WHO 2022 classification of penile and scrotal cancers: updates and evolution.

Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)-associated and HPV-independent types. HPV-associated penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive HPV- associated SCC, whereas differentiated PeIN is a precursor lesion of HPV-independent SCC. Block-type positivity of p16 immunohistochemistry is the most practical daily utilised method to separate HPVassociated from HPVindependent penile SCC. If this is not feasible, the term SCC, not otherwise specified (NOS) is appropriate. Certain histologies that were previously classified as "subtypes" are now grouped, and coalesced as "patterns", under the rubric of usual type SCC and verrucous carcinoma (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma). If there is an additional component of the usual type of invasive SCC (formerly termed hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, reporting of the relative percentages in mixed tumours may be useful. The consistent use of uniform nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations. The classification of scrotal tumours is provided for the first time in the fifth edition of the WHO Blue book, and it follows the schema of penile cancer classification for both precursor lesions and the common SCC of the scrotum. Basal cell carcinoma of the scrotum may have a variable clinical course and finds a separate mention.

ERRATUM: Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

No abstract available.

Ultralow-frequency Raman system down to 10 cm(-1) with longpass edge filters and its application to the interface coupling in t(2+2)LGs.

Ultralow-frequency (ULF) Raman spectroscopy becomes increasingly important in the area of two-dimensional (2D) layered materials; however, such measurement usually requires expensive and nonstandard equipment. Here, the measurement of ULF Raman signal down to 10 cm(-1) has been realized with high throughput by combining a kind of longpass edge filters with a single monochromator, which are verified by the Raman spectrum of L-cystine using three laser excitations. Fine adjustment of the angle of incident laser beam from normal of the longpass edge filters and selection of polarization geometry are demonstrated how to probe ULF Raman signal with high signal-to-noise. Davydov splitting of the shear mode in twisted (2+2) layer graphenes (t(2+2)LG) has been observed by such system in both exfoliated and transferred samples. We provide a direct evidence of twist-angle dependent softening of the shear coupling in t(2+2)LG, while the layer-breathing coupling at twisted interfaces is found to be almost identical to that in bulk graphite. This suggests that the exfoliation and transferring techniques are enough good to make a good 2D heterostructures to demonstrate potential device application. This Raman system will be potentially applied to the research field of ULF Raman spectroscopy.

Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed a radiologically-diagnosed lung nodule 26 months after mastectomy, was given a course of radiotherapy and remained well 8-months following identification of the lung nodule.

Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer that has basal-like characteristics and is perceived to have poorer prognosis when compared with conventional no specific type/ductal carcinomas (ductal/NST). However, current data on MBC are largely derived from small case series or population-based reports. This study aimed to assess the clinicopathological features and outcome of MBC identified through an international multicentre collaboration. METHODS: A large international multicentre series of MBC (no=405) with histological confirmation and follow-up information has been included in this study. The prognostic value of different variables and outcome has been assessed and compared with grade, nodal status and ER/HER2 receptor-matched ductal/NST breast carcinoma. RESULTS: The outcome of MBC diagnosed in Asian countries was more favourable than those in Western countries. The outcome of MBC is not different from matched ductal/NST carcinoma but the performance of the established prognostic variables in MBC is different. Lymph node stage, lymphovascular invasion and histologic subtype are associated with outcome but tumour size and grade are not. Chemotherapy was associated with longer survival, although this effect was limited to early-stage disease. In this study no association between radiotherapy and outcome was identified. Multivariate analysis of MBC shows that histologic subtype is an independent prognostic feature. CONCLUSIONS: This study suggests that MBC is a heterogeneous disease. Although the outcome of MBC is not different to matched conventional ductal/NST breast carcinoma, its behaviour is dependent on the particular subtype with spindle cell carcinoma in particular has an aggressive biological behaviour. Management of patients with MBC should be based on validated prognostic variables.

Validation of a nomogram in the prediction of local recurrence risks after conserving surgery for Asian women with ductal carcinoma in situ of the breast.

AIMS: At our centre, ductal carcinoma in situ (DCIS) was commonly treated with breast-conservation therapy (BCT). Local recurrence after BCT is a major concern. The aims of our study were to review the outcomes of DCIS treatment in our patients and to evaluate a nomogram from Memorial Sloan Kettering Cancer Centre (MSKCC) for predicting ipsilateral breast tumour recurrence (IBTR) in our Asian population. MATERIALS AND METHODS: Chart reviews of 716 patients with pure DCIS treated from 1992 to 2011 were carried out. Univariable Cox regression analyses were used to evaluate the effects of the 10 prognostic factors of the MSKCC nomogram on IBTR. We constructed a separate National Cancer Centre Singapore (NCCS) nomogram based on multivariable Cox regression via reduced model selection by applying the stopping rule of Akaike's information criterion to predict IBTR-free survival. The abilities of the NCCS nomogram and the MSKCC nomogram to predict IBTR of individual patients were evaluated with bootstrapping of 200 sets of resamples and the NCCS dataset, respectively. Harrell's c-index was calculated for each nomogram to evaluate the concordance between predicted and observed responses of individual subjects. RESULTS: Study patients were followed up for a median of 70 months. Over 95% of patients received adjuvant radiotherapy. The 5 and 10 year actuarial IBTR-free survival rates for the cohort were 95.5 and 92.6%, respectively. In the multivariate analysis, independent prognostic factors for IBTR included use of adjuvant endocrine therapy, presence of comedonecrosis and younger age at diagnosis. These factors formed the basis of the NCCS nomogram, which had a similar c-index (NCCS: 0.696; MSKCC: 0.673) compared with the MSKCC nomogram. CONCLUSION: The MSKCC nomogram was validated in an Asian population. A simpler NCCS nomogram using a different combination of fewer prognostic factors may be sufficient for the prediction of IBTR in Asians, but requires external validation to compare for relative performance.

ALDH1 expression is enriched in breast cancers arising in young women but does not predict outcome.

BACKGROUND: Tumours arising in younger women appear to be biologically more aggressive and tend to have a poorer outcome. Being relatively resistant to conventional treatments, breast cancer stem cells (CSCs) have been postulated as a possible cause of disease recurrence after treatment. In this study, we used ALDH1 as a CSC marker and determined whether ALDH1 expression correlated with clinical outcome in young women with breast cancer. METHODS: The expression of ALDH1 was evaluated through immunohistochemistry on microarrayed cores obtained from 141 consecutive patients up to 35 years of age. RESULTS: The expression of ALDH1 was observed in 25% (35 of 141) of tumours, in a median of 5% of cells. Younger women were 14 times more likely to have ALDH1-positive tumours (P<0.01, OR 14.4, 95% CI 4.34-48.09). The ALDH1 correlated independently with ER negativity (P=0.01, OR 0.33, 95% CI 0.15-0.77). There was no correlation with disease recurrence or breast cancer-related deaths. CONCLUSION: In younger women, ALDH1 was more highly expressed, and it correlated with ER negativity. It, however, did not predict survival in this study.

Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Mesenchymal stem cells differentially mediate regulatory T cells and conventional effector T cells to protect fully allogeneic islet grafts in mice.

AIMS/HYPOTHESIS: Limited information is available on the cellular interactions between regulatory T (T(reg)) cells and mesenchymal stem cells (MSCs). In particular, a direct effect of MSCs on the survival and proliferation of T(reg) cells has not been demonstrated. METHODS: We investigated the effects of MSCs on effector T (T(eff)) cells and T(reg) cells, and the molecular mechanisms involved in the distinct regulation of these two cell populations by MSCs in vivo and in vitro. RESULTS: We show that MSCs are capable of selectively suppressing T(eff) cells and fostering the generation of T(reg) cells. T(eff) cells, but not T(reg) cells, fail to respond to IL-2 and undergo profound apoptosis in the presence of MSCs. The differential regulations of these two T cell subsets by MSCs are associated with their distinct expressions of CD25, with MSCs specifically reducing the expression of CD25 on T(eff) and sparing T(reg) cells intact. In vivo, the administration of MSCs significantly delays the rejection of allogeneic islet grafts in adaptive transferred recipients by favouring the induction of T(reg) cells. In this model, MSCs inhibit the proliferation and development of alloreactive T(eff) but potently enhance the induction of T(reg) cells. CONCLUSIONS/INTERPRETATION: We demonstrate that MSCs are capable of regulating T(eff) and T(reg) cells differentially in vitro. MSCs inhibit T(eff) cells by inducing apoptosis and impairing the proliferative response to IL-2 in T(eff) cells, but favour the survival and expansion of T(reg) cells. This result is further demonstrated in mice that have undergone allogeneic islet transplantation, in which MSCs suppress alloreactive T(eff) cells while favouring the induction of T(reg) cells, thus protecting the islet allografts from rejection.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

Controlling the cost of breast cancer.

Breast cancer management is an important part of the health-care system. In the current harsh economic climate, these costs have to be controlled, and achieving this without compromising quality of care is a daunting challenge. This article discusses the need to find effective and well-targeted chemotherapeutic regimens, which, when combined with appropriate implementation of novel strategies, will provide the optimum treatment for patients while maintaining economic viability.

The effect of transoesophageal echocardiography probe insertion on tracheal cuff pressure.

Increased tracheal cuff pressure during mechanical ventilation is associated with reduced mucosal blood flow and ischaemia, as well as postoperative sore throat. We assessed the potential effects of transoesophageal echocardiography probe insertion on the tracheal cuff pressure in patients undergoing cardiac surgery. Using a manometer, the cuff pressure of a high-volume, low-pressure tracheal tube (inner diameter 7.0 mm for women and 7.5 mm for men) was adjusted to 25-30 cm H(2)O before blind insertion of a transoesophageal echocardiography probe. The pressure changes were then recorded for 1 min. After probe insertion, the mean (SD) intra-cuff pressure increased from 27.7 (1.5) to 36.2 (6.4) cm H(2)O (p < 0.001) and was > 35 cm H(2)0 in 17/38 patients (45%). Our results suggest that transoesophageal echocardiography probe insertion may increase the tracheal cuff pressure more than that is generally recommended and therefore the latter should be routinely monitored under such circumstances.

A prospective study to compare the diagnostic performance of breast elastography versus conventional breast ultrasound.

AIM: To compare the diagnostic performance of breast elastography versus conventional ultrasound in the assessment of breast lesions. MATERIALS AND METHODS: The study was approved by the hospital's institutional review board. A prospective study involving 99 consecutive women who gave informed consent were enrolled from September 2007 to March 2008. One hundred and ten breast lesions were evaluated separately by conventional ultrasound, elastography and combined conventional ultrasound with elastography. Ultrasound assessment was based on the BIRADS classification, whereas elastographic assessment was based on strain pattern and the elastographic size ratios. Histological diagnosis was used as the reference standard. The sensitivity, specificity, and accuracy of each technique were compared. RESULTS: The mean age of the patients was 46.7 years. Twenty-six lesions were malignant and 84 were benign. Sensitivity, specificity, and accuracy were 88.5, 42.9 and 53.6%, respectively, for conventional ultrasound, 100, 73.8, and 80%, respectively, for elastography, and 88.5, 78.6, and 80.9%, respectively, for combined imaging. The specificity and accuracy of elastography and combined imaging were significantly better than that of conventional ultrasound (p<0.0001), whereas there was no statistically significant difference in the sensitivity between all three groups. Two-thirds (66.7%) of sonographic false-positive lesions had benign elastogram findings, which might have been spared from biopsy. CONCLUSION: This initial experience with ultrasound breast elastography showed that it was more specific and more accurate than conventional ultrasound. Combining elastography with ultrasound improved specificity and accuracy of ultrasound and can potentially reduce unnecessary breast biopsies.

The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades.

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.

A right renal angiomyolipoma with IVC thrombus and pulmonary embolism.

Angiomyolipomas (AML) are benign lesions, commonly found in the kidney, where they may be single or multiple. There is a high association with tuberous sclerosis or lymphangioleiomyomatosis. When found as a solitary lesion, they are usually found in females in the forties to fifties age group. One of the rare complications is that of involvement of the lymph nodes and vascular spread via the inferior vena cava. We review the available literature and present a case of invasive AML with fat embolism.

LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer.

Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, using both loss of heterozygosity analysis and customized microarray comparative genomic hybridization. LARG (leukemia-associated Rho guanine-nucleotide exchange factor) (also called ARHGEF12), identified from the analysed region, is frequently underexpressed in breast and colorectal carcinomas with a reduced expression observed in all breast cancer cell lines (n=11), in 12 of 38 (32%) primary breast cancers, 5 of 10 (50%) colorectal cell lines and in 20 of 37 (54%) primary colorectal cancers. Underexpression of the LARG transcript was significantly associated with genomic loss (P=0.00334). Hypermethylation of the LARG promoter was not detected in either breast or colorectal cancer, and treatment of four breast and four colorectal cancer cell lines with 5-aza-2'-deoxycytidine and/or trichostatin A did not result in a reactivation of LARG. Enforced expression of LARG in breast and colorectal cancer cells by stable transfection resulted in reduced cell proliferation and colony formation, as well as in a markedly slower cell migration rate in colorectal cancer cells, providing functional evidence for LARG as a candidate tumor suppressor gene.

Manipulation of indoleamine 2,3 dioxygenase; a novel therapeutic target for treatment of diseases.

BACKGROUND: The discovery of indoleamine 2,3-dioxygenase (IDO) as a modulator for the maintenance of fetomaternal immuno-privileged state has been heralded as a significant step in further defining the role of IDO in immunobiology. IDO is an IFN-inducible, intracellular enzyme that catalyzes the initial and rate-limiting step in the degradation of the essential amino acid, tryptophan. It has been suggested that IDO has the capacity to regulate the immune system via two discrete mechanisms; firstly the deprivation of tryptophan, which is essential for T cell proliferation and via the cytotoxic effects of tryptophan metabolites on T(H)1 cell survival. METHODS: The sources of information used to prepare the paper are published work on Pubmed/Medline. In this review, we examine the therapeutic role of modulating IDO activity a variety of disease states including tumour tolerance, chronic infection, transplant rejection, autoimmunity and asthma. We propose that IDO represents a novel therapeutic target for the treatment of these diseases. We also explore the diverse strategies which are being employed, either to augment or to inhibit IDO activity in order to modify various disease processes. The limitations associated with these strategies are also scrutinized.

Adenoid cystic carcinoma of the breast.

Adenoid cystic carcinoma of the breast is a rare neoplasm that constitutes less than one percent of all mammary carcinomas. To date, there have been about 140 cases reported in the literature. It is a rare variant of adenocarcinoma that usually occurs in the salivary glands. In contrast to the aggressive nature of adenoid cystic carcinoma that occurs in the head and neck region, adenoid cystic carcinoma of the breast has a very favourable prognosis. Little has been published to date on its radiological features. We describe a 63-year-old woman with adenoid cystic carcinoma detected on mammography in our national breast screening programme, the radiological findings at presentation, the surgical management and a review of the literature.

The role of immunohistochemistry in the differential diagnosis of papillary lesions of the breast.

Papillary lesions of the breast represent a heterogeneous group with differing biological behaviour. Correct diagnosis is crucial but may be difficult, as many benign and malignant papillary lesions have similar appearances. Immunohistochemistry plays a useful role in their differentiation. Myoepithelial markers can help in differentiating papilloma from papillary carcinoma, as the former usually shows a continuous layer of myoepithelial cells. In intracystic papillary carcinoma, there is controversy as to the presence of a complete myoepithelial cell layer around these lesions. p63 is the marker of choice as the staining is nuclear, cross-reactivity is minimal, and sensitivity is high. Papilloma may frequently be complicated by superimposed different types of epithelial hyperplasia, which range from usual to atypical or even ductal carcinoma in situ, and they many be morphologically similar. Basal cytokeratins (CKs) are useful to differentiate these entities; as usual hyperplasia is positive for basal CKs with a mosaic staining pattern. CK5/6 is probably the best marker. Neuroendocrine markers (chromogranin A and synaptophysin) may be positive in papillary carcinoma, particularly in the solid type, and there may be some overlap with the ductal carcinoma in situ with spindle cells or endocrine ductal carcinoma in situ. A panel of CK5/6, p63 and neuroendocrine markers can be useful in the diagnostic investigation of problematic papillary lesions of the breast. As the experience with these markers remains rather limited, it is too early to recommend basing treatment choices on these marker studies alone. Complete removal of lesion is probably still the treatment of choice.