NRF2 modulation in TRAMP mice: an in vivo model of prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers worldwide and oxidative stress is involved in its occurrence, development and progression. In fact, in transgenic adenocarcinoma of mouse prostate (TRAMP) mice, prostate cancer onset is associated with the methylation of the first five CpG in the nuclear factor erythroid 2-related factor 2 (NRF2) promoter, a key regulator of oxidative stress response, leading to its downregulation and accumulation of reactive oxygen species (ROS). It has been demonstrated that both natural and synthetic compounds can reactivate NRF2 expression inhibiting the methylation status of its promoter by downregulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Interestingly, NRF2 re-expression significantly reduced prostate cancer onset in TRAMP mice highlighting an important role of NRF2 in prostate tumorigenesis. METHODS AND RESULTS: We analysed the current literature regarding the role of natural and synthetic compounds in modulating NRF2 pathway in TRAMP mice, an in vivo model of prostate cancer, to give an overview on prostate carcinogenesis and its possible prevention. CONCLUSION: We can conclude that specific natural and synthetic compounds can downregulate DNMTs and/or HDACs inhibiting the methylation status of NRF2 promoter, then reactivating the expression of NRF2 protecting normal prostatic cells from ROS damage and tumorigenesis.

Predicting future cancer burden in the United States by artificial neural networks.

Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018-2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs.

AT-rich interactive domain 1A protein expression in normal and pathological pregnancies complicated by preeclampsia.

AT-rich interactive domain 1A (ARID1A, as known as BAF250a) is a subunit of human switch/sucrose nonfermentable chromatin remodeling complex with tumour suppressor function. Mutations of Arid1a have been reported in many human cancers and low expression of this protein has been correlated to a poor prognosis outcome in patients affected by some types of cancer. Although there are many studies regarding ARID1A functions in cancer, little is known about its role in regulating cell differentiation and normal tissues homeostasis. Here, we investigate ARID1A expression in normal placental tissues of first and third trimester of gestation and in pathological placental tissues of pregnancy complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) to evaluate a possible role of this protein in trophoblast differentiation. We found that ARID1A was specifically expressed in villous and extravillous cytotrophoblastic cells in normal placentas whereas syncytiotrophoblast was negative. Interestingly, ARID1A was expressed in both cytotrophoblastic cells and syncytiotrophoblast in placentas affected by PE and PE-IUGR. Moreover, ARID1A was also present in syncitial knots of pathological placentas. The present results indicate that ARID1A is a good marker of poor trophoblast differentiation in these pathologies, because the significant high positive staining in syncytiotrophoblast nuclei may suggest a poor differentiation of this trophoblast layer due to the cytotrophoblast cells fusion with the syncytiotrophoblast overlaying before arresting their cell cycle.

Update on histopathological evaluation of lymphadenectomy specimens from prostate cancer patients.

BACKGROUND: Metastases to lymph nodes (LNs) represent an unfavorable prognostic factor in patients with prostate cancer (PCa). Histological examination represents the gold standard in the evaluation of the lymphadenectomy (LND) specimens for the presence of secondary deposits. METHODS AND RESULTS: The metastatic detection rate can vary according to the approach adopted in the microscopic analysis of the LNs, which includes frozen-section examination, total inclusion of the tissue with and without whole-mount sections, serial sectioning, and the application of immunohistochemistry. The assessment of the sentinel LN, the search for micrometastases, and the evaluation of atypical LN metastatic sites further contribute to the detection of the metastatic spread. CONCLUSION: In this review, an update on the histopathological evaluation of LND specimens in patients with PCa is given, and focus is made on their clinical and prognostic significance.

Prostate changes related to therapy: with special reference to hormone therapy.

Hormone and radiation therapy have traditionally been used in prostate cancer (PCa). Morphological effects are often identified in needle biopsies and surgical specimens. A range of histological changes are seen in the non-neoplastic prostate and in the pre-neoplastic and neoplastic areas. Other ablative therapies, including cryotherapy, and emerging focal therapies, such as high-intensity focused ultrasound, photodynamic therapy and interstitial laser thermotherapy, may induce changes on the prostate. As new compounds are developed for prostate cancer treatment, it is important to document their effects on benign and neoplastic prostate tissue.

Pathological issues in biopsy specimens of men with prostate cancer eligible for active surveillance.

Active surveillance (AS) is an important management option for men with lowrisk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts become mature. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and accurately reported by pathologists. Repeated biopsy after initial diagnosis of prostate cancer is recommended before inclusion in active surveillance for early detection of significant cancer.

Diagnostic Biomarkers in Renal Cell Tumors According to the Latest WHO Classification: A Focus on Selected New Entities.

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments in the nomenclature for certain pathologies. Notably, each tumor entity now includes minimum essential and desirable criteria for reliable diagnosis. This classification highlights the importance of biological and molecular characterization alongside traditional cytological and architectural features. In this view, immunophenotyping through immunohistochemistry (IHC) plays a crucial role in bridging morphology and genetics. This article aims to present and discuss the role of key immunohistochemical markers that support the diagnosis of new entities recognized in the WHO classification, focusing on critical topics associated with single markers, in the context of specific tumors, such as the clear cell capillary renal cell tumor (CCPRCT), eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and so-called "other oncocytic tumors", namely the eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). Their distinctive characteristics and immunophenotypic profiles, along with insights regarding diagnostic challenges and the differential diagnosis of these tumors, are provided. This state-of-the-art review offers valuable insights in biomarkers associated with novel renal tumors, as well as a tool to implement diagnostic strategies in routine practice.

The Oncological and Functional Prognostic Value of Unconventional Histology of Prostate Cancer in Localized Disease Treated with Robotic Radical Prostatectomy: An International Multicenter 5-Year Cohort Study.

BACKGROUND AND OBJECTIVE: The impact of prostate cancer of unconventional histology (UH) on oncological and functional outcomes after robot-assisted radical prostatectomy (RARP) and adjuvant radiotherapy (aRT) receipt is unclear. We compared the impact of cribriform pattern (CP), ductal adenocarcinoma (DAC), and intraductal carcinoma (IDC) in comparison to pure adenocarcinoma (AC) on short- to mid-term oncological and functional results and receipt of aRT after RARP. METHODS: We retrospectively collected data for a large international cohort of men with localized prostate cancer treated with RARP between 2016 and 2020. The primary outcomes were biochemical recurrence (BCR)-free survival, erectile and continence function. aRT receipt was a secondary outcome. Kaplan-Meier survival and Cox regression analyses were performed. KEY FINDINGS AND LIMITATIONS: A total of 3935 patients were included. At median follow-up of 2.8 yr, the rates for BCR incidence (AC 10.7% vs IDC 17%; p < 0.001) and aRT receipt (AC 4.5% vs DAC 6.3% [p = 0.003] vs IDC 11.2% [p < 0.001]) were higher with UH. The 5-yr BCR-free survival rate was significantly poorer for UH groups, with hazard ratios of 1.67 (95% confidence interval [CI] 1.16-2.40; p = 0.005) for DAC, 5.22 (95% CI 3.41-8.01; p < 0.001) for IDC, and 3.45 (95% CI 2.29-5.20; p < 0.001) for CP in comparison to AC. Logistic regression analysis revealed that the presence of UH doubled the risk of new-onset erectile dysfunction at 1 yr, in comparison to AC (grade group 1-3), with hazard ratios of 2.13 (p < 0.001) for DAC, 2.14 (p < 0.001) for IDC, and 2.01 (p = 0.011) for CP. Moreover, CP, but not IDC or DAC, was associated with a significantly higher risk of incontinence (odds ratio 1.97; p < 0.001). The study is limited by the lack of central histopathological review and relatively short follow-up. CONCLUSIONS AND CLINICAL IMPLICATIONS: In a large cohort, UH presence was associated with worse short- to mid-term oncological outcomes after RARP. IDC independently predicted a higher rate of aRT receipt. At 1-yr follow-up after RP, patients with UH had three times higher risk of erectile dysfunction post RARP; CP was associated with a twofold higher incontinence rate. PATIENT SUMMARY: Among patients with prostate cancer who undergo robot-assisted surgery to remove the prostate, those with less common types of prostate cancer have worse results for cancer control, erection, and urinary continence and a higher probability of receiving additional radiotherapy after surgery.

HtrA1 in human urothelial bladder cancer: a secreted protein and a potential novel biomarker.

Our aim was to analyze the expression of the serine protease HtrA1 in human bladder tissue and urine in order to point out its possible association with the presence of urothelial bladder cancer. Bladder tissue and urine specimens from cancer patients with different tumor grades and stages (n = 68) and from individuals with cystitis (n = 16) were collected along with biopsy specimens and urine from healthy individuals (n = 68). For the first time, we demonstrated by immunohistochemistry that HtrA1 protein is produced by bladder urothelium in both physiological and inflammatory conditions, whereas it is not detectable in urothelial cancer cells regardless of tumor grade and stage. A different HtrA1 expression between normal-looking and neoplastic bladder tissue, despite similar HtrA1 mRNA levels, was also found by western blotting, which disclosed the presence of two forms of HtrA1, a native form of ∼50 kDa and an autocatalytic form of ∼38 kDa. Our investigations documented the presence of the two forms of HtrA1 also in urine. The ∼38 kDa form was significantly down-regulated in neoplastic tissue, whereas significantly higher amounts of both HtrA1 forms were found in urine from cancer patients compared with both healthy subjects and patients with cystitis. Our findings suggest that HtrA1 is a downexpressed molecule since an early stage of bladder urothelial carcinoma development and that urinary HtrA1 protein may be considered, if successfully validated, as an early and highly sensitive and specific biomarker for this neoplasia (the sensitivity and specificity of HtrA1 are 92.65% and 95.59%, respectively).

Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common malignancy in men worldwide. Prostate cancer can be treated by surgery, radiotherapy and hormone therapy. The latter, in the form of androgen-deprivation therapy is needed to reduce prostate cancer progression at an advanced stage. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development and progression and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway is affected by reactive oxygen species (ROS). Furthermore, the NRF2/KEAP1 signaling pathway has been investigated by several studies related to anti-androgen therapy, biochemical recurrence and radiotherapy. In this review we analysed the current literature regarding the indirect modulators involved in NRF2/KEAP1 pathway regulation and their role as possible therapeutic targets in prostate cancer cells.

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.

Diagnostic imaging of a rare case of incidental adrenal ganglioneuroma.

A 53-year-old man complaining of pain in the right hypochondrium underwent an abdominal ultrasound that showed a left adrenal lesion. Further instrumental investigations (CT and MRI, both with contrast medium) were performed which diagnosed an adrenal ganglioneuroma, confirmed by the histological examination. The patient also underwent an endocrinological examination. The treatment was surgical and consisted of an adrenalectomy through video-laparoscopic access. Adrenal ganglioneuromas are rare tumors but well described and known in the literature. For this reason, this case report has primarily an educational purpose: the totality of the data collected (clinical, laboratoristic, instrumental, and histopathological) constituted a multidisciplinary case, with the focus on imaging.

Histopathology of Prostate Cancer and its Precursors.

Starting in the mid-1970s, we formed a group of pathologists with a major interest in uropathology. Originally, it included 2 (R.M. and M.S.). In the years the followed, the group was enlarged to include 4 more people, 2 in the mid- and late-1980s (A.L.B. and L.C.) and another in the mid-1990s (R.Ma.); a sixth (A.C.) joined the group ∼5 years ago. Two have reached the retirement age (R.M. and M.S.), while others are in the process of joining the group to replace them. A fruitful collaboration spanned for ∼45 years. This contribution is based on a series of personal recollections of the successive changes in the interpretation of prostate cancer and its precursors, starting in the mid-1970s. Here we have retraced our involvement steps, sharing issues related to them with a junior uropathologist (A.C.).

Clinical progression of megacalycosis in a girl with a solitary kidney: The lesson learned.

Introduction: Megacalycosis is a rare disorder related to congenital underdevelopment of the renal papilla or structural defect of the renal calyces. Megacalycosis has a wide spectrum of clinical presentations ranging from simple variants without any significance on renal function to severe complications. Any prevention strategy is recommended yet since megacalycosis is mostly asymptomatic and usually discovered either accidentally or as result of its complications. Case presentation: We observed megacalycosis progression in a young female with a single kidney toward progressive calyx dilatation for years, which ended in acute pyelonephritis. Conservative management, urinary drainage, and large-spectrum antibiotics were unsuccessful and nephrectomy was required. Conclusion: This rare case and literature review add evidence to identify prognostic factors to select patients with a high risk of complications (single kidney, bilateral disease, female gender, associated genetic syndromes, vesicoureteral reflux, and contralateral renal disorder). One o more factors should activate close monitoring and prophylactic therapy if needed.

Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy.

BACKGROUND: The prostate may often harbor a prostate cancer (PC) which will not cause morbidity if left untreated. Screening for PC leads to increased detection of these insignificant cancers. Objective of this study is to compare PC detected by PSA screening at subsequent screening rounds and treated by radical prostatectomy (RP) with PC incidentally found in cystoprostatectomy specimens. METHODS: Radical prostatectomy specimens of 617 screen-detected PC were compared with 123 PC identified in cystoprostatectomy specimens. Surgical specimens were systematically examined and stage, grade, tumor volume were recorded. Next, we classified PC as clinically significant or insignificant (i.e., tumor volume <0.5 cm(3), absence of Gleason pattern 4/5, organ confined). Pathological features of incidentally detected PC were compared with PC detected in subsequent screening rounds and with screen-detected T1c PC. RESULTS: Screen-detected PC overall were more often multifocal, larger in volume, more advanced in tumor stage and of higher grade, while the frequency of insignificant PC was lower as compared to those in cystoprostatectomy specimens. This effect became more pronounced during subsequent screening rounds. Screen-detected T1c PC were also more often multifocal (73% vs. 37%) in average fivefold larger (0.85 cm(3) vs. 0.16 cm(3)), less often organ confined (81% vs. 94%), and less frequently clinically insignificant (33% vs. 81%). CONCLUSIONS: Screen-detected (T1c) PC treated with RP shows more aggressive features than incidentally found PC. This PSA screening-related selection seems to be mainly driven by tumor volume and-in later screening rounds-by the preferential treatment by prostatectomy of more aggressive PC.

The spectrum of morphology in non-neoplastic prostate including cancer mimics.

The spectrum of morphology in non-neoplastic prostate includes lesions of prostatic epithelial origin, the most common being atrophy, including partial atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia and crowded benign glands, as well as those of non-prostatic origin, such as seminal vesicle epithelium. These lesions often mimic lower-grade prostatic adenocarcinoma whereas others, such as granulomatous prostatitis, for example, are in the differential diagnosis of adenocarcinoma, Gleason grades 4 or 5. Diagnostic awareness of the salient histomorphological and relevant immunohistochemical features of these prostatic pseudoneoplasms is critical to avoid rendering false positive diagnoses of malignancy.

Pathology of Urologic Cancers.

We are pleased to present this Special Issue of Cancers, entitled "Pathology of Urologic Cancers" [...].

Lumbar malignant peripheral nerve sheath tumor: a rare case in a young patient.

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma that originate from peripheral nerves or from cells associated with the nerve sheath. We report the case of a 30­year­old male patient with a history of neurofibromatosis type I (NF-1) and a MPNST located in the lumbar region. The mass was resecated but surgical margins weren't clear. Recurrence of disease was observed after few months. A close monitoring of subjects with NF-1 is crucial to diagnose MPNST at an earlier stage and allow a complete surgical resection.

Identification of BRAF V600E mutation in odontogenic tumors by high-performance MALDI-TOF analysis.

Odontogenic tumors are rare lesions with unknown etiopathogenesis. Most of them are benign, but local aggressiveness, infiltrative potential, and high recurrence rate characterize some entities. The MAP-kinase pathway activation can represent a primary critical event in odontogenic tumorigenesis. Especially, the BRAF V600E mutation has been involved in 80-90% of ameloblastic lesions, offering a biological rationale for developing new targeted therapies. The study aims to evaluate the BRAF V600E mutation in odontogenic lesions, comparing three different detection methods and focusing on the Sequenom MassARRAY System. 81 surgical samples of odontogenic lesions were subjected to immunohistochemical analysis, Sanger Sequencing, and Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometry (Sequenom). The BRAF V600E mutation was revealed only in ameloblastoma samples. Moreover, the presence of BRAF V600E was significantly associated with the mandibular site (ρ = 0.627; P value <0.001) and the unicystic histotype (ρ = 0.299, P value <0.001). However, any significant difference of 10-years disease-free survival time was not revealed. Finally, Sequenom showed to be a 100% sensitive and 98.1% specific, suggesting its high-performance diagnostic accuracy. These results suggest the MAP-kinase pathway could contribute to ameloblastic tumorigenesis. Moreover, they could indicate the anatomical specificity of the driving mutations of mandibular ameloblastomas, providing a biological rational for developing new targeted therapies. Finally, the high diagnostic accuracy of Sequenom was confirmed.