment results. Arch Gynecol Obstet 2004;269:278–81. [17] Pezner RD, Schultheiss TE, Paz IB. Malignant phyllodes tumor of the breast: local control rates with surgery alone. Int J Radiat Oncol Biol Phys 2008;71:710–3. [18] Telli ML, Horst KC, Guardino AE, Dirbas FM, Carlson RW. Phyllodes tumors of the breast: natural history, diagnosis, and treatment. J Natl Compr Canc Netw 2007;5:324–30. [19] Burton GV, Hart LL, Leight Jr GS, Iglehart JD, McCarty Jr KS, Cox EB. Cystosarcoma phyllodes. Effective therapy with cisplatin and etoposide chemotherapy. Cancer 1989;63:2088–92. [20] Confavreux C, Lurkin A, Mitton N, Blondet R, Saba C, Ranche`re D, et al. Sarcomas and malignant phyllodes tumours of the breast–a retrospective study. Eur J Cancer 2006;42:2715–21. [21] Kessinger A, Foley JF, Lemon HM, Miller DM. Metastatic cystosarcoma phyllodes: a case report and review of the literature. J Surg Oncol 1972;4:131–47. [22] Motawy M, El Hattab O, Fayaz S, Oteifa M, Ali J, George T, et al. Multidisciplinary approach to breast cancer management in Kuwait, 1993–1998. J Egypt Natl Canc Inst 2004 Jun;16 (2):85–91. [23] Barrio AV, Clark BD, Goldberg JI, Hoque LW, Bernik SF, Flynn LW, et al. Clinicopathologic features and long-term outcomes of 293 phyllodes tumors of the breast. Ann Surg Oncol 2007;14:2961–70.
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
6 [24] Mallick S, Joshi NP, Roy S, Gandhi AK, Pandit S, Sharma D, et al. Malignant and borderline phyllodes tumor of breast treated with a multi-modality approach in a tertiary cancer care centre in North India. South Asian J Cancer 2016 Jan–Mar;5(1):1–3. [25] Tavassoli FA, Devilee P. Pathology and genetics of tumours of the breast and female genital organs. In: World Health Organization classification of tumors. Lyons: IARC Press; 2003. p. p. 99. [26] Ben Hassouna J, Damak T, Gamoudi A, Chargui R, Khomsi F, Mahjoub S, et al. Phyllodes tumors of the breast: a case series of 106 patients. Am J Surg 2006;192(2):141–7.
G.A. Demian et al. [27] Jang JH, Choi MY, Lee SK, Kim S, Kim J, Lee J, et al. Clinicopathologic risk factors for the local recurrence of phyllodes tumors of the breast. Ann Surg Oncol 2012;19 (8):2612–7. [28] NCCN guidelines of treatment of cancer by site: breast cancer. Ver. 1.2016. http://www.nccn.org/professionals/physician_gls/ pdf/breast.pdf. [29] Mylvaganam S, Toro C, Frank L, Vestey S, Thrush S. Phyllodes tumors of the breast: best practice for follow-up. Updates Surg 2015;67(1):91–5.
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
Cairo University
Journal of the Egyptian National Cancer Institute www.elsevier.com/locate/jnci www.sciencedirect.com
Full Length Article
Phyllodes tumors of the breast: Analysis of 35 cases from a single institution Gerges Attia Demian *,1, Salah Fayaz, Heba El-Sayed Eissa, Nashwa Nazmy, Suzanne Samir, Thomas George, Mustafa El-Sherify, Sadeq Abuzalouf Radiation Oncology Department, Kuwait Cancer Control Center, Kuwait Received 17 May 2016; revised 11 June 2016; accepted 21 June 2016
KEYWORDS Breast; Phyllodes; Surgery; Radiotherapy
Abstract Background: Phyllodes tumors are rare fibroepithelial breast tumors with diverse biological behavior. Our study aim is to review the clinico-pathological features, prognostic factors and treatment outcome for patients presenting with phyllodes tumors of the breast to the Kuwait Cancer Control Center (KCCC). Patients and methods: We retrospectively reviewed the clinical and pathological data of 35 women of histologically proved phyllodes tumors of the breast retrieved between January 1994 and December 2012. Results: The median age was 40 years (21–63 years). The median pathological tumor size was 6.8 cm (3–25 cm). Histologically, one patient (3%) presented with benign, 13 (37%) with borderline and 21 (60%) with malignant phyllodes. Twenty-eight patients (80%) were premenopausal. Twenty (57%) were ultimately treated with mastectomy (3 borderline, and 17 malignant) and 15 (43%) with conservative surgery (1 benign, 10 borderline and 4 malignant). Axillary staging was carried out in 9 patients (1 borderline and 8 malignant), none of them had nodal metastasis. Four patients with malignant phyllodes received postoperative radiotherapy. After a median follow-up period of 52 months (range 5–211 months), 5 developed local recurrence (1 benign, 2 borderline and 2 malignant). One patient with malignant phyllodes developed distant lung metastasis. The overall 5-year relapse free survival (RFS) was 74% (68% for borderline and 84% for malignant phyllodes). According to the treatment modality, the 5-year RFS was 69% for conservative surgery compared to 87% for mastectomy. It was 100% for irradiated patients versus 71% for non irradiated patients. Conclusion: Phyllodes tumors are rare tumors that occur in relatively young women, when compared with the classical adenocarcinoma of the breast. They have a tendency to reach large sizes with absence of nodal metastasis. Although surgery is the mainstay of management, postoperative radiotherapy also appears to decrease the local recurrence rates in certain presentations. Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
* Corresponding author at: National Cancer Institute, Cairo, Egypt. E-mail address: [email protected] (G.A. Demian). 1 Postal address: Al-Hassan Al-Basry St. district 8, Hawally, Kuwait. Fax: +965 24840838. Peer review under responsibility of The National Cancer Institute, Cairo University. http://dx.doi.org/10.1016/j.jnci.2016.06.004 1110-0362 Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
2
G.A. Demian et al.
Introduction
Patients and methods
Phyllodes tumors are rare fibroepithelial breast tumors that account for fewer than 0.5% of all breast malignancies [1,2]. They are characterized by a diverse range of biologic behavior. The least aggressive form may behave similar to fibroadenomas, yet with a high local recurrence rate if excised without wide margins, while its malignant form can give distant metastasis [3,4]. Phyllodes tumors are classified as benign, borderline or malignant [1,3,5] according to the degree of stromal cellular atypia, mitotic activity, infiltrative versus circumscribed tumor margins and presence or absence of stromal overgrowth [6–9]. The stromal elements are key components in the differentiation of phyllodes tumors from fibroadenomas and in distinguishing a benign from a malignant phyllodes tumor [7]. The main treatment of phyllodes tumors remains surgical excision. Wide local excision, with a margin of at least 1 cm is the most effective surgery [1,4,10] for nonmalignant as well as malignant lesions. Re-excision is indicated when necessary to ensure adequate margins as the recurrence rates are unacceptably high following excision with inadequate margins [11–17]. The local recurrence rates following wide local excision are 8% for benign phyllodes tumors and 21–36% for borderline and malignant tumors [10,12]. Adjuvant radiotherapy (RT) for phyllodes tumors is controversial. Radiotherapy is unnecessary for benign phyllodes tumors that are widely excised. However, adjuvant RT appears to be effective in decreasing recurrences after breast conserving resection for borderline or malignant phyllodes tumors [10,14,17] particularly when it is not possible to obtain a wide margin of P1 cm of resection. For some tumors a 1 cm margin may not be possible even with a total mastectomy due to their size or location. Available data indicate that RT will substantially reduce recurrence for these patients [10]. There is less agreement about the role of adjuvant RT when wide margins P1 cm can be obtained. The benefit of adjuvant chemotherapy is controversial. It should be administered only for a minority of patients with large, high-risk or recurrent malignant tumors, and only after a thorough discussion about the risks and benefits of treatment. Hormone therapy is not effective for phyllodes tumors despite the presence of positive hormone receptors in the epithelial component of some of these tumors [18,19]. The majority of patients with benign and borderline phyllodes tumors are cured with surgery. The survival rate for malignant phyllodes tumors is reported as approximately 60– 80% at 5 years [4,11,20]. Metastatic disease has been reported in 13–40% of patients [1,3,4]. Metastases most frequently involve the lungs. After the development of metastases, mean overall survival is 30 months [21].
The medical index of the KCCC is a computerized record of all the diagnoses made or revised at the KCCC. The KCCC is the only multidisciplinary cancer center in the State of Kuwait to which all patients are referred from different provinces of Kuwait. A search of the index from January 1994 to December 2012, using the term phyllodes tumors, revealed 35 cases. The clinical and pathological data were retrospectively studied from the medical and pathologic records. Disease free survival was estimated using Kaplan Meier method. DFS was defined as the time from diagnosis to the date of first recurrence. Patients without documented recurrent disease were censored at the last date of their follow up. Statistical significance was calculated by using the log-rank test and defined as P < 0.05.
Aim of the study This is a retrospective study that aims at revision of the clinicopathological features, prognostic factors and treatment outcome for patients who presented with phyllodes tumors of the breast to the Kuwait Cancer Control Center (KCCC).
Results The characteristics of the 35 patients are summarized in Table 1. All patients were females with a median age at diagnosis of 40 years (range 21–63). The median follow-up was 52 months (range 5–211 months). Twenty-eight (80%) were premenopausal. No patients reported family history of breast cancer. All patients presented with a breast mass, four with tumor ulceration. Mammography was employed in 11 patients, 5 were reported as BIRADS 3, 4 as BIRADS 4 and 2 as BIRADS 5. One patient presented with benign phyllodes, thirteen had borderline phyllodes (37%) and 21 had malignant phyllodes (60%). Initially 18 were subjected to conservative surgery however 7 showed inadequate surgical margin. Secondary surgery was wider excision in 4 and mastectomy in 3. Overall mastectomy was the definitive surgery in 20 (57%). Surgical axillary staging was performed in 9 patients (axillary sampling in 5 patients and formal dissection in 4 patients), all of them showed no nodal metastasis. The most frequent tumor site was the upper outer quadrant reported in 17 patients (48.5%) while the second frequent was the involvement of the whole breast in 11 patients (31.5%). The median pathologic tumor size was 6.8 cm (range 3–25 cm), however for ulcerative tumors it was 18 cm (range 12–25). Adjuvant RT was employed in 4 patients (following mastectomy in 3 patients and conservative surgery in one). The four patients presented with large malignant phyllodes tumors (median size of 16 cm). The dose of postmastectomy RT was 50 Gy/25 fractions in two and 60 Gy/30 fractions in the third. Following conservative surgery, the RT dose was 50 Gy/25 fractions + 14 Gy/7 fractions as a tumor bed boost. None of the 4 patients experienced local recurrence. Local recurrence was experienced in 5 patients (one benign, 2 borderline and 2 malignant phyllodes). Histopathology of recurrence was similar to the original pathology in all cases. Two patients were treated with wide local excision and 3 with mastectomy. One patient treated for malignant phyllodes developed distant lung metastasis and lost follow-up. One patient who was treated for malignant phyllodes with wide excision and RT developed ipsilateral DCIS after 10 years and was managed with mastectomy (see Figs. 1–4). The relapse group had a median age of 37 years (25–63 years) and a median tumor size of 5 cm (3–16 cm).
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
Phyllodes tumors of the breast Table 1
3
Patients and tumor characteristics of 35 cases of phyllodes tumors of the breast presented to KCCC from 1994 to 2012. All cases
Borderline phyllodes
Malignant phyllodes
Age Median Range
40 years 21–63 years
40 years 30–63 years
39 years 21–53 years
Differentiation Benign Borderline Malignant
1 (3%) 13 (37%) 21 (60%)
NA NA NA
NA NA NA
Menopausal status Premenopausal Postmenopausal
28 (80%) 7 (20%)
10 3
17 4
Clinical tumor size Median Range
5.7 cm 3–20 cm
4 cm 3–14 cm
7.5 cm 3–20 cm
Site of the tumor UOQ LOQ UIQ LIQ Retroareolar More than 1 quadrant
17 (48.6%) 3 (8.6%) 2 (5.7%) 1 (2.9%) 1 (2.9%) 11 (31.3%)
7 2 1 1 1 1
(53.8%) (15.4%) (7.7%) (7.7%) (7.7%) (7.7%)
9 (42.9%) 1 (4.8%) 1 (4.8%) 0 0 10 (47.6%)
Initial surgery Mastectomy Conservative surgery
17 (48.5%) 18 (51.5%)
3 (23%) 10 (77%)
14 (66.7%) 7 (33.3%)
Pathologic size Median Range
6.8 cm 3–25 cm
4.5 cm 3–20 cm
11.5 cm 3.5–25 cm
Surgical margin Negative Positive
28 (80%) 7 (20%)
11 (85%) 2 (15%)
16 (76%) 5 (24%)
Overall surgery Mastectomy Conservative surgery
20 (57%) 15 (43%)
3 (23%) 10 (77%)
17 (81%) 4 (19%)
Axillary staging Yes No
9 (26%) 26 (74%)
1 (7.7%) 12 (92.3)
8 (38%) 13 (62%)
Radiation therapy Yes No
4 (11.5%) 31 (88.5%)
0 13 (100%)
4 (19%) 17 (81%)
Recurrence Yes No
5 (14%)* 29 (86%)
2 (15.5%) 11 (84.5%)
2 (9.5%) 19 (89.5%)
Surgery of recurrence Wide excision Mastectomy
2 (40%) 3 (60%)
2 (100%) 0
0 3 (100%)
Distant metastasis Yes No
1 (3%) 34 (97%)
0 13 (100%)
1 (5%) 20 (95%)
Follow-up Median Range
52 months 5–211 months
52.5 months 12–154 months
45 months 5–211 months
*
One patient treated for benign phyllodes had local recurrence.
The 5-year relapse free survival (RFS) was 74 ± 10%. It was 68 ± 20% for borderline and 84 ± 8% for malignant phyllodes (P = 0.9). The four patients who received adjuvant RT did not develop relapse (5-years RFS 71 ± 11% for non
irradiated versus 100% for irradiated patients, P = 0.3). According to the type of surgery the 5-year RFS was 69 ± 14% for WLE versus 87 ± 9% for mastectomy patients (P = 0.4).
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
G.A. Demian et al. 1.0
1.0
.9
.9
.8
.8
Relapse Free Survival
Relapse Free Survival
4
.7 .6 .5 .4 .3
.7 .6 .5 .4
Radiotherapy
.3
Adj RT
.2
.2
.1
Survival Function
.1 0.0
Censored 0
2
4
6
8
10
12
14
16
18
No RT
0.0 0
20
2
4
6
8
10
12
14
16
18
20
Follow-up in years
Follow-up in years
Figure 1 Relapse free survival curve for the 35 patients presented with phyllodes tumor of the breast.
Figure 3 Relapse free survival curve for patients treated with and without adjuvant radiotherapy for phyllodes tumors of the breast.
1.0 1.0
.9 .9
.8
.6 .5 .4
Differentiation
.3
Malignant
.2
Relapse Free Survival
Relapse Free Survival
.8
.7
.7 .6 .5 .4
Type of Surgery
.3
Mastectomy
.2
.1
Borderline
.0 0
2
4
6
8
10
12
14
16
18
20
Follow-up in years
Figure 2 Relapse free survival curve for patients presented with malignant and borderline phyllodes tumors of the breast.
.1
WLE
0.0 0
2
4
6
8
10
12
14
16
18
20
Follow-up in years
Figure 4 Relapse free survival curve for patients treated mastectomy versus conservative surgery for phyllodes tumors of the breast.
Discussion Phyllodes tumors are rare tumors with an average annual incidence rate of 2.1 per million women [6]. We retrieved 35 female patients diagnosed in KCCC in a 19 year period. Phyllodes tumors of the breast present in a younger age population compared to adenocarcinoma. The median age is 40 years compared to 52 years for breast adenocarcinoma in Kuwait [22] and comparable to the reported 42–45 years worldwide [6,23,25]. Phyllodes tumors are generally first identified as a breast mass or an abnormal mammographic finding. The median tumor size in our study is 5.7 cm, larger for malignant phyllodes (7.5 cm) compared to the borderline subtype (4 cm) likely due to more rapid growth pattern. Larger tumors ulcerated by pressure necrosis to the skin. The reported median size in the
literature is 4–7 cm [1,23]. However, for borderline and malignant phyllodes, Mallick et al. reported a median size of 13.6 cm [24]. The typical appearance of a phyllodes tumor on mammography is a smooth, polylobulated mass resembling a fibroadenoma explaining why five out of the eleven mammographies done reported a probably benign mass (BIRADS 3). Generally, mammography was underused in our patients as many patients were managed in general hospitals and in the early 1990s. Also, many patients presented with locally advanced disease making the mammographic assessment of no value. Suspicion for a phyllodes tumor rather than a fibroadenoma is based on large tumor size at presentation or rapid growth [3]. Image guided core biopsy is now our standard of care before surgical management of any breast mass.
Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004
Phyllodes tumors of the breast Only one patient presented with benign phyllodes in our series while in many series, benign phyllodes represented 50% of phyllodes tumors [3,8]. This may be explained by the reluctance of surgeons operating on benign phyllodes to refer patients to a cancer center. In our study, the probability of having a positive surgical margin after conservative surgery is higher with malignant phyllodes compared to borderline (24% vs. 15%) likely due to the infiltrative nature of the tumor. The overall mastectomy rate for the malignant phyllodes was 81% compared to 23% for the borderline secondary to larger tumor size and higher positive margin rate. Despite axillary node metastases being rare (only eight of 498 women in the SEER database) [11], nine patients had axillary surgical staging (sentinel lymph node biopsy in 3, axillary sampling in 2 and axillary dissection in 4) mostly for malignant phyllodes. None of them had nodal metastasis. Axillary dissection is not recommended, however many patients were referred to our center following surgery. Adjuvant radiotherapy lowered the rates of local recurrence in malignant and borderline tumors [17]. Radiotherapy was underused in our study. It was employed in only 4 patients with large malignant tumors, none of them experienced local relapse. The local recurrence rate was 14% comparable with the recurrence rates reported in the literature (8–19%). In some reports, it reached to 36% [17]. Only one patient developed distant metastasis in our study, the reported rates of distant metastasis ranged from 2.4% to 7.5% [1,14,26,27]. The number of patients who relapsed was relatively small. The tumor, patients and treatment characteristics were not significantly different between the relapsed and non relapsed groups. The follow-up of our patients who were treated for phyllodes tumors follows the same breast cancer follow-up protocol as defined by NCCN guidelines [28]. However, a report from UK advices against routine follow up of these cases [29]. Conclusion Phyllodes tumors are rare tumors that occur in relatively young women, when compared with the classical adenocarcinoma of the breast. They have a tendency to reach large sizes with absence of nodal metastasis. Although surgery is the mainstay of management, postoperative radiotherapy also appears to decrease the local recurrence rates in certain presentations. Conflict of interest None declared. References [1] Reinfuss M, Mitus´ J, Duda K, Stelmach A, Rys´ J, Smolak K. The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 1996;77:910–6. [2] Geisler DP, Boyle MJ, Malnar KF, McGee JM, Nolen MC, Fortner SM, et al. Phyllodes tumors of the breast: a review of 32 cases. Am Surg 2000;66:360–6. [3] Calhoun KE, Lawton TJ, Kim JN, Lehman CD, Anderson BO. Phyllodes tumors. In: Harris J, Lippman ME, Osborne CK, Morrow M, editors. Diseases of the breast. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 781–92.
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Please cite this article in press as: Demian GA et al. Phyllodes tumors of the breast: Analysis of 35 cases from a single institution, J Egyptian Nat Cancer Inst (2016), http://dx.doi.org/10.1016/j.jnci.2016.06.004