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Background An increasing number of breast cancer patients in Asian countries has been found to consume dietary supplements including phytoestrogen-rich Chinese herbal medicines with an expectation to alleviate the side effects of conventional cancer therapies. Purpose The question of whether estrogenic Chinese herbal medicines are beneficial or detrimental to the health of breast cancer patients remains uncertain. Study Design The present study aimed at establishing a systematic approach to look at the safety profiles of estrogenic Chinese herbal medicines (CHM). Methods The effects of estrogenic CHM on the growth of human breast cancer cells as well as the progression of breast tumors in mice have been investigated. Results Our results demonstrated that among 10 selected estrogenic CHM, the aqueous extracts of Cistanche deserticola (CD) and Dioscorea opposita (DO) at 0.4 to 1.6 mg/ml significantly stimulated cell viability in both estrogen receptor (ER)-positive (MDA-MB-361 and MCF-7) and ER-negative (SKBR3 and MDA-MB-231) breast cancer cells. However, results from animal studies showed that no significant difference was found on the size of mouse 4T1 breast tumors in CD- and DO-treated mice when compared with the control group, while the number of proliferative cells were found to be increased in DO-treated group. Besides, CD and DO treatments induced significant immunomodulatory effects on 4T1 tumor-bearing mice by increasing the production of cytokines IL-2 and IFN-γ and modulation of regulatory T-cells. Furthermore, CD and DO treatments did not stimulate, but in fact suppressed human triple-negative MDA-MB-231 breast xenografts growth in immunodeficiency mice. Conclusion The considerable concerns on the use of CD and DO in breast cancer patients could be relieved to some extents upon the findings of this pre-clinical study. The potential harmful effects of estrogenic Chinese herbal medicines on breast cancer growth should be verified in both cell-based and tumor-bearing mice models.

Aim We evaluated pathological features of the ductal carcinoma in situ component of 241 triple negative invasive breast cancers. Results We found that 151 (62.6%) in situ lesions were of high nuclear grade, and 236 (97.9%) were triple negative (oestrogen receptor, progesterone receptor, cerbB2 negative). Immunohistochemistry for cytokeratin (CK)5/6, CK14, CK17, epidermal growth factor receptor (EGFR), CD117, 34βE12, p63 and smooth muscle actin (SMA) revealed positive staining in 5 (2.1%), 60 (24.9%), 69 (28.6%), 37 (15.4%), 69 (28.6%), 137 (56.8%), 3 (1.2%) and 22 (9.1%) in situ ductal components respectively, with fair to substantial agreement of staining results (positive versus negative) between in situ and corresponding invasive elements for CK5/6, CK14, CK17, EGFR, CD117 and 34βE12; but none to fair agreement for p63 and SMA respectively. When the tri-panel of CK14, EGFR and 34βE12 was used to define the basal phenotype, 68% revealed basal-like expression of both in situ and invasive components of the same case. Conclusions Our data support the notion that triple negative ductal carcinoma in situ is the precursor of the corresponding invasive counterpart, and that basal-like expression is maintained in the majority of invasive cancers associated with basal-like in situ disease. Future studies that prospectively evaluate morphological and biological characteristics of invasive cancers that develop from triple negative and basal-like ductal carcinoma in situ lesions will assist in validating these findings.

Iqbal J, Thike A A, Cheok P Y, Tse G M-K & Tan P H (2012) Histopathology 61, 652–659 Insulin growth factor receptor-1 expression and loss of PTEN protein predict early recurrence in triple-negative breast cancer Aims: Insulin-like growth factor receptor-1 (IGFR-1) and its signalling axis promote tumorigenesis, metastasis, and resistance to existing forms of cancer therapy, and have become a major focus for the development of anticancer drugs. As oncological management options for triple-negative breast cancers (TNBCs) are limited, there is potential for the rapid development of novel selective anticancer agents specifically targeting components of the PTEN–phosphoinositide 3-kinase–AKT pathway, including the phosphorylated form of AKT (pAKT) and the tumour suppressor molecule PTEN. The aim of this study was to conduct immunohistochemical analyses to examine the levels of PTEN, IGFR-1 and pAKT expression in TNBCs, and determine whether these levels correlated with poor prognosis in this subset of aggressive breast cancers. Methods and results: Immunohistochemistry was performed on paraffin-embedded tumour tissues from a consecutive cohort of 144 female patients diagnosed with TNBC. Associations of IGFR-1, PTEN and pAKT expression with clinicopathological parameters, disease-free survival (DFS) and overall survival (OS) were evaluated. There were significant increases in IGFR-1 expression (99%) and pAKT expression (92%) with concomitant loss of PTEN expression in the majority of cases (63%). Increased IGFR-1 expression and loss of PTEN expression were associated with reduced OS and DFS, respectively. pAKT expression showed a strong correlation with basal-like expression. Combinatorial immunophenotypic analyses showed that loss of PTEN expression with concomitant IGFR-1 expression correlated with poor DFS. Conclusions: A high percentage of PTEN loss with overexpression of IGFR-1 and pAKT in TNBC indicates the potential of these molecules for predicting early recurrence and/or as targets in the formulation of effective alternative therapy regimens.

Aim To determine the frequency, pattern and distribution of stromal keratin expression in phyllodes tumours if any, which may impact diagnostic approaches. Methods The clinicopathological features of 109 phyllodes tumours comprising 70 (64.2%) benign, 30 (27.5%) borderline and nine (8.3%) malignant grades were evaluated, and the immunohistochemical expression of a keratin panel (MNF116, 34βE12, CK7, CK14, AE1/3, Cam5.2), p63 and CD34 in their stromal component was assessed. Results There was focal and patchy cytoplasmic keratin staining in 1–5% of stromal cells in 13 (11.9%), 24 (22%), 31 (28.4%), 2 (1.8%), 9 (8.3%) and 2 (1.8%) cases for MNF116, 34βE12, CK7, CK14, AE1/3, Cam5.2, respectively. CD34 was expressed in 79 (72.5%) cases. There was no stromal staining for p63. Stromal MNF116, 34βE12 and Cam5.2 reactivity was significantly associated with phyllodes tumour grade (p=0.027, p=0.034, p=0.009 respectively), while MNF116 stromal staining was observed in tumours with increasing cellularity (p=0.036), necrosis (p=0.015) and cystic change (p=0.048). Contrary to common understanding, these findings confirm that stromal cells in phyllodes tumours can sometimes express keratins, albeit focal and in a patchy distribution. In comparison, fibromatosis and dermatofibrosarcoma were uniformly negative for the same keratin panel, while spindle cell components of eight metaplastic carcinomas expressed at least two or more keratins in a wider distribution of up to 90% of positively stained spindle cells. All eight spindle cell sarcomas were negative for keratins. Conclusion The use of keratins as an adjunctive immunohistochemical diagnostic tool in the differential work-up of spindle cell tumours of the breast has to be interpreted with caution especially on limited core biopsy material.

Breast cancer is conventionally treated by surgery and radiotherapy, with adjuvant chemotherapy and hormonotherapy as supplementary treatments. However, such treatments are associated with adverse side effects and drug resistance. In this study, Pheophorbide a (Pa), a photosensitizer isolated from Scutelleria barbata, was analysed for its antiproliferative effect on human breast tumour cells. The IC (inhibitory concentration)(50) of the combined treatment of Pa and photodynamic therapy (Pa-PDT) on human breast tumour MCF-7 cells was 0.5 µm. Mechanistic studies in MCF-7 cells demonstrated that Pa was localized in the mitochondria, and reactive oxygen species were found to be released after Pa-PDT. Apoptosis was the major mechanism responsible for the tumour cell death, and mitochondrial membrane depolarization and cytochrome c release highlighted the role of mitochondria in the apoptotic mechanism. Up-regulation of tumour suppressor protein p53, cleavage of caspase-9 and poly (ADP-ribose) polymerase suggested that the caspase-dependent pathway was induced, while the release of apoptosis-inducing factors demonstrated that the apoptosis was also mediated by the caspase-independent mechanism. In vivo study using the mouse xenograft model showed a significant inhibition of MCF-7 tumour growth by Pa-PDT. Together, the results of this study provide a basis for understanding and developing Pa-PDT as a cure for breast cancer.

Jara-Lazaro A R, Akhilesh M, Thike A A, Lui P C-W, Tse G M-K & Tan P H (2010) Histopathology 57, 220–232 Predictors of phyllodes tumours on core biopsy specimens of fibroepithelial neoplasms Aims: To establish histological and biological parameters that can predict phyllodes tumours on core biopsy specimens of indeterminate fibroepithelial neoplasms. Methods and results: Core biopsy specimens of fibroepithelial lesions diagnosed at the Department of Pathology, Singapore General Hospital from 2002 to 2007 were reviewed. Cases in which phyllodes tumour was favoured, or could not be ruled out, were evaluated for stromal cellularity/distribution, nuclear atypia and mitoses, stromal overgrowth, epithelial fronding, epithelial hyperplasia, configuration of lesional edge, presence of pseudoangiomatous stromal hyperplasia and of adipose tissue. Antibodies to Ki67, topoisomerase IIα, CD34, CD117 and Bcl-2 were applied to sections subjected to immunohistochemistry using the streptavidin–biotin method. Findings were correlated with subsequent excisions. Of 261 core biopsy specimens of fibroepithelial lesions, 98 (37%) comprised cases in which phyllodes tumour could not be excluded and 57 (58%) had subsequent open surgical excisions. Marked stromal hypercellularity (5/5; 100%) and nuclear atypia (1/1; 100%), stromal overgrowth (17/17; 100%), mitoses ≥2/10 high-power fields (18/18; 100%) and ill-defined lesional borders (16/16 phyllodes tumours; 100%) were features in core biopsy specimens that exclusively predicted phyllodes tumour on excision. Moderate stromal hypercellularity (20/27 phyllodes tumours; 74%), stromal overgrowth, moderate nuclear atypia (14/16 phyllodes tumours; 87%), pseudoangiomatous stromal hyperplasia (19/23 phyllodes tumours; 83%) significantly correlated with their subsequent excisions. Immunohistochemical markers Ki67 ≥5% and topoisomerase IIα≥5%, and reduced or patchy CD34 on core biopsy specimens correlated significantly with a diagnosis of phyllodes. Conclusions: Stromal hypercellularity, combined with key histological features and immunohistochemical markers Ki67, topoisomerase IIα and CD34, reinforced by clinical findings, can predict phyllodes tumours on core biopsy specimens.

Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. They are not always analyzed in distant metastatic and locally recurrent breast cancers. We compared immunohistochemical expression in a series of primary breast carcinomas with their distant metastases (n = 72) and local recurrences (n = 45) and analyzed the impact of any changes on survival. Discordance rates between primary and metastatic and between primary and locally recurrent lesions, respectively, were 18% (13/72) and 13% (6/45) for ER, 42% (30/72) and 33% (15/45) for PR, and 7% (5/72) and 2% (1/45) for c-ERBB2. There was statistically significant discordance between primary and metastatic PR status (P = .017; κ = 0.201). Among locally recurrent tumors, 15 (33%) of 45 revealed discordance for PR (P = .006; κ = 0.366). We observed a trend for shorter survival among women with ER– metastatic and locally recurrent tumors regardless of the primary tumor ER status. Our findings suggest a benefit for routine evaluation of ER, PR, and c-ERBB2 status in distant metastatic and locally recurrent breast cancer for therapeutic and prognostic purposes. Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. About 60% to 70% of breast carcinomas express ER protein, and these tumors are associated with better prognosis. 1 Detecting ER expression in a tumor depends on physiologic and technical factors, including menopausal status, endocrine therapy, tumor sampling and intratumoral heterogeneity, tissue fixation, method of examination (biochemical, immunohistochemical), and type of antibody used. 2-4

Previous studies have suggested that breast cancer in young women has more aggressive biological features and poorer prognosis. However, the role of biological markers in these patients is not well understood. We aimed to learn more about this disease in a cohort of 125 young women from Singapore, Japan and Hong Kong, aged 35 years or less, with invasive breast cancer by evaluating the expression of vimentin and the basal cytokeratins CK14, CK5/6 and 34 beta E12. Both standard paraffin sections and tissue microarrays were used in the immunohistochemical evaluation of expression patterns of these four biological markers. CK5/6, CK14, vimentin and 34 beta E12, in increasing order of proportion, were detected in invasive carcinomas. Basal cytokeratins and vimentin showed significant inverse relationship with estrogen and progesterone receptor status while CK14 expression was found to be directly associated with c-erbB2 status. Basal cytokeratins and vimentin immunoreactivities were directly associated with CD117 and EGFR expression. Vimentin and 34 beta E12 immunopositivity correlated with tumor size, while vimentin was associated with higher histological grade. Our findings are in concert with reports that expression of basal cytokeratins and vimentin is correlated with adverse pathological parameters.

This study was to assess whether fine needle aspiration (FNA) or core biopsy would allow diagnosis of mucinous carcinoma of breast. In 37 mucinous carcinoma in 34 patients, 20 lesions had FNA and 24 lesions with core biopsy. FNA achieved a sensitivity of 66.7% in diagnosis of malignant lesions and 56% sensitivity in diagnosis of mucinous carcinoma. Core biopsy achieved 100% sensitivity and accuracy in the diagnosis of malignant lesions and mucinous carcinoma.

Phyllodes tumors are fibroepithelial neoplasms typified by stromal proliferation. We have previously shown the role of pathologic parameters and the prognostic significance of p53 and CD117 protein expression in these tumors. In this study, we evaluated the expression of heparan sulfate, which has been implicated in many biological processes such as cell adhesion, embryogenesis, and tumorigenesis (including malignant transformation of mammary cells) in 232 breast phyllodes tumors. We used a monoclonal antibody, 10E4, to examine the localization of heparan sulfate in phyllodes tumors by immunohistochemistry. The immunoreactivity of both epithelial and stromal components was examined and analyzed with pathological parameters and other immunohistochemical markers, including p53, MIB1, bcl2, and CD117. Stromal 10E4 expression was significantly associated with tumor grade, stromal p53, and MIB1 expression in proliferating cells, suggesting that heparan sulfate may participate in malignant tumor growth.

Background: Severe acute respiratory syndrome (SARS) is a newly described form of atypical pneumonia linked to a novel coronavirus. Aims: To review the sputum cytology of 15 patients who fulfilled the World Health Organisation clinical criteria for SARS in an attempt to evaluate whether early diagnosis is feasible with routine sputum examination. Methods: All sputum samples from patients with SARS from the four major hospitals in Hong Kong were reviewed; abnormalities were sought in the cellular component, including abnormal numbers and morphology of the component cells compared with those from age matched controls taken over the same period one year ago. Results: Fifteen sputum samples from patients were compared with 25 control samples. In the patients with SARS, loose aggregates of macrophages were seen more frequently in the sputum. These macrophages frequently showed morphological changes, such as cytoplasmic foaminess, vacuole formation, and nuclear changes (including multinucleation and a ground glass appearance) when compared with the control samples. Conclusions: The cytological features of SARS are non-specific, but the observation of any of the described features should prompt further investigations, especially in patients with suspicious clinical features.

Expression of epidermal growth factor receptor in head and neck cancers correlates with clinical progression: a multicentre immunohistochemical study in the Asia–Pacific region Aims: With ongoing efforts to target the epidermal growth factor receptor (EGFR)-mediated tumour growth in the treatment of selected human malignancies, there is a need to determine the expression levels of EGFR and to evaluate its prognostic value in various malignancies in the Asia–Pacific region. Methods and results: A total of 172 patients with head and neck squamous cell carcinomas from Australia, Hong Kong, Singapore, and Taiwan were selected for EGFR detection. Immunohistochemical staining was performed to evaluate EGFR expression. EGFR expression was present in 88.4% (152/172) of all cases tested. Specifically, EGFR expression was found in 91.3% (42/46), 84.6% (22/26), 84.1% (37/44), 96.0% (24/25), and 87.1% (27/31) cases of head and neck squamous cell carcinomas from the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx, respectively. The results demonstrate a stronger EGFR expression in T4 tumours (P=0.017) and later clinical stages (P=0.016). No significant correlation was seen with risk factors, primary tumour site and ethnicity. Conclusions: The majority of head and neck squamous cell carcinomas express EGFR, indicating the importance of studying the efficacy of anti-cancer therapy through this pathway. The results also show similar rates of receptor expression in head and neck squamous cell carcinoma patients from our region compared with other parts of the world.

Increased microvessel density in malignant and borderline mammary phyllodes tumours Aims: Tumour vascularity is considered a prognostic indicator in breast carcinoma, but its utility in mammary phyllodes tumour has not been explored. The authors report the correlation between intratumoral microvessel density and the histological grade of phyllodes tumour. Methods and results: Forty cases of phyllodes tumour were reviewed for stromal cellularity, overgrowth, cytological pleomorphism, mitotic count and margin pattern. Using established criteria, these were diagnosed as benign (n=28), borderline (n=10) and malignant (n=2). Microvessel density was counted on CD31-stained slides as the number of vessels per high power field. For benign phyllodes tumour, the range was 7–26.2 (mean 13.1); for borderline phyllodes tumour the range was 17.2–32.5 (mean 22.4); for malignant phyllodes tumour the range was 25.9–33.3 (mean 29.6). The difference between the benign and borderline groups was significant (P

Objective The purpose of this study was to compare the sonographic features of acalculous and calculous sialadenitis of the submandibular gland. Methods A retrospective review of sonograms of the neck was performed in 25 patients with submandibular sialadenitis: 8 with acalculous and 17 with calculous disease. The submandibular glands were assessed for size, shape, border, and echogenicity; presence of dilated ducts or other intraglandular lesions; inflammatory changes in adjacent tissues; lymphadenopathy; and involvement of other salivary glands. Results In the group with acalculous sialadenitis, 4 (50%) of the 8 patients had unilateral disease, and 11 (92%) of 12 glands were rounded. In all cases (100%), multiple hypoechoic lesions were diffusely distributed throughout the submandibular glands against a heterogeneous parenchymal background. The lesions ranged from 3 to 15 mm and were oval or round. Confluent lesions were noted in 2 glands (17%). There was no sonographic evidence of duct dilatation, calculi, or abnormal lymph nodes. All patients with calculous sialadenitis had unilateral disease; 9 had a main duct calculus (53%), 7 had intraglandular calculi (41%), and 1 had both (6%). In 14 (82%) of 17 glands, normal shape was maintained, and 11 (65%) of 17 had duct dilatation. Conclusions Acalculous submandibular sialadenitis differs from the calculous form of the disease. The former has characteristic sonographic features, including a round gland with numerous hypoechoic lesions in a heterogeneous parenchymal background. Sonographic imaging in conjunction with fine-needle aspiration is useful for detection of this disorder. © 2001 John Wiley & Sons, Inc. J Clin Ultrasound 29:332–338, 2001.

Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34βE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin–biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan–Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34βE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498–0.994; P=0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468–0.974; P=0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.

Insulin-like growth factor receptor-1 (IGFR-1) and its signalling axis promote tumorigenesis, metastasis, and resistance to existing forms of cancer therapy, and have become a major focus for the development of anticancer drugs. As oncological management options for triple-negative breast cancers (TNBCs) are limited, there is potential for the rapid development of novel selective anticancer agents specifically targeting components of the PTEN-phosphoinositide 3-kinase-AKT pathway, including the phosphorylated form of AKT (pAKT) and the tumour suppressor molecule PTEN. The aim of this study was to conduct immunohistochemical analyses to examine the levels of PTEN, IGFR-1 and pAKT expression in TNBCs, and determine whether these levels correlated with poor prognosis in this subset of aggressive breast cancers.Immunohistochemistry was performed on paraffin-embedded tumour tissues from a consecutive cohort of 144 female patients diagnosed with TNBC. Associations of IGFR-1, PTEN and pAKT expression with clinicopathological parameters, disease-free survival (DFS) and overall survival (OS) were evaluated. There were significant increases in IGFR-1 expression (99%) and pAKT expression (92%) with concomitant loss of PTEN expression in the majority of cases (63%). Increased IGFR-1 expression and loss of PTEN expression were associated with reduced OS and DFS, respectively. pAKT expression showed a strong correlation with basal-like expression. Combinatorial immunophenotypic analyses showed that loss of PTEN expression with concomitant IGFR-1 expression correlated with poor DFS.A high percentage of PTEN loss with overexpression of IGFR-1 and pAKT in TNBC indicates the potential of these molecules for predicting early recurrence and/or as targets in the formulation of effective alternative therapy regimens.

Histiocytoid breast carcinoma is an uncommon entity that is mostly regarded as a variant of lobular carcinoma. Its occurrence with apocrine lobular carcinoma in situ and consistent expression of gross cystic disease fluid protein 15 suggest apocrine differentiation. Its recognition is often challenging, particularly when histiocytoid tumour cells occur in a metastatic site before the primary diagnosis of breast carcinoma, or in limited core biopsy or cytology material. In the breast, its bland histological appearances can lead to a benign diagnosis. Clues to the correct conclusion include finding tumour cells with more cytological atypia, the presence of cytoplasmic vacuoles and secretions, coexistence with more traditional invasive lobular carcinoma patterns and/or lobular neoplasia, and the use of immuohistochemistry to confirm their epithelial nature. Close clinicoradiological correlation and awareness of histological mimics are needed to achieve an accurate diagnosis of this enigmatic condition that should be appropriately subsumed within the invasive lobular histological subtype.

Breast cancer is conventionally treated by surgery and radiotherapy, with adjuvant chemotherapy and hormonotherapy as supplementary treatments. However, such treatments are associated with adverse side effects and drug resistance. In this study, Pheophorbide a (Pa), a photosensitizer isolated from Scutelleria barbata, was analysed for its antiproliferative effect on human breast tumour cells. The IC (inhibitory concentration)(50) of the combined treatment of Pa and photodynamic therapy (Pa-PDT) on human breast tumour MCF-7 cells was 0.5 µm. Mechanistic studies in MCF-7 cells demonstrated that Pa was localized in the mitochondria, and reactive oxygen species were found to be released after Pa-PDT. Apoptosis was the major mechanism responsible for the tumour cell death, and mitochondrial membrane depolarization and cytochrome c release highlighted the role of mitochondria in the apoptotic mechanism. Up-regulation of tumour suppressor protein p53, cleavage of caspase-9 and poly (ADP-ribose) polymerase suggested that the caspase-dependent pathway was induced, while the release of apoptosis-inducing factors demonstrated that the apoptosis was also mediated by the caspase-independent mechanism. In vivo study using the mouse xenograft model showed a significant inhibition of MCF-7 tumour growth by Pa-PDT. Together, the results of this study provide a basis for understanding and developing Pa-PDT as a cure for breast cancer.

To establish histological and biological parameters that can predict phyllodes tumours on core biopsy specimens of indeterminate fibroepithelial neoplasms.Core biopsy specimens of fibroepithelial lesions diagnosed at the Department of Pathology, Singapore General Hospital from 2002 to 2007 were reviewed. Cases in which phyllodes tumour was favoured, or could not be ruled out, were evaluated for stromal cellularity/distribution, nuclear atypia and mitoses, stromal overgrowth, epithelial fronding, epithelial hyperplasia, configuration of lesional edge, presence of pseudoangiomatous stromal hyperplasia and of adipose tissue. Antibodies to Ki67, topoisomerase IIalpha, CD34, CD117 and Bcl-2 were applied to sections subjected to immunohistochemistry using the streptavidin-biotin method. Findings were correlated with subsequent excisions. Of 261 core biopsy specimens of fibroepithelial lesions, 98 (37%) comprised cases in which phyllodes tumour could not be excluded and 57 (58%) had subsequent open surgical excisions. Marked stromal hypercellularity (5/5; 100%) and nuclear atypia (1/1; 100%), stromal overgrowth (17/17; 100%), mitosesor =2/10 high-power fields (18/18; 100%) and ill-defined lesional borders (16/16 phyllodes tumours; 100%) were features in core biopsy specimens that exclusively predicted phyllodes tumour on excision. Moderate stromal hypercellularity (20/27 phyllodes tumours; 74%), stromal overgrowth, moderate nuclear atypia (14/16 phyllodes tumours; 87%), pseudoangiomatous stromal hyperplasia (19/23 phyllodes tumours; 83%) significantly correlated with their subsequent excisions. Immunohistochemical markers Ki67or =5% and topoisomerase IIalphaor =5%, and reduced or patchy CD34 on core biopsy specimens correlated significantly with a diagnosis of phyllodes.Stromal hypercellularity, combined with key histological features and immunohistochemical markers Ki67, topoisomerase IIalpha and CD34, reinforced by clinical findings, can predict phyllodes tumours on core biopsy specimens.

We earlier evaluated the relationship of 653 triple negative breast cancers (TNBC) with basal immunophenotypic expression by using antibodies to basal cytokeratins (CK5/6, CK14, CK17, 34betaE12), p63, smooth muscle actin (SMA), epidermal growth factor receptor, and CD117, and found that a triple panel of CK14, 34betaE12 and epidermal growth factor receptor determined 84% of our cases to be basal-like. Women with basal-like TNBC tended to be younger (P=0.04), have histologically higher-grade tumors (P=0.047), with positive nodal status (P=0.047), than those whose tumors were nonbasal-like. Using univariate Cox regression analysis, tumor size (P=0.003), histologic grade (P=0.006), and nodal status (P=0.017) were significant factors for disease-free survival (DFS) among TNBC, whereas age (P=0.004), tumor size (P=0.001), histologic grade (P

Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. They are not always analyzed in distant metastatic and locally recurrent breast cancers. We compared immunohistochemical expression in a series of primary breast carcinomas with their distant metastases (n = 72) and local recurrences (n = 45) and analyzed the impact of any changes on survival. Discordance rates between primary and metastatic and between primary and locally recurrent lesions, respectively, were 18% (13/72) and 13% (6/45) for ER, 42% (30/72) and 33% (15/45) for PR, and 7% (5/72) and 2% (1/45) for c-ERBB2. There was statistically significant discordance between primary and metastatic PR status (P = .017; kappa = 0.201). Among locally recurrent tumors, 15 (33%) of 45 revealed discordance for PR (P = .006; kappa = 0.366). We observed a trend for shorter survival among women with ER- metastatic and locally recurrent tumors regardless of the primary tumor ER status. Our findings suggest a benefit for routine evaluation of ER, PR, and c-ERBB2 status in distant metastatic and locally recurrent breast cancer for therapeutic and prognostic purposes.

Columnar cell lesions of the breast refer to the morphological spectrum of alterations of the epithelial lining of variably dilated acini of the terminal duct lobular unit (TDLU), often related to secretions and calcifications. After decades of varied terminologies, the term of 'flat epithelial atypia' by the World Health Organization (WHO) consensus group encompasses the part of the spectrum where columnar cell change or columnar cell hyperplasia acquires low grade cytological atypia, merging with atypical ductal hyperplasia and low grade ductal carcinoma in situ. Its association with low grade invasive carcinoma and lobular neoplasia, whether by proximity to these lesions, or by similar molecular expressions, has prompted greater scrutiny into its clinical significance. Although recent literature attempts to refine the term 'flat epithelial atypia', the applicability of its morphological criteria in routine diagnostic practice remains to be seen, and interobserver variability is highly possible. This poses even greater challenges especially in limited samples of breast tissue, such as in core biopsies, for pre-operative decision-making. The purpose of this review is to elucidate evolving clinical and diagnostically relevant principles that surround and influence the significance of this still controversial entity, especially when discovered on core biopsy in the initial phase of breast diagnosis and management.

Phyllodes tumors of the breast are uncommon fibroepithelial neoplasms, typified by hypercellular stroma and elongated ducts with irregular leaf-like patterns due to stromal proliferation. Its numbers are much fewer than breast carcinomas, with a proportion of only 1.5% compared to breast carcinomas. Phyllodes tumors have a higher frequency in Asian women (Tan et al., 2005b). Classification into three categories of benign, borderline, and malignant is based on a spectrum of histological features such as stromal hypercellularity and cytologic atypia, stromal overgrowth, mitotic rate, and nature of microscopic margins. However, there are still difficulties in accurate categorization of phyllodes tumors and predicting their clinical outcome. Histologic features such as grade (Moffat et al., 1995; Reinfuss et al., 1996), stromal overgrowth (Chaney et al., 2000), tumor necrosis and heterologous stromal elements (Cohn-Cedermark et al., 1991), as well as a combination of morphologic parameters (Moffat et al., 1995), are reported to be predictive. However, specific parameters that are associated with recurrence are not agreed upon; with a substantial number of reports concluding that adequate margins are the most important (Barth, 1999; Kleer et al., 2001; Tan et al., 2005b), and that histologic factors have an inconsistent influence on biologic behavior. Biological markers have been studied in phyllodes tumors using immunohistochemistry, with p53 perhaps being the most widely evaluated (Feakins et al., 1999; Kuenen-Boumeester et al., 1999; Tse et al., 2002; Millar et al., 1999). Whilst p53 expression in stromal cells has been associated with malignant histological features, it does not appear to predict likelihood of recurrence. c-kit (CD117) expression is also reported in the stroma of malignant phyllodes tumors (Sawyer et al., 2003; Chen et al., 2000), and CD117 stromal staining has been shown to correlate with disease recurrence (Tan et al., 2005d). Other studies have demonstrated that heparan sulfate expression (Koo et al., 2006), epidermal growth factor receptor 19 Phyllodes Tumors of the Breast: The Role of Immunohistochemistry in Diagnosis

A 56 year old man with previously unsuspected recurrence of squamous cell carcinoma of the oesophagus presented with dyspnoea. Bronchoscopy and computed tomography suggested bronchopneumonic changes with an infectious cause. He suffered a rapidly deteriorating course and died despite active treatment, including antibiotics and mechanical ventilation. Necropsy revealed a florid pulmonary tumour microembolism mimicking alveolitis. No bronchopneumonia was seen. The emboli arose from loosely attached tumour vegetations in the tricuspid valve. In a patient with known malignancy, tumour microembolism should be considered as an uncommon cause of rapid respiratory failure, refractory to antibiotic treatment.

We described a rare case of carcinoma expleomorphic adenoma in which mucoepidermoid carcinoma arise from a previous incompletely excised pleomorphic adenoma of the submandibular gland. The tumor was surgically resected along with a modified radical neck dissection and postoperative radiotherapy. The patient remained disease free 3 years after the last operation. The pathology showed concurrent presence of Warthin's tumor in the specimen. The concurrent presence of mucoepidermoid carcinoma, pleomorphic adenoma, and synchronous Warthin's tumor make this case unique, and such a combination associated with the submandibular gland has not been documented in the literature before.

Aims: To review 25 cases of breast hamartoma and discuss the pathological criteria, and the usefulness of imaging modalities, fine needle aspiration cytology (FNAC), and needle core biopsy in the diagnosis. Methods: The hamartomas were assessed for interlobular fibrotic stroma, stromal adipose tissue content, pseudo-angiomatous stromal hyperplasia, and epithelial changes (hyperplasia, adenosis or apocrine metaplasia, and cyst formation). All imagings, previous FNACs, and biopsies were also reviewed. Results: Imaging (mammography, ultrasound, and magnetic resonance imaging) was performed in 18 cases, and mostly showed encapsulated masses with a heterogeneous appearance. Microscopically, all hamartomas demonstrated good demarcation with fibrous tissue condensation. Adipose tissue was noted in all cases (5–90%; mean, 31%), and interlobular fibrosis in 21 cases. Benign epithelial hyperplasia occurred in 10 cases, and pseudo-angiomatous stromal hyperplasia or cystic ducts in eight cases each. Apocrine metaplasia, calcification, stromal giant cells, and adenosis occurred in four cases or less. Two cases showed coexisting ductal carcinoma in situ limited to within the hamartoma. Needle core biopsies (four cases) and FNAC (14 cases) were largely insufficient, inconclusive, or non-specific. Conclusions: Hamartomas do not possess specific diagnostic histological features. The role of FNAC and needle core biopsy in making the diagnosis is limited, and requires clinical and radiological correlation to avoid underdiagnosis.

Hamartoma of the breast is an uncommon lesion. Although it can possess characteristic radiological features, the pathological appearance is not distinctive. Hamartoma is generally considered benign, but four cases have been reported with ductal and lobular carcinoma arising in hamartomas. This report describes further cases of hamartoma from which ductal carcinoma in situ arose, with one showing early invasion. In both cases, the tumours were within the hamartomas and were adequately excised during lumpectomies of the hamartomas, and the patients were well afterwards. This report emphasises the importance of adequate sampling of mammary hamartoma.