Faculty Bibliography

We present single-shot high-performance quantitative phase imaging with a physics-inspired plug-and-play denoiser for polarization differential interference contrast (PDIC) microscopy. The quantitative phase is recovered by the alternating direction method of multipliers (ADMM), balancing total variance regularization and a pre-trained dense residual U-net (DRUNet) denoiser. The custom DRUNet uses the Tanh activation function to guarantee the symmetry requirement for phase retrieval. In addition, we introduce an adaptive strategy accelerating convergence and explicitly incorporating measurement noise. After validating this deep denoiser-enhanced PDIC microscopy on simulated data and phantom experiments, we demonstrated high-performance phase imaging of histological tissue sections. The phase retrieval by the denoiser-enhanced PDIC microscopy achieves significantly higher quality and accuracy than the solution based on Fourier transforms or the iterative solution with total variance regularization alone.

INTRODUCTION/BACKGROUND:Delay between targeted prostate biopsy (PB) and pathologic diagnosis can lead to a concern of inadequate sampling and repeated biopsy. Stimulated Raman histology (SRH) is a novel microscopic technique allowing real-time, label-free, high-resolution microscopic images of unprocessed, unsectioned tissue. This technology holds potential to decrease the time for PB diagnosis from days to minutes. We evaluated the concordance of pathologist interpretation of PB SRH as compared with traditional hematoxylin and eosin (H&E) stained slides. METHODS:, to create SRH images. The cores were then processed as per normal pathologic protocols. Sixteen PB containing a mix of benign and malignant histology were used as an SRH training cohort for four genitourinary pathologists, who were then tested on a set of 32 PBs imaged by SRH and processed by traditional H&E. Sensitivity, specificity, accuracy, and concordance for prostate cancer (PCa) detection on SRH relative to H&E were assessed. RESULTS:The mean pathologist accuracy for the identification of any PCa on PB SRH was 95.7%. In identifying any PCa or ISUP grade group 2-5 PCa, a pathologist was independently able to achieve good and very good concordance (κ: 0.769 and 0.845, respectively; p < 0.001). After individual assessment was completed a pathology consensus conference was held for the interpretation of the PB SRH; after the consensus conference the pathologists' concordance in identifying any PCa was also very good (κ: 0.925, p < 0.001; sensitivity 95.6%; specificity 100%). CONCLUSION/CONCLUSIONS:SRH produces high-quality microscopic images that allow for accurate identification of PCa in real-time without need for sectioning or tissue processing. The pathologist performance improved through progressive training, showing that ultimately high accuracy can be obtained. Ongoing SRH evaluation in the diagnostic and treatment setting hold promise to reduce time to tissue diagnosis, while interpretation by convolutional neural network may further improve diagnostic characteristics and broaden use.

OBJECTIVES/OBJECTIVE:To determine the prognostic significance of the maximum allowable percentage of Gleason pattern 4 (GP4) at prostate biopsy compared with adverse pathology observed at radical prostatectomy (RP) to expand active surveillance eligibility among a cohort with intermediate risk of prostate cancer. METHODS:A retrospective study of patients with grade group (GG) 1 or 2 prostate cancer on prostate biopsy with subsequent RP was performed at our institution. A Fisher exact test was used to understand the relationship among GP4 subgroups (0%, ≤5%, 6%-10%, and 11%-49%) assigned at biopsy and adverse pathologic findings at RP. Additional analyses comparing the GP4 ≤5% cohort's prebiopsy prostate-specific antigen (PSA) level and GP4 length with adverse pathology at RP were also performed. RESULTS:No statistically significant difference in adverse pathology at RP was observed between the active surveillance-eligible control (GP4 0%) and the GP4 ≤5% subgroup. In total, 68.9% of the GP4 ≤5% cohort showed favorable pathologic outcomes. A separate analysis of the GP4 ≤5% subgroup revealed that neither prebiopsy serum PSA levels nor GP4 length showed statistical correlation with adverse pathology at RP. CONCLUSIONS:Active surveillance may be a reasonable option for management of patients in the GP4 ≤5% group until long-term follow-up data become available.

BACKGROUND:For the representative problem of prostate cancer grading, we sought to simultaneously model both the continuous nature of the case spectrum and the decision thresholds of individual pathologists, allowing quantitative comparison of how they handle cases at the borderline between diagnostic categories. METHODS:Experts and pathology residents each rated a standardized set of prostate cancer histopathological images on the International Society of Urological Pathologists (ISUP) scale used in clinical practice. They diagnosed 50 histologic cases with a range of malignancy, including intermediate cases in which clear distinction was difficult. We report a statistical model showing the degree to which each individual participant can separate the cases along the latent decision spectrum. RESULTS:The slides were rated by 36 physicians in total: 23 ISUP pathologists and 13 residents. As anticipated, the cases showed a full continuous range of diagnostic severity. Cases ranged along a logit scale consistent with the consensus rating (Consensus ISUP 1: mean -0.93 [95% confidence interval {CI} -1.10 to -0.78], ISUP 2: -0.19 logits [-0.27 to -0.12]; ISUP 3: 0.56 logits [0.06-1.06]; ISUP 4 1.24 logits [1.10-1.38]; ISUP 5: 1.92 [1.80-2.04]). The best raters were able to meaningfully discriminate between all 5 ISUP categories, showing intercategory thresholds that were quantifiably precise and meaningful. CONCLUSIONS:We present a method that allows simultaneous quantification of both the confusability of a particular case and the skill with which raters can distinguish the cases. IMPLICATIONS/CONCLUSIONS:The technique generalizes beyond the current example to other clinical situations in which a diagnostician must impose an ordinal rating on a biological spectrum. HIGHLIGHTS/CONCLUSIONS:

BACKGROUND:Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS:Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS:T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.

BACKGROUND:Magnetic resonance imaging (MRI)-targeted prostate biopsy has become an increasingly common method of diagnosing prostate cancer. A previous study from our institution demonstrated that the biopsy global Grade Group (gGG, aggregate GG of all positive cores) and highest Grade Group (hGG in any core) both show substantial concordance with the Grade Group at radical prostatectomy (RPGG) while the discordance predominantly consists of upgrading in gGG and downgrading in hGG. We performed a larger cohort study focused on biopsy cases in which gGG and hGG differ, to determine their relative concordance with RPGG. METHODS:We conducted a retrospective review of radical prostatectomy specimens with prior MRI-targeted biopsies from our institution between 2016 and 2020. Separate gGG and hGG were assigned to each MRI-targeted lesion. Targeted lesions with different gGG versus hGG were segregated from those with identical gGG and hGG. The concordance of biopsy GG with RPGG was evaluated using κ coefficient analysis. RESULTS:Of the 489 lesions with MRI-targeted biopsies, 82 (17%) differed in gGG versus hGG. The gGG of 46 (56%), 33 (40%), and 3 (4%) lesions were unchanged, upgraded, and downgraded at radical prostatectomy, respectively (κ= 0.302, weighted κ = 0.334). The hGG of 24 (29%), 9 (11%), and 49 (60%) lesions were unchanged, upgraded, and downgraded at radical prostatectomy, respectively (κ = 0.040, weighted κ = 0.198). When stratified by the biopsy GG, gGG showed the highest concordance in GG2 (61%) and GG3 (54%) lesions. The hGG resulted in substantial downgrading (60%) with less optimal concordance regardless of the biopsy GG. Neither the prebiopsy prostate specific antigen level nor the PI-RADS score was predictive of upgrading of gGG. CONCLUSIONS:When gGG and hGG differ, gGG method more accurately predicts the RPGG than hGG, particularly in GG2 and GG3 lesions which comprised the majority of targeted lesions.

Myoepithelial carcinoma (MEC) of soft tissue, also known as malignant myoepithelial tumor, is an uncommon malignancy. Cytologic diagnosis of this entity is challenging due to its rarity and heterogeneous morphology. We report a case of MEC in a 22-year-old man, who presented with a 6.5 cm soft tissue mass on his right distal forearm that has been enlarging over the past 3 months. Ultrasound-guided fine-needle aspiration (FNA) revealed abundant isolated neoplastic cells ranging from spindled cells to epithelioid and plasmacytoid morphology in a myxoid background. These cells showed moderate cytologic atypia characterized by high-nuclear/cytoplasmic ratio, irregular nuclear contours, and prominent nucleoli. The cytoplasm varied from dense to vacuolated and occasionally rhabdoid with intracytoplasmic inclusions. Scattered bi- and multinucleated cells were identified. A diagnosis of high-grade malignancy was made with the differential diagnosis including rhabdomyosarcoma and melanoma. A subsequent core biopsy of the tumor showed immunoreactivity for pan-cytokeratins, calponin, p63, and smooth muscle actin. INI-1 was lost. SOX-10 and Melan-A were negative. Molecular studies showed loss of SMARCB1 (INI-1) and CDKN2A. Gene fusion studies did not detect any fusion. A diagnosis of soft tissue MEC was made which is a challenge on FNA due to several cytologic mimickers including rhabdomyosarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, extra-axial chordoma and melanoma. Recognition of the biphasic cell population in a myxoid background and a battery of immunohistochemical stains are crucial for accurate diagnosis.

BACKGROUND:Prostate cancer (PCa) is the most common malignant tumor found among men in the United States. Incidence rates of PCa have recently grown in Asian countries, partially due to the comprehensive implementation of early detection systems. Interestingly, a prospective cohort study showed that adopting a westernized dietary pattern was associated with a higher risk of being diagnosed with PCa among Korean and Japanese men. However, a comparison of current clinicopathological features of PCa between American and Chinese men is lacking. In this study, we report the current clinicopathological features of PCa in Chinese men and compare them to those of patients in the USA. MATERIALS AND METHODS/METHODS:Case cohorts included, in total, 871 PCa cases with prostatectomy sequentially treated since 2017, including 299 cases from USA and 572 cases from two different academic hospitals in China. The parameters, including patient's age, preoperative Prostate-Specific Antigen (PSA) level, Gleason score, Grade Group, stage and tumor focality, were collected, analyzed and compared using two sample t-test, Wilcoxon rank sum test, Pearson's Chi-squared test and Fisher's exact test. RESULTS:Significant differences were demonstrated in the mean age of patients, preoperative PSA levels, extra-prostatic extension, Gleason scores, and Grade Groups (p < 0.05). PCa patients in the Chinese group were older than patients in the USA group (67.81 vs. 63.53, p < 0.01). The preoperative PSA levels in the Chinese group were higher than those in the USA group (11.69 v.s 6.30, p < 0.01). A higher percentage of high Grade Groups (Groups 4 and 5) was observed in the Chinese group (25.7%) compared to the USA cohort (17.11%), while Grade Group 2 was more common in the USA group than in the Chinese group (51.68% vs. 32.52%, p < 0.01). CONCLUSIONS:All these data suggest that the clinicopathologic features of PCa are different between the USA and Chinese populations, which may be influenced by treatment strategies (including surgical case selection criteria).

Background: Magnetic resonance imaging (MRI) targeted prostate biopsy has become an increasingly common method of diagnosing prostate cancer. Previous study from our institution demonstrates the biopsy global Gleason grade (gGG) and highest Gleason grade (hGG) show substantial concordance with the radical prostatectomy Gleason grade (RPGG) while the discordance predominantly comprise of upgrading in gGG and downgrading in hGG. We performed a larger cohort focused analysis on the agreement of gGG and hGG to the RPGG when they differ.
Design(s): A retrospective review of radical prostatectomy specimens between 10/2016 and 12/2020 from our institution with prior MRI-targeted biopsies was conducted. A gGG (aggregate GG of all positive cores) and a hGG (highest GG in any core) was assigned to each MRI-targeted lesion. Only cases with different gGG versus hGG were selected for further analysis. The concordance of gGG and hGG with RPGG was evaluated using kappa coefficient analyses. The power of pre-biopsy PSA and PIRADS scores to predict upgrading based on gGG was also analyzed.
Result(s): Of the 489 radical prostatectomy specimens with prior MRI-targeted biopsies, 82 cases (17%) differed in gGG versus hGG. Using the gGG, 33 cases (40%), 46 cases (56%), and 3 cases (4%) were upgraded, unchanged, and downgraded at radical prostatectomy, respectively (Kappa = 0.302, weighted Kappa = 0.334). Based on the hGG, 9 cases (11%), 24 cases (29%), and 49 cases (60%) were upgraded, unchanged, and downgraded at radical prostatectomy, respectively (Kappa = 0.040, weighted Kappa = 0.198) (Figure 1). When stratified by RPGG, gGG shows the best concordance in RPGG2 and RPGG3 lesions. The hGG resulted in substantial downgrading at RPGG4 or less and upgrading at RPGG5 (Figure 2). No significant difference in the mean PSA [H(2) = 5.89, p = 0.053] or PI-RADS score [H(2) = 4.48, p = 0.107] was found among the cases upgraded, unchanged, and downgraded based on the gGG. Neither the pre-biopsy PSA (OR = 1.92, 95% CI = 0.65-5.64, p = 0.117) nor the PI-RADS score (OR = 0.899, 95% CI = 0.31-2.607, p = 0.423) was predictive of upgrading based on gGG.
Conclusion(s): When the gGG and hGG differ, the gGG correlates better with the RPGG than the hGG in the majority of cases for RPGG2 and RPGG3 lesions (46 cases, 74%). It results in upgrading in high grade lesions (GG4 and GG5) with potentially minimal impact on clinical management. Further studies are needed to substantiate a standard GG reporting method for MRI-targeted prostate biopsies