Percentage of Gleason pattern 4 and tumor volume predict adverse pathological stage and margin status at radical prostatectomy in grade Group 2 and grade Group 3 prostate cancers.

BACKGROUND: Increasing percentages of Gleason pattern 4 (GP4%) in radical prostatectomy (RP) correlate with an increased likelihood of nonorgan-confined disease and earlier biochemical recurrence (BCR). However, there are no detailed RP studies assessing the impact of GP4% and corresponding tumor volume (TV) on extraprostatic extension (EPE), seminal vesicle (SV) invasion (SV+), and positive surgical margin (SM) status (SM+). METHODS: In 1301 consecutive RPs, we analyzed each tumor nodule (TN) for TV, Grade Group (GG), presence of focal versus nonfocal EPE, SV+ , and SM+. Using GG1 (GP4% = 0) TNs as a reference, we recorded GP4% for all GG2 or GG3 TNs. We performed a multivariable analysis (MVA) using a mixed effects logistic regression that tested significant variables for risk of EPE, SV+, and SM+, as well as a multinomial logistic regression model that tested significant variables for risks of nonorgan-confined disease (pT2+, pT3a, and pT3b) versus organ-confined disease (pT2). RESULTS: We identified 3231 discrete TNs ranging from 1 to 7 (median: 2.5) per RP. These included GG1 (n = 2115), GG2 (n = 818), GG3 (n = 274), and GG4 (n = 24) TNs. Increasing GP4% weakly paralleled increasing TV (tau = 0.07, p < .001). In MVA, increasing GP4% and TV predicted a greater likelihood of EPE (odds ratio [OR]: 1.03 and 4.41), SV+ (OR: 1.03 and 3.83), and SM+ (1.01, p = .01 and 2.83), all p < .001. Our multinomial logistic regression model demonstrated an association between GP4% and the risk of EPE (i.e., pT3a and pT3b disease), as well as an association between TV and risk of upstaging (all p < .001). CONCLUSIONS: Both GP4% and TV are independent predictors of adverse pathological stage and margin status at RP. However, the risks for adverse outcomes associated with GP4% are marginal, while those for TV are strong. The prognostic significance of GP4% on BCR-free survival has not been studied controlling for TV and other adverse RP findings. Whether adverse pathological stage and margin status associated with larger TV could decrease BCR-free survival to a greater extent than increasing RP GP4% remains to be studied.

Loss of Limb-Bud-and-Heart (LBH) attenuates mammary hyperplasia and tumor development in MMTV-Wnt1 transgenic mice.

WNT/ß-catenin signaling plays pivotal roles in mammary development and tumorigenesis; and aberrant activation of this pathway is frequently observed in human breast cancer, correlating with poor outcome. However, the mechanisms underlying WNT-driven mammary tumorigenesis remain incompletely understood. Here, we used mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice, which develop aggressive mammary adenocarcinomas, to examine whether Limb-Bud-and-Heart (LBH) - a WNT/ß-catenin target transcription co-factor overexpressed in human triple-negative breast cancers with WNT pathway hyperactivation, contributes to WNT-induced tumorigenesis. We found LBH is specifically overexpressed in basal epithelial tumor cells of MMTV-Wnt1 mammary tumors reminiscent of its basal cell-restricted expression in the normal postnatal mammary gland. To determine the role of LBH in mammary tumorigenesis, we crossed MMTV-Wnt1 mice with basal epithelial-specific Keratin 14/K14-Cre;LbhloxP knockout mice. Mammary glands from virgin LBH-deficient MMTV-Wnt1 mice exhibited reduced hyperplasia, cell proliferation and increased apoptosis. Importantly, LBH inactivation in mammary epithelium significantly delayed tumor onset in MMTV-Wnt1 transgenic mice, with a median tumor-free survival of 32.5 weeks compared to 22.5 weeks in control LBH wild type MMTV-Wnt1 mice (p < 0.05). This data provides the first evidence that LBH plays an essential role in WNT-induced mammary tumorigenesis by promoting hyperplastic growth and tumor formation.

Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians.

Racial disparities in breast cancer incidence and outcome are a major health care challenge. Patients in the black race group more likely present with an early onset and more aggressive disease. The occurrence of high numbers of macrophages is associated with tumor progression and poor prognosis in solid malignancies. Macrophages are observed in adipose tissues surrounding dead adipocytes in "crown-like structures" (CLS). Here we investigated whether the numbers of CD163+ tumor-associated macrophages (TAMs) and/or CD163+ CLS are associated with patient survival and whether there are significant differences across blacks, non-black Latinas, and Caucasians. Our findings confirm that race is statistically significantly associated with the numbers of TAMs and CLS in breast cancer, and demonstrate that the highest numbers of CD163+ TAM/CLS are found in black breast cancer patients. Our results reveal that the density of CD206 (M2) macrophages is a significant predictor of progression-free survival univariately and is also significant after adjusting for race and for HER2, respectively. We examined whether the high numbers of TAMs detected in tumors from black women were associated with macrophage proliferation, using the Ki-67 nuclear proliferation marker. Our results reveal that TAMs actively divide when in contact with tumor cells. There is a higher ratio of proliferating macrophages in tumors from black patients. These findings suggest that interventions based on targeting TAMs may not only benefit breast cancer patients in general but also serve as an approach to remedy racial disparity resulting in better prognosis patients from minority racial groups.

Outcome of Gleason 3 + 5 = 8 Prostate Cancer Diagnosed on Needle Biopsy: Prognostic Comparison with Gleason 4 + 4 = 8.

PURPOSE: ISUP (International Society for Urologic Pathology) and WHO adopted prognostic Grade Groups 1 to 5 that simplify prostate cancer grading for prognosis. Grade Group 4 is Gleason score 8 cancer, which is heterogeneous, and it encompasses Gleason score 4 + 4 = 8, 3 + 5 = 8 and 5 + 3 = 8. The comparative prognostic implications of these various Gleason scores had not been studied by urological pathologists after a re-review of slides. MATERIALS AND METHODS: Patients with a highest biopsy Gleason score of 3 + 5 = 8 or 4 + 4 = 8 were included in the study. Controls were cases with a highest Gleason score of 4 + 3 = 7 or 9-10. A total of 423 prostatic biopsy cases accessioned from 2005 to 2013 at 2 institutions were reviewed. Clinicopathological findings and followup (median 33.4 months) were assessed. RESULTS: Among Gleason score 8 cancers the cancer status outcome in 51 men with Gleason score 3 + 5 = 8 was marginally worse than in 114 with Gleason score 4 + 4 = 8 (p = 0.04). This was driven by a persistent nonmetastatic (after radiation/hormone therapy) cancer rate of 37% among Gleason score 3 + 5 = 8 cases vs 24% among Gleason score 4 + 4 = 8 cases. Conversely, cancer specific survival at 36-month followup was 97.8% in 3 + 5 cases vs 92.6% in 4 + 4 cases but this was not significant (p = 0.089). Cancer specific survival in the Gleason score 8 group was dichotomized by the presence of cribriform growth (p = 0.018). All Gleason score categories did not differ in the fraction of biopsy cores positive, clinical presentation or pathological findings, including the frequency of Gleason pattern 5, in 70 patients who underwent prostatectomy. CONCLUSIONS: Using the most current standards of prostate cancer grading the prognosis is not different in Gleason score 3 + 5 = 8 and 4 + 4 = 8 cancers. This justifies including both in Grade Group 4.

Impact of 2004 ISUP/WHO classification on bladder cancer grading.

PURPOSE: To determine whether implementation of the 2004 WHO/ISUP bladder cancer (BCa) grading system caused a grade migration, i.e., more tumors being graded as high grade (HG). METHODS: Data on 1040 BCa cases from 668 patients treated at our institution between 2000 and 2013 and reviewed by six pathologists were evaluated: low grade (LG): 249; HG: 791; Ta: 389; T1: 214; CIS: 95; ≥T2: 342. Differences in LG or HG cases (expressed as %BCa cases/year) were analyzed by Mann-Whitney test. Correlation between the year of diagnosis and clinical/pathological parameters was evaluated by logistic regression analyses. RESULTS: During the study period, BCa cases diagnosed as LG significantly decreased with a corresponding increase in HG cases. Nonlinear regression analysis indicated that ~2008 was the crossover point for grade migration; %LG: 31.8 ± 4.8 (2000-2007); 14.1 ± 7.0 (2008-2013); %HG: 68.2 ± 4.8 (2000-2007); 85.9 ± 6.9 (2008-2013), P = 0.004. The grade migration was confined to Ta cases with %LG Ta cases diagnosed decreasing by 3.6-fold from 2000-2007 to 2008-2013 (P = 0.004). Univariate and multivariate analyses confirmed the grade migration following the adoption of the 2004 system (P < 0.0001). Kaplan-Meier curves showed no significant differences between the two time intervals in terms of disease progression (P > 0.05). CONCLUSIONS: Implementation of the 2004 WHO/ISUP system caused a significant increase in pathologists grading Ta cases as HG; however, this increase did not seem to correlate with disease progression. Since LG and HG Ta tumors are treated differently, grade migration may impact the clinical management of BCa patients.

The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation.

BACKGROUND: Recent advances have revealed a significant contribution of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. The CXC chemokine receptor-7 (CXCR7) is the latest chemokine receptor implicated in cancer. Although over expressed in breast cancer cell lines and tumor tissues, its mechanism of action in breast cancer (BrCa) growth and metastasis is unclear. Studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. The present study was initiated to examine the pattern of CXCR7 expression and its role in regulation of growth signaling in breast cancer. METHODS: The contribution of CXCR7 in BrCa cell proliferation was investigated in representative cell lines using real time quantitative PCR (q-PCR), proliferation assays, immunohistochemistry and immunoblotting. Phenotypic changes were examined after CXCR7 specific cDNA and siRNA transfection and expression levels were monitored by q-PCR. Further, the association of CXCR7 with epidermal growth factor receptor (EGFR) and modulation of its activity were investigated by western blotting, immunofluorescence, and in-situ proximity ligation assays in human BrCa cells and tissues. RESULTS: CXCR7 was expressed in both, estrogen receptor (ER) positive and negative BrCa cell lines. CXCR7 was also expressed unevenly in normal breast tissues and to a much higher extent in ER + cancer tissues. Depletion of CXCR7 in MCF7 BrCa cells by RNA interference decreased proliferation and caused cell cycle arrest. Further, proximity ligation assay (PLA) revealed colocalization of CXCR7 with EGFR in cancer tissues and cancer cell lines. CXCR7 depletion reduced levels of phospho-EGFR at Tyrosine1110 after EGF-stimulation and also reduced phosphorylation of ERK1/2, indicating a potentially direct impact on mitogenic signaling in MCF7 cells. Using siRNA to knockdown ß-arrestin2 in cells with EGFR over expression we were able to nearly deplete the CXCR7-EGFR colocalization events, suggesting that ß-arrestin2 acts as a scaffold to enhance CXCR7 dependent activation of EGFR after EGF stimulation. CONCLUSIONS: These results demonstrate coupling of CXCR7 with EGFR to regulate proliferation of BrCa cells and suggest an important ligand-independent role of CXCR7 in BrCa growth. Thus, the CXCR7-EGFR axis is a promising target for breast cancer therapy.

Haemangiomas in kidneys with end-stage renal disease: a novel clinicopathological association.

AIMS: The study of haemangiomas in end-stage renal disease (ESRD). METHODS AND RESULTS: Twenty ESRD nephrectomies from 16 patients (aged 9 months-68 years) were due to hypertension (four), focal segmental glomerulosclerosis (four), lupus nephritis (three), diabetes (one), IgA nephropathy (one), hereditary nephritis (one), congenital nephrotic syndrome (one) and unknown cause (one). Haemangiomas appeared as a single mass (15), two masses (one), three masses (one), four masses (two) and eight masses (one) per kidney. Tumours measured 0.2-3.5 cm. Four patients had bilateral haemangiomas. All tumours were in the medulla and often abutted renal sinus fat. All except one of the tumours were anastomosing haemangiomas, showing isolated or interconnected sinusoidal capillary-sized vascular channels lined by a single layer of benign cuboidal CD34(+) , CD31(+) , D2-40(-) endothelial cells, separated by loose stroma with spindle cells. One tumour was a cellular capillary haemangioma. Intravascular growth was seen in nine specimens. All haemangiomas had extramedullary haematopoiesis. Acquired cystic kidney disease (ACKD) was seen in 11 kidneys (nine patients), renal cell carcinoma (RCC) in five, ACKD-associated RCC precursors in three, Wilms' tumour in one and papillary adenomas in five. CONCLUSIONS: Anastomosing haemangioma appears as a distinctive clinicopathological entity developing in kidneys with ESRD, with or without ACKD.

Urinary Tract Cytopathology: Current and Future Impact on Patient Care.

Urine cytology is a non-invasive, cost-efficient, and sensitive test to detect high-grade urothelial carcinoma. The Paris System (TPS) for Reporting Urinary Cytology is an evidence-based system that uses the risk of malignancy to guide patient management. Since its inception, TPS has standardized urine cytology reports, facilitating communication among pathologists and between pathologists and clinicians. It is imperative to correlate the urine cytology findings with the concurrent tissue sample to avoid false-negative and false-positive results when possible. Several ancillary tests and artificial intelligence algorithms are being developed to increase the accuracy of urine cytology interpretation.

Stromal and Epithelial Architectural Alterations Mimicking Invasion (Pseudoinvasion) in Noninvasive Papillary Urothelial Carcinoma.

CONTEXT.­: Retraction artifact, paradoxic maturation/differentiation, desmoplasia, and complex irregular growth are morphologic criteria of invasion in urothelial carcinoma. OBJECTIVE.­: To describe changes mimicking invasion in noninvasive papillary urothelial carcinoma (NPUC). DESIGN.­: We reviewed 159 consecutive in-house patients with NPUC for either the presence of pseudoinvasion (irregular carcinoma nests within dense hyalinized stroma in the absence of other criteria of invasion) or precursor findings (stromal hyalinization not yet associated with epithelial architectural alteration). We assessed the correlation of these findings with age, sex, evidence of peripheral vascular disease, tumor grade, tumor infarction, and tumor size. We then followed up the patients clinically for tumor recurrence or progression. RESULTS.­: We identified 233 separate NPUCs (136 high grade and 97 low grade) in 125 men and 34 women. Of the 233 tumors, 26 (11.2%) had pseudoinvasion and 24 of 233 tumors (10.3%) had precursor findings. Except for complex irregular growth, no other criteria for invasion were seen. Pseudoinvasion and precursor findings were more common in men (47 of 183 [26%] versus 3 of 50 [6%]; P = .003), larger tumors (mean size, 2.6 versus 1.2 cm; P < .001), and tumors with infarction (33 of 50 [66%] versus 29 of 183 [15.8%]; P < .001). In multivariable analysis, tumor size (odds ratio, 1.49; P =.006), male sex (odds ratio, 6.48; P = .007), and the presence of infarction (odds ratio, 6.59; P < .001) were significant variables. Recurrence rates did not differ between patients with and those without pseudoinvasion (31% [5 of 16] versus 42% [45 of 107], respectively; P = .41). None of the tumors with pseudoinvasion progressed to invasive carcinoma. CONCLUSIONS.­: Given the correlation with size and presence of infarcted papillae, we suggest the possibility of tumor ischemia/infarction as a plausible etiology of pseudoinvasion. Awareness of this phenomenon is important for the accurate diagnosis of invasion in papillary urothelial carcinoma.

Don't SUMP it! Utility of PLAG1 immunocytochemistry in basaloid SUMP subcategory.

BACKGROUND: Basaloid salivary gland neoplasm of uncertain malignant potential (B-SUMP) is an indeterminate diagnostic subcategory, with pleomorphic adenoma (PA) representing the most common benign neoplasm. Pleomorphic adenoma gene 1 (PLAG1) staining is frequently seen in PAs and could aid in distinguishing them from other basaloid neoplasms. The authors evaluated the utility of PLAG1 immunocytochemistry (ICC) in differentiating PAs from other basaloid neoplasms in smears and liquid-based cytology (LBC) specimens. METHODS: In total, 45 B-SUMP cytology aspirates and corresponding surgical excision specimens were identified. PLAG1 immunostaining was performed in all aspirates and surgical excision specimens and was scored as positive (strong/diffuse), equivocal (focal/weak), or negative. RESULTS: PLAG1 ICC was performed directly on 38 smears and seven LBC specimens. PLAG1 was positive in 29 of 45 cases (64%), whereas six of 45 (13%) were equivocal, and 10 of 45 (22%) were negative. PLAG1-positive aspirates included 26 (90%) PAs, two (7%) basal cell adenomas (BCAs), and one (3%) carcinoma ex-PA. PLAG1-equivocal aspirates included four (67%) PAs and two (33%) BCAs, whereas negative aspirates included five (50%) BCAs, four (40%) adenoid cystic carcinomas, and one (10%) metastatic adenosquamous carcinoma. The sensitivity, specificity, positive, and negative predictive values were 87%, 86%, 93%, and 75%, respectively. Diagnostic accuracy was 87%. CONCLUSIONS: PLAG1 ICC is useful when positive (strong/diffuse) and can be reliably performed on smears and LBC specimens. PLAG1 was positive in most PAs and in a small subset of BCAs. Therefore, in the absence of atypical cytologic features, PLAG1-positive tumors could be diagnosed as benign, with a note favoring PA versus BCA. In contrast, PLAG1-negative/equivocal tumors should remain in the B-SUMP category.

Exploring the atypia of undetermined significance: Malignant ratio, ThyroSeq v3 positive call rate, molecular-derived risk of malignancy, and risk of malignancy as possible quality metric tools in thyroid cytology.

BACKGROUND: The atypia of undetermined significance (AUS) category is heterogeneous, leading to variations in its use. To prevent excessive usage, the AUS rate should be ≤10%. Although this recommendation aims to maintain diagnostic quality, it lacks supporting data. The AUS:Malignant (AUS:M) ratio has been proposed as a metric tool to evaluate AUS use. Furthermore, integrating ThyroSeq v3 (TSV3) positive call rate (PCR) and the molecular-derived risk of malignancy (MDROM) have been put forward as performance improvement tools. The authors reviewed their AUS:M ratios, TSV3 PCR, MDROM, and ROM. METHODS: Thyroid aspirates evaluated in the laboratory (from August 2022 to September 2023) by seven cytopathologists (CPs) were identified. AUS:M ratio, MDROM, ROM, and TSV3 PCR results for the laboratory and each CP were recorded and analyzed. RESULTS: A total of 2248 aspirates were identified (462 AUS and 80 malignant). The AUS:M ratio for the laboratory was 5.8 (CPs range, 2.8 to 7.3). The TSV3 PCR for the laboratory was 23% (CPs range, 11% to 41%). The MDROM for the laboratory was 19% (CPs range, 9% to 31%), whereas the ROM was 36% (CPs range, 29% to 50%). Linear regression analysis of AUS:M ratio versus TSV3 PCR and MDROM demonstrated a moderate positive correlation but a weak negative correlation to the ROM. Deviations from established targets were attributed to multiple factors. CONCLUSION: The findings of this study underscore the importance of using a combination of metrics to evaluate diagnostic practices. By dissecting the practice patterns of each CP, the authors can measure different aspects of their performance and provide individualized feedback.

Metastatic Pleomorphic Lobular Carcinoma of the Breast to the Urinary Bladder: A Report of 10 Cases and Assessment of TRPS1 in the Differential Diagnosis With Plasmacytoid Urothelial Carcinoma.

CONTEXT.­: Metastatic pleomorphic lobular carcinoma (MPLC) to the bladder is rare and has considerable histologic and immunohistochemical overlap with plasmacytoid urothelial carcinoma (PUC). OBJECTIVE.­: To distinguish MPLC from PUC morphologically and immunohistochemically, including a newer marker, TRPS1. DESIGN.­: Ten MPLCs to the bladder were reassessed and stained with estrogen, progesterone, and androgen receptors; GATA3; keratin 5/6; HMWK; GCDFP-15; and TRPS1. Sixteen PUCs constituted controls. RESULTS.­: We studied 4 transurethral resections of bladder tumors and 6 biopsies from 10 women (median age, 69 years) who had breast cancer on average 15 years prior. Microscopic patterns included single cells and cords of cells (n = 4), nests/sheets of dyscohesive cells (n = 2), or both (n = 4). All tumors had cells with voluminous eosinophilic cytoplasm and eccentric nuclei mimicking PUC, and 7 of 10 tumors had signet ring cells. MPLCs were positive for estrogen (8 of 10), progesterone (3 of 7), and androgen (4 of 10) receptors; GCDFP-15 (7 of 10); GATA3 (9 of 10); HMWK (7 of 8); and TRPS1 (7 of 10). No MPLCs stained for keratin 5/6 (n = 9). Of 16 PUCs, 2 showed faint and 2 demonstrated strong TRSP1 staining; 7 of 16 were negative for p63. CONCLUSIONS.­: MPLC to bladder often presents in patients with a remote history of breast cancer, exhibiting significant histologic and immunohistochemical overlap with PUC. Based on prior works and the current study, estrogen receptor (particularly SP-1), mammaglobin, and p63 help differentiate MPLC from PUC. Keratin 5/6 may aid in distinguishing a less frequent basal-type PUC because it is typically negative in MPLC. Some PUCs express TRPS1. Caution should be exercised because immunophenotypes of these tumors greatly overlap, and ramifications of misclassification are major.

Atypia of undetermined significance and ThyroSeq v3-positive call rates as quality control metrics for cytology laboratory performance.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated. METHODS: A retrospective analysis of all thyroid cytology cases in a 4.5-year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report. RESULTS: A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%-35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%-42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases. CONCLUSIONS: The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology.

Radical prostatectomy cancer grade and percentage of Gleason pattern 4 estimated by global vs individual tumor grading correlate differently with the risk of biochemical recurrence in Grade Group 2 and 3 cancers.

OBJECTIVES: There are 2 grading approaches to radical prostatectomy (RP) in multifocal cancer: Grade Group (GG) and percentage of Gleason pattern 4 (GP4%). We investigated whether RP GG and GP4% generated by global vs individual tumor grading correlate differently with biochemical recurrence. METHODS: We reviewed 531 RP specimens with GG2 or GG3 cancer. Each tumor was scored separately with assessment of tumor volume and GP4%. Global grade and GP4% were assigned by combining Gleason pattern 3 and 4 volumes for all tumors. Correlation of GG and GP4% generated by 2 methods with biochemical recurrence was assessed by Cox proportional hazard regression and receiver operating characteristic curves, with optimism adjustment using a bootstrap analysis. RESULTS: Median age was 63 (range, 42-79) years. Median prostate-specific antigen was 6.3 (range, 0.3-62.9) ng/mL. In total, the highest-grade tumor in 371 (36.9%) men was GG2 and in 160 (30.1%) men was GG3. Global grading was downgraded from GG3 to GG2 in 37 of 121 (30.6%) specimens with multifocal disease, and 145 of 404 (35.9%) specimens had GP4% decreased by at least 10%. Ninety-eight men experienced biochemical recurrence within a median of 13 (range, 3-119) months. Men without biochemical recurrence were followed up for a median of 47 (range, 12-205) months. Grade Group, GP4%, and margin status correlated with the risk of biochemical recurrence using highest-grade tumor and global grading, but the degrees of these correlations varied and were statistically significantly different between the 2 grading approaches. CONCLUSIONS: Grade Group, GP4%, and margin status derived by global vs individual tumor grading predict postoperative biochemical recurrence statistically significantly differently. This difference has important implications if results derived from cohorts graded using different methods are compared.

Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.

Prognostic implications of partial sampling of radical prostatectomy specimens: comparison of 3 methods.

PURPOSE: We analyzed the prognostic implications of positive margins and extraprostatic extension missed by different methods of partially sampling prostatectomy specimens. MATERIALS AND METHODS: The study group consisted of 1,499 patients treated with radical prostatectomy. All specimens were processed uniformly and submitted entirely. For each patient with a positive margin or extraprostatic extension we determined whether these pathological characteristics would have been diagnosed had the specimen been examined by 3 partial sampling techniques. The Harrell concordance index was used to quantify the predictive performance of the Cox models based on the potential findings of the different sampling methods. RESULTS: Partial sampling methods 1 and 2, which included the examination of alternate slides, missed 13% to 21% of positive margins and 27% to 46% of extraprostatic extensions. The effect on biochemical recurrence-free survival of these undetected pathological features was similar to that of positive margins and extraprostatic extension that would have been diagnosed by corresponding techniques. Method 3, which sampled the entire posterior region, the mid anterior prostate and the rest of the ipsilateral anterior gland (if sizeable tumor was seen), detected 95% of positive margins and 94% of extraprostatic extensions. The extraprostatic extension missed by this method was not associated with a significant increase in the risk of biochemical recurrence. The Harrell concordance index of the multivariate models was 0.806, 0.797, 0.795 and 0.804 based on the results of complete sampling, and methods 1, 2 and 3, respectively. CONCLUSIONS: Examining alternate sections of prostatectomy specimen results in missing clinically important positive margins and extraprostatic extension. It decreases our ability to predict biochemical recurrence-free survival.

Atherosclerosis within the non-neoplastic margin of partial nephrectomy specimens: implications for medical management.

PURPOSE: To describe the frequency and severity of atherosclerosis contained within the non-neoplastic tissue of partial nephrectomy (PN) specimens. METHODS: Archived open PN specimens were evaluated for histological evidence of atherosclerosis. Clinically significant atherosclerosis was defined as arterial luminal narrowing of >25% due to fibrointimal thickening. Histological findings were correlated with clinical data including history of major medical comorbidities and preoperative statin use. RESULTS: The study cohort was comprised of 114 patients (71 men and 43 women). The mean age at the time of surgery was 59.3 years, and 69 (60.5%) patients had a history of at least one major medical comorbidity including hypertension (54.5%), diabetes (16.7%) and coronary artery disease (12.3%). Clinically significant atherosclerosis was observed in 29 (25.4%) patients. These individuals were older (p = 0.001), and three times more likely to have greater than one major medical comorbidity (p = 0.002). In addition, only 17 (58.6%) were prescribed a statin at the time of surgery. CONCLUSIONS: Atherosclerosis is frequently observed in the non-neoplastic tissue of PN specimens. Patients found to have atherosclerosis can potentially benefit from intensive lifestyle modification and medical therapy with lipid-lowering medications. These measures would likely have the greatest clinical impact on those patients without an existing history of major medical comorbidities.

Pathologic evaluation of non-neoplastic renal parenchyma in partial nephrectomy specimens.

PURPOSE: This study aimed to identify non-neoplastic pathologic changes in partial nephrectomy specimens of patients without a known history of medical comorbidities. Routine analysis of this tissue may allow the clinician to identify subclinical renal disease. METHODS: We retrospectively reviewed our database of patients who underwent open partial nephrectomy for a small renal mass. Non-neoplastic tissue of partial nephrectomy specimens of patients without a known history of chronic kidney disease, diabetes mellitus, hypertension, or coronary artery disease was evaluated for glomerular, interstitial, and vascular pathologic changes. RESULTS: A rim of non-neoplastic tissue was adequate for pathologic evaluation in 91.8% of specimens. A total of 45 patients were studied with a median age of 52.0 years. Atherosclerosis was the most commonly identified pathologic finding in 9 (20%) patients, followed by mesangial expansion and interstitial fibrosis, each found in 8 (17.8%) patients. Linear regression found interstitial fibrosis to be the only pathologic lesion associated with preoperative serum creatinine (coefficient = 0.697, P = 0.001). Male gender was also associated with a higher preoperative creatinine (coefficient = 0.270, P = 0.034). Postoperative serum creatinine was not associated with any of the examined lesions. CONCLUSIONS: Current surgical techniques provide adequate non-neoplastic tissue for pathologic evaluation. We observed a striking degree of pathologic disease in patients without a known history of medical comorbidities. Routine inspection of the non-neoplastic parenchyma of partial nephrectomy specimens should be performed as it can alert the clinician to presence subclinical renal disease allowing for medical intervention.

p16INKa immunocytochemistry in fine-needle aspiration cytology smears of metastatic head and neck squamous cell carcinoma.

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) may initially present with neck metastases diagnosed by fine-needle aspiration (FNA). In these patients, it is critical to locate the primary site so that targeted therapy can be administered. Nearly a quarter of HNSCC are associated with human papillomavirus (HPV) infection. The great majority of HPV-related primaries originate in the oropharynx. p16INKa (p16) functions as a surrogate marker of HPV infection. We sought to determine if expression of p16 by immunocytochemistry (ICC) in neck metastases could assist in localizing the primary site to the oropharynx. STUDY DESIGN: Diagnostic FNA cytology smears of neck metastases from 90 patients with biopsy-proven primary HNSCC were reviewed. Papanicolaou-stained slides were directly subjected to ICC, using p16 antibody. RESULTS: Twenty-seven (30%) tumors expressed p16 by ICC; 74% of these p16-positive tumors were metastases from oropharynx. There was a significantly higher proportion of p16 expression in patients with primary oropharyngeal carcinoma (47%) versus those whose primary tumor was non-oropharyngeal (15%; p = 0.0013). CONCLUSIONS: p16 expression in FNA cytology smears of metastatic HNSCC is a useful indicator of oropharyngeal origin and can be used to help localize the primary site in cases where this is not clinically evident.

Adenocarcinomas of the Gynecologic Tract Involving the Urinary Bladder: A Series of 16 Cases Potentially Mimicking Urothelial Malignancy.

CONTEXT.­: There is limited literature describing gynecologic adenocarcinomas involving the urinary bladder, and potential diagnostic pitfalls. OBJECTIVE.­: To describe key features distinguishing metastatic (or extension of) gynecologic adenocarcinomas from urothelial carcinomas with glandular differentiation. DESIGN.­: Retrospective review of surgical pathology cases of gynecologic adenocarcinomas involving the bladder, from 2 different institutions, retrieved from surgical pathology archives, was performed. Morphologic features were recorded, along with immunohistochemistry results when available. Electronic medical records were reviewed for clinical and radiographic information. RESULTS.­: Sixteen cases of gynecologic adenocarcinomas (9 endometrial endometrioid adenocarcinomas, 4 endometrial serous carcinomas, 2 high-grade tubo-ovarian serous carcinomas, and 1 cervical adenosquamous carcinoma) involving the bladder were identified. All included cases had mucosal involvement potentially mimicking primary bladder neoplasms, including 4 cases originally diagnosed as urinary carcinomas. Tumors expressed keratin 7 (12 of 13; 92%), PAX8 (11 of 12; 92%), estrogen receptor (11 of 15; 73%), p16 (8 of 11; 73%), progesterone receptor (8 of 14; 57%), GATA3 (5 of 12; 42%), and p63 (3 of 11; 27%); all tumors were negative for keratin 20 (0 of 12). Features supportive of Müllerian origin included prior history of gynecologic malignancy, lack of morphologic heterogeneity in nonendometrioid tumors, and immunophenotypic coexpression of PAX8 and estrogen receptor with absent GATA3. Potential pitfalls seen in a subset of cases included misleading radiologic and cystoscopic findings, replacement of the overlying urothelial mucosa by tumor mimicking precursor lesions, focal GATA3 and/or p63 positivity, and areas of squamous differentiation in tumors of endometrioid histology. CONCLUSIONS.­: A combination of clinical history, certain morphologic features, and proper selection of immunohistochemical stains is key for the correct diagnosis of secondary gynecologic adenocarcinomas involving the urinary bladder.