Malignant Phyllodes Tumour Dr. Puay Hoon Tan

Clinical History A 44 year old Chinese lady underwent screening mammography in November 2002 which detected left breast microcalcifications and two right breast nodules at 3 o'clock and 9 o'clock. Stereotactic-guided mammotome biopsies of the left breast microcalcifications revealed benign fibrocystic changes, while ultrasound guided trucut biopsies of the right breast nodules showed histological features consistent with derivation from fibroadenomas. In August 2003, she presented with a palpable enlarging right breast mass measuring up to 9.3 cm on ultrasonography. Correlation with the previous mammograms and ultrasound scans performed in November 2002 disclosed that this enlarging right breast mass was in fact the nodule discovered in the right breast at the 3 o'clock position nine months ago, which was approximately 3 cm in size then. The patient had been advised to undergo excision of this nodule in November 2002, but had defaulted follow-up. When she first started to experience progressive enlargement of the right breast lump the following year, the country and its hospitals were facing serious issues with SARS (severe acute respiratory distress syndrome). The patient therefore delayed seeking treatment, and only returned to the hospital in August 2003, whereupon the mass was surgically excised. The section is from this excised mass. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic appearances The submitted section showed sheets and fascicles of spindle cells with moderate hypercellularity and obvious stromal cytologic atypia. Mitoses numbered up to 25 per 10 high power fields, with occasional atypical mitoses. No necrosis was present in this section. Zones composed of only spindle cells devoid of epithelial elements were present. A fibroepitheliomatous appearance was noted at the edge of the lesion, resembling the intracanalicular growth pattern of a fibroadenoma. A few small epithelial islands were embedded within the hypercellular spindled areas, the latter merging fairly imperceptibly with the fibroepitheliomatous compartment. Elsewhere, not represented in this section, the borders of the lesion were permeative and spindle cells percolated into surrounding adipose stroma. No heterologous elements were found. There were no atypical or malignant epithelial areas. Lesional tissue abutted the surgical margins in a few foci. The diagnostic conclusion was of malignant phyllodes tumour. Review of the previous trucut biopsies (three3 cores were taken) showed features characteristic of a fibroadenoma, and did not reveal changes that would have altered the histologic diagnosis rendered then. Differential diagnosis Malignant phyllodes tumour Metaplastic carcinoma Primary breast sarcoma. Follow up The patient underwent a simple mastectomy in September 2003 that did not disclose any residual tumour. She remained on regular follow-up, and was disease free at her last hospital visit in March 2006. Discussion The presence of fibroepitheliomatous areas of the lesion with perithelial hypercellularity, compressed epithelium lining elongated clefts, merging with hypercellular zones of stromal overgrowth, stromal cytologic atypia and permeative margins, warranted a diagnosis of malignant phyllodes tumour. Phyllodes tumours, also known as cystosarcoma phyllodes, are fibroepithelial neoplasms that generally occur in an older age group than fibroadenomas. They tend to be large, seen mammographically as round or lobulated, sharply defined, opaque masses. Indistinct borders are noted in a minority of cases. On ultrasound, they are well circumscribed, but the presence of cysts and epithelium-lined clefts may lead to an inhomogeneous appearance. Histologically, there is a leaf-like architecture with an exaggerated intracanalicular growth pattern and increased stromal cellularity. Benign, borderline and malignant phyllodes tumours are classified based on assessment of a constellation of histological features that include stromal cellularity, stromal atypia, mitotic activity, stromal overgrowth, invasive versus pushing margins and the presence of necrosis and haemorrhage. All phyllodes tumours, regardless of its benign or malignant nature, have a propensity for local recurrence, especially if inadequately excised by enucleation without a surrounding rim of tissue. The need to separate benign phyllodes tumour from fibroadenoma traditionally has been related to the recurrent and progressive potential of the former contrasted with the innocuous nature of the latter. Fibroadenomas can occur synchronously with 4.2% of phyllodes tumours, as reported in one study. The relationship between these two entities, however, is not fully understood. Early reports documented the presence of areas of fibroadenoma within otherwise characteristic phyllodes tumours and alluded to fibroadenoma being the possible precursor or progenitor of phyllodes tumour. More recently, molecular evidence for the progression of fibroadenoma to phyllodes tumour was described, with Kuijper et al expressing that fibroadenomas might progress not only in a stromal manner into phyllodes tumour, but also in an epithelial direction toward carcinoma in situ. Because fibroadenoma-like areas are not encountered uncommonly in phyllodes tumours, adequate macroscopic sampling is required for excision specimens to avoid overlooking areas typical of phyllodes tumours, which might be focal within the tumour. In the current age of pre-operative core biopsy diagnoses, the possibility of undersampling also raises important management issues. The trucut biopsies carried out earlier were deceptive in that there were no histologic clues to suggest the presence of an underlying phyllodes tumour. The subsequent excision also disclosed focal areas at the periphery of the mass that resembled fibroadenoma. It is presumed that the trucut biopsies may have sampled this fibroadenomatous part of the lesion, and therefore were not representative. An accurate preoperative distinction of phyllodes tumour from fibroadenoma cannot always rely purely on histological appearances, as demonstrated in this case where only benign fibroadenomatous features were present on the core biopsies. Whether additional cores would have been more elucidative is uncertain, as in general, recommendation is for about three biopsy cores to be sampled from radiologic breast densities, which was accomplished in this case. Clinico-radiologic correlation with consideration of lesion size and patient age are other factors in deciding whether or not to advocate excision biopsy. This lady was advised to undergo excision in view of the size of the lesion, but had defaulted, with further subsequent delay occurring due to unforeseen circumstances. Adjunctive biologic markers have been explored as possible predictors of the behavior of phyllodes tumours, including p53, c-myc, c-kit, MIB-1 and S-phase fraction, microvessel density, CD34 and factor XIIIa stromal expression. Some of these have also been investigated as potential adjudicators in core biopsy findings of fibroepithelial neoplasms, but their utility needs further validation. The two main differential diagnoses of malignant phyllodes tumours are metaplastic breast carcinoma and primary breast sarcoma, both of which feature malignant spindle cell or sarcomatoid appearances. Sometimes, the sarcomatoid component in all these three pathologic entities may be in the form of malignant chondroid, osteiod or rhabdomyosarcomatous elements. The key to the diagnosis of malignant phyllodes tumour is the presence of typical epithelium lined fronds, which may be focal within the tumour, therefore requiring adequate macroscopic sampling. In metaplastic breast carcinoma with sarcomatoid features, there are malignant epithelial elements in the biphasic subtype, either in the form of ductal carcinoma in situ (DCIS) or invasive carcinoma. In the monophasic spindle cell variety of metaplastic breast carcinoma, immunohistochemistry with epithelial markers can confirm keratin positivity and therefore epithelial differentiation in the malignant spindle cells. CD34 and bcl2 have also been reported to be useful in distinguishing phyllodes tumour from spindle cell/metaplastic carcinoma, as the former tends to express CD34 and bcl2 in their stromal cells. Metaplastic carcinomas are treated as for primary breast carcinomas with axillary dissection, as opposed to malignant phyllodes tumours in which removal of axillary lymph nodes is not indicated. In primary breast sarcoma, malignant spindle cell areas are neither associated with the fronding appearance of phyllodes tumour nor malignant epithelial component of metaplastic carcinoma. Further immunohistochemical workup to determine the cell of origin may be needed. Final Diagnosis: Malignant phyllodes tumour References Kuijper A, Buerger H, Simon R et al. Analysis of the progression of fibroepithelial tumours of the breast by PCR based clonality assay. J Pathol 2002; 197: 575-581. Noguchi S, Yokouchi H, Aihara T et al. Progression of fibroadenoma to phyllodes tumour demonstrated by clonal analysis. Cancer 1995; 76: 1779-1785. Ellis IO, Humphreys S, Michell M et al. Guidelines for non-operative diagnostic procedures and reporting in breast cancer screening. 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