Faculty Bibliography

Conflicting practice recommendations regarding the grading of intraductal carcinoma of the prostate (IDCP) from two leading uropathology societies, the Genitourinary Pathology Society (GUPS) and the International Society of Urological Pathology (ISUP), are confusing for both pathologists and treating clinicians. The objectives of this consultation were to clarify unresolved issues regarding IDCP and atypical intraductal proliferation (AIP) terminology, diagnostic criteria, grading, and management implications, as well as to develop uniform reporting guidelines for IDCP and AIP, endorsed by both societies. A 32-member expert panel, composed of five core members, 25 expert urological pathologists, and two expert urologists, employed a modified Delphi process consisting of multiple rounds of consultation and voting. These were supplemented by discussions at the 2025 United States and Canadian Academy of Pathologists Annual Meeting to achieve expert consensus (defined as at least 67% agreement). Consensus was reached on several key issues. IDCP was regarded most commonly as reflecting the retrograde spread of invasive prostate cancer (PCa). IDCP diagnosis should be based on the Guo and Epstein criteria, supported by basal cell immunohistochemistry in cases that are difficult to distinguish from invasive PCa. The term AIP should be used only in equivocal proliferations where IDCP is favoured but the criteria are not fully met, and these should be reported as 'AIP, suspicious for IDCP'. In the presence of invasive PCa, IDCP should generally be incorporated into Gleason grading irrespective of Grade Group (GG). However, a significant minority (30%) favoured excluding IDCP from the Gleason score if the invasive component was solely Gleason pattern (GP) 3. Pure IDCP (not associated with invasive PCa) and AIP, suspicious for IDCP, should not be graded. IDCP should not be incorporated in the grading of invasive PCa when it is spatially distinct from invasive PCa. A second opinion from a senior or dedicated GU pathologist and discussion within a multidisciplinary management setting should be considered, in the rare settings of pure IDCP or GP3 + IDCP (formerly GG1 + IDCP scenario). This joint GUPS-ISUP consultation provides unified recommendations for the diagnosis, terminology, grading, and reporting of IDCP and AIP, and will pave the way for the development of future IDCP/AIP WHO guidelines. Their adoption should reduce interobserver variation, facilitate consistent communication with clinicians, and improve patient management.

Renal neoplasms are morphologically and molecularly heterogeneous, with their diagnosis often hindered by interobserver variability and overlapping microscopic features. A subset of cases is unclassifiable despite immunohistochemical, mutation, and cytogenetic-based diagnostic workup. Through examination of the genome-wide DNA methylation signatures of over 2000 renal neoplasms, we identified 23 coherent groups that correlate with known neoplasm types and identified novel clinically relevant subtypes of existing neoplasm types. We used machine learning models to develop and validate a classifier trained on DNA methylation profiles of 1284 samples. The classifier was tested on an external data set of 287 renal neoplasms with >90% concordance between expected neoplasm type and high-score DNA methylation-based classification. Discordance between the original histologic label and methylation class led to potential reclassification of some cases. This work demonstrates proof of principle for the feasibility of a DNA methylation classifier as a clinically useful tool to assist in the diagnosis of renal neoplasms.

INTRODUCTION/BACKGROUND:High-volume (≥ 50 %) biopsy core involvement (HVCI) is an independent risk factor for unfavorable intermediate-risk prostate cancer by NCCN guidelines. The studies demonstrating increased recurrence in high-volume disease were conducted in an era of conventional fractionation, often without dose-escalation. In the SBRT era, we explore the value of this pathologic criteria in intermediate-risk disease. METHODS:A large institutional database was reviewed to identify patients diagnosed with localized intermediate-risk (Gleason Grade [GG] 2 and 3) disease, who were treated with definitive five-fraction SBRT without ADT. HVCI was analyzed (1) traditionally with all positive cores given equal weight as well as weighted with a positive core of GG1 to GG3 given (2) linearly and (3) exponentially increased weight. Oncologic outcomes were analyzed using Cox and linear regression analysis. RESULTS:From 2009 to 2018, 888 patients with intermediate-risk prostate cancer were treated with five-fraction SBRT monotherapy to a median dose of 3500 cGy. The majority (68 %) had GG2 disease. HVCI was present in the 22 % and was inversely related to prostate volume and directly related to T-stage. Biochemical disease-free survival (BDFS) was not significantly associated with HVCI in the cohort (p = 0.47) nor in the GG2 (p = 0.85) and GG3 (p = 0.26) sub-cohorts. Similarly, when linear or exponential weight was given to a core with higher-grade disease, there was no association with BDFS. Finally, PSA nadir was not associated with HVCI; however, time to PSA nadir (TTN) was negatively associated with HVCI in the GG3 sub-cohort (p = 0.04). CONCLUSION/CONCLUSIONS:With a median follow-up of 4.1 years, HVCI was not associated with BDFS following SBRT monotherapy, particularly in patients with otherwise favorable intermediate-risk disease (GG2). TTN analysis suggests that HVCI may remain prognostic in GG3 disease (by definition unfavorable intermediate-risk). Further work should prospectively confirm whether HVCI is unnecessary in risk-stratifying GG2 disease in the SBRT era.

CONTEXT.—/UNASSIGNED:The use of hormonal therapy and gender-affirming surgery in the transgender community has been rising during the last several years. Although it is generally safe, hormonal therapy's link to testicular cancer remains uncertain. OBJECTIVE.—/UNASSIGNED:To review the incidence of testicular cancer in specimens from gender-affirming orchiectomies at our institution and evaluate the tumors for histologic and genetic alterations. DESIGN.—/UNASSIGNED:Pathology reports for gender-affirming orchiectomies (January 1, 2018, to August 1, 2023) were reviewed for testicular neoplasms, with additional analysis for chromosome 12 abnormalities. Incidence and chromosome variations were compared with those in the general population. RESULTS.—/UNASSIGNED:Among 458 cases during 5.5 years, 5 germ cell neoplasms in 4 patients emerged. Our institution's annual incidence rate (159 per 100 000) is 26.5 times higher than the National Cancer Institute's previous report (6.0 per 100 000). Although they were morphologically no different from germ cell neoplasms in the general population, fluorescence in situ hybridization tests showed no i(12p) in 4 of 5 neoplasms (80%) in our cohort. CONCLUSIONS.—/UNASSIGNED:The cause behind this rise in incidence remains uncertain but may be due to long term pretreatment with hormones or blockers. The lower isochromosome 12p frequency suggests an alternative mechanism driving tumor development, which requires more detailed molecular studies.

INTRODUCTION AND OBJECTIVE/OBJECTIVE:For localized kidney tumors, size and growth kinetics generally predict malignant potential. Thus, for patients with multifocal renal masses, treatment priority often revolves around the largest or index tumor first. We reviewed our kidney surgery database to examine histologic concordance of sporadic multifocal renal tumors and to determine if size is also the greatest determinant of tumor aggressiveness. METHODS:We conducted a retrospective chart review at a tertiary referral center of 1983 patients undergoing nephrectomy (radical and partial) from January 2010 to December 2019. We identified 138 patients with multifocal renal masses (n = 138). Surgical pathology parameters, including tumor size, TNM grading, and staging, were collected through electronic medical records. Patients with syndromic diseases were excluded (n = 10), resulting in a total sample of 128 patients with sporadic multifocal tumors. Overall, the sample included 307 tumors total, with a mean number of 2.4 lesions per patient. RESULTS:About 128 patients (6.45%) had sporadic multifocal renal tumors. Among these, 82 out of 128 (64%) had concordant histologic subtypes, while 46 out of 128 (36%) had discordant histology. In 99 patients (77.3%), the index tumor demonstrated a more aggressive histology. There were 29 patients (22.6%) with a benign or less aggressive index tumor. Among those, 21 patients (16%) had a benign index tumor, 5 (24%) of which had a malignant secondary tumor. CONCLUSION/CONCLUSIONS:Multifocal tumors frequently have discordant histology. While size tends to predict oncologic risk, many patients harbor more aggressive disease in nonindex lesions, highlighting the limitations of relying on size alone for managing sporadic multifocal RCC.

BACKGROUND:Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS:(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS:18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION/CONCLUSIONS:DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

BACKGROUND:In-field or in-margin recurrence after partial gland cryosurgical ablation (PGCA) of prostate cancer (PCa) remains a limitation of the paradigm. Stimulated Raman histology (SRH) is a novel microscopic technique allowing real time, label-free, high-resolution microscopic images of unprocessed, un-sectioned tissue which can be interpreted by humans or artificial intelligence (AI). We evaluated surgical team and AI interpretation of SRH for real-time pathologic feedback in the planning and treatment of PCa with PGCA. METHODS:About 12 participants underwent prostate mapping biopsies during PGCA of their PCa between January and June 2022. Prostate biopsies were immediately scanned in a SRH microscope at 20 microns depth using 2 Raman shifts to create SRH images which were interpreted by the surgical team intraoperatively to guide PGCA, and retrospectively assessed by AI. The cores were then processed, hematoxylin and eosin stained as per normal pathologic protocols and used for ground truth pathologic assessment. RESULTS:Surgical team interpretation of SRH intraoperatively revealed 98.1% accuracy, 100% sensitivity, 97.3% specificity for identification of PCa, while AI showed a 97.9% accuracy, 100% sensitivity and 97.5% specificity for identification of clinically significant PCa. 3 participants' PGCA treatments were modified after SRH visualized PCa adjacent to an expected MRI predicted tumor margin or at an untreated cryosurgical margin. CONCLUSION/CONCLUSIONS:SRH allows for accurate rapid identification of PCa in PB by a surgical team interpretation or AI. PCa tumor mapping and margin assessment during PGCA appears to be feasible and accurate. Further studies evaluating impact on clinical outcomes are warranted.

INTRODUCTION/UNASSIGNED:Balancing surgical margins and functional outcomes is crucial during radical prostatectomy for prostate cancer. Stimulated Raman Histology (SRH) is a novel, real-time imaging technique that provides histologic images of fresh, unprocessed, and unstained tissue within minutes, which can be interpreted by either humans or artificial intelligence. METHODS/UNASSIGNED:Twenty-two participants underwent robotic-assisted laparoscopic radical prostatectomy (RALP) with intraoperative SRH surgical bed assessment. Surgeons resected and imaged surgical bed tissue using SRH and adjusted treatment accordingly. An SRH convolutional neural network (CNN) was developed and tested on 10 consecutive participants. The accuracy, sensitivity, and specificity of the surgical team's interpretation were compared to final histopathological assessment. RESULTS/UNASSIGNED:A total of 121 SRH periprostatic surgical bed tissue (PSBT) assessments were conducted, an average of 5.5 per participant. The accuracy of the surgical team's SRH interpretation of resected PSBT samples was 98%, with 83% sensitivity, and 99% specificity. Intraoperative SRH assessment identified 43% of participants with a pathologic positive surgical margin intraoperatively. PSBT assessment using the CNN demonstrated no overlap in tumor probability prediction between benign and tumor infiltrated samples, mean 0.30% (IQR 0.10-0.43%) and 26% (IQR 18-34%, p<0.005), respectively. CONCLUSION/UNASSIGNED:SRH demonstrates potential as a valuable tool for real-time intraoperative assessment of surgical margins during RALP. This technique may improve nerve-sparing surgery and facilitate decision-making for further resection, reducing the risk of positive surgical margins and minimizing the risk of recurrence. Further studies with larger cohorts and longer follow-up periods are warranted to confirm the benefits of SRH in RALP.

CONTEXT.—/UNASSIGNED:The morphologic features of different entities in genitourinary pathology overlap, presenting a diagnostic challenge, especially when diagnostic materials are limited. Immunohistochemical markers are valuable when morphologic features alone are insufficient for definitive diagnosis. The World Health Organization classification of urinary and male genital tumors has been updated for 2022. An updated review of immunohistochemical markers for newly classified genitourinary neoplasms and their differential diagnosis is needed. OBJECTIVE.—/UNASSIGNED:To review immunohistochemical markers used in the diagnosis of genitourinary lesions in the kidney, bladder, prostate, and testis. We particularly emphasized difficult differential diagnosis and pitfalls in immunohistochemistry application and interpretation. New markers and new entities in the 2022 World Health Organization classifications of genitourinary tumors are reviewed. Recommended staining panels for commonly encountered difficult differential diagnosis and potential pitfalls are discussed. DATA SOURCES.—/UNASSIGNED:Review of current literature and our own experience. CONCLUSIONS.—/UNASSIGNED:Immunohistochemistry is a valuable tool in the diagnosis of problematic lesions of genitourinary tract. However, the immunostains must be carefully interpreted in the context of morphologic findings with a thorough knowledge of pitfalls and limitations.

BACKGROUND/OBJECTIVE/UNASSIGNED:The frequency of hematospermia in transgender women is unknown. This report aimed to describe the development of hematospermia in a transgender woman. CASE REPORT/UNASSIGNED:A 35-year-old transgender woman treated with estradiol valerate and leuprolide presented with painless rust-tinged ejaculate, urethral bleeding after ejaculation, and intermittent hematuria. Her medical history included gastroesophageal reflux disease, internal hemorrhoids, and attention deficit hyperactivity disorder with negative tobacco smoking and urologic history. Additional medications included emtricitabine-tenofovir disoproxil fumarate and fexofenadine. Physical examination did not reveal constitutional or genitourinary abnormalities. Urinalysis and culture disclosed rare white blood cells with gram-variable bacilli. The chlamydia, gonorrhea, and human immunodeficiency virus test results were negative. Abdominal computed tomography did not reveal bladder or prostate cancer, calcifications, inflammation, or cysts. She continued to have symptoms after this initial workup. One year after the initial symptom onset, transrectal ultrasound disclosed a 1.7-cm midline posterior prostatic cyst with hemorrhagic products, later revealed by magnetic resonance imaging as communicating with the left seminal vesicle. Two ultrasound-guided transperineal biopsy samples revealed benign prostatic tissue with a small focus of Müllerian or endometrial-type tissue, evidenced by immunopositivity for paired-box gene 8 and estrogen receptor in epithelium and cluster of differentiation 10 immunopositivity in stroma. After medical consultation, the patient underwent prostatic cyst aspiration, resection of the transurethral ejaculatory ducts, and orchiectomy. She did not experience any complications after these procedures. DISCUSSION/UNASSIGNED:The etiology of hematospermia may be idiopathic, iatrogenic, anatomic, or pathologic. CONCLUSION/UNASSIGNED:Occult endometriosis or ectopic Müllerian epithelial tissue growth may occur in transgender women taking feminizing gender-affirming hormone therapy.