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The Arabidopsis thaliana early in short days6 (esd6) mutant was isolated in a screen for mutations that accelerate flowering time. Among other developmental alterations, esd6 displays early flowering in both long- and short-day conditions. Fine mapping of the mutation showed that the esd6 phenotype is caused by a lesion in the high expression of osmotically responsive genes1 (HOS1) locus, which encodes a RING finger-containing E3 ubiquitin ligase. The esd6/hos1 mutation causes decreased flowering locus C expression and requires CONSTANS (CO) protein for its early flowering phenotype under long days. Moreover, CO and HOS1 physically interact in vitro and in planta, and HOS1 regulates CO abundance, particularly during the daylight period. Accordingly, hos1 causes a shift in the regular long-day pattern of expression of flowering locus T (FT) transcript, starting to rise 4 h after dawn in the mutant. In addition, HOS1 interacts synergistically with constitutive photomorphogenic1, another regulator of CO protein stability, in the regulation of flowering time. Taken together, these results indicate that HOS1 is involved in the control of CO abundance, ensuring that CO activation of FT occurs only when the light period reaches a certain length and preventing precocious flowering in Arabidopsis.

Aim: To document and clarify the nature of intranuclear inclusions of luminal epithelium in benign proliferative breast lesions., Methods and Results: Five benign breast lesions were selected which showed intranuclear inclusions within epithelial cells on light microscopy. Following confirmation of their luminal epithelial (non-myoepithelial) localisation by immunohistochemistry, ultrastructural examination was performed with the following observations: (1) presence of deep nuclear indentations occasionally verging on nuclear inclusions; (2) inclusions with features of helioid bodies; and (3) a morphological spectrum of helioid bodies and their focal coexistence., Conclusion: Intranuclear inclusions of breast epithelium are likely of cytoplasmic origin. Helioid bodies may be formed by a stepwise process, the nature of which needs further study.

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 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%), mitoses > or =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 > or =5% and topoisomerase IIalpha> or =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 IIalpha and CD34, reinforced by clinical findings, can predict phyllodes tumours on core biopsy specimens.

Aims: To assess the accuracy of diagnosing papillary breast lesions in core needle biopsy., Methods and Results: One hundred biopsy specimens of papillary breast lesions were reviewed and compared with the final excisional diagnoses. The discordant biopsy specimens were stained for oestrogen receptor (ER), cytokeratin (CK) 14 and p63, and these specimens were reclassified based on these results. The overall core biopsy accuracy, false-positive and false-negative rate were 79%, 5% and 16%, respectively. A benign core biopsy specimen diagnosis gave a false-negative rate of 10%, and malignant core biopsy specimen diagnosis did not give any false-positive results. Using homogeneous ER (epithelial), positive CK14 (epithelial) and p63 (myoepithelial) immunoreactivity as benign criteria, the discordant rate was reduced by 30% and 69% when using all three or two of these three criteria for diagnosis. However, false-positive and -negative cases could not be totally eliminated., Conclusions: Immunohistochemistry is helpful in core biopsy diagnosis of papillary breast lesions, but some cases remained misdiagnosed.

Triple-negative breast cancer, defined as that with negative expression of estrogen and progesterone receptors and cerbB2, accounted for 11% of invasive breast cancers in our study, drawn from an original cohort of 7048 women diagnosed with breast cancer from the files of the Department of Pathology, Singapore General Hospital, over 14 years. Women with triple-negative breast cancer were generally postmenopausal, with adverse pathological characteristics of high histological grade and frequent nodal metastases. Using a set of 61 invasive breast cancers earlier profiled into molecular subtypes with expression arrays, we defined specificity and sensitivity values for different immunohistochemical panels of basal keratins (CK5/6, CK14, CK17, 34 beta E12), CD117, EGFR, p63 and SMA in defining basal-like breast cancer. Subsequent application of a tri-panel of CK14, EGFR and 34 beta E12 (specificity 100% and sensitivity 78%) to our group of 653 triple-negative breast cancers delineated 84% to be basal-like. Immunohistochemical expression of individual biological markers correlated with unfavorable pathological parameters. We conclude that triple-negative breast cancers in an Asian population harbor adverse pathobiological features, and an immunohistochemical surrogate panel can be reliably used to define basal-like cancers among them.

There has been a recent upsurge in worldwide attention on digital pathology, which has transformed from static snapshots from camera-equipped microscopes to its modern form that encompasses scanning of whole glass slides with evaluation of histological images on a computer screen, along with management of its accompanying information. Although it has been widely accepted in education and research, its implementation in diagnostic surgical pathology practice is not without challenges in workflow integration, technological infrastructure, pathologist acclimatisation, global standardisation for clinical practice, and cost issues, among others. Nonetheless, early adopters have harnessed its benefits in specific niches, like frozen section services and remote second opinion consultations. Its tremendous potential is worthy of further validation to compare with conventional glass slide evaluation, even while it is already paving the way for advancement into virtual three-dimensional imaging technology, with a glimpse into a possible future digital diagnostic pathology practice.

Aim: The increase in early detection of prostate cancer in the Asian population has bolstered second opinion consultations in prostate pathology in this region. In this review, we aimed to identify the spectrum of lesions and queries submitted to a pathologist with uropathology interest at the Singapore General Hospital., Method: Request forms for second opinion prostate consultations from pathologists and clinicians were retrieved from central laboratory records and a specialist's correspondence files within 2004-2007. Histomorphological queries raised in the referrals, and comparison of original diagnosis and Gleason scoring with the review diagnoses were collated., Results: Discordant diagnoses (183/323, 57%) were more common than concordant diagnoses (143/326, 44%) between original diagnosis and subspecialist review. The majority of discordances comprised initial undergrading of Gleason scores (132/183, 72%; p < 0.01) especially in needle core biopsies. Among the significantly altered pathological diagnoses, 24 cases (13%; p < 0.01) were changed from benign to malignant (n = 9, 5%; p < 0.01), and malignant to benign (n = 11, 6%; p < 0.01) or high grade prostatic intraepithelial neoplasia (n = 4, 2%; p < 0.01). Benign mimics of malignancy such as atypical adenomatous hyperplasia and atrophy, and small foci of adenocarcinoma, were some examples of morphological pitfalls., Conclusion: Prostate biopsy review is important because of management and prognostic implications that vary among Gleason scores, and predictive parameters that are detailed in prostate pathology reports.

Breast cancer is the commonest malignancy among Singapore women, accounting for 29.7% of all female cancers, with an age-standardized rate of 54.9 per 100,000 per year. It has been the most frequent cancer in Singapore women for the last 30 years, with the highest rates previously reported in those aged between 45 and 49 years, but with a more recent observation of a change in peak age group to women in their late 50s. About 1,100 new cases are diagnosed annually and approximately 270 women die in Singapore each year from breast cancer. In the multiethnic population of Singapore, it has been noted that rising breast cancer incidence is consistent across all three ethnic groups (Chinese, Malays, and Indians). Singapore has among the highest breast cancer incidence in Asia. Possible explanations include rapid urbanization, improvement in socio-economic status, and adoption of a western lifestyle. Our experience with the Singapore breast screening pilot project (1994-1997) and the national breast-screening program (BreastScreen Singapore) has led to increased understanding of this disease in the country. Data from the pilot project showed that breast screening is just as effective in a predominantly Asian population as in the west. Early breast cancer accounted for most breast cancers detected, with pre-invasive ductal carcinoma in situ (DCIS) comprising 26% of all screen-detected cancers in the pilot study. In the currently on-going BreastScreen Singapore, DCIS forms >30% of all breast cancers among pre-menopausal women, a relatively high proportion probably accounted for partially by the greater participation of women aged between 40 and 49 years. Despite the ready availability of subsidized mammographic screening, there are still women in Singapore who present with locally advanced breast cancer. Clinical management of an increasing number of women with breast cancer embraces a multidisciplinary team-based approach, with regular discussions of therapeutic strategies at tumor boards. In order to improve breast cancer diagnostics and therapeutics in our country, it is important that there are continual breast cancer and breast disease-related educational activities for medical professionals engaged in diagnosing and managing breast cancer. The role of public education in raising awareness is also essential.

Breast phyllodes tumors are rare fibroepithelial neoplasms that need to be distinguished from the common morphologically similar fibroadenomas, because phyllodes tumors can recur and progress to malignancy. Their potentially recurring and metastasizing behavior is attributed to their stromal characteristics, for which categorization between benign, borderline and malignant tumors have not been universally established. Previous clonality studies revealing monoclonal stromal cells versus a polyclonal epithelial component theorized that phyllodes tumors are mainly stromal neoplasms, possibly arising from fibroadenomas. More recent chromosomal imbalances in both epithelium and stroma have challenged this theory to favor neoplasia of both epithelium and stroma, with initial interdependence between the two components. Inverse correlations between epithelial and stromal overexpression for various biological markers like estrogen receptor, p53, c-kit, Ki-67, endothelin-1, epidermal growth factor receptor, heparan sulfate, in addition to findings of epithelial Wnt signalling with stromal insulin growth factors and beta-catenin expression, suggest an initial epithelial-stromal interdependence at the benign phase. Upon progression to malignancy, the stroma is hypothesized to assume an autonomous growth overriding any epithelial influence. Frequent genetic alterations are chromosomal gains of 1q and losses at chromosome 13. Acquisition of new genetic imbalances within the tumor consistent with intratumoral heterogeneity, and subclones within histologically benign phyllodes tumors that recur or metastasize are the current theories explaining these tumors' unpredictable clinical behavior.

We have studied the MICA alleles of 196 unrelated subjects from three South American Indian tribes (Toba, Wichi and Terena). They are members of isolated tribes located in the Gran Chaco area in northeastern Argentina and in Mato Grosso do Sul in South Central Brazil. Of 55 previously known alleles, nine were observed in South American Indians, compared with 16 that were found in North American Caucasians, suggesting a more restricted allelic distribution of MICA in these tribes. In South American Indians, MICA*00201 was the most frequent allele, with a gene frequency of 33% in Toba, 47% in Wichi and 44% in Terena. MICA*00201, MICA*027 (external domain sequence like MICA*008/TM allele A5) and MICA*010 accounted for more than 90% of all the MICA genes in South American Indians. In North American Caucasians, MICA*00801 (*008/A5.1) accounted for 42% of the genes and was the most common allele. We observed a high degree of linkage disequilibrium between certain alleles of MICA and of HLA-B in the South American Indian populations. Phylogenetic trees constructed using gene frequencies of the transmembrane short tandem repeats in the populations reported here, and in other populations taken from published reports, suggest that South American Indians are more closely related to Asians than to Europeans.