Phyllodes tumours of the breast: a clinicopathological review of thirty-two cases

We have reviewed the histological features and clinical outcome in 32 women with phyllodes tumours of the breast diagnosed in Nottingham between 1975 and 1990. We assessed 23 tumours as histologically benign, four as borderline and five as malignant. After clinical follow up for periods ranging from 36 months to 221 months (median 135 months), six of 23 benign tumours have recurred locally; in all these cases the original tumours had been incompletely excised. There were no recurrences amongst 10 benign tumours in which excision had been complete. Benign tumours which recurred showed a tendency to greater stromal cellularity and more pronounced stromal overgrowth than incompletely excised lesions which did not recur, but these differences were not statistically significant. The recurrent tumours resembled the respective original lesions histologically, except in one case in which two local recurrences were histologically malignant. The recurrent tumours were controlled by further excision or mastectomy in all cases and none have metastasized. All four borderline tumours were completely excised at initial surgery and none have recurred or metastasized. One of the five malignant tumours recurred within two months of incomplete excision, with widespread infiltration of the chest wall, although the patient died of unrelated causes. The other four malignant tumours have not recurred. We conclude that presence of tumour at the margins of the excised specimen is the major determinant of local recurrence in phyllodes tumours and that the histological features are of secondary importance. These findings are discussed in relation to other published series in the literature.     

Expression of CD34 and bcl-2 in phyllodes tumours, fibroadenomas and spindle cell lesions of the breast

AIMS: Strong expression of CD34 and bcl-2 has been described in solitary fibrous tumours. It has been proposed that these lesions arise from long-lived mesenchymal cells. We tested the hypothesis that spindle cell lesions of the breast arise from similar mesenchymal cells in the mammary stroma. METHODS and RESULTS: Sections of phyllodes tumours (26), fibroadenomas (15), myofibroblastomas (two), pseudoangiomatous hyperplasia (five) and myoid hamartoma (one) were stained immunohistochemically for CD34 and bcl-2. Conventional mammary carcinoma is known to be CD34-negative: we therefore stained 11 spindle cell carcinomas and one adenosquamous carcinoma. The mammary stroma, particularly around lobules, stained for CD34. All the lesions (except the carcinomas) showed spindle cell staining for CD34. There was more staining in fibroadenomas than in phyllodes tumours (especially malignant tumours). The staining in phyllodes tumours was typically patchy. In some there was increased or decreased staining adjacent to the epithelium. There were occasional spindle cells positive for bcl-2 in the normal perilobular stroma. bcl-2 was frequently expressed in spindle cells in fibroadenomas, phyllodes tumours and pseudoangiomatous hyperplasia, and rarely in the other lesions. CONCLUSIONS: The combined expression of CD34 and bcl-2 suggests that fibroadenomas, phyllodes tumours and pseudoangiomatous hyperplasia may arise from long-lived bcl-2-positive mesenchymal cells in the breast in a manner similar to that proposed for solitary fibrous tumours. The absence of CD34 staining in spindle cell carcinomas is of potential diagnostic value in the distinction from malignant phyllodes tumours in difficult cases.     

Spindle cell lesions of the breast: diagnostic issues

Spindle cell lesions of the breast encompass a broad spectrum of entities. In addition to breast-specific spindle cell lesions, soft tissue and cutaneous spindle cell lesions can also present in the breast. The prognosis and proper management of each entity varies considerably and thus calls for a systemic approach in diagnosis. A simple two-step approach is described in this review, where spindle cell lesions are classified into biphasic (with both spindle and epithelial components) and monophasic (spindle cell only) types, followed by histologic grading. This diagnostic algorithm is easy to use and adequately reflects the pathogenesis and clinical behavior of the entities. When supplemented by careful histologic examination and judicious use of immunostains, this algorithm will aid in the correct labeling of most spindle cell lesions of the breast.     

Spindle cell lipoma of the breast: A case report and literature review

Fine-needle aspiration cytology (FNA) was performed on a breast lump in a 66-year-old female, clinically thought to be a carcinoma. The cytological findings were reported as suspicious of malignancy. Subsequent histological examination showed a tumour macroscopically and microscopically identical with six other cases previously described as benign spindle cell tumours of the breast. This report highlights yet another diagnostic pitfall in FNA cytology of the breast. The presence of floret cells in this case has not been previously reported but supports the concept that this lesion is the same as a spindle cell lipoma, from which it is virtually indistinguishable on light microscopy. The lesion affects both mate and female breast, is predominantly single but may be multiple, and follows a benign course. Local excision is curative.     

Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast

This article reviews recent advances in the diagnosis of these three unusual tumours of the breast. Spindle cell carcinoma needs to be considered in the differential diagnosis of many mammary spindle cell lesions: it is important to be aware of the wide range of appearances, including the recently described fibromatosis-like variant. Immunohistochemistry using a broad panel of cytokeratin antibodies is needed to exclude spindle cell carcinoma; there is frequent expression of basal cytokeratins and p63. CD34 is often expressed by the stroma of phyllodes tumours, but does not appear to be expressed by spindle cell carcinoma or fibromatosis. Nuclear β-catenin is found in about 80% of fibromatoses, but can also be seen in spindle cell carcinomas and phyllodes tumours. Two recent studies have described features useful in the distinction of phyllodes tumour and fibroadenoma on core biopsy, including increased cellularity, mitoses and overgrowth of the stroma, adipose tissue in the stroma and fragmentation of the biopsy specimen. Periductal stromal tumour is a recently described biphasic tumour composed of spindle cells around open tubules or ducts (but no leaf-like architecture) with frequent CD34 expression. The overlap of morphology with phyllodes tumour suggests that it may be best regarded as a variant of phyllodes tumour.     

Myoepithelial carcinoma of the breast with distant metastasis and accompanied by adenomyoepitheliomas

A breast tumour in a 47-year-old female with axillary lymph node metastasis was interpreted as the rare malignant adenomyoepithelioma based on morphological and immunohistochemical studies. Multiple bone metastases developed and the patient died after 7 months. The malignant neoplasm consisted of cords and interlacing bundles of spindle cells with indistinct cell borders and clear cytoplasm. The cells stained positively for cytokeratin. S-100 protein, GFAP, and muscle-specific actin, and possessed basal lamina, pinocytic vesicles, tonofilaments, desmosomes, and intermediate filaments with dense bodies. In some areas, cells with microvillous projections enclosed small spaces. In the breast, foci of myoepithelioma with various morphological subtypes and infiltration coexisted, demonstrating the origin of the malignant tumour. The histogenesis of the myoepithelial tumours is discussed.     

Analysis of the progression of fibroepithelial tumours of the breast by PCR-based clonality assay

Fibroadenoma and phyllodes tumour of the breast are both fibroepithelial tumours. Although progression to epithelial malignancy has been described, the behaviour of most fibroadenomas is benign. Phyllodes tumours, on the other hand, can display locally destructive growth and can even metastasize. A relationship between the two tumours has been suggested in the literature. This study investigated the clonality of both the stroma and the epithelium of these fibroepithelial tumours and attempted to construct a model in which fibroadenoma can progress in both an epithelial and a stromal direction. Fibroadenomas (n=25) and phyllodes tumours (n=12) were selected for analysis. Tissue was microdissected and analysed for clonality using a polymerase chain reaction (PCR)-based assay targeted at an X-linked polymorphic marker, the human androgen receptor gene (HUMARA). Nineteen fibroadenomas and nine phyllodes tumours could be analysed. Normal-appearing epithelium, hyperplastic epithelium, and stroma removed from fibroadenomas were polyclonal. As expected, carcinoma in situ (CIS) removed from four fibroadenomas was monoclonal. Three areas of apparent stromal expansion within fibroadenoma were monoclonal, suggesting stromal progression. Mostly, the stroma of phyllodes tumours was monoclonal and the epithelium polyclonal. In two cases, however, the epithelium seemed to be monoclonal, whereas in three other cases the stromal component was polyclonal. These findings indicate that fibroadenoma can progress in an epithelial direction to CIS and in a stromal direction to phyllodes tumour.     

A practical approach to immunohistochemical diagnosis of ovarian germ cell tumours and sex cord–stromal tumours

Immunohistochemistry can be useful in the diagnosis of ovarian germ cell tumours and sex cord–stromal tumours. A wide variety of markers are available, including many that are novel. The aim of this review is to provide a practical approach to the selection and interpretation of these markers, emphasizing an understanding of their sensitivity and specificity in the particular differential diagnosis in question. The main markers discussed include those for malignant germ cell differentiation (SALL4 and placental alkaline phosphatase), dysgerminoma (OCT4, CD117, and D2‐40), yolk sac tumour (α‐fetoprotein and glypican‐3), embryonal carcinoma (OCT4, CD30, and SOX2), sex cord–stromal differentiation (calretinin, inhibin, SF‐1, FOXL2) and steroid cell tumours (melan‐A). In addition, the limited role of immunohistochemistry in determining the primary site of origin of an ovarian carcinoid tumour is discussed.     

Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Spindle cell carcinoma of the breast

A case of spindle cell carcinoma of the breast in association with myoepithelial cell hyperplasia is presented. Immunocytochemistry demonstrated labelling of tumour cells for cytokeratin, vimentin and S-100 protein. Electronmicroscopy showed desmosomes and bundles of tonofilaments as well as fine filaments in the cytoplasm. The findings in the present case point to the metaplastic spindle cell nature of squamous carcinoma of the breast. The possible role of myoepithelial cells in the origin of the spindle cell component is discussed.     

Dendritic cell sarcomas/tumours of the breast: report of two cases

Extranodal follicular dendritic cell sarcoma/tumours (FDCS/Ts) and interdigitating dendritic cell sarcoma/tumours (IDCS/Ts) are rare neoplasms. We present two cases of FDCS/T and IDCS/T of the breast. The FDCS/T case (case 1) presented in a 31-year-old woman and the IDCS/T case (case 2) in a 67-year-old woman who both showed a firm lump in the left breast. The FDCS/T lesion superficially appeared as an anaplastic carcinoma and the IDCS/T was reminiscent of a spindle cell sarcomatoid carcinoma. Nevertheless both lesions were negative for keratins while case 1 displayed neoplastic cells strongly positive for CD21, vimentin and focally for CD68 and S-100 protein. The tumour cells of case 2 were positive for S-100, CD68 and CD45. In breast, an unusual keratin negative tumour composed predominantly of spindle cells arranged in fascicles, storiform pattern or whorls with a lymphoid rich stroma should raise suspicion for FDCS/Ts or IDCS/Ts. The distinction from malignant tumours with similar features is discussed.     

Spindle cell lesions of the bladder and urinary tract

Spindle cell lesions of the urinary tract encompass a variety of benign and malignant tumours as well as a group of lesions of controversial nomenclature that is the subject of ongoing debate. This review focuses on our current and evolving understanding of the lesion variably referred to as inflammatory myofibroblastic tumour, pseudosarcomatous myofibroblastic proliferation or inflammatory pseudotumour and the main differential diagnoses of sarcomatoid carcinoma and sarcoma. Other spindle cell lesions of the bladder are described.     

Malignant phyllodes tumours of the breast display increased stromal p53 protein expression

AIMS: To determine the variation in p53 protein expression in phyllodes tumours and fibroadenomas of the breast. METHODS AND RESULTS: Fifteen phyllodes tumours (six malignant, nine benign) and 20 fibroadenomas were examined for p53 expression by immunohistochemistry. Five of the six malignant phyllodes tumours showed moderate or strong p53 positivity at sites of peri-epithelial stromal condensation and atypia. All 20 fibroadenomas, nine benign phyllodes tumours and one malignant phyllodes tumour showed either negativity or focal weak nuclear positivity of scattered stromal cells. CONCLUSIONS: Increased p53 immunoreactivity is present in malignant phyllodes tumours in contrast to benign phyllodes tumours and fibroadenomas. Malignant phyllodes tumours display a distinctive pattern of p53 immunostaining which may be of diagnostic value. These findings suggest that p53 protein may be important in the progression of benign to malignant phyllodes tumours.     

Breast neuroendocrine neoplasms: practical applications and continuing challenges in the era of the 5th edition of the WHO classification of breast tumours

The classification and nomenclature for breast neuroendocrine neoplasms have undergone several iterations. The most recent (5th) edition of the World Health Organization (WHO) classification of breast tumours defines pure primary neuroendocrine neoplasms into neuroendocrine tumour (NET) and neuroendocrine carcinoma (NEC), in alignment with other organ systems, and segregates other lesions that exhibit neuroendocrine morphology/markers into alternative categories. This review will provide an update of the nomenclature evolution, diagnostic criteria and ancillary studies, and prognostic and clinical management of breast neuroendocrine neoplasia, focusing on a practical approach and highlighting remaining issues in this field.     

An update on the classification of phyllodes tumours of the breast

Phyllodes tumour (PT) is a rare fibroepithelial neoplasm of the breast, histologically categorized into 3 grades, namely benign, borderline and malignant; each with distinct clinical behaviour and implications for management. This article addresses challenges in the diagnosis, grading and management of PT in excisional and core needle biopsy specimens, with a brief review of recent molecular findings.     

Spindle cell carcinoma of the mandible: a case report

Spindle cell carcinoma is a rare highly malignant squamous cell carcinoma. Here, we describe a case of a 74-yearold Chinese female who presented with a 2-week history of pain and swelling in the left retromolar region. Surgical resection and titanium plate prosthesis were performed and histological analysis revealed spindle squamous cell carcinoma.     

乳腺叶状肿瘤的形态学和免疫组织化学研究

目的观察乳腺叶状肿瘤（phyllodes tumours,PTs）的形态学和免疫组织化学特征,并探讨其诊断标准。方法对21例PTs进行组织学观察和免疫组化SP法检测,并选取5例乳腺纤维腺瘤和5例乳腺腺病标本作为对照组。使用一抗包括CK-pan、EMA、SMA、p53、S-100蛋白、CD117、CD34、CD99、bc l-2、ER、PR、K i-67、CD10。结果21例PTs大体上均表现为界限清楚的肿块,且呈分叶状。肿瘤由具有双层排列的上皮成分以及过度生长的间质成分组成。根据间质的过度生长程度、细胞的异型程度、核分裂数、肿瘤边缘情况、有无异源性成分以及肿瘤性坏死等继发性改变将其分为良性、交界性和恶性3个级别。间质细胞免疫组化表达情况：CKpan：0/21、EMA：0/21、SMA：17/21、CD117：6/21、CD34：18/21、S-100蛋白：2/21、CD99：13/21、CD10：8/21、PR：5/21、ER：4/21、p53：18/21、K i-67：3%~10%、bc l-2：15/21。结论PTs的诊断主要依据组织学观察,免疫组化CD117、CD34、CD99、CD10、bc l-2的检测可以起到一定的辅助作用。     

Sarcomatoid/metaplastic carcinoma of the breast: a clinicopathological study of 12 cases

AIMS: To analyse the clinical and pathological features with long-term follow-up of a series of 12 cases of sarcomatoid carcinoma of the breast. methods and results: The cases were selected from the surgical files of the Department of Pathology, University of Edinburgh, between 1977 and 1988. The following clinical parameters were recorded: the age of the patients, size of tumour, presence or absence of lymph node or distant metastases, and patient survival. Pathological assessment included: the type of epithelial and mesenchymal components, the proportion of monophasic to biphasic tumours and the presence of adjacent in-situ carcinoma/atypical epithelial proliferation. The mean age of the patients was 61 years with a median of 64 and range 46-82 years. The mean size of the tumour was 52 mm (range 22-100 mm). None of the patients had distant metastasis at presentation and only one case had local lymph node metastasis which had a carcinomatous appearance. Five women were still alive after a minimum 12-year follow-up period. Four patients died of their disease (three with lung metastasis only and one with lung and bone metastases), one died of carcinoma of the cervix and two patients were lost to follow-up. Pathologically, four cases (33.3%) had no or almost undetectable epithelial structures by light microscopy, i.e. "monophasic sarcomatoid carcinoma". The remaining cases revealed varying proportions of both epithelial and mesenchymal elements, i.e. "biphasic sarcomatoid carcinoma". Of the epithelial component, six (50%) tumours had predominantly carcinoma of no special type, one lobular and one tubular carcinoma. The mesenchymal component was fibromatosis/nodular fasciitis-like, malignant fibrous histiocytoma-like (MFH), osteosarcoma-like and fibrosarcoma-like in five (42%), four (33%), two (17%) and one (8%) tumours, respectively. In 3/4 monophasic tumours, the mesenchymal component was of a low-grade fibromatosis/nodular fasciitis type. In 6/12 (50%) of the cases there was associated in-situ atypical epithelial proliferation (five ductal carcinoma in situ (DCIS) and one atypical ductal hyperplasia). CONCLUSIONS: From this small series it appears that sarcomatoid carcinoma is an uncommon tumour, which is large in size and tends to lack local or distant metastasis at presentation. Pathologists should be alert to the presence of the bland monophasic sarcomatoid carcinoma which has a pure mesenchymal appearance on light microscopy, but epithelial components demonstrated by cytokeratin immunohistochemistry. These showed metastases on long-term follow-up, similar to other histological patterns of sarcomatoid carcinoma.     

Fine-needle aspiration cytology of sarcomatoid carcinoma of the breast: A cytologically overlooked neoplasm

Sarcomatoid carcinoma of the breast is a very uncommon neoplasm. Fine-needle aspiration findings have been rarely reported. We report a case of sarcomatoid carcinoma of the breast that was diagnosed as a typical ductal carcinoma cytologically. The patient was a 45-year-old female who had a right breast mass for a short duration. Fine-needle aspiration (FNA) showed smears predominantly composed of single cells exhibiting plasmacytoid features with moderate degree of pleomorphism. A granular bluish background was noted on the Papanicolaou-stained smears. This background was thought to represent tumor diathesis, and the diagnosis of grade II ductal carcinoma of the breast was rendered. The patient underwent a subsequent lumpectomy with axillary node dissection. Histological examination of the lumpectomy revealed a neoplasm predominantly composed of a grade II chondrosarcoma with increased cellularity. A small (10%) component showed grade II invasive ductal carcinoma of the breast. No in situ component was seen. The sarcomatoid component was positive for S-100 protein and vimentin and negative for keratin, whereas the carcinomatous component was positive for vimentin, epithelial membrane antigen, and low molecular weight keratin. Ultrastructurally, the tumor showed features of a poorly differentiated epithelial neoplasm without evidence of chondrosarcoma. Metastases were seen in seven of ten axillary lymph nodes with exclusive epithelial component. Retrospective evaluation of the FNA smears revealed an extensive metachromatic stroma on the DIFF QUIK™-stained smears. Our findings and review of the literature suggest that sarcomatoid carcinoma of the breast will be very frequently overlooked or misdiagnosed either because of the subtlety of the stroma or the predominance of the mesenchymal component. Our findings also provide supportive evidence that the use of the DIFF QUIK™ stain can be very helpful in the identification of the stroma in this neoplasm. The predominance of epithelium in the metastases in our case is further proof that tumors with dual differentiation such as sarcomatoid carcinomas and mixed muellerian tumors are truly carcinomas with metaplastic features. Diagn. Cytopathol. 16:242–246, 1997. © 1997 Wiley-Liss, Inc.