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Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.

The presence of two or more prostate cancer foci separated by intervening benign tissue in a single core is a well-recognized finding on prostate biopsy. Cancer involvement can be measured by including intervening benign tissue or only including the actual cancer involved area. Importantly, this parameter is a common enrollment criterion for active surveillance protocols. We hypothesized that spatially distinct prostate cancer foci in biopsies may arise from separate clones, impacting cancer involvement assessment. Hence, we used dual ERG/SPINK1 immunohistochemistry to determine the frequency of separate clones-when separate tumor foci showed discordant ERG and/or SPINK1 status-in discontinuously involved prostate biopsy cores from two academic institutions. In our cohort of 97 prostate biopsy cores with spatially discrete tumor foci (from 80 patients), discontinuous cancer involvement including intervening tissue ranged from 20 to 100% and Gleason scores ranged from 6 to 9. Twenty-four (25%) of 97 discontinuously involved cores harbored clonally distinct cancer foci by discordant ERG and/or SPINK1 expression status: 58% (14/24) had one ERG(+) focus, and one ERG(-)/SPINK1(-) focus; 29% (7/24) had one SPINK1(+) focus and one ERG(-)/SPINK1(-) focus; and 13% (3/24) had one ERG(+) focus and one SPINK1(+) focus. ERG and SPINK1 overexpression were mutually exclusive in all tumor foci. In summary, our results show that ~25% of discontinuously involved prostate biopsy cores showed tumor foci with discordant ERG/SPINK1 status, consistent with multiclonal disease. The relatively frequent presence of multiclonality in discontinuously involved prostate biopsy cores warrants studies on the potential clinical impact of clonality assessment, particularly in cases where tumor volume in a discontinuous core may impact active surveillance eligibility.

Metanephric adenoma (MA) is a rare benign renal tumor comprised of a neoplastic proliferation of primitive metanephric tubular cells. A previous study identified BRAF V600E mutations in approximately 90% of MA and found that similar BRAF exon 15 mutations are exceedingly rare in other common renal tumors, including renal cell carcinoma and oncocytoma. A recent follow-up study has validated mutation-specific immunohistochemistry (IHC) for detection of BRAF V600E mutations in a small cohort of MA. Here, we extend these findings to a larger, independent cohort of MA, demonstrating an overall 88% sensitivity and 100% specificity for BRAF V600E IHC. In addition, we report 2 cases of MA with novel BRAF exon 15 mutations, including a V600D missense mutation and a compound V600D and K601L missense mutation. Finally, we evaluate BRAF V600E IHC in a large tissue microarray cohort of common renal tumors and find no significant expression in several renal cell carcinoma subtypes. These data support a role for BRAF V600E IHC in diagnostically challenging cases of MA and expand the spectrum of BRAF exon 15 mutations in this uncommon but unique renal neoplasm.

An optimal immunohistochemical panel to distinguish poorly differentiated prostate (PCa) from urothelial (UCa) carcinoma was selected from a panel consisting of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), high-molecular-weight cytokeratin (HMWCK), clone 34betaE12, cytokeratin (CK) 7, CK20, p63, and alpha-methylacyl-coenzyme A racemase. The pilot group was composed of poorly differentiated UCa (n = 36) and PCa (n = 42). PSA and PAP stained 95% of PCa vs 0% and 11% of UCa cases, respectively. HMWCK and p63 stained 97% and 92% of UCa vs 2% and 0% of PCa cases respectively. CK7/CK20 coexpression was noted in 50% of UCa cases, whereas 86% of PCa cases were negative with both. A panel of PSA, HMWCK, and p63 was optimal for separating 95% PCa (PSA+/HMWCK and/or p63-) vs 97% UCa (PSA-/HMWCK and/or p63+). This panel was used on 26 diagnostically challenging cases and resolved 81% of cases as UCa vs PCa. The majority of PCa cases retain PSA. Negative PSA with positive HMWCK and/or p63 establishes a diagnosis of UCa.

Aims: Biphasic hyalinizing psammomatous (BHP) renal cell carcinoma (RCC) is a newly described emerging entity within the spectrum of papillary RCC in the WHO 2022 classification. Molecular analyses have discovered that BHP RCC consistently harbour somatic mutations in the neurofibromin 2 (NF2) gene. The NF2 gene product, merlin, is known to primarily function as a tumour suppressor. Merlin protein loss correlates closely with the presence of NF2 mutations in benign and malignant tumours arising in different sites. In the present study we explored the role of merlin immunohistochemistry (IHC) in tumours within the spectrum of BHP RCC to determine the diagnostic utility of this marker. Materials and Methods: We performed merlin IHC in 13 BHP RCC, 18 papillary RCC, 10 TFE3-translocation RCC, 15 TFEB-altered RCC (including 13 TFEB-rearranged and 2 TFEB-amplified), and 10 mucinous tubular and spindle cell carcinomas of unknown mutational status. Results: Unequivocal loss of merlin expression in >90% of the tumour cells was observed in 12/13 BHP-RCC (92%), with the remaining tumour demonstrating weak focal cytoplasmic expression in ~10% of the tumour. In contrast, merlin was diffusely or multifocally expressed in all papillary RCC, TFE3- translocation RCC, and TFEB-altered RCC, as well as in 70% of mucinous tubular and spindle carcinomas. Conclusions: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC. Conclusions: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC. [ABSTRACT FROM AUTHOR]

Primary glandular tumors of the urachus and urinary bladder are an intriguing group of clinically and morphologically diverse neoplasms for which there have been recent refinements in diagnostic subclassification and advances in molecular pathology. In addition, the urachus and urinary bladder may be secondarily involved by tumors with glandular differentiation that demonstrate remarkable morphologic, immunophenotypic, and molecular overlap. Thus, surgical pathologists need to be aware of the broad differential diagnosis of glandular tumors that involve the urachus and urinary bladder and have a practical diagnostic framework to evaluate these lesions in routine clinical practice. In this review, we summarize the salient clinical, morphologic, immunohistochemical, and molecular features of glandular tumors of the urachus and urinary bladder, including mucinous cystic tumors of the urachus, noncystic urachal adenocarcinomas, urothelial carcinomas with glandular or pseudoglandular features, primary urinary bladder adenocarcinomas, and Müllerian-type carcinomas, highlighting the strengths and limitations of various diagnostic features and ancillary tests, as well as the need for close clinical and radiographic correlation. [ABSTRACT FROM AUTHOR]

Context.--While biopsies are now increasingly being performed for the diagnosis of renal cortical neoplasms, the influence of the rendered pathological diagnoses on the clinical management is only rarely documented. Objectives.--To report our experience with consecutively performed renal biopsies and the potential impact of the diagnosis on subsequent clinical management. Design.--Material from needle biopsies performed consecutively at our institution between 2006 and 2011 was reviewed. The influence of the reported pathology results on the clinical management was determined from patient follow-up medical record review. Results.--In total, 218 percutaneous biopsies for renal masses were performed during this period. Among them, 181 (83%) yielded neoplastic tissue, including 81 clear cell renal cell carcinomas, 29 low-grade oncocytic neoplasms, 7 papillary renal cell carcinomas, 5 clear cell papillary renal cell carcinomas, 5 angiomyolipomas, and 14 urothelial carcinomas. Fourteen additional cases (6%) contained lesional material from clinically known nonneoplastic processes, for a total diagnostic yield of 89%. Twenty-three (11%) were nonrepresentative of lesional tissue. In 10 of these, repeat biopsies or resections established the diagnosis of renal tumors. Biopsy diagnosis was confirmed in 29 of 30 cases (97%) on subsequent nephrectomy. Following the biopsy diagnosis, there were significant differences in the clinical management; overall, 79% of clear cell renal cell carcinomas received therapeutic interventions, and 17% were put on active surveillance. In contrast, 77% of the benign or low-grade lesions were put on active surveillance. Conclusions.--Accurate and specific diagnosis can be rendered on renal core biopsy in most renal tumors, and the biopsy diagnosis can have a definitive role in their clinical management. [ABSTRACT FROM AUTHOR]

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare, highly aggressive renal cell carcinoma (RCC), thought to arise mostly in the setting of hereditary leiomyomatosis-renal cell carcinoma syndrome (HLRCC) with germline mutation of fumarate hydratase (FH). Due to the aggressiveness of these tumors and frequent lack of ascertainable family history, these tumors may first present as metastases, which may be sampled for cytology. Nonetheless, cytologic features of FH-deficient RCC have not been reported. Herein, a total of eight cytologic samples from seven patients (two women and five men, 25–69 years old) with confirmed FH-deficient RCCs were identified and evaluated retrospectively. Cytology samples included three cases of malignant effusions (one pleural and two ascites), two direct renal aspirates, and one each aspirates of supraclavicular node, liver metastasis, and pleural/chest wall metastasis. Cytologic preparations were generally sparsely cellular but with striking, markedly enlarged malignant cells, presenting as small clusters and abortive papillae in a hemorrhagic and inflammatory background. Individual cells showed markedly enlarged, pleomorphic nuclei with prominent or macronucleoli and moderate amount of cytoplasm. On Diff-Quik-stained smears and cell blocks, cytoplasmic vacuolation, ranging from delicately flocculent to bubbly or vacuolated, was visible. Prominent, inclusion-like nucleoli with perinucleolar halos (hallmark of FH-deficient RCC) were visible, focally in every case, particularly on Pap stain and H&E cell block sections. In conclusion, in cytologic preparations, rudimentary features characteristic of FH-deficient RCC may be identified. While identified retrospectively here, we argue that with appropriate clinical correlation, especially with ascertainment of any syndromal stigmata as context, the cytomorphology is sufficiently distinctive to trigger recognition and confirmatory workup for this aggressive variant. [ABSTRACT FROM AUTHOR]

Context.--Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an uncommon disorder with germline-inactivating mutations in the fumarate hydratase (FH) gene. The kidney cancers that develop in patients with HLRCC are often unilateral and solitary, with a potentially aggressive clinical course; morphologic identification of suspicious cases is of the utmost importance. Objective.--To review classic morphologic features of HLRCC-associated renal cell carcinoma, the reported morphologic spectrum of these tumors and their mimics, and the evidence for use of immunohistochemistry and molecular testing in diagnosis of these tumors. Data Sources.--University of Michigan cases and review of pertinent literature about HLRCC and the morphologic spectrum of HLRCC-associated renal cell carcinoma. Conclusions.--Histologic features, such as prominent nucleoli with perinucleolar halos and multiple architectural patterns within one tumor, are suggestive of HLRCC-associated renal cell carcinoma. However, the morphologic spectrum is broad. Appropriate use of FH immunohistochemistry and referral to genetic counseling is important for detection of this syndrome. [ABSTRACT FROM AUTHOR]

Translocation-associated renal cell carcinoma (t-RCC) is a relatively uncommon subtype of renal cell carcinoma characterized by recurrent gene rearrangements involving the TFE3 or TFEB loci. TFE3 and TFEB are members of the microphthalmia transcription factor (MiT) family, which regulates differentiation in melanocytes and osteoclasts, and MiT family gene fusions activate unique molecular programs that can be detected immunohistochemically. Although the overall clinical behavior of t-RCC is variable, emerging molecular data suggest the possibility of targeted approaches to advanced disease. Thus, distinguishing t-RCC from its morphologic, immunophenotypic, and molecular mimics may have important clinical implications. The differential diagnosis for t-RCC includes a variety of common renal neoplasms, particularly those demonstrating clear cell and papillary features; in addition, because of immunophenotypic overlap and/or shared molecular abnormalities (ie, TFE3 gene rearrangement), a distinctive set of nonepithelial renal tumors may also warrant consideration. Directed ancillary testing is an essential aspect to the workup of t-RCC cases and may include a panel of immunohistochemical stains, such as PAX8, pancytokeratins, epithelial membrane antigen, carbonic anhydrase IX, HMB-45, and Melan-A. Dual-color, break-apart fluorescent in situ hybridization for TFE3 or TFEB gene rearrangement may be helpful in diagnostically challenging cases or when molecular confirmation is needed. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most common type of tumor found in American men and is the second leading cause of cancer death in males. To identify biomarkers that distinguish prostate cancer from normal, we compared multiple gene expression profiling studies. Through meta-analysis of expression array data from multiple prostate cancer studies, we identified GOLM1 (Golgi membrane protein 1, Golm 1) as consistently up-regulated in clinically localized prostate cancer. This observation was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and validated at the protein level by immunoblot assay and immunohistochemistry. Prostate epithelial cells were identified as the cellular source of GOLM1 expression using laser capture microdissection. Immunohistochemical staining localized the GOLM1 signal to the subapical cytoplasmic region, typical of a Golgi distribution. Surprisingly, GOLM1 immunoreactivity was detected in the supernatants of prostate cell lines and in the urine of patients with prostate cancer. The mechanism by which intact GOLM1 might be released from cells has not yet been elucidated. GOLM1 transcript levels were measured in urine sediments using quantitative PCR on a cohort of patients presenting for biopsy or radical prostatectomy. We found that urinary GOLM1 mRNA levels were a significant predictor of prostate cancer. Further, GOLM1 outperformed serum prostate-specific antigen (PSA) in detecting prostate cancer. The area under the receiver-operating characteristic curve was 0.622 for GOLM1 (P = .0009) versus 0.495 for serum PSA (P = .902). Our data indicating the up-regulation of GOLM1 expression and its appearance in patients' urine suggest GOLM1 as a potential novel biomarker for clinically localized prostate cancer. [ABSTRACT FROM AUTHOR]

Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC). To characterize the gene expression and biomarker signatures associated with ChRCC. We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors. The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression. All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187 , and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing. We demonstrate a pipeline for the identification and validation of RCC subtype–specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors. FOXI1 , RHCG , and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma. We performed integrative RNA sequencing analysis from >1000 renal cell carcinoma (RCC) specimens, identified genes enriched in chromophobe RCC, experimentally validated the expression pattern of the top three genes (FOXI1 , RHCG , and LINC01187), and revealed that the cell of origin of chromophobe RCC is intercalated cells. [ABSTRACT FROM AUTHOR]

TMPRSS2-ERG gene fusions occur in 50% of prostate cancers and result in the overexpression of a chimeric fusion transcript that encodes a truncated ERG product. Previous attempts to detect truncated ERG products have been hindered by a lack of specific antibodies. Here, we characterize a rabbit anti-ERG monoclonal antibody (clone EPR 3864; Epitomics, Burlingame, CA) using immunoblot analysis on prostate cancer cell lines, synthetic TMPRSS2-ERG constructs, chromatin immunoprecipitation, and immunofluorescence. We correlated ERG protein expression with the presence of ERG gene rearrangements in prostate cancer tissues using a combined immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. We independently evaluated two patient cohorts and observed ERG expression confined to prostate cancer cells and high-grade prostatic intraepithelial neoplasia associated with ERG-positive cancer, as well as vessels and lymphocytes (where ERG has a known biologic role). Image analysis of 131 cases demonstrated nearly 100% sensitivity for detecting ERG rearrangement prostate cancer, with only 2 (1.5%) of 131 cases demonstrating strong ERG protein expression without any known ERG gene fusion. The combined pathology evaluation of 207 patient tumors for ERG protein expression had 95.7% sensitivity and 96.5% specificity for determining ERG rearrangement prostate cancer. In conclusion, this study qualifies a specific anti-ERG antibody and demonstrates exquisite association between ERG gene rearrangement and truncated ERG protein product expression. Given the ease of performing IHC versus FISH, ERG protein expression may be useful for molecularly subtyping prostate cancer based on ERG rearrangement status and suggests clinical utility in prostate needle biopsy evaluation. [ABSTRACT FROM AUTHOR]