Acceptance of emerging renal oncocytic neoplasms: a survey of urologic pathologists.

Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities.

Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1.

Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-independent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the progression to NEPC suggests a model of lineage plasticity whereby AR-dependent luminal-like tumors progress towards an AR-independent NEPC state. Genetic analysis of human NEPC identified frequent loss of RB1 and TP53, and the loss of both genes in experimental models mediates the transition to a neuroendocrine lineage. Transcriptomics studies have shown that lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we modeled the progression of prostate adenocarcinoma to NEPC by establishing prostate organoids and subsequently generating subcutaneous allograft tumors from genetically-engineered mouse models harboring Cre-induced loss of Rb1 and Trp53 with Myc overexpression (RPM). These tumors were heterogeneous and displayed adenocarcinoma, squamous, and neuroendocrine features. ASCL1 and NEUROD1 were expressed within neuroendocrine-defined regions, with ASCL1 being predominant. Genetic loss of Ascl1 in this model did not decrease tumor incidence, growth, or metastasis; however, there was a notable decrease in neuroendocrine identity and an increase in basal-like identity. This study provides an in vivo model to study progression to NEPC and establishes the requirement for ASCL1 in driving neuroendocrine differentiation in prostate cancer.

The role of the radiologist in the prostate cancer multidisciplinary conference.

The broad range of disease aggressiveness together with imperfect screening, diagnostic, and treatment options in prostate cancer (PCa) makes medical decision-making complex. The primary goal of a multidisciplinary conference is to improve patient outcomes by combining evidence-based data and expert opinion to discuss optimal management, including for those patients with challenging presentations. The primary purpose of the genitourinary imaging specialist in the prostate cancer multidisciplinary conference is to use imaging findings to reduce uncertainty by answering clinical questions. In this review, we discuss the role and the opportunities for an imaging specialist to add value in the care of men with prostate cancer discussed at multidisciplinary conferences.

Renal Cell Carcinoma Associated With TSC/MTOR Genomic Alterations: An Update on its Expanding Spectrum and an Approach to Clinicopathologic Work-up.

Renal cell carcinoma (RCC) with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) pathway-related genomic alterations have been classically described in hereditary TSC syndrome setting involving germline mutations, whereby cells with a bi-allelic inactivation of genes originate tumors in a classic tumor-suppressor "two-hit" Knudson paradigm. Initial studies of TSC-associated RCC categorized tumors into 3 broad heterogeneous morphologic groups: RCC with smooth muscle stroma, chromophobe-like, and eosinophilic-macrocytic. Recently, a similar morphologic spectrum has been increasingly recognized in novel and emerging entities characterized by somatic mutations in the TSC1/2 and MTOR in patients who do not suffer from the TSC. Correct recognition of RCC with TSC / MTOR mutations is critical for accurate prognostication because such tumors with aggressive behavior have the potential to be tailored to mTOR inhibitors. Whether TSC/MTOR mutated renal epithelial neoplasms represent a distinct molecular class has been confounded by the fact that TSC1/2 , and the gene encoding the downstream protein MTOR, are mutated secondarily in ∼5% of the more common subtypes of RCC, including the commonest subtype of clear cell RCC. This review summarizes the expanding morphologic spectrum of renal tumors with TSC/mTOR pathway alterations, specifically for sporadically occurring tumors where these genomic alterations likely are primary pathologic events. Finally, a practical surgical pathology approach to handling these tumors, and a conceptual framework of renal epithelial tumors with TSC/MTOR mutations as a "family of tumors", is presented.

Preoperative Multiparametric Prostate Magnetic Resonance Imaging Structured Report Informs Risk for Positive Apical Surgical Margins During Radical Prostatectomy.

BACKGROUND: The prostatic apex is the most frequent location of positive surgical margin (PSM) after surgery. Data regarding the ability of multiparametric magnetic resonance imaging (mpMRI) to prospectively identify men at risk for apical PSMs (aPSMs) using a structured report are lacking. OBJECTIVES: The aims of the study are to determine and to compare the rate of aPSM in men with versus without prospectively flagged at-risk prostate lesions during clinical mpMRI interpretation using whole-mount histopathology as the reference standard. METHODS: This single-center, retrospective study of prospectively collected data included treatment-naive men with abnormal 3T mpMRI (PI-RADS v2 score ≥3) between January 2016 and December 2018 followed by surgery. During routine clinical interpretation, radiologists flagged prostate lesions abutting the apical most gland and/or encircling the distal most prostatic urethra using standardized language available as a "pick list" option in the structured report. Logistic regression was used to compare the rate of PSM in 2 groups (flagged vs nonflagged men). Propensity score covariate adjustment corrected for potential selection bias according to age, prostate-specific antigen (PSA), PSA density, grade group, and pT stage. The estimate was further adjusted by including surgeon as a covariate. RESULTS: A total of 428 men were included. A statistically significant higher proportion of aPSMs was noted in flagged (56% [51/91]) compared with nonflagged apical lesions (31% [105/337]; adjusted odds ratio, 2.5; 95% confidence interval, 1.6-4.1; P < 0.01). The difference in aPSM between both groups also varied according to the surgeon performing the RP. Prostate-specific antigen, PSA density, lesion size, apical location, Prostate Imaging Reporting & Data System score, grade group, pT stage, and surgeon's experience were associated with higher PSM rate. Biochemical recurrence, defined as PSA greater than 0.2 ng/mL on 2 measurements after RP, was significantly associated with PSM status (propensity score adjusted odds ratio, 3.1; 95% confidence interval, 1.8-5.3; P < 0.0001); however, patients flagged by radiologists did not have a significant difference in biochemical recurrence rates as compared with nonflagged patients ( P = 0.11). CONCLUSIONS: Standard language built into structured reports for mpMRI of the prostate helps identify preoperatively patients at risk for aPSM. CLINICAL IMPACT: Multiparametric MRI is able to identify patients at increased risk for aPSM, and this information can be conveyed in a structured report to urologists, facilitating patient counseling and treatment decisions.

Myxoid Pseudotumor Involving the Renal Sinus: Clinicopathologic Study of 33 Cases Supporting a Distinct Benign Non-neoplastic Lesion.

We describe 33 cases of myxoid pseudotumor involving the renal sinus from 31 patients. Patients included 21 men and 10 women, ages 30 to 95 years. Twenty-seven cases (82%) had an associated malignancy, including urothelial carcinoma of the renal pelvis (22 cases), clear cell renal cell carcinoma (3 cases), urothelial carcinoma of the bladder (1 case), and poorly differentiated carcinoma of uncertain lineage (1 case). The remaining 6 (18%) had no associated malignancy and included 3 nephrectomies for ureteral stricture, 2 ureteropelvic junction repairs, and 1 resection of a "periureteral mass" (subsequently shown to be myxoid pseudotumor). Myxoid pseudotumor was identified by preoperative computed tomography imaging in 2 patients (6%) and identified by the gross dissector in 9 cases (27%). The mean size was 14 mm (range: 5 to 38 mm). All cases had an admixture of adipocytes, myxoid stromal matrix, variable collagenization, and a hypocellular population of bland spindled and stellate stromal cells. No multilobated atypical stromal cells were present. Clinical follow-up was available for 28 patients (90%), ranging from 1 to 132 months (mean: 24.6 mo). No patients had adverse events related to the myxoid pseudotumor. Myxoid pseudotumor of the renal sinus is often associated with a variety of adjacent neoplastic and non-neoplastic conditions and may present as a mass lesion detectable by imaging and/or gross inspection. Awareness of this benign process is important to avoid confusion with a neoplasm, especially liposarcoma.

Reporting Trends, Practices, and Resource Utilization in Neuroendocrine Tumors of the Prostate Gland: A Survey among Thirty-Nine Genitourinary Pathologists.

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.

Should grade group 1 prostate cancer be reclassified as "non-cancer"? A pathology community perspective.

Overdiagnosis and overtreatment of Grade Group 1 (GG 1) prostate cancer remains a significant health care problem despite of its improved risk assessment and uptake in conservative management. Removing the cancer label from these non-lethal cancers has been proposed as an expedient way to reduce potential physical, psychological and financial harm to patients. Such a nomenclatural change necessitates a multidisciplinary team effort by clinicians and pathologists. Genitourinary Pathology Society recently conducted a survey of its members, gauging their awareness of this controversy and their position on whether GG 1 prostate cancer should be reclassified. Most respondents (196, 81.7%) opposed removing the cancer label from GG 1 cancer, 33 (13.8%) supported a change in nomenclature, while 11 (4.6%) responded that they were uncertain. Of those who supported the reclassification, 17 (51.5%) supported the change for radical prostatectomy only, 4 (12.1%) for biopsy only, and 12 (36.4%) for both biopsy and radical prostatectomy. This survey results highlight the gap between pathologists and clinicians in whether GG 1 prostate cancer should be labeled as "non-cancer," and calls for continued debates and conversations between pathologists and clinicians, and further studies on the biology, diagnostic reproducibility, and ideal management of GG 1 prostate cancer in order to make a more evidence-based decision for patients.

Cribriform Lesions of the Prostate Gland.

"Cribriform lesions of the prostate represent an important and often diagnostically challenging spectrum of prostate pathology. These lesions range from normal anatomical variation, benign proliferative lesions, premalignant, suspicious to frankly malignant and biologically aggressive entities. The concept of cribriform prostate adenocarcinoma (CrP4) and intraductal carcinoma of the prostate (IDC-P), in particular, has evolved significantly in recent years with a growing body of evidence suggesting that the presence of these morphologies is important for clinical decision-making in prostate cancer management. Therefore, accurate recognition and reporting of CrP4 and IDC-P architecture are especially important. This review discusses a contemporary diagnostic approach to cribriform lesions of the prostate with a focus on their key morphologic features, differential diagnosis, underlying molecular alterations, clinical significance, and reporting recommendations."

Sensitivity of multiparametric MRI and targeted biopsy for detection of adverse pathologies (Cribriform gleason pattern 4 and intraductal carcinoma): Correlation of detected and missed prostate cancer foci with whole mount histopathology.

PURPOSE: Accurate preoperative detection of prostate cancer (PCa) exhibiting "cribriform" morphology (intraductal carcinoma [IDC-P] or cribriform Gleason pattern 4 [CrP4]) is important as it is independently associated with a variety of adverse clinical outcomes. The sensitivity of multiparametric magnetic resonance imaging (mpMRI) in the detection of PCa exhibiting "cribriform" morphology remains controversial. MATERIALS AND METHODS: A total of 117 eligible men with prospectively reported mpMRI who underwent in-bore MRI targeted biopsy followed by whole-mount radical prostatectomy (RP) were analyzed for lesion-level imaging-pathology correlation. RESULTS: Of the 206 PCa foci at RP (117 index and 89 non-index), 74% (152/206) were detected by mpMRI. Of the 54 tumors missed by mpMRI, most were non-index (98%, 53/54), grade group (GG) 1 (68%, 37/54) or GG 2 (26%, 14/54), with a median size of 1.0 cm (range, 0.7-1.5 cm), and non-cribriform morphology (96%, 52/54). Cribriform morphology was detected in 26% (53/206) of all tumors, and although targeted biopsies identified 96% (51/53) of these cancers, the cribriform component was depicted in only 45% (24/53). Of these, mpMRI detected all (100%, 44/44) index and 78% (7/9) of the non-index tumors. At univariable analysis, tumor size greater than 5 mm, % pattern 4 > 5%, cribriform morphology, zone (transition versus peripheral zone), and region (apex versus mid/base) were significantly associated with tumor visibility at mpMRI. At multivariable analysis, only tumor size, presence of any pattern 4, and peripheral zone remained significant predictors for visibility by mpMRI. CONCLUSION: At a lesion level, mpMRI offers high sensitivity for the detection of cribriform morphologies, however, the cribriform component is frequently missed by targeted biopsies. The MRI visibility is significantly associated with larger tumor size, presence of Gleason pattern 4, and peripheral zone location.

Enrichment of "Cribriform" morphologies (intraductal and cribriform adenocarcinoma) and genomic alterations in radiorecurrent prostate cancer.

Locally relapsed prostate cancer (PCa) after radiation therapy (RT) is associated with substantial morbidity and mortality. Morphological and molecular consequences that may contribute to RT resistance and local recurrence remain poorly understood. Locally recurrent PCa tissue from 53 patients with clinically localized PCa who failed with primary RT and subsequently underwent salvage radical prostatectomy (RP) was analyzed for tumor focality, clinicopathological, molecular, and genomic characteristics. Targeted next-generation sequencing with full exon coverage of 1,425 cancer-related genes was performed on 10 representative radiorecurrent PCas exhibiting no RT effect with matched adjacent benign prostate tissue. At RP, 37 (70%) of PCas had no RT effect with the following characteristics: grade group (GG) ≥ 3 (70%), unifocal tumor (75%), extraprostatic disease (78%), lymph node metastasis (8%), and "cribriform" morphologies (84%) [cribriform PCa (78%) or intraductal carcinoma (IDC-P) (61%)] at a median percentage of approximately 80% of tumor volume. In the setting of multifocal tumors (25%) at RP, the cribriform morphologies were restricted to index tumors. Of 32 patients with available pre-RT biopsy information, 16 had GG1 PCa, none had cribriform morphologies at baseline but 81% demonstrated cribriform morphologies at RP. Notable alterations detected in the sequenced tumors included: defects in DNA damage response and repair (DDR) genes (70%) (TP53, BRCA2, PALB2, ATR, POLQ), PTEN loss (50%), loss of 8p (80%), and gain of MYC (70%). The median tumor mutational burden was 4.18 mutations/Mb with a range of 2.16 to 31.86. Our findings suggest that most radiorecurrent PCas are enriched in cribriform morphologies with potentially targetable genomic alterations. Understanding this phenotypic and genotypic diversity of radiorecurrent PCa is critically important to facilitate optimal patient management.

Renal Cell Carcinoma With Fibromyomatous Stroma-The Whole Story.

Renal cell carcinoma (RCC) with fibromyomatous stroma (FMS) was included as an "emerging/provisional" entity in the 2016 World Health Organization (WHO) classification as a "RCC with (angio) leiomyomatous stroma." It has been debated whether RCCFMS represents a separate entity or a group of RCCs with overlapping morphologies. Accordingly, various names have been used to refer to the RCCs that exhibited clear cells and prominent smooth muscle and fibromatous stroma. Recent studies have demonstrated that RCCFMS indeed represents a distinct entity with subtle but distinguishable features that can be separated from other RCCs that exhibit clear cells, as well as tubulopapillary morphology and smooth muscle/fibromatous stroma, such as clear cell RCC and clear cell papillary RCC. Microscopically, the epithelial component forms tumor nodules composed of elongated and frequently branching tubules, lined by clear or mildly eosinophilic cells containing voluminous cytoplasm. Focal papillary morphology is also frequently present. Diffuse CK7 positivity is typical and is required for the diagnosis. Molecular analysis of these tumors demonstrated recurrent mutations involving the TSC/mTOR pathway. A subset of tumors with similar morphology has shown mutations involving ELOC (previously referred to as TCEB1), typically associated with monosomy 8. Finally, in addition to the more common RCCFMS that are sporadic, essentially identical tumors have been found in patients with tuberous sclerosis complex, suggesting the existence of hereditary and sporadic counterparts of this tumor. It is currently debated whether TSC/mTOR and ELOC mutated RCCFMS should be grouped together, based on their shared and overlapping morphology and common CK7 reactivity, despite the differing molecular alterations. This review outlines evidence supporting the recognition of RCCFMS as a novel subtype of RCC with morphologic, immunohistochemical, and molecular characteristics distinct from clear cell RCC and clear cell papillary RCC.

SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial.

PURPOSE: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa. METHODS AND MATERIALS: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events. RESULTS: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively. CONCLUSIONS: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations.

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.

The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.

The Genitourinary Pathology Society Update on Classification of Variant Histologies, T1 Substaging, Molecular Taxonomy, and Immunotherapy and PD-L1 Testing Implications of Urothelial Cancers.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.