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The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin‐like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of 'other oncocytic tumours' with oncocytoma/chRCC‐like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so‐called 'low‐grade' oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma. [ABSTRACT FROM AUTHOR]

The 5th edition of the World Health Organisation Blue Book was published recently and includes a comprehensive update on testicular tumours. This builds upon the work of the 4th edition, retaining its structure and main nomenclature, including the use of the term 'germ cell neoplasia in situ' (GCNIS) for the pre‐invasive lesion of most germ cell tumours and division from those not derived from GCNIS. While there have been important developments in understanding the molecular underpinnings of testicular cancer, this updated classification paradigm and approach remains rooted in morphology. Nomenclature changes include replacement of the term 'primitive neuroectodermal tumour' by 'embryonic neuroectodermal tumour' based on the non‐specificity of the former term and to separate these tumours clearly from Ewing sarcoma. Seminoma is placed in a germinoma family of tumours emphasising relation to those tumours at other sites. Criteria for the diagnosis of 'teratoma with somatic transformation' have been modified to not include variable field size assessments. The word 'carcinoid' has been changed to 'neuroendocrine tumour', with most examples in the testis now classified as 'prepubertal type testicular neuroendocrine tumour'. For sex cord‐stromal tumours, the use of mitotic counts per high‐power field has been changed to per mm2 for malignancy assessments, and the new entities, 'signet ring stromal tumour' and 'myoid gonadal stromal tumour', are defined. Well‐differentiated papillary mesothelial tumour has now been defined as tumour type with a favourable prognosis. Sertoliform cystadenoma has been removed as an entity from testicular adnexal tumours and placed with Sertoli cell tumours. [ABSTRACT FROM AUTHOR]

Aim: Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined. Methods and results: We reviewed institutional databases for in‐house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post‐ androgen–deprivation therapy (ADT), and 33 post‐RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small‐cell/high‐grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high‐grade PCa and small‐cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet‐like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single‐cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with 'Paneth cell‐like' change: all primary. Conclusions: In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small‐cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high‐grade PCa + small‐cell/HGNEC and 'Paneth cell‐like' change occur in primary disease. [ABSTRACT FROM AUTHOR]

Objective: To determine whether subclassification of positive surgical margins (PSMs) increases predictive ability for biochemical recurrence (BCR) and aids clinical decision‐making in patients undergoing radical prostatectomy. Patients and Methods: We studied 2147 patients with pT2 and pT3a prostate cancer with detailed surgical margin parameters and BCR status. We compared a base model, a linear predictor calculated from the Memorial Sloan Kettering Cancer Center postoperative nomogram (prostate‐specific antigen, pathological tumour grade and stage), with the addition of surgical margin status to five additional models (base model plus surgical margin subclassifications) to evaluate enhancement in predictive accuracy. Decision curve analysis (DCA) was performed to determine the clinical utility of parameters that enhanced predictive accuracy. Results: Among 2147 men, 205 had PSMs, and 231 developed BCR. Discrimination for the base model with addition of surgical margin status was high (c‐index = 0.801) and not meaningfully improved by adding surgical margin subclassification in the full cohort. In analyses considering only men with PSMs (N = 55 with BCR), adding surgical margin subclassification to the base model increased discrimination for total length of all PSMs – alone or with maximum Gleason grade at the margin (c‐index improvement = 0.717 to 0.752 and 0.753, respectively). DCA demonstrated a modest benefit to clinical utility with the addition of these parameters. Conclusions: Specific subclassification parameters add predictive accuracy for BCR and may aid clinical utility in decision‐making for patients with PSMs. These findings may be useful for patient counselling and future adjuvant therapy trial design. [ABSTRACT FROM AUTHOR]

Background: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. Methods: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6‐month progression‐free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression‐free survival (PFS), overall survival (OS), and safety. Correlative analyses included next‐generation sequencing (NGS) from tumor and germline across >341 genes of interest. Results: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation‐associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6‐month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8‐16.4 months), and the ORR was 35%. With a median follow‐up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3‐71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. Conclusion: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population. The combination of everolimus plus bevacizumab demonstrates robust activity in patients who have papillary variant renal cell carcinoma. These data support this regimen as a standard first‐line treatment option in this patient population. [ABSTRACT FROM AUTHOR]

Inverted urothelial papilloma (IUP) and urothelial papilloma (UP) are rare urothelial neoplasms that typically follow a benign clinical course. Oncogenic mutations in FGFR3, HRAS, and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed. We sought to characterize the genomic landscape of IUP and UP using whole‐exome and targeted next‐generation sequencing. In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation. None of the IUP tumors harbored TERT promoter or FGFR3 mutations. In UP, 8 of 11 tumors had oncogenic KRAS mutations and two had oncogenic HRAS mutations. One UP tumor had oncogenic mutations in FGFR3, PIK3CA, and the TERT promoter, and arose in a patient with recurrent non‐invasive papillary urothelial carcinomas. In contrast to urothelial carcinoma, the APOBEC mutational signature was not present in any IUP and UP tumors, and oncogenic alterations in chromatin remodeling genes were uncommon in both IUP and UP. The current study suggests that IUP and UP are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial cancers. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We here describe the development of an evidence‐based cancer dataset by an International Collaboration on Cancer Reporting expert panel for the reporting of primary testicular neoplasia, and present the 'required' and 'recommended' elements to be included in the pathology report, as well as a commentary. This dataset encompasses the updated 2016 World Health Organisation classification of urological tumours, the results of an International Society of Urological Pathology consultation, and also staging with our preferred method: the American Joint Committee on Cancer version 8. Implementation of this dataset will facilitate consistent and accurate data collection between different cohorts, facilitate research, and hopefully result in improved patient management. [ABSTRACT FROM AUTHOR]

The World Health Organization ( WHO) released a new tumour classification for the genitourinary system in early 2016 after consensus by pathologists with expertise in these organs. It utilized the framework of the 2004 classification, and incorporated the most up-to-date information concerning these tumours. In testicular tumours, the majority of the changes occurred in the nomenclature and classification of germ cell tumours; however, several modifications were also made for non-germ cell tumours. Among sex cord-stromal tumours, sclerosing Sertoli cell tumour ( SCT) is no longer recognized as a separate entity but as a morphological variant of SCT not otherwise specified ( NOS), as CTNNB1 gene mutations have been noted in both neoplasms but not in the other forms of SCT. Similarly, the lipid cell variant is not separately classified, but is considered to be a morphological variant of SCT NOS. Large-cell calcifying SCT is recognized as a distinct entity that occurs either sporadically or in association with Carney complex, with the latter patients having a distinct germline PRKAR1A gene mutation. Intratubular large-cell hyalinizing Sertoli cell neoplasia is also accepted as a separate entity linked with Peutz-Jeghers syndrome. The subcategories of 'mixed' and 'incompletely differentiated' forms of sex cord/gonadal stromal tumours have been replaced by 'mixed and unclassified sex cord-stromal tumours'. New entities introduced in the latest WHO revision include: myoid gonadal stromal tumour and 'undifferentiated gonadal tissue', a putative precursor lesion of gonadoblastoma, whereas juvenile xanthogranuloma and haemangioma are included in the miscellaneous category of tumours. [ABSTRACT FROM AUTHOR]

Since the last World Health Organization (WHO) classification scheme for tumours of the urinary tract and male genital organs, there have been a number of advances in the understanding, classification, immunohistochemistry and genetics of testicular germ cell tumours. The updated 2016 draft classification was discussed at an International Society of Urological Pathology Consultation on Testicular and Penile Cancer. This review addresses the main updates to germ cell tumour classification. Major changes include a pathogenetically derived classification using germ cell neoplasia in situ (GCNIS) as a new name for the precursor lesion, and the distinction of prepubertal tumours (non-GCNIS-derived) from postpubertal-type tumours (GCNIS-derived), acknowledging the existence of rare benign prepubertal-type teratomas in the postpubertal testis. Spermatocytic tumour is adopted as a replacement for spermatocytic seminoma, to avoid potential confusion with the unrelated usual seminoma. The spectrum of trophoblastic tumours arising in the setting of testicular germ cell tumour continues to expand, to include epithelioid and placental site trophoblastic tumours analogous to those of the gynaecological tract. Currently, reporting of anaplasia (seminoma or spermatocytic tumour) or immaturity (teratoma) is not required, as these do not have demonstrable prognostic importance. In contrast, overgrowth of a teratomatous component (somatic-type malignancy) and sarcomatous change in spermatocytic tumour indicate more aggressive behaviour, and should be reported. [ABSTRACT FROM AUTHOR]

Aim To study prostate cancer zonal differences in TMPRSS2- ERG gene rearrangement. Methods and results We examined 136 well-characterized dominant anterior prostatic tumours, including 61 transition zone ( TZ) and 75 anterior peripheral zone ( PZ) lesions, defined using strict anatomical considerations. TMPRSS2- ERG FISH and ERG protein immunohistochemistry were performed on tissue microarrays. FISH results, available for 56 TZ and 71 anterior PZ samples, were correlated with ERG staining and TZ-associated 'clear cell' histology. Fewer TZ cancers (four of 56; 7%) were rearranged than anterior PZ cancers (18 of 71; 25%) ( P = 0.009); deletion was the sole mechanism of TZ cancer rearrangement. ERG protein overexpression was present in 4% (two of 56; both FISH+) and 30% (21 of 71; 17 FISH+) of TZ and anterior PZ tumours, respectively. 'Clear cell' histology was present in 21 of 56 (38%) TZ and eight of 71 (11%) anterior PZ tumours. Seven per cent of cancers with and 21% without this histology had rearrangement, regardless of zonal origin. Conclusions TMPRSS2- ERG rearrangement occurs in dominant TZ and anterior PZ prostate cancers, with all rearranged TZ cancers in this cohort showing deletion. ERG immunohistochemistry demonstrated excellent sensitivity (86%) and specificity (96%) for TMPRSS2- ERG rearrangement. TMPRSS2- ERG fusion is rare in TZ tumours and present at a low frequency in tumours displaying 'clear cell' histology. [ABSTRACT FROM AUTHOR]

The BMI1 gene is overexpressed in -90% of human neuroblastomas. However, little is known about the regulation of BMI1 expression. Using microarray and immunohistochemical analysis, we show that BMI1 expression correlated with MYCN levels in MYCN-amplified human neuroblastomas, and with MYC levels in the MYCN-nonamplified group. We further demonstrated that BMI1 is a direct target gene of MYCN/MYC in 3 neuroblastoma cell lines: BE (2)-C, LAN1, and SH-SY5Y. Overexpression of MYCN or MYC transactivated the BMI1 promoter and up-regulated BMI1 gene expression, shRNA-mediated knockdown of MYCN or MYC decreased BMI1 gene expression. Chromatin immunoprecipitation and point-mutation assays revealed that both MYCN and MYC bind to the E-box within the BMI1 promoter. Overexpression of BMI1, MYCN, and MYC independently increased both cell proliferation and tumor growth. Conversely, specific inhibition of BMI1, MYCN, and MYC decreased tumor cell proliferation and tumor growth. Interestingly, BMI1 suppression in MYCN/ MYC-overexpressing cells resulted in significantly greater inhibition compared to that in mock-transduced and parental cells. Our results indicate that MYCN and MYC regulate BMI1 gene expression at the transcriptional level and that dysregulation of the BMI1 gene mediated by MYCN or MYC overexpression, confers increased cell proliferation during neuroblastoma genesis and tumor progression. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the rationale for using targeted therapies against hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways in urothelial carcinoma of the bladder, by studying the immunohistochemical expression of molecules of these pathways in urothelial carcinoma, as recent pre-clinical studies and clinical trials have shown the potential utility of such targeted therapies. PATIENTS AND METHODS Immunohistochemical stains were performed on a tissue microarray prepared from 92 cases of ⩾ pT2 urothelial (transitional cell) carcinoma of bladder, using antibodies against HIF-1α and VEGF-R2, and phospho-S6 and phospho-4E BP1, molecules of HIF and activated mTOR pathways, respectively. Immunoreactivity was graded from 0 to 3 + (0, 0-5%; 1 + , 6-25%; 2 + , 26- 50%; 3 + , > 50% tumour cells positive). RESULTS In all, 58, 34, 35 and 17% of the tumours showed grade 2-3 + expression of phospho- 4E BP1, phospho-S6, HIF-1α and VEGF-R2, respectively. Moderate correlation for immunoreactivity was observed between molecules within the same pathway [(phospho-4E BP1 with phospho-S6 (rho = 0.411), and HIF-1 α with VEGF-R2 (rho = 0.265)], but not between molecules across pathways. CONCLUSIONS Urothelial carcinomas of the bladder express molecules of the HIF and mTOR pathways, providing a rationale for clinical trials evaluating agents targeting these pathways. Correlation between molecules within the same pathway, and not across pathways, suggests that investigating the usefulness of a specific targeted agent might benefit from pre-treatment evaluation of pathway marker expression. [ABSTRACT FROM AUTHOR]

We read with great interest the invited commentary by Akgul I et al i [1] on our report on the genomic landscape of urothelial papilloma (UP) and inverted urothelial papilloma (IUP) published in a recent issue of I The Journal of Pathology i [2]. Unlike UC, IUP and UP have low tumor mutational burden and do not exhibit a predominant APOBEC mutation signature. Furthermore, oncogenic alterations in I HRAS i and I KRAS i were present in nearly all cases of IUP and UP, whereas alterations common to UC, including mutations in I FGFR3, TP53 i , chromatin-modifying genes and the I TERT i promoter, were rarely observed. [Extracted from the article]