The origin of intraductal carcinoma of the prostate (IDC-P) in presence of prostate adenocarcinoma (PCa) is a matter of debate. This study evaluates trophoblast cell-surface antigen 2 (Trop-2) expression in prostatic high-grade intraepithelial neoplasia (HGPIN), IDC-P and PCa to explain the possible mechanism for IDC-P arising. Trop-2 was localized in the luminal epithelium of normal prostate gland, HGPIN and IDC-P. The quantitative analysis of immunohistochemistry showed no difference of Trop-2 expression between HGPIN and IDC-P, while statistically significant differences were observed comparing the two pathologies with normal tissues. Contrarily, Trop-2 was expressed in 2.5% of the basal cells in normal prostate gland and in 1% of HGPIN while Trop-2 was expressed in 8% of cells in IDC-P samples. We suggest that Trop-2 present in the basal cells may acquire neoplastic changes. The neoplastic cells could grow into the glandular lumen as HGPIN and/or spread into the duct as IDC-P or spread into the stroma as PCa. In conclusion, our data in part support the theory of intraductal carcinoma origin through retrograde glandular colonization.

The recent introduction of “molecularly defined renal cell carcinomas” in the World Health Organization classification has significantly expanded the diagnostic spectrum of renal neoplasia, highlighting entities characterized by specific genetic alterations with potential clinical and therapeutic relevance. However, the recognition of these tumors in routine practice remains challenging due to overlapping morphological features and variable access to molecular testing. In this context, immunohistochemistry (IHC) has emerged as a practical and widely available tool that can act as a surrogate for underlying molecular alterations. Depending on the biological context, IHC may reflect genetic events either through protein overexpression, as in fusion-driven tumors, or through loss of expression associated with gene inactivation in metabolically or chromatin remodeling-deficient neoplasms. Accordingly, IHC plays a central role as a screening and triage method within the diagnostic workflow of these entities. Overall, IHC remains an indispensable component in the evaluation of molecularly defined renal cell carcinomas, but its optimal use requires integration with morphological assessment and, in most cases, confirmatory molecular testing. The aim of this review is to provide a comprehensive and evidence-based overview of the main immunohistochemical surrogates used in molecularly defined renal cell carcinomas, including TFE3-, TFEB-, and ALK-rearranged tumors, as well as SDH-, FH-, and SMARCB1-deficient neoplasms, highlighting their diagnostic applications, strengths, pitfalls, and role within an integrated diagnostic workflow. For each marker, the biological rationale, expected staining patterns, diagnostic applications, and major pitfalls are discussed, with particular emphasis on variability across studies and technical limitations.

BRCA1/2 alterations have emerged as clinically relevant biomarkers in prostate cancer because of their prognostic significance and predictive value for response to poly(ADP-ribose) polymerase inhibitors. As indications for molecular testing expand, histopathologists play a pivotal role in ensuring the quality and reliability of somatic BRCA testing. This narrative review provides a histopathologist-oriented overview of the principal pre-analytical, technical, and morphological issues influencing BRCA testing in PC, with emphasis on tissue selection, specimen processing, nucleic acid preservation, and genotype–phenotype correlations. The success of somatic BRCA testing depends on several pre-analytical variables, including fixation, storage time, tumor cellularity (generally ≥10–20% neoplastic cells for reliable NGS analysis), specimen type, and DNA quality. Bone metastasis specimens require special attention because decalcification procedures may compromise nucleic acid integrity and molecular testing performance. From a morphological perspective, BRCA-associated PCs, especially those harboring BRCA2 alterations, are characterized by adverse clinicopathological features, including a higher grade and stage at diagnosis. Although intraductal carcinoma of the prostate and cribriform architecture are associated with genomic instability and poor prognosis, their value as surrogate markers of BRCA1/2 alterations remains uncertain. Histopathologists play a central role in optimizing BRCA testing through appropriate specimen selection, tissue handling, and multidisciplinary collaboration, thereby supporting precision medicine in prostate cancer.

Non-muscle invasive bladder cancer (NMIBC) accounts for the majority of bladder cancer diagnoses and remains a clinical challenge due to its high recurrence and progression rates despite intravesical Bacillus Calmette–Guérin (BCG) therapy. In recent years, tumor-infiltrating lymphocytes (TILs) have emerged as promising biomarkers, reflecting the interplay between the tumor and host immune system. However, the evidence regarding their prognostic and predictive role is still conflicting, largely due to methodological heterogeneity, lack of standardized evaluation criteria, and limited prospective validation. This narrative review summarizes the current knowledge on TILs in NMIBC, focusing on their compartmental distribution (stromal, intraepithelial, and tumor–stroma interface), compositional diversity (CD4+, CD8+, Treg, B cells), and spatial dynamics. Special attention is given to their role in predicting response to BCG immunotherapy, the contribution of tumor-associated macrophages and tertiary lymphoid structures, and the emergence of immune escape pathways, including Programmed Death-Ligand 1 (PD-L1) and the HLA-E/NKG2A axis. Advances in digital pathology, spatial transcriptomics, and integrated immunoscore models provide more accurate metrics compared to simple cell counts, highlighting the importance of functional and spatial signatures. Despite encouraging progress, TILs are not yet ready for routine incorporation into histopathological reporting. Future directions include standardized assessment, integration with molecular biomarkers, and prospective multicenter validation to enable their translation into risk stratification and personalized therapeutic decision-making.

An accurate histopathological evaluation of radical cystectomy (RC) specimens is crucial for optimal tumor staging, prognosis, and therapeutic decision making. The increasing demand for precision medicine and multidisciplinary oncological management emphasizes the necessity for standardized protocols in the handling and sampling of bladder cancer specimens. The effective processing of RC specimens begins with the integration of clinical and anamnestic data, along with appropriate formalin fixation methods to meet diagnostic needs. The pathologist must meticulously document the macroscopic characteristics and dimensions of the surgical specimen, especially in post-neoadjuvant chemotherapy (post-NAC) cases where the primary tumor may not be macroscopically visible. Sampling strategies should ensure a comprehensive assessment of the primary tumor and any extra-organ or metastatic involvement. Despite international guidelines, variability in pathology practices persists, particularly concerning prostate sampling in RC and the use of frozen sections for margin assessment. Addressing these challenges necessitates a consensus-driven, standardized approach to improve the reproducibility and quality of histopathological data. By addressing gaps in current pathology practices, this review advocates for uniform protocols that enhance diagnostic accuracy, ultimately improving patient care and clinical decision making.

Introduction:Primary hyperoxaluria type 1 (PH1) is an inherited disease due to deficient activity of the liver enzyme AGT due to a mutation of the AGXT gene, leading to impairment in the glyoxylate metabolism with excessive oxalate urinary excretion (uOx) causing nephrolithiasis, renal failure, and systemic oxalosis. The historical treatment for renal failure was combined liver-kidney transplantation (CLKT) to restore normal function of AGT enzyme, but in mutations fully responsive to pyridoxine, an isolated kidney transplant (IKT) is feasible. Recently, RNA-interference (RNAi) agents such as lumasiran that reduce the oxalate synthesis in PH1 patients open new therapeutic challenges such as IKT irrespective of the type of AGXT gene mutation. Nevertheless, to decide for IKT instead of CLKT, clinicians must be aware of lumasiran efficacy. At present, the biomarker used to evaluate the lumasiran efficacy is the plasma oxalate (pOx). However, in dialyzed patients, pOx might be influenced by the release of oxalate from the deposits to the blood. Case Presentation:We report the case of a PH1 36-year-old male patient who underwent IKT combined with lumasiran. Two years after transplantation, graft function is good without lithiasis or nephrocalcinosis. 24-h uOx varies from 0.55 to 1.2 mmol/day and pOx remains stable at 12 μmol/L. Allograft biopsies at 1, 6, 12, and 22 months show negligible oxalate crystals deposits. Conclusion:The novelty of our case lies in the methods we adopted to evaluate the lumasiran efficacy during dialysis prior listing for IKT. Specifically, we decided to list the patient for IKT according to the high plasma levels of glycolate reached after lumasiran treatment together with the significant reduction of the pOx.

Prostate cancer (PCa) is the second most frequent cancer type in the male population over 66 years. Curcumin is a polyphenolic natural compound extract from the rhizomes of Curcuma longa Linn (Zingiberaceae family) which showed important anticancer effects by inhibiting cell proliferation and inducing apoptosis in several cancer types. Recently, some studies reported that oral curcumin lowered PSA levels, but it did not modify the clinical outcomes in patients with prostate cancer who received intermittent androgen deprivation (IAD). Other studies reported that high concentrations of curcumin were toxic for patients. In this study we showed that low doses of curcumin can induce senescence-like effects in 22Rv1 cell line while higher concentrations have cytotoxic effects. Five,15 and 30 µM curcumin blocked cell cycle in G2/M phase but only 15 and 30 µM curcumin induced cell death. In addition, an increased expression of p21, a known senescence marker, was detected in 22Rv1 cells treated with curcumin in every experimental condition. However, the expression of p16, another known senescence marker, increased only to 30 µM curcumin. In the context of personalized approach in PCa care, we suggest that the appropriate concentration of curcumin used in combination with radiotherapy or with androgen deprivation therapy (ADT) could be taken into consideration.

Urothelial carcinoma in situ (UCIS) is a high-grade non-muscle-invasive neoplasm with significant clinical implications due to its potential for progression to muscle-invasive disease. Accurate diagnosis and risk stratification are crucial for appropriate management, particularly given the variability in response to intravesical Bacillus Calmette-Guérin (BCG) therapy. While the diagnosis of UCIS primarily relies on morphological criteria, immunohistochemical (IHC) markers serve as valuable ancillary tools, particularly in challenging cases. Markers such as CK20, CD44, p53, and Ki-67 have been extensively studied, though none demonstrate complete sensitivity or specificity. Additionally, molecular classification has identified luminal and basal subtypes, with potential prognostic and therapeutic implications. Recent studies have also explored predictive biomarkers for BCG response, including PD-L1, whose expression correlates with recurrence and potential responsiveness to immune checkpoint inhibitors. Emerging targeted therapies, such as enfortumab vedotin, have shown promise, with nectin-4 overexpression observed in most UCIS cases. Despite these advancements, challenges remain, including interobserver variability in morphological assessment, heterogeneous IHC methodologies, and the need for standardized molecular testing. This review highlights the current understanding of diagnostic, prognostic, and predictive tissue biomarkers in UCIS, underscoring the potential role of molecular profiling in guiding personalized treatment strategies. Future research should focus on refining biomarker-driven classification systems to improve risk stratification and therapeutic decision-making in UCIS patients.

Glandular lesions involving the bladder are less common than conventional urothelial carcinoma, and they are often diagnostically challenging diseases, carrying different clinical outcomes. As a group, they encompass both primary and secondary neoplasms, with sometimes overlapping morphological features. In this scenario, proper clinical information is important, in that secondary involvement of the bladder may occur by direct extension or lymphatic/hematogenous spread from carcinomas at other sites, comprising prostate, colon, cervix, breast, and lung. According to the 5th edition of the WHO Classification of urological tumors, glandular morphology is a major hallmark of the following entities: urothelial carcinoma with glandular differentiation, adenocarcinoma, NOS, urachal carcinoma, and tumors of Mullerian type. The distinction among these entities, and between primary and secondary tumors, heavily relies on their biological and immunophenotypical features. This article will review glandular neoplasms of the bladder, highlighting their main immunophenotypical markers. Furthermore, molecular data associated with their pathogenesis, prognosis, and treatment will be described. The aim of this study is to provide a practical and comprehensive up-to-date overview of this complex topic.

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.

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.

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.).

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.

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.

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.

Abstract Background and Aims Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of the purine metabolism which results in the conversion of adenine into 2,8 dihydroxyadenine (DHA) due to the activity of the xanthine oxidoreductase (XOR). Patients affected by APRT deficiency if not treated with inhibitors of XOR may develop 2,8-DHA nephropathy that might progress to end-stage kidney disease (ESKD) with the need of kidney transplant. The high rate of misdiagnosis of 2,8-DHA nephropathy in native kidneys could lead to the failure of kidney graft in transplanted patients affected by APRT deficiency. Method Here, we report the case of a female, 63-years old patient with ESKD of unknown cause on regular hemodialysis treatment from 2018 after a period of three years on peritoneal dialysis, who underwent kidney transplantation in our Center in 2022. Her medical history showed a metabolic syndrome. She did not experience episodes of renal colic whereas family history reported a brother affected by frequent renal colic of unknown cause. In March 2022, she underwent kidney transplantation from a deceased death brain donor. Induction therapy includes basiliximab, tacrolimus, mycophenolic acid and steroids. Due to the persistence of delay graft function, ten days after kidney transplantation an allograft biopsy has been performed. The histological examination revealed tubular damage surrounded by inflammation cells and intratubular crystals in the renal cortex. The crystals were reddish brown tinged in hematoxylin and eosin stain and were birefringent under polarized light Fig. 1 A, B, so they were strongly related to the hypothesis of DHA crystals. Consistently, the urinalysis showed yellow-brown crystals of DHA. Thus, a genetic analysis of APRT gene has been performed showing two novel heterozygous variants c.388_397p.(Leu130ValfsTer4) and exon 3 deletion, expected pathogenic. The patient was treated with bolus of methylprednisolone (4mg/kg alternate to 50 mg) and a therapy with febuxostat 80 mg/die was started to reduce the amount of plasma DHA. In addition, based on our previous experience of recurrence DHA nephropathy after transplantation, we treated the patient with six consecutive hemodiafiltration (HDF) sessions without ultrafiltration, to promptly remove the serum DHA avoiding their precipitation in the graft while waiting for the lowering effect of febuxostat. At discharge the patient showed an increase of the urine output not associated with a complete recovery of kidney function (sCr 3.88 mg/dl, uric acid 1.6 mg/dl), so two other hemodialysis treatments were performed in the next two weeks. Results At present, almost one year after kidney transplant, the patient is doing well and the graft function is stable with a sCr of 1.6 mg/dl without significant presence of DHA crystals in the urine. Conclusion In conclusion, we find out an unexpected recurrence of 2,8-DHA nephropathy due to novel expected pathogenetic variants of APRT gene in patient without medical history of kidney stones successfully treated with steroid, febuxostat and hemodiafiltration.

PDF file, 214KB, SAHA targets the AR pathway in androgen-dependent CaP cells.