Jasreman Dhillon

Thyroid-like follicular carcinoma of the kidney with metastases to the lungs and retroperitoneal lymph nodes

Thyroid-like follicular carcinoma of the kidney is an extremely rare variant of renal cell carcinoma. Most previously reported cases presented as incidental small tumors confined to the kidney. Here we report a unique case in which the patient presented with flank pain and hematuria. Imaging studies demonstrated a large tumor in the right kidney and metastases to the lungs and retroperitoneal lymph nodes. Both the renal tumor and the sampled lung metastasis were composed almost entirely of follicles with dense, colloid-like material resembling thyroid follicular carcinoma. However, no lesion was found in the thyroid gland; and the patients thyroid function test results were normal. The tumor cells were immunoreactive for PAX2 and PAX8 but lacked reactivity for thyroglobulin and thyroid transcription factor-1. To our knowledge, this is the first case of thyroid-like follicular carcinoma of the kidney to be initially associated with marked symptoms and widespread metastases, providing evidence that this rare variant of renal cell carcinoma can be clinically aggressive.

Integrative Molecular Profiling Reveals Asparagine Synthetase Is a Target in Castration-Resistant Prostate Cancer

The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy-resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen-responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells.

Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin As a Therapeutic Target in Castration-Resistant Prostate Cancer

The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason–grade hormone-sensitive prostate cancer (P<0.0001). Expression profiling of chemotherapy-resistant CRPC samples (n = 25) was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n = 10) and hormone-sensitive prostate cancer cases (n = 108). Our results showed enrichment of mitosis-phase genes and pathways, with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. We found concordant gene expression of MCAK between our parent and murine CRPC xenograft pairs and increased MCAK protein expression with clinical progression of prostate cancer to a castration-resistant disease stage. Knockdown of MCAK arrested the growth of prostate cancer cells suggesting its utility as a potential therapeutic target.

Quantification of sarcomatoid differentiation in renal cell carcinoma on magnetic resonance imaging

Background Sarcomatoid differentiation in renal cell carcinoma (sRCC) is histologically characterized by anaplastic changes of renal cell carcinoma (RCC) subtypes, which has been associated with a poor prognosis. sRCC is managed more aggressively than RCC without sarcomatoid components, so pre-operative detection of sarcomatoid differentiation would significantly affect surgical management. The purpose of this study is to compare the quantification of sarcomatoid features in RCCs on pre-operative magnetic resonance imaging (MRI) to standard histological examination. Methods Patients who had nephrectomy at our institution between 2000 and 2015 with pathology proven RCC and pre-operative contrast enhanced MRI abdominal scans were retrospectively reviewed. A custom MATLAB routine calculated the portion of each manually segmented whole tumor with MRI signal suggestive of sarcomatoid involvement based on prior research (MRI%SARC). The primary endpoint compared MRI%SARC to percent sarcomatoid involvement estimated by histological examination (HIST%SARC) using Pearson correlation and Bland Altman analysis. Results A total of 17 patients with sRCC (10 males, age 60.3±11.1 years) and 17 consecutive control patients with clear cell RCC (ccRCC) without sarcomatoid components (10 males, age 64.5±7.6 years) were evaluated. Pearson correlation analysis revealed a strong association between MRI%SARC and HIST%SARC (r=0.782, P<0.001). Bland-Altman analysis demonstrated proportional bias, with a mean bias of 19.29 [95% confidence interval (CI): 9.79-28.79] and with 95% limits of agreement of -16.93 (95% CI: -33.38 to -0.48) to 55.51 (95% CI: 39.06-71.96), suggesting MRI%SARC underestimated values compared to HIST%SARC by 19%. Conclusions Multiparametric pre-operative MRI analysis to quantify sarcomatoid features in RCC correlates with standard histological examination but underestimates percent sarcomatoid involvement.

Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma

The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ≥1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan–Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.

Impact of PI3K-AKT-mTOR Signaling Pathway Up-regulation on Prognosis of Penile Squamous-Cell Carcinoma: Results From a Tissue Microarray Study and Review of the Literature

Purpose To assess the prognostic value of PI3K‐AKT‐mTOR signaling pathway up‐regulation in a contemporary cohort of penile squamous‐cell carcinoma (PSCC) patients. Patients and Methods Tissue microarrays were constructed for 57 patients with invasive PSCC treated at our institution between 2000 and 2013. Immunohistochemical staining was performed for PTEN, AKT, and S6. Human papillomavirus (HPV) in‐situ hybridization for high‐risk subtypes was also performed. Biomarker expression was evaluated by a semiquantitative H score. Overall survival, disease‐specific survival and recurrence‐free survival stratified by biomarker expression (low vs. high) were estimated by the Kaplan‐Meier method. Multivariable Cox regression models were used to determine predictors of mortality and recurrence. Results HPV in‐situ hybridization was positive in 23 patients (40%). PTEN was down‐regulated in 43 patients (75%), while phosphorylated‐AKT (p‐AKT) and phosphorylated‐S6 (p‐S6) were up‐regulated in 27 (47%) and 12 patients (21%), respectively. In multivariable Cox regression models, patients with low expression of p‐AKT had an increased risk of recurrence (hazard ratio [HR] = 3.95; 95% confidence interval [CI], 1.47‐10.59; P = .02), while those with low expression of p‐S6 had an increased risk of overall mortality (HR = 6.15; 95% CI, 1.55‐24.36; P = .01). HPV status was an independent predictor of overall survival (HR = 6.99; 95% CI, 2.42‐20.16; P < .001) and disease‐specific survival (HR = 6.74; 95% CI, 2.02‐22.48; P = .002). Conclusion PI3K‐AKT‐mTOR signaling pathway up‐regulation and HPV coinfection in PSCC are associated with favorable disease. mTOR pathway biomarkers along with HPV status may represent novel prognosticators for risk stratification of PSCC patients and may help guide treatment decisions and follow‐up strategies. These findings require further investigation. Micro‐Abstract PI3K‐AKT‐mTOR signaling pathway dysregulation has been linked to the development of various malignancies, with only limited and conflicting reports in penile squamous‐cell carcinoma (PSCC). Tissue microarrays of 57 cases of invasive PSCC were immunohistochemically stained for 3 proteins of the mTOR pathway: PTEN, AKT, and S6. Up‐regulation of PI3K‐AKT‐mTOR and human papillomavirus coinfection in PSCC were associated with favorable disease.

Understanding the Pathophysiology of Penile Cancer and Its Preneoplastic Lesions

Squamous cell carcinoma of the penis is a rare malignancy that can develop anywhere on the penis. The epidemiology, risk factors, and pathophysiology of penile carcinoma are described here. Human papillomavirus has been proven to play a pivotal role in a significant subset of cases and is discussed in detail. Penile intraepithelial neoplasia refers to the penile preneoplastic lesions. These lesions demonstrate variable risk to progression to invasive cancer and are reviewed in completeness.

Rare urologic tumors

Purpose of review Management of genitourinary malignancy is likely to encompass a large portion of most of the urologists practice. The challenge for the modern urologist is not only in understanding the management of commonly seen genitourinary malignancies, but also in recognizing unusual variants and their differences in management. This is evermore important as new technologies have refined the ability to identify rare entities. This review presents a brief overview of the various genitourinary malignancy subtypes seen within urology. Recent findings All major organ subtypes are highlighted along with an overview of the current understanding of their associated malignancies. An update on the current state management paradigms as well as future directions is also outlined. Summary After reading this review, the urologist should have a deeper understanding of the breadth of disorders in genitourinary oncology and a clearer approach to the management of these problems. Additionally, ongoing avenues for research are highlighted.