Malignant Phyllodes Tumour

Malignant phyllodes tumour is a fibroepithelial breast neoplasm with a malignant stromal component, a leaf like architecture, high stromal cellularity, marked atypia and frequent mitoses. It metastasises haematogenously and rarely to lymph nodes.

Phyllodes tumours make up 0.3% to 1% of breast tumours. Of these, roughly 60% to 75% are benign, 15% to 25% borderline and 10% to 20% malignant. Median age at presentation is 40 to 50 years, about a decade older than for fibroadenoma.

Associations are Li-Fraumeni syndrome (TP53), higher incidence in Asian and Latin American women, and MED12 mutations in the fibroepithelial lineage. Malignant tumours also carry TERT promoter mutations and sometimes RARA, EGFR amplification or TP53 and RB1 alterations.

Pathophysiology. The stromal component is the neoplastic element, with an epithelial component that is reactive. Malignant transformation follows progression from benign and borderline types.

Histological grading. Malignant tumours show marked stromal cellularity, marked nuclear atypia, 10 or more mitoses in 10 high power fields, marked stromal overgrowth and infiltrative borders. Malignant heterologous elements (liposarcoma, osteosarcoma, chondrosarcoma, rhabdomyosarcoma) may be present.

Behaviour. Local recurrence is about 20% to 30% for malignant tumours, usually within 2 to 3 years and related to margin status. Distant metastasis occurs in about 20% to 30% of malignant tumours, to lung (commonest), bone, liver and brain. Axillary node involvement is under 5%.

• Rapidly growing painless mass over weeks to months, smooth or lobulated, mobile, with a median size of 4 to 5 cm and some over 10 cm.
• Stretched shiny skin with dilated veins, and skin ulceration from pressure necrosis rather than invasion.
• Nipple retraction and fixation to the chest wall are uncommon and suggest sarcomatous overgrowth.
• Palpable axillary nodes are usually reactive.

• Ultrasound shows a well defined, lobulated heterogeneous mass with cystic clefts. Mammography shows a round or lobulated density. MRI shows lobulated features with enhancing septa.
• Core biopsy cannot reliably distinguish phyllodes tumour from fibroadenoma. Features favouring phyllodes tumour are size over 3 cm, rapid growth, age over 35 to 40 and a cellular stroma. Where phyllodes is suspected, excisional biopsy with the whole tumour allows full grading.
• Immunohistochemistry: stromal CD34 often positive, with the epithelial component positive for cytokeratin.
• Staging for malignant tumours: CT of the chest. Further imaging by symptoms. Axillary imaging only if nodes are palpable.
• Baseline FBC, creatinine and liver tests.

Differential diagnosis.

• Fibroadenoma (including giant and juvenile types)
• Borderline and benign phyllodes tumour
• Metaplastic (spindle cell) carcinoma
• Primary breast sarcomas (angiosarcoma, liposarcoma, fibrosarcoma)
• Fibromatosis
• Pseudoangiomatous stromal hyperplasia
• Hamartoma and breast abscess

Surgery is the only curative treatment.

Surgery.

• Wide local excision with a margin of at least 1 cm. Enucleation is not appropriate.
• Mastectomy for large tumours relative to breast size, multifocal disease or recurrent disease. Immediate reconstruction is possible.
• Axillary surgery is not needed unless nodes are clinically positive.
• Local recurrence needs re-excision with wide margins or mastectomy.

Radiotherapy. Not routine. Consider chest wall or breast radiotherapy (about 50 Gy in 25 fractions) for malignant tumours over 5 cm, positive margins that cannot be re-excised, or recurrence. It reduces local recurrence without improving survival.

Systemic therapy. Not routine in localised disease. In metastatic or unresectable disease, treatment follows soft tissue sarcoma practice, and endocrine therapy and breast cancer regimens have no role.

• Doxorubicin: 75 mg/m2 IV every 3 weeks for up to 6 cycles; maximum cumulative working ceiling 450 mg/m2; monitoring: echocardiography at baseline and every 2 cycles, FBC before each cycle; adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid; consider reduction when eGFR is under 30 mL/min/1.73 m2. Dexrazoxane is used if cumulative exposure exceeds 450 mg/m2.
• Resection of isolated pulmonary metastases is considered in selected fit patients.

Monitoring. Clinical examination and breast imaging every 6 months for 2 to 3 years, then annually. Chest imaging every 6 to 12 months for 3 to 5 years in malignant tumours. Recurrence is usually local first.

Referral and escalation.

• Referral to a sarcoma multidisciplinary team for malignant tumours, recurrent disease and metastatic disease.
• Early surgical referral for any rapidly growing breast mass over 3 cm.

Special groups.

• Adolescents: most are benign. Treat by complete excision with breast conservation.
• Pregnancy: tumours can grow rapidly. Excise with wide margins in any trimester.
• Li-Fraumeni carriers: avoid radiotherapy where possible, and arrange genetic counselling.