Surgical management in phyllodes tumors of the breast: a systematic review and meta-analysis
Original Article

Surgical management in phyllodes tumors of the breast: a systematic review and meta-analysis

Yufan Wei1,2#, Yanying Yu3#, Yashuang Ji4, Yuting Zhong2,5, Ningning Min1,2, Huayu Hu1,2, Qingyu Guan1,2, Xiru Li2

1School of Medicine, Nankai University, Tianjin, China; 2Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China; 3Eight-Year MD Program, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 4Department of Galactophore Surgery, Tongzhou District Hospital of Integrated TCM & Western Medicine, Beijing, China; 5Medical School of Chinese PLA, Beijing, China

Contributions: (I) Conception and design: X Li, Y Wei; (II) Administrative support: X Li; (III) Provision of study materials or patients: X Li; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Xiru Li. Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China. Email: 2468li@sina.com.

Background: Information is still controversial in the studies regarding the current optimal surgical management of phyllodes tumors (PTs) of the breast. Local recurrence (LR) may occur with an upgraded in the pathological grade, influencing the prognosis of patients with PT. This systematic review and meta-analysis aimed to investigate the association of LR risk with margin status and margin width which could have significant implications on the surgical management of PT.

Methods: Independent and comprehensive searches were performed by two authors through five databases including PubMed, Medline, Embase, ScienceDirect and Cochrane Library from January 1990 to October 2021. Studies investigating the association between margin width, margin status and LR rates were considered for inclusion. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS). Meta-analysis was performed using RevMan5.3 software, and statistical heterogeneity was assessed using the Chi-square test and quantified using the I2 statistic. Visual inspection of funnel plots was used to judge publication bias.

Results: A total of 34 articles were included in this article, all of which with NOS scores above 5. Regardless of the PT grade, positive margin significantly increased the risk of LR [odds ratio (OR) 3.64, 95% confidence interval (CI): 2.60–5.12]. No significant difference was found in the risk of LR between the margins <1 and ≥1 cm (OR 1.39, 95% CI: 0.67–2.92). For benign and borderline PTs, there were no significant differences of the LR risk between breast-conserving surgery (BCS) and mastectomy (benign OR 0.68, 95% CI: 0.12–3.78; borderline OR 1.14, 95% CI: 0.29–4.51). While the LR risk was significantly increased by BCS for malignant PT (OR 2.77, 95% CI: 1.33–5.74).

Discussion: Different surgical management strategies should be considered for different PT grades. BCS was a feasible option and margins <1 cm was not significantly associated with LR risk for all grade of PT. After BCS, benign PT with positive margin could adopt the “wait and watch” strategy with regular follow-up, while borderline and malignant PTs were expected to underwent re-excision to ensure negative margins. More studies are still needed to clarify and update the existing conclusions and improve the prognosis of PT patients.

Keywords: Phyllodes tumors of the breast; surgical management; margin; local recurrence (LR); systematic review and meta-analysis

Submitted Nov 22, 2021. Accepted for publication Jan 24, 2022.

doi: 10.21037/gs-21-789

Introduction

Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial lesions (FELs), accounting for about 0.3–1% of breast tumors and 2–3% of FELs (1,2). This disease was first reported by Johannes Müller in 1838 and called cystosarcoma phyllodes (3). Since then, up to 60 names have been reported such as pseudosarcomatoid adenoma and carcinosarcoma. In 1982, the World Health Organization (WHO) officially named it as PT, and divided it into three grades including benign, borderline and malignant. Studies have shown that LR might occur in every grade with the rate of 10–17%, 14–25% and 23–30% respectively. Some recurrent cases could also have an upgrading of the pathological grade (4). It is of great significance to achieve effective resection of PT for reducing the rate of local recurrence (LR) and prolonging the disease-free survival of patients.

Margin width and status are two important factors affecting the prognosis. Previously, National Comprehensive Cancer Network (NCCN) guidelines recommended a margin of at least 1cm regardless of tumor grade with many studies supporting, including a meta-analysis conducted by Toussaint et al. (2,5-9). While some studies investigated that for benign PT, no significant difference of LR between <1 and ≥1 cm margins was found (10). Thind et al. even indicated that margin <1 cm was also acceptable for borderline and malignant PTs (11). As for margin status, some studies suggested that positive margin was significantly related to the increase of LR risk (12,13). However, Lu et al. proposed that margin status was only found to be associated with LR risk for malignant PT (14).

Surgical management of breast-conserving surgery (BCS) and mastectomy is still controversial as the main treatment of PT. Studies have shown that for benign and borderline PT, wide local excision (WLE) can reduce the LR rate from 21–46% to 8–29% (15,16). However, some studies indicated that regular follow-up was adequate since the LR rate of benign PT with positive margin was very low. And re-excision was only suitable for borderline and malignant PTs if safe margin <1 cm (17). Recently, a retrospective study of 550 cases by Rosenberger et al. found that ensuring a wider margin had nothing to do with reducing the risk of LR. They proposed that re-excision was not necessary for benign PT to ensure negative margin and suggested a revision of NCCN guidelines (18). In 2021, the fourth edition of NCCN guidelines modified the treatment option of benign PT from WLE to observation after excisional biopsy (19).

The object of this study is to explore the correlation between margin status, margin width, surgical treatment and LR risk for different grade of PT, supposing to contribute to the formulation of surgical method of PT and improve the prognosis of patients. We presented the following article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-21-789/rc).

Methods

This study has been registered in the International Prospective Register of Systematic Reviews ‘PROSPERO’ database (ID: CRD42021292859).

Eligibility criteria

The literature included in this study contained prospective or retrospective studies of female patients diagnosed pathologically with primary breast PTs. The cases included in the literature should be reviewed by pathologists which clearly report the tumor grade, surgical margins (margin width or margin status), and LR rate. For surgical margins, literature that only reported the surgical process (lumpectomy, WLE, or mastectomy, etc.) without precise definition of margin width and positive or negative criteria for margins should be excluded. If the margin information was only evaluated in patients treated by BCS, then the number of mastectomy cases was subtracted from the total number of cases. If a re-excision was performed, the margin was determined by the information of the last operation. To reduce publication bias, studies only included margin status and with fewer than 50 cases were also excluded. In addition, we only included research articles published in English. All case reports, reviews and comments were excluded.

Search strategy

A three steps search strategy was performed in this study. First, we searched the MeSH terms and free terms of PT, surgical margin and LR in PubMed database, and formulated corresponding search strategies according to the search methods of different databases. A full search strategy was detailed in Appendix 1. Then, a comprehensive second search was conducted through the five databases including PubMed, Medline, Embase, ScienceDirect, and Cochrane Library for the articles published between January 1990 and October 2021. Finally, the retrieved studies were screened for follow-up research.

Selection of studies

All retrieved articles were uploaded for screening with the duplicate studies deleted. Then, two authors conducted independent screening based on the title and abstract of the literature, and initially deleted the literature that did not meet the inclusion criteria. Finally, the full texts were read in detail and the included studies were confirmed. The disagreement between the two authors in the process of selection was resolved through discussion or discussion with the third author.

Assessment of methodological quality

All the included studies were independently evaluated for methodological quality by two authors using the modified NOS, which mainly included three modules (subject selection, comparability, and exposure/outcome). Scores were assigned in the form of ‘*’. The final score was among 0–9 points.

Data extraction

The two authors independently extracted the data at the same time, and confirmed the final data through comparison and review. The extraction data included the author’s name, publication year, the basic information of the included cases (nationality, age, and the total number of cases), the pathological classification of the cases, the surgical treatment, and the follow-up time to form a table of the features of included literature. The margin status, margin width, the surgical treatment and LR of different grades were extracted for subsequent analysis. All the extracted data was input into the Microsoft Excel database. Funnel plots were drawn to assess the publication bias.

Statistical analysis

The analyses were performed using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). The odds ratios (OR) were used to compare dichotomous variables and all results were reported with 95% confidence intervals (CIs). The random effects model was used to analyze the pooled data. Sensitivity analysis was carried out by deleting a study every time and checking whether the effect size changed. Statistical heterogeneity between studies was assessed using the Chi-square test and quantified using the I2 statistic. A significant statistical difference was considered when P<0.05.

Results

Literature search results

A total of 1,089 articles were retrieved in this study with 274 duplicate articles eliminated. By reading the title of the article, searching the full text, and rigorously screening according to the inclusion and exclusion criteria, 34 articles were finally included for subsequent research and analysis. A PRISMA flow diagram summarizing the process of literature selection were presented in Figure 1. All studies included had a quality score of 5 or higher were considered to have good quality (Table S1).

Figure 1 Article retrieval process.

Characteristics of the included studies

All 34 articles included in this study were retrospective studies, including 6,431 patients from 1944 to 2019 (Table 1). Among them, 3,898 cases were benign, 1,322 were borderline, and 1,221 were malignant. The age of the patients was the median or average age which ranged from 34 to 51 years old. Surgical treatment included BCS and mastectomy, with 4,779 cases and 803 cases respectively. The median follow-up time was between 19.2 and 120 months.

Table 1

Characteristics of the included studies

Study Time frame Country Age (years)a Total patients (N) Grade (n) Surgery Median follow-up time (months) Ref.
Benign Borderline Malignant BCS M
Mangi 1999 1980–1997 USA 41.3 40 34 3 3 31 9 43.01 (6)
Chaney 2000 1944–1998 USA 41 101 59 12 30 47 54 47 (20)
Kapiris 2001 1947–1999 UK 47 48 0 0 48 24 24 108 (7)
Sotheran 2005 1982–2000 UK n/a 50 29 12 9 46 4 35 (21)
Tan 2005 1992–2002 Singapore 42 335 250 54 31 311 23 20.4 (22)
Chen 2005 1985–2003 China 37 172 131 12 29 126 46 71 (8)
Abdalla 2006 n/a Egypt 42 79 31 27 21 46 33 60 (9)
Akin 2010 1998–2002 Turkey 45.5 10 7 0 3 7 3 62 (23)
Jung 2010 1998–2006 Korea 37.6 67 39 16 12 61 5 n/a (24)
Jang 2012 1995–2009 Korea 43 164 82 42 40 148 16 33.6 (13)
Tsang 2012 n/a China 45 185 120 48 17 n/a n/a 42 (25)
Kim 2013 2000–2010 South Korea 41 193 145 33 15 182 11 65 (12)
Spitaleri 2013 1999–2010 Italy 44 172 68 42 62 137 35 85 (26)
Wei 2014 1997–2012 China 40 192 80 63 49 145 47 72.9 (27)
Onkendi 2014 1971–2008 USA 47 67 0 15 52 32 35 120 (28)
Yom 2015 1989–2008 Korea 36.44 285 191 61 33 271 14 81.4 (29)
Bellezza 2016 1988–2009 Italy 42 62 40 13 9 53 9 n/a (30)
Borhani-Khomani 2016 1999–2014 Denmark 45.6 443 354 89 0 395 10 98 (15)
Moutte 2016 2003–2013 France 37.9 76 67 9 0 75 1 58 (31)
Ruvalcaba-Limón 2016 2005–2015 Mexico 41.7 305 222 50 35 213 92 36.2 (32)
Moo 2017 2003–2013 USA 35 246 216 30 0 243 3 35.5 (33)
Rodrigues 2017 1999–2014 The Netherlands 48 183 83 50 49 163 19 65 (34)
Tremblay-LeMay 2017 1998–2010 Canada 44.4 114 81 20 13 112 2 15.48/59.88/65.04b (35)
Chng 2018 2006–2015 Singapore 37.7 240 196 27 17 n/a n/a 19.2 (36)
Choi 2018 1981–2014 Korea 43 362 0 127 235 247 84 60 (37)
Sevinc 2018 1994–2017 Turkey 40.6 122 14 0 122 n/a n/a 39 (38)
Mitus 2018 1952–2013 Poland 51 334 187 40 107 248 86 121 (39)
Zhou 2018 2002–2013 China 41 404 168 184 52 378 26 46 (40)
Gulben 2019 2008–2014 Turkey 34 89 68 14 7 85 4 n/a (41)
Li 2019 1999–2009 China 43.2 290 181 76 33 233 36 n/a (42)
Wen 2020 2008–2017 Canada 43 96 75 10 11 88 8 47.3 (43)
Genco 2021 2005–2019 USA 36 205 191 14 0 n/a n/a n/a (44)
Lim 2021 2002–2014 Canada 45.8 150 110 21 19 120 30 36 (45)
Rosenberger 2021 2007–2017 USA 44 550 379 108 58 512 34 36.7 (18)

a, age is represented by the average or the median age of the study. b, the median follow-up time was 15.48 months for benign, 59.88 months for borderline, and 65.05 months for malignant PTs. BCS, breast conservative surgery; M, mastectomy; n/a, not available; PTs, phyllodes tumors.

Margin status

A total of 26 articles evaluated the correlation between surgical margin status (positive or negative) and LR risk. Overall, compared with negative margins, positive margins could significantly increase the risk of LR (OR 3.64; 95% CI: 2.60–5.12) (Figure 2). Ten, eight and eight studies reported LR rates for the benign, borderline and malignant PTs (Figure S1). A positive margin was significantly associated with a high LR risk regardless of tumor grade (benign OR 3.32, 95% CI: 1.18–9.34; borderline OR 2.88, 95% CI: 1.16–7.14 and malignant OR 4.70, 95% CI: 1.63–13.62).

Figure 2 Forest plot showing the pooled odds ratios of local recurrence by surgical margin (positive vs. negative).

Margin width

Most studies still use 1 cm as the boundary to explore the impact of margin width on the risk of LR. Pooling of data from 14 studies showed no significant difference in the LR risk between patients with margin ≥1 and <1 cm (OR 1.39, 95% CI: 0.67–2.92) (Figure 3). The subgroup analysis included 10 studies for benign, 9 studies for borderline, and 9 studies for malignant PT. The results showed that there was no significant difference in the LR risk between margin width <1 and ≥1 cm in all subgroup analysis (benign OR 1.19, 95% CI: 0.57–2.48; borderline OR 1.37, 95% CI: 0.42–4.47 and malignant OR 2.15, 95% CI: 0.64–7.19) (Figure S2). The borderline and malignant PTs were combined and analyzed with a total of 13 articles included. No significant difference in the LR risk of the margin width between the two groups was found (OR 1.68, 95% CI: 0.81–3.47) (Figure S3).

Figure 3 Forest plot showing the pooled odds ratios of local recurrence by surgical margin (margin <1 vs. ≥1 cm).

Surgical treatment

A total of 15 studies which contained LR rates for different surgical treatments were extracted. Four, five and six studies reported LR rates for the benign, borderline, and malignant PTs respectively (Figure 4). No significant difference between BCS and mastectomy in benign and borderline PT were found (benign OR 0.68, 95% CI: 0.12–3.78; borderline OR 1.14, 95% CI: 0.29–4.51). But BCS was significantly associated with a higher LR risk for malignant PT (OR 2.77, 95% CI: 1.33–5.74).

Figure 4 Forest plot showing the pooled odds ratios of local recurrence by surgical treatment (breast-conserving surgery vs. mastectomy) stratified by the phyllodes tumor grade.

Sensitivity analysis and publication bias

All studies carried out sensitivity analysis and publication bias analysis. Exclusion of Motte et al. or Li et al., as part of the sensitivity analysis, achieved no statistical significance between positive and negative margin for benign PT (Motte exclusion: OR 2.66, 95% CI: 0.99–7.18; Li exclusion: OR 2.64, 95% CI: 0.85–8.22). After Li et al. or Wen et al. was excluded, the LR risk achieved no statistically difference between different margin status for borderline PT (Li exclusion: OR 2.13, 95% CI: 0.71–6.43; Wen exclusion: OR 2.43, 95% CI: 0.96–6.17). The rest of the analysis showed no significant changes in outcomes. No obvious publication bias was observed in the funnel plots (Figures S4,S5). No significant heterogeneity was statistical in this study.

Discussion

In this systematic review and meta-analysis grounded on a total of 6,431 patients from 34 studies, we assessed the correlation of margin, surgical treatment and LR risk for different grade of PT.

For benign PT, no significant difference in the LR rate between margin <1 and ≥1 cm and BCS and mastectomy was found, suggesting that BCS even lumpectomy was adequate for benign PT. As for margin status, we found a significant correlation between positive margin and LR risk, indicating that benign PT with positive margin required re-excision to reduce LR risk. Many studies concluded the same results (8,26,46,47). While some studies suggested that margin status was related to LR only in terms of malignant PT and whether benign PT with positive margins need further resection still required further exploration (14). Shaaban et al. reviewed cases of benign PT and indicated that positive margins increased the LR rate. However, in view of the low LR rate of benign PT with positive resection margin (12.9%), the strategy of “wait and see” could still be adopted, and re-excision is only applicable for borderline and malignant PTs (10). Moo et al. performed a study of 246 benign PT patients with positive margins and found no significant difference in LR between patients underwent re-excision and observation (33). Since the benefits of re-excision on the prognosis of the patient are uncertain and a second operation may bring psychological pressure or cosmetic damage to the patients, “wait and watch” strategy with regular following-up may be an optimal option for benign PT with positive margin.

For borderline PT, we found no significant correlation of LR risk neither with margin width nor surgical treatment, indicating that BCS with a margin less than 1 cm might be feasible for borderline PT. Ogunbiyi et al. also found that margin ≥1 and <1 cm had no significant difference in the LR risk for borderline PT, which was consistent with the result of this study (48). Thind et al. conducted a systematic review and meta-analysis on borderline and malignant PTs, and proposed that the correlation between margin width and LR was not statistically different as well (11). However, there were also studies indicated that borderline PT was resemble to malignant PT in terms of chromosomal variation and gene mutation and suggested that borderline PT should be given the same attention as malignant PT in making surgical decision (14,49,50). Barth et al. found that 12/50 (24%) borderline PT locally recurred and indicated BCS with negative margins was not enough for borderline PT to meet a good prognosis (51). Whether the 1 cm margin is sufficient for borderline PT is still controversial with more cases to supplement.

As for malignant PT, no significant difference in the LR rate between margin ≥1 and <1 cm was found which was consistent with the meta-analysis conducted by Thind et al. (11). Some studies also indicated that there was no real advantage to obtain ≥1 cm margins as thinner surgical excisions did not impact LR and the disease-free survival (13,28,35). Neron et al. conducted a multicenter nationwide retrospective study of malignant PT and suggested that a 3 mm threshold was sufficient with no impact of wide margins on overall-survival (52). However, the vast majority of studies still recommended WLE with margins ≥1 cm and more studies were needed to identify a precise margin threshold (12,27,53-55). A clearly correlation between positive margin and LR risk was found in terms of margin status. Re-excision was required for malignant PT to obtain negative margin and reduce LR risk (12,56,57). In this study, mastectomy was found having a positive impact on LR risk than BCS which was probably linked to the surgical procedure indicated by Neron et al., that is, en bloc resection along the muscle fascia (52). Mastectomy should be recommended in the situations where the tumor was too large or if the inability to obtain negative margin to reduce LR risk (7,58).

This study also had some limitations. The studies included were all retrospective studies, and there were only few articles that could be analyzed in the subgroup analysis. Studies are still needed to confirm the reliability of the conclusions. Meanwhile, few studies on <1 and 1–10 mm margins were reported, causing it impossible to evaluate the impact of this threshold on LR risk. In addition, by sensitivity analysis, we found that the correlation between the margin status and LR rate was not statistically significant after the exclusion of some individual studies for benign and borderline PTs. More studies on margin status need to be updated in the future research.

Conclusions

Different surgical management strategies should be considered for different PT grades. Regardless of the tumor grade, there was a significant correlation between positive margin and LR risk. And BCS was a feasible option as margins <1 cm was not significantly associated with LR risk. After BCS, “wait and watch” strategy was adequate for benign PT with positive margin, while borderline and malignant PTs were expected to underwent re-excision to ensure negative margins. Mastectomy was recommended in the situations where the tumor was too large or if the inability to obtain negative margin to reduce LR risk. At present, more retrospective or prospective studies are still needed to clarify and update the existing conclusions and improve the prognosis of PT patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-21-789/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-21-789/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-21-789/coif). XL serves as an Editor-in-Chief of Gland Surgery from May 2012 to April 2022. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Wei Y, Yu Y, Ji Y, Zhong Y, Min N, Hu H, Guan Q, Li X. Surgical management in phyllodes tumors of the breast: a systematic review and meta-analysis. Gland Surg 2022;11(3):513-523. doi: 10.21037/gs-21-789

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