Prostate Adenocarcinoma Grade Group 1: Rationale for Retaining a Cancer Label in the 2022 World Health Organization Classification.

We present the rationale for keeping the "cancer" label for grade group 1 (GG1) prostate cancer. Maintaining GG1 as the lowest grade outweighs the potential benefits that a benign designation may bring. Patient and surgeon education on the vital role of active surveillance for GG1 cancers and avoidance of overtreatment should be the focus rather than such a drastic change in nomenclature.

The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.

The fifth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "Blue Book"), published in 2022, contains significant revisions. This review summarises the most relevant changes for renal, penile, and testicular tumours. In keeping with other volumes in the fifth edition series, the WHO classification of urogenital tumours follows a hierarchical classification and lists tumours by site, category, family, and type. The section "essential and desirable diagnostic criteria" included in the WHO fifth edition represents morphologic diagnostic criteria, combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has been introduced, taking recent discoveries in renal tumour genomics into account. Such novel molecularly defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The diverse morphologic patterns of penile squamous cell carcinomas are grouped as human papillomavirus (HPV) associated and HPV independent, and there is an attempt to simplify the morphologic classification. A new chapter with tumours of the scrotum has been introduced. The main nomenclature of testicular tumours is retained, including the use of the term "germ cell neoplasia in situ" (GCNIS) for the preneoplastic lesion of most germ cell tumours and division from those not derived from GCNIS. Nomenclature changes include replacement of the term "primitive neuroectodermal tumour" by "embryonic neuroectodermal tumour" to separate these tumours clearly from Ewing sarcoma. The term "carcinoid" has been changed to "neuroendocrine tumour", with most examples in the testis now classified as "prepubertal type testicular neuroendocrine tumour".

The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs-Part B: Prostate and Urinary Tract Tumors.

The 2022 World Health Organization (WHO) classification of the urinary and male genital tumors was recently published by the International Agency for Research on Cancer. This fifth edition of the WHO "Blue Book" offers a comprehensive update on the terminology, epidemiology, pathogenesis, histopathology, diagnostic molecular pathology, and prognostic and predictive progress in genitourinary tumors. In this review, the editors of the fifth series volume on urologic and male genital neoplasms present a summary of the salient changes introduced to the classification of tumors of the prostate and the urinary tract.

Standing in the GAP : To formulate a novel radioimmunotherapy regime to improve the long-term outcome in breast cancer.

AIM: The new radioimmunotherapeutic regime GAP15R aims to stimulate glucocorticoid-induced TNF-related protein (G) to overcome Treg suppression; add IFN-α (A) to promote inflammatory milieu; block PD1 (P) to disinhibit T effector cytotoxicity; add IL-15 (15) to enhance danger signals & T-cell expansion; and apply radiation (R) at critical time point to sustain localized inflammation. Patients & methods/materials & methods: This was tested in a murine 4T1 metastatic breast carcinoma model given GAP15R with regular monitoring of tumor volume and complications. RESULTS: We had demonstrated long-term complete remission up to 50% of treated mice, which is not associated with major treatment-related complication, in cases with specific tumor burden. CONCLUSION: GAP15R is efficacious with potential to be applicable to other tumors.

Recurrent phyllodes tumours of the breast: pathological features and clinical implications.

BACKGROUND: Phyllodes tumours (PT) of the breast are fibro-epithelial neoplasms that are known to recur locally in up to 19% of patients. The failure to achieve adequate surgical margins is an important risk factor for local recurrence. This, however, is a common problem as PT are clinically similar to the more common fibro-adenoma and are therefore often locally excised without any gross surgical margins. It is still debatable as to whether it is necessary to subject the patient to repeat surgery to obtain pathologically negative margins after a diagnosis of a benign or borderline PT is made. Although the majority of recurrences are histologically similar to the initial tumour, a malignant recurrence is possible. Malignant tumours can metastasize through the haematogenous route and metastases are associated with a poor prognosis as they are poorly responsive to conventional chemotherapy. METHODS: We retrospectively reviewed 37 women who presented with local recurrence over a 10-year period to the Singapore General Hospital. Data, including age at the time of diagnosis, clinical presentation, histological features, type of surgery carried out, clinical progression and characteristics of locally recurrent disease, were analysed. Comparisons were made between those with benign, borderline and malignant tumours, as well as between those who developed a malignant recurrence and those who did not. RESULTS: The mean age at the time of diagnosis was 39.6 +/- 7.4 years and the mean tumour size was 6.0 +/- 5.1 cm. A total of 22 patients were classified as having benign tumour, 9 as having borderline tumour and 6 as having malignant tumour. Tumour grade did not influence the tumour size, the adequacy of surgical margins or the time interval to local recurrence or the number of recurrences. Local recurrence occurred after a median interval of 20 months. Although malignant tumours tended to recur earlier, this was not found to be statistically significant. The majority of recurrent tumours were histologically similar to the initial tumour; however, seven patients (19%) developed a malignant recurrence from an initially benign or borderline tumour. Although these tumours were larger, recurred more frequently and within a shorter interval, no significant predictive factor was found on multivariate analysis. Distant metastasis developed only in patients with malignant tumours and accounted for all three mortalities in the study. CONCLUSIONS: It may be acceptable to use an expectant management towards benign and borderline tumours that are excised without adequate surgical margins. However, surgery for locally recurrent tumours, as well as malignant tumours, should aim to achieve adequate surgical margins to reduce the risk of local recurrence, particularly that of a malignant recurrence.

Oncological outcomes following robotic-assisted radical prostatectomy in a multiracial Asian population.

This study evaluates the oncological outcomes of RARP in a multiracial Asian population from a single institution. All suitable patients from 1st January 2003-30th June 2013 were identified from a prospectively maintained cancer registry. Peri-operative and oncological outcomes were analysed. Significance was defined as p < 0.05. There were n = 725 patients identified with a mean follow-up duration 28 months. The mean operative time, EBL and LOS were 186 min, 215 ml and 3 days, respectively. The pathological stage was pT2 in 68.6% (n = 497/725), pT3 in 31.3% (n = 227/725) and n = 1 patient with pT4 disease. The pathological Gleason scores (GS) were 6 in 27.9% (n = 202/725), GS 7 in 63.6% (n = 461/725) and GS ≥ 8 in 8.0 % (n = 58/725). The node positivity rate was 5.8% (n = 21/360). The positive margin rates were 31.0% (n = 154/497) and 70.9% (n = 161/227) for pT2 and pT3, respectively, and decreasing PSM rates are observed with surgical maturity. The biochemical recurrence rates were 9.7% (n = 48/497) and 34.2% (n = 78/228) for pT2 and pT3/T4, respectively. On multivariate analysis, independent predictors of BCR were pathological T stage and pathological Gleason score. Post-operatively, 78.5% (n = 569/725) of patients had no complications and 17.7% (n = 128/725) had minor (Clavien grade I-II) complications. This series, representing the largest from Southeast Asia, suggests that RARP can be a safe and oncologically feasible treatment for localised prostate cancer in an institution with moderate workload.

Novel Karyotypes and Cyclin D1 Immunoreactivity in Clear Cell Sarcoma of the Kidney.

Pathological diagnosis of clear cell sarcoma of the kidney (CCSK) is challenging as it resembles blastemal Wilms tumor (WT) and other pediatric sarcomas, and does not have any distinctive immunophenotype. The YWHAE-FAM22 translocation t(10;17)(q22;p13) has been reported in a subset of CCSK. This translocation also occurs in high-grade endometrial sarcoma, in which it is associated with cyclin D1 overexpression. Hence we seek to determine YWHAE-FAM22 translocation status and cyclin D1 immunoreactivity in a series of local CCSK cases. Of 8 CCSK cases from 7 patients identified, no CCSK had the YWHAE-FAM22 fusion transcript by reverse transcriptase-polymerase chain reaction. Novel karyotypes were identified for 2 cases: 1 had t(2;13)(q13;q22) and the other t(3:17)(q29;p11.2). Excluding a case with poor tissue section antigenicity, 7 of 7 CCSKs (100%) showed diffuse and strong nuclear cyclin D1 staining. Cyclin D1 immunohistochemistry was also performed on tissue microarrays of other pediatric renal tumors: blastemal areas of 18 WT cases were negative; 6 rhabdoid tumors and 1 metanephric adenoma showed patchy and weak staining; 3 mesoblastic nephromas and 18 of 29 neuroblastomas had positive staining. Cyclin D1 immunohistochemistry helps distinguish CCSK from blastemal WT and metanephric adenoma and rhabdoid tumors, but not from neuroblastomas and mesoblastic nephromas. Cyclin D1 overexpression in CCSK is not contingent on YWHAE-FAM22 translocation, and cyclin D1 inhibition may potentially be explored as a targeted therapeutic strategy in CCSK.

Fluorescence confocal microscopy and image analysis of bladder cancer using 5-aminolevulinic acid.

5-aminolevulinic acid mediated changes in tissue specific fluorescence were studied in bladder cancer. Bladders of normal patients and also patients diagnosed with cancer were instilled with 5-aminolevulinic acid and the resultant protoporphyrin IX mediated fluorescence intensity was imaged and quantified with confocal laser microscopy and fluorescence image analysis. Urothelial tumour cells were observed to fluoresce more intensely than normal urothelial cells. Submucosa and muscle tissues exhibited minimal fluorescence compared to urothelial cells of malignant origin and also normal urothelial cells. Degree of fluorescence intensity was in the order of malignant urothelium > normal urothelium > normal submucosa > normal muscles. Fluorescence intensity was also found to increase with duration of ALA instillation. Grade 3 malignant cells produced more fluorescence compared to grade 2 and grade 1. Similarly, T1 transitional cell carcinoma (TCC) showed increased fluorescence intensity than that of Ta TCC. Also, tumour blood vessels fluoresced more intensely compared to blood vessels found in normal bladder tissue. Tissue specific ALA mediated PpIX micro fluorescence can be used as a diagnostic technique for early detection of neoplasms and confocal laser microscopy and fluorescence image analysis are advantageous diagnostic tools for the photodynamic diagnosis of bladder neoplasms in vivo.

Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor.

Recent work using expression profiling to computationally predict the estrogen receptor (ER) status of breast tumors has revealed that certain tumors are characterized by a high prediction uncertainty ('low-confidence'). We analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ER subtype discrimination. Patients with 'low-confidence' ER+ tumors exhibited a significantly worse overall survival (P=0.03) and shorter time to distant metastasis (P=0.004) compared with their 'high-confidence' ER+ counterparts, indicating that the 'high-' and 'low-confidence' binary distinction is clinically meaningful. We then discovered that elevated expression of the ERBB2 receptor is significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction, and this association was subsequently validated across multiple independently derived breast cancer expression datasets employing a variety of different array technologies and patient populations. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2+ samples are not known to be estrogen responsive, and a recently described bioinformatic algorithm (DEREF) was used to demonstrate the absence of potential estrogen-response elements (EREs) in their promoters. We propose that a significant portion of ERBB2's effects on ER+ breast tumors may involve ER-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.