Treatment and outcome of cystosarcoma phyllodes in Brunei: a 13-year experience

K.Y.Y KOK*, P.U. TELESINGHE# and S.K.S. YAPP*
*Department of Surgery and #Department of Pathology, Ripas Hospital, Bandar Seri Begawan, Brunei

Introduction Materials and Methods Results

Discussion Conclusion References

The purpose of this article is to discuss the benefits of and to illustrate a framework for appraisal. The place of career advice in this process is mentioned, as is a brief discussion on Assessment. From the point of view of the individual doctor, information to help him/her choose an appropriate career path should be readily available. It is more likely that a doctor will perform well throughout their career, if in a career or occupation that suits them.

Key words: Adjuvant therapy, cystosarcoma phyllodes, histological categories, recurrence, surgery

J.R.Coll.Surg.Edinb., 46, August 2001, 198-201

INTRODUCTION

Cystosarcoma phyllodes (CSP) was first named and described by Johannes Muller in 1838, based on a gross pathological description of a ‘bulky, cystic, fleshy and leafy tumour of the breast.’1 It is a neoplasm of the breast characterised by the presence of both stromal and epithelial components. Cystosarcoma phyllodes is rare and its incidence is estimated to be 0.3% to 0.5% of all breast tumours. ^2,3

Several classifications of CSP have been proposed over the years, based on certain histopathological criteria - Treves and Sunderland (1951), Pietruszka and Barnes (1978), Azzopardi (1979) and the World Health Organization classifications -Anon (1982). ^4-7 These criteria consist of cellular atypia, stromal cellularity, sarcomatous differentiation and mitotic index. The WHO classification was proposed in 1982 in order to promote uniformity in the recording and reporting of breast diseases and to facilitate international comparisons. Numerous reports have attempted to correlate the histological features with clinical outcome. These reports generally showed a poor correlation between the two and histo-pathology does not necessarily predict the clinical course. ^8,9 As a result, the incidence of malignant CSP has been variably quoted to be between 3% and 54%.3 This lesion was recently renamed ‘phyllodes tumour’ but the term CSP will be retained in this report as it has been in common usage and was used for all the recorded cases described in this article.
Over the years, there has been debate regarding the optimal management of CSP and clinical management still remains controversial. This report was undertaken to review our experience with CSP and to attempt to provide a practical approach to these rare and unpredictable breast tumours.

MATERIALS AND METHODS

Brunei is a small country with an area of 5765 km2 and a population of 350 000. ¹⁰ The Pathology Department of the State Laboratory at Ripas Hospital functions as a central laboratory for the whole country. Histopathological specimens from all the district general hospitals are sent to this laboratory for examination and documentation. Cases indexed as CSP or phyllodes tumours, between 1986 and 1998 inclusive, were obtained from the Pathology Department. Cases diagnosed as pure sarcomas or giant fibroadenomas of the breast were excluded from the study. The records were retrieved and the cases were reviewed retrospectively. Histopathological material from each case was reviewed by one of the authors (PUT). The WHO Classification of CSP was used and the lesions were categorised as benign, borderline or malignant, based on the frequency of mitoses, infiltrative margins, cellular atypia and cellularity.7 Data was obtained with regard to age, presentation, histological diagnosis, treatment, recurrence and follow-up.

RESULTS

There were 27 patients diagnosed with CSP during the 13-year study period (1986-1998 inclusive). Clinical details and follow-up were complete for 26 cases. One case (benign CSP) was lost to follow-up. All patients were female. The clinical, pathological and therapeutic features of the 26 cases are summarised in Table 1. There were 19 (73%) histologically benign lesions, three (12%) borderline lesions and four (15%) malignant lesions. The mean follow-up period was 37 months (range 13-156 months).

The mean age at the time of diagnosis was 35 years (range 11-58 years). The mean ages of patients with histologically benign, borderline and malignant lesions were 34, 34 and 43 years, respectively. All patients presented with a palpable breast lump and eight cases (31%) also had associated pain. The mean duration of symptoms was 6 months (range 1-36 months). There appeared to be a predominance for involvement of the left side. There were 20 (77%) left-sided lesions and six (23%) right-sided lesions. The mean size of the presenting breast lump was 7 cm (range 1-25 cm). The mean size of malignant lesions was larger (12 cm) than benign and borderline lesions (7 cm and 3 cm, respectively). Only two cases (8%) occurred in post-menopausal women.

Initial investigations included breast ultrasonography in one case (which was misdiagnosed as a fibroadenoma), mammography in five cases (which correctly diagnosed CSP in two cases) and fine needle aspiration cytology (FNAC) of the breast lump in four cases. The FNAC results were diagnostic in two cases; one case was misdiagnosed as fibroadenoma and the other as fibrocystic disease.

Primary treatment included excisional biopsy in 16 cases, wide local excision (WLE) in 7 cases and simple mastectomy in three cases. All the 19 patients with benign CSP underwent either excisional biopsy or WLE only. Wide local excision was used in all three borderline lesions and in one of the four patients with malignant lesions. The other three malignant lesions were treated by mastectomy.

Four recurrences were noted in the present study (16%). Tumours recurred in one benign (5%), one borderline (33%) and two malignant (50%) cases. The time to recurrence ranged from 2 to 15 months, with recurrences occurring within 6 months in the two cases with malignant lesions. The benign lesion (Case 3) that recurred was initially treated by excisional biopsy and the original histopathology revealed involved resection margins. This patient subsequently underwent WLE. Recurrence occurred in one borderline lesion (Case 18) 14 months after initial WLE. A simple mastectomy was performed for the recurrent tumour and the patient remained disease free at 21-month follow-up. One malignant lesion (Case 11), initially treated by mastectomy, developed local recurrence after 2 months. Histopathology of the lesion showed a necrotic tumour with hypercellular stroma and marked mitotic activity. Despite excision of the recurrent tumour followed by chemotherapy, the patient died 10 months later with metastatic disease in the liver and brain. The other malignant lesion (Case 25) had a WLE as the primary treatment in another country; she developed local recurrence 3 months later. This patient subsequently under-went a simple mastectomy She remained disease-free 14 months later and received no chemotherapy.
Axillary lymph nodes were sampled in two of the three patients in whom mastectomy was performed, as part of the primary treatment. None showed evidence of metastases. Similarly, no lymph node involvement was seen in the patient who underwent mastectomy for recurrent disease. 
The other two malignant lesions (Cases 13 and 20) underwent mastectomy as primary treatment. Histopathology of Case 13 showed a highly cellular and vascular stroma. Case 20 showed marked mitotic activity. Both patients received adjuvant radiotherapy and chemotherapy and remained disease-free at 30 and 16 months follow-up, respectively.

Table 1: Clinical, pathological and therapeutic features of patients with cystosarcoma phyllodes 

E = excisional biopsy, WLE = wide local excision, SM = simple mastectomy, SM + A = simple mastectomy and axillary sampling, * adjuvant radiotherapy and chemotherapy

DISCUSSION

Cystosarcoma phyllodes is an unusual neoplasm of the breast that demonstrates extremes of biological activity. It continues to present problems to both histopathologists and surgeons alike because of its atypical and unpredictable behaviour. ‘Benign’ lesions have been noted to metastasise, and can recur locally.¹¹ In one study, local recurrence was seen to occur in 5% of benign tumours, 45% of borderline tumours and 37% of malignant tumours. ¹² Another study noted more recurrence with benign lesions, ¹³ whereas others noted no difin recurrence rates between benign and malignant. ¹⁴ Overall recurrence in the current series was 16% and this was similar to that noted by Bennett et al (1992) (16.5%) and Holthouse et al (1999) (15.4%). ^14,15 Metastasis in this series was 4%, which was lower than the reported frequency of metastases in the literature (10% - 30%). ^11,16

The difficulty of predicting the clinical behaviour of CSP is well known. Norris and Taylor (1967) were among the first to use histopathological features in an attempt to predict prognosis, but highlighted the fact that no single feature was reliable.⁹ Further studies have found certain pathological criteria to be useful in predicting the tumours that are likely to behave in a malignant fashion. These include stromal overgrowth, nuclear pleomorphism, high mitotic rate and infiltrating margins. ¹⁷ Other studies have also reported the significance of the presence of necrosis and increased vascularity within the tumour.¹⁸ In general, malignant lesions tend to be larger than benign ones, as noted in the present series; it is, however, well recognised that even small lesions may behave in an aggressive manner and conversely large lesions may be benign.

Cystosarcoma phyllodes has been described as occurring in women over a wide range of ages - pre-pubertal to elderly. ¹⁹ The mean age of patients in this series was 35 years which is younger than that noted in most published series (in their 40’s). ^12,14,16 This observation was also reported by Chua et al (1988) and Iau et al (1998), whose patients consisted of a non-caucasian population similar to ours. ^20,21 The mean age of patients with malignant lesions is generally reported to be greater than that for those with benign lesions and this was observed in this study. Malignant lesions also exhibited a tendency to recur early; both malignant recurrences in the present series recurred within 6 months of the initial surgery.

Certain guidelines on the surgical treatment of CPS have been proposed 22 but the optimal management of patients with CSP remains controversial. Mammography is unreliable since many of the lesions do not have typical mammographic characteristics of malignant disease. ^15,23 Fine needle aspiration cytology has been shown to be of limited value, as seen in this and other studies, ^15,24 primarily because of the difficulty in obtaining adequate numbers of stromal cells for cytogenic analysis. ²⁵ Recently, core needle biopsy has been reported to be useful in differentiating a CSP from a fibroadenoma. ^26,27 A high index of suspicion, therefore, is required for the initial diagnosis of CSP. In general, these tumours are large, palpable and painless on presentation. Skin fixation, ulceration and nipple changes are rare. A rapid growth is often noted. It tends to present in younger patients than carcinoma of the breast. ^4,5

Surgery remains the primary treatment. The aim is to excise the lesion with adequate margins to prevent local recurrence, including mastectomy if required. This is advocated for benign lesions. It is felt that local recurrence is due to inadequate local excision; as seen in the only recurrence in a benign lesion in the present series. If the lesion is found to be malignant, a simple mastectomy is recommended. Malignant CSP, unlike carcinoma, is generally not responsive to radiotherapy or chemotherapy and mastectomy is the best procedure to prevent local recurrence. Routine axillary lymph node dissection is not generally done, as this disease rarely spreads by lymphatics. ^9,16 No involved nodes were seen in this series in which axillary dissections were performed. For borderline lesions, the optimal primary treatment is more controversial. Breast-conserving surgery with WLE was employed as the primary treatment in the present series. As seen in other series, ^15-17 this primary treatment for borderline lesions seemed to be adequate. However, when a borderline lesion recurs after primary surgery, a simple mastectomy may be required. This more radical treatment may be justifiable as most reports have shown that recurrent tumours tend to be more aggressive with a higher mitotic count and greater degree of nuclear pleomorphism than the original lesions. ^14,28

Although no conclusive evidence supports adjuvant radiotherapy or chemotherapy for malignant CSP, encouraging results using radiotherapy and chemotherapy for soft tissue sarcomas suggest consideration be given for their use in cases of malignant CSP. 29 Effective radiotherapy and chemotherapy have been reported in isolated cases. Radiotherapy was shown to lead to a slow regression of CSP 2,30 and Chaney et al (1998) had found adjuvant radiotherapy to be beneficial in eight patients whose CSP showed adverse features (bulky tumours, positive margins, recurrence and malignant histology). ³¹

Effective chemotherapy in four patients using ifosfamide alone or in combination with doxorubicin was reported by Hawkin et al (1992). ³² We have also used ifosfamide in combination with doxorubicin in two of our malignant cases who had poor prognostic histopathological features. Both patients were alive and disease-free at 30 and 16 months follow-up. Others have also reported effective chemotherapy with cisplatin and etoposide. ³³ The use of tamoxifen in CSP has not been fully investigated. However, oestrogen and progesterone receptors have been documented in these tumours and future studies with hormonal manipulation in CSP may be warranted. ³⁴

CONCLUSION

Cystosarcoma phyllodes is a rare breast tumour whose clinical behaviour is often unpredictable and unanticipated from the histopathological findings. Surgery remains the main primary treatment and an adequate resection margin must be obtained in all cases. In benign and borderline lesions, breast- conserving surgery should be employed, except when the tumour size is large. For malignant lesions, simple mastectomy without routine axillary dissection is recommended. Anecdotal cases have shown that adjuvant radiotherapy and chemotherapy may be beneficial in CSP with poor prognostic histological features (hypercellular stroma, high nuclear pleomorphism, high mitotic rate, infiltrating margins, the presence of necrosis and increased vascularity within the tumour). However, further research is required to determine the role of radiotherapy and chemotherapy in the management of CSP. In all cases of CSP careful long-term follow-up is recommended.

REFERENCES

1. Muller J. Uber den feineran Bau and die Fromen der Krankhaften Geschwulste. Berlin: Reimer, 1838: 54-60.
2. Kessinger A, Foley JF, Loron HM, Miller DM. Metastatic cystosarcoma phyllodes: a case report and review of the literature. J Surg Oncol 1972; 4: 131-47
3. Vorherr H, Vorherr UF, Kutvirt DM, Key CR. Cystosarcoma phyllodes: epidemiology, patho-physiology, pathobiology, diagnosis, therapy and survival. Arch Gynaecol 1985; 236: 173-81
4. Treves N, Sunderland DA. Cystosarcoma phyllodes of the breast: a malignant and a benign tumour. A clinicopathologic study of 77 cases. Cancer 1951; 4: 1286-332
5. Pietruszka M, Barnes L. Cystosarcoma phyllodes: a clinicopathologic analysis of 42 cases. Cancer 1978; 41: 1974-83
6. Azzopardi JG. Problems in breast pathology. In: Bennington J, ed. Major Progress in Pathology. Philadelphia: WB Saunders, 1979: 346-65
7. Anon. The World Health Organization Histological Typing of Breast Tumor, 2nd edition. Am J Clin Pathol 1982; 78: 806-16
8. Hart WR, Bauer R, Oberman H. Cystosarcoma phyllodes: a clinico-pathologic study of 26 hyper-cellular peri-ductal stromal tumours of the breast. Am J Clin Pathol 1978; 70: 211-6
9. Norris HJ, Taylor HB. Relationship of the histologic appearance to behaviour of cystosarcoma phyllodes: analysis of 94 cases. Cancer 1967; 20: 2090-9
10. Ministry of Health. An official handbook. Negara Brunei Darussalam, 1995
11. Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Silfversward C. Prognostic factors in cystosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer 1991; 68: 2017-22
12. Salvadori B, Cusumano F, Del-Bo R. Surgical treatment of phyllodes tumors of the breast. Cancer 1989; 63: 2532-6
13. Hadju SI, Espinosa MH, Robbing GF. Recurrent cysto-sarcoma phyllodes: a clinico-pathological study of 32 cases. Cancer 1976; 38: 1402-6
14. Bennett IC, Khan A, DeFreitas R, Charding MA, Millis RR. Phyllodes tumour: a clinico-pathological study review of 30 cases. Aust N Z J Surg 1992; 62: 628-33
15. Holthouse DJ, Smith PA, Naunton-Morgan R, Minchin D. Cystosarcoma phyllodes: the Western Australian experience. Aust N Z J Surg 1999; 69: 635-8
16. McGregor GI, Knowling MA, Este FA. Sarcoma and cysto-sarcoma phyllodes. Tumours of the breast: a retrospective review of 58 cases. Am J Surg 1994; 167: 447-80
17. Hawkins RE, Schfield JB, Fisher C, Wiltshaw E, McKinna JA. The clinical and histologic criteria that predict metastases from cystosarcoma phyllodes. Cancer 1992; 69: 141-7
18. Ward RM, Evans HL. Cystosarcoma phyllodes. A clinicopathologic study of 20 cases. Cancer 1986; 68: 2286-9
19. Keish JM. Cystosarcoma phyllodes in a 12-year-old girl. N C Med J 1974; 35: 295-6
20. Chua CL, Thomas A, Ng BK. Cystosarcoma phyllodes -Asian variations. Aust NZJ Surg 1988; 58: 301-5
21. Iau PT, Lim TC, Png DJ, Tan WT. Phyllodes tumour: an update of 40 cases. Ann Acad Med Singapore 1998; 27:200-3
22. Mangi AA, Smith BL, Gadd MA, Tanabe KK, Ott MJ, Souba WW. Surgical management of phyllodes tumors. Arch Surg 1999; 134: 487-92
23. Liberman L, Bonaccio E, Hamele-Bena D, Abramson AF, Cohen MA, Dershaw DD. Benign and malignant phyllodes tumors: mammographic and sonographic findings. Radiology 1996; 198: 121-4
24. Rowell MD, Perry RR, Hsiu JG, Barranco SC. Phyllodes tumour. Am J Surg 1993; 165: 376-9
25. Shimizu K. Cytologic evaluation of phyllodes tumors as compared to fibroadenomas of breast. Acta Cytol 1994; 38: 891-7
26. Florentine BD, Cobb CJ, Frankel K, Greaves T, Martin SE. Core needle biopsy. A useful adjunct to fine-needle aspiration in select patients with palpable breast lesions. Cancer 1997; 81: 33-9
27. Berg WA, Hruban RH, Kumar D, Singh HR, Brem RF, Gatewood OM. Lessons from mammographic-histologic correlation of large-core needle breast biopsy. Radiographics 1996; 16: 1111-30
28. Hughes LE, Mansel RE, Webster DJT, eds. Benign Disorders and Diseases of the Breast: Concepts and Clinical Management. London: Bailliere-Tindall, 1989: 69-73
29. Carabell SC, Goodman RT. Radiation therapy for soft tissue sarcoma. Semin Oncol 1981; 8: 201-6
30. Long RT, Hesker AE, Johnson RE. Surgical management of cystosarcoma phyllodes with a report of 8 cases. Mo Med 1962; 59: 1179-81
31. Chaney AW, Pollack A, McNeese MD, Zagars GK. Adjuvant radiotherapy for phyllodes tumor of breast. Radiat Oncol Investig 1998; 6: 264-7
32. Hawkins RE, Schofield JB, Wiltshaw E, Fisher C, McKinna JA. Chemotherapy for metastatic cysto-sarcoma phyllodes: Ifosfamide is an active drug. Cancer 1992; 69: 2271-5
33. Burton GV, Hart LL, Leight GS, Iglehart JD, McCarty KS, Cox EB. Cystosarcoma phyllodes: effective therapy with cisplatin and etoposide chemotherapy. Cancer 1989; 63: 2088-92
34. Palshof T, Blickert-Taft M, Daehnfelt L. Estradiol binding protein in cystosarcoma phyllodes of the breast. Eur J Cancer 1980; 16:591-3

Copyright date: 21st February 2001
Correspondence: Mr KYY Kok, Department of Surgery, Ripas Hospital, Bandar Seri Begawan BA1710, Brunei
E- mail: koky@brunet.bn

©2001 The Royal College of Surgeons of Edinburgh, J.R.Coll.Surg.Edinb.