Recurrent KRAS mutations are early events in the development of papillary renal neoplasm with reverse polarity.

We evaluated the clinicopathologic and molecular characteristics of mostly incidentally detected, small, papillary renal neoplasms with reverse polarity (PRNRP). The cohort comprised 50 PRNRP from 46 patients, divided into 2 groups. The clinically undetected (<5 mm) neoplasms (n = 34; 68%) had a median size of 1.1 mm (range 0.2-4.3 mm; mean 1.4 mm), and the clinically detected (≥5 mm) neoplasms (n = 16; 32%) which had a median size of 13 mm (range 9-30 mm; mean 16 mm). Neoplasms were positive for GATA3 (n = 47; 100%) and L1CAM (n = 34/38; 89%) and were negative for vimentin (n = 0/44; 0%) and, to a lesser extent, AMACR [(n = 12/46; 26%; weak = 9, weak/moderate = 3)]. KRAS mutations were found in 44% (n = 15/34) of the clinically undetected PRNRP and 88% of the clinically detected PRNRP (n = 14/16). The two clinically detected PRNRP with wild-type KRAS gene were markedly cystic and contained microscopic intracystic tumors. In the clinically undetected PRNRP, the detected KRAS mutations rate was higher in those measuring ≥1 mm vs <1 mm [n = 14/19 (74%) vs n = 1/15 (7%)]. Overall, the KRAS mutations were present in exon 2-codon 12: c.35 G > T (n = 21), c.34 G > T (n = 3), c.35 G > A (n = 2), c.34 G > C (n = 2) resulting in p.Gly12Val, p. Gly12Asp, p.Gly12Cys and p.Gly12Arg, respectively. One PRNRP had a G12A/V/D complex mutation. Twenty-six PRNRP were concurrently present with other tumors of different histologic subtypes in the ipsilateral kidney; molecular testing of 8 of the latter showed wild-type KRAS gene despite the presence of KRAS mutations in 5 concurrent PRNRP. On follow up, no adverse pathologic events were seen (range 1-160 months; mean 44 months). In conclusion, the presence of KRAS mutations in small, clinically undetected PRNRP provides a unique finding to this entity and supports its being an early event in the development of these neoplasms.

EWSR1-PATZ1 fusion renal cell carcinoma: a recurrent gene fusion characterizing thyroid-like follicular renal cell carcinoma.

Thyroid-like follicular renal cell carcinoma is an uncommon kidney tumor with no distinct molecular alteration described to date. This cohort of eight women with mean and median ages of 45 and 46 years, respectively (range 19-65 years), had unencapsulated, well-circumscribed tumors composed of tightly packed anastomosing follicle-like cysts filled with eosinophilic colloid-like material and lined by cuboidal cells with high nuclear to cytoplasmic ratios, oval to elongated nuclei with perpendicular arrangement toward the lumens, and prominent nuclear overlapping. The stroma between these was minimal with the exception of two tumors. Calcifications and necrosis were absent. Immunohistochemically, the tumors were positive for KRT19 (7/7), PAX8 (5/5), cyclin D1 (6/6), KRT7 (5/7), and AMACR (1/5; focal, weak), and were negative for WT1, TTF1 (transcription termination factor-1), and thyroglobulin. In three of three tumors tested molecularly, EWSR1-PATZ1 fusion was identified by RNA sequencing and confirmed by RT-PCR and Sanger sequencing. Over a follow-up period of 1-7 years, no evidence of recurrence or metastasis has been detected. The EWSR1-PATZ1 fusion has been recognized as a recurrent alteration in a subset of round to spindle cell sarcomas with EWSR1-non-ETS fusions (EWSR1-PATZ1 sarcoma) and in several central nervous system tumors. The finding of an EWSR1-PATZ1 fusion in all three of the thyroid-like follicular renal cell carcinomas for which sufficient tissue was available for genomic profiling provides the first distinct molecular abnormality in thyroid-like follicular renal cell carcinomas, supporting its designation as a distinct diagnostic entity.

Distal Tubular Hyperplasia: A Proposal for a Unique Form of Renal Tubular Proliferation Distinct From Papillary Adenoma.

We identified an unusual pattern of renal tubular proliferation associated with chronic renal disease, found in 23 patients, diffusely (n=12), or focally (n=11). Incidence was 5% of end-stage renal disease kidneys from one institution (8/177) and 7/23 patients with acquired cystic kidney disease-associated renal cell carcinoma from another. Most (19 patients) had 1 or more neoplasms including papillary (n=9), acquired cystic kidney disease (n=8), clear cell (n=4), or clear cell papillary (n=3) renal cell carcinoma. All (20 men, 3 women) had end-stage renal disease. The predominant pattern (n=18) was the indentation of chronic inflammation into renal tubules forming small polypoid structures; however, 5 had predominantly hyperplastic epithelium with less conspicuous inflammation. In 14 patients both patterns were appreciable, whereas the remainder had only the inflammatory pattern. Immunohistochemistry was positive for cytokeratin 7, high-molecular-weight cytokeratin, PAX8, and GATA3. Staining for alpha-methylacyl-CoA racemase was negative or weak, dramatically less intense than papillary neoplasms or proximal tubules. CD3 and CD20 showed a mixture of B and T lymphocytes in the inflammatory areas. Fluorescence in situ hybridization showed no trisomy 7 or 17 or loss of Y (n=9). We describe a previously uncharacterized form of renal tubular proliferation that differs from papillary adenoma (with weak or negative alpha-methylacyl-CoA racemase, lack of trisomy 7 or 17, and sometimes diffuse distribution). On the basis of consistent staining for high-molecular-weight cytokeratin and GATA3, we propose the name distal tubular hyperplasia for this process. Future studies will be helpful to assess preneoplastic potential and etiology.

[Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference]. / Molekularpathologie bei urologischen Tumoren : Empfehlungen der Konsenskonferenz der Internationalen Gesellschaft für Uropathologie (ISUP) 2019.

Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.

Primary Amyloidosis of the Genitourinary Tract.

CONTEXT.­: Amyloidosis is caused by the deposition of misfolded proteins as insoluble eosinophilic material in the extracellular tissues of the body, leading to impairment of organ function. It can be systemic or localized. Localized genitourinary tract amyloidosis is rare and can be incidentally seen; however, in some cases, it can be the only presenting disease. OBJECTIVE.­: To review the clinical presentation and pathologic findings related to primary amyloidosis of the urogenital system and highlight some of the associated pathologic findings based on our personal experience. DATA SOURCES.­: Published peer-reviewed literature and personal experience of the senior author. CONCLUSIONS.­: Primary localized amyloidosis within the urogenital tract can present as a neoplastic process and may be clinically and radiologically considered as a mass. Awareness of primary amyloidosis by pathologists and clinicians is required for accurate diagnosis and proper patient management.

Morphologic and Immunohistochemical Characteristics of Fluorescent In Situ Hybridization Confirmed TFE3-Gene Fusion Associated Renal Cell Carcinoma: A Single Institutional Cohort.

TFE3-fusion associated renal cell carcinoma (TFE3-RCC) accounts for up to 5% adults and 40% of childhood RCC. Their comprehensive immunohistochemical (IHC) profile in correlation to fluorescence in situ hybridization (FISH) testing and their role in the diagnostic approach are not well documented because of lacking published data. FISH confirmed TFE3-RCC between years 2010 and 2020 were identified from institutional electronic database and retrospectively reviewed. Eighty-five TFE3-RCC were identified. Seventy-six of 85 (89.4%) TFE3-RCC cases had positive TFE3 expression, with diffuse and strong/moderate TFE3 expression in 45 (54.2%). Three (3.5%) TFE3-RCC had negative TFE3 expression whereas 6 (7%) cases had equivocal TFE3 expression. On the other hand, positive TFE3-IHC expression was observed in 17/29 (58.6%) TFE3-FISH negative RCC cases, although only 8 (27.5%) had diffuse and moderate/strong TFE3 expression. Diffuse and strong TFE3-IHC expression was statistically significant in predicting TFE3-FISH positivity (P<0.0001) regardless of morphologic features. After univariate and multivariate analyses, TFE3-IHC was the only parameter with significant predictive value for detecting positive TFE3-FISH (P<0.0001). On univariate analysis, sex, classic morphology, age, negative AE1/AE3 or cytokeratin 7 were not predictive of TFE3-FISH positivity. Diffuse and strong nuclear TFE3-IHC expression is significantly associated with TFE3-FISH positivity and can be used as a surrogate marker to confirm translocation associated cases. TFE3-rearranged RCCs show variable histomorphologic features and TFE3-FISH should be performed in cases presenting at a younger age or, regardless of the age, tumors with unusual morphology. Despite previous reports, negative pancytokeratin and positive cathepsin K expression may not be reliable markers for TFE3-RCC.

The 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

The International Society of Urological Pathology Consultation on Molecular Pathology of Urogenital Cancer.

The 2019 Consultation Conference on the molecular pathology of urogenital cancers was organized by the International Society of Urological Pathology (ISUP) to have an understanding of the current use of molecular-genetic markers and to make recommendations on their application in prostate, bladder, renal, testicular, and penile cancer. This brief introductory article describes the organization of this conference and provides its rationale and main findings.

Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer.

Renal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive fluorescence in situ hybridization result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB/VEGFA/6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.

Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers V: Recommendations on the Use of Immunohistochemical and Molecular Biomarkers in Penile Cancer.

Penile cancer and its precursor lesions are morphologically and clinically heterogenous and they can be further characterized by immunohistochemical (IHC) and molecular genetic analyses. According to the current World Health Organization (WHO) classification, penile intraepithelial neoplasia (PeIN) and invasive penile carcinomas can be grouped into human papillomavirus (HPV)-related and non-HPV-related neoplasms. This distinction is clinically relevant for etiological and prognostic reasons. To gain insight into the current use of molecular testing and IHC in their diagnostics, a survey was held among the membership of the International Society of Urological Pathology (ISUP). About 250 pathologists from 51 countries answered the survey on the practice and use of IHC/molecular technique as aids in the diagnosis of penile squamous neoplasia. More than half (60%) of the respondents worked at an academic hospital. The questions focused on condylomas, precancerous squamous lesions, and squamous cell carcinoma (SCC). About 35% to 45% of the pathologists considered the use of IHC or molecular tests of value in the pathologic evaluation of precancerous and invasive neoplasms. The vast majority of the respondents do not use IHC for the diagnosis and subtyping of condylomas. There is emerging evidence that some condylomas may participate in the penile carcinogenesis process, especially the high-risk HPV-related atypical condylomas. We recommend the use of p16 in such cases. For most PeIN cases, about half of the responding pathologists make the diagnosis on hematoxylin and eosin slides only. For their subtyping, 50% to 55% of the pathologists use IHC in warty or basaloid PeINs and 40% in differentiated PeIN. To separate HPV-related PeIN from non-HPV-related PeIN, 80% reported using p16 and 20% Ki-67. On the basis of literature review and our practice, the ISUP working group recommends the use of Ki-67 to separate non-HPV-differentiated PeIN from squamous hyperplasia and the use of p16 to distinguish the pleomorphic variant of differentiated PeIN from HPV-related PeIN. With respect to SCCs, according to the survey, immunostaining is only applied in 15% of conventional invasive SCCs, the majority being diagnosed by hematoxylin and eosin. To separate HPV and non-HPV tumors, most (80%) would use p16 and 25% would use p53. For subtype classification, they consider IHC necessary to identify verrucous, papillary, warty, warty-basaloid, and basaloid carcinomas. p16 is used as a surrogate of polymerase chain reaction for the identification of high-risk HPV. We recommend the use of p16 immunostain in cases where the tumoral histologic features of the SCCs are not classical for HPV-related neoplasms, especially in poorly differentiated tumors. Because the majority of these neoplasms harbor high-risk HPV (HPV16), identifying the presence of the virus is rather more important than documenting its specific genotype.

Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: IV: Current and Future Utilization of Molecular-Genetic Tests for Testicular Germ Cell Tumors.

The International Society of Urological Pathology (ISUP) organized a Consultation Conference in March 2019 dealing with applications of molecular pathology in Urogenital Pathology, including testicular tumors (with a focus on germ cell tumors [GCTs]), preceded by a survey among its members to get insight into current practices in testicular germ cell tumor (TGCT) diagnostics and adoption of the ISUP immunohistochemical guidelines published in 2014. On the basis of the premeeting survey, the most commonly used immunomarker panel includes OCT3/4, placental alkaline phosphate, D2-40, SALL4, CD117, and CD30 for GCTs and the documentation of germ cell neoplasia in situ (GCNIS). Molecular testing, specifically 12p copy gain, is informative to distinguish non-GCNIS versus GCNIS related GCTs, and establishing germ cell origin of tumors both in the context of primary and metastatic lesions. Other molecular methodologies currently available but not widely utilized for TGCTs include genome-wide and targeted approaches for specific genetic anomalies, P53 mutations, genomic MDM2 amplification, and detection of the p53 inactivating miR-371a-3p. The latter also holds promise as a serum marker for malignant TGCTs. This manuscript provides an update on the classification of TGCTs, and describes the current and future role of molecular-genetic testing. The following recommendations are made: (1) Presence of GCNIS should be documented in all cases along with extent of spermatogenesis; (2) Immunohistochemical staining is optional in the following scenarios: identification of GCNIS, distinguishing embryonal carcinoma from seminoma, confirming presence of yolk sac tumor and/or choriocarcinoma, and differentiating spermatocytic tumor from potential mimics; (3) Detection of gain of the short arm of chromosome 12 is diagnostic to differentiate between non-GCNIS versus GCNIS related GCTs and supportive to the germ cell origin of both primary and metastatic tumors.

Smooth muscle hyperplasia of the testicular adnexa: a clinicopathologic study of 12 cases.

Smooth muscle hyperplasia of the testicular adnexa (SMH-TA) is a rare mass-forming intrascrotal lesion. Although benign, it can be a diagnostic challenge, as we have seen in our consult practice. Herein, we discuss our experience with these lesions over 14 years. Twelve SMH-TA cases were identified in our institutional records between 2005 and 2019. The morphologic features were reviewed. Clinical information was obtained from physicians' notes. The mean age was 51 years (range, 24-82 years). Six cases were on the left side, five on the right, and one was bilateral. The most common presentations were orchialgia (n = 10) and mass (n = 6). Two patients had a concurrent incarcerated inguinal hernia, and one had a recent groin trauma. Past medical history included 5 patients with previous surgeries in the inguinal region, 2 with a history of treated infections, and 1 with persistent chronic orchitis. Eight patients have undergone ultrasound imaging which showed lesions (n = 4), hematoma (n = 1), undescended testis (n = 1), or no abnormalities (n = 2). Grossly, the mean size was 1.7 cm (range, 1.0-3 cm). The lesions had ill-defined, focally cystic, pink-tan nodular surface. Microscopically, the lesions were comprised of an ill-defined smooth muscle proliferation arranged in fascicles or haphazard fashion, growing in a periductal, perivascular, interstitial, or most commonly in a mixed pattern. SMH-TA is a rare benign entity that can present clinically as orchialgia and/or a suspicious intrascrotal mass. As suggested in previous studies, we believe that this lesion represents a reactive process.

Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers. I. Molecular Biomarkers in Prostate Cancer.

The combined clinical and molecular heterogeneity of prostate cancer necessitates the use of prognostic, predictive, and diagnostic biomarkers to assist the clinician with treatment selection. The pathologist plays a critical role in guiding molecular biomarker testing in prostate cancer and requires a thorough knowledge of the current testing options. In the setting of clinically localized prostate cancer, prognostic biomarkers such as Ki-67 labeling, PTEN loss or mRNA-based genomic signatures can be useful to help determine whether definitive therapy is required. In the setting of advanced disease, predictive biomarkers, such as the presence of DNA repair deficiency mediated by BRCA2 loss or mismatch repair gene defects, may suggest the utility of poly-ADP ribosylase inhibition or immune checkpoint blockade. Finally, androgen receptor-related biomarkers or diagnostic biomarkers indicating the presence of small cell neuroendocrine prostate cancer may help guide the use of androgen receptor signaling inhibitors and chemotherapy. In this review, we examine the current evidence for several prognostic, predictive and diagnostic tissue-based molecular biomarkers in prostate cancer management. For each assay, we summarize a recent survey of the International Society of Urology Pathology (ISUP) members on current testing practices and include recommendations for testing that emerged from the ISUP Working Group on Molecular Pathology of Prostate Cancer and the 2019 Consultation Conference on Molecular Pathology of Urogenital Cancers.

Report From the International Society of Urological Pathology (ISUP) Consultation Conference On Molecular Pathology Of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer: Progress and Challenges.

During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into "molecular subtypes," based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended. Mutations in the TERT promoter are present in the majority of bladder cancers, including the noninvasive stage of tumor evolution, but not in reactive conditions. Mutational analysis of the TERT promoter thus distinguishes histologically deceptive cancers from their benign mimics in some cases. A minority of pathologists employ this test. FGFR3 mutations are common in bladder cancer, and metastatic urothelial carcinoma (UC) with such mutations frequently responds to erdafitinib, an FGFR inhibitor. Testing for FGFR3 alterations is required before using this drug. Metastatic UC responds to immune-oncology (IO) agents in 20% of cases. These are approved as first and second-line treatments in metastatic UC. Several biological parameters associate with response to IO agents, including tumor mutational burden, molecular subtype, and infiltration by programmed death-ligand 1-positive lymphocytes, detected by immunohistochemistry. Programmed death-ligand 1 immunohistochemistry is mandatory before administering IO agents in the first-line setting. In conclusion, much has been learned about the biology of bladder cancer, and this understanding has improved the care of patients with the disease.

Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.

BACKGROUND: An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading. METHODS: We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa. FINDINGS: The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994-0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972-0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95-0·97) for the independent test dataset and 0·87 (0·84-0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60-0·73). INTERPRETATION: An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist. FUNDING: Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.

Recurrent KRAS mutations in papillary renal neoplasm with reverse polarity.

We recently proposed that an epithelial renal tumor "papillary renal neoplasm with reverse polarity" represents a distinct entity. It constituted 4% of previously diagnosed papillary renal cell carcinoma at the participating institutions. Histologically, it is characterized by papillary or tubulopapillary architecture covered by a single layer of eosinophilic cells with finely granular cytoplasm and apically located nuclei. It is characteristically positive for GATA3 and L1CAM and lack vimentin and, to a lesser extent, α-methylacyl-CoA-racemase (AMACR/p504s) immunostaining. To investigate the molecular pathogenesis of these tumors, we performed targeted next-generation sequencing on ten previously reported papillary renal neoplasms with reverse polarity, followed by a targeted polymerase chain reaction analysis for KRAS mutations in a control series of 30 type 1 and 2 papillary renal cell carcinomas. KRAS missense mutations were identified in eight of ten papillary renal neoplasms with reverse polarity. These mutations were clustered in exon 2-codon 12: c.35 G > T (n = 6) or c.34 G > C (n = 2) resulting in p.Gly12Val and p.Gly12Arg alterations, respectively. One of the wild-type tumors had BRAF c.1798_1799delGTinsAG (p.Val600Arg) mutation. No KRAS mutations were identified in any of the 30 control tumors. In summary, this study supports our proposal that papillary renal neoplasm with reverse polarity is an entity distinct from papillary renal cell carcinoma and the only renal cell neoplasm to consistently harbor KRAS mutations.

Renal cell tumors with an entrapped papillary component: a collision with predilection for oncocytic tumors.

Renal cell tumors with mixed morphology resembling multiple renal cell carcinoma (RCC) subtypes are generally regarded as unclassified RCC. However, occasionally, papillary adenoma or RCC appears admixed with a larger, different tumor histology. We retrieved 17 renal tumors containing a papillary adenoma or papillary RCC component admixed with another tumor histology and studied them with immunohistochemistry and fluorescence in situ hybridization (FISH). Larger tumors were oncocytomas (n = 10), chromophobe RCCs (n = 5), borderline oncocytic tumor (n = 1), and clear cell RCC (n = 1). The size of papillary component ranged from 1 to 34 mm. One tumor was an oncocytoma encircled by a cyst (2.0 cm) with papillary hyperplasia of the lining. The papillary lesions were diffusely cytokeratin 7 positive (17/17), in contrast to "host" tumors. Alpha-methylacyl-coA-racemase labeling was usually stronger in the papillary lesions (13/15). KIT was negative in all papillary lesions and the clear cell RCC and positive in 16/16 oncocytic or chromophobe tumors. Eight of 15 (53%) collision tumors had differing FISH results in the two components. A papillary renal cell proliferation within another tumor is an uncommon phenomenon with predilection for oncocytoma and chromophobe RCC, possibly related to their common entrapment of benign tubules. When supported by distinct morphology and immunohistochemistry in these two components, this phenomenon should be diagnosed as a collision of two processes. A diagnosis of unclassified RCC should be avoided, due to potential misrepresentation as an aggressive renal cancer.

Primary Renal Synovial Sarcomas: PAX 8 Immunostaining and Unusual Molecular Findings.

Synovial sarcoma (SS) is a high-grade sarcoma that rarely involves the kidney. Eleven renal SS cases were collected in our institution. Immunostaining features and molecular changes of renal SS were further elucidated in this study. PAX 8 was focally positive in 1 monophasic SS and diffusely positive in both the spindled and epithelial components in 1 biphasic SS. These 2 PAX8 expressing renal SS were confirmed by the presence of the classic t(X;18) translocation. Our study also revealed the presence of extra copies of the SS18 in one biphasic SS and one poorly differentiated SS. The SS18 (SYT) gene rearrangement is useful for confirming the SS diagnosis. However, a negative test (FISH or RT-PCR) does not rule out the diagnosis. Although not as common, other chromosomal alterations, such as polysomy 18, indeed occur in renal synovial sarcoma.

Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline.

PURPOSE: This guideline provides recommendations for available tissue-based prostate cancer biomarkers geared toward patient selection for active surveillance, identification of clinically significant disease, choice of postprostatectomy adjuvant versus salvage radiotherapy, and to address emerging questions such as the relative value of tissue biomarkers compared with magnetic resonance imaging. METHODS: An ASCO multidisciplinary Expert Panel, with representatives from the European Association of Urology, American Urological Association, and the College of American Pathologists, conducted a systematic literature review of localized prostate cancer biomarker studies between January 2013 and January 2019. Numerous tissue-based molecular biomarkers were evaluated for their prognostic capabilities and potential for improving management decisions. Here, the Panel makes recommendations regarding the clinical use and indications of these biomarkers. RESULTS: Of 555 studies identified, 77 were selected for inclusion plus 32 additional references selected by the Expert Panel. Few biomarkers had rigorous testing involving multiple cohorts and only 5 of these tests are commercially available currently: Oncotype Dx Prostate, Prolaris, Decipher, Decipher PORTOS, and ProMark. With various degrees of value and validation, multiple biomarkers have been shown to refine risk stratification and can be considered for select men to improve management decisions. There is a paucity of prospective studies assessing short- and long-term outcomes of patients when these markers are integrated into clinical decision making. RECOMMENDATIONS: Tissue-based molecular biomarkers (evaluating the sample with the highest volume of the highest Gleason pattern) may improve risk stratification when added to standard clinical parameters, but the Expert Panel endorses their use only in situations in which the assay results, when considered as a whole with routine clinical factors, are likely to affect a clinical decision. These assays are not recommended for routine use as they have not been prospectively tested or shown to improve long-term outcomes-for example, quality of life, need for treatment, or survival. Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Reporting Practices and Resource Utilization in the Era of Intraductal Carcinoma of the Prostate: A Survey of Genitourinary Subspecialists.

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.